contents. page . network scientific research plan progress report.....3. i. translational research...

CONTENTS

Page Network Scientific Research Plan Progress Report ................................................................ 3 I. Translational Research and Drug Development (TRADD) Scientific Committee.................... 4 II. Optimization of Antiretroviral Therapy Scientific Committee ................................................. 14 III. Optimization of Management of Co-Infections and Co-Morbidities Scientific Committee ..... 26 IV. Hepatitis Scientific Committee .............................................................................................. 34 V. Women’s Health Inter-Network Scientific Committee (WHISC) ............................................ 37 VI. International Program............................................................................................................ 44 Challenges or Barriers to Implementing Research Plans ..................................................... 47 Performance Evaluation Committee ........................................................................................... 51 Cross-Network and External Collaborations.......................................................................... 56 Network Laboratory Summary .................................................................................................... 66 Appendices

Appendix A. ACTG Studies................................................................................................... 99 Appendix B. ACTG Protocol Status and Scientific Priority.................................................. 115 Appendix C. Publications and Meeting Abstracts ............................................................... 121

Network Scientific Research Plan Progress Report The ACTG network has had a very productive year, as summarized in this document. For ease of presentation, we have included the protocol list and the requested details related to all current studies in tables appended to the end of the narrative section of the report. These tables include the current status, projected or actual open dates, projected or actual end of accrual dates, projected and actual end of follow-up dates, and assessment of the protocol’s relative scientific priority (see Appendices A and B). A separate bibliography in alphabetical order incorporating publications and scientific presentations of ACTG network studies for this grant year is also included as an appendix to the narrative portion of this report (see Appendix C). The written narrative provides brief updates for all studies currently enrolling, continuing in follow-up, recently completed within this grant year and undergoing analysis, as well as those that have been presented or published in this grant year. A separate section of the written narrative describes protocols in development. The Statistical and Data Management Center is based at the Harvard School of Public Health Center for Biostatistics in AIDS Research, Statistical and Data Analysis Center. The SDMC grant is separate from but integrally linked with the ACTG Network Leadership Group Core and Network Laboratory grant. As such, the SDMC annual progress report has been independently prepared by Michael Hughes, Ph.D., as the Principal Investigator of the SDMC grant, and is a separate document submitted concurrently with this annual progress report.

2009-2010 ACTG Annual Progress Report 3

TRADD Scientific Committee Progress Report

I. Translational Research and Drug Development (TRADD) Scientific Committee 1. Progress in Each DAIDS Research Priority Area A. Translational Research and Drug Development ♦ Studies with HIV-1 Integrase Inhibitors A5244 is a study to measure the effect of treatment intensification with the integrase inhibitor raltegravir on the level of persistent low-level plasma RNA (<50 copies/mL as measured by the single copy assay) in subjects on suppressive, stable PI or NNRTI regimens. Baseline results showed that low level viremia persists in the majority of subjects with pretherapy plasma HIV-1 RNA >100,000 copies/mL despite years of suppressive ART, and longer duration of suppressive ART is associated with lower levels of viremia (Gandhi, International AIDS Conference 2009). Primary analysis results showed that raltegravir intensification did not further lower the level of low level residual viremia. The study is currently closed to follow-up and the team is performing T-cell activation, 2-LTR circle, and integrated proviral DNA analyses. A5248 is a prospective, open-label, multicenter, 72-week pilot study in HIV-1-infected antiretroviral (ARV)-naïve subjects to estimate the first-phase viral decay rate in subjects receiving raltegravir (RAL) and emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). A5249s is a viral dynamics substudy of A5248, which uses intensive HIV-1 RNA sampling measurements over the first several days of therapy to more fully characterize the early kinetics of HIV levels following the initiation RAL and FTC/TDF. Preliminary analyses showed that decay of HIV-1 RNA in patients initiating the RAL-based ARV was best described by a biphasic decay model. The finding that first phase decay rates dominated for a longer period, and extended to a lower HIV-1 RNA level in patients given a RAL- versus EFV-based regimens is consistent with RAL blocking the transition of cells in a state of “pre-integration latency” into a productively-infected, slower decaying pool of cells that contribute to second phase decay rates (Andrade, CROI 2010). The protocol has completed enrollment and secondary analyses are underway. A5262 is a pilot efficacy and safety trial of RAL plus darunavir/ritonavir (DRV/RTV) for treatment-naïve HIV-1-infected subjects. The hypothesis is that in treatment-naïve subjects, combination ART with RAL plus DRV/RTV is well tolerated and comparable in efficacy to standard of care. The protocol is currently closed to accrual with subjects in long-term follow-up. ♦ Anti-HIV Drugs with Other Novel Mechanisms of Action . NWCS 283R, in collaboration with investigators at the Laboratory of Immunoregulation (LIR), NIH Clinical Center, and the National Institute of Dental and Craniofacial Research, is exploring mechanisms of interferon alpha-mediated suppression of HIV in chronically infected individuals treated with PEG-IFN. The hypothesis is that antiviral effect of IFN on HIV is mediated by the cytidine deaminase activity of APOBEC genes.



NWCS 300 is a pilot study exploring the frequency of the CD4+ T-cell population identified as Tr1 T-cells using IL-10, TGF-β, and IL-4 intracellular cytokine staining on stored peripheral blood mononuclear cells (PBMCs) among HIV-1 infected study participants prior to and 6 weeks after receiving PEG IFN alfa-2A, and the plasma IL-10 levels at weeks 0 and 6, and changes therein among the study participants. The study will also compare the Tr1 frequencies in HIV-infected subjects before and 6 weeks after initial treatment with PEG IFN alfa-2A. The hypothesis is that the proposed assay, when run on PBMC samples collected and stored under A5192, will yield measurable Tr1 frequencies defined as CD4+ T cells that secrete IL-10 but not IL-4 when cocultured with an HIV-1 antigen. Observed variability will be comparable to variability reported in published studies looking into Tr1 cells in HCV+/HIV-infected subjects. Provided meaningful assay results are obtained for a majority of subjects and that variability is small enough, the team also hypothesizes that treatment with PEG IFN alfa-2A will lead to an increase in the frequency of Tr1 cells. NWCS 311, in collaboration with investigators at the Morehouse School of Medicine, is exploring the levels of Nef in the plasma of infected individuals and correlating the parameters of infection that have already been collected for ACTG 384. The study is also exploring levels of 48 cytokines/chemokines in plasma and correlating these with immune activation and Nef levels in the plasma. Nef may represent a novel target for intervention in chronic infection. ♦ Immune-Based Therapies for Treatment of HIV The Immune Activation Focus Group was convened by the TRADD Scientific Committee in 2008 in response to the growing body of evidence suggesting a role for HIV-associated immune activation and inflammation in predicting HIV-associated and non-AIDS adverse clinical events. This group is working to develop the following:

1. Therapeutic strategies that could be utilized to evaluate/modulate immune activation in HIV+ patients.

2. A standardized panel of serum markers of immune activation and inflammation that could be evaluated in new ACTG trials or evaluated on stored samples from completed trials to assess the immunopathogenesis of immune activation during ART.

3. Strategies that might be used by the ACTG to evaluate gut mucosal immune responses either by assessing mucosal immune reconstitution or evaluating therapeutic agents that specifically target mucosal sites, especially the GI tract.

A5212 is a double-blind, phase II study designed to determine whether multiple doses of Palifermin (recombinant human keratinocyte growth factor, rHuKGF) will increase CD4+ lymphocyte counts through enhanced thymopoiesis in HIV-1-infected subjects with suppressed viral loads but inadequate CD4+ T-cell counts and is in collaboration with an investigator at the Canadian Network for Vaccines and Immunotherapeutics. This study is closed to follow-up and data are currently being analyzed.

A5256 is a single-arm, pilot trial to assess whether adding maraviroc (MVC) to an existing suppressive ARV regimen for 24 weeks will lead to increased CD4+ T-cell counts in subjects whose CD4+ counts have not risen substantially despite full virologic suppression on ART (i.e., discordant immune responses). Subjects are being followed for an additional 24 weeks off MVC. The hypotheses are (1) that adding the CCR5 inhibitor MVC will result in a significant CD4+ T-cell count increase over 24 weeks in subjects on sustained, suppressive ART with suboptimal CD4+ T-cell recovery, and (2) that the strategy will be considered successful if a CD4+ T-cell



count increase of less than 20 cells/µL can be excluded. Primary results showed that although addition of MVC did not result in an increase in CD4+ cell count, there was significant suppression of several markers of immune activation, suggesting a possible role for CCR5 antagonism to reverse or prevent HIV-associated immune activation (Wilkin, CROI 2010). ♦ Immune-Based Therapies for Coinfections and Comorbidities A5232 is a pilot study investigating the innate and adaptive immune defects present in HCV--infected, HIV-1-infected, and HCV/HIV-1-coinfected individuals, and whether these defects predict response to neoantigen and memory recall antigen, i.e., the immunopathogenesis of the previously observed impaired neoantigen response in HIV-1 and HCV coinfection, as well as have potential implications for timing of HCV treatment. This study was closed early due to low accrual and is currently being analyzed. A5240, a collaborative protocol with the AIDS Malignancy Consortium (AMC) and the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT), is a phase II, open-label, single-arm study with stratification by CD4+ cell count and HIV-1 RNA viral load to assess the immunogenicity, safety, and tolerability of the quadrivalent human papillomavirus (HPV) recombinant vaccine (GARDASIL) directed against types 6, 11, 16, and 18 HPV in HIV-infected women. The hypothesis is that this vaccine is safe, well-tolerated and will generate antibody titers to types 6, 11, 16, and 18 above levels of type-specific serologic responses shown to be protective against cervical carcinoma in non-HIV-1-infected subjects. The protocol is currently enrolling. ♦ Studies of Pharmacokinetics, Pharmacodynamics, and Drug-Drug Interactions A5283 is an open-label, non-randomized study of PK interactions between depo-medroxyprogesterone acetate (DMPA) and lopinavir/ritonavir (LPV/R/r) and of the effects of DMPA on cellular immunity and regulation in HIV-infected women. The hypothesis is that LPV/R/r will have an effect on the PK profile of DMPA through induction and/or inhibition of the cytochrome p450 3A4 (CYP3A4) enzyme. The study is currently in development. ♦ Pathogenesis Studies A5102 secondary studies evaluated the evolution of plasma RNA HIV measured as a genetic distance from archival, proviral DNA among subjects on suppressive ART regimens. Results suggest that after treatment interruption, plasma RNA evolves from proviral DNA over a continuum of genetic distance but with frequent evolution of drug resistance. Significant drug resistance mutations were associated with early rebound to higher levels of steady state viremia and a trend toward a greater genetic distance between DNA and RNA. Archived provirus persisting in PBMCs during suppressive ART may harbor HIV drug resistance mutations that can emerge in plasma RNA following treatment interruption (Winters, International HIV Drug Resistance Workshop 2005). NWCS 250 compared the sensitivity and specificity of different V3 loop algorithms in determining HIV-1 X4-use in well-characterized archived clinical isolates. Viral tropism, and particularly CXCR4 tropism, is thought to be an important factor in predicting more rapid HIV disease progression and response to CCR5 inhibitor based ART. Results suggested that current algorithms for predicting tropism from V3 loop sequences lack sensitivity for detecting X4-using virus from consensus sequence of clinical HIV-1 culture isolates. The PSSMSI/NSI algorithm achieved the highest sensitivity in predicting syncytium inducing (SI) (inferred X4-use).



The investigators concluded that newer sequence-based methods that can detect minority variants and/or better algorithms are needed (Huang, International Workshop on Targeting HIV Entry 2007). Additionally, results showed that SI viruses were identified in 30% of subjects with > 200 CD4+ cells in association with significantly higher HIV-1 RNA. There was no relationship between SI virus and zidovudine (ZDV) resistance or specific thymidine analogue drug resistance mutations among monotherapy recipients. ZDV resistance was associated with plasma HIV-1 RNA, the duration of monotherapy and age, but not CD4+ cell counts or envelope coreceptor tropism (Shin, IDSA 2009). NWCS 261 evaluated the association between baseline plasma HIV-1 replication capacity and pre-therapy/on-therapy virologic and immunologic parameters in treatment-naïve subjects initiating ART. Results showed that higher baseline replication capacity was associated with lower absolute baseline CD4+ count and higher baseline HIV-1 RNA. Baseline replication capacity was not associated with overall virologic or immunologic outcomes (Skowron, IAS 2007). In selected treatment-naïve subjects, baseline DM/X4 tropism was associated with lower baseline memory, naïve and total CD4+ count, higher baseline HIV-1 RNA, and higher CD4+ and CD8+ percent activation. Baseline tropism was not associated with change in CD4+ by week 48, controlling for the baseline covariates above (Skowron, CROI 2009). An abstract using data from NWCS 261 showed that in cohorts of HIV-1-infected individuals at different stages of infection, trofile ES detected 8-13% more patients with DM virus than the original assay. Lower CD4+ counts were consistently associated with detection of DM virus/X4 virus (Wilkin, CROI 2010). DACS 248, in collaboration with investigators at the United States Military HIV Research Program, is assessing whether the 80% or 90% Neut. Titer of 1, 2 or 3 isolates prior to ART interruption predicts CD4 decline over the Acute Phase (0-12 weeks) after treatment interruption or during the Chronic Phase (12 weeks-time of failure) after treatment interruption. The working hypothesis is that strong neutralizing antibodies at the beginning of treatment interruption predict slower disease progression as marked by a slower decline in CD4+ T-cells. A5173 was a pilot study designed to measure clearance of replication-competent HIV-1 in resting memory CD4+ T cells in HIV-1-infected subjects receiving combination ART plus enfuvirtide, an entry inhibitor. The hypothesis is whether addition of an entry inhibitor as a component of initial ART will result in a measurable decrease in the latent cell reservoir. Strategies aimed at reducing latent viral reservoirs as one of several approaches that might ultimately lead to a cure of HIV-1 infection are important priorities within the ACTG research agenda. Primary results showed that in previously treatment-naïve HIV-1-infected subjects who received enfuvirtide-containing ART there was no detectable decline in latent reservoir size over 96 weeks. The half-life of latent reservoir decay with intensified, suppressive therapy is <11 months (Gandhi, JID 2010). B. Vaccine Research and Development The Therapeutic Vaccine Task Force was convened by the TRADD Scientific Committee in 2008 in an effort to introduce a more rational process for making decisions about the evaluation of therapeutic HIV-1 vaccine candidates, especially in the context of analytical treatment interruptions (ATIs). The focus group was specifically tasked to address the following three questions:



1. What preclinical data (including animal model studies) should be available before studies of immunogenicity and safety are undertaken in HIV-1-infected individuals?

2. What immunogenicity and safety data should be available before ATIs are contemplated?

3. Are there other approaches to evaluating putative therapeutic vaccines that the ACTG should consider?

HIV-1 vaccine candidates most recently analyzed in clinical trials include Ad5 Gag vaccine (Merck, A5197), ALVAC-HIV VCP 1452 canarypox vaccine administered alone or as ALVAC-HIV VCP 1452-infected dendritic cells (A5130), and DermaVir topical DNA vaccine (A5176). A5197 evaluated the ARV effect of the Merck Ad5 HIV-1 Gag vaccine in chronically HIV-1-infected individuals after interrupting ART (ATI). Results showed that there was a nonsignificant trend of reduction in viral load during the ATI for vaccine recipients (Schooley, Submitted to JID 2009). A5130, in collaboration with investigators at Rockefeller University and Walter Reed Army Institute of Research, evaluated whether subcutaneous vaccination with autologous dendritic cells pulsed with ALVAC-HIV vCP1452 versus ALVAC-HIV vCP1452 alone resulted in improved virologic control after ATI. Results showed a nonsignificant trend toward a greater percentage of subjects who received a dendritic cell-based vaccine achieving virologic control, albeit transient, after ATI (Gandhi, Vaccine 2009). A5176 is a phase I/II, randomized, double-blind study designed to evaluate safety and immunogenicity of a novel, topical therapeutic DNA vaccine, DermaVir, administered to individuals with chronic HIV-1 infection receiving ART with durable suppression of viral replication. This study is currently closed to follow-up. A5181 is an observational study designed to systematically evaluate which of the multiple assays that measure HIV-specific T-cell function most consistently distinguishes subjects achieving virologic suppression during stable ART from untreated subjects who spontaneously control viral replication. The results of this trial showed that a combination of the standard assays (i.e., lymphocyte proliferation, supernatant interferon γ (IFNγ) cytokine production, single cell IFNγ production by enzyme linked immunospot (ELISPOT), with and without Epstein-Barr virus-transformed B lymphoblastoid cell lines (B-LCLs) as antigen presenting cells, and intracellular cytokine production for IFNγ and IL-2 by flow cytometry) is adequate to describe the immune response in various immunotherapeutic strategies (Macatangay, Submitted to AIDS Research and Human Retroviruses 2009). NWCS 314 is exploring the effect of a therapeutic HIV-1 Gag vaccine and treatment interruption on HIV-1 gag and pol evolution and diversity. The study will perform PCR amplification and population sequencing of HIV-1 gag and pol from pre-ART plasma of participants in A5197, determine the presence of HLA-associated gag and pol escape mutations, compare HLA-associated HIV-1 gag and pol escape mutations found during the pre-ART and post-vaccination treatment interruption time periods and determine whether correlations exist with vaccine use and viral load, and perform ultra-deep sequencing to determine the HIV-1 gag, pol, and nef sequence diversity in pre-ART and ATI plasma samples both in subjects receiving the Gag vaccine and placebo. C. Prevention of Mother-to-Child Transmission A5207 is an ongoing study comparing three ARV strategies administered for 7 or 21 days to determine whether a 21-day course of ZDV/3TC, TDF/FTC, or LPV/r coupled with single-dose NVP is more effective than a 7-day course of ZDV/3TC for reducing the emergence of NVP-



resistant HIV variants at 2 and 6 weeks following delivery, as determined by standard genotyping. This study, which is fully enrolled and closed to accrual, will provide critical information on the clinical management of HIV-1 infection in pregnancy in resource-limited settings worldwide. 2. Scientific Research Plans (Proposals and Studies in Development) With the Next 12-

to-24 Months The following areas of research have been determined to be of highest priority for the TRADD in the coming years:

1. The impact of novel drugs and new drug classes in development on viral kinetics (as an early predictor of drug activity and potency) and the use of ART to perturb the system to evaluate new concepts in HIV disease pathogenesis, including better understanding of viral reservoirs and possible approaches to eradication

2. The role of immune activation and inflammation in HIV-1 disease progression,

manifestations, and complications, including senescence and premature senescence.

3. Innovative approaches using novel drugs and new drug classes to enhance the effectiveness, potency, and safety of combination ART

4. The use of immunotherapies, including therapeutic vaccines, to evaluate immune

responses associated with reduction in disease progression or control of HIV-1 disease pathogenesis and as adjuncts to improve magnitude and duration of response to ART

♦ Immune Activation and Inflammation The major objectives in this priority area are: 1) standardizing measures of immune activation and inflammation across ACTG trials; 2) investigating HIV-1-associated inflammation and its impact on disease progression, treatment response, and HIV-1-associated coinfections and comorbidities, such as cardiovascular and metabolic complications; 3) evaluating the role of suppressors of immune activation on regulation of HIV-1 infection and HIV-1-associated coinfections and comorbidities; and 4) determining the clinical relevance of gut mucosal immunopathogenesis, including gastrointestinal T-cell depletion and associated microbial translocation, and whether treatment aimed at decreasing or eliminating inflammation or microbial translocation at this anatomic site might impact HIV-1 disease pathogenesis, particularly during early events after HIV transmission and acute infection. The TRADD is working with the Immune Activation Focus Group to develop NWCS/DACS to correlate immune activation and inflammatory biomarkers with clinical outcomes both to AIDS-defining and other non-AIDS-defining comorbidities (e.g., cardiovascular disease, cancer). The group is also exploring novel therapies directed against relevant inflammatory targets (e.g., IL-6) for which immunomodulatory agents are available or in development. Recent activities in this priority area include:

• A5258 is a randomized, double-blind, placebo-controlled, multicenter clinical trial utilizing a crossover design to evaluate the effect of 12 weeks of chloroquine compared to placebo on CD8+ T-cell activation in chronically infected subjects not receiving ART. The



hypothesis is that chloroquine, a toll-like receptor antagonist, will reduce the state of immune activation associated with chronic, untreated HIV-1 infection. The protocol is currently enrolling, with 25/30 subjects accrued as of February 2010.

♦ Viral Kinetics and Pathogenesis The objective in this area is to develop innovative pilot studies of viral kinetics and measurement of HIV reservoirs that might predict outcome of therapy, including effects on biomarkers of disease progression, thus providing new insight into HIV-1 pathogenesis and pharmacologic mechanism of action in vivo. The approach that we are undertaking involves 1) developing protocols and protocol substudies to characterize kinetics of viral decay in different patient populations (including acute HIV infection, and HIV-infected patients receiving cytotoxic chemotherapy) and with different drug combinations; 2) developing a protocol template for viral decay kinetics that can improve efficiency of development and allow cross-study comparisons; and 3) studying various biomarkers of disease and treatment effect that might facilitate comparison of regimens in viral kinetic studies. Recent activities in this priority area include:

A5275 is a pilot study evaluating the effect of atorvastatin on biomarkers of inflammation, coagulopathy, angiogenesis, and T-lymphocyte activation in HIV-1 infected individuals with suppressed HIV-1 RNA and LDL cholesterol < 130mg/dl. The hypothesis is that atorvastatin will reduce inflammatory and coagulopathy biomarkers associated with mortality in HIV-infected persons as well as markers of angiogenesis and CD8+ T-cell activation. The study is currently in development. A5286 is a pilot study of rifaximin as a modulator of gut microbial translocation and systemic immune activation in untreated HIV-infected individuals. The hypothesis is that the use of rifaximin will decrease the levels of translocated gut microbial products in untreated HIV-infected subjects. The decline in translocated gut microbial products will lead to lower levels of immune activation in these individuals. The study is currently in development. ♦ Immune-Based Therapies including Therapeutic Immunization Recent activities in this priority area include:

A5281, in collaboration with the HIV Vaccine Trials Network Immunology Laboratory, is a phase I randomized, partially double-blind, placebo-controlled, dose-escalation study to evaluate the safety and immunogenicity of a cytokine enhanced HIV-1 multi-antigen pDNA vaccine delivered intramuscularly (IM) or IM in combination with in vivo electroporation (IM/EP) in HIV-1 infected adults receiving HAART. The study is currently in development. 3. Challenges or Barriers to Implementing Research Plans Lack of availability of selective clinical pharmacophores that block immune activation: Although basic science discoveries suggest a number of possible pathways that may be involved in HIV-mediated activation and inflammation, few approved drugs are available for testing these concepts in HIV clinical trials. Pharmaceutical companies developing such drugs for indications in other therapeutic areas have been reluctant to make them available for study in HIV-infected patients prior to approval. The TRADD and Immune Activation Focus Group



members will continue to work with companies and interact with investigators from related fields (rheumatology, oncology, gastroenterology) to gain access to relevant anti-inflammatory agents for testing in the setting of HIV-1 infection. Disappointing results of recent preventive and therapeutic vaccine studies: Although the ACTG has tested numerous candidate therapeutic vaccines in chronically or acutely HIV-infected individuals, as previously described, the responses have been modest, albeit in the direction of the desired effect. However, the pipeline has been substantially reduced as the field has been impacted by the disappointing results with vaccines using the current prime-boost paradigm with vaccines aimed at impacting cell-mediated immune responses. The vaccine research field is moving in different directions, with renewed focus on the investigation of neutralizing antibody responses and combined vaccine approaches; however, few novel agents are currently available, limiting this avenue of investigation.

Lack of availability of laboratory assays of immune activation or inflammation that are consistently associated with disease outcomes: As previously described, the investigation of the role of inflammation and immune activation in HIV-1 disease pathogenesis and its associated coinfections and comorbidities is a high scientific priority of the network. However, while the currently available biomarker assays are myriad, they are either insensitive or inconsistently predictive of the outcomes of interest. Further investigation of new or novel biomarkers of inflammation and immune activation is underway, as is further exploration of how existing biomarkers can be more effectively utilized to elucidate the role of inflammation and immune activation and of interventions aimed at reducing these. TRADD Protocol Collaborations NWCS 311 Outside Proposing Investigators: Michael D. Powell, Ph.D., Associate Professor Department of Microbiology, Biochemistry, and Immunology Morehouse School of Medicine (MSM) Vincent C. Bond, Ph.D., Associate Professor Department of Microbiology, Biochemistry, and Immunology Morehouse School of Medicine Collaborating Statistician: Alexander Quarshie, MBChB, MSc MSM Statistical Core *All assay testing to be performed at MSM. NWCS 283R Outside Proposing Investigators: Shyam Kottilil MD, Ph.D., Staff Clinician Immunopathogenesis Section Laboratory of Immunoregulation/NIAID Juan J.L. Lertora, M.D., Ph.D.



Director, Clinical Pharmacology Program NIH Clinical Center Sharon M. Wahl, Ph.D. Chief, Oral Infection and Immunity Branch, NIDCR Collaborating Statistician: Michael Proschan Ph.D. Biostatistics Research Branch, NIAID *Laboratory testing to be performed at Immunopathogenesis Section. Laboratory of Immunoregulation, NIAID Ongoing analyses being performed at NIH with no SDAC support. DACS 248 Outside Proposing Investigators: Robert J. McLinden, Jr., Ph.D. Commercial Services Lab Manager Advanced Bioscience Laboratories Jerome H. Kim, MD, COL, MC Chief, Department of Retrovirology USAMC-AFRIMS *All NAb testing has already been performed by the Division of Retrovirology at the (United States Military HIV Research Program), who will manage this analysis. Analyses will be performed by Robert McLinden and Jerome Kim. A5130 Vice Chairs: Nina Bhardwaj, M.D., Ph.D. Laboratory of Cellular Physiology and Immunology The Rockefeller University Outside expertise on dendritic cells Sarah S. Frankel, M.D. Division of Retrovirology Walter Reed Army Institute of Research Mary A. Marovich, M.D. Division of Retrovirology Walter Reed Army Institute of Research A5212 Protocol Vice Chair: Rafick-Pierre Sekaly, Ph.D. CANVAC (Canadian Network for Vaccines and Immunotherapeutics) Universite´ de Montreal




*The TREC and advanced flow assays are being performed at Rafick Sekaly’s lab. A5281 Collaborator: Julie McElrath, M.D., Ph.D. Associate Professor University of Washington Fred Hutchinson Cancer Research Center Program in Infectious Diseases *There has been discussion that the HVTN may provide peptides for the study. Alan Landay, protocol team immunologist, is collaborating with Julie McElrath (Head of HVTN Immunology Lab) on costing and provision of the peptide pools.

OpMAN Scientific Committee Progress Report

II. Optimization of Antiretroviral Therapy Scientific Committee 1. Progress in Each DAIDS Research Priority Area A. Translational Research and Drug Development ♦ Evaluate safety and efficacy of anti-HIV compounds aimed at novel mechanisms of

action/ new targets, including small-molecule entry inhibitors, uncoating inhibitors, integrase inhibitors, and maturation inhibitors

♦ Evaluate the role of new classes of molecules with unique and improved features

such as different resistance profiles and better pharmacologic or toxicologic properties in optimal treatment of HIV disease

A5211, a phase II study of vicriviroc (an investigational small-molecule CCR5 antagonist) vs. matching placebo, demonstrated potent virologic and immunologic responses in treatment-experienced subjects with drug-resistant viral strains for up to 3 years of follow-up (Wilkin, JAIDS 2010). Although eight malignancies, including four lymphomas, were observed early in the study, causality could not be determined, and vicriviroc did not increase Epstein-Barr (EBV) viral load levels nor were three of the lymphomas EBV-associated (Tsibris, Clin Infect Dis 2009). Although hypothesized that a mechanism of viral neurotoxicity is mediated by CCR5 neuronal receptors, vicriviroc (VCV) did not affect peripheral neuropathy on this study (Yeh, HIV Clin Trials, in press). Drug resistance to vicriviroc most commonly occurred with emergence of X4 virus and in only three subjects, with a change in drug susceptibility that rapidly reverted due to reduced fitness (Tsibris, submission pending) and deep sequencing revealed extensive sequence heterogeneity existed at baseline, shifted rapidly, and predicted emergence of failure sequences (Tsibris, PLoS One 2009). An enhanced viral tropism assay demonstrated improved detection of minor X4 variants in subjects; in a reanalysis of A5211 using this assay, removing those patients found to have dual/mixed virus resulted in improved virologic responses to vicriviroc (Su, JID 2009 and Wilkin, CROI 2010). Use of replicating (as opposed to psuedityped) viruses did not improve detection of X4 tropic virus (Hosoya, J Clin Micro 2009) In pharmacokinetic and pharmacodynamic models, VCV concentrations were predictors of virologic responses (Crawford, JIADS 2010). Study subjects continue in long-term follow-up in this study, to assess safety and efficacy over 5 years. A5241 is a strategy study aimed at evaluating treatment options for triple-class ART-experienced HIV-infected subjects failing their current regimen with evidence of drug-resistant virus. The study will determine whether nucleoside reverse transcriptase inhibitors (NRTIs) are a necessary component of treatment regimens that include potent newer agents such as etravirine (NNRTI), tipranavir (protease inhibitor [PI], darunavir (PI), enfuvirtide (fusion inhibitor), maraviroc (small-molecule CCR5 antagonist), and/or raltegravir (integrase inhibitor). Upon study entry, subjects undergo genotypic and phenotypic drug resistance testing and viral tropism testing, as well as a review of their ART history. From this information, a continuous phenotypic susceptibility score (cPSS) is calculated and used to design potential regimens; subjects also are randomized to include or not include NRTIs in the subsequent regimen. The primary objective is to compare virologic suppression rates between subjects taking a new regimen of more than two active agents (cPSS > 2.0) with or without NRTIs. The study is over 85% enrolled (301 of a planned 354 randomized subjects).



♦ Test new hypotheses generated by pathogenesis studies A number of substudies and secondary analyses of ACTG trials have explored pathogenesis-related hypotheses. These studies have focused on antiretroviral (ARV) drug resistance, ART responses in treatment-naïve subjects, differences in responses among subjects from diverse geographic regions, and racial and ethnic backgrounds as well as the role of human genomics in pathogenesis and treatment response. A5095 demonstrated that in treatment-naïve subjects, the presence of minority Y181C variants at baseline (as detected by an allele-specific PCR assay that could detect variants comprising <1% of the population) also was associated with a greater than three-fold increased risk of virologic failure of efavirenz-based regimens as compared to that seen in adherent subjects with wild-type virus (Parades, JID 2010). Similarly, among treatment-experienced patients, minor NNRTI-resistant variants, determined by allele specific PCR or single genome sequencing, were more prevalent in NNRTI-experienced patients and were associated with reduced virologic response to efavirenz-containing multidrug regimens in ACTG 398 (Halvas, JID 2010). Analyses using pooled data from ACTG 384 and A5095 showed that in subjects with baseline CD4+ counts of 200–500 cells/mm3, the pretreatment percent CD4+ naïve cells distinguished those most likely and least likely to achieve significant increases in CD4+ cell count rises on treatment (Schacker, JAIDS, in press). Another analysis showed that proteinuria correlated with immune activation in ACTG 384 but not A5095 (Gupta, JID 2009) DACS 238 compared treatment responses in 220 pre- and 47 postmenopausal women from ACTG 5095 and 5142 and found no differences in virologic or immunologic responses to ART (Patterson, Clin Infect Dis 2009). In the A5175 study conducted at U.S. and eight international sites, a number of baseline observations were reported on the 1571 subjects analyzed thus far: (1) There was significant diversity in pre-ART plasma HIV-1 RNA concentrations across the nine study countries not explained by differences in CD4+, gender, body mass index (BMI), functional performance, or a past or current AIDS-related infection or malignancy (Kumarasamy, manuscript in development). (2) A moderate positive correlation was identified between absolute lymphocyte count (ALC) and CD4+ count; the correlation coefficient ranged by country from 0.29 in Haiti to 0.56 in the United States (Firnhaber, manuscript in development). (3) In one of the first standardized assessments of quality of life (QOL) among HIV-infected patients receiving different regimens for ART across international sites, higher QOL in every category was associated with higher CD4+ category and higher levels of perceived social support (all p< 0.007), while general health, physical and role functioning, and energy/fatigue varied by HIV viral load categories (all p<0.02); and every subscale of QOL varied by race (all p<0.002) and by study site (all p<0.001) (Safren, manuscript in development). (4) Finally, comparison of anemia, thrombocytopenia and neutropenia at initiation of ART were described for study subjects from Africa, Asia, South America, the Caribbean, and the United States. They found that the frequency of neutropenia, anemia and thrombocytopenia was 14%, 12%, and 7%, respectively, and varied by country (p<0.0001 for each). In multivariable models, anemia was associated with gender, platelet count and country; neutropenia with CD4+ lymphocyte and platelet counts; and thrombocytopenia with country, gender, and chronic hepatitis B infection (Firnhaber, manuscript submitted to JAIDS).



The creation of a large repository of DNA samples from subjects in ACTG studies who have consented to human genetic testing (A5128) has provided a rich resource for genomics studies conducted by the ACTG in collaboration with leading genomics investigators. For example, pharmacogenomics analyses of ACTG 384 showed that certain mitochondrial subhaplogroups were associated with peripheral neuropathy (Canter, manuscript in preparation). NWCS 259 sought to identify single nucleotide polymorphisms (SNPs) in select candidate genes (more than 250 SNPs) associated with increased risk of developing pronounced metabolic changes after initiating highly active ART in ACTG 5142. ART regimen, hepatitis C coinfection, and genetic variation in the adiponectin receptor R1 and resistin were significantly associated with this subgroup (Ranade, manuscript in development). From the same study, mitochondrial DNA haplogroups were found to influence plasma lipid and peripheral fat parameters (Hulgan, Adverse Drug Reactions 2009; manuscript in preparation). Several metabolic or inflammatory genes were found to influence response to ART. In NWCS 266/ACTG 384, a suboptimal virological response was associated with interleukin 1 alpha (IL1A) S889 and IL1AR4845, though the relationship was different across different racial groups. Two major papers have evaluated HLA types and HIV evolution and immune escape in large groups of untreated patients (Brumme, PLoS One 2009; John, Human Genetics 2010). Finally a study that evaluated a genome-wide association of class I and II MHC alleles with CD4/CD8 ratio found evidence that two independent quantitative trait loci regulate the CD4:CD8 T cell ratio in the HIV negative population. Although neither variant showed a statistically significant association with CD4:CD8 ratio, the A allele of rs2524054 was strongly associated with immune control of HIV-1 viremia when the controllers were compared to a group of HIV-1 progressors (Ferreira, Am J Hum Genetic 2010). B. Optimization of Clinical Management, Including Co-Morbidities ♦ Evaluate the effectiveness of new regimens, particularly those that incorporate

agents with novel mechanisms of action or new treatment strategies A5142 randomized 757 treatment-naïve subjects and found that efavirenz (EFV)-based regimens were virologically superior to a two NRTI + lopinavir/ritonavir (LPV/r) regimen, but drug resistance occurred more commonly with EFV, and CD4+ responses were superior in the LPV/r-containing arms (Riddler, NEJM 2008). Additional evaluation of virologic associations of therapy revealed that virologic failure of two NRTI + EFV was associated with the frequent selection of mutations in the polymerase domain but not in the connection or RNase H domains of RT. Previously reported mutations in the connection and RNase H domains of RT were probably not detected, because failure was identified early using a sensitive, protocol-specified definition, and the treatment regimen contained EFV and not nevirapine, which can select N348I (Brehm, Drug Resistance Workshop 2009; manuscript in preparation). A5202 is a study of initial treatment regimens in 1864 treatment-naïve subjects randomized to receive either tenofovir/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC) together with either EFV or atazanavir (ATV/r). In February 2008, the NIAID DSMB recommended stopping the ABC/3TC portion of the regimen in subjects who entered the study with pretreatment viral load levels ≥100,000 copies/mL due to a significantly increased risk of virologic failure. The estimated hazard ratio for cumulative virologic failure in this stratum was 2.33 (95% CI: 1.46, 3.72; p =0.0003) (Sax, NEJM 2009). Subjects with HIV-1 RNA <100,000 copies/mL continued the study and the comparison of EFV versus ATV/r was continued through completion of the study in September 2009. Final analyses of A5202 showed that the time to



virologic failure for ABC/3TC was shorter than TDF/FTC with either ATV/r or EFV. In contrast, for the extended follow-up in the low viral load group there was no difference in the time to virologic failure between ABC/3TC and TDF/FTC with either ATV/r or EFV. However, the time to a Grade 3 or 4 protocol-defined safety event was shorter for those treated with ABC/3TC than TDF/FTC with EFV, and the time to regimen modification was shorter for those given ABC/3TC compared to TDF/FTC with either ATV/r or EFV, the latter appearing to be driven by increased frequency of hypersensitivity reactions. For the comparison between ATV/r and EFV with either ABC/3TC or TDF/FTC there was no difference in the time to virologic failure. There was a shorter time to safety events and regimen change in those given EFV compared to ATV/r when combined with ABC/3TC, a difference not seen when these drugs were combined with TDF/FTC (Daar, CROI 2010; manuscripts in preparation). A5073 compared the strategy of using once-daily versus twice-daily combination ART, with or without directly observed or self-administered drug in treatment-naïve patients. The study randomized 321 subjects to LPV/r soft gel capsules 400/100 mg BID or 800/200 mg QD plus either FTC 200 mg QD and extended-release stavudine (d4T-XR) 100 mg QD, or tenofovir 300 mg QD. Randomization was stratified by screening HIV-1 RNA with a cut-point at 100,000 copies/ mL. Overall there was no difference between the study arms for the primary efficacy endpoint of sustained virologic suppression defined as plasma HIV-1 RNA <200 copies/mL through week 48. However, the comparison depended on the screening HIV-1 RNA stratum (p=0.038); in the higher RNA stratum, the estimated probability of sustained virologic response through 48 weeks was significantly better in the BID arm, 0.89 (95% CI 0.79, 0.94) compared to 0.76 (95% CI 0.64, 0.84) in the QD arm, for a difference of 0.13 (0.01, 0.25). In addition, LPV trough plasma concentrations were higher with BID dosing, but adherence to prescribed doses of LPV/r was higher in the QD arm (p<0.001) (Flexner, JID, in press). An open-label, randomized comparison in A5073 assessed the virologic response at week 48 in those receiving Monday through Friday directly-observed once-daily therapy (DOT) for 24 weeks followed by self-administered treatment for 24 weeks (n=82) compared to 48 weeks of self administered therapy (n=161). Over 24 weeks the DOT arm had greater virologic success compared to self-administered therapy, but the difference did not reach the pre-specified threshold for superiority. Over 48 weeks, virologic success was not significantly different between the two study arms (Gross, Arch Intern Med 2009). A5201 evaluated the risk of virologic failure in subjects 48 weeks after treatment with ATV/r (alone) maintenance therapy. A total of 34 subjects simplified to ATV/r alone, of whom 30 (88%) did not experience virologic failure by 48 weeks after simplification. This study suggested that simplified maintenance therapy with ATV/r alone could be effective in maintaining virologic suppression in carefully selected subjects with HIV infection. Residual viremia (defined by a single copy assay) did not change significantly after NRTI discontinuation among those without virologic failure but did increase prior to confirmed virologic failure. Using single-genome sequencing to detect low-frequency resistant variants, PI resistance-associated mutations were not detected in subjects experiencing virologic failure on ATV/RTV monotherapy (Wilkin, J Infect Dis 2009). A5257 is a randomized, comparative, stratified, open-label, multicenter study of three compact, NNRTI-sparing ARV regimens for treatment-naïve HIV-infected subjects. The three regimens are two NRTI + ATV/r (control arm), two NRTI + darunavir/r (DRV/r), and two NRTI + raltegravir. The study will enroll 1800 subjects, and is accruing exceedingly well, ahead of schedule. To date, accrual is 798/1800. The SASC approved IMPAACT coendorsement of the protocol allowing IMPAACT sites not colocated with ACTG sites to enroll women into the study. The letter of agreement between the networks is signed, and IMPAACT sites are now eligible to



enroll. Enrollment is predicted to be completed by the end of 2010. Protocol substudies will assess metabolic parameters, pharmacokinetics in pregnant women, and sexual behavior. ♦ Evaluate strategies to provide safe and affordable therapies for HIV-infected persons

globally A5175 is a multinational randomized, open-label study designed to evaluate three first- line ART regimens for treatment-naïve, HIV-1-infected subjects with CD4+ count < 300 cell/mm3 in U.S. and international settings. The study regimens are (1) ZDV/3TC + EFV; (2) ddI EC + FTC + ATV; and (3) FTC/TDF + EFV. These regimens were selected based on their availability in all participating countries, the desire of international investigators to explore viable alternatives for once daily treatment regimens, and to compare the efficacy of the latter with a standard of care arm (ZDV/3TC + EFV) used as a first-line therapy option in all countries. The study was fully enrolled with 1571 subjects, and active study follow-up continues. In May 2008, the NIAID Data Safety Monitoring Board (DSMB) reviewed the study and found that the ddI EC + FTC + ATV arm was virologically inferior; consequently, those subjects were unblinded and their regimens changed (Campbell, IAS 2009; manuscript in preparation). The two remaining arms continue follow-up with recent DSMB review recommending that study closure be initiated. The team is planning to complete final study visits in approximately May 2010. A5095 showed that subjects substituting NVP for EFV for treatment-limiting toxicities, such as central nervous system symptoms or rash, most often tolerated nevirapine (NVP) well (Schouten, CID 2010). Although first-line regimens are becoming better defined for resource-limited settings, the available options are limited after failure of the initial NNRTI-based regimen in many countries. Issues such as limited NRTI drugs, incomplete availability of HIV-1 RNA monitoring and drug resistance testing add to the complexity of designing and studying second and third-line regimens in this setting. Currently, we have two studies for first-line failures in the resource-limited settings and two other studies in development to evaluate newer agents for second- and third-line regimens at our international sites. Monotherapy with a boosted PI is also being studied in A5230, a pilot study to evaluate the safety and virologic efficacy of LPV/r monotherapy in subjects who have experienced virologic relapse on an initial NNRTI-containing regimen in resource-limited settings. As subjects will not take an NRTI in their regimen, the need for drug resistance testing is obviated. This study is currently open to enrollment internationally and 94 (of a planned 120) subjects have been enrolled. A5234 is an international, prospective, randomized study for subjects in resource-limited settings who are experiencing virologic failure on their first NNRTI-containing regimen. The study is designed to determine whether a locally developed strategy of modified directly observed therapy (mDOT) results in a higher virologic response rate compared with the standard of care in these subjects experiencing failure on the first regimen. Five sites are currently enrolling participants (IMPACTA Lima, INMENSA Lima, Johannesburg, Uganda, and Haiti). Zambia and Botswana are working to obtain local IRB approval. Fiocruz is still working to obtain CONEP approval. Although enrollment was initially slow due to long delays in site IRB review, the study currently has 103 of 496 subjects enrolled. ♦ Optimize therapies on the basis of safety, adherence, resistance, durability of

response, and prevention of transmission



When to start ART in asymptomatic individuals remains an important clinical question in both highly resourced domestic and resource-limited settings. As the HIV-1 epidemic and access to potent combination ART have evolved, the answer to this question has changed, and it has become apparent that there is no single best answer for all HIV-1-infected individuals. There are, however, specific components within this research question that remain fertile areas for further investigation to assess the impact of earlier initiation of ART on disease progression and morbidity. A5245/HPTN 052 will determine whether ART administered earlier at higher CD4+ T cell counts in serodiscordant couples can prevent the sexual transmission of HIV-1 and whether earlier initiation of ART will decrease the risk for and incidence of both AIDS-defining and non-AIDS-associated events and comorbidity. The primary objective of the full study is to compare the rates of HIV-1 infection among partners of HIV-1-infected subjects in two study arms: (1) ART immediately upon enrollment for the infected partner who has a CD4+ count between 350-550 cells/µL plus HIV primary care, and (2) HIV primary care, without initiation of ART until the infected partner has two consecutive CD4+ measurements of <200 cells/µL or develops an AIDS-defining illness. The design of the study supports a second strategy question: What is the optimal time to start ART in resource-limited settings – immediately or not until the CD4+ cell count falls to <200 cells/ mL. This study is actively enrolling serodiscordant couples. Approximately 1577 of a planned 1750 couples in total have been enrolled. Enrollment should close in March or April of 2010. Two studies have been developed to address possible strategies to improve adherence to ART. A5250 is a randomized, multicenter study of an adherence intervention for treatment-naïve subjects being developed in collaboration with the National Institute of Nursing Research (NINR). The study will develop and use self-management strategies of adherence for subjects coenrolled in an ACTG treatment-naïve study and then assess the durability of adherence. The study is open for enrollment and will enroll 210 patients. A5251 is a second multicenter study being developed in collaboration with the NINR of a randomized enhanced nursing support strategy through telephone contact to improve self-management, adherence, and outcomes of ART in treatment-experienced subjects. Eligible subjects may be coenrolled in A5241, a study of newer ARV agents for treatment-experienced subjects, or other studies. The study will enroll 296 subjects. The protocol is complete and will open soon. Safety, adherence, resistance, and durability of response are secondary objectives of nearly all ART intervention trials conducted by the ACTG. ♦ Evaluate long-term toxicities and the role of pharmacogenomics in predicting or

managing toxicities Secondary analyses of A5095 assessed changes in high-sensitivity CRP following initiation of ABC or non-ABC-containing regimens in ARV-naïve subjects. All subjects selected for analysis had HIV-1 RNA < 50 copies/mL at 24 and 96 weeks. Over 96 weeks, hsCRP levels increased in both groups despite control of HIV replication. There were no significant differences in those with and without ABC, but women had higher hsCRP levels than men (Shikuma, manuscript ready for submission). These results do not explain possible increased cardiovascular disease seen in cohort studies with abacavir use. In NWCS 253, frequent non-synonymous CYP2B6 polymorphisms that predict increased EFV exposure may affect responses to EFV-containing regimens, but treatment responses were not as consistent as exposure results (Ribaudo, submitted to JID).



A5001/ALLRT is a prospective, longitudinal, linked series of cross-protocol and meta-analysis aimed at evaluating the long-term immunologic, virologic, and clinical outcomes associated with randomized choices of ART. Analyses of A5001, evaluating factors associated with an increased risk of developing non-AIDS-defining events, including cardiovascular disease, non-AIDS-defining malignancies, metabolic complications, and other non-AIDS-defining end organ co-morbidities, are ongoing, following the findings by the D:A:D and SMART studies linking recent abacavir use with increased risk of myocardial infarction. In an analysis of this potential association in A5001, which included only treatment-naïve subjects who were randomized to receive abacavir vs. comparator NRTIs, there was no association with recent abacavir use, similar to findings from other studies in which participants were randomized to receive abacavir (Benson, 16th CROI 2009). Further analyses related to this question as well as to other non-AIDS-defining events are underway with two manuscripts in preparation. Additional analyses from this cohort found that higher markers of TNF-α activity 48 weeks after ART initiation were associated with increased risk of subsequent diabetes mellitus. These findings suggest that systemic inflammation, even after ART-induced viral suppression, may contribute to diabetes pathogenesis among HIV-infected subjects (Brown, Workshop on Adverse Drug Reactions, 2009). In A5142, the incidence of lipoatrophy (defined as >20% loss of limb fat by DEXA) at 96 weeks was significantly lower in subjects randomized to the NRTI-sparing arm (LPV/r + EFV) compared to those receiving LPV/r or EFV together with two NRTIs (Haubrich, AIDS 2009). Lipoatrophy was most frequent in subjects receiving d4T-containing regimens. An unexpected finding was the more frequent occurrence of lipoatrophy in the EFV + two NRTI arm than the LPV/r + two NRTI arm; this difference was consistent across all NRTI strata, and provided further support for recent changes in treatment guidelines that support the removal of d4T from first-line therapy, and the use of EFV + two NRTIs as preferred first-line therapy in developed countries. A5224s, the metabolic substudy of A5202, is designed to evaluate the long-term metabolic effects of treatment with TDF/FTC compared with ABC/3TC plus either EFV or ATV/RTV. A5224s will be the first randomized comparison of TDF/FTC with ABC/3TC using objective measures of long-term metabolic outcomes in ART-naïve subjects. The study closed in September 2009. The primary analyses were change in bone mineral density (BMD) and subcutaneous fat as the development of protocol-defined lipoatrophy, both assessed by DEXA. Comparisons were between those given ABC/3TC versus TDF/FTC and ATV/r versus EFV. Early loss of BMD was seen with both NRTIs in hip and spine but to a greater extent with TDF/FTC. There was also a greater decline in spine, but not hip BMD in those assigned ATV/r compared to EFV. Overall there was an increase in subcutaneous fat in all study arms with relatively low frequencies of protocol-defined lipoatrophy that did not differ by treatment (McComsey, CROI 2010). A5260s is a metabolic substudy of the currently enrolling A5257 that will assess regimens with TDF/FTC with either ATV/RTV, DRV/RTV, or raltegravir (RAL). The primary objects of this intensive metabolic substudy are to: to compare the effects of an initial ART regimen containing RAL with regimens containing the HIV PIs ATV/r and DRV/r on progression of carotid artery intima-media thickness (CIMT), a measure of atherosclerosis progression; to compare the effects of two distinct RTV-boosted, PI-containing initial ART regimens (ATV/r and DRV/r) on progression of CIMT; to compare the short-term effects of an the three regimens on brachial artery flow-mediated vasodilation (FMD), a measure of endothelial function and to look at



inflammatory and endothelial markers of cardiovascular disease. The protocol opened to accrual on 05/18/09 and current accrual is 121/330. A5206 evaluated the lipid-lowering effects of tenofovir in a randomized, double-blind, placebo-controlled, crossover, multicenter study of HIV-infected adults with triglyceride values of ≥150 mg/dL and <1000 mg/dL or non-high-density lipoprotein (non-HDL) cholesterol values of ≥100 mg/dL and <250 mg/dL who had HIV-1 RNA <400 copies/mL. Lipid parameters (non-HDL-C, total cholesterol, and LDL-C), with the exception of HDL-C and TG, improved significantly over the TDF treatment period in comparison to the placebo treatment period, findings that support recent changes to treatment guidelines moving TDF into first-line preferred regimens (Tungsiripat, 16th CROI 2009; manuscript reviewed by OpART and ready for submission). A5229 was a phase II/III, randomized, double-blind, placebo-controlled study evaluating uridine supplementation with NucleomaxX for thymidine analogue-induced lipoatrophy. Eligible subjects were HIV-infected adults with clinical lipoatrophy and a cumulative duration of thymidine NRTI (ZDV or d4T) treatment for at least 24 weeks prior to study entry. The primary objective was to examine the effect of uridine supplementation on limb fat in HIV-1-infected subjects with clinical lipoatrophy, by comparing changes from baseline to week 48 in DEXA-measured limb fat between the uridine arm and placebo arm. The study fully enrolled 167 subjects and showed that uridine supplementation with NucleomaxX was poorly tolerated with less than 50% of subjects able to tolerate the medication for 48 weeks. Moreover, after 48 weeks there was no significant difference in limb fat between the treatment arms, a finding that was true in both the intent-to-treat and as-treated analyses (McComsey, CROI 2010). ♦ Assess the role of early interventions in acutely infected individuals in modifying viral

set-point, and the impact of early interventions on long-term outcomes and transmission rates

A5217, a study of the effects on the virologic set-point of 36 weeks of potent ART administered during early, but not acute, HIV-1 infection, compared the virologic set-point 72 weeks after study entry in individuals with recent HIV-1 infection randomized not to receive ART. The DSMB met to review this study in June 2009 at which point 130 of the targeted 150 subjects had been enrolled and the efficacy analysis included 79 subjects randomized at least 72 weeks prior. The DSMB found that the results were largely informed by higher rates of progression to meeting virologic or immunologic criteria for starting ART. They also showed that those assigned to early initiation of therapy had better outcomes for the primary endpoint of log10 HIV-1 RNA level at 72 weeks (p=0.005) as well as at week 72 for the early treatment arm compared with week 36 for the deferred treatment arm (p=0.002). At that time, the DSMB recommended stopping the study due to the inability to answer the primary question regarding virologic set-point since so many subjects met criteria for starting therapy and the fact that there was a low probability that the outcomes would change with further enrollment and follow-up (Hogan, CROI 2010). The study team is planning to follow those that are currently on study but not yet requiring initiation of ART to assess whether differences between arms are sustained over time. ♦ Evaluate the clinical effectiveness of strategies to provide safe and affordable

therapies A5146 compared the strategy of therapeutic drug monitoring (TDM) versus standard of care (i.e., no drug monitoring) in subjects with virologic failure on at least one PI-based ART regimen. Although TDM with PI dose adjustment led to higher concentrations of PIs, this strategy ultimately was not associated with improved virologic outcome. Interestingly, in post hoc



subgroup analyses, significantly better virologic responses were seen in blacks/Latinos and in subjects with better baseline susceptibility to PIs (Demeter, AIDS 2008). Several analyses are ongoing and manuscripts are in preparation. One manuscript detailed the quality assurance aspects of A5146 and provided clinicians and researchers with an assessment that could be used to prospectively design new studies and prioritize resources for TDM program implementation in HIV treatment practices (DiFrancesco, Manuscript in preparation) and an additional manuscript is evaluating adherence and outcome in the study. ♦ Study the pathogenesis of coinfections, complications related to ART, or progressive

HIV disease such as malignancies, metabolic abnormalities, and other co-morbidities A5202 is prospectively evaluating the incidence, spectrum, and presentation of immune reconstitution inflammatory syndrome (IRIS) and the immune mechanisms in established IRIS cases compared with controls. Subjects who had CD4+ cell counts ≤200 before entry were randomly assigned to have blood drawn for PBMC collection at weeks 4, 8, 16, or 24. Cases of IRIS are identified and verified with the team in real time. Additional data collected include concomitant medications; clinical assessment; stored samples; viable PBMCs; plasma; and serum at IRIS diagnosis and 2, 4, 8, 16, and 24 weeks later. More than 1800 treatment-naïve subjects were enrolled to one of four different regimens with the incidence of IRIS being 6.05 cases per 100 person years, predominantly occurring during the first 24 weeks of therapy. The most common IRIS events included varicella zoster and Mycobacterium avium-intracellular complex. Risk factors for IRIS were prior AIDS illnesses, lower CD4+ and CD8+ T cells, and amongst those with the lower CD4+ T-cell count, the use of ABC/3TC relative to TDF/FTC (Fischl, CROI 2010). A5245/HPTN 052 will also explore the incidence and pathogenesis of IRIS in individuals randomized to earlier initiation of ART at CD4+ cell counts from 350-550 cells/µL compared to standard of care initiation of ART at CD4+ cell counts <200 cells/µL in resource-limited international settings, and will look at the incidence of AIDS-defining OIs, serious bacterial infections, tuberculosis, and other non-AIDS-defining clinical events in the two treatment arms to evaluate the impact of early initiation of ART on disease progression and death. C. Prevention of Mother-to-Child Transmission

♦ Develop options to prevent or minimize development of drug resistant strains of

HIV-1 that would compromise clinical outcome and/or limit future treatment options ♦ Optimize drug regimens pre-, peri-, and postpartum in resource-limited settings A5150 was designed to characterize the incidence, magnitude, mechanisms, and consequences of postpartum viral rebound during the initial 24 weeks postpartum. HIV-1-infected women receiving ART were enrolled between 22 and 30 weeks gestation to obtain prepartum viral loads on stable ART. This study explored the mechanisms of this viral rebound by (1) monitoring changes in plasma HIV-1 RNA level, CD4+ count, adherence, PK, and drug exposure in a subgroup of subjects; (2) monitoring genotypic viral resistance, and quantified proviral DNA pre- and postpartum to rule out volume contraction as an etiologic mechanism of postpartum plasma viral load increases; and (3) assessing whether prepartum HIV-specific cytotoxic T-lymphocyte responses decrease the likelihood of postpartum viral rebound. A manuscript incorporating the results is under review by the team.



A5153s, a pharmacology substudy of A5150, assessed whether the area under the plasma concentration versus time curve (AUC) of nelfinavir (NFV) or LPV/r is altered in pregnancy, and whether changes in exposure affect HIV-1 virologic control. Both RTV and the active metabolite of NFV, M8, had significantly lower AUC exposures during pregnancy, with trends toward diminished AUC exposure for LPV, but not for NFV. These results suggest dosage adjustments for PIs during pregnancy may not be necessary for the majority of women. A manuscript incorporating these results is under review. A5208 was designed to compare a nevirapine-based regimen with a LPV/r-based regimen in two groups of women: (1) those who took prior NVP prophylaxis to prevent mother-to-child transmission and (2) those without prior NVP exposure. The goal was to evaluate the difference in the effect of NNRTI-based and PI-based ART on the time to virologic failure or death in subjects with prior NVP prophylaxis versus no prior NVP exposure. The study also will test directly whether minority viral variants with resistance to NVP are responsible for subsequent virologic failure in NVP-exposed women. The study has fully accrued with a total of 745 women. In October 2008, the DSMB stopped the first part of the study when it found that in NVP-experienced women, NVP-based therapy was inferior virologically compared to LPV/r-based therapy. Significantly more women in the NVP (32, or 26%) than LPV/r arm (10, or 8%) reached the primary endpoint of viral failure or death (adjusted p=0.001). Of these, 37 had viral failure (NVP: 28; LPV/r: nine) and five died without preceding VF (NVP: four; LPV/r: one). The length of time since taking the single-dose NVP influenced the outcome; those with longer duration since NVP were more likely to not experience virologic failure on NVP. Interestingly, discontinuation due to adverse events was also greater in the NVP group (Lockman, manuscript under review, NEJM). Additional analyses from this study evaluated the role of minority drug resistant variants in predicting the failure of the NVP based regimens. Six months or more after sdNVP, NNRTI-resistant variants were detected by allele specific PCR (ASP) in 35% of women with negative standard genotype and were associated with higher risk of failure of NVP-containing ART across the entire range of mutants frequencies detected (0.3% - >30%). Standard resistance testing did not identify the majority of women at increased risk for failure of NVP-containing ART after sdNVP (Boltz, CROI 2010). The results of study II were recently presented as a late breaker (MacIntyre, CROI 2010). In this study, 500 ARV-naïve HIV-infected women with CD4+ cell count <200 cells/mm3 and no prior single dose NVP were randomized to initiate open-label ART with TDF/FTC once daily and either NVP (n=249) or LPV/r (n=251) twice daily. Overall, 42 (17%) women in the NVP arm and 50 (20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56-1.29). At 48 weeks, the proportions alive without virological failure were 85.7% and 86.3% for the NVP and LPV/r arms (difference 0.6%, 95% CI -5.5%-6.8%). However, 35 women in the NVP versus none in the LPV/r arm stopped ART due to an adverse event (p<0.001), most in the first 8 weeks. A5227 is an open-label treatment study for HIV-1-infected women with a history of prior combination ART administered solely for prevention of mother-to-child transmission (pMTCT) of HIV-1, who now have an indication to restart an ARV regimen for treatment of their HIV-1 infection. The study goal is to estimate virologic response, measured as <400 copies/mL of plasma HIV-1 RNA at week 24, of a standard NNRTI-based regimen for initial therapy among these “nearly naïve” women. The hypothesis is that the virologic response to standard combination ART for initial therapy for HIV-1 infection, consisting of TDF/FTC plus EFV, will not be compromised by the prior use of a short-course ARV regimen for pMTCT of HIV-1 infection.



The study was closed to accrual on December 31, 2009, with 54 of the targeted 47 patients enrolled. 2. Scientific Research Plans (proposals and studies in development) Within the Next 12

to 24 Months To assist in the development of the OpART Committee’s scientific research plans, focus groups have worked on selected areas and resulted in development of studies for bone disease, second- and third-line regimens for resource-limited settings and use of statins to target HIV-related immune activation. Currently, there are two task forces and one focus group (all in collaboration with the TRADD) working on evaluating the feasibility of new concepts: 1) Acute//Recent Infection focus group is working to address the scientific priorities of the committee; 2) Long-Acting Drugs Task Force is looking to find ARVs that can be dosed at extended intervals; and 3) PK Enhancers Task Force is evaluating new agents that may augment the concentration of other ARVs (such as PI or integrase inhibitors) without the tolerability or toxicity of ritonavir. B. Optimization of Clinical Management of Antiretroviral Therapy ♦ Evaluate strategies to provide safe and affordable therapies for HIV-infected persons

globally A5273 (Multicenter Study of Options for SEcond-Line Effective Combination Therapy [SELECT]) will evaluate regimens for those in resource-limited settings. This study is a phase III, dual-arm, open-label, randomized study for subjects who are on a failing NNRTI-containing first-line regimen. The study will evaluate the difference in virologic failure rate between two treatment arms: LPV/r+ RAL and LPV/r plus best available NRTIs, to be specified by the site prior to randomization. A total of 510 subjects will be enrolled from ACTG international sites. Subjects will be stratified by screening HIV-1 RNA (≥100,000 vs. <100,000 copies/mL), screening CD4+ cell count (≥100 vs. <100 cells/mm3), and selection of ZDV in the NRTI regimen (yes/no). Randomization will be balanced by site. The protocol development is nearly complete. A5288 (Evaluation of Antiretroviral Combinations and Contemporary Management Tools) is designed to fill the gap in available regimens in the RLS when both a first- and second-line regimen has failed. The primary objective of the study is to evaluate whether, in resource-limited settings, novel agents and contemporary management tools (including standard genotyping to select an appropriate third-line regimen, intervention to improve adherence and plasma viral load monitoring), can achieve virologic control in at least 65% of enrollees. Subjects will be triple-class (NRTI, NNRTI, and PI) treatment-experienced and will be considered to be failing a PI-based regimen based upon local criteria. Standard genotyping will be performed at screening and used to place subjects in one of four management groups (A, B, C, and D). All subjects will be followed until 48 weeks. Treatment will depend on the results of the genotype (the team is considering ways to have core team review of the genotype to ensure uniform interpretation during the study). The management groups are: A: genotype shows no evidence of resistance- local standard of care regimens plus adherence intervention; B: no evidence of high levels resistance to DRV or ETR, 0-2 TAMs: RAL+DRV/R+NRTI(s) plus adherence intervention; C: no evidence of high levels of resistance to DRV or ETR, 3 or more TAMs: RAL+DRV/R+ ETR +3TC plus adherence intervention; D: higher level resistance to ETR or DRV treatment with individualized regimen of any drugs available in country and via study plus adherence



intervention. The sample size for the study is 500 subjects. The protocol is currently in development. ♦ Evaluate long-term toxicities and the role of pharmacogenomics in predicting or

managing toxicities Two new studies will evaluate strategies to prevent potential long-term complication of HIV, aging and the possible effects of ART. A5280 (A Prospective, Randomized Trial of High-Dose Vitamin D and Calcium for Bone Health in HIV-Infected Individuals Initiating Highly Active Antiretroviral Therapy [HAART]) will examine the effects of high-dose vitamin D and calcium supplementation on bone mineral density in HIV-infected patients who are initiating HAART with FTC/TDF/EFV. After stratification by screening 25-OH vitamin D levels (≤20 and >20 ng/mL), subjects will be randomized to one of two arms: 1) 4000 IU vitamin D3 daily and 1000 mg calcium carbonate daily versus 2) vitamin D placebo and calcium placebo. All subjects will initiate a regimen of FTC/ TDF/ EFV. Major inclusion criteria are naïve to ART, no mutations that would contraindicate the study regimen, serum calcium <10.5mg/dL, and vitamin D level between 10 and 75. The sample size is 168 subjects, 84 per arm. The protocol is in final stages of sign off. A5292 is a randomized controlled trial to compare the effects of ART versus statin therapy on endothelial function and markers of inflammation/coagulation in HIV-infected individuals with high CD4+ cell counts. In order to understand the relative benefits of ART in patients with higher CD4+ cell counts, the study is a focused, pathogenesis-driven randomized clinical study of HIV-infected patients with CD4+ cell counts >500/mm3 and at least moderate CVD risk to compare the effects of ART with minimal lipid impact versus statin therapy on endothelial function - a validated predictor of CVD - as well as markers of inflammation and coagulation. The primary objective is to compare the effects of a) statin therapy alone, b) potent ART alone, and c) potent ART combined with statin therapy on change over 8 weeks in endothelial function as measured by brachial artery FMD. Secondary objectives will evaluate differences between the strategies in markers of immune activation, inflammation, coagulation as well as non-HDL-c and fasting triglycerides, to compare self-reported HIV transmission risk behaviors across the study arms over 24 weeks and to compare strategies on FMD at 24 weeks. Eligible subjects will be those with CD4 > 500 and Framingham Risk Score (FRS) > 10% OR FRS > 6% if hsCRP > 3.0 mg/L OR CHD risk equivalent. A total of 215 subjects will be randomized 1:2:1 to Arm A: simvastatin 40 mg daily alone; Arm B: simvastatin 40 mg daily plus tenofovir/emtricitabine/raltegravir; or Arm C: tenofovir/emtricitabine/raltegravir alone for 8 weeks then simvastatin 40 mg daily added.

COLLABORATIONS WITH OTHER NETWORKS A5190: Collaborating with IMPAACT A5241: Collaborating with ATN and IMPAACT; also funding from NINDS A5245/HPTN 052: Collaborating with HPTN A5250 and A5251: Collaboration and funding from NINR A5257: Collaborating with IMPAACT A5260s: Funding from NHLBI PROMISE: Collaborating with IMPAACT Elite Controllers Project: Collaboration with Walker Group/Ragon Institute; Broad



III. Optimization of Management of Co-Infections and Co-Morbidities Scientific Committee

1. Progress in Each DAIDS Research Priority Area A. Translational Research and Drug Development ♦ Tuberculosis (TB)

Pharmacokinetic drug interactions with rifampin: Rifampin and other rifamycins are mainstays of anti-TB regimens, but these drugs have significant PK interactions with some antiretroviral (ARV) drugs, particularly HIV-1 protease inhibitors, and management of these drug interactions is often difficult. GS-9350, a more specific CYP3A4 inhibitor than ritonavir, is being developed by Gilead Sciences as an alternative to ritonavir for protease inhibitor boosting. At present, protease inhibitor therapy is contraindicated with rifampin based on the strength of the inhibition effect of ritonavir and the induction effects of rifampin on CYP3A4. Should GS-9350 be shown to be a safe and effective booster of anti-HIV protease and integrase inhibitors it will likely emerge as a replacement for ritonavir boosting of these and other antiretroviral drugs. The extent of PK interactions between rifampin and GS-9350 will be critical information to design appropriate antiretroviral regimens for treatment of HIV-infected individuals with active tuberculosis who are unable to take NNRTIs or who require protease inhibitor drugs for treatment of their HIV infection. A5284 is designed to evaluate potential drug-drug interactions when GS-9350 is co-administered with rifampin and a protease inhibitor in HIV-negative participants who do not have TB. In late 2009 development of this study was put on hold by Gilead Sciences based on their competing priorities but they are still considering support of the study in the third quarter 2010. Rifabutin is commonly used in the developed world to replace rifampin in ARV-treated patients since it is a weaker inducer of cytochrome enzymes. DACS 261 will use a population approach to model information from existing studies on PK, treatment response and adverse event data on the use of rifabutin with HIV-1 protease inhibitors to inform of the optimal dosing of rifabutin with protease inhibitors.

B. Optimization of Clinical Management Over the course of the past year, the OpMAN Committee has undertaken an enthusiastic effort to significantly expand our research portfolio to include other infectious diseases of global health significance and that have a major impact on HIV-infected individuals as well as uninfected populations. Hepatitis B and C and their complications are addressed by a separate committee and are discussed elsewhere in this report. Other major infectious diseases under the purview of the OpMAN Committee for which substantial work is in development now include tuberculosis (both multidrug and extensively drug resistant TB), cryptococcal meningitis in resource-limited settings with a high burden of this infection, malaria in both HIV-infected and where appropriate uninfected individuals, influenza, and serious bacterial infections that occur at high rates among those with HIV infection. Investigative efforts underway in these areas are indicated below. ♦ Tuberculosis (TB) Treatment of active TB in persons with HIV infection: As indicated in our research plan in the original grant application, optimizing the management of TB coinfection in people infected with HIV continues to be the highest research priority for the OpMAN Committee. A5221 is



designed to answer one of the most critical questions in HIV-TB coinfection: when to start antiretroviral therapy (ART) following the initiation of anti-TB therapy. This prospective, randomized trial has completed enrollment of 809 participants and will complete study follow-up in the third quarter of 2010. Results will provide critical information to inform guidelines for treatment of TB-HIV coinfection. The impact of TB on early mortality after initiation of ART in resource-limited settings: In the developing world there is a high rate of early mortality of uncertain etiology among patients initiating ART. Retrospective analyses and limited autopsy reports of causes of death for patients who do access medical care but have early mortality suggest a high proportion have TB at the time of death. We hypothesize that empiric treatment for TB in carefully screened patients without overt evidence of TB might improve the early mortality rates of patients with advanced HIV disease (<50 CD4+ cells/uL) initiating ART. This hypothesis will be investigated by A5274, which is in development with planned implementation in the second quarter of 2010.

Development of TB treatment regimens that can be coadministered with second-line ART: With the rollout of ART in resource-limited areas of the world it is expected that there will be an increasing need to treat active TB in persons who are receiving second-line ART with an HIV protease inhibitor. In addition, as results of A5208 become available and are addressed in treatment guidelines, there may be a shift in recommendations such that women previously exposed to single dose nevirapine for prevention of mother to child transmission may be treated first line with a protease inhibitor regimen. As such, we expect that a substantial number of patients in resource-limited settings may require second line ART. As TB coinfection remains one of the most common infectious complications of HIV in resource-limited settings, A5290 was designed to investigate three different strategies for TB treatment in persons on second-line ART with a protease inhibitor.

Treatment of MDR/XDR TB: Very high priorities for the ACTG are the transformation of first and second line TB treatment with new drugs to improve TB treatment outcomes, particularly in coinfected patients with MDR/XDR TB. In order to effectively evaluate the activity of a novel anti-TB agent in HIV-infected individuals, A5267 will assess the safety, tolerability, and PK interactions of efavirenz with TMC207, a promising anti-TB agent with activity against multidrug resistant TB, in healthy volunteers. This protocol was developed as a result of an ongoing and productive collaboration of the ACTG and the TB Trials Consortium (TBTC), sponsored by the Centers for Disease Control and Prevention (CDC) and is now open for enrollment. A study to evaluate TMC207 as TB prophylaxis in household contacts of MDR TB patients has been proposed and is under consideration and review by the ACTG scientific leadership to be jointly developed and jointly conducted by the TBTC and the ACTG. Evaluation of novel anti-TB drugs for treatment of drug-sensitive TB: An initial step in redefining first line anti-TB treatment is to evaluate novel investigational anti-TB drugs in the setting of drug-susceptible TB by replacing one of the conventional drugs used in first line TB treatment. Through a collaboration with the Global TB Alliance and Tibotec, A5289 is in development and will evaluate the substitution of ethambutol with TMC207 for treatment of drug sensitive TB in HIV-infected persons. Ongoing discussions with the Global TB Alliance and their partners may also facilitate the development of clinical trials that combine two or more new investigational TB drugs to more rapidly accelerate the evaluation of agents that will change the treatment paradigm for TB. TB diagnosis: Diagnosis of active TB in resource-limited settings is hampered by the lack of rapid lower cost laboratory tests and the lack of evidence-based diagnostic algorithms. Two



studies of novel approaches to improve TB diagnosis and case detection in resource-limited settings recently opened. A5255 will evaluate novel techniques for rapid diagnostic testing for detection of TB and rapid identification of MDRTB using a novel line probe assay; sensitivity and specificity of this assay compared to conventional testing has not been evaluated in HIV co-infected individuals. This study will also evaluate the ability to train staff in local laboratories to perform these assays in real-time. A5253 will evaluate an algorithm to improve the sensitivity and specificity of screening for TB in HIV infection. Both of these studies are enrolling with 21 of the 800 (A5253) and 48 of the 639 (A5255) target sample size accrued. The ACTG leadership is working with the network laboratory infrastructure to continue to build capacity and ensure quality control in TB diagnostics across all ACTG sites. We have negotiated with Cepheid a collaboration with the ACTG to further evaluate the performance characteristics and sensitivity and specificity of their GeneXpert technology for rapid point of care detection of TB and MDRTB in HIV coinfected individuals in resource-limited settings. To facilitate this collaboration, we have amended A5253 and A5255 to incorporate this technology, and have submitted an application in response to an ARRA RFA for supplemental funds to support the purchase of and training of local staff to use this equipment. Treatment of latent TB in HIV-infected persons: The ongoing collaboration with the TBTC has resulted in several joint projects. The ACTG has cosponsored TBTC Study 26 (A5259), which is evaluating a short course of a long-acting rifamycin (rifapentine) coupled with isoniazid compared to standard of care INH to treat latent TB infection. The ACTG is recruiting HIV co-infected patients into this study, and recruitment continues with currently approximately 240 HIV-infected individuals enrolled out of 620 expected. This study is currently being conducted only in countries with low to moderate TB prevalence. Conversely, A5279 will evaluate an even shorter course treatment regimen for latent TB in HIV-infected persons, evaluating daily rifapentine and INH for one month in resource-limited settings with high prevalence of TB coinfection. Data from these two trials have the potential, if successful, to revolutionize the treatment of latent TB infection by significantly shortening the course to improve regimen completion rates and ultimately reduce the risk of developing active TB in both HIV-infected and uninfected individuals. ♦ Opportunistic Infections (OIs) Other than Tuberculosis

Antiretroviral treatment in the setting of active OIs: A5164 evaluated the critical question of when to start ART in the setting of acute opportunistic infections (excluding TB) and found that early initiation reduced mortality and AIDS progression. The primary results of this study were published in PLos One (Zolopa, 2009) and have changed clinical practice, and have been incorporated into U.S. Public Health Service/IDSA/CDC guidelines. Secondary analyses are ongoing.

OI Prevention: Led by the HIV Prevention Trials Network (HPTN 052) A5245 is an ongoing collaborative component of the study designed to examine, as a co-primary endpoint, the imperative question of whether earlier initiation of ART (at CD4+ cell counts between 350 and 550 cells/µL) can reduce the incidence of AIDS-defining illnesses, non-AIDS events, serious bacterial infections, and death in HIV-1-infected individuals in resource-limited settings. Accrual is on target and more than 1580 of the planned 1750 couples are enrolled. This study provides an excellent opportunity to examine the impact of ART on incident opportunistic diseases, particularly TB, in areas of high prevalence as well as on HIV transmission among serodiscordant couples, and represents an efficient and collaborative means to address many aspects of the “when to start ART” research question in resource-limited settings with a study statistically powered to do so. As secondary endpoints in the study, we are also carefully



evaluating serious non-AIDS conditions such as non-AIDS malignancies, cardiovascular disease, renal disease, hepatotoxicity, and neurologic dysfunction related to timing of the initiation of ART. A5270 is under development as a large, randomized, placebo-controlled clinical trial to evaluate co-trimoxazole discontinuation in patients with CD4+ cell counts above 200 cells/mm3 in areas of low malaria endemicity. The protocol is near completion, however, questions about study design and overall scientific priority are under discussion, and a decision will be made shortly whether or not to implement the study. NWCS 284 is a collaborative effort using external R21 funding by an external investigator and will use existing data from ACTG protocols as well as stored samples to evaluate correlates of cytomegalovirus (CMV)-specific immune reconstitution during ART. Studies such as this and others underway will help to identify predictors of systemic IRIS reactions that might be used to target approaches to preventing serious IRIS reactions in patients newly starting ART.

. OI Treatment: Evaluation of affordable and effective alternatives to amphotericin-based regimens for the treatment of cryptococcal meningitis (CM) in resource-limited settings, and for adjunctive 5-flucytosine, which is generally not available in most resource-limited settings, remains a high priority research area within our international research agenda. A5225 is a prospective dose-escalation study to determine the maximum tolerated dose of fluconazole in patients with active CM and is now open to accrual. The study is designed to identify an effective high dose regimen of fluconazole that will be useful in areas where amphotericin B and 5-flucytosine are not available or are too costly. OI Diagnosis. As previously described, evaluation of low-cost, point-of-care, rapid diagnostic tests for TB is a high priority for that component of our agenda, and our efforts in this regard are described above. Additional OI diagnostic efforts include secondary analyses of A5164, which have been completed as part of NWCS 299, and evaluated the utility of the beta-glucan assay for the diagnosis of Pneumocystis jiroveci pneumonia (49th Interscience Conference on Antimicrobial Agents & Chemotherapy, San Francisco, CA). Additional efforts are being considered for evaluation in the context of the malaria agenda as described below. ♦ Malaria The ACTG has developed a new Malaria Working Group composed of a number of investigators from international sites where malaria is prevalent as well as malaria investigators and experts from outside the ACTG, most notably representatives of the malaria efforts of the U.S. Army in Thailand, Kenya, and Walter Reed Army Institute of Research. The members of the working group have collaborated to develop concept proposals on the treatment of subclinical malaria and evaluation of potential PK interactions between ARV drugs and antimalarial treatments. One of these studies is in development to prospectively evaluate the observation that protease inhibitors, in particular, lopinavir/ritonavir, have in vitro activity against malaria. NWCS 285 will examine the effect of protease inhibitors on the incidence of malaria in A5208 participants. Further work in this area is continuing to expand with outreach malaria vaccine researchers underway to bring promising vaccines into testing in HIV-infected individuals.



♦ Immune Reconstitution and Inflammatory Syndrome (IRIS) A manuscript on risk factors for IRIS in A5164 has been submitted for publication, and an abstract on immunological correlates of IRIS was presented at the 17th Conference on Retroviruses & Opportunistic Infections 2010. A number of ongoing or in-development ACTG studies have secondary objectives to evaluate IRIS (A5175, A5221, A5263/AMC066, A5264/AMC067, NWCS 284). ♦ Neurologic Complications in Collaboration with the Neurology AIDS Research

Consortium (NARC)

Peripheral neuropathy: Optimizing the management of painful peripheral neuropathy (PN) remains the highest research priority for the Neurology Subcommittee of the OpMAN Committee, supported by the NARC. A5252 will study combination analgesic therapy using duloxetine, methadone, or both drugs for the treatment of painful PN and is enrolling with 15 of the target 120 participants accrued. As a corollary to this effort, identification of potential genetic markers for neuropathy in the mitochondrial genome is underway in NWCS 256 and 273.

HIV dementia: HIV-associated cognitive impairment (HACI) also remains a high scientific priority and is one for which there is no specific treatment. Data have convincingly shown that even in the presence of potent combination ART that is fully suppressive in peripheral blood, HACI occurs and progresses, albeit at different rates depending on the degree of immunosuppression and amount of impairment present at the time ART is initiated. Further studies are in progress with A5001 and A5199 to further characterize HACI and progression on ART in both U.S. and international settings. Interventions to treat HACI have also been conducted, although appropriate candidate drugs are limited. A5235 evaluated minocycline for this condition and enrolled 107 of a planned 110 participants, but this study was discontinued upon recommendation of the DSMB because it was clear that the study would not be able to demonstrate a benefit of minocycline. As described, neurological complications of HIV-1 infection and its therapies in resource-limited settings are being evaluated prospectively in A5199. This ground-breaking study represents a significant achievement for the group in the development and implementation of appropriate neurologic screening and diagnostic tools in diverse populations and regions of the world. The study is fully accrued and follow-up will be completed May 31, 2010. A5271 is in the final stages of protocol development and will be implemented in 2010 to study HIV-uninfected control subjects to provide critical control data for local norms to better inform the interpretation of neuropsychological testing across diverse countries and cultures. Unfortunately, the NARC was not successful in being refunded during its recompetition this year. Sufficient funds are available to complete the planned studies, A5252 in particular, but future intervention trials for treatment of neurologic complications are in question without the resources provided for neurology specialty procedures and follow-up through the NARC. Malignancies: Optimization of the treatment and prevention of AIDS-related malignancies is a high priority for the OpMAN Committee, with our priorities focused on Kaposi’s sarcoma and human papillomavirus realized through our collaboration with the NCI-funded AIDS Malignancy Consortium (AMC). In addition to the HPV vaccine studies discussed below, two complementary randomized clinical trials for patients with limited stage (A5264/AMC067) and advanced (A5263/AMC066) AIDS-related Kaposi’s sarcoma are in the final stages of protocol development and will be implemented in the third quarter of 2010. Designed for international settings, A5264/AMC067 will compare ART alone or with delayed chemotherapy, to ART with immediate chemotherapy in oral form. A5263/AMC066 is being designed to compare three



different chemotherapy regimens as an adjunct to ART for advanced KS disease. A5278s is a pharmacological substudy of both A5263/AMC066 and A5264/AMC067 that is also a collaboration with the AMC and will evaluate potential PK interactions between ARV drugs and chemotherapies. A5282, a protocol to evaluate a pragmatic test-and-treat strategy for prevention of high-grade cervical dysplasia in resource-limited settings is in development. DACS 249 conducted multi-state modeling of HPV acquisition and clearance in HIV-positive women initiating ART and findings were presented at the17th Conference on Retroviruses & Opportunistic Infections (Kang CROI 2010). The Non-AIDS-Related Malignancies Working Group was formed to investigate rates and risks of these in the international setting. The members have identified local registries and databases for analysis and findings should be available in the fourth quarter of 2010. ♦ Oral Complications in Collaboration with the Oral HIV/AIDS Research Alliance

(OHARA) Addressing priorities set by the NIDCR, and articulated in our research plan, the OHARA has continued to further their research agenda. A5254 will validate oral examinations by site personnel in comparison to oral medicine-trained specialists across ACTG sites, and to define the scope of HIV-related oral diseases observed. This is the first study of its kind to evaluate this question at multiple sites and has accrued 66/360 participants thus far. The utility of oral candidiasis as a marker of HIV disease progression and need for initiation of ART will be evaluated in A5253, and use of oral fluid for laboratory diagnostics has been embedded in the human papillomavirus (HPV) vaccine trials, A5240 and A5246/AMC052. Evaluation of KSHV salivary shedding will be evaluated through secondary objectives of A5263/AMC066 and A5264/AMC067. A5265 will assess gentian violet as an inexpensive topical therapy for candidiasis, and is nearing the final stages of development. Oral warts/HPV infection is the third priority for the OHARA, and A5272 is open to enrollment and will examine the effect of ART on oral HPV shedding and the natural history of oral warts in A5257 (OpART Committee) participants. C. Vaccine Research and Development As indicated in our research plan, the issue of safety and performance characteristics of vaccines against HPV in persons infected with HIV requires urgent attention, particularly in light of the high rates of HPV infection, low and high grade cervical and anal squamous intraepithelial lesions, and risk for cervical, anal, and genital tract carcinoma in this patient population. In collaboration with the AMC of the NCI, two protocols were developed to evaluate the safety and immunogenicity of a quadrivalent HPV vaccine (Gardasil) in HIV-infected women and men, as this vaccine has previously been shown in HIV-uninfected persons to prevent HPV infection, cervical precancerous lesions, and cancers. A5240 is being led by the ACTG and is currently enrolling participants to examine this important question in HIV-infected women with 263 of the planned 402 participants enrolled, and A5246/AMC052 is being led by the AMC; enrollment of HIV-infected men has been completed and follow-up of the 112 men is ongoing. Herpes zoster is one of the most common OIs and a common manifestation of IRIS in HIV-infected individuals. A5247 is evaluating the safety, tolerability, and immunogenicity of a live virus vaccine for prevention of varicella zoster (Zostavax, Oka/Merck) in HIV-1-infected adults on ART and with well-preserved immune function. Accrual to the higher CD4+ stratum is complete, and the study has accrued 240 of the 400 participants planned to enroll.



2. Scientific Research Plans (Proposals and Studies in Development) Within Next 12-24

Months Protocols A5263/AMC066, A5264/AMC067, A5265, A5270, A5271, A5274, A5278s, A5279, A5282, A5289, and A5290, discussed above, are being developed in response to priorities specified in the research plan for the ACTG network application. Development and implementation of these protocols will continue over the next 12 to 24 months. A5199, A5221, A5235, A5240, A5246/AMC052, A5247, A5252, A5253, A5254, A5255, A5259/TBTC Study 26, A5272, and A5267, also discussed above, are underway at ACTG CRSs. Enrollment and/or follow-up will continue in these protocols over the forthcoming 12-24 months. During this period we also expect to develop additional new protocols in the area of TB coinfection through the efforts of the TB Working Group. We also expect to develop several new protocols in the area of malaria coinfection through the efforts of the Malaria Working Group in collaboration with investigators and research groups outside the ACTG including the U.S. military. 3. Challenges or Barriers to Implementing Research Plans The four major challenges for implementation of the OpMAN scientific agenda are study drug provision, delays in regulatory approvals for protocol implementation at international CRSs, diagnostic laboratory capacity at international CRSs, and the defunding of the Neurological AIDS Research Consortium (NARC). Much of the OpMAN scientific agenda is focused on opportunistic diseases more commonly seen in resource-limited settings. In addition, many of the currently approved treatments are generic drugs. While these are relatively inexpensive, the generic manufacturers do not have prior experience with donation for NIAID-sponsored clinical trials and the associated regulatory and contractual requirements. The ability to conduct A5263/AMC066, A5270, and A5274 is dependent on either donation or purchase of generic drugs. Generic bleomycin will be purchased for A5263/AMC066. Negotiations are ongoing to obtain generic co-trimoxazole for A5270 and generic anti-TB therapy for A5274. The ability to use modest amounts of research funds for purchase of generic non-ARV drugs is critical to overcoming this barrier. The prolonged, complex, and many-layered approval processes required of the international sites is a barrier for protocol implementation to overcome. There is no uniform solution because there are unique issues that must be addressed on a site-by-site and country-by-country basis. Some international investigators have developed relationships with the local regulatory agencies, and local agencies have become more familiar with the ACTG, and these factors help to facilitate local protocol review and approval. It is important for the ACTG leadership and protocol teams to continue to provide support and flexibility for international CRSs in this area. Implementation of the OpMAN scientific agenda in many cases requires site capacity for clinical and laboratory diagnosis of bacterial, mycobacterial, and/or fungal coinfections and malignant or pre-malignant conditions. This is an important issue for the studies related to TB, malaria, KS, cryptococcal meningitis, and bacterial coinfection described above. It will be important for the ACTG to continue to enhance site laboratory capacity to conduct studies of coinfections in order to meet the stated intent of the NIAID to expand the networks to conduct broader infectious disease research. Moreover, the development of guidelines and evaluation criteria for QA/QC of TB laboratory diagnostics, fungal cultivation, KS biopsy histology, and sample processing, storage, and shipment that is currently underway must be expeditiously completed.




As stated above, the NARC recently learned that its revised application for continued NIH funding of its research agenda was not successful. The NARC leadership has communicated to the OpMAN leadership that it expects to have sufficient carry-over funds for a no-cost extension to allow completion of all ongoing NARC-supported protocols. So defunding of the NARC is not expected to impact ongoing ACTG studies. However, the NARC defunding will decrease the ability of the ACTG to implement new studies to address neurologic issues over the coming years unless investigators are able to secure support through other mechanisms (i.e., R01 or special RFAs). We are exploring alternatives for collaboration with other entities that are responsible for the support and conduct of research related to neurocognitive and neurologic dysfunction associated with HIV. Another important challenge for the OpMAN scientific committee over the forthcoming 12-24 months will be the prioritization of the coinfection-related research agenda. The OpMAN oversees a robust TB research agenda as well as a number of studies of other important coinfections and malignancies. Most of these studies address questions of high importance for optimal management of HIV/AIDS in resource-limited settings. We have been given guidance that HIV-uninfected cohorts should be considered as well. Undoubtedly there are many other important questions that are not currently addressed by the portfolio of studies currently overseen by the OpMAN, and as new proposals are brought forward it will be important for the committee not only to evaluate them for individual merit but also to evaluate them for priority relative to other coinfection questions and other priorities within and external to the ACTG network.

Hepatitis Scientific Committee Progress Report

IV. Hepatitis Scientific Committee 1. Progress in Each DAIDS Research Priority Area A. Translational Research and Drug Development The design and implementation of protocols intended to address key issues in the development of new direct acting agents as well as other classes of agents with activity against hepatitis C virus (HCV) is central to the Hepatitis Committee’s scientific agenda. During this year protocol development teams devoted considerable effort to establish studies that evaluate cyclophilin inhibitors, scavenger receptor B antagonists, interferon enhancers, and ribavirin substitutes. Nitazoxanide is a well-established antiparasitic agent that recently was found to improve treatment response when added to standard HCV therapy in genotype 4 HCV-monoinfected patients. A pilot protocol (A5269) to evaluate this agent in HCV/HIV genotype 1 subjects was developed and has opened at numerous sites. A phase I study of an entry inhibitor in the scavenger receptor B (SR-B) class of antagonists was developed rapidly and is under final regulatory review (A5277). This study will be the first ACTG therapeutic study in HCV monoinfected subjects. The cyclophilin B inhibitor, Debio 025 is a promising HCV-active agent, and pharmacokinetic studies have been planned (A5285 and A5287). The current HCV treatment pipeline remains very active, and committee investigators are in active discussions with pharmaceutical sponsors to study protease inhibitors, polymerase inhibitors, other cyclophilin inhibitors, and other novel classes in partnership with the ACTG. However, there is great volatility in the developmental marketplace as well, and corporate mergers and acquisitions have put some planned trials in jeopardy. A5266 was a large study designed to evaluate the efficacy and safety of a ribavirin prodrug in HCV/HIV-coinfected subjects, but it was discontinued late in development due to the withdrawal of Valeant Pharmaceuticals from the infectious disease segment of the marketplace. B. Optimization of Clinical Management A5178 tested the hypothesis that the use of pegylated interferon (PEG IFN) alone would suppress fibrosis progression even in individuals who failed to have sustained virologic response on PEG IFN plus weight-based ribavirin (RBV). The trial was stopped early because of the inability to demonstrate improvement in fibrosis when comparing untreated controls to the active treatment arm. These data were presented at the 15th CROI in 2008, and had significant impact on the use of empiric maintenance therapy in the coinfected population. A manuscript describing Step 1 and Step 2 outcomes is under review by a high impact journal. Step 3 of the study involved continuation of treatment among early viral responder subjects for an extended 72-week treatment cycle. Near-final results were presented as a late-breaker oral abstract at the 16th CROI in 2009 and demonstrated a low tolerability for extended treatment after week 48. However, subjects who were able to complete 72 weeks of therapy had excellent treatment responses. This study also highlighted the significant racial disparities in response, with Caucasian subjects having much higher early and late response rates than African Americans or Hispanics. The final manuscript for this phase of the study is under development. A5178 also generated a large amount of data for planned substudies. An analysis of anemia in the treatment cohort was completed and presented at the 17th CROI in 2010, and a manuscript team is working on preparation of a paper (Butt, CROI 2010, manuscript in preparation). An analysis of metabolic consequences and outcomes of HCV treatment is in progress, and an analysis of quality-of-life measures is also in development.



A5239 will evaluate the HCV response rates among prior treatment nonresponders who are pretreated with pioglitazone to reduce insulin resistance and then retreated with PEG IFN plus ribavirin. This trial is open and has enrolled approximately half its expected accrual to date. A secondary analysis of A5071 and A5091s samples, focused upon HCV quasispecies evolution during early treatment, revealed that baseline HCV quasispecies were an independent marker of HCV treatment response (Sherman, J Infect Dis. 2010). A secondary analysis of HBV mutations in subjects enrolled in A5127 has been completed, and the manuscript is in the ACTG publications review process, following which it will be submitted to an appropriate journal. NWCS 234R focused upon HCV viral evolution in patients enrolled in ACTG 384. An abstract of this work was presented at the American Association for the Study of Liver Diseases (AASLD) annual meeting. Subjects were evaluated for degree of viral evolution before and after ART exposure. Twenty percent of subjects exhibited genetic variability but only 10% was attributable to positive immune selection (Zamor, AASLD 2009). NWCS 260 will look at the impact of chronic hepatitis B virus (HBV) on response to HIV therapy, the contribution of HBV to hepatotoxicity associated with HIV therapy, and the effect of combination treatment (emtricitabine/tenofovir) versus monotherapy (lamivudine or emtricitabine) in persons who receive those agents, an important clinical question in the field for both HIV/HBV coinfection and HBV monoinfected individuals. Data from one arm of A5175, which has two agents with activity against HBV, will also address this question in NWCS 260, which is funded in part by an R01 from NIAID. Data presented at CROI 2010 described significant levels of variability in HBV prevalence between enrolling countries. Those with detectable HBeAg had higher levels of circulating HBV DNA. Interestingly, HBV/HIV-coinfected subjects had lower CD4+ counts than those with HIV monoinfection (Thio, CROI 2010; manuscript in preparation). NWCS 270R represents a collaboration between the ACTG and the Neurologic AIDS Research Consortium (NARC). A study examining the relationship between HCV and neurologic status in coinfected subjects was published during the reporting period. HCV viremia was not associated with neurocognitive performance or distal sensory neuropathy in this study of subjects with suppressed HIV viremia (Clifford, Neurology 2009). DACS 242 and 243 used data from the three largest HIV-HCV treatment trials to determine whether there are gender-specific effects of treatment in coinfected persons. DACS 243 demonstrated higher rates of adverse events requiring treatment discontinuation or dose modification in women compared with men (Bhattacharya, JAIDS 2009). DACS 242 analysis is in progress.




C. Vaccine Research and Development A5220 tested the hypothesis that the use of granulocyte macrophage-colony stimulating factor (GM-CSF) will improve the response to the current HBV vaccine. GM-CSF was not found to improve vaccine response rates. The primary manuscript from this study is in press. Further immunologic studies are in progress to understand the pathogenic mechanisms associated with the failure to respond to HBV vaccine (Kang, Vaccine 2010). 2. Scientific Research Plans (Proposals and Studies in Development) Within the Next 12-

to-24 Months The Hepatitis Committee is in active discussions with some potential pharmaceutical and biotechnology partners to implement studies in subjects with both HCV/HIV coinfection and, where appropriate, those with HCV monoinfection. A working group was recently created to explore opportunities to study a new vector system designed to introduce key cytotoxic T lymphocyte epitopes in subjects with HCV or HBV infection. The scientific team from Aduro Technology presented current data, and ideas for study development are being explored by the working group. The Hepatitis Committee has also had discussions with, and formal presentations from, Scynexis, Inc. regarding a new cyclophilin inhibitor for HCV, and continues to negotiate with makers of protease and polymerase inhibitors to obtain access to HCV active agents. There are also proposals being developed to use stored specimens from prior HCV treatment studies to examine the potential associations between treatment response and single nucleotide polymorphisms linked to the IL28B gene and immunologic parameters such as NK cell phenotype. The Hepatitis Committee is working assiduously to expand research efforts to include HCV monoinfected patients in addition to the coinfected population, and to participate in novel agents and regimens for HCV treatment in both mono- and coinfected populations. 3. Challenges and Barriers There are challenges working with small biotechnology companies. The Hepatitis Committee has had to place several protocols evaluating novel new agents that were in the late stages of development on hold due to acquisitions of small companies or their products by competitors. Unfortunately, as newer compounds developed by small companies show promise, they or the product are targeted, potentially jeopardizing collaborations with the ACTG. When possible, protocol teams are trying to substitute other compounds within the same therapeutic class into the pre-existing protocols.

Women’s Health Inter-Network Scientific Committee Progress Report

V. Women’s Health Inter-Network Scientific Committee (WHISC) 1. Progress in Each DAIDS Research Priority Area The Women’s Health Internetwork Scientific Committee (WHISC) was developed as a collaboration between the IMPAACT (International Maternal, Pediatric, and Adolescent AIDS Clinical Trials) and ACTG networks to facilitate the development and implementation of clinical trials that address scientific priorities essential to improve short- and long-term outcomes for women. The primary mission of the WHISC is to develop strategies for the prevention and treatment of HIV disease and related complications among women and to determine the pathogenesis of manifestations that are unique to women. The WHISC serves as liaison with other groups conducting research relevant to HIV-infected women and serves as an advisory committee in addressing issues such as reproductive decisions and contraception in clinical trials. In addition the WHISC has developed collaborations with the Food and Drug Administration (FDA) and with the Women’s Interagency HIV Study to explore areas of mutual interest. The activities of the WHISC over the last year are described below. A. Translational Research and Drug Development Research plans for evaluating the safety and efficacy of new drugs in pregnant women are being led by the IMPAACT Network and will not be further discussed in the ACTG progress report. There are translational objectives nested into the P1077, Promoting Maternal and Infant Survival Everywhere (PROMISE) P1077HS study. This study is described below in more detail. However, one area of investigation is to examine changes in markers of inflammation during pregnancy (NWCS 101, submitted to IMPAACT) and to evaluate how these are modified by stopping or continuing ART postpartum. B. Optimization of Clinical Management In keeping with the major research priority area of the ACTG related to optimizing clinical management of women over the course of their lifetime, the WHISC has been engaged in a collaborative effort with IMPAACT to develop an ambitious protocol, PROMISE, which will study strategies not only for prevention of perinatal HIV transmission but also for addressing important management issues related to the health of HIV-infected women during and after their pregnancy.

P1077HS (Maternal-Health HAART Standard version of PROMISE, Promoting Maternal and Infant Survival Everywhere). Our major accomplishment over the last year was the development and implementation of the Maternal Health component within the PROMISE protocol. Currently, 15 sites have been activated, and the team continues to screen site implementation plans for site activation approval. This component of PROMISE will open for enrollment in Brazil, Thailand, Argentina, Haiti, Peru, Botswana, and other select international sites. Site training and initiation of international sites are expected throughout 2010. The first subject was enrolled in the United States in January 2010. Currently, the protocol team is engaged in reviewing protocols in development or capsules from teams seeking coendorsement or collaboration. The team has also worked with chairs of approved protocols to facilitate coenrollment of patients if appropriate, such as P1026. Two of the WHISC leaders serve as chair and vice chair of this protocol, which attests to the



collaboration of the IMPAACT and ACTG networks in the development and execution of this protocol. This study has been designed to address the following objectives among women randomized to stop or continue highly active antiretroviral therapy (HAART) after delivery:

• Clinical outcomes including death, AIDS-defining illness, and serious non-AIDS events (cardiovascular, renal, and hepatic events)

• Moderate and severe signs and symptoms and laboratory toxicity • Quality of life • Rates of HIV drug resistance

The impact of continued HAART on maternal health for women in resource-limited settings after breast feeding, formula feeding, or late entry to care will also be evaluated. Thus, the results of this study should guide future recommendations regarding antiretroviral (ARV) drugs for women started on HAART for PMTCT. Additionally, cost-effectiveness analyses included in the domestic and international components of the PROMISE study will allow us to quantify the risk, benefits and cost of strategies to improve maternal health during and after pregnancy in resource-limited settings.

The WHISC also anticipates that this large prospective study will serve as the framework for smaller substudies or coendorsed protocols that address contraceptive options and treatment of coinfections which will be discussed under the pertinent sections of this report.

A5240, “A Phase II Study to Evaluate the Immunogenicity and Safety of a Quadrivalent Human Papillomavirus Vaccine in HIV-1-Infected Females,” was developed within the ACTG by the Women’s Health Committee (a predecessor of the WHISC) to assess the immunogenicity, safety, and tolerability of the quadrivalent human papillomavirus (HPV) recombinant vaccine (GARDASIL) directed against types 6, 11, 16, and 18. The rationale for its development lies in the realization that as HIV-infected women live longer with the introduction of HAART and other therapeutic strategies, non-AIDS-defining conditions are likely to affect this population in increasing numbers. Preventing infection of the four vaccine HPV types could decrease the impact of HPV infection among HIV-infected individuals. To date, the immunogenicity and safety of an HPV vaccine in HIV-infected adults has not been studied. Thus, this study is the initial step in evaluating an HPV vaccine in adult HIV-infected females. In April 2009, A5240 was approved by the ACTG and the IMPAACT networks for co-enrollment at IMPAACT sites with an initial cap of 100 subjects across IMPAACT sites. There are currently 264 women enrolled; 17 of these subjects are enrolled at IMPAACT sites. Other Studies: WHISC interacts and collaborates with many other committees within IMPAACT and ACTG. Specifically, within the IMPAACT network we have worked jointly with the Complications Scientific Committee (e.g., IMPAACT P1078) and the Prevention of Mother to Child Transmission (PMTCT) Committee (e.g., PROMISE and IMPAACT P1081, P1025, and P1026s) in areas of mutual interest. We have supported enrollment of women into protocols that address unique circumstances experienced by HIV-infected women based on special recommendations such as need for MTCT prevention or those that avail nonpregnant women the opportunity to participate in studies evaluating novel treatment modalities. Listed below are protocols within both networks that address women’s health issues, are supported within our agenda, and include members of our committee as chairs, vice chairs, or investigators.



• A5175: A Phase IV, Prospective, Randomized, Open-Label Evaluation of the Efficacy of Once-Daily PI & Once-Daily Non-NRTI - Containing Therapy Combinations for Initial Treatment of HIV-1 Infected individuals from Resource - Limited Settings (PEARLS) Trial

• A5207: A Phase II Randomized Comparison of Three Antiretroviral Strategies

Administered for 7 or 21 Days to Reduce the Emergence of Nevirapine Resistant HIV-1 Following a Single Intrapartum Dose of Nevirapine – Maintaining Options for Mothers Study (MOMS)

• A5208: Optimal Combination Therapy after Nevirapine Exposure (OCTANE) • A5227: The Effect of Prior Short Course Combination Antiretroviral Therapy

Administered for the Prevention of Mother-to-Child” Transmission (PMTCT) of HIV-1 on Subsequent Treatment Efficacy in Treatment-“Nearly Naïve” Participants

• A5257: A Phase III Comparative Study of Three Non-Nucleoside Reverse Transcriptase

Inhibitor (NNRTI)-Sparing Antiretroviral Regimens for Treatment-Naïve HIV-1-Infected Volunteers (The ARDENT Study: Atazanavir, Raltegravir, or Darunavir with Emtricitabine/Tenofovir for Naïve Treatment)

• IMPAACT P1025: Perinatal Core Protocol • IMPAACT P1026: Pharmacokinetic Properties of Antiretroviral Drugs during Pregnancy • IMPAACT P1081: A Randomized Trial to Evaluate the Virological Response and

Pharmacokinetics of Three Different Potent Regimens in HIV- Infected Women Initiating HAART Between 28 and 36 Weeks of Pregnancy for the Prevention of Mother-to-Child Transmission

C. Prevention of Mother-to-Child Transmission The scientific research plans related to this DAIDS priority area are being led by the IMPAACT network and are described in detail in their annual progress report. Two protocols ongoing in the ACTG, however, do address aspects of prevention of MTCT directly (A5207) and indirectly (A5208). These studies and their progress and milestones for this grant year are described in detail in the TRADD and OpART sections of this report. 2. Scientific Research Plans (Proposals and Studies in Development) Within the Next 12-

to-24 Months

Goals for 2010:

• Promote accrual into P1077HS. • Promote the development of PROMISE substudies addressing women’s health issues. • Complete accrual into A5240. • Complete study development and start accrual into P1081. • Continue to monitor and encourage new protocols that address the WHISC research

agenda.



• Encourage updates of the progress or completed results of the studies mentioned above (in section B) at our face-to-face meetings and at outside scientific meetings.

• Develop a symposium addressing effective strategies to increase enrollment of women to clinical trials based on the experience of sites with track records of high enrollment within IMPAACT and ACTG networks. We will work jointly with the ACTG Outreach, Recruitment, & Retention Resource Committee as well as the IMPAACT and ACTG Community Advisory Boards to review strategies or models that work within our respective networks.

• Work with the representative of the ACTG Underrepresented Populations Committee. We plan to evaluate the role of race-ethnicity, age, and type of protocol on recruitment of women to clinical trials.

• Continue to develop strategies with selected protocol teams to ensure adequate participation of women over the age spectrum.

• Expand collaboration with FDA. • Expand collaboration with Women’s Interagency HIV Study (WIHS). • Promote the use of the new gynecological forms in studies where target enrollment of

women is 20% or higher, in order to gather data on the most frequent conditions, treatment strategies, and outcomes among HIV infected adolescents, reproductive age women, and older women. Such data could also foster development of future treatment interventions in this population.

• Finalize and open the following studies in development: Hepatitis B Substudy of P1077BF and P1077FF (breastfeeding and formula feeding versions of PROMISE): “Impact of HIV MTCT Interventions on Anemia and HBV Disease Outcomes in HIV/HBV Coinfected Pregnant Women.” This substudy will examine the impact of ARV therapy used as PMTCT among pregnant HIV-infected women coinfected with HBV participating in the breastfeeding or formula feeding versions of PROMISE, respectively. This substudy was integrated into the primary design of these parent studies as a collaboration of the WHISC and the Hepatitis Working Group of the ACTG, which is reflected by the scope of the proposing investigators.

The primary objective of this substudy is to compare the anti-HBV efficacy of antepartum lamivudine-zidovudine and lopinavir/ritonavir (single HBV active therapy) vs. emtricitabine-tenofovir and lopinavir/ritonavir (combination HBV-active therapy) as measured by changes in maternal HBV DNA viral loads during the antepartum period (primary endpoint at 8 weeks), a key predictor of HBV vertical transmission. Other HBV outcomes that will be evaluated are: 1) PMTCT of HBV and HBV characteristics (including genotype, drug resistance, pre-core and core promoter mutants and DNA viral load) among babies contracting HBV and among transmitting mother-infant pairs, 2) maternal HBV DNA viral loads and presence of HBV drug resistance at delivery and postpartum, 3) HBV virologic and biochemical changes after HAART cessation, and 4) maternal anemia at delivery among HIV/HBV-coinfected women.

This substudy has been approved by the WHISC, Hepatitis Committee, and IMPAACT Scientific Oversight Committee. This study is integrated into P1077BF and P1077FF and will open to enrollment in spring 2010.

IMPAACT P1078, “A Randomized Clinical Trial to Evaluate the Safety of Immediate versus Deferred Isoniazid Preventive Therapy and Reduction in TB among HIV-Infected Women and Their Infants in High TB Incidence Settings.” There is controversy regarding the utility, safety, and efficacy of initiating isoniazid (INH) preventive therapy (IPT) in the antepartum period for



latent tuberculosis (TB) infection among HIV-infected pregnant women in resource-limited settings such as sub-Saharan Africa and India. This Phase III open label randomized study is being designed under the auspices of the IMPAACT Complications Scientific Committee to evaluate the safety and efficacy of maternal IPT initiation during the antepartum period among HIV-infected women to reduce the incidence of maternal TB, maternal mortality, infant TB, and infant mortality in low-income countries with high TB/HIV burden. This protocol has been reviewed and co-endorsed by the WHISC as a scientific priority of relevance to women of reproductive age.

A5282, “A Randomized Trial to Compare an HPV Test-and-Treat-Strategy to a Cytology-Based Screening for Prevention of CIN 2+ in HIV-infected Women.” Cervical cancer is the second leading cancer in women in the world and the leading cause of cancer in women in many parts of the resource-limited settings. Women with HIV are at increased risk for cervical cancer, and with the increased availability of ARV drugs in these countries through PEPFAR and the global fund, women are living longer and have increased risk of developing cervical dysplasia with progression to cervical cancer. While Pap smear screening programs have greatly reduced the prevalence of cervical cancer in the developed world, most resource-limited settings do not have the financial and skills capacity for such a program. Other modalities of screening and treating cervical dysplasia are necessary to prevent an epidemic in cervical cancer in HIV-positive women in these areas. An alternative strategy has been proposed which relies on testing for cancer-causing or “high-risk” types of HPV (hr-HPV) as the screening test for cervical cancer. The underlying principle is that hr-HPV infection is a necessary cofactor for the vast majority of cervical cancers. If hr-HPV is present, women undergo ablative treatment of the transformation zone with same-visit cryotherapy to treat presumptive CIN2+ and/or areas of hr-HPV infection without actual CIN2+. In A5282 all participants are screened with the careHPV test to detect hr-HPV infection. If hr-HPV is detected, participants are randomized to Arm A, immediate cryotherapy (HPV test-and-treat) or Arm B, cytology-based screening. If hr-HPV is not detected or if cervical lesions are seen that are inappropriate for cryotherapy, participants are eligible for Arm C. All participants will be seen at regular intervals post-entry for cervical colposcopy and directed biopsies, cervical cytology, HPV DNA PCR, and careHPV tests. This study will provide important data for the conduct of future studies to evaluate HPV vaccination in addition to the HPV test-and-treat strategy to combine two effective cervical cancer screening modalities.

A5283, “An Open-Label, Non-Randomized Study of Pharmacokinetic Interactions between Depo-Medroxyprogesterone Acetate (DMPA) and Lopinavir/ritonavir (LPV/r) and of the Effects of DMPA on Cellular Immunity and Regulation in HIV-Infected Women.” DMPA is an injectable depot formulation of medroxyprogesterone (MPA) for intramuscular administration. Worldwide, about 150 million women use hormonal contraceptives. Injectable progestins such as depo-medroxyprogesterone acetate (DMPA) have been used in many areas of the world with high HIV prevalence. Boosted protease inhibitors could have an effect on the pharmacokinetic (PK) profile of DMPA through induction or inhibition of the CYP3A4 enzyme, and likewise the induction of CYP3A4 activity by MPA may have a significant impact on the PK of protease inhibitors metabolized through the cytochrome P450 enzyme system. Thus, it is important to study the potential drug interactions of this contraceptive and commonly used ARV drugs such as lopinavir, fosamprenavir, darunavir, and atazanavir when given boosted with ritonavir in order to ensure that women of reproductive age receiving both drugs achieve optimal PK of ARVs as well as adequate prevention of unintended pregnancies.



After review by the ACTG Scientific Agenda Steering Committee and the IMPAACT Complications Scientific Committee the protocol team limited the scope of their proposal to: Conduct an open-label, multicenter, steady-state PK study of drug-drug interactions in HIV-infected women treated with DMPA while receiving nucleosides and/or nucleotide (e.g., tenofovir) nucleoside reverse transcriptase inhibitors (NRTIs) in combination with lopinavir/ritonavir, and if no interactions are observed it is not likely that other ritonavir-boosted protease inhibitors would be affected. The team was given approval for protocol development which was supported by the WHISC and approved by the IMPAACT SOC and Network Executive Committee. The protocol is scheduled for review by the CSRC on February 11, 2010, and version 1.0 is anticipated by April 2010. D. Other Accomplishments Recruitment and retention of women globally in HIV research, particularly clinical trials, is essential to elucidate the scientific gaps currently observed in the Women’s HIV Research Agenda of our committee and as defined by the Office of AIDS Research. It is essential that we promote the participation of underrepresented racial minorities in the U.S. who carry the biggest burden of the disease, experience the highest mortality rates, and have been disenfranchised from the benefits of ARV treatment. Likewise, as we engage women of reproductive age in resource-limited settings we must ascertain the risks and benefits of therapy, potential drug interactions and cost effectiveness of the strategies proposed. To that effect, a cost effectiveness analysis has been incorporated in the PROMISE study to provide each geographical region with risk/benefit algorithms and cost of novel treatment strategies. We anticipate that PROMISE and many of the other smaller studies discussed in this report will allow us to increase participation of women in trials. We have presented and discussed the PROMISE study with the International CAB in conference calls and have worked with the CABs of both ACTG and IMPAACT to understand and address their research priorities within the scope of our agenda. As delineated in the 2008 annual report, one of our priorities has been to foster the development of proposals to evaluate safety and efficacy of current contraception methods used by HIV-infected women and potential drug interactions of these modalities with ART. To that end, the Gynecological forms were updated to include current gynecological conditions and incorporated into PROMISE. ♦ New Initiatives WHISC/FDA Task Force: The goal of this collaboration is to develop a mechanism to evaluate safety, efficacy and long-term effect of the treatment of HIV disease or its co-morbid conditions among women over the age spectrum by merging data from completed studies within the clinical trials networks and reports captured by the FDA. The analysis of such robust data can more effectively ascertain the impact of ART alone or in combination with the treatment of other co-morbid conditions experienced by this population on ARV toxicities or treatment failures. The goal for 2010 is to propose and complete one analysis within this year.




WHISC/ Women’s Interagency HIV Study (WIHS) Collaboration Task Force: The goal of this collaboration is to promote the development of concept proposals that address treatment needs or clinical conditions that adversely impact the health of HIV-infected women. The large database and ongoing analysis pursued by the WIHS investigators can provide background information on prevalence and scientific priorities. The networks can embark on protocol development in which WIHS patients could participate, e.g., designing clinical trials to address issues related to bone loss in HIV-infected women and the role of vitamin D, neurocognitive disease, or optimal treatment of menopause. This collaboration can also pursue combined analysis of samples or outcomes of selected treatment or medical conditions through a DACS or NWCS between the networks. Only one face-to-face meeting has been held between representatives of the two groups. The goal for 2010 will be to define the scope of the collaboration and propose a concept proposal based on data analysis of a priority topic.

ACTG International Program Progress Report

VI. International Program Introduction Over the past 12 months several high-priority research questions of relevance to HIV therapeutics in the international setting have been answered. Much of this progress is discussed in detail in the relevant scientific committee/DAIDS priority sections of this Progress Report. Nonetheless, we include below a brief summary of these findings and a summary of the new directions the ACTG has developed within its international research agenda as the program has matured and continued to evolve both its scientific leadership structure and its agenda. Clinical operations: By March 1, 2010, over 5700 study participants had been enrolled into clinical trials at ACTG’s international sites. Over the past year enrollment at international sites (~1200 participants) accounted for approximately 40% of the ACTG’s total enrollment. Site performance at the international research sites was also outstanding in terms of data management and laboratory performance. Site development activities related to the most recent recompetition were completed with the initiation of enrollment at the BJMC Medical Center site in Pune, India. As in the domestic program, performance-based metrics were utilized in making budgetary commitments and decisions about ongoing participation in the Group. Accordingly, site development efforts were suspended in Panama City, Panama, when the U.S. Clinical Trials Unit that the Panama City site had been funded through was closed for non-performance. Administrative disputes between the NIH and the Federal University of Rio de Janeiro (UFRJ) resulted in the suspension of new enrollment at the UFRJ site in early 2009 and initiation of site closeout in early 2010. Antiretroviral Chemotherapeutic Studies Major clinical trials completed in 2009: Among the major clinical trials, the primary research objectives outlined in A5175 were completed. As previously reported, in 2008 the DSMB recommended closure of the ddI-FTC-atazanavir arm of A5175 because of inferiority to the AZT/3TC/efavirenz and tenofovir/FTC/efavirenz arms of the trial. Based on a very low treatment failure rate and excellent performance of each of the remaining arms of the study which were comparing TDF/FTC and efavirenz to AZT/3TC and efavirenz, the DSMB recommended that the study not be extended beyond May 2010. A5175 has demonstrated that either of these options is associated with extremely good treatment outcomes for more than 3 years of median follow-up. Part 1 of A5208 demonstrated that ritonavir-boosted lopinavir was superior to nevirapine in HIV-infected women who previously received single-dose nevirapine for PMTCT. A manuscript describing these data has been provisionally accepted by the New England Journal of Medicine. An allele-specific PCR (ASP) assay with sensitivity for 0.1% at codons 103 and 190 and 0.3% at codon 181 demonstrated that the presence of minority variants at these locations among women treated with nevirapine (but not lopinavir/r) predicted virologic failure, whether or not such variants could be detected by routine sequencing. Treatment failure on the nevirapine arm was tracked to the K103N and Y181C mutations but not those at codon 190. The likelihood of failure increased continuously with the frequency of minority variants above a value of 0.8%. Although the overall risk of treatment failure among women assigned to nevirapine declined over time from MTCT-associated nevirapine exposure, this risk did not decline over time in



those with detectable minority variants. This analysis provided important further insights into the virologic determinants of treatment failure among individuals with archived drug resistant mutants from remote drug exposure, and was presented at the 17th CROI in San Francisco in 2010. Part 2 of A5208 was conducted in parallel with Part 1 to explore the extent to which any differences in response between nevirapine- and lopinavir/r- based regimens among mothers who had received single-dose nevirapine might be due to the relative efficacy of the regimens themselves (as opposed to prior nevirapine exposure). The study was completed in September 2009, and it demonstrated that nevirapine- and lopinavir/r-based regimens were equally efficacious in women who had not previously received nevirapine with respect to the primary endpoints of virologic failure or death. The treatment success rate at 2 years in each arm was roughly 80%. A5208 has now been transitioned to a study that will examine longer term treatment success rates as women are transitioned to community-based care. Major ART studies with projected completion dates over the coming 12 – 24 months. A5207 completed enrollment of 980 participants in 2009. This study, which is examining the impact of the use of nucleosides given during the nevirapine “tail,” will be completed in 2010 and will provide key information about second generation approaches to preventing MTCT of HIV-1 in HIV-1 infected women presenting in late stages of pregnancy. A5230, a pilot study of lopinavir/ritonavir monotherapy for treatment of patients who have failed first-line therapy with an NNRTI regimen opened in late 2008 and is nearing full enrollment. Opportunistic Infections and AIDS-associated Malignancies The ACTG substantially expanded its research agenda related to tuberculosis in 2009. With leadership from the Tuberculosis Working Group, key alliances with the CDC’s Tuberculosis Trials Consortium were expanded. Enrollment of the ACTG’s major intervention study (A5221), the opening of a study of novel approaches to secondary prophylaxis of latent tuberculosis (A5259), and two protocols focused on TB diagnostics (A5253 and A5255) were further indicators of a greatly intensified focus on the tuberculosis research agenda. In view of the high mortality rates associated with Mycobacterium tuberculosis infection in late-stage HIV-1 infection, enrollment into A5221 remains one of the highest priorities for the ACTG. The ACTG invested supplemental funds in sites with capacity to expand accelerate enrollment in the study and was successful in completing full enrollment of the trial during 2009. The study will be completed in the latter half of 2010 and will provide additional critical insight into the management of patients with advanced HIV-1 infection presenting with active tuberculosis. The ACTG continued to expand its research agenda related to tuberculosis with the recent opening of A5259, a study that is designed to examine alternative approaches to the secondary prophylaxis of latent tuberculosis. The ACTG has also initiated a broad research effort focused on more robust diagnostic technologies both in terms of diagnosis and definition of drug resistance with the opening of A5253 and A5255. Collaborative studies with the OHARA network will be initiated in the coming year with the opening of a study designed to evaluate the effect of dilute solutions of gentian violet (A5265) as a therapy for oral candidiasis in those with advanced HIV-1 infection. The ACTG continued to cement its close working relationship with the National Cancer Institute’s AIDS Malignancy Consortium with the completion of protocol designs for two major studies directed at Kaposi’s sarcoma. A5264 is a study of ART alone or with delayed chemotherapy versus ART with immediate chemotherapy for limited AIDS-KS. Treatment options for those with more advanced KS will be evaluated in A5263. Site preparation is nearing completion. Both studies are projected to open over the coming year.




Prevention Research The ACTG continued to work closely with the HPTN with completion of enrollment of HPTN 052/A5245, a study of the use of antiretroviral therapy to prevent sexual transmission between HIV-1 serodiscordant couples in stable relationships. This study will also address whether earlier initiation of ART in persons with CD4+ cell counts above 350 cells/μL is associated with reduced morbidity and mortality in resource-limited settings compared to standard of care. The progress and co-primary objectives and endpoints of this study are described in the OpART and OpMAN sections of this report. A proposal that is designed to evaluate the feasibility and to provide pilot effectiveness data related to the “test-and-treat” hypothesis and that would be conducted in an international setting is under active review by the ACTG’s scientific leadership. Malaria Research The ACTG continued its collaborative development of a malaria research agenda with the Department of Defense (DoD) Walter Reed Army Institute for Research (WRAIR). This effort is designed to address high-priority scientific questions aimed at the diagnosis, treatment, and prevention of malaria in patients with and without HIV-1 infection. A workshop focused on the malaria research agenda was held at the ACTG Research Retreat following CROI at which time the research agenda was further refined. A Malaria Working Group was formed, which has developed a focused research agenda in this area. Ten concept proposals have been evaluated and prioritized by this group. It is expected that several of these concept proposals will advance to protocol status within the next several months. New Leadership for the International Effort In anticipation of the upcoming recompetition, the ACTG has restructured its network leadership to recognize the priority of its international agenda and the ongoing maturation of this research effort by creating a Vice Chair for International Activities. ACTG Principal Investigators elected Ian Sanne of the University of the Witswatersrand to this position at the Leadership Retreat in December 2009. This is an important development for the ACTG, in that it recognizes both the priority that the ACTG has placed on its international research agenda and the maturation of the program by transferring coordination and leadership to an ACTG investigator based in sub-Saharan Africa.

Challenges and Barriers Encountered

Challenges or Barriers to Implementing Research Plans and Suggested Ways to Overcome Challenges and Barriers The following is our description the challenges or barriers encountered by the ACTG network in implementing the research agenda during Year 4 and the mechanisms suggested to overcome these challenges. Insufficient clinical research site (CRS) protocol implementation funds (PIF) The amount of PIF available to the network to fully support the work remains insufficient at many of the CRSs, particularly relative to the ever-increasing regulatory burden for human subject research, and the lack of research support for site investigators who participate in the cognitive and scientific work at the site, and on committee and protocol team levels. We are facing serious constraints on our ability to execute our TB agenda, despite redirecting resources from protocols that are experiencing delays in development for other reasons, and continuing our efforts to defund poorly performing sites. Thus far, the defunding of poorly performing sites has not resulted in reinvestment of those funds for use by the network, so the PIF pool has been further decreased in each grant year. Of particular concern is that the base funding at the CRS level is insufficient to support the personnel required at the CRS (i.e., one cannot hire a person when only 10% of the person’s salary is supported on the grant unless that individual has funding from other sources). Therefore, more of the PIF has had to be directed toward supporting salaries of personnel, and as the PIF pool fluxes lower each year, the ability to retain trained and experienced personnel and investigators at the site is jeopardized. As turnover rates increase, more time is spent in retraining staff for specific roles, which takes time away from the research effort and further negatively impacts accrual performance. This is a particularly serious situation at international sites where there is less flexibility on the part of local institutions to support personnel through other means, and where the pool of trained staff is being constantly diverted to other more robustly funded enterprises. This is also particularly serious with regard to maintaining interest, enthusiasm, and involvement of new and young investigators in HIV/AIDS research. With other constraints on NIH budgets, young investigators (and senior investigators) are having substantial difficulty procuring stable research funding to support salaries, and work with the ACTG does not provide sufficient support to sustain salaries for investigator involvement. Lastly, it is becoming increasingly clear that the complexities of conducting therapeutic intervention research in the current environment, both in the U.S. and internationally, is not adequately recognized in the allocation of funding. For those CTUs that are pluripotent and involved in more than one clinical trials network, the amount of PIF allocated for participation in other non-ACTG network studies is significantly larger than for ACTG work, and there is intense pressure not to have those funds redirected to support ACTG protocols at the CTU and CRS level. An additional challenge in working with the current system of PIF allocation has been experienced at the Network Leadership Group (NLG) level; the phase shift of the grant year anniversary date between the NLG and the sites, and the necessity to provide estimates of PIF needed for the following grant year, before the performance evaluation data are available and when the sites have only just received their next year NOAs in the preceding two to three months, has negatively impacted our ability to predict the forward progress of funding needs in a realistic way. We are currently providing PIF requests to the DAIDS 9-12 months in advance of those funds actually being deployed to the sites and based on site and protocol accrual



performance from the preceding funding year. If actual performance and accrual does not proceed along the course predicted that far in advance, we may either seriously overestimate or seriously underestimate the actual PIF needs for the sites, resulting in further year-to-year fluctuations. When this is coupled with the net loss of funds to the PIF pool each grant year, we are having increasing difficulty maintaining the resources and personnel needed to implement and conduct our clinical trials. We are also spending an inordinate amount of staff time and effort on the protocol costing and site resource allocation issues, which is diverting an increasing amount of Core funds to this effort. Exploration of additional funds to support the research work of the ACTG network is critical. Mechanisms to address this challenge have included (1) successful applications by individual investigators or the network for external funds through other grant mechanisms, such as K24, R21, R01, R03, and P01 applications focused on specific projects; we have been very successful with this approach, as evidenced by many of the collaborations described in the scientific committee sections and the external collaborations sections of this report; (2) collaborating with other institutes to use supplemental funds for specific projects (e.g., NIMH collaboration for international neurocognitive studies in A5199; NIDCR collaboration for OHARA and its protocols; NCI for support of Kaposi’s sarcoma studies), again an approach that has been highly successful. However, this latter approach has also met with significant challenges as described in the section below. Philanthropic external funding is not a viable approach, with many efforts launched and none successful. As Year 4 ends it will be imperative to again consider defunding CRSs that are not contributing adequately to the scientific agenda, but also explore mechanisms with NIAID and DAIDS that will allow funds recovered from defunded sites to be redeployed to support research work at remaining sites. Lastly, as we have discussed in previous years, support for investigator effort must be addressed by us and DAIDS in a mutually agreeable solution; we are losing valuable scientific expertise in the group because the sites are unable to support investigator salaries on available funds, and investigators must seek grant support elsewhere. As a consequence, we have fewer investigators to assume leadership positions on scientific committees and on protocol teams, and the burden of new ideas and new concepts to keep up with the changing research needs in the field are being borne by a smaller group of more senior investigators being stretched more thinly each year, with the eventual outcome being a decrease in scientific productivity if we do not address this obstacle. We will be further exploring options with the DAIDS and NIAID leadership as discussions about the next recompetition of the networks continues. Challenges working with other NIH institutes Although collaborations with other NIH institutes have been tremendously successful as described above, and we are grateful for this component of our work, it is becoming increasingly clear that other institutes do not fully understand how the NIAID and the HIV/AIDS ACTG Network operate, and significant ongoing effort is required both at the institute level and the network level to provide information about NLG and site operations, study budgets, Statistical and Data Management Center operations, investigator support, peer review of clinical trials, DSMB interactions, etc., and to manage unrealistic expectations that staff from other institutes might have for their ACTG collaborative efforts. One example of a serious obstacle to working with other NIH institutes in this grant year has been the defunding and dissolution of the Neurology AIDS Research Consortium (NARC) by the NINDS. The NARC has worked with the ACTG for nearly two decades and has been responsible for the significant contributions the ACTG has made to the study of and development of appropriate interventions for treatment of neurologic complications of HIV/AIDS. Without the partnership with the NARC, there will be a significant gap in both expertise and resources to address neurologic complications of HIV at a



time when the neurocognitive dysfunction associated with untreated HIV has taken on particular importance. The ACTG is struggling with how to replace this necessary component of our network agenda, but it is clear that decisions made at the institute level at the NINDS never took into consideration the potential impact on the work being conducted in this important area by the ACTG. Mechanisms to address this challenge include: 1) clearer articulation of expectations at the outset when other institutes provide supplemental funding for collaborative efforts to the networks; 2) initial and ongoing contact and information-sharing between NIAID staff and staff from other institutes that are working with the ACTG, which includes representation from the ACTG leadership and investigators, to work through issues of research funding and network operations, and to manage expectations in a proactive manner that defuses tensions and to resolve issues in a mutually agreeable fashion. Integration of approach among U.S. sites and international sites from different regions The partnership of U.S. and international investigators to address areas of keen interest to our international sites, which were highlighted in the Year 3 NLG progress report, including 1) development of appropriate approaches to second-line and third-line ART in patients failing their first regimen in resource-limited settings; 2) lessening of early mortality associated with initiation of ART in treatment-naïve individuals; and 3) the development of a robust TB research agenda, have all come to fruition in this year, as described in other sections of this report. We have made tremendous progress in truly integrating our domestic and international agendas to complement each other, and we no longer find this as great a challenge as had been described in previous years. The challenges now will be to keep the momentum going in the face of serious funding constraints and to identify additional resources that could be used make these components of our agenda successful. Willingness of pharmaceutical companies to participate and provide antiretroviral drugs for ACTG trials This is an ever present issue for the ACTG, although we continue to have success in collaborating with many key pharmaceutical industry partners. In reference to the second- and third-line ART trials previously discussed, we have procured agreements to supply study drugs including raltegravir, darunavir, and etravirine for those studies (although again with the exception of ritonavir for darunavir boosting). We successfully resolved the problems with procurement of fluconazole for A5225, and this study has now finally opened to enrollment. However, access to novel investigational drugs for studies, particularly in the areas of hepatitis B and C, remains a challenge primarily based on the fact that the developmental plans and timelines for new drug development by industry often place HIV coinfection studies late in their progress, and companies are unwilling to have their drugs tested in this more complicated patient population until they are more secure about the critical path development in non-HIV-infected populations. As we previously described there are also constraints on using investigational study medications in international settings where the drugs are not likely to be widely available for clinical use due to cost or regulatory hurdles, or when the research question being evaluated is a high priority for the field but not for the pharmaceutical companies. Our approach to address this challenge has not changed. We continue to (1) engage pharmaceutical companies early in study development to discuss approaches that could be mutually beneficial; (2) invite them to join protocol teams and encourage their active participation in study design discussions to develop more and better information about how best to use their drugs; (3) reach out to generic drug companies that manufacture FDA-approved ARV drugs and have greater visibility in resource-limited settings; and (4) require that the sites




provide certain of the ARV agents by prescription, when possible. This last option continues to pose a significant challenge for international sites, where some of the drugs may not be available or the cost by prescription is prohibitive and is an impediment to participation for many patients. Additional work to overcome the challenge of differential development timelines for novel agents in HIV-uninfected and HIV-infected populations has included engaging the FDA and other regulatory approval agencies in discussions about the need to accelerate the development and approval process for new drugs that address a critical disease process in HIV-infected individuals. Our investigators participate in advisory groups to the FDA on key areas such as hepatitis drug development, and this has helped raise the visibility of this issue at levels that can influence the approach taken by industry. We have also reached out to partnerships with small biotech companies at very early stages of drug development. These latter two efforts have met with some success in breaking the bottleneck of earlier access to novel agents for treatment of hepatitis C, and new agents are now moving into clinical trials for this disease in HIV-infected individuals, as described in the Hepatitis Committee section of this report. Another approach we have proposed is to allow the network flexibility in making use of research dollars in modest or limited amounts to purchase supplies of some study drug(s) for some protocols, with appropriate DAIDS approval. We continue to feel this approach is necessary for future studies, particularly as the field of pharmaceutical companies working in HIV constricts. Lastly, discussions continued with PEPFAR and Global Fund program leadership about the prior constraints on the use of PEPFAR resources to support research. With the advent of new leadership of PEPFAR, we initiated discussions early on relative to this issue. There is now a new initiative not only to allow closer partnerships between PEPFAR ARV sites and clinical investigation programs, but also specific funds set aside for investigator-initiated research within PEPFAR programs which can be used for supporting research to address important cross-cutting areas of need for patients enrolled in PEPFAR programs. This initiative is just getting underway and will unfold over the next year. Prolonged delays in international site approval before protocols can be opened This challenge continues, although the situation has improved significantly at a number of our international research sites. We have been aggressive in providing our investigators with support for engaging and educating local institutional review boards and regulatory review committees about key research issues. As investigators have developed stronger relationships with the leaders of their local IRBs and review committees, and those committees more familiar with NIH-sponsored research and in particular therapeutic research through the ACTG, the frustrations have eased in a number of areas. We still have continued difficulty in particular in Brazil – a situation that has not been successfully ameliorated by ACTG site investigators, despite continued Fogarty Center and State Department staff intervention. India, too, had been a particular problem for the network, however, with new leadership at the Indian Council on Medical Research (ICMR), and improved relationships between the ICMR and local Indian investigators, the turnaround time for review and approval of new protocols appears to have been substantially reduced in this past grant year. We will continue to monitor this challenge.

Performance Evaluation Committee Progress Report

Performance Evaluation Committee The Performance Evaluation Committee (PEC) of the ACTG network has an established system for the evaluation of the network’s clinical research sites (CRSs) and specialty laboratories. Performance metrics and standards are re-assessed regularly to assure relevance to the evaluation process. The PEC monitors site performance via ongoing monthly reviews of performance data. Formal site performance evaluations are conducted annually; the 2009 evaluation included data for the 12-months June through May. Interim evaluation of CRSs not meeting the performance standards in the annual evaluation is conducted in early December. CRSs new to the Network are subject to interim evaluations performed 6 months after the site receives approval to begin enrolling subjects into the site’s first protocol. Summary results of site and specialty laboratory evaluations for the grant period December 2008 through November 2009 are outlined below. I. Summary of Site Performance In 2009, the ACTG secured supplemental funding from the Division of AIDS to support training of new CRSs through a site mentoring program to ensure the sites’ success in meeting the Network’s performance standards. Thirteen CRSs participated in the mentoring program, which was implemented beginning in May 2009. Personnel from experienced sites were recruited to conduct on-site training in the key performance areas of protocol implementation, regulatory compliance, data management, and laboratory processing. While the majority of new and established CRSs continued to meet or exceed the Network’s standards during the December 2008 through November 2009 period, six new sites were placed on probationary status for performance that consistently fell below standards. Accrual: The ACTG network-specific standard ensures that sufficient subjects are enrolled for the network to conduct its scientific agenda. This standard requires that each CRS maintain a minimum average census of 40 subjects on study per month over a 12-month period, enrolled in all trials, and is inclusive of the DAIDS requirement that a CRS maintain a minimum average of 20 subjects on study per month over a 12-month period, enrolled in intervention trials. For the period of December 2008 through November 2009, 57 of the 60 (95%) established CRSs, met the ACTG accrual standard, and 59 (98%) met the DAIDS minimum requirement. A majority of the 14 CRSs new to the network showed progress toward meeting both accrual standards, and two met the DAIDS minimum requirement. Retention: The retention of study participants is essential to the successful conduct of clinical trials and to achieving the clinical research objectives. As a performance measure, retention is a potential indicator of site performance in developing and managing effective relationships with research participants, including adequate informed consent processes. Analyzing retention at the individual study level provides insight into protocol design, the quality of the recruitment process and the effectiveness of the strategies for protocol management. In recognition of the various factors that might affect premature discontinuation of study treatment and modified lost-to-study rates, domestic and international sites are evaluated as separate groups, and the standard/goal for these measures is based on the median of the specific group’s performance. To ensure that retention metrics provide objective and meaningful markers of CRS performance, the PEC evaluates retention data in the context of individual CRS performance, monitors outliers, and reviews the reasons subjects discontinued participation in studies to



identify either site-specific or protocol-specific issues that may require attention or remedial intervention. A review of the 2008-09 data indicates that overall, 53 of 76 CRSs (70%) met the current standard for the modified lost-to-study rate and 55 of 75 CRSs (73%) met the standard for premature discontinuation of study treatment rate. Accrual Demographics: ACTG demographic enrollment is compared with national and global data at the network level. We are pleased to note that the demographic breakdown of the ACTG’s enrollment by gender (global) and ethnicity (domestic) over the ten-year span from 1999 to 2009 clearly demonstrates that ACTG enrollment demographics are becoming closely aligned with the prevalence of the epidemic. Currently, there is no imposed demographic standard at the CRS level; however, site-specific statistics are monitored regularly in the monthly site performance review. The percent enrollment for women, African Americans, Hispanics, Asians/Pacific Islanders, and American Indians/Alaska Natives, compared to the total CRS enrollment, is monitored at domestic sites; monitoring at international CRSs is limited to the percentage of women enrolled. The ACTG remains committed to assuring that participants in its clinical trials accurately reflect the affected populations of the HIV/AIDS epidemic; the PEC will determine whether a formal standard could be developed as access to reliable statistical data for regional demographics improves, with the understanding that such a standard should not be so stringent that coercive recruitment could result. Data Management Performance: Data management performance includes metrics for data completeness, timeliness of submission, quality of data, and responsiveness to queries, with each site assigned an overall data management performance rating based on the number of points earned for each item evaluated. Group performance continues to be excellent overall, with 100% of the sites meeting or exceeding the standards. Regulatory Affairs: Performance criteria for regulatory affairs include the timeliness of submission of protocol registration packets for amended protocols and the timeliness of serious adverse event (SAE) reporting to the Regulatory Compliance Center (RCC). Completed protocol amendment registration packets must be received at the RCC within 90 days of the date of distribution; all but four of the 34 domestic sites submitting protocol amendment registrations met the standard while two of eight international sites met the standard during this grant year. The PEC has been collecting data on the length of time it takes international sites to secure IRB/EC approvals to gain a better understanding of the barriers to compliance with this standard. Timely recognition and reporting of adverse events are critical to the proper execution of clinical trials, and the ACTG is committed to maintaining a high standard of performance in complying with the existing standards for SAE reporting. Thirty four of the 45 domestic CRSs (76%) that reported an SAE met the 3-day requirement for SAE reporting, while 11 of the 25 international CRSs (44%) that reported an SAE met the standard. Overall, 392 SAEs were reported in this 12-month period; of these, 348 (89%) were reported as required within 3 business days of site awareness and 378 (96%) were reported within 7 days of site awareness; for U.S. sites, 172/184 (93%) were reported within the 3-day time compared with 176/208 (85%) for international sites. Descriptions of the reasons for late submissions, which are reviewed monthly by the PEC, suggest that a number of delayed submissions were attributed to technical difficulties using the new online Division of AIDS Adverse Event Reporting System (DAERS) implemented in early 2009.



Monitoring Initial informed consent: The PEC monitors site performance on a quarterly basis to ensure informed consent criteria are met prior to subject enrollment. CRSs continued to perform well in this area with72 of 76 CRSs (95%) having met the standard (100%) The PEC reviewed informed consent violations and determined that none of the four compromised the informed consent process. Entry criteria met: The PEC monitors site adherence to the protocol inclusion/exclusion criteria. During the 2008-09 grant year, 65 of 76 CRSs (86%) met the standard (95%) with 98% of the 1208 entry criteria verified in compliance. Source documentation adequacy: The PEC monitors site compliance with the requirement that adequate source documentation is available for confirmation of events (eligibility, endpoints, SAEs, death) data in Case Report Form (CRF). All but one CRS met the standard (95%) and 99% of records reviewed were in compliance. Clinical endpoint determination: The PEC monitors whether study endpoints are correctly recognized and properly entered into CRFs. All CRSs but one met the standard (95%) with 99% percent of the records reviewed found to be in compliance. Laboratory Shipment Score: The laboratory shipment score is obtained based on compliance with safe shipping and appropriate documentation requirements for specimen shipments to the central laboratory for HIV RNA testing at the Johns Hopkins University and to the ACTG specimen repository. Ninety-six percent of the domestic sites and 38% of the 14 international sites subject to evaluation for this metric met the standard ≥ 90 points. Formal evaluation of the international sites that have limited shipping data (e.g., less than two shipments) are conducted once the number of their specimen shipments are sufficient to provide evaluable data. Specimen Shipping to the Repository: The ACTG requires sites to ship specimens to the Biomedical Research Institute (BRI) repository within 6 months of specimen collection, excluding those samples designated for protocol testing within 6 months of collection. Forty seven of the 50 (94%) domestic CRSs met the requirement to ship at least 90% of their eligible specimen within 6 months of collection. Due to variations in their local specimen shipping requirements, international sites are excluded from formal evaluation in this metric. Financial Disclosure: The financial disclosure measure evaluates compliance with the ACTG requirement that eligible members of a CRS submit the mandatory financial disclosure statements within the 30-day annual or 60-day new member time requirement; the standard for this metric is 100% compliance. Sixty-eight sites (89%) met the requirement, while eight sites had between one and three late financial disclosure statements; ultimately, all CRSs were compliant. Overall Performance: The Network as a whole achieved its target accrual with the majority of established sites meeting or exceeding the accrual standard. Overall network performance continues to conform consistently to the established standards, with the majority of sites meeting the criteria in the performance areas evaluated. We expect an increase in enrollment activity and adherence to performance standards as those sites that were new to the network in this grant cycle develop the skills and expertise necessary to rigorously conduct therapeutic clinical trials.



II. Specialty Laboratory Evaluation Specialty laboratories provide diverse expertise to the ACTG in the areas of virology, immunology, and pharmacology. Nine virology specialty laboratories (VSLs), four of which are international genotyping laboratories, four immunology specialty laboratories (ISLs) and four pharmacology specialty laboratories (PSLs) provide vital support to the ACTG Research Agenda. The Laboratory Evaluation Subcommittee (LES) of the Performance Evaluation Committee (PEC) develops performance metrics for the specialty laboratories and conducts bi-annual and annual reviews of laboratory-specific data in order to identify workload and performance issues and provide appropriate feedback to the PEC. The LES also monitors the DAIDS Immunology Quality Assurance (IQA) Cryopreservation Proficiency Assessment program and provides quarterly CRS performance reports to the PEC. Types of data reviewed by the LES include (1) volume of assay testing, (2) data management performance, (3) quality assurance efforts, and (4) scientific contributions to the network. Assay Count: The LES has developed a standard weighting system to acknowledge and account for varying degrees of complexities and time requirements inherent in different laboratory studies. A review of assays performed December 2008 through November 2009 reveal a total weighted assay count 19,313, which represents a 19% increase from 2008. The weighted assay count data also show a gradual narrowing of the gap in the distribution of assay work among the three specialties with virology and immunology having an increase in assay volume of 92% and 42% respectively during the 2009 grant year. Data Management: The ACTG recognizes that the timely and accurate reporting of specimen and assay data to the central database is essential to ensure sample integrity and current study datasets. Data management performance is an indicator for the accuracy, efficiency, and reliability of the laboratory’s data and specimen handling processes. The timeliness of assay data export measure evaluates the completeness and timeliness of assay data transfer to the Data Management Center (DMC) central database at FSTRF Frontier Science and Technology Research Foundation, Inc. (FSTRF). Monitoring for timely data export is currently limited to real-time assays but the measure will be expanded to include all assay data that are captured in the DMC database. Improvements in data capture mechanisms have allowed for better tracking of timeliness of data export to the central laboratory database, which in 2009 showed overall, 85% of data subjected to monitoring submission timeliness were submitted within the required 4-week window. In its ongoing effort to improve the timeliness of laboratory data reporting, the LES began tracking the frequency of sample data exports to the Laboratory Data Management System (LDMS) and, in September 2009, implemented a new data management metric, timeliness of sample data exports to the central laboratory database. Laboratories are required to export sample data to the LDMS at a minimum once every 14 days. Quality Assurance: Participation in the IQA Proficiency Assessment Program by site processing laboratories shows significant improvement, with 85% of laboratories that perform cryopreservation of Peripheral Blood Mononuclear Cells (PBMCs) participating in the quarterly proficiency testing program in Q4, 2009 compared to 72% in Q4, 2008. Other quality improvement initiatives undertaken during the past year include piloting of a new metric, Lab




Query Responsiveness, to assess how quickly laboratories respond to queries concerning laboratory data quality. Scientific Contribution: Specialty laboratory scientific contribution to the network is measured on a credit point system that awards credit points for contributions on protocol teams, committees, and masthead authorship. A review of the scientific contribution performance indicates the level of contribution to the ACTG scientific agenda remains consistent across the three specialties. In addition, the 2009 data indicate that there has been increased activity in the area of masthead authorship, with the data showing an 8 percentage point increase from 2008 for publication credits.

Cross-Network and External Collaborations

Cross-Network and External Collaborations Scientific Collaborations The ACTG has continued its long and productive track record of extensive collaborations beyond our own network to include collaborative research with multiple NIAID-sponsored HIV/AIDS research networks, HIV/AIDS networks outside the U.S. sponsored by other governments or agencies, other NIH institutes, the pharmaceutical industry, and outside investigators funded through mechanisms external to the ACTG. Examples of the types of scientific collaborations outside the network involving the ACTG include HPTN 052/ACTG A5245 (collaboration with HPTN); PROMISE (with IMPAACT); Study 26/ACTG A5259 (with the CDC Tuberculosis Trials Consortium); complementary protocols developed with NEAT (European Union HIV/AIDS Treatment Network); OHARA (with NIDCR); ACTG A5263 and A5264 (with NCI); RO1 and CFAR-funded investigator-initiated projects, and others. Our numerous collaborations with external investigators and other entities are described in detail in the sections for each scientific committee, and key collaborations both in the conduct of ongoing ACTG or joint protocols as well as work proposed by individual outside investigators are outlined in detail in Tables 1 and 2 below, identified by protocol number and title and by collaborating institutes, networks, pharmaceutical companies, and/or outside investigator-initiated grants. Administrative Cross-Network Collaborations (Office of HIV/AIDS Network Collaboration [HANC]) During the course of this grant year, the ACTG network has been actively involved with the HANC staff and other networks in coordinating several cross-network activities as indicated below. Training: ACTG Core staff, including Lisa Kessels, Kate Maffei, Debbie Slamowitz, Linda Naini, and Stephanie Warner, have been regular participants in the cross-network Training Committee during the past year. The Training Committee identifies and addresses cross-network core operations center and clinical trial unit training needs. The committee serves as the primary point of contact for training-related requests and issues, and consists of 35 invitees/members from DAIDS, PPD, FSTRF, the Military HIV Research Program, Community Partners, and each network. ACTG staff participation has included collaborating with other networks to offer joint training opportunities, distributing information about training opportunities, sharing existing ACTG training materials, and participating in the development of new training materials Evaluation: ACTG Core staff members Sue Koletar, Dorothy O’Neil, and Lisa Patton are regular participants in the Evaluation Measurement Task Force (EMTF) and its Operations, Policies and Resources Working Group which is responsible for providing detailed, technical input about indicators, tools, resources, and potential measures to be considered for use in the development of an evaluation system plan for the networks and DAIDS. Clinical Trial Logistics and Site Coordination: The Financial Disclosure Working Group, a cross-network working group, has endeavored to meet the federal requirements, standardize reporting deadlines, standardize reporting thresholds and categories, and considered the



possibility of creating a cross-network online database to capture all reports. ACTG representation on this working group has included Lisa Patton and David Thomas. A cross-network working group was instituted in December 2009 to address issues of common concern and harmonize policies and procedures regarding site-level operations. The request for this working group came from multiple network site coordinators as well as the CDC Office of the Chief Science Officer. ACTG representation includes Christina Blanchard Horan, Todd Lusch, and Debbie Slamowitz. Communication: Since its initiation in June 2009, the Communications Working group has hosted eight conference calls. The WG composition includes IT, communications, and outreach staff from all six DAIDS-funded networks as well representatives from the U.S. Military HIV Research Program, the cross-network Legacy Project, and invited guests. ACTG representative Lisa Patton is involved in the Communications Working Group. Network Laboratory: A number of ACTG Core Operations Center, Network Laboratory, and site staff, as well as Network Leadership (Dr. Benson) have been regular and active participants in at least one of twelve active laboratory working groups, including the ACTG/IMPAACT Laboratory Technician Committee (LTC), the Cryopreservation Optimization Working Group, the Lab PI/Manager Committee, the Lab Focus Group, the LFG-DCLOT Collaborative Working Group, the Clinical Pharmacology Quality Assurance (CPQA) Advisory Board, the CPQA Cross-Network Laboratory Group, the Immunology Quality Assurance (IQA) CD4 Working Group , the IQA PBMC Cryopreservation Proficiency Testing Advisory Group (ICAG), the PBMC SOP Working Group, the TB Diagnostics Working Group, and VQAAB. ACTG members have been instrumental in the development of the new cross-network PBMC SOP, review/revision of working group guidelines for the Total Quality Management (TQM) Program, review and revision of “Guidelines for Use of Back-Up Equipment and Back-Up Clinical Laboratories for Safety Testing in DAIDS-Sponsored Clinical Trials,” development of “Communication Plan for Lab Audit Reports and SMILE Action Plans,” development of the CPQA By-Laws, review of the CPQA AVR/SOP Review SOP, development of the CPQA online AVR/SOP utility, completion of Cryopreservation Optimization Study, compilation of the “PBMC Laboratory Audit Readiness Guide and Resources,” revision of the standard wording for Laboratory Processing Charts, development of a laboratory technician work load tracking system, finalization of new performance criteria for the IQA PBMC Cryopreservation Proficiency Testing Program and development of an implementation plan for an appropriate control for the new Abbott PCR-based viral load assay adopted by the networks. Notably, ACTG investigators have lead the development of guidelines for TB sample storage and transportation for use in the development and review of network protocols, and have worked with the SMILE and PPD contract staff to monitor site readiness for TB protocol participation. This task in particular has contributed to the development of a cadre of ACTG CRSs with capability and capacity to conduct scientifically rigorous clinical trials of TB prevention and treatment and studies to evaluate new/novel TB diagnostic assays. Data Management Center: ACTG DMC staff Adel Ahmed, Marlene Cooper, Kristine Coughlin, Linda Marillo, Greg Pavlov, Lucinda Phillips, and Sue Siminski have been active members of the DMC Harmonization Working Group, which addresses the data management coordination objectives outlined in the HANC work plan. Ten teleconferences have been held as of February 9, 2010. Participation has included collaboratively identifying and documenting new shared processes, sharing current activities or issues, and ensuring that infrastructure changes at sites do not negatively impact other DMCs’ systems.



Miriam Chernoff, Kristine Coughlin, Katie Mollan, Ray Griner, Lynn Howells, Bob Kalayjian, Linda Marillo, Robert Murphy, Laura Smeaton, and Paige Williams are members of the AIDS-Defining Event Definitions Working Group. This working group includes representation from DMC and Core Operations Center staff involved in clinical coding and statistical analysis. The intent is to develop AIDS-event queries in order to better review safety data to determine HIV-related events in relation to safety profiles. Ideally, SMQs (Standardized MedDRA Queries) will be tools applicable to both datasets if the DMCs want to combine data with that of another network. Five conference calls and two joint in-person meetings have been held for the working group to map CDC and WHO guidelines, draft example mini-SMQs, and share current practices related to AIDS-defining events. Kris Coughlin and Lucinda Phillips are also involved in the Sex and Gender Data Collection Working Group, which includes representation from DMC and Core Operations center staff involved with data collection issues, Community Partners and/or other community members, and DAIDS staff. The working group is determining how data collection for transgender participants in DAIDS-funded HIV/AIDS clinical trials should be best conducted. Community: ACTG members Allegra Cermak, Flávio Pontes, Karl Shaw, Michael Stewart, William Strain, and Tshepo Ledwaba served this past year as members of Community Partners, which represents cross-network community research needs and priorities to network leadership and DAIDS. Community Partners is a venue for sharing resources and experiences across the networks, avoiding duplicative efforts, and identifying and addressing challenges to participation in trials. Five active cross-network community working groups address specific areas or needs. Two individuals from the ACTG are member of the Executive Committee. Allegra Cermak, Flávio Pontes, Yaa Simpson, Will Strain, and Butch McKay from the ACTG are member of the Community Training Working Group, which considers areas of community training common across networks and standardizes or develops materials that have broad application to community issues around HIV/AIDS clinical research and participation in trials. Tshepo Ledwaba from the ACTG is a member of the Community Research Priorities Working Group, which is working to identify, articulate, and communicate scientific priorities of communities, areas of divergence from scientific researchers’ priorities, and unaddressed issues or unmet community needs. Allegra Cermak and William Strain from ACTG are members of the Community Site-Level Funding Working Group. Allegra Cermak and Flávio Pontes are also members of the Community Evaluation Working Group. Flávio Pontes is a member of the Network Leadership Operations Group/Strategic Working Group. Legacy Project: Kimberly Smith, Chair of the ACTG Underrepresented Populations Committee, has had two meetings with Kaijson Noilmar, HANC Legacy Project Coordinator, to discuss ACTG-Legacy collaborations. Karl Shaw, an ACTG community representative, is a member of the Legacy Project Working Group. Leadership: ACTG Leadership, Constance Benson and Daniel Kuritzkes, have participated in AIDS Clinical Trials Network Leadership Operations Group teleconferences and the Network Leaders Team, cross-network bodies established by DAIDS. ACTG Leadership has participated in the eight HANC-facilitated focused monthly conference calls as of February 2010 with the six network principal investigators/chairs and co-PIs/co-chairs to address cross-cutting network leadership issues. ACTG leadership has continued to provide strategic input into the supervision of the above-described cross-network activities sponsored by the HANC as well as the research priority setting activities conducted at the Strategic Working Group meetings.



Table 1. Protocol Collaboration

Abstracted Title Collaboration Pharmaceutical Support

A5001 ACTG Longitudinal Linked Randomized Trials (ALLRT) Protocol

Several

A5235 Trial of Minocycline for HIV-Associated Cognitive Impairment

NARC/NINDS

A5252 Combination Analgesic Therapy in HIV-associated Painful Peripheral Neuropathy

NARC/NINDS Lilly

A5150 Virologic and Immunologic Changes in HIV-Infected Women Postpartum

NICHD sites

A5153s Pharmacology Substudy of A5150 NICHD sites

A5241 Optimized Tx that Includes/Omits NRTIs:Using the cPSS to Select a Regimen

IMPAACT/NICHD/ATN Pfizer, Merck, Tibotec

A5190 Safety/Toxicity of Infants of HIV-Infected Women in ART Protocols

IMPAACT/NICHD, HPTN

A5207 Three ART Strategies to Reduce NVP-Resistant HIV After Intrapartum Single Dose NVP

IMPAACT, HPTN Abbott, Gilead, GSK

A5208 Optimal Combined Therapy After Nevirapine Exposure IMPAACT, HPTN Abbott, Gilead, GSK, Merck

A5257 Study of Three Compact ARV Regimens for Treatment of Naive HIV-1 Volunteers

IMPAACT/NICHD BMS, Gilead, Merck, Tibotec

P1077 Promotion of Maternal Infant Survival Everywhere (PROMISE)

IMPAACT/NICHD

A5282 HPV Test-and-Treat-Strategy vs. Cytology-based Screening for Prevention of CIN2+

IMPAACT

A5175 Once-Daily PI + NNRTI Regimens for Initial Tx in Resource-Limited Settings

HPTN/OAR BMS, Gilead, GSK

A5245 HPTN 052

When to Start ART in Resource-Limited Settings HPTN Abbott, BIPI, BMS, Gilead, GSK,

A5199 International Neurological Study: A Stand Alone Study for Participants of A5175

NIMH

A5271 Collection of Comparison Neurocognitive Data in Resource Limited Settings

NIMH

A5240 Immunogenicity and Safety of a Quadrivalent HPV Vaccine in HIV Infected Women

NIDCR/OHARA, AMC/NCI, IMPAACT

Merck

A5246 Safety & Immunogenicity of Human Papillomavirus Vaccine in HIV-1-Infected Men

NIDCR/OHARA, AMC Merck

A5254 HIV-Related Oral Mucosal Disease & Use of Saliva in Measuring HIV Viral Load

NIDCR/OHARA

A5272 The Effect of HIV Antiretroviral Therapy Initiation on Oral HPV Shedding and Oral Warts

NIDCR/OHARA

A5265 Gentian Violet Vs. Nystatin Oral Suspension for Tx of Oropharyngeal Candidiasis

NIDCR/OHARA

A5272 Oral HPV Shedding and Oral Warts After Initiation of ART NIDCR/OHARA

A5263 Three Chemo Regimens as an Adjunct to ARV Therapy for Treatment of AIDS-KS

AMC/NCI, NIDCR/OHARA Bristol-Myers Squibb, Centocor, Gilead,

Johnson&Johnson, Merck



Table 1. Protocol Collaboration Cont’d


A5264 Randomized Comparison of ART Alone vs ART with Immediate C

AMC/NCI, NIDCR/OHARA Bristol-Myers Squibb, Gilead, Merck

A5278 Pharmacology Substudies of A5263 and A5264 AMC/NCI

A5250 Durability of Adherence in Self-Management of HIV (DASH)

NINR

A5251 Enhanced Nursing Support to Improve Self-Management and Outcomes of ART

NINR

A5187

Safety/Immunogenicity of HIV DNA Vaccine VRC-HIVDNA0009-00-VP in Acute Infection

NIAID/Vaccine Research Center (VRC). Study

proposed by Eric Rosenber, Dan Barouch and Barney

Graham.

A5214 Safety of Single Dose IL-7 in HIV-1-Infected Subjects on ART

Collaboration with Irini Sereti, NIAID, NIH Clinical

Research Center

Cytheris

A5217 TDF+FTC+LPV/r vs. no ART in New Infections NIAID/AIEDRP Abbott, Gilead

A5255 Rapid TB Diagnostics Study NIAID Supplemental Funding through DMID

A5253 Sensitivity & Specificity of TB & Diagnostics in Individuals Initiating ARV Tx

CDC (Kevin Cain)

A5259 Weekly Rifapentine/Isoniazid vs. Daily Isoniazid for the Treatment of Latent TB

CDC/TB Trials Consortium

A5224s Metabolic Substudy of A5202 R01 - Grace McComsey Gilead, GSK

A5229 Uridine Supplementation in HIV Lipoatrophy NIH/R21 - Grace McComsey

A5260s ARV Initiation with TFV/Emtricitabine plus ATV/r, DRV/r, or RTG:A5257 Substudy

NHLBI R01 - Judith Currier, Jim Stein

BMS, Gilead, Merck, Tibotec

A5130

Safety/Immunogenicity of ALVAC-Infected Autologous DC SQ vs ALVAC SQ

Collaboration with Nina Bhardwaj, Rockefeller University and Sarah

Frankel, and Mary Marovich, Walter Reed Army Institute

of Research

Sanofi Pasteur

A5173 Replication-Competent Clearance of HIV in Resting Memory CD4s w/Enfuvirtide+ART

Collaboration with Robert Siliciano, JHU

Roche

A5212

Palifermin for the Treatment of Inadequate CD4+ Lymphocyte Recovery in Subjects on ART with Low Plasma Viral Load

Collaboration with Rafick-Pierre Sekaly, Canadian Network for Vaccines and Immunotherapeutics, Universite´ de Montreal

Amgen

A5178 Suppressive Long-term Antiviral Management of HCV/HIV Coinfection (SLAM C)

Roche

A5191 Safety and PK among AMD11070 in HIV-Seronegative Men after one or More Doses

AnorMED






A5192 Antiretroviral Activity & Safety, of PEG IFN Alpha 2-A in HIV Infected Subjects

Roche

A5202 EFV or ATV with RTV combined with FTC/TDF or ABC/3TC in Naive Subjects

Abbott, BIPI, BMS, GSK, Gilead

A5210 Dose-Finding Safety/Activity Study of AMD11070 (Oral CXCR4 Entry Inhibitor)

AnorMED

A5211 Safety/Efficacy of SCH 417690 (Oral HIV Entry Inhibitor) in HIV-1 Subjects

Schering Plough

A5223 Differences in LPV/r PK among HIV-Infected Men and Women

Abbott

A5253 Sensitivity and Specificity of Mycobacterium Tuberculosis Screening and Diagnostics in HIV-Infected Individuals

Cepheid

A5255 A5255/FASTER, Faster AFB Identification, Speciation of TB, and Evaluation of Drug Resistance in HIV-Infected Persons Initiating TB Treatment

Cepheid

A5256 MVC for Subjects on ARV tx w/CD4+ T-Cell Recovery Despite Virologic Suppression

Pfizer

A5262 RAL plus DRV/RTV in ARV-Naive Subjects Merck, Tibotec

A5267 Safety, Tolerability & PK Interaction Study of TMC207 & Efavirenz

BMS, Tibotec

A5268 Interactions when ATV/RTV Dosed is Followed by RIF in Healthy Volunteers

BMS

A5269 Nitazoxanide plus Peginterferon Alfa-2a & Ribavirin in Hep C Naive Subjects

Roche, Romark

A5273 Study of Options for Second-Line Effective Combination Therapy (SELECT)

Abbott, Gilead, GSK, Merck

A5274 REMEMBER: Reducing Early Mortality & Morbidity by Empiric TB Treatment

Gilead

A5275 Atorvastatin on Biomarkers of Inflammation, Coagulopathy, Angiogenesis & T-cells

Pfizer

A5277 Safety and Activity of the HCV Entry Inhibitor ITX 5061 in Mono-Infected Adults

Study proposed to ACTG by Flossie Wong-Staal, iTherax

iTherax

A5279 Short-Course Rifapentine/Isoniazid for Prevention of Active TB in HIV-Infected

Sanofi

A5280 High Dose Vitamin D and Calcium for Bone Health in Individuals Initiating HAART

Gilead, BMS

A5281

Cytokine HIV-1 Multi-Antigen pDNA Vaccine IM or IM + In Vivo Electroporation

Study proposed to ACTG by Michael Egan and John

Eldridge, Profectus Biosciences

Ichor Medical Systems, Profectus BioSciences

A5283 Pharmacokinetic Interactions between DMPA and LPV/rit Among HIV-Infected Women

GSK

A5284 Open-Label Study of GS-9350 and Rifampin in HIV-Uninfected Individuals

Gilead



Abstracted Title Collaboration Pharmaceutical

Support

A5285 Pharmacokinetics of the Cyclophilin Inhibitor Debio025 and ARV Medications

BMS, Abbott, Debio

A5286 Rifaximin as a Modulator of Microbial Translocation and Immune Activation

Salix Pharmaceuticals

A5288 Evaluation of Antiretroviral Combinations and Contemporary Management Tools

Tibotec, Merck,GSK, Gilead

A5289 TMC-207 Added to TB Therapy vs TB Therapy Alone in the Tx of Drug Sensitive TB

Global TB Alliance Tibotec, Wyeth

A5290 Rifampin-Based TB Treatment vs. Rifabutin-Based TB Treatment

GSK, Barr National, Pharmacia & Upjohn, Dura,Wyeth, Rugby

A5291 Lexgenleucel-T in Treatment Experienced Subjects with Multi-drug Resistance

Study proposed to ACTG by Steve Deeks (UCSF) and Tessio Rebello(VIRxSYS)

VIRxSYS

A5292 Effect of HAART Vs. Statin Tx on Endothelial Function & Inflammation/Coagulation

Merck, Gilead



Table 2. NWCS and DACS Collaborations NWCS/ DACS

Number Abstract Title External Collaborators

NWCS 243 HIV-1 Adaptation to HLA-Restricted Immune Responses in ACTG A5142 Specimen

Collaboration with Simon Mallal PI, Centre for Clinical Immunology and Biomedical Statistics, Royal Perth Hospital, Western Australia; support from R01 AI 060460. (Presented)

NWCS 266R1

Associations Between IL1 Variants & Response to ART Therapy in ACTG 384

Collaboration with Patricia Price, PI, University of Western Australia. Laboratory testing performed at Royal Perth Hospital, Perth, Australia. (Published)

NWCS 270R The Effect of Active HCV on Neurocognitive Function and Neuropathy in HIV-Infected Subjects with HIV Viral Suppression

Collaboration with Max Arens, Ph.D., Washington University, St. Louis, Neurologic AIDS Research Consortium.

NWCS 275 Pharmacogenomics of Antiretroviral Treatment Response

Collaboration with CEPAC group to perform cost effectiveness analyses, Kenneth Freedberg, PI. R01 [5R01AI077505-02] to support the proposed work (awarded to David Haas).

NWCS 279 Host Genetics of Control of HIV Infection Collaboration Harvard University Program on AIDS (HUPA), Bruce Walker, PI.

NWCS 280 Mitochondrial Genomics and Metabolic Complications in A5142

Collaboration with Todd Hulgan, PI, Vanderbilt University School of Medicine. R21 to complete full length mitochondrial sequencing secondary analyses 5R21NS059330-02. (Manuscript in review)

NWCS 281 Study to Evaluate the Effect of Aging on CD8 T-cell Phenotypes in HIV-infected Individuals Receiving Potent Antiretroviral Therapy

Collaboration with Risa Hoffman, M.D. and Christina Kitchen, Ph.D., UCLA CARE Center, using samples from ALLRT Costs covered by the investigators via a grant supplement from an external funding source. (Manuscript in review)

NWCS 283R IFN Alpha-Mediated Suppression of HIV Individuals Treated w/Pegylated IFN-Alpha

Collaboration with Shyam Kottilil, M.D., Ph.D. Immunopathogenesis Section, Laboratory for Immunoregulation, NIAID, NIH, PI. (Included in manuscript for A5192)

NWCS 284 CMV-Specific Immune Reconstitution in HIV-Infected Individuals on HAART

Collaboration with Adriana Weinberg, PI, University of Colorado Health Sciences Center. Funded R21 [5R21AI073121-02] titled, "Reconstitution of Protective CMV Immunity and Immune Regulation after HAART."

NWCS 285 Effect of Protease Inhibitors on the Incidence of Malaria: A Study to A5208

Collaboration with James McCarthy, Department of Infectious Diseases, Royal Brisbane and Women's' Hospital, Brisbane, Queensland, Australia, Co-PI; Steven Meshnick, Co-PI, UNC.

NWCS 292 HIV-1 Dynamics with and without HSV-2 Coinfection Starting Potent ARV Therapy

Collaboration with Dr. Lawrence Corey, U. Washington, Seattle.

NWCS 295

Identification of HLA Associated Mutations in Chronic HIV Infection

Collaboration with Bruce Walker and Todd Allen (Ragon Institute), and Mary Carrington (NCI). Funded in part by a grant from the Bill and Melinda Gates Foundation.

NWCS 304 ZDV Mutations and RNase H Domains in Patients Receiving ZDV Monotherapy

Collaboration with Nicholas Sluis-Cremer, U. Pittsburgh.

NWCS 307 Predicting Co-Receptor Usage and Susceptibility for CCR5 Inhibitor Therapy Through Episomal cDNA Genotype

Collaboration with Dr. Mario Stevenson, University of Massachusetts Medical School, to determine viral tropism from episomal envelope. (abstract presented at CROI 2010; manuscript in preparation)

NWCS 309 Changes in HIV-1 Immune Responses Associated with Pregnancy

Collaboration with Vlada V. Melekhin, M.D., M.P.H. and Spyros A. Kalams, M.D., Vanderbilt. Funded by the Vanderbilt Physician Scientist Development Award to Vanderbilt-Meharry CFAR Immunopathogenesis Core laboratory.

NWCS 311 Correlation of Plasma Nef Levels with Markers of Immune Activation

Collaboration with Michael Powell, Morehouse School of Medicine, Atlanta.



Table 2. NWCS and DACS Collaborations (Cont’d)

NWCS/ DACS


NWCS 314 Effect of a Therapeutic HIV-1 Gag Vaccine and Treatment Interruption on HIV-1 Gag and Pol Evolution and Diversity

Collaboration with Mary Carrington (NCI), Zabrina Brumme (Ragon Institute) and Bruce Walker (Ragon Institute) to study association of HLA haplotype and response to therapeutic vaccine.

NWCS 315 Prevalence, Incidence and Clinical Significance of Human Herpesvirus 8 (HHV-8) During Highly Active Antiretroviral Therapy

Collaboration with Dr. Whitby, AIDS and Cancer Virus Program, SAIC-Frederick, NCI-Frederick to study HHV-8 prevalence in patients on ART.

NWCS 317 Genetic risk factors for non-Hodgkin’s Lymphoma in AIDS

Collaboration with NA-ACCORD and NCI to analyze genetic risk factors associated with non-Hodgkin’s lymphoma.

NWCS 318 Sex Difference in TLR Signaling and IFN-alpha Responses in Treatment-Naïve Chronic HIV-1 Infected Individuals Recruited into ACTG 384 and the Downstream Affect on Immune Activation

Collaboration with Marcus Altfeld, Ragon Institute of MGH, MIT and Harvard.

NWCS 320 Determinants of T Cell Exhaustion Based on Surface Expression of Potential Negative Regulators of CD8 T Cells: An Analysis from A5142

Collaboration with Dr. Nason and Dr. Richard Koup, Vaccine Research Center, NIH.

NWCS 322 Immune Predictors of IFN- Based Therapy Response in HCV-HIV Infection

Collaboration with Katrina Goddard of Kaiser-Permanente Center for Health Research to perform analyses of genetic predictors. Blanton Laboratory at Case to perform assays for genetic studies. Funded by R01 AI073963 (Blanton), Genetic Contribution to HCV Treatment Outcomes.

DACS 241 Efficacy vs. Effectiveness of HAART vs. ART-CC Observational Cohort Studies

Collaboration with the ART Cohort Collaboration (ART-CC) and Margaret May, University of Bristol, to conduct a prospective observation study of ART-naïve patients initiating ART and ACTG protocols A5095 and A5142.

DACS 242 Meta-analysis with Outcome in HIV/HCV Subjects Receiving PEG/Ribavirin

Collaboration with APRICOT and RIBAVIC study groups. (Manuscript in preparation)

DACS 243 Effect of Gender on Safety and Tolerability of HCV Therapy in HIV Co-Infection

Collaboration with APRICOT and RIBAVIC study groups, Debika Bhattacharya, PI, UCLA.

DACS 245 Analysis of Genetic Predictors of Discordance among CD4+ Count, RNA and Phenotype

Work will be supported by R01 grants, including all of the methods research. Victor De Gruttola, SDAC.

DACS 246R Biological Cofactors for HIV Transmission Collaboration with Laith Abu-Raddad, PI, Fred Hutchinson Cancer Research Center to use ALLRT and other data to compare viral loads from ART naïve cohorts at sites in Africa, Americas and possibly Europe.

DACS 248 Correlation of HIV Disease Progression, as MeasureD by Either a Decline in CD4 T-cell Count or an Increase in HIV-1 RNA Copy Number, with the Presence of High Titer HIV-1Neutralizing Antibodies in a Cohort of HIV-1 Individuals Who have Discontinued ART

Collaboration with Jerome H. Kim, MD., COL, MC at the Division of Retrovirology at the Untied States Military HIV Research Program, USAMC-AFRIMS. Analyses will be performed by: Robert J. McLinden, Jr. (formerly of WRAIR) Commercial Services Lab Manager, Advanced Bioscience Laboratories.

DACS 252 A Pilot Analysis of Mitochondrial Genomics and Endothelial Function in A5152s/A5128

Collaboration with Jeffrey A. Canter, MD, MPH, Center for Human Genetics Research (CHGR), Vanderbilt University School of Medicine.

DACS 254 Analysis of Schwann Cell Densities in Skin Biopsies from A5117 (statistical analysis based on new measurement made on existing skin biopsy samples)

Collaboration with Justin C. McArthur MBBS MPH, Johns Hopkins University Cutaneous Nerve laboratory.




Table 2. NWCS and DACS Collaborations (Cont’d) NWCS/ DACS


DACS 256 Developing a Statistical Methodology to Address Statistical Challenges in Population Pharmacokinetic and Pharmacogenetic Studies: Application to Data from ACTG384 and A5097s

Collaboration with Dr. Choi, Vanderbilt University School of Medicine.

DACS 261 Population PK-PD of RBN: an Analysis of the Existing Data

Collaboration with Dr. Helen McIlleron, University of Cape Town, South Africa and Dr. Stefanie Hennig, Uppsala University, Department of Pharmaceutical Bioscience.

ACTG Network Laboratory Progress Report


Network Laboratory Summary Overview This progress report for the AIDS Clinical Trials Group Network Laboratory (ACTG NL) covers the grant period from March 1, 2009, through February 28, 2010. Three Core Laboratories comprise the ACTG NL: Immunology, Pharmacology, and Virology laboratories; each Core Laboratory in turn comprises four or five Specialty Laboratories that provide a broad range of assays and services required to conduct the scientific agenda of the ACTG and to complement laboratory services, where appropriate, with that of other DAIDS-sponsored HIV/AIDS clinical trials networks. The ACTG NL has two specimen repositories, one for protocol specimens and one (which also has an integrated laboratory component) for human DNA. The ACTG NL provides centralized laboratory services for HIV-1 RNA quantification and viral sequencing for drug resistance, support for U.S. specimen-processing laboratories, support for international service laboratories (safety testing, CD4+ cell count, TB diagnostics and HIV-1 RNA quantification), and support for the Oral HIV/AIDS Research Alliance (OHARA; funded by the National Institute for Dental and Cranial Research [NIDCR]). There are 25 non-U.S. clinical research sites (CRS) supported by 24 main laboratories. Through the coordinating efforts of the HIV/AIDS Network Coordinating Center (HANC), the ACTG NL participates in a plan to harmonize laboratory testing across networks to improve efficiency and collaboration through an established Total Quality Management (TQM) program that emphasizes good clinical laboratory practice (GCLP) and real-time monitoring of proficiency testing (PT) results. As new assays are validated analytically and clinically, they are transferred to U.S. and non-U.S. ACTG laboratories; in this regard, four non-U.S. laboratories are approved for regional HIV genotype sequencing, and 22 are approved or provisionally approved for HIV RNA quantification, along with routine laboratory safety monitoring and CD4+ cell counts. In addition, 9/23 non-U.S. laboratories that participate in external quality assurance (EQA) programs for Mycobacterium tuberculosis (MTB) diagnosis are certified for sputum, culture, identification, and drug susceptibility testing; the remaining 14 laboratories are in various stages of certification. The ACTG NL has maintained its operational and administrative structure to accommodate the coordination of pluripotent non-U.S. laboratories to partner with the HIV-1 Prevention Trials Network (HPTN); the Non-U.S. Maternal, Pediatric, and Adolescent AIDS Clinical Trials (IMPAACT) Network; the Microbicides Trials Network (MTN); and the HIV-1 Vaccine Trials Network (HVTN) (See Figure 1: Organizational Chart.) Finally, the ACTG NL provides both standard and specialized laboratory support for the specific aims under each of the five major research priorities identified by the ACTG network leadership: (1) Translational Research and Drug Development; (2) Optimization of Clinical Management, including Co-Morbidities; (3) Vaccine Research and Development with the emphasis on immunotherapeutics (in collaboration with the HVTN); (4) Prevention of Mother-to-Child Transmission of HIV-1, with the emphasis on the treatment of nonpregnant women (in collaboration with the IMPAACT Network); and (5) Prevention of HIV-1 Infection, with the emphasis on identifying and treating primary/early infection (in collaboration with the HPTN). Details of this support, which is critical for the success of ACTG protocols, may be found in the relevant scientific committee progress reports (Hepatitis Committee, Optimization of Antiretroviral Therapy Committee, Optimization of Co-Infection and Co-Morbidity Management Committee, Translational Research and Drug Development Committee, and Women’s Health Inter-Network Scientific Committee). Our Administrative Progress Report for the ACTG NL is accompanied by supporting data, which are presented in a series of referenced tables (3-7), and a summary of the Network Laboratories’ scientific accomplishments for the 2009-2010 reporting period.


Administrative Progress Report A. Cross-Network Laboratory Communications and Accomplishments Cross-network laboratory communication among the laboratory PIs and laboratory network managers is coordinated through the auspices of the HANC. To facilitate the implementation of the TQM program among all of the NLs (ACTG, HPTN, HVTN, MTN, and IMPAACT), a Laboratory Focus Group (LFG) was established in 2007-2008, under the leadership of Dr. Susan Eshleman (HPTN), to develop an overarching, web-based communication structure among the non-U.S. laboratories and their respective NLs. Because many of the non-U.S. clinical trial units (CTUs) serve more than one network, the LFG developed and implemented the concept of a designated Primary Network Laboratory (PNL) for each of the non-U.S. laboratories. The function of the PNL is to act as a primary laboratory contact to facilitate communication between a CRS laboratory and SMILE (Safety Monitoring in Non-U.S. Laboratories), to identify trends in poor proficiency performance, resolve audit findings in collaboration with other networks, and institute remedial action with the respective quality assurance (QA)/proficiency-testing (PT) partner (e.g., Virology Quality Assurance Program [VQAP]). Of the 24 non-U.S. ACTG-affiliated CRS laboratories, the ACTG NL serves as the PNL for 11 ACTG laboratories, the HPTN for 9 laboratories, the MTN for 2 laboratories, and IMPAACT for 2 laboratories; HVTN has no main CRS laboratory (Table 3; Table 4). The ACTG NL in collaboration with the LFG and the HANC accomplished the following in 2009-10:

• Participated in the development of the new cross-network PBMC Standard Operating Procedure (SOP)

• Revised working group guidelines for the TQM Program • Revised “Guidelines for Use of Back-Up Equipment and Back-Up Clinical Laboratories

for Safety Testing in DAIDS-Sponsored Clinical Trials” • Developed “Communication Plan for Laboratory Audit Reports and SMILE Action Plans;”

developed the Clinical Pharmacology Quality Assurance (CPQA) By-Laws and reviewed the CPQA Analytical Validation Report AVR/SOP Review SOP, and online CPQA AVR/SOP utility

• Participated in and completed the Cryopreservation Optimization Study • Compiled the “PBMC Laboratory Audit Readiness Guide and Resources” along with

revision of the standard wording for Laboratory Processing Charts (LPCs) • Developed a laboratory technician work load tracking system • Finalized new performance criteria for the Immunology Quality Assurance (IQA) PBMC

Cryopreservation Proficiency Testing Program • Developed guidelines for TB sample storage and transportation for use in the

development and review of network protocols and monitoring of site readiness for TB protocol participation

• Developed and implemented with the VQAP a plan for an appropriate 200 HIV-1 RNA copy/mL control for the Abbott PCR-based viral load assay adopted by the networks

• Maintained the current LFG membership and basic operation procedures • Held 2-4 conference calls per month with key laboratory personnel from all the networks • Continued negotiations with Roche to maintain their HIV-1 Monitor v1.5 assay beyond

2011 until all enrolled and open protocols are completed



Plans for 2010: The ACTG NL and other members of the LFG will continue with the refinement of the HANC web portal used to facilitate communication, document development, and storage, as well as capture key milestones of these very active cross-network laboratory groups. The ACTG NL and the LFG will also continue to streamline the handling of proficiency testing problems and failures through efficient use of the various tracking tools. The LFG and ACTG NL will continue to monitor the transition to the new Abbott HIV-1 real-time m2000 platform. B. Implementation of Quality Assurance for U.S. and Non-U.S. Laboratories ♦ Protocol-Related Safety Testing, HIV-1 RNA Quantification and Drug Susceptibility

Genotype, PBMC Cryopreservation and CD4 Flow Cytometry The objective of the ACTG NL is to have all U.S. and non-U.S. laboratories rigorously certified to perform safety laboratory testing for various protocol analytes and, where indicated, specialized laboratory testing for support of ACTG clinical protocols, e.g., HIV-1 RNA quantification, HIV-1 resistance genotype, PBMC cryopreservation, and CD4+/CD8+ cell counts. To this end, all of the ACTG U.S. specialty laboratories are either CLIA- or CAP-certified, or both (Table 4). A comprehensive listing of PT laboratory performance for non-U.S. (N=25) and U.S. (N=51) CRSs is summarized in Table 5. Of note, all of the 24 non-U.S. laboratories participate in the CAP safety PT program. Twenty-two of 24 laboratories are certified by the VQAP for HIV-1 RNA, and five are certified for ViroSeq and in-house HIV-1 resistance genotyping assays by the VQAP. Twenty-two of the 24 laboratories participate in UKNEQAS for CD4+/CD8+. Fifty-one (91%) of the 56 U.S. and 14 of the 16 (88%) non-U.S. laboratories that participate in the IQAP PBMC Cryopreservation Program have achieved a certified or provisionally certified status (Table 6). In conjunction with the VQAP, validation of the Abbott m2000rt System for HIV-1 RNA quantification is underway. To date, the Abbott m2000 platform has been distributed to10 sites, with secondary validation completed at three. A New Work Concept Sheet to validate the Roche COBAS AP/COBAS TM version 2 versus the Roche Amplicor Monitor v1.5 ultrasensitive assay and the Abbott m2000 System is nearing completion. ♦ Expanding Network Laboratory Capacity for Mycobacterium tuberculosis (MTB),

Cryptococcus Neoformans Infection, and Kaposi’s Sarcoma (HHV-8) The cross-network TB Diagnostic Working Group (WG) has worked closely with the DAIDS and SMILE to implement proficiency testing for laboratory TB diagnosis and implement safer laboratory working conditions at selected non-U.S. CRSs. To this end, the ACTG NL hired a laboratory-based mycobacteriologist consultant, Adriano Duse, WITS Medical School, with experience in establishing mycobacterium TB (MTB) PT programs internationally. Seven (30%) of the 23 non-U.S. laboratories that participate in EQA programs for MTB diagnostics are certified for sputum, culture, identification, and drug susceptibility; of the remaining laboratories, 3 are proficient for sputum only, 11 for sputum and culture, and the remaining lab and sites not covered send specimens to another EQA proficient laboratory for MTB diagnosis. An EQA program for cryptococcal quantification by culture has been developed and is being tested at one U.S. and nine non-U.S. laboratories that are participating in protocol A5225.



♦ Point-of-Care (POC) Diagnostics A POC Diagnostic Working Group (WG) was established (Chair, David Katzenstein, MD) and is charged with facilitating the validation of promising POC diagnostics in the area of TB (in conjunction with the TB Diagnostic WG), HIV-1 RNA quantification, CD4+ cell count, and malaria. Workshops in June and December 2009 and a recent workshop in February 2010 were directed at reviewing several promising POC diagnostic technologies worth considering for validation in the ACTG Network Laboratory system. Plans for 2010: The major initiative with the IQAP, a formal scoring system for PBMC cryopreservation, was completed and has been submitted to the Performance Evaluation Committee/Laboratory Evaluation Subcommittee (PEC/LES) for inclusion in the site evaluation scores. An ACTG-specific, standardized operation procedure for the cryopreservation of PBMC is in place and was implemented as part of a new cross-network PBMC cryopreservation protocol, which was completed in December 2009; laboratories were notified in January 2010, and we will facilitate implementation during 2010. The TB Diagnostic WG will continue to work on validating POC diagnostics for MTB and standardizing specimen collection procedures for sputum. The NL will also continue to work with the protocol A5225 team to oversee the cryptococcal EQA quantification program, and will also assist with the developing EQA issues for KS histopathology (A5263/A5264), and cytopathology/molecular diagnostic EQA for upcoming HPV protocols (e.g., A5282). The POC Diagnostic WG will begin work with the VQA Program to validate a promising HIV-1 RNA assay (Liat) and will also help with the initial validation of a low-cost Liat assay platform. For MTB, the GeneXpert and, for CD4, the PIMA platforms are the two most promising POC assays for initial validation in ACTG international protocols. In conjunction with the development of EQA for malaria detection by thick-smear microscopy, the validation of a malaria antigen and PCR assays will be explored in collaboration with the Malaria Working Group of the OpMAN Committee. C. Preparation and Certification for Non-U.S. Laboratories to Participate in ACTG

Network Trials The ACTG Operations Center facilitates preparedness of non-U.S. CRSs to participate in NIH/NIAID-funded ACTG protocols. Once a site submits a protocol to its local IRB for approval, the Operations Center Laboratory Sciences Group reviews the laboratory requirements for the protocol. Once the site submits to RCC for approval, the Laboratory Sciences Group sends the site and laboratory a Protocol Analyte List (PAL) for the protocol in question. The PAL includes an assay detail that captures the method/kit, primary and backup laboratories, and EQA information, and a specimen flow chart that illustrates where all assays are performed. The Laboratory Sciences Group works closely with the site and laboratory to complete the PAL, and with SMILE to make sure the laboratory is enrolled in the required EQA to cover the protocol analytes. Once the PAL is reviewed and approved by the ACTG Laboratory Sciences Group, it is sent to the DAIDS Clinical Laboratory Oversight Team (DCLOT) for their approval, after which the sites are notified by the ACTG Operations Center to proceed with protocol implementation. The PAL is critically important for final protocol implementation and tracking of laboratory capabilities. For a listing of all non-U.S. sites that have laboratory approval to support specific protocols, see Table 7.



Plans for 2010: It is not clear what laboratory support will be required for the participation of the NICHD-sponsored Adolescent Trials Network (ATN) in ACTG protocols. Nevertheless, participation from Westat (NICHD contractor) will be encouraged for the VQAP Quality Assurance Subcommittee (VQASC), IQAP Quality Assurance Subcommittee (IQASC), and laboratory managers of the Cross-Network PI Working Group (HANC). The ACTG is continuing to explore ways to enhance staff retention using the information collected from the laboratory staff survey, which was presented at the IAS 2009 meeting in Cape Town, South Africa (Abstract A-155-0175-03548). D. Laboratory Training, Including Specimen and Data Management All laboratories have completed LDMS training. (See Table 4 for a complete listing of laboratories and LDMS-assigned numbers.) Non-U.S. sites use the Saf-T-Pak program for IATA-compliant shipping training. An online GCLP training module has been presented to the LTC and LFG for final review, with implementation expected in the second quarter of 2010. The ACTG NL provided extensive laboratory-related training at the June 2009 meeting and will do so again at the June 2010 meeting. Laboratory Technologists Committee. The Laboratory Technologists Committee (LTC) has standardized laboratory-related procedures for the successful implementation of the IMPAACT and ACTG protocols. Laboratorians from U.S. and non-U.S. processing, virology, immunology, pharmacology, and cross-network laboratories comprise the LTC. In addition, the committee has representatives from SDMC, FSTRF, DAIDS, HANC, WESTAT, VQA, IQA, PQA, BRI, and the IMPAACT and ACTG Laboratory Operations Center groups. The major accomplishments of the LTC are as follows: • ACTG/IMPAACT Protocol team activities: The LTC has 24 voting members who currently

serve on approximately 83 protocol teams (19 IMPAACT and 64 ACTG). The LTC membership has generated more than 10 new LPCs and dozens of updated LPCs over the last calendar year. Each new LPC was fully reviewed by at least one additional laboratory technologist (LT) prior to formal posting of the LPC. In the past year LTs have also assisted in preparation of Manuals of Operations, Site Implementation Plans, Clarification Memos, and other documents for multiple protocols. LTs have prepared presentations for start-up calls and served as a resource for laboratory-based questions.

• New Membership Training Program: Two additional LTs from non-U.S. laboratories were

added to the LTC (7 total) in our ongoing effort to diversify the composition of the committee. With a growing non-U.S. membership come logistic issues in training for LPC preparation and committee work. To meet this challenge, the LTC has implemented a formal LTC training and mentoring program to promote rapid integration of all new members into the committee work flow. Our first formal, face-to-face and phone training sessions were implemented in December, with the first formal training session at the December meetings. All new members selected in 2009 have established mentors and all have been placed onto protocol teams with their respective mentors at the time of this report.

• Major Revisions to the LPC Template Document: The LPC Template is the primary guide for

LPC development and is undergoing a major revision/update this year. Our goal is to generate a first draft in March 2010 and present a substantially complete draft to the cross-network laboratory leadership for review later this spring.



• Implementation of Document Management Processes through HANC. Important documents established to date include a repository of all laboratory SOPs with accessible document management capabilities (to LTC members). The repository is fully operational and in use. A membership workload repository site has been established to help LTs keep track of all LTC work (minimum participation requirements have been defined to maintain good standing) and to help direct with workload distribution.

• Dangerous Goods Shipping Training: One session was conducted at the June 2009 ACTG

meeting. Due to low laboratory technologist attendance at the 2009 IMPAACT spring meeting, no shipping training was presented at that session.

• LDMS Preload Function for ACTG/IMPAACT Protocols: The LTC has opened discussions

with FSTRF to establish guidelines for ACTG and IMPAACT use of the LDMS Preload function. The preload function, if managed appropriately, will help to reduce LDMS entry errors by having protocol-specific visit requirements and patient information preload into LDMS fields as often as allowed by well-defined protocol requirements.

• Guides for a Successful PBMC Processing Lab Audit: In an effort to help laboratories

prepare for PPD laboratory audits, the LTC has written procedures, draft sample policies, and SOPS to guide all processing laboratories into compliance with the PPD standards and GCLP. A final document is expected in the next few months.

• Cross-Network Committee and Working Group Participation: In addition to preparing a

cross-network Peripheral Blood Mononuclear Cell (PBMC) SOP, which was implemented in the second half of 2009, the LTC also completed a SOP for the collection, processing, storage, and shipping of dried blood spots.

• Communications: LTC committee members collaborated to prepare and publish two articles

about the LTC in 2009 editions of ACTG-related newsletters and hosted a laboratory/clinical site staff interactive at the ACTG June 2009 meeting.

The ACTG has had an on-line pharmacokinetic (PK) tutorial in place since 2003; the tool was developed to educate clinical trials site personnel regarding PK clinical trials performance. The ACTG has been working over the past year to implement the training at new CRSs planning to participate in PK studies. As of 2009, this training was the responsibility of the Pharmacology Quality Assurance Program (DAIDS-sponsored). The ACTG-IMPAACT Laboratory Technician Committee (LTC) created a Dangerous Goods Shipping training video for distribution to laboratories during the October 2007 ACTG Meeting and an update of the video is in preparation. Plans for 2010: The LTC will continue to work with the LFG and the DAIDS/PPD to deploy web-based GCLP training and the DAIDS Learning Management System (DLMS). The ACTG also supports the development of a web-based LDMS training module and will work toward this goal over the next year. E. Standardization of Future Use of Specimens, Including Genomic Samples The ACTG Network has a SOP for archiving protocol specimens after a protocol has been closed. The electronic inventory of specimens guarantees location and tracking of all protocol



specimens from the time of procurement at a clinic to storage and scheduled shipment to the specimen repository at Biomedical Research Institute (BRI). To conserve repository space at BRI, all protocol specimens that warrant long-term storage are archived after the primary protocol publications have been completed, and the protocol has been closed for 5 years or more. To this end, critically important specimens from study enrollment, midpoint in the protocol, and at study completion (or discontinuation) are placed into archival storage at BRI at -70°C, including cryopreserved PBMC in liquid nitrogen. The remaining specimens are culled by de-linking identifiers and either discarded or distributed to interested investigators. The primary objective of the ACTG Human DNA Repository (HDR) continues to be the maintenance, optimization, and utilization of an established, well-characterized ACTG DNA repository. The HDR, housed at Vanderbilt University Medical Center, now contains extracted high-quality DNA specimens from more than 11,000 participants from ACTG clinical trials. In addition, HDR specimens continue to be distributed to HIV/AIDS investigators (collected via protocol A5128). Specimens have now been used for at least 25 different ACTG-approved projects (NWCSs), and many additional proposals for genomic analyses are under review by the ACTG. This effort has resulted in a growing number of presentations at scientific meetings, publications, and new NIH grant applications (see Scientific Accomplishments for further details). In short, the HDR continues to be a unique and outstanding resource that is increasingly used for genomic discovery. Plans for 2010: In addition, considerable effort has been devoted to extend human DNA banking to non-U.S. ACTG sites. This has included final approval and implementation of ACTG protocol A5243 (“Plan for Obtaining Human Biological Samples at Non-U.S. Clinical Research Sites for Currently Unspecified Genetic Analyses,” D. Haas, chair). The Repository Advisory Group (RAG) is reviewing the utilization of requested specimens from several closed protocols and will re-evaluate the archiving protocol based on this specimen utilization with the objective of more critically culling older repository specimens (see next section). F. Coordination of Central Repository Activities The Repository Advisory Group (RAG) provides oversight of the ACTG/IMPAACT BRI Specimen Repository and the Vanderbilt HDR contracts and reports directly to the ACTG Executive Committee. The RAG monitors shipping for U.S. and non-U.S. laboratories and works with protocol teams, when necessary, to execute protocol-specific shipping events. In addition, the RAG oversees the repatriation of specimens from phase-out sites, addresses delinquencies in shipping specimens to BRI, organizes specimen archiving, manages freezer resources at BRI, and oversees the implementation of specimen bar coding. As of February 2010, there were 2,927,936 specimens in storage at BRI from a total of 257 protocols (300-series protocols [664,076 specimens], 5000-series protocols [2,185,417 specimens], and other protocols [78,443 specimens]). For the reporting period between March 2009 and February 2010, there were 252,905 specimens shipped to BRI from U.S. and non-U.S. CRSs, and 19,921 specimens were shipped from BRI to testing laboratories in support of protocol-mandated testing. Specifically, as of February 5, 2010, there were 533,575 specimens in storage at U.S. and non-U.S. sites, of which 26,119 high-priority specimens were from protocols ACTG 320, 368, 372, 384, and 388; and 93,499 specimens were from protocol series ACTG 301-981. There were 413,957 outstanding specimens from protocol series A5000, of which 39,162 (9.5 %) were at 61



U.S. sites; only 142 (<1%) at the one defunded laboratory; and, importantly, 374,795 (90.5 %) were at 23 non-U.S. CRSs. To facilitate specimen shipping from the non-U.S. CRSs, the ACTG NL has instituted electronic shipping forms. The NL surveyed the A5175, A5207, and A5208 teams started scheduled specimen shipments from the non-U.S. CRSs in 2009. As of February 2010, there were 18,425 cryopreserved PBMC stored at U.S. and non-U.S. sites. There were 7,873 PBMC at the U.S. sites; the median was 46 vials per site (range 1-1,722). At the non-U.S. sites there were 10,552 PBMC; the median was 747 vials (range 177-1,741). The ACTG has an optimized PBMC cryopreservation processing, shipment, and storage protocol and is working with the ICAG to develop real-time QA for PBMC storage at BRI. This QA program will be coordinated with the ongoing ICAG PBMC Cryopreservation PT Program. A real-time PBMC storage PT program for BRI that involves the participation of the sites and the IQA was developed and implemented in the third quarter of 2009. The non-participation of the BRI in an EQA program was a noted deficiency that we addressed following a PPD audit of the repository in June 2009. Plans for 2010: The BRI will continue to serve as a central laboratory supply distribution site for both U.S. and non-U.S. ACTG protocols. The second round of specimen archiving will start for completed protocols ACTG 384, A5071, A5095, A5142, and A5197; we will also be reevaluating the archiving protocol to see if further streamlining is possible. We are also developing a plan to evaluate the integrity of cryopreserved PBMCs collected for ACTG protocols that predate the stringent cryopreservation protocol implemented in April 2009. G. Centralization of Laboratory Testing The ACTG NL currently mandates that all primary, real-time endpoint HIV-1 RNA quantification be done using a single assay platform at a central testing laboratory which, generally, is Johns Hopkins University. The reasons for this centralized testing are to minimize assay variation and facilitate data management. The cost for this testing is incorporated into protocol implementation funds. To minimize pre- and post-analytical errors associated with HIV-1 RNA quantification, the ACTG will continue to use centralized HIV-1 RNA testing for clinical protocols with HIV-1 RNA as the primary protocol endpoint. The ACTG NL and SDAC will continue to evaluate the efficiency of central laboratory testing based on the precision and inter-laboratory variation of the new Abbott real-time HIV-1 RNA platform; any changes in the definition of virological failure; and capability of all testing laboratories to participate in the VQAP and use the LDMS for electronic data management. Plans for 2010: Although an evidence-based decision was made with regard to the choice of the Abbott real-time PCR m2000sp/rt platform for ACTG protocols, we will be initiating a similar evaluation of the Roche COBAS AP/TM version 2.0 assay, either before or coincident with its being FDA-cleared sometime in early 2010. In the next couple of years we will consider either continuing with centralized, primary endpoint HIV RNA quantification or, if appropriate and after considering the various data management issues associated with decentralized testing, site-directed testing using different FDA-cleared platforms for primary HIV-1 RNA endpoint determinations.



Scientific Accomplishments (2009-2010) The major scientific aim of the ACTG NL is to support the five major research priorities of the ACTG Network by providing protocol-mandated immunology, pharmacology, and virology laboratory support. The ACTG NL’s contribution to these priorities is summarized elsewhere in the progress report. Thirteen specialty laboratories, four non-U.S. genotyping laboratories, the Human DNA Repository, and the four OHARA laboratories funded by NIDCR support the ACTG Network Laboratory’s scientific agenda. Additional activities center on the development of new research assay tools to elucidate the virologic, immunologic, and pharmacologic interactions in the HIV-infected study subject. As such, the network laboratories use good clinical laboratory practice to validate new assays, and use quality assurance of these assays to generate the most reliable test results. These assay validation efforts are critically important for translational work among U.S. and non-U.S. laboratories. Participation in, and oversight of, proficiency testing and other quality assurance activities is reviewed in the Network Laboratory Administrative Progress Report. The OHARA laboratory program is composed of four laboratories in oral pathogenesis/ virology (University of North Carolina), human papillomavirus (HPV) (University of California San Francisco), mycology/immunology (Case Western), and herpesvirus infection (Wayne State University). These OHARA laboratories were externally reviewed in August 2009. The OHARA laboratory programs are associated with the ACTG Network Laboratory administratively, but develop their laboratory scientific agenda independently, for reasons of funding. The scientific accomplishments of the Core Specialty Laboratories for March 1, 2009 through February 29, 2010, are briefly summarized below.

Immunology Specialty Laboratories

• Demonstrated the increased expression of the procoagulant tissue factor on circulating monocytes of persons with HIV infection which was linked to both immune activation and microbial translocation.

• Developed assays for the measurement of translocated bacterial DNA in circulation and demonstrated their relationship to CD4+ T cell homeostasis in chronic HIV infection. (A5014) (Jiang, 2009)

• Demonstrated that plasma levels of sTNFRI, sCD27, sCD40L, and IL6 predicted a greater risk of AIDS or death. (A5015, A5284) (Kalayjian, 2010)

• Demonstrated that treatment intensification with raltegravir neither decreased low-level viremia nor decreased immune activation in treated HIV infection.

• Demonstrated that a single dose of recombinant IL-7 increased circulating naïve and memory CD4+ T cell counts in persons with chronic HIV infection, and was associated with increased cell cycling and expression of bcl-2. (A5214) (Sereti, 2009)

• Demonstrated desensitization to type 1 interferon at both the receptor and post-receptor levels in persons with chronic HIV infection.

• Demonstrated an increased T regulatory cell frequency in circulation of older HIV-infected persons.

• Demonstrated a modest effect of immunization with an adenovirus-based gag vaccine on rebound levels of viremia in treated HIV infection.

• Demonstrated regulatory T cell suppression of Gag-specific CD8+ T cell polyfunctional response following therapeutic immunization of HIV-1-infected patients on ART.



• Completed a multisite comparison of immunologic assays for detecting immune responses in HIV immunotherapeutic studies.

• Demonstrated that addition of maraviroc to a virologically suppressive regimen in immune non-responders reduced immune activation, but did not increase CD4+ T cell numbers. (A5256)(Wilkin, 2010)

• Demonstrated that chloroquine blocks plasmacytoid dendritic cell activation and production of interferon alpha as well as CD8+ T cell activation.

• Developed and evaluated a point of care CD4+ cell enumeration assay. • Demonstrated that GBV-C viremia affects CD4+ T cell expansion in IL-2 treated

subjects. (ACTG 328) (Stapleton, 2009) • Showed that sex differences in TLR-mediated activation of plasmacytoid dendritic cells

may account for higher immune activation in women than men at a given HIV-1 viral load, and suggested a mechanism by which the same level of viral replication might result in faster HIV-1 disease progression in women. (ACTG 384) (Meier, 2009)

• Showed that proteinuria may serve as a marker of immune activation in HIV- infected persons initiating antiretroviral therapy. (ACTG384, A5001, A5095) (Gupta, 2009)

• Showed that measurement of naïve CD4+ percentage in patients can identify those least likely to reconstitute immunity. (ACTG 384, 388, A5001, A5014, A5095) (Schacker, 2010)

• Showed that treatment with growth hormone enhanced CD4+ lymphocyte reconstitution. (A5174) (Smith, 2010)

Pharmacology Specialty Laboratories

• Developed a sensitive and specific liquid chromatography/mass spectrometry method for measuring tenofovir and emtricitabine in plasma, using liquid chromatography, mass spectroscopy, and isotopically labeled internal standards. (A5202) (Delahunty, 2009)

• Developed and validated a high-performance liquid chromatography/tandem mass spectroscopy method for measuring artemether, and its active metabolite, dihydroartemisinin, in human plasma.

• Determined pharmacokinetic parameters for several antiretroviral drugs in ACTG protocols, including:

• Long-term impact of efavirenz on neuropsychological performance (NWCS 270R) (Clifford, 2010)

• Hepatotoxicity and gastrointestinal intolerance of rifampin, atazanavir, and ritonavir in healthy volunteers (A5213) (Haas, 2009)

• Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy (A5201) (Wilkin 2009)

• Evaluated the pharmacokinetics of unbound protease inhibitors to determine the effect of pharmacokinetics-adjusted phenotypic susceptibility on response to ritonavir-enhanced protease inhibitors. (A5126) (Eron, 2009)

• Evaluated abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. (A5202) (Sax, 2009)

Human Genomics The Human DNA Repository (HDR) is a unique and outstanding resource that is available for genomic discovery. Permission to store and access human genomic specimens from ACTG protocols is orchestrated through ACTG protocol A5243, which has been submitted for review by numerous non-U.S. ethics committees. Thus far, this protocol has opened at



two non-U.S. sites (Lima, Peru and Johannesburg, South Africa). Over the past year, the HDR has contributed to the following:

• Determined the effect of HIV-1 infection on human DNA yield from saliva. (A5128, A5243) (Basham, 2009)

• Showed that IL1A alleles are associated with virological response to ART (Price, 2009; NWCS 266), and that HLA-associated immune escape pathways are determined by gag, pol, and nef proteins in HIV-1 subtype B. (Brumme, 2009;NWCS 243)

• Showed that quantitative trait loci for CD4:CD* lymphocyte ratio are associated with risk of type 1 diabetes and HIV-1 immune control. (Ferreira, 2010)

• Described the adaptive interactions between HLA and HIV diversity in the contemporary United States HIV-1 epidemic.

Virology Specialty Laboratories Antiretroviral Therapy and HIV-1 Drug Resistance • Revealed similar performance of the inhibitory quotient and instantaneous inhibitory

potential in predicting antiretroviral drug efficacy in phase 3 clinical trials. • Showed that changes in residual viremia below 50 copies/mL precede virologic failure in

patients, simplifying therapy to boosted atazanavir alone. (A5201) (Wilkin, JID 2009) • Identified that, in patients with screening HIV-1 RNA levels of 100,000 copies/mL or

more, drug resistance at virologic failure was more frequent in patients randomized to ABC/3TC than TDF/FTC (combined with ATZ or EFV) ,with major drug-resistance mutations noted in 25 patients in the ABC/3TC group (6% of those randomly assigned to the group and 45% of those with virologic failure) versus 10 patients in the TDF/FTC group (3% and 38%, respectively). (A5202) (Sax et al., 2009)

• Provided reference laboratory and genotyping expertise to the Treat Asia Quality Assurance Scheme including 19 laboratories in Asia.

• Validated subtype C sequencing in Chennai, India. • Identified diverse HIV-1 resistance profiles after failure of first-line therapy in South

Africa. • Applied Bayesian phylogenetics and a molecular clock to characterize subtype C in

Zimbabwe. • Demonstrated late development of vicriviroc resistance after long-term follow-up of

patients with R5 virus and virologic failure on a VCV-containing regimen. (A5211) (Wilkin et al., JAIDS 2010)

Importance of Minor Drug-resistant HIV-1 Variants • Demonstrated that, in treatment-naïve adherent patients, pre-existing minority Y181C

mutants more than tripled the risk of virologic failure of first-line EFV-based ART. (A5095) (Paredes, J Infect Dis. 2010)

• Showed that minor NNRTI-resistant variants at frequencies of > 1% were associated with virologic failure of multidrug combination therapy in treatment-experienced patients. (ACTG 398) (Halvas et al., J Infect Dis. 2010)

• Demonstrated frequent selection of resistance to drugs with low genetic barriers in women who received pregnancy-limited ART.

Coreceptor Usage • Demonstrated superior performance of the enhanced sensitivity Trofile assay in

detecting CXCR4-using variants in subjects screening for a phase 2b trial of vicriviroc. (A5211) (Su et al., J Infect Dis. 2009)



• Compared the performance of tropism assays using replication-competent or pseudotyped viruses in a variety of cell culture systems. (A5211) (Hosoya et al., J Clin Microbiol. 2009)

• Reviewed different assays for assessing coreceptor usage by HIV-1. • Used quantitative deep sequencing to dynamic HIV-1 escape and large population shifts

during CCR5 antagonist therapy in vivo. (A5211) (Tsibris et al., PLoS One. 2009) Viral Fitness • Described replication capacity in relation to immunologic and virologic outcomes in HIV-

1 infected, treatment-naïve subjects. (NWCS 261R) (Skowron et al., JAIDS 2009) • Collaborated on fitness of subtype C isolates compared to B and A in an in vitro

competition assay.

Interactions among HIV-1 and Other Viruses • Defined the effect of HSV-2 suppression on mucosal shedding of HIV-1 at genital

mucosal sites in both men and women, using validated genital HIV-1 quantification methods developed by the UW-VSL.

• Characterized prevalence of different HPV genotypes in Nairobi, Kenya.

Compartmentalization of HIV-1 and Response to Therapy • Collaborated on quantitation of antiretroviral agents from Sno-strips® by developing an

extraction method for this matrix, and measured drug concentration using current, validated HPLC/UV methodology, since sub-optimal antiretroviral concentrations could lead to the development of resistant virus in the female genital track.

• Evaluated the effect of ART on the CSF HIV burden and neurocognitive performance. (ACTG 736) (Marra et al., AIDS. 2009)

• Evaluated the compartmentalization of HIV-1 in the cervix and showed that the assessment of viral compartmentalization is a reflection of proliferation of provirus-containing mononuclear cells in the vaginal cervix.

Assay Development • Reported on the high cost of repeat testing of plasma viral load specimens when a new

commercial viral load assay was implemented at the university HIV clinic by a clinical hospital laboratory.

• Validated a stratified squamous epithelial model and used it to show that HIV-1 fails to trigger innate immune factor synthesis in differentiated oral epithelium. As a prelude to understating the protective correlates of HIV-1 infection in clinical trials, this oral tissue model has potential use for studying similar questions in the vagina and the effect of innate immune factors on the sexual acquisition of HIV-1.

Non-U.S. Genotyping Laboratory Contributions Over the past year, our four VQA-certified non-U.S. genotyping laboratories have provided both protocol support for resistance genotyping and insight into local antiretroviral drug resistance (the fifth certified laboratory is at IMPACTA, Lima, Peru and has not participated in sequencing for ACTG protocols at this time). In addition to, but with funding separate from the Virology Core and Immunology Core laboratories, the sites are involved in investigator-initiated research into the validation and design of affordable HIV RNA and CD4+ diagnostic assays for implementation in resource-limited settings, and studies into the significance of ART resistance in their respective geographic regions. The following HIV-1 genotyping research and assay validation was supported in part by the ACTG Network Laboratory genotyping program:




• Described breast-milk transmission of nevirapine resistance in India. • Demonstrated the relationship between high replication fitness and transmission

efficiency of HIV-1 subtype C from India. • Described gp41 mutations in proviral DNA among ART-naïve persons in India and

extent of ART resistance among private care clinic patients in Mumbai, India. • Demonstrated lack of primary mutations for integrase inhibitors. • Characterized a unique CRF31_BC recombinant in Brazil. • Surveyed ART resistance among newly diagnosed HIV infections in Brazil. • Showed a decline in HIV-1 subtype C and CRF31_BC epidemics in southern Brazil. • Described immune activation and antibody responses in non-progressing elite

controllers infected with HIV-1. • Showed the emergence of ART resistance following ART interruption at delivery in a

cohort of HIV-infected women. • Showed low prevalence of drug resistance mutations with salvage therapy among HIV-1

patients failing ART in Rio de Janeiro, Brazil. The HIV Research Group in the Department of Molecular Medicine and Hematology (Lab 350, Director Wendy Stevens) has had 23 publications and 18 abstracts in the areas of interest to the ACTG for the reporting period 2009-2010. • The Pittsburgh VSL (Mellors) also worked closely with the WITS laboratory to resolve

protocol A5175 sequencing problems associated with the ViroSequ platform. • Investigated the mutation patterns that emerge in adults and children accessing failing

first- and second-line regimens, and the impact these mutations will have on newer antiretrovirals, etravirine, and integrase inhibitors.

• Characterised and investigated subtype C genetic diversity polymorphisms. • Evaluated and validated viral load assays, options for point-of-care monitoring. • Use of dried blood spots for resistance testing. • Development of an affordable in-house resistance assay, which is now used routinely in

South Africa and overcomes limitations of the commercially available ViroSeq assay. • Work in the field of HIV-related malignancies, and inflammation and coagulation factors

linked to ARV therapy.

OHARA Oral Virology and DNA Viruses Laboratories

• Described the relationship between oropharyngeal carcinoma and HPV infection. (Andrews et al., Oral Oncology. 2009)

• Reported concurrent HPV-associated tonsillar carcinoma in two couples. (Andrews E, et al., J Infect Dis. 2009)

• Developed assays for determining BK virus in saliva and blood, and demonstrated BK tropism in salivary gland cells in vitro. (Jeffers et al. Virology. 2009)

• Described the relationship among human herpesvirus replication, CD8+ cell activation and low CD4+ cell count in ART-suppressed patients. (Jacobson, PLos ONE. 2009).

• Defined oral disease endpoints for use in clinical trials. (Shiboski et al., J Oral Pathol Med. 2009)

• Described the in vitro activity of inexpensive topical alternatives against Candida species. (Traboulsi et al., Intl J Antimicrob Agents. 2008)

• Described the oral fungal microbiome in healthy adults. (Ghannoum et al., PLoS Pathogens. 2010)



Table 3: Primary Network Laboratory (PNL) Assignment

Network Affiliation

Laboratory Title and City Country HPTN MTN IMPAACT ACTG HVTN

Primary Network

Lab LDMS

number

Botswana-Harvard HIV Reference Laboratory, Gaborone Botswana ACTG 219 Hospital Universitario Clementino Frafa Filho (HUCFF), Rio de Janeiro Brazil ACTG 274 Ozwaldo Crux Foundation (FIOCRUZ), Rio de Janeiro Brazil HPTN 319 Hospital Nossa Senhora da Conceicao, Porto Allegre Brazil HPTN 327 Diagnostic America, Rio de Janeiro Brazil HPTN 354 GHESKIO, Port-au-Prince Haiti ACTG 267 National AIDS Research Institute (NARI), Pune India HPTN 297/315 YRG Medical Center Voluntary Health Services, Chennai India HPTN 316 BJ Medical College Biochemistry Laboratory, Pune India IMPAACT 460 AMPATH, Eldoret Kenya ACTG 358 KMRI/Walter Reed Project Clinical Research Center, Kericho Kenya ACTG 352 Univ. of North Carolina Project, Lilongwe Malawi HPTN 245/291/305 Univ. of Malawi/Johns Hopkins Univ. Project Laboratory, Blantyre Malawi HPTN 304 Quintilles Federated Svcs Med. Res. Ctr, Complejo Medico Marbella Panama ACTG 455/457 CTU Peru Lab, Lince Peru ACTG 310 CAPRISA Research Laboratory, Durban South Africa ACTG 281 Contract Laboratory Services (CLS), Johannesburg South Africa ACTG 350 BARC-Lancet Laboratory, Durban South Africa MTN 262 BARC-Lancet Laboratory, Johannesburg South Africa IMPAACT 410 KCMC Biotechnology Laboratory, Moshi Tanzania ACTG 338/411 RIHES - Chiang Mai University, Chiang Mai Thailand HPTN 317/474 JCRC, Kampala Uganda ACTG 392 CIDRZ Central Laboratory, Lusaka Zambia MTN 332 UZ-UCSF Research Laboratory, Harare Zimbabwe HPTN 306

HPTN ACTG HVTN IMPAACT MTN



Table 4: ACTG Domestic and International Laboratory Contact List with CLIA Certifications LDMS # SITE LAB LAB CONTACT INFORMATION CLIA CAP

DOMESTIC LABORATORIES IMMUNOLOGY SPECIALTY LABS

49 Case Western Reserve University Case Western Reserve University Cleveland, Ohio USA Lab Director: Michael Lederman 36D0991665

EXP 02/20/12

161 Rush University Rush ISL/Rush Medical Center Chicago, Illinois USA Lab Director: Alan Landay No intentions of

pursuing

224 University of California - Davis UC Davis Virology & Immunology Research Lab Sacramento, California USA Lab Director: Richard Pollard No intentions of

pursuing

268 University of Pittsburgh PMS Laboratory Pittsburgh, Pennsylvania Lab Director: Charles Rinaldo 39D1010503

EXP 04/04/11

271 Beth Israel Deaconess - Harvard Hepatitis Immunological Support Lab Lab Director: Nadia Alatrakchi No intentions of pursuing

PHARMACOLOGY SPECIALTY LABS

190 University of Nebraska Medical Center

Antiretroviral Pharmacology Lab Omaha, Nebraska Lab Director: Courtney Fletcher 06D1003719

EXP 02/24/11

191 University of Alabama at Birmingham

University of Alabama at Birmingham Birmingham, Alabama Lab Director: Ed Acosta 01D0988693

EXP 05/08/10

192 University California, San Francisco

University of California at San Francisco San Francisco, California Lab Director: Francesca Aweeka No intentions of

pursuing

195 State University of New York at Buffalo

Laboratory for Antiviral Research Buffalo, New York Lab Director: Gene Morse 33D0999173

EXP 06/30/10

VIROLOGY SPECIALTY LABS

1 Harvard University Partners AIDS Research Center Cambridge, Massachusetts Lab Director: Dan Kuritzkes 22D1007095

EXP 04/28/11

6 Stanford University Stanford University Stanford, California Lab Director: David Katzenstein 05D0643688

EXP 02/09/11

15 University of Washington Retrovirus Laboratory Seattle, Washington Lab Director: Robert Coombs 50D0631627

EXP 06/30/11 2463716 EXP

09/05/11

54 University of Alabama University of Alabama Birmingham, Alabama Lab Director: Victoria Johnson 01D1006284

EXP 12/19/10

366 University of Pittsburgh Mellor's Laboratory Pittsburgh, Pennsylvania Lab Director: John Mellors 39D1010503

EXP 05/04/11




DOMESTIC LABORATORIES (Cont'd)

ORAL HIV/AIDS RESEARCH ALLIANCE LABORATORIES (OHARA)

444 Case Western Reserve University Cleveland, OH Lab Director: Mahmoud Ghannoum

441 University of North Carolina, Chapel Hill Chapel Hill, NC Lab Director: Jennifer Webster-Cyriaque

INTERNATIONAL LABORATORIES

219 BH School of Public Health Botswana-Harvard HIV Reference Laboratory (BHHRL) Gaborone, Botswana

Lab Director: Rosemary Musonda Lab Manager: Sikhulile Moyo QA/QC Manager: Phibeon Mangwendeza

7180396

319 Oswaldo Cruz Foundation (FIOCRUZ) Rio de Janerio, Brazil

Lab Director: Mariza Goncalves Morgado, PhD Lab Manager: Deise Luci Alves QA/QC Manager: Saada Chequer-Fernandez

7154901

327 Hospital Nossa Senhora da Conceicao

Laboratorio Centra Porto Alegre, Brazil

Lab Director: Breno Riegel Santos Lab Manager: Andrea Cauduro de Castro QA/QC Manager: Consuelo Perez

7168301

364 HUCFF, FIOCRUZ, PORTO ALEGRE

Diagnostics America (DiAM-RJ) Rio de Janeiro, Brazil Diagnostics America (DiAM-SP) Sao Palo, Brazil

Lab Directior: Dr. Luiz Rosenfeld DiAM-RJ Lab Manager: Maria Rabello MaluDiAM-SP Lab Manager: Marcia Molina

718184

274 HUCFF Hospital Universitario Clementino Frafa Filho Rio de Janeiro, Brazil

Lab Director: Dr. Mauro Schechter Lab Manager: Maria de Fatima de Melo QA/QC Manager: Priscila Freitas and Christiani Buffoni

7177695

267 Les Centres GHESKIO Port-au-Prince, Haiti

Lab Director: Dr. Jean William Pape Lab Manager: Marie-Eugenie Beaulieu QA/QC Manager: Marc Germain, QA – Manager Lab Supervisor (ACTG Contact): Alexandra Apollon

7177687

297 National AIDS Research Institute (NARI) Pune, India

Lab Director: Dr. Ramesh Paranjpe Lab Manager: Smita Kulkarni, PhD QA/QC Manager:Anjali Panchhnadikar, PhD

7146701

460 BJ Medical College Biochemistry Laboratory Pune, India

Lab Director: Dr. Renu Bharadwaj Lab Manager: Vandana Kulkarni 7190816

316 YRG Medical Center Voluntary Health Services Chennai, India

Lab Director/Manager: Dr. P. Balakrishnanl Lab Supervisor: Mr. Syed H. Iqbal Lab Manager: Ms. Arul Selvi Genotyping Lab Director: Dr. S. Saravanan

7154601

352 KMRI/Walter Reed Project Clinical Research Center

KMRI/Walter Reed Project Clinical Research Center Kericho, Kenya

Lab Director: Kibet Shikuku Lab Manager: Rukia Kibaya QA/QC Manager: Francis Opiyo and Ruth Chirchir

7191519

358 MOI University Faculty of Health Sciences

Ampath Lab Eldoret, Kenya

Lab Director: Dr. Nathan Buziba Lab Manager: Wilfred Emonyi QA/QC Manager: Fidelis Mambo

7195622

304 Kachere Rehabilitation Centre Univ. of Malawi-JHU Project Laboratory Blantyre, Malawi

Lab Manager: Nicole Carpanetti QA/QC Manager: Chifundu Chipungu 7146001




INTERNATIONAL LABORATORIES (Cont'd)

245/291/305 UNC Project-Lilongwe UNC Project Laboratory Lilongwe, Malawi

Lab Consultants: Deborah Kamwendo, Robert Krysiak QA/QC Coordinator: Lebah Lugalia, Enoch Gamah 7146101

455/457 Quintiles Federated Services: Med Res Ctr

Complejo Medico Marbella Panama City, Panama

Medical Director: Juan Luis Correa Lab Manager (Marbella Lab): Rosa de Sarlat QA/QC Manager: Naegeli Navarro

7205654

310 Asociacion Civil Impacta Salud y Education

Impacta Lince Lab Lima, Peru

Lab Director: Carmela Ganoza Lab Manager: Norma Noda QC/QA Manager: Cecilia Chang

7146501

281 CAPRISA CAPRISA Research Laboratory Durban, South Africa

Lab Director: Thumbi Ndung'u Lab Manager: Natasha Samsunder 7193816

262 Univ. KwaZulu-Natal, CAPRISA BARC-Lancet Lab Durban, South Africa

Medical Director: Jessica Trusler Regional Lab Manager: Peter Meewes Laboratory Manager: Anupa Singh QA/QC Manager: Glenda Kuntashula

7146601

410 Univ KwaZulu-Natal, CAPRISA BARC-Lancet Lab (BARC HQ) Johannesburg, South Africa

Medical Director: Jessica Trusler Regional Lab Manager: Peter Meewes QA/QC Manager: Glenda Kuntashula

7195992

350 Univ. of Witwatersrand (UW) Contract Lab Svcs - NHLS Johannesburg, South Africa

Lab Director: Wendy Stevens Lab Project Manager: Odette Lazarus Lab Manager: Ischell Doddameade

1018901

411 Duke University-Kilimanjaro Christian Medical Centre (KCMC)

KCMC Biotechnology Laboratory - MIT Project Moshi, Tanzania

Lab Director: John Crump Lab Manager: Caroline Chebalir 7180525

317 Research Institute for Health Sciences (RIHES)

RIHES Clinical Labs Chiang Mai, Thailand

Lab Manager (Clinical): Rassamee Keawvicht Lab Manager (Processing): Kittipong Rungruengthanakit 7080301

392 Joint Clinical Research Center (JCRC)

JCRC Kampala, Uganda

Lab Director: Prof. Peter Mugyeni Lab Manager: Pauline Katundu QA/QC Manager: James Nkalubo

7184461

332 CIDRZ-Kalingalinga Health Centre

CIDRZ Central Laboratory Lusaka, Zambia

Lab Director: Ron Brown Lab Manager: Darius Simbeye QA/QC Manager: Balbina T. Marzova

7175497

306 Parienyatwa Hospital-Univ. of Zimbabwe

UZ-UCSF Research Laboratory Harare, Zimbabwe

Lab Director: Zar (Alfred) Gomo Lab Manager: Marshall Munjoma QA/QC Coordinator: Shingai Mabambe

7146301


Table 5: ACTG Clinical Research Site (CRS) Proficiency Testing Coverage IQA VQA

CRS Title CRS Country Site ID LDMS

# UKNEQAS

# Safety

Testing/CAP #

PBMC Cryopreservati

on

CD4/CD8

UKNEQAS CD4/CD8 RNA DNA Genotyping

PQA

International CRS Gaborone Prevention/ Treatment Trials CRS Botswana 12701 219 40570 7180396 x N/A x x x

Molepolole Prevention/ Treatment Trials CRS (Molepolole PTT CRS)

Botswana 12702 219 40570 7180396 x N/A x x x

Les Centres GHESKIO CRS Haiti 30022 267 40666 7177687 x N/A x x PROJECTO PRACA ONZE/HESFA CRS Brazil 30333 274 40509 7177695 x N/A x x

CAPRISA eThekweni CRS South Africa 31422 281 40803 7193816 N/A x x

NARI Pune CRS India 11601 297 40537 7146701 N/A x x x x College of Med. JHU CRS Malawi 30301 304 40539 7146001 x N/A x x x UZ-Parienyatwa CRS Zimbabwe 30313 306 40532 7146301 N/A x x x Asociacion Civil Investigaciones Medica' en Salud - Inmensa, Lince CRS

Peru 11302 310 40664 7146501 x N/A x x x

Asociacion Civil Impacta Salud y Educacion - Mira Flores CRS Peru 11301 310 40664 7146501 x N/A x x x

YRG CARE Medical Ctr. VHS CRS India 11701 316 40571 7154601 x N/A x x x x

Chiang Mai Univ. ACTG CRS Thailand 11501 317, 474 40316 7080301 x N/A x x

Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS Brazil 12101 319,

461 40534 7154901 x N/A x x x x

Hospital Nossa Senhora da Conceicao CRS Brazil 12201 327 40550 7168301 x N/A x x

Kalingalinga Clinic CRS Zambia 12801 332 40559 7175497 N/A x x

Soweto ACTG CRS South Africa 12301 350 40306 1018901 x N/A x x x x

Wits HIV CRS South Africa 11101 350 40306 1018901 x N/A x x x x

KMRI/Walter Reed Project Clinical Research Center (Kericho)

Kenya 12501 352 40946 7191519 N/A x x x

MOI University Faculty of Health Kenya 12601 358 40947 7195622 N/A x





# UKNEQAS

# Safety

Testing/CAP #

PBMC Cryopreservati

on CD4/CD

8


PQA

Sciences (Eldoret)

Joint Clinical Research Ctr. CRS Uganda 12401 392 40723 7184461 N/A x x x Kilimanjaro Christian Medical CRS Tanzania 12901 411 41067 7180525 x N/A x x

Medical and Research Center CRS Panama 31461 457 41371 7205654 N/A x

University of North Carolina Lilongwe CRS Malawi 12001

245,291,30

5 40540 7146101 x N/A x x x

International CRS (Cont'd)

Durban Adult HIV CRS South Africa 11201 262/4

10 40766/409

22 7146601 x N/A x x x

BJ Medical College CRS India 31441 460 41522 7190816 N/A

Domestic CRS BMC ACTG CRS USA 104 1 N/A x x N/A x Brigham and Women's Hosp. ACTG CRS USA 107 1 N/A x x N/A x

Massachusetts General Hospital ACTG CRS USA 101 1 N/A x x N/A x

Stanford CRS USA 501 6 N/A x x N/A x Harbor-UCLA Med. Ctr. CRS USA 603 7 N/A x x N/A UCLA CARE Center CRS USA 601 7 N/A x x N/A UCSF AIDS CRS USA 801 9 N/A x x N/A x x Pitt CRS USA 1001 12 N/A x x N/A University Washington AIDS CRS USA 1401 15 N/A x x N/A x x Duke Univ. Med. Ctr. Adult CRS USA 1601 17 N/A x x N/A NY Univ. HIV/AIDS CRS USA 401 21 N/A x x N/A New Jersey Medical School - Adult Clinical Research Ctr. CRS USA 31477 22 N/A x x N/A

The Ohio State Univ. AIDS CRS USA 2301 23 N/A x x N/A Univ. of Cincinnati CRS USA 2401 24 N/A x x N/A Northwestern University CRS USA 2701 29 N/A x x N/A x x x Rush Univ. Med. Ctr. ACTG CRS USA 2702 29 N/A x x N/A x x x





# UKNEQAS

# Safety

Testing/CAP #

PBMC Cryopreservati

on CD4/CD

8


PQA

Washington U CRS USA 2101 31 N/A x x N/A Moses H. Cone Memorial Hosp. CRS USA 3203 32 N/A x x N/A x x x

UNC AIDS CRS USA 3201 32 N/A x x N/A x x x Georgetown University CRS (GU CRS) USA 1008 33 N/A x N/A x

Beth Israel Deaconess Med. Ctr. ACTG CRS USA 103 1, 2 N/A x x N/A x

AIDS Community Health Ctr. ACTG CRS USA 1108 40 N/A x x N/A x x

Univ. of Rochester ACTG CRS USA 1101 40 N/A x x N/A x x University of Colorado CRS USA 6101 48 N/A x x N/A x Case CRS USA 2501 49 N/A x x N/A

Domestic CRS (Cont'd) MetroHealth CRS USA 2503 49 N/A x x N/A Puerto Rico - AIDS CRS USA 5401 53 N/A x x N/A x x Henry Ford Hosp. CRS USA 31472 77 N/A x x N/A Alabama Therapeutics CRS USA 5801 81 N/A x x N/A Johns Hopkins Adult AIDS CRS USA 201 113 N/A x x N/A x x The Ponce de Leon Ctr. CRS USA 5802 117 N/A x x N/A Hosp. of the Univ. of Pennsylvania CRS USA 6201 119 N/A x x N/A

USC CRS USA 1201 145 N/A x x N/A x Harlem ACTG CRS USA 31483 177 N/A x x N/A HIV Prevention & Treatment CRS USA 30329 177 N/A x x N/A The Miriam Hosp. ACTG CRS USA 2951 202 N/A x N/A Vanderbilt Therapeutics CRS USA 3652 203 N/A x x N/A x HIV Baltimore Treatment CRS USA 4651 237 N/A x x N/A Peabody Health Ctr. CRS USA 31443 465 N/A x x N/A Univ. of Miami AIDS CRS USA 901 293 N/A x x N/A Bronx-Lebanon Hosp. Ctr. CRS USA 31469 425 N/A x N/A Houston AIDS Research Team CRS USA 31473 445 N/A x N/A





# UKNEQAS

# Safety

Testing/CAP #

PBMC Cryopreservati

on CD4/CD

8


PQA

Thomas Jefferson Univ. Med. Ctr. CRS USA 31482 448 N/A x N/A

Virginia Commonwealth Univ. Medical Ctr. CRS USA 31475 449 N/A x x N/A

The Research & Education Group - Portland CRS USA 31474 450 N/A x N/A

Wayne State Univ. CRS USA 31478 451 N/A x x N/A Cooper Univ. Hosp. CRS USA 31476 453 N/A x N/A Denver Public Health CRS USA 31470 456 N/A x N/A

Cornell CRS USA 7804 160, 178 N/A x N/A

UCSD, AVRC CRS USA 701 8, 28 N/A x x N/A x Harlem Hospital Ctr./Columbia University CRS (Gordin) USA 31471 177 N/A x N/A

Specialty Laboratories University of California, Davis Medical Center ISL USA 224 N/A x x N/A

Rush University ISL USA 161 N/A x x N/A University of Pittsburg ISL USA 268 N/A x x N/A Beth Israel Deaconess Medical Center/Harvard ISL USA 271 N/A x N/A

Case Western Reserve University School of Medicine ISL USA 49 N/A x x N/A

University of Buffalo PSL USA 195 N/A N/A x University of Nebraska PSL USA 190 N/A N/A x University of Alabama at Birmingham PSL USA 191 N/A N/A x

University of California, San Fransisco PSL USA 192 N/A N/A x

University of Washington VSL USA 15 N/A x x N/A x x University of Alabama at Birmingham VSL USA 54 N/A N/A x

Harvard University VSL USA 1 N/A x x N/A x Stanford University VSL USA 6 N/A x x N/A x University of Pittsburgh VSL USA 366 N/A N/A x x



Table 6: Viable PBMC Freezing - Results of % viable cells at IQA after Thaw

Laboratory Lab # March '09 June '09 Sept '09 Dec'09

Total Score from the

Last Four Rounds of

Testing Status of Lab Partners AIDS Research Center Massachusetts 1 98% 97% 98% 96% 99% 99% 98% 98% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Stanford University California 6 98% 97% 91% 94% 99% 98% 99% 99% 16 Approved ( A ) 2 2 2 2 2 2 2 2

UCLA Care Center California 7 99% 99% 94% 95% 97% 98% 99% 99% 16 Approved ( A ) 2 2 2 2 2 2 2 2

University of California at San Diego California 8 95% 96% 82% 83% 92% 93% 95% 95% 16 Approved ( A ) 2 2 2 2 2 2 2 2

ARI/UCSF Laboratory of Clinical Virology California 9 97% 95% 94% 94% 96% 97% 95% 95% 16 Approved ( A ) 2 2 2 2 2 2 2 2

University of Miami- Miller School of Medicine Florida 11 97% 99% NRS NRS 99% 99% NRS NRS 8

Not Approved (NA)

2 2 0 0 2 2 0 0

University of Pittsburgh Pennsylvania 12 95% 96% 96% 97% 99% 99% 97% 97% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Baylor College of Medicine Texas 14 98% 99% 4 Not Approved

(NA) 2 2

U.Wash-VSL Washington 15 96% 97% 95% 99% 98% 98% 97% 99% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Univ Minnesota Minnesota 16 Not on list from IQA

Not Approved (NA)

No longer listed by the

IQA




Laboratory Lab # March '09 June '09 Dec'09


Last Four Rounds of

Testing Status of Lab Sept '09

Duke University North Carolina 17 90% 91% 99% 99% 95% 95% 71% 71% 16 Approved ( A ) 2 2 2 2 2 2 2 2

NYU/Bellevue Hospital Medical Center New York 21 98% 97% 95% 93% 93% 96% 99% 98% 16 Approved ( A ) 2 2 2 2 2 2 2 2

New Jersey Medical School New Jersey 22 96% 95% 98% 99% 97% 97% 98% 94% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Ohio State Medical Center Ohio 23 96% 96% 98% 99% 98% 97% 99% 97% 16 Approved ( A ) 2 2 2 2 2 2 2 2

University of Cincinnati Ohio 24 97% 95% 92% 91% 99% 99% 98% 97% 16 Approved ( A ) 2 2 2 2 2 2 2 2

UCSD AVRC California 28 92% 93% 91% 93% 97% 98% 98% 97% 16 Approved ( A ) 2 2 2 2 2 2 2 2 Rush University Medical Center Illinois 29 97% 96% 94% 94% 98% 97% 96% 95% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Wash U (St Louis) Missouri 31 94% 96% 91% 93% 94% 96% 90% 88% 16 Approved ( A ) 2 2 2 2 2 2 2 2

University of North Carolina at Chapel Hill North Carolina 32 95% 96% 98% 93% 99% 99% 99% 98% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Quest Diagnostics Maryland 33 92% 95% 92% 93% 99% 100% 92% 87% 16 Approved ( A ) 2 2 2 2 2 2 2 2

University of Rochester New York 40 94% 98% 94% 96% 98% 98% 98% 99% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Columbia University HIV Lab New York 47 97% 97% 98% 98% 97% 97% 12 Provisionally

Approved (PA)






Last Four Rounds of

Testing Status of Lab Sept '09 2 2 2 2 2 2

University of Colorado Colorado 48 98% 96% 93% 96% 97% 98% 96% 97% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Case Western Ohio 49 98% 98% 95% 93% 99% 99% 99% 99% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Puerto Rico Puerto Rico 53 95% 89% 97% 96% 97% 93% 98% 99% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Henry Ford Michigan 77 93% 98% 91% 88% 98% 98% 95% 95% 16 Approved ( A ) 2 2 2 2 2 2 2 2 University of Alabama Birmingham Alabama 81 96% 94% 94% 95% 99% 96% 95% 96% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Johns Hopkins Pathology Maryland 113 99% 98% 97% 95% 99% 99% 98% 99% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Emory University Georgia 117 92% 87% NRS NRS NRS NRS 4 Not Approved

(NA) 2 2 0 0 0 0

No longer listed by the

IQA

University of Pennsylvania Pennsylvania 119 96% 95% 89% 82% 99% 97% 97% 99% 16 Approved ( A ) 2 2 2 2 2 2 2 2 UCSF Pediatric Specimen Processing Lab California 134 99% 100% 99% 97% 8

Not Approved (NA)

2 2 2 2

HSC.USC California 145 93% 85% 95% 98% 98% 94% 91% 92% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Cornell Med New York 160 NRS NRS 94% 97% 98% 80% 98% 99% 12 Provisionally

Approved (PA) 0 0 2 2 2 2 2 2

Rush ISL Illinois 161 98% 96% 90% 97% 99% 99% 94% 95% 16 Approved ( A )






Last Four Rounds of

Testing Status of Lab Sept '09 2 2 2 2 2 2 2 2

Childrens Hospital of Philadelphia Pennsylvania 169 96% 97% 98% 98% 97% 94% 94% 95% 16 Approved ( A ) 2 2 2 2 2 2 2 2 University of Colorado Denver Colorado 174 94% 96% 99% 99% 89% 89% 98% 98% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Columbia University New York 177 91% 81% 84% 91% 100% 96% 93% 92% 16 Approved ( A ) 2 2 2 2 2 2 2 2

CORNELL New York 178 96% 97% 98% 98% 99% 97% 97% 97% 16 Approved ( A ) 2 2 2 2 2 2 2 2

LA County USC California 188 96% 98% 94% 95% 99% 100% 97% 98% 16 Approved ( A ) 2 2 2 2 2 2 2 2

MIRIAM HOSP Rhode Island 202 95% 96% 96% 98% 91% 95% 96% 97% 16 Approved ( A ) 2 2 2 2 2 2 2 2

VANDERBILT Tennessee 203 95% 94% 97% 98% 99% 99% 96% 93% 16 Approved ( A ) 2 2 2 2 2 2 2 2 Botswana-Harvard HIV Refernce Lab Botswana 219 73% 65% 4

Not Approved (NA)

2 2

UC Davis Vir and Immun California 224 97% 94% 96% 97% 99% 100% 92% 97% 16 Approved ( A ) 2 2 2 2 2 2 2 2

UNC Immunology ISL North Carolina 232 96% 96% 95% 97% 99% 99% 99% 99% 16 Approved ( A ) 2 2 2 2 2 2 2 2

University of Maryland, Institute of Human Virology Maryland 237 97% 97% 88% 89% 95% 98% 96% 95% 16 Approved ( A ) 2 2 2 2 2 2 2 2




Laboratory Lab # March '09 Sept '09 Dec'09


Last Four Rounds of

Testing Status of Lab June '09 Lilongwe Central Hospital Malawi 245 97% 95% 86% 92% 91% 93% 99% 98% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Lancet laboratory - Durban Durban 262 NRS NRS 98% 99% 99% 99% NRS NRS 8 Provisionally

Approved (PA) 0 0 2 2 2 2

California 263 82% 81% 97% 98% 80% 88% 97% 98% 16 UCSF-AIDS Spec Approved ( A ) 2 2 2 2 2 2 2 2

SUNY-Brooklyn New York 264 97% 93% 92% 97% 98% 98% 99% 97% 16 Approved ( A ) 2 2 2 2 2 2 2 2 Les Centeres GHESKIO Laboratory Haiti 267 87% 89% 99% 92% 95% 88% 12

Provisionally Approved (PA)

2 2 2 2 2 2

MACS Pitt Pennsylvania 268 98% 97% 95% 96% 99% 100% 99% 99% 16 Approved ( A ) 2 2 2 2 2 2 2 2 Hospital Universitário Clementino Fraga Filho (HUCFF)-Laboratório de Pesquisas Brazil 274 95% 91% 96% 99% 98% 92% 97% 96% 16 Approved ( A ) 2 2 2 2 2 2 2 2

University of Miami Florida 292 69% 66% 98% 98% 97% 96% 10 Provisionally

Approved (PA) 1 1 2 2 2 2

Papper Clin Immu Florida 293 97% 95% 93% 95% 99% 97% 93% 90% 16 Approved ( A ) 2 2 2 2 2 2 2 2 Johns Hopkins Research Project Malawi 304 93% 91% 4

Not Approved (NA)

2 2 UZ-UCSF Laboratory Malawi 306




Laboratory Lab # March '09 Sept '09 Dec'09


Last Four Rounds of

Testing Status of Lab June '09

HPTN-LIMA PERU Peru 310 95% 97% 91% 93% 94% 96% 96% 98% 16 Approved ( A ) 2 2 2 2 2 2 2 2 YRG Care Infectious Disease Laboratory India 316 93% 90% NRS NRS 98% 97% 8


2 2 0 0 2 2

Specimen Processing Unit Research Institute for Health Sciences Thailand 317 96% 97% 92% 95% 90% 91% 12


2 2 2 2 2 2 CIDRZ Central Laboratory Zambia 332

Hospital Nossa Senhora da Conceição SA - Porto Alegre, Brasil Brazil 327 94% 96% 95% 92% 98% 99% 96% 95% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Contract Laboratory Services

Johannesburgh, South Africa 350 95% 94% 96% 98% 97% NRS 99% NRS 12


2 2 2 2 2 0 2 0 AMPATH Reference Lab Kenya 358 Duke-KCMC Biotechnology Laboratory/FCMC Kilimanjaro Christian Medical Center Tanzania 411 93% 94% NRS NRS NRS NRS 96% 98% 8


2 2 0 0 0 0 2 2 Children's Research Institute Immunodiagnostics Laboratory Florida 417 98% 99% 98% 99% 8


2 2 2 2





Laboratory Lab # March '09 June '09 Sept '09 Dec'09


Last Four Rounds of

Testing Status of Lab

The Emory Hope Clinic Infectious Diseases Clinical Research Lab Georgia 438 89% 90% 96% 93% 99% 94% 12


2 2 2 2 2 2

HART- Thomas Street Clinic Texas 445 82% 90% 88% 93% 92% 89% 92% 96% 16 Approved ( A ) 2 2 2 2 2 2 2 2

VA Commonwealth Virginia 449 85% 88% 92% 93% 100% 99% NRS NRS 12 Provisionally

Approved (PA) 2 2 2 2 2 2 0 0

Research Education Group Oregon 450 97% 94% 91% 87% 96% 97% 72% 77% 16 Approved ( A ) 2 2 2 2 2 2 2 2

Wayne State Michigan 451 94% 97% 92% 95% 90% 93% 90% 92% 16 Approved ( A ) 2 2 2 2 2 2 2 2 Laboratorio de Pequisa Clinica

Rio de Janeiro-Brazil 461 92% 84% 94% 93% 93% 97% 98% 98% 16 Approved ( A )

2 2 2 2 2 2 2 2

Peabody Dallas Texas 465 NRS NRS NRS NRS 97% 98% 98% 98% 8 Provisionally

Approved (PA)

0 0 0 0 2 2 2 2

Key

International Laboratories NRS No Results Submitted

Change in Status


Table 7. International Sites with Laboratory Approval to Support Specific Protocols Site ID Site Protocol 11101 Wits HIV CRS Johannesburg South Africa

5175 5185

5190

5199

5208

5221

5230

5234

5243

5240

5245

5207

5255

5253 11201 Durban Adult HIV CRS Durban South Africa

5175

5199

5208

5221

5207 11301 Asociacion Civil Impacta Salud y

Educacion - Miraflores, CRS Lima Peru

5175

5185

5190

5199

5221

5227

5234

5243

5217

5253 11302 Asociacion Civil Investigaciones

Médicas en Salud - Lince, CRS Lima Peru

5175

5185

5190

5199

5221

5227

5234

5243



Table 7. International Sites with Laboratory Approval to Support Specific Protocols Site ID Site Protocol

5217

5253 11501 Chiang Mai Univ. ACTG CRS Chiang Mai Thailand

5175

5199

5221

5230 11601 NARI Pune CRS Pune India

5175

5190

5199

5221 11602 -NARI Clinic at Gadikhana Dr.

Kotnis Municipal Dispensary CRS Pune India

5175

5199 11603 -NARI Clinic at NIV CRS Pune India

5175

5190

5199 11701 YRG CARE Medical Ctr., VHS

CRS Chennai India

5175

5185

5190

5199

5221

5230

5207 12001 University of North Carolina

Lilongwe CRS Lilongwe Malawi

5175

5185

5190

5199

5208

5221

5230 12101 Instituto de Pesquisa Clínica

Evandro Chagas Clinical Research Site (IPEC CRS)

Rio de Janeiro Brazil

5175

5185

5190




5199

5221

5227

5240 12201 Hospital Nossa Senhora da

Conceicao CRS Porto Alegre Brazil

5175

5190

5199

5221 12301 Soweto ACTG CRS Soweto South Africa

5190

5208

5221

5253 12401 Joint Clinical Research Ctr. CRS Kampala Uganda

5208

5221

5234

5207 12501 Walter Reed Project - Kenya Med.

Research Institute Kericho CRS Kericho Kenya

5208

5221 12601 Moi University International CRS Eldoret Kenya

5208

5221 12701 Gaborone Prevention/Treatment

Trials CRS Gaborone Botswana

5208

5221 12702 Molepolole Prevention/Treatment

Trials CRS (Molepolole PTT CRS) Molepolole Botswana

5208

5221 12801 Kalingalinga Clinic CRS Lusaka Zambia

5208

5221 12901 Kilimanjaro Christian Medical CRS Moshi Tanzania

5230

5207 30022 Les Centres GHESKIO CRS Port au Prince Haiti

5175

5221





5234

5207

5254 30301 College of Med. JHU CRS Blantyre Malawi

5175

5185

5190

5199

5221

5207 30313 UZ-Parirenyatwa CRS Harare Zimbabwe

5175

5185

5190

5199

5208

5221 30333 Projeto Praça Onze/HESFA CRS Rio de Janeiro Brazil

5221 31422 CAPRISA eThekwini CRS Durban South Africa

5221 31441 BJ Medical College CRS Pune India

5207

Network Scientific Research Plan Appendices

Appendix A. ACTG Studies

Protocol Number Title

A5001 AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT) Protocol

A5005s A5005s is a Substudy of ACTG 384: Glucose Metabolism, Lipid Disorders and Body Composition Changes in Subjects Treated with Nelfinavir (NFV) or Efavirenz (EFZ)

A5007s A5007s is a Substudy of ACTG 384: Influence of Aggressive Antiretroviral Therapy on Programmed Cell Death of Naïve and Memory T-cell Subpopulations, Thymus Size, and Immune Restoration

A5014 A Randomized, Open-Label, Pilot Treatment Trial Evaluating Cellular Dynamics and Immune Restoration in Treatment Naive HIV-Infected Subjects Receiving the Protease Inhibitor LPV or the Nucleoside Analogue Reverse Transcriptase Inhibitors d4T/3TC/ABC

A5015 A Phase II Study Examining Immunologic and Virologic Indices in Two Age-Differentiated Cohorts of HIV-Infected Subjects to Explore the Basis of Accelerated HIV Disease Progression Associated with Aging

A5029 Assessment of Prevalence and Persistence of Human Papilloma Virus (HPV) DNA in HIV-Infected Women Who are Protease Inhibitor Naïve and have Initiated HAART

A5071 A Prospective, Multicenter, PhaseII/III, Open-Label, Controlled Randomized Trial Evaluating Safety, Efficacy & Tolerability of IFN-alfa-2a + Ribavirin Versus PEG-IFN-alfa-2a + Ribavirin for Chronic HCV Infection in Individuals Coinfected with HIV-1

A5073 A Randomized Phase II Open Label Study to Compare Twice Daily Potent Antiretroviral Therapy With Once Daily Potent Antiretroviral Therapy and to Compare Self-Administered Therapy and Therapy Administered Under Direct Observation

A5077 Virologic Studies in Compartmental Samples from HIV-Infected Subjects Changing or Initiating Potent Antiretroviral Therapy

A5084 Evaluation of Metabolic Complications Associated with Antiretroviral Medications in HIV-1-Infected Pregnant Women

A5090 Phase II, Placebo-Controlled, Double-Blind Study of the Selegiline Transdermal System (STS) in the Treatment of HIV Associated Cognitive Impairment

A5091s A5091s is a Substudy of A5071: Hepatitis C Viral Kinetics In Subjects Coinfected With Human Immunodeficiency Virus -1 (HIV-1) And Hepatitis C Virus Genotype 1 (HCV- 1)



Appendix A. ACTG Studies (Cont’d)


A5095 Phase III, Randomized, Double-Blind Comparison of Three Protease Inhibitor-Sparing Regimens for the Initial Treatment of HIV Infection

A5097s A5097s is a Substudy of A5095: Impact of Efavirenz on Neuropsychological Performance, Mood and Sleep Behavior in HIV + Individuals

A5102 An Open Label Pilot Study Utilizing CD4+ T-Cell Counts < 350 Cells/mm3 as the Threshold for Restarting Therapy with Potent Antiretroviral Therapy +/- Interleukin -2 to Determine the Effect of Pulse Therapy on the Characteristics of Treatment Interruptions

A5110 A Restrictively Randomized, Open-Label, Controlled, Pilot Study of the Effect of a Thymidine Analogue Substitution or Change to a Nucleoside-Sparing Regimen on Peripheral Fat Wasting

A5113 A Study of Immune Function in Healthy Adults Aged 18-30 and 45 and Older

A5115 A Phase II Randomized, Controlled, Pilot Study of Antiretroviral Switch at Lower versus Higher HIV-1 RNA Levels in Subjects Experiencing Virologic Relapse on a Current HAART Regimen

A5117 A Pathophysiologic Study of Development of Distal Symmetrical Polyneuropathy in Individuals with Advanced HIV-1 Infection and Prior Antiretroviral Exposure

A5126 A Phase II Study of the Predictive Value of Pharmacokinetic-Adjusted Phenotypic Susceptibility (C12h/IC50) on Antiretroviral Response to Ritonavir-Enhanced Protease Inhibitors in Subjects with Failure of Previous Protease Inhibitor-Based Regimens

A5127 A Randomized, Phase II, Controlled Trial Comparing the Efficacy of Adefovir Dipivoxil and Tenofovir Disoproxil Fumarate for the Treatment of Hepatitis B Virus in Subjects Who Are Co-Infected with HIV

A5128 Plan For Obtaining Informed Consent to Use Stored Human Biological Materials (HBM) for Currently Unspecified Analysis

A5130 A Phase I/II Study to Evaluate the Safety and Immunogenicity of the Subcutaneous Administration of ALVAC-HIV vCP1452 Infected, Autologous Dendritic Cells versus the Subcutaneous Administration of ALVAC-HIV vCP1452 to HIV-Infected Subjects

A5138 Augmenting the Magnitude of HAART-Induced Immune Restoration by the Use of Cyclosporine




Protocol Number

Title

A5142 A Phase III, Randomized, Open-Label Comparison of Lopinavir/Ritonavir plus Efavirenz vs. Lopinavir/Ritonavir plus 2 NRTIs vs. Efavirenz plus 2 NRTIs for the Initial Therapy for HIV-1 Infection

A5143 A Randomized, Comparative Study of LPV/RTV vs. GW433908 + RTV vs. LPV/RTV + GW433908 (in Combination with Tenofovir Disoproxil Fumarate and One or Two Nucleoside Reverse Transcriptase Inhibitors) in HIV-1-Infected Subjects with Virologic Treatment Failure

A5146 A Phase II Randomized Controlled Trial Evaluating the Impact of Therapeutic Drug Monitoring (TDM) on Virologic Response to a Salvage Regimen in Subjects with a Normalized Inhibitory Quotient (NIQ) <= 1 to One or More Protease Inhibitors

A5150 A Prospective Observational Study of Virologic and Immunologic Changes in HIV-Infected Women During the Postpartum Period

A5152s A Substudy of A5142: Endothelial Function in HIV-Infected Subjects Prior to and After Starting a Potent Antiretroviral Regimen

A5153s A Substudy of A5150: Pharmacology Substudy

A5157 An Open-Label Dose-Escalation Pilot Study of Acetyl L-Carnitine (ALC) for the Treatment of Dideoxynucleoside Associated Distal Symmetric Peripheral Neuropathy

A5160s A Substudy of A5142: Viral Dynamics Substudy

A5164 A Phase IV Study of Antiretroviral Therapy for HIV-Infected Adults Presenting with Acute Opportunistic Infections: Immediate versus Deferred Initiation of Antiretroviral Treatment

A5170 Predictors of Immunologic and Clinical Progression in Subjects with CD4+ Cell Counts >350 Cells/mm3 Who Discontinue Antiretroviral Therapy

A5173 A Pilot Study to Measure the Clearance of Replication-Competent HIV-1 in Resting Memory CD4+ Cells in HIV Infected Subjects Who Receive Enfuvirtide + Oral Combination Antiretroviral Therapy

A5174 Improving Immune Reconstitution with Growth Hormone in HIV Infected Subjects with Incomplete CD4+ Lymphocyte Restoration on HAART





A5175 A Phase IV, Prospective, Randomized, Open-Label Evaluation of the Efficacy of Once-Daily PI and Once-Daily Non-NRTI-Containing Therapy Combinations for Initial Treatment of HIV-1 Infected Individuals from Resource-Limited Settings (PEARLS) Trial

A5176 A Phase I/II, Randomized, Double-Blind Study to Evaluate Safety, Tolerability, and Immunogenicity of LC002, a DermaVir Vaccine, in HIV-1-Infected Subjects Under Tx w/HAART

A5177 An Observational Study of the Pharmacokinetics of Efavirenz, Nevirapine, and Lopinavir/ritonavir in HIV Subjects Requiring Hemodialysis

A5178 Suppressive Long-term Antiviral Management of Hepatitis C Virus (HCV) and HIV-1 Coinfected Subjects (SLAM-C)

A5181 HIV Antigen Specific Immune Responses - A Comparison of Alternative in Vitro Assays from Subjects Characterized as Either "Stable HAART" or Efficient Immune Control

A5185s A Substudy of A5175: Effect of Initial Antiretroviral Treatment on Genital Compartment Virus in Individuals from Diverse Areas of the World

A5186 A Phase II Trial of the Effect of Combination Therapy with Fish Oil Supplement and Fenofibrate on Triglyceride (Tg) Levels in Subjects on Highly Active Antiretroviral Treatment (HAART) Who are Not Responding to Either Fish Oil or Fenofibrate Alone

A5187 A Phase I/II Clinical Trial to Evaluate the Safety and Immunogenicity of the HIV-1 DNA Vaccine VRC-HIVDNA0009-00-VP (GAG-POL-NEF-MULTICLADE ENV) in HIV-1-Infected Subjects Treated During Acute Infection

A5190 Assessment of Safety and Toxicity among Infants Born to HIV-Infected Women Enrolled in Antiretroviral Treatment Protocols in Diverse Areas of the World

A5191 A Phase I, Dose-Rising Study of AMD11070 in HIV-Seronegative Men to Assess the Safety and Pharmacokinetics after Single or Multiple Doses

A5192 A Phase II Open Label Pilot Trial of the Antiretroviral Activity, Safety, and Tolerability of Pegylated Interferon Alpha 2-A (40KD) (PEGASYS) in HIV-1 Infected Subjects

A5197 A Phase II, Double-blinded, Randomized, Placebo-Controlled Study to Evaluate the Antiretroviral Effect of Immunization With the MRK Ad5 HIV-1 Gag Vaccine in HIV-1 Infected Individuals Who Interrupt Antiretroviral Drug Therapy





A5199 International Neurological Study: A Stand Alone Study for Participants of A5175

A5200 A Randomized, Placebo-Controlled, Phase I/II Trial of the Anti-HIV Activity and Safety of (VGX-410) Mifepristone at Three Dose Levels in HIV-1-Infected Subjects

A5201 A Prospective, Open-Label, Pilot Trial of Regimen Simplification to Atazanavir/Ritonavir Alone as Maintenance Antiretroviral Therapy after Sustained Virologic Suppression

A5202 A Phase IIIB, Randomized, Trial of Open-Label Efavirenz or Atazanavir with Ritonavir in Combination with Double-Blind Comparison of Emtricitabine/Tenofovir or Abacavir/Lamivudine in Antiretroviral-Naïve Subjects

A5206 A Pilot Study to Determine the Impact on Dyslipidemia of the Addition of Tenofovir to Stable Background Antiretroviral Therapy in HIV-Infected Subjects

A5207 A Phase II Randomized Comparison of Three Antiretroviral Strategies Administered for Seven or Twenty-One Days to Reduce the Emergence of Nevirapine Resistant HIV-1 Following a Single Intrapartum Dose of Nevirapine

A5208 Optimal Combined Therapy After Nevirapine Exposure (OCTANE)

A5209 A Pilot Study of Safety, Efficacy, and Tolerability of Ezetimibe (ZETIA) in Combination with Statin Therapy for the Treatment of Elevated LDL Cholesterol in HIV-Infected Subjects

A5210 Phase Ib/IIa Dose-Finding Safety and Activity Study of AMD11070 (An Orally Administered CXCR4 Entry Inhibitor) in HIV-Infected Subjects

A5211 Phase II, Randomized, Double-Blind Study of the Safety and Efficacy of SCH 417690 (an Orally Administered HIV-1 Entry Inhibitor) in HIV-Infected Treatment-Experienced Subjects

A5212 A Double Blind Phase II Study of Multiple Doses of Palifermin (rHuKGF) for the Treatment of Inadequate CD4+ Lymphocyte Recovery in Subjects on Potent Antiretroviral Therapy with Plasma HIV-1 RNA Levels <=200 copies/mL

A5213 Safety, Tolerability, and Pharmacokinetic Interactions of Atazanavir and Rifampin in Healthy Volunteers





A5214 A Phase I, Randomized, Placebo - Controlled, Double-Blind Study Evaluating the Safety of Subcutaneous Single Dose Interleukin-7 in HIV-1-Infected Subjects Who are Receiving Antiretroviral Treatment

A5217 The SETPOINT Study - A Randomized Study of the Effect of Immediate Treatment with Potent Antiretroviral Therapy versus Observation with Treatment as Indicated in Newly Infected HIV-1-Infected Subjects: Does Early Therapy Alter the Virologic Setpoint?

A5220 Improving Immune Response to Hepatitis B Vaccine in HIV-Positive Subjects Using Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) as a Vaccine Adjuvant: A Phase II Open-Label Pilot Study

A5221 A Strategy Study of Immediate Versus Deferred Initiation of Antiretroviral Therapy for HIV-Infected Persons Treated for Tuberculosis with CD4 <250 Cells/mm3

A5224s A Substudy of A5202: Long-Term Metabolic Assessments in Subjects Treated with Emtricitabine/Tenofovir or Abacavir/Lamivudine with either Efavirenz or Atazanavir with Ritonavir

A5225 A Phase I/II Dose-Finding Study of High-Dose Fluconazole Treatment in AIDS-Associated Cryptococcal Meningitis

A5227 The Effect of Prior Short Course Antiretroviral Therapy Administered for the Prevention of Mother to Child Transmission (pMTCT) of HIV on Subsequent Treatment Efficacy in Treatment-Nearly Naïve Subjects

A5229 A Phase II/III, Randomized, Double-Blind, Placebo-Controlled Trial of Uridine Supplementation in HIV Lipoatrophy

A5230 A Pilot Study of Lopinavir/ritonavir in Subjects Experiencing Virologic Relapse on NNRTI-Containing Regimens

A5232 Optimizing Vaccine Responsiveness in HIV-1 and HCV Infections and Identifying Determinants of Responsiveness: A Pilot Study

A5234 International Trial of Directly Observed Therapy versus Standard of Care for Patients with First Virologic Failure on a Non-Nucleoside Reverse Transcriptase Inhibitor- Containing Antiretroviral Regimen

A5235 Phase II, Placebo-Controlled, Double-Blind Study of Minocycline in the Treatment of HIV-Associated Cognitive Impairment





A5239 A Pilot Study of Therapy with Pioglitazone Prior to HCV Treatment in HIV and HCV Genotype 1 -Infected Subjects with Insulin Resistance Who are Prior Nonresponders to Peginterferon and Ribavirin Therapy

A5240 A Phase II Study to Evaluate the Immunogenicity and Safety of a Quadrivalent Human Papillomavirus Vaccine in HIV-1-Infected Females

A5241 The Optimized Treatment that Includes or Omits NRTIs (OPTIONS) Trial: A Randomized Strategy Study for HIV-1-Infected Treatment-Experienced Subjects Using the cPSS to Select an Effective Regimen

A5243 Plan for Obtaining Human Biological Samples at Non-U.S. Clinical Research Sites for Currently Unspecified Genetic Analyses

A5244 Double-Blind, Randomized, Pilot Study to Measure the Effect of Treatment Intensification with a Potent Integrase Inhibitor, Raltegravir (MK-0518), on the Level of Persistent Plasma Viremia below 50 copies/mL in Subjects on PI- or NNRTI-Containing Regimens

A5245 A Randomized Trial to Evaluate the Effectiveness of Antiretroviral Therapy plus HIV Primary Care versus HIV Primary Care Alone to Prevent the Sexual Transmission of HIV-1 In Serodiscordant Couples and to Compare Survival and HIV Disease Progression

A5246 A Single-Arm, Open-Label Trial of the Safety and Immunogenicity of a Human Papillomavirus Vaccine in HIV-1-Infected Men (AMC052)

A5247 A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate Safety, Tolerability, & Immunogenicity of ZOSTAVAX (Zoster Vaccine Live) in HIV-1-Infected Adults on Potent Combination ART with Conserved Immune Function

A5248 First-Phase Viral Decay Rates in Treatment-Naive Subjects Initiating Treatment with Raltegravir (RAL) and Emtricitabine (FTC)/Tenofovir Disoproxil Fumarate (TDF): A Pilot Study

A5249s A Substudy of A5248: Intensive Viral Dynamics

A5250 Durability of Adherence in Self-Management of HIV (DASH)

A5251 A Randomized Trial of Enhanced Nursing Telephone Support to Improve Self-Management and Outcomes of ART





A5252 A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Duloxetine and Methadone for the Treatment of HIV-Associated Painful Peripheral Neuropathy

A5253 Sensitivity and Specificity of Mycobacterium Tuberculosis Screening and Diagnostics in HIV-Infected Individuals

A5254 Assessment of HIV-Related Oral Mucosal Disease and Use of Saliva in Measuring HIV Viral Load

A5255 Faster AFB Identifcation, Speciation of Tuberculosis, and Evaluation of Drug Resistance in HIV-Infected Persons Initiating TB Therapy

A5256 A Pilot Trial of Maraviroc (MVC) for Treatment of Subjects on Antiretroviral Therapy with Suboptimal CD4+ T-cell Count Recovery Despite Sustained Virologic Suppression

A5257 A Phase III Comparative Study of Three Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)-Sparing Antiretroviral Regimens for Treatment-Naive HIV-1-Infected Volunteers

A5258 A Phase II, Double Blind, Randomized, Exploratory Study of Chloroquine for Reducing HIV-Associated Immune Activation

A5259 A Study of the Effectiveness and Tolerability of Weekly Rifapentine/Isoniazid for Three Months Versus Daily Isoniazid for Nine Months for the Treatment of Latent Tuberculosis Infection

A5260s Cardiovascular, Anthropometric, and Skeletal Effects of Antiretroviral Therapy (ART) Initiation with Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) plus Atazanavir/Ritonavir (ATV/r), Darunavir/Ritonavir (DRV/r), or Raltegravir (RAL): Metabolic Substudy of A5257

A5261 A Pilot Efficacy and Safety Trial of Raltegravir Plus Atazanavir for Treatment-Naive HIV-1-Infected Subjects

A5262 A Pilot Efficacy and Safety Trial of Raltegravir Plus Darunavir/Ritonavir for Treatment-Naive HIV-1-Infected Subjects

A5263 A Randomized Comparison of Three Chemotherapy Regimens as an Adjunct to Antiretroviral Therapy for Treatment of Advanced AIDS-KS in Resource-Limited Settings





A5264 A Randomized Comparison of Antiretroviral Therapy Alone or with Delayed Chemotherapy versus Antiretroviral Therapy with Immediate Adjunctive Chemotherapy for Treatment of Limited Stage AIDS-KS

A5265 A Phase III, Open-Label, Randomized, Assessment-Blinded Clinical Trial to Compare the Safety and Efficacy of Gentian Violet to that of Nystatin for the Treatment of OC in HIV-Infected Participants in Non-U.S. Settings

A5266 A Randomized Trial to Assess the Safety and Tolerability of Taribavirin vs. Ribavirin in Combination with Pegylated-Interferon Alfa-2a in the Management of HCV Genotype 1/HIV-Coinfected Participants

A5267 A Phase I, Safety, Tolerability, and Pharmacokinetic Interaction Study of Single Dose TMC207 and Efavirenz in Healthy Volunteers

A5268 Safety, Tolerability, and Pharmacokinetic Interactions when Atazanavir/Ritonavir Dosed to Steady State is Followed by Rifampin in Healthy Volunteers

A5269 The Efficacy of Nitazoxanide in Addition to Peginterferon Alfa-2a and Ribavirin in Chronic Hepatitis C Treatment-Naive Genotype 1 Subjects with HIV Co-Infection

A5270 A Randomized, Placebo-Controlled Non-inferiority Trial of Co-trimoxazole Dscontinuation in HIV-Infected Adults Receiving Antiretroviral Therapy in Areas of Low Malaria Endemnicity with CD4+ Cell Counts above 200/mm3 for at Least 3 Months

A5271 Collection of Comparison Neurocognitive Data in Resource Limited Settings: Application to Neurocognitive Treatment Response in A5199

A5272 The Effect of HIV Antiretroviral Therapy Initiation on Oral HPV Shedding and Oral Warts

A5273 Multicenter Study of Options for Second-Line Effective Combination Therapy (SELECT)

A5274 Reducing Early Mortality and Early Morbidity by Empiric Tuberculosis Treatment Regimens (REMEMBER)

A5275 A Pilot Study Evaluating the Effect of Atorvastatin on Biomarkers of Inflammation, Coagulopathy, Angiogenesis, and T-Lymphocyte Activation in HIV-1 Infected Individuals with Suppressed HIV RNA and LDL Cholesterol < 130mg/dL





A5277 Phase 1b Study to Assess the Safety and Activity of the HCV Entry Inhibitor ITX 5061 in Treatment-Naïve HCV Mono-Infected Adults

A5278s Pharmacology Substudies of A5263 and A5264

A5279 Phase III Clinical Trial of Short-Course Rifapentine/Isoniazid for the Prevention of Active Tuberculosis in HIV-Infected Adults with Latent Tuberculosis Infection

A5281 Phase 1 Randomized, Partially Double-Blind, Placebo-Controlled Dose-Escalation Study to Evaluate Safety and Immunogenicity of Cytokine Enhanced HIV-1 Multi-Antigen pDNA Vaccine Delivered Intramuscularly (IM) or IM in Combination w/in Vivo Electroporation

A5282 A Randomized Phase II Trial to Compare an HPV Test-and-Treat-Strategy to a Cytology-Based Screening for Prevention of CIN 2+ in HIV-Infected Women

A5283 An Open-Label, Non-Randomized Study of Pharmacokinetic Interactions Between Depo-Medroxyprogesterone Acetate (DMPA) and Lopinavir/ritonavir (LPV/r) and of the Effects of DMPA on Cellular Immunity and Regulation in HIV-Infected Women

A5285 Evaluation of the Pharmacokinetics of the Cyclophilin Inhibitor Debio025 when Used in Combination with Antiretroviral Medications in Healthy Volunteers

A5286 A Pilot Study of Rifaximin as a Modulator of Gut Microbial Translocation and Systemic Immune Activation in Untreated HIV-Infected Individuals

A5287 A Pilot Study of the Cyclophilin Inhibitor Debio025 in Combination with Pegylated Interferon plus Ribavirin for Chronic Genotype 1 Hepatitis C Virus (HCV) Infection in HIV-1 Co-infected Subjects on Raltegravir Based Antiretroviral Therapy

A5288 Evaluation of Antiretroviral Combinations and Contemporary Management Tools

A5289 A Randomized, Controlled, Phase II Study of TMC-207 versus Ethambutol in Intensive Phase Treatment of Drug Sensitive Tuberculosis (TB) in HIV Infected and Uninfected Individuals with Pulmonary Tuberculosis

A5290 A Randomized, Phase 2 Study of a ''Super Boosted'' (Double Dose) Lopinavir/Ritonavir Based Antiretroviral Regimen with Rifampin-Based Tuberculosis Treatment versus a Lopinavir/Ritonavir Antiretroviral Regimen with Rifabutin-Based Tuberculosis Treatment





A5292 A Randomized Controlled Trial to Compare the Effects of HAART Versus Statin Therapy on Endothelial Function and Markers of Inflammation/Coagulation In HIV-Infected Individuals with High CD4 cell Counts

ACTG 301 A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial of Memantine for AIDS Dementia Complex (ADC) Alone or as Concurrent Treatment with Antiretroviral Therapy

ACTG 328 A Phase II Study of Intermittent rhIL-2 by Intravenous or Subcutaneous Administration in Subjects with HIV Infection on Highly Active Antiretroviral Therapy (HAART) or HAART Alone

ACTG 359 Activity of the Soft Gelatin Capsule of SQV in Combination with RTV or Nelfinavir and Combinations of DLV, and/or Adefovir Dipivoxil in HIV Infected Subjects with Prior IDV use and Viral Loads of >/= 2,000 and </= 200,000 copies HIV RNA/mL

ACTG 362 Long-Term Assessment for Metabolic, Cardiovascular and Neurologic Complications in Subjects with Past CD4 Cells/mm3 <50 Who Increased CD4 Cells/mm3 to >100 on HAART

ACTG 363 Pilot Study on the Effect of Cidofovir For the Treatment of Progressive Multifocal Leukoencephalopathy (PML) in Patients with the Acquired Immunodeficiency Syndrome (AIDS)

ACTG 371 Trial to Evaluate the Safety and Efficacy of Induction Treatment with Lamivudine plus Stavudine plus Abacavir plus Amprenavir/Ritonavir Followed by Supervised Treatment Interruption in Subjects with Acute HIV Infection or Recent Seroconversion

ACTG 384 Study of Protease Inhibitor and/or Non-Nucleoside Reverse Transcriptase Inhibitor with Dual Nucleosides in Initial Therapy of HIV Infection

ACTG 388 Phase III Randomized, Controlled Trial of Efavirenz (EFV) or Nelfinavir (NFV) in Combination w/Fixed-Dose Combination Lamivudine/Zidovudine (3TC/ZDV) & Indinavir (IDV) in HIV-infected Subjects with <200 CD4 cell/mm3 or > 80,000 HIV RNA copies/mL in Plasma

ACTG 392 Evaluation of High Protein Supplementation in HIV-1-Positive Subjects with Stable Weight Loss

ACTG 398 A Phase II, Rand Trial of APV as Pt of Dual PI Regimens (Placebo Controlled) in Comb w/ ABC, EFV & ADV vs. APV Alone in HIV Infected Subjects w/Prior Expo. to Apprvd PIs and Loss of Virologic Supp. as Reflected By A Plasma HIV-1 RNA of >= 1000 copies/ml

ACTG 700 Substudy of ACTG 301: In Vivo Proton Magnetic Resonance Spectroscopy Studies of Cerebral Injury in HIV Dementia





ACTG 709 ACTG 709 is an Immunology Substudy of ACTG 371

ACTG 710 ACTG 710 is a Substudy of ACTG 371: Compartment Substudy

ACTG 723 Effect of Antiretroviral Therapy on Viral Burden and Immune Function in the Lungs of HIV-Infected Subjects

ACTG 729 ACTG 729 is a Substudy of ACTG 371: Medication Compliance Substudy

ACTG 736 Cerebrospinal Fluid Human Immunodeficiency Virus and Cognitive Function in Individuals Receiving Potent Antiretroviral Therapy

HPTN 052 Randomized Placebo-Controlled Trial to Evaluate the Effectiveness of Antiretroviral Therapy to Reduce the Sexual Transmission of HIV-1 in Serodiscordant Couples

P1025 Perinatal Core Protocol

P1026s Pharmacokinetic Properties of Antiretroviral Drugs During Pregnancy

P1077BF Breastfeeding Version of the PROMISE Study (Promoting Maternal and Infant Survival Everywhere)

P1077FF Formula Feeding Version of PROMISE (Promoting Maternal and Infant Survival Everywhere)

P1077HS HAART Standard Version of the PROMISE Study (Promoting Maternal and Infant Survival Everywhere)

P1078 A randomized clinical trial to assess the safety and efficacy of latent TB screening and targeted isoniazid preventive therapy among pregnant women to reduce TB incidence and mortality among





P1081 A Randomized Trial to Evaluate the Virologic Response and Pharmacokinetics of Three Different Potent Regimens in HIV-infected Women Initiating HAART Between 28 and 36 Weeks of Pregnancy for the Prevention of Mother-to-Child Transmission

NWCS 092 Correlates of Protection against Herpes Zster in HIV-Infected Children on HAART

NWCS 101-P1025

Inflammatory and Coagulation Biomarkers in HIV-Infected Women During Pregnancy and Postpartum

NWCS 223 Effect of IL-2 on GBV-C infection, and the In Vivo Effect of GBV-C on Immunologic Assessments in HIV Disease

NWCS 224R

A Pilot Study of the Genetics of Antiretroviral-Associated Dyslipidemia in HIV Infection

NWCS 227R

Comparison of Alternative Methods for Monitoring Viral Load: the Perkin Elmer Heat-Dissociated P24 Antigen Assay and the Cavidi Exavir RT Assay Compared to the Roche Monitor RNA Assay

NWCS 234R

Hepatitis C Virus (HCV) Evolution in ACTG 384

NWCS 239 Emergence of NNRTI Resistance Mutations After Discontinuation of NNRTI-Containing Antiretroviral Therapy

NWCS 242R

Impact of Viral Resistance on Risk for Opportunistic Infections or Death

NWCS 243 Study of HIV-1 Adaptation to HLA-Restricted Immune Responses in AACTG A5142 Baseline Specimens

NWCS 248 CYP2B6, MDR1 and CYP3A5 Polymorphisms in ACTG A5177 Study Participants

NWCS 249 Proposal to Evaluate Power of Gene Expression Profile Analysis to Classify & Prognosticate Progression of HIV-1 Disease in Seropositive Persons Subsequent to Cessation of ART in the Context of Well Defined Clinical, Immunologic, Virologic & Host Factors





NWCS 250 Measuring HIV Co-receptor Tropism Using Different Methods

NWCS 253 Polymorphisms in Drug Transporter and Metabolism Genes, and Responses to Efavirenz-containing Regimens in A5095

NWCS 254 Relationships between Human Genetic Variants and Antiretroviral Treatment Responses in ACTG 384: A Validation Study

NWCS 255 The Effect of Perinatal Antiretroviral (ARV) Therapy on Mitochondrial Indices in Antiretroviral Exposed Children Enrolled in A5084

NWCS 256 Whole Mitochondrial Genome Sequencing to Identify Functional Polymorphisms Associated with Peripheral Neuropathy in ACTG 384

NWCS 257 Modulation of HIV-Specific CD8+ T Cell Function During and After Dessation of HAART

NWCS 258 Disapproved

Role of Socioeconomic Status and Allostatic Load on HAART Effectiveness in Initial Therapy for HIV-1 Infection: A Secondary Analysis of ACTG 384

NWCS 259 A Candidate Gene Study to Identify Polymorphisms Associated with Susceptibility to Developing Dyslipidemia and Insulin Resistance: Analysis of Data from ACTG 5142 Trial

NWCS 260 Comprehensive Analysis of Chronic Hepatitis B in HIV-Infected Persons in AACTG Protocol A5175: Prevalence, Effect on HAART Response, Efficacy of anti-HBV Treatment, and Development of Drug-Resistant HBV

NWCS 261 Retrospective, Pilot Study of HIV-1 Pol Replication Capacity as a Predictor of CD4 Lymphocyte Counts in Naive Patients who Received PI and/or Non-Nucleoside Reverse Transcriptase Inhibitors with Dual Nucleosides as Their Initial Drug regimen in ACTG 384

NWCS 263R T Regulatory Cells and HIV

NWCS 266R Associations between IL1 Variants and Response to Antiretroviral Therapy in ACTG 384





NWCS 269 Cord Blood Lipids and Oxidative Markers in Infants Born to HIV-1-Infected Women Treated with Combination Antiretroviral Therapy

NWCS 270R

The Effect of Active HCV on Neurocognitive Function and Neuropathy in HIV-Infected Subjects with HIV Viral Suppression

NWCS 273 Whole Mitochondrial Genome Sequencing and Peripheral Neuropathy in ACTG 384 and A5117

NWCS 280 Mitochondrial Genomics and Metabolic Complications in A5142

NWCS 283R

Mechanisms of Interferon Alpha-Mediated Suppression of HIV in Chronically Infected Individuals Treated with Pegylated Interferon-Alpha

NWCS 284 Correlates of CMV-Specific Immune Reconstitution in HIV-Infected Individuals on HAART

NWCS 285 The Effect of Protease Inhibitors on the Incidence of Malaria: An Ancillary Study to AACTG 5208

NWCS 299 Use of (1,3)-beta-glucan in the Diagnosis of HIV-Related Pneumocystis jiroveci Pneumonia (PCP):Analysis of A5164 Study Subjects

NWCS 300 Evaluation of Type 1 Regulatory T cells in HIV-1 Infected Subjects Who Received Pegylated Interferon alfa-2A (Pegasys)

NWCS 311 Correlation of Plasma Nef Levels with Markers of Immune Activation

NWCS 314 Effect of a Therapeutic HIV-1 Gag Vaccine and Treatment Interruption on HIV-1 Gag and Pol Evolution and Diversity

DACS 234 Mitochondrial Haplogroups and Limb Fat Changes in Studies ACTG 384/A5005s/NWCS 238






DACS 235 Boosting, Bagging, and Discriminant Analysis to Improve Prediction of Fibrosis in HIV/HCV Coinfected Patients from A5178

DACS 238 Describing the Immunologic and Virologic Response to Antiretroviral Therapy in HAART Naïve Younger and Older Women.

DACS 242 Meta-analysis of the Association of Gender with Outcome in HIV/HCV Coinfected Subjects Receiving PEG/Ribavirin in Clinical Trials

DACS 243 Effect of Gender on Safety and Tolerability of HCV Therapy in HIV Co-Infection

DACS 248 Correlation of HIV Disease Progression, as Measure by Either a Decline in CD4 T-cell Count or an Increase in HIV-1 RNA Copy Number, with the Presence of High Titer HIV-1 Neutralizing Antibodies in a Cohort of HIV-1 Individuals Who have Discontinued ART

DACS 249 Multi-State Modeling of HPV Acquisition and Clearance in HIV Positive Women Initiating ART

DACS 261 Population PK-PD of RBN: An Analysis of the Existing Data


Appendix B. ACTG Protocol Status and Scientific Priority

Protocol Number Phase Research

Area Abstracted Title Open

Actual or Projected

Closed to Accrual

Actual or Projected

Follow Up

Complete Actual or Projected

Actual Accrual

as of 3/01/10

Target Accrual

Network Priority

Status as of

3/01/10

A5001 N/A O ACTG Longitudinal Linked Randomized Trials (ALLRT) Protocol 12/99 05/13 05/13 5,058 6,100 1 Enrolling

A5128 N/A O Stored Human Biological Materials For Currently Unspecified Analysis *collection of a single sample for genomics work

01/02 12/12 12/12 11,789 20,000 2 Enrolling

A5175 IV O Once-Daily PI + NNRTI Regimens for Initial Tx in Resource-Limited Settings 04/05 08/07 05/10 1,571 1,520 1

Closed to

Accrual

A5176 I/II V Tolerability, Safety, Immunogenicity of LC002 (DermaVir vaccine) in HIV Subjects 02/06 10/08 12/09 26 26 2 Cld to

FU

A5178 II O Suppressive Long-term Antiviral Management of HCV/HIV Coinfection (SLAM C)

07/04 05/07 02/09 333 300 2 Cld to FU

A5185s IV Trans A5175 Genital Compartment Substudy 04/05 11/06 05/10 371 315 2 Closed

to Accrual

A5190 N/A MTCT Safety/Toxicity of Infants of HIV-Infected Women in ART Protocols 05/06 12/08 09/10 236 410 3

Closed to

Accrual

A5197 II V Antiretroviral Effect MRK Ad5 HIV-1 Gag Vaccine in HIV Individuals Stopping ART 06/04 06/06 11/10 114 120 1

Closed to

Accrual

A5199 N/A O International Neurological Study: A Stand Alone Study for Participants of A5175 02/06 08/07 05/10 860 960 1

Closed to

Accrual

A5202 III O EFV or ATV with RTV combined with FTC/TDF or ABC/3TC in Naive Subjects 09/05 12/07 11/09 1,864 1,800 2 Cld to

FU

A5207 II MTCT 3 ART Strategies to Reduce NVP-Resistant HIV After Intrapartum Single Dose NVP 03/06 01/10 12/11 980 960 1

Closed to

Accrual



Appendix B. ACTG Protocol Status and Scientific Priority (Cont’d)



Actual or Projected

Closed to Accrual

Actual or Projected

Follow Up


Actual Accrual

as of 3/01/10

Target Accrual

Network Priority

Status as of

3/01/10

A5208 III MTCT Optimal Combined Therapy After Nevirapine Exposure 04/05 07/08 02/11 745 740 2

Closed to

Accrual

A5211 II Trans Safety/Efficacy of SCH 417690 (Oral HIV Entry Inhibitor) in HIV-1 Subjects 05/04 10/05 12/10 118 120 2

Closed to

Accrual

A5212 II Trans Palifermin for inadequate increase in CD4+ cells 12/06 04/08 09/08 99 96 3 Cld to

FU

A5217 II O TDF+FTC+LPV/r vs. no ART in New Infections 01/05 06/09 03/12 131 150 2

Closed to

Accrual

A5221 IV O STRIDE: Immediate vs. Deferred ART in Subjects with TB and CD4<200 08/06 09/09 08/10 809 800 1

Closed to

Accrual

A5223 N/A O Differences in LPV/r PK among HIV infected Men and Women 10/05 07/07 07/07 114 78 3 Cld to

FU

A5224s III O Metabolic Substudy of A5202 09/05 12/07 09/09 271 250 2 Cld to FU

A5225 I/II O Dose Finding of High Dose Fluconazole in AIDS-Associated Cryptococcal Meningitis 02/10 03/11 09/11 192 2 Open

A5227 IV O Short Course ART for Prev of Maternal/Child Transmission on Subseq Tx Efficacy 05/07 12/09 12/10 54 47 2

Closed to

Accrual

A5230 PILOT O Study of LPV/r in Subjects with Virologic Relapse on NNRTI-Containing Regimens 01/08 12/10 03/12 92 120 1 Enrolling

A5234 III O mDOT vs. Self-Administered Therapy for First Virologic Failure on NNRTI 03/09 12/10 12/11 117 496 2 Enrolling

A5235 II O Trial of Minocycline for HIV-Associated Cognitive Impairment 12/06 10/09 01/10 107 110 3

Closed to

Accrual

A5239 PILOT O Pioglitazone Prior to HCV in NonResp. to Peg/IFN & RBV w/ Insulin Resistance 03/09 07/10 07/12 15 30 3 Enrolling






Actual or Projected

Closed to Accrual

Actual or Projected

Follow Up


Actual Accrual

as of 3/01/10

Target Accrual

Network Priority

Status as of

3/01/10

A5240 II V Immunogenicity and Safety of a Quadrivalent HPV Vaccine in HIV Infected Women 02/08 05/11 10/12 262 402 1 Enrolling

A5241 III O OPTIONS: Optimized Tx that Includes/Omits NRTIs:Using the cPSS to Select a Regimen 01/08 07/10 06/12 429 577 1 Enrolling

A5243 N/A O Obtaining Samples from Non-U.S. Sites for Genetic Testing *collection of a single sample for genomics work

11/09 10/13 10/13 76 5,000 2 Enrollilng

A5244 PILOT Trans Treatment Intensification w/Raltegravir on level of Persistent Plasma Viremia 11/07 06/08 11/08 53 55 2 Cld to

FU

A5245 IV O When to Start ART Outside the U.S *Collaboration with HPTN 052 - HPTN is primary network

08/06 03/10 03/15 HPTN 1577 1,750 1 Enrolling

A5246 II V

Safety & Immunogenicity of Human Papillomavirus Vaccine in HIV-1-Infected Men **Collaboration with AMC - AMC is the primary network

12/07 11/08 05/10 N/A 110 N/A Closed

to Accrual

A5247 II V Evaluate the Immunogenicity of Zoster Vaccine Live (Oka/Merck) in HIV-Infected 04/09 05/10 08/10 239 400 1 Enrolling

A5248 PILOT Trans First-Phase Viral Decay Rates in Treatment-Naive Subjects Tx w/MK-0518 & TNF/FTC 05/08 01/09 04/10 39 39 1

Closed to

Accrual

A5249s PILOT Trans Intensive Viral Dynamics Substudy of A5248 05/08 08/08 09/08 11 10 2 Cld to FU

A5250 N/A O Durability of Adherence in Self-Management of HIV (DASH) 01/10 01/13 07/14 8 210 2 Enrolling

A5251 N/A O Enhanced Nursing Support to Improve Self-Management and Outcomes of ART 03/10 02/12 09/13 296 2 Pending

A5252 II O Combination Analgesic Therapy in HIV-associated Painful Peripheral Neuropathy 05/09 04/11 10/11 5 120 2 Enrolling

A5253 N/A O Sensitivity & Specificity of TB Diagnostics 12/09 06/11 07/11 19 800 1 Enrolling






Actual or Projected

Closed to Accrual

Actual or Projected

Follow Up


Actual Accrual

as of 3/01/10

Target Accrual

Network Priority

Status as of

3/01/10

A5254 N/A O HIV-Related Oral Mucosal Disease & Use of Saliva in Measuring HIV Viral Load 09/09 08/10 09/10 64 360 2 Enrolling

A5255 N/A O FASTER: Rapid TB Diagnostics Study 08/09 01/11 07/11 48 639 1 Enrolling

A5256 PILOT Trans MVC for subjects on ARV tx w/CD4+ T-cell recovery despite virologic suppression 12/08 05/09 05/10 34 32 1

Closed to

Accrual

A5257 III O Study of Three Compact ARV Regimens for Treatment of Naive HIV-1 Volunteers 05/09 03/11 12/12 858 1,800 1 Enrolling

A5258 II Trans Phase II Study of Chloroquine for Reducing HIV-associated Immune Action 03/09 05/10 09/10 25 30 2 Enrolling

A5259 III O Weekly Rifapentine/Isoniazid vs. Daily Isoniazid for the Treatment of Latent TB 12/08 11/10 11/11 15 50 1 Enrolling

A5260s III O ARV Initiation with TFV/Emtricitabine plus ATV/r, DRV/r, or RTG:A5257 Substudy 05/09 03/11 12/13 131 330 2 Enrolling

A5262 PILOT Trans RAL plus DRV/RTV in ARV-naive subjects 04/09 08/09 01/11 113 111 1 Cld to Accrual

A5263 III O Three Chemo Regimens as an Adjunct to ARV Therapy for Treatment of AIDS-KS 09/10 09/12 06/17 706 1 In Dev

A5264 III O ART Alone or w/Delayed Chemo vs ART w/Immediate Chemo for Limited AIDS-KS 09/10 09/12 06/17 468 1 In Dev

A5265 III O Gentian Violet Vs. Nystatin Oral Suspension for Tx of Oropharyngeal Candidiasis 06/10 06/11 08/11 454 2 In Dev

A5267 I Trans Safety, Tolerability & PK Interaction Study of TMC207 & Efavirenz 12/09 04/10 06/10 35 1 Open

A5269 II O Nitazoxanide plus Peginterferon Alfa-2a & Ribavirin in Hep C Naive Subjects 01/10 06/10 11/11 28 67 1 Enrolling

A5270 IV O Co-trimoxazole Discontinuation in Adults Receiving ART w/ CD4+ above 200/mm3 09/10 09/12 09/14 1,210 2 In Dev

A5271 N/A O Collection of Comparison Neurocognitive Data in Resource Limited Settings 06/10 06/11 06/12 2,400 2 In Dev

A5272 N/A O Oral HPV Shedding and Oral Warts After Initiation of ART 12/09 03/11 03/12 14 500 2 Enrolling






Actual or Projected

Closed to Accrual

Actual or Projected

Follow Up


Actual Accrual

as of 3/01/10

Target Accrual

Network Priority

Status as of

3/01/10

A5273 III O Study of Options for Second-Line Effective Combination Therapy (SELECT) 05/10 11/11 11/13 700 1 In Dev

A5274 IV O REMEMBER: Reducing Early Mortality & Morbidity by Empiric TB Treatment 01/11 01/13 12/13 I - 200

II - 836 1 In Dev

A5275 PILOT Trans Atorvastatin on Biomarkers of Inflammation, Coagulopathy, Angiogenesis & T-cells 05/10 01/11 01/12 84 1 In Dev

A5276s N/A Trans Residual Viremia Substudy of A5001 (ALLRT) 06/10 05/13 05/13 270 1 In Dev

A5277 I O Safety and Efficacy of the HCV Entry Inhibitor ITX 5061 in Mono-Infected Adults 06/10 12/11 07/12 40 1 In Dev

A5278s PILOT Trans Pharmacology Substudies of A5263 and A5264 06/10 06/12 07/12 105 1 Pending

A5279 III O Short-Course Rifapentine/Isoniazid for Prevention of Active TB in HIV-Infected 10/10 10/12 10/15 3,440 1 In Dev

A5280 IV O High Dose Vitamin D and Calcium for Bone Health in Individuals Initiating HAART 07/10 12/10 12/11 168 2 In Dev

A5281 I V Cytokine HIV-1 Multi-Antigen pDNA Vaccine IM or IM + In Vivo Electroporation 07/10 01/12 09/12 60 1 In Dev

A5282 N/A O HPV Test-and-Treat-Strategy vs. Cytological Screening for Prevention of CIN2+ 08/10 08/12 03/15 700 2 In Dev

A5283 N/A Trans Pharmacokinetic Interactions between DMPA and LPV/rit Among HIV-Infected Women 09/10 03/11 06/11 15 2 In Dev

A5284 N/A Trans Open-Label Study of GS-9350 and Rifampin in HIV-Uninfected Individuals TBD TBD TBD TBD 1 On Hold

A5285 N/A Trans Pharmacokinetics of the Cyclophilin Inhibitor Debio025 and ARV Medications TBD TBD TBD 32 1 On Hold

A5286 PILOT Trans Rifaximin as a Modulator of Microbial Translocation and Immune Activation 09/10 11/11 03/12 54 1 In Dev

A5287 PILOT O Debio025 + PEG- Interferon + Ribavirin for HCV + HIV infected Subjects TBD TBD TBD 36 1 On Hold







Actual or Projected

Closed to Accrual

Actual or Projected

Follow Up


Actual Accrual

as of 3/01/10

Target Accrual

Network Priority

Status as of

3/01/10

A5288 N/A O Evaluation of Antiretroviral Combinations and Contemporary Management Tools 01/11 01/13 01/14 500 1 In Dev

A5289 II O TMC-207 Added to TB Therapy vs TB Therapy Alone in the Tx of Drug Sensitive TB 03/11 09/12 05/13 372 1 In Dev

A5290 II O Rifampin-Based TB Treatment vs Rifabutin-Based TB Treatment in HCV Adults 03/11 08/12 08/13 420 1 In Dev

A5291 II Trans Evaluation of Lexgenleucel-T in Treatment Experienced Subjects with Multi-drug Resistance

01/11 01/12 01/16 30 2 In Dev

A5292 O Effect of HAART Vs. Statin Tx on Endothelial Function & Inflammation/Coagulation 01/11 07/13 01/14 215 2 In Dev

1077HS III MTCT

Promoting Maternal and Infant Survival Everywhere (PROMISE) HAART Standard Version of the PROMISE Study * Collaboration with IMPAACT - IMPAACT is primary network

10/09 10/13 10/15 2 500 1 Enrolling


Appendix C. Publications and Meeting Abstracts Executive Committee (AEC) Abstracts Ellis R, Smurzynski M, Wu K, Bosch R, Robertson K, Evans S, Collier A, Letendre S. Effects of CNS antiretroviral (ARV) distribution on neurocognitive (NC) impairment in the AIDS clinical trials group (ACTG) longitudinal linked randomized trials (ALLRT) study. 2009 American Neurological Association Annual Meeting, Baltimore, MD, 10/11/2009 - 10/14/2009. (A5001) Holubar M, Taylor L, Wu K, Bosch R, Mayer K, Tashima K. Hepatitis C virus (HCV) antibody seroconversion in a U.S. HIV-infected male clinical trials population. 60th American Association for the Study of Liver Diseases Annual Meeting, Boston, MA, 10/30/2009 - 11/03/2009. (A5001) Krishnan S, Schouten J, Mitsuyasu R. Incidence of non-AIDS defining cancer (NADC) in anti-retroviral treatment (ART) naive subjects after ART initiation: an ALLRT (ACTG Longitudinal Linked Randomized Trials) analysis. 47th Infectious Diseases Society of America Annual Meeting, Philadelphia, PA, 10/29/2009 - 11/01/2009. (A5001) Krishnan S, Wu K, Smurzynski M, Bosch R, Benson C, Collier A, Koletar S. Incidence rate (IR) and factors associated with loss-to-follow-up (LTFU) in a longitudinal study of HIV-infected subjects receiving antiretrovirals: an AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) analysis. Accepted, 2/11/2010. 14th International Workshop on HIV Observational Databases, Barcelona, Spain, 03/25/2010 - 03/27/2010. (A5001) Lok J, Bosch R, Benson C, Hughes M. Long-term CD4 responses to potent antiretroviral treatment (ART): an ALLRT (ACTG longitudinally linked randomized trial) database analysis. 13th International Workshop on HIV Observational Databases, Lisbon, Portugal, 03/26/2009 - 03/28/2009. (A5001) Manuscripts *Basham R, Richardson D, Sutcliffe C, Haas D. Effect of HIV-1 infection on human DNA yield from saliva. HIV Clin Trials Jul-Aug 2009; 10(4):282-5. PMCID: PMC2761620 (A5128, A5243) Brown T, Smurzynski M, Wu K, Bosch R, McComsey G. Statin therapy and changes in hip circumference among HIV-infected subjects in the ALLRT cohort. Antivir Ther 10/05/2009; 14(6): 853-8. (A5001) (PMCID number is pending.) Deeks S, Gange S, Kitahata M, Saag M, Justice A, Hogg R, Eron J, Brooks J, Rourke S, Gill M, Bosch R, Benson C, Collier A, Martin J, Klein M, Jacobson L, Rodriguez B, Sterling T, Kirk G, Napravnik S, Rachlis A, Calzavara L, Horberg M, Silverberg M, Gebo K, Kushel M, Goedert J, McKaig R, Moore R. Trends in multidrug treatment failure and subsequent mortality among antiretroviral therapy experienced patients with HIV infection in North America. Clin Infect Dis 11/15/2009; 49(10):1582-90. (A5001) (PMCID number is pending.) *Gupta S, Smurzynski M, Franceschini N, Bosch R, Szczech L, Kalayjian R. The effects of HIV type-1 viral suppression and non-viral factors on quantitative proteinuria in the highly active antiretroviral therapy era. Antivir Ther 2009; 14(4): 543-9. PMCID: PMC2720522 (A5001)



Appendix C. Publications and Meeting Abstracts Cont’d Kitahata M, Gange S, Abraham A, Merriman B, Saag M, Justice A, Hogg R, Deeks S, Eron J, Brooks J, Rourke S, Gill M, Bosch R, Martin J, Klein M, Jacobson L, Rodriguez B, Sterling T, Kirk G, Napravnik S, Rachlis A, Calzavara L, Horberg M, Silverberg M, Gebo K, Goedert J, Benson C, Collier A, Van Rompaey S, Crane H, McKaig R, Lau B, Freeman A, Moore R. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 04/30/2009; 360(18):1815-26. (A5001) (PMCID number is pending.) Linas B, Wang B, Smurzynski M, Losina E, Bosch R, Schackman B, Rong J, Sax P, Walensky R, Schouten J, Freedberg K. The impact of HIV/HCV co-infection on health care utilization and disability. Clin Infect Dis. Accepted, 03/01/2010. (A5001) Hepatitis (HEP) Committee Abstracts Butt AA, Umbleja T, Andersen J, Sherman K, Chung R. Incidence and predictors of anemia in HCV/HIV coinfected subjects treated with pegylated interferon (PEG) and ribavirin (RBV) in A5178 (SLAM-C). [Abstract Q-157]. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (A5178) Thio CL, Smeaton LM, Saulynas M, Hwang HS, Kumarasamy N, Flanigan TP, Hakim JG, Amod F, Campbell TB, Currier JS. Characterization of hepatitis B virus (HBV) and its association with HIV in an antiretroviral therapy (ART)-naïve, multi-national cohort from 2 randomized controlled trials (RCT) of the AIDS Clinical Trials Group (ACTG). [Abstract Q-130]. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (NWCS 260R2) Zamor P, Blackard J, Martin C, Sherman K. HCV Viral Evolution in HCV/HIV Coinfected Subjects After Initiation of HAART. 60th American Association for the Study of Liver Diseases Annual Meeting, Boston, MA, 10/30/2009 - 11/03/2009. (ACTG 384) Manuscripts Clifford D, Smurzynski M, Park L, Yeh T, Zhao Y, Blair L, Arens M, Evans S. Effects of active HCV replication on neurological status in HIV RNA virally suppressed patients. Neurology 07/28/2009; 73(4): 309-14. PMCID: PMC2715213 (NWCS 270R) Sherman KE, Rouster SD, Stanford S, Blackard JT, Shire N, Koziel M, Peters M, Chung RT. Hepatitis C virus (HCV) quasispecies complexity and selection in HCV/HIV-coinfected subjects treated with interferon-based regimens. J Infect Dis 01/27/2010. [Epub ahead of print] (A5071, A5091s) Shire N, Rao M, Succop P, Buncher C, Andersen J, Butt A, Chung R, Sherman K Improving noninvasive methods of assessing liver fibrosis in patients with hepatitis C virus/human immunodeficiency virus co-infection. Clin Gastroenterol Hepatol 04/01/2009; 7(4):471-80. (DACS 235, A5178) (PMCID number is pending.)



Appendix C. Publications and Meeting Abstracts Cont’d Optimization of Antiretroviral Therapy (OPART) Committee Abstracts Boltz V, Zheng Y, Lockman S, Hong F, Halvas E, McIntyre J, Schooley R, Hughes M, Coffin J, Mellors J. NNRTI-resistant variants detected by allele-specific PCR predict outcome of nevirapine (NVP)-containing antiretroviral therapy in women with prior exposure to single dose NVP: results from the OCTANE/A5208 study. [Abstract T-145]. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (A5208) Brehm J, Sheen C, Hughes M, Lalama C, Haubrich R, Riddler S, Sluis-Cremer N, Mellors J. Virologic failure of regimens containing 2 NRTI + efavirenz is not associated with the selection of mutations in the connection or RNase H domains of reverse transcriptase. XVIII International HIV Drug Resistance Workshop, Fort Myers, FL, 06/09/2009 - 06/13/2009. (A5142) Brown T, Tassiopoulos K, Shikuma C, McComsey G. Higher markers of TNF activity 48 weeks after ART-initiation are associated with incident diabetes mellitus in the ALLRT cohort: A nested case-control study. International Workshop on Adverse Drug Reactions & Comorbidities in HIV, Philadelphia, PA, 10/26/2009 - 10/28/2009. (ACTG 384, ACTG 388, A5001, A5095, A5142, NWCS 302) Daar E, Tierney C, Fischl M, Sax P, Mollan K, Budhathoki C, Godfrey C, Jahed N, Katzenstein D, Collier A. ACTG 5202: Efavirenz (EFV) or atazanavir/ritonavir (ATV/r) as part of initial three-drug regimens with abacavir/lamivudine (ABC/3TC) or tenofovir DF/emtricitabine (TDF/FTC). 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (A5202) Fischl M, Mollan K, Pahwa S, Pollard R, Aberg J, Myers L, Tierney C. Immune inflammatory reconstitution syndrome (IRIS) among U.S. subjects starting antiretroviral therapy (ART) in AIDS clinical trials group (ACTG) study A5202. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010. (A5202) Hogan C, DeGruttola V, Daar E, Sun X, del Rio C, Fiscus S, Frazier T, Hare C, Markowitz M, Little S. A finite course of antiretroviral therapy (ART) during early HIV-1 infection modestly delays need for subsequent ART initiation: ACTG A5217, the SETPOINT study. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (A5217) Hulgan T, Haubrich R, Riddler S, Tebas P, Ritchie M, McComsey G, Haas D, Canter J. Mitochondrial DNA haplogroups and metabolic changes during antiretroviral therapy (ART) in AIDS clinical trials group (ACTG) study A5142. International Workshop on Adverse Drug Reactions & Comorbidities in HIV, Philadelphia, PA, 10/26/2009 - 10/28/2009. (NWCS 280) Lockman S, Halvas E. Lopinavir/ritonavir (LPV/r)-compared to nevirapine (NVP)-based ART following receipt of single-dose nevirapine for prevention of mother-to-child HIV transmission (PTMCT) in South Africa: a cost-effectiveness analysis of the OCTANE (ACTG A5208) trial. 5th IAS Conference on HIV Pathogenesis, Treatment & Prevention, Cape Town, South Africa, 07/19/2009 - 07/22/2009. (A5208)



Appendix C. Publications and Meeting Abstracts Cont’d McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Tebas P, Myers L, Sax PE. Bone and limb fat outcomes of ACTG A5224s, a substudy of ACTG A5202: a prospective, randomized, partially blinded phase III trial of abacavir/lamivudine (ABC/3TC) or tenofovir DF/emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir/ritonavir (ATV/r) for initial treatment of HIV-1 infection. [Abstract O-1006]. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (A5224s) McComsey G, Walker U, Budhathoki C, Su Z, Currier J, Kosmiski L, Naini L, Charles S, Medvik K, Aberg J. Uridine supplementation in the management of HIV lipoatrophy: results of ACTG 5229. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (A5229) McIntyre J, Hughes M, Mellors J, Zheng Y, Hakim J, Asmelash A, Conradie F, Schooley R, Currier J, Lockman S. Efficacy of antiretroviral treatment (ART) with nevirapine (NVP)+tenofovir/emtricitabine (TDF/FTC) vs.lopinavir/ritonavir (LPV/r)+TDF/FTC among antiretroviral-naive women in Africa: OCTANE Trial 2 / ACTG A5208. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (A5208) Nielsen K, Komarow L, Cu-Uvin S, Jourdain G, Klingman K, Shapiro D, Mofenson L, Campbell T, Hitti J, Currier J. Assessment of safety and toxicity among infants born to HIV-1-infected women enrolled in antiretroviral treatment protocols in diverse areas of the world (ACTG 5190/ PACTG 1054) in the first six months of life. Accepted for presentation. 2010 Pediatric Academic Societies Annual Meeting, Vancouver, BC, Canada, 05/01/2010 - 05/04/2010. (A5190) Wilkin T, Goetz M, Leduc R, Skowron G, Su Z, Chan E, Heera J, Chapman D, Gulick R, Coakley E. Reanalysis of coreceptor tropism in HIV-1-infected adults using a phenotypic assay with enhanced sensitivity. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010. (ACTG 384, A5211, NWCS 261R) Manuscripts *Brumme Z, John M, Carlson J, Brumme C, Chan D, Brockman M, Swenson L, Tao I, Szeto S, Rosato P, Sela J, Kadie C, Frahm N, Brander C, Haas D, Riddler S, Haubrich R, Walker B, Harrigan P, Heckerman D, Mallal S. HLA-associated immune escape pathways in HIV-1 subtype B Gag, Pol and Nef proteins. PLoS One 08/19/2009; 4(8): e6687. PMCID: PMC2723923 (NWCS 243) Crawford KW, Li C, Keung A, Su Z, Hughes MD, Greaves W, Kuritzkes D, Gulick R, Flexner C. Pharmacokinetic/Pharmacodynamic modeling of the antiretroviral activity of the CCR5 antagonist vicriviroc in treatment experienced HIV-infected subjects (ACTG protocol 5211) . J Acquir Immune Defic Syndr 01/12/2010. [Epub ahead of print] (A5211) (PMCID number is pending.) *Delahunty T, Bushman L, Robbins B, Fletcher CV. The simultaneous assay of tenofovir and emtricitabine in plasma using LC/MS/MS and isotopically labeled internal standards. J Chromatogr B Analyt Technol Biomed Life Sci 07/01/2009; 877(20-21): 1907-14. PMCID: PMC2714254 [Available on 2010/7/1] (A5202)



Appendix C. Publications and Meeting Abstracts Cont’d Ferreira MA, Mangino M, Brumme CJ, Zhao ZZ, Medland SE, Wright MJ, Nyholt DR, Gordon S, Campbell M, McEvoy BP, Henders A, Evans DM, Lanchbury JS, Pereyra F, Walker BD, Haas DW, Soranzo N, Spector TD, de Bakker PI, Frazer IH, Montgomery GW, Martin NG. Quantitative trait loci for CD4:CD8 lymphocyte ratio are associated with risk of type 1 diabetes and HIV-1 immune control. Am J Hum Genet 01/01/2010; 86(1); 88-92. PMCID: PMC2801744 [Available on 2010/7/8] Flexner C, Tierney C, Gross R, Andrade A, Lalama C, Eshleman S, Aberg J, Sanne I, Parsons T, Kashuba A, Rosenkranz S, Kmack A, Ferguson E, Dehlinger M, Mildvan D. Comparison of once-daily versus twice-daily combination antiretroviral therapy in treatment-naive patients: results of AIDS clinical trials group (ACTG) A5073, a 48-week randomized controlled trial. J Infect Dis. Accepted, 01/05/2010. (A5073) Gross R, Tierney C, Andrade A, Lalama C, Rosenkranz S, Eshleman S, Flanigan T, Santana J, Salomon N, Reisler R, Wiggins I, Hogg E, Flexner C, Mildvan D. Modified directly observed antiretroviral therapy compared with self-administered therapy in treatment-naive HIV-1-infected patients: a randomized trial. Arch Intern Med 07/13/2009; 169(13):1224-32. PMCID: PMC2771688 (A5073) Gupta S, Komarow L, Gulick R, Pollard R, Robbins G, Franceschini N, Szczech L, Koletar S, Kalayjian R. Proteinuria, creatinine clearance, and immune activation in antiretroviral-naive HIV-infected subjects. J Infect Dis 08/15/2009; 200(4): 614-8. (DACS 236R, ACTG 384, A5001, A5095) (PMCID number is pending.) *Haubrich R, Riddler S, DiRienzo G, Komarow L, Powderly W, Klingman K, Garren K, George T, Rooney J, Brizz B, Bolivar H, Goldman M, Haas D, Mellors J, Havlir D. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment. AIDS 06/01/2009; 23(9):1109-18. PMCID: PMC2739977 (A5142) *Halvas E, Wiegand A, Boltz V, Kearney M, Nissley D, Wantman M, Hammer S, Palmer S, Vaida F, Coffin J, Mellors J. Low frequency nonnucleoside reverse-transcriptase Inhibitor-resistant variants contribute to failure of efavirenz-containing regimens in treatment-experienced patients. J Infect Dis 2010;201(5):672-80. [Epub ahead of print] PMCID: PMC2835354 [Available on 2011/3/1] (ACTG 398) *Hosoya N, Su Z, Wilkin T, Gulick R, Flexner C, Hughes M, Skolnik P, Giguel F, Greaves W, Coakley E, Kuritzkes D. Assessing human immunodeficiency virus type 1 tropism: comparison of assays using replication-competent virus versus plasma-derived pseudotyped virions. J Clin Microbiol 08/01/2009; 47(8):2604-6. PMCID: PMC2725648 (A5211) John M, Heckerman D, Park L, James I, Carlson J, Chopra A, Gaudieri S, Nolan D, Riddler SA, Haubrich R, Mallal S. Genome-wide HIV-1 adaptation to HLA-restricted immunity: Evidence of viral evolution towards neutral and actively harmful effects on host immunological control. Human Genetics. Accepted, 02/11/2010. (NWCS 243, A5128)



Appendix C. Publications and Meeting Abstracts Cont’d *Meier A, Chang J, Chan E, Pollard R, Sidhu H, Kulkarni S, Wen T, Lindsay R, Orellana L, Mildvan D, Bazner S, Streeck H, Alter G, Lifson J, Carrington M, Bosch R, Robbins G, Altfeld M. Sex differences in the Toll-like receptor–mediated response of plasmacytoid dendritic cells to HIV-1. Nat Med 08/15/2009; 15(8): 955-9. PMCID: PMC2821111 (ACTG 384) Paredes R, Lalama C, Ribaudo H, Schackman B, Shikuma C, Giguel F, Meyer W, Johnson V, Fiscus S, D'Aquila R, Gulick R, Kuritzkes D. Pre-existing minority drug-resistant HIV-1 variants, adherence and risk of antiretroviral treatment failure. J Infect Dis 01/26/2010. [Epub ahead of print] PMCID: PMC2825289 [Available on 2011/3/1] (A5095) Patterson K, Cohn S, Uyanik J, Hughes M, Smurzynski M, Eron J. Treatment responses in antiretroviral treatment-naive premenopausal and postmenopausal HIV-1-infected women: an analysis from AIDS clinical trials group studies. Clin Infect Dis 08/01/2009; 49(3):473-6. PMCID: PMC2712125 (DACS 238) *Price P, James I. IL1A alleles associate with a virological response to antiretroviral therapy in patients beginning therapy with advanced disease. AIDS 06/01/2009; 23(9): 1173-6. (NWCS 266) (PMCID number is pending.) Robertson K, Su Z, Margolis DM, Krambrink A, Havlir DV, Evans SR, Skiest DJ. Neurocognitive function before and after antiretroviral treatment discontinuation in patients with immunological preservation: neurological substudy of ACTG 5170. Neurology. Accepted, 02/02/2010. (A5170) *Sax P, Tierney C, Collier A, Fischl M, Mollan K, Peeples L, Godfrey C, Jahed N, Myers L, Katzenstein D, Farajallah A, Rooney J Ha B, Woodward W, Koletar S, Johnson V, Geiseler PJ, Daar E. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med 12/03/2009; 361(23): 2230-40. PMCID: PMC2800041 [Available on 2010/6/3] (A5202) *Schacker T, Bosch R, Bennett K, Pollard R, Robbins G, Collier A, Gulick R, Spritzler J, Mildvan D. Measurement of pretreatment peripheral blood naive CD4+ T cells more reliably predicts magnitude of immune reconstitution than measurement of total pretreatment CD4+ T cells. J Acquire Immune Defic Syndr. Accepted, 11/13/2009. (DACS 229R, ACTG 384, ACTG 388, A5001, A5014, A5095) Schouten JT, Krambrink A, Ribaudo HJ, Kmack A, Webb N, Shikuma C, Kuritzkes DR, Gulick R. Substitution of nevirapine because of efavirenz toxicity in AIDS clinical trials group A5095. Clin Infect Dis 01/01/2010. [Epub ahead of print] (A5095) *Su Z, Gulick R, Krambrink A, Coakley E, Hughes M, Han D, Flexner C, Wilkin T, Skolnik P, Greaves W, Kuritzkes D, Reeves J. Response to vicriviroc in treatment-experienced subjects, as determined by an enhanced-sensitivity coreceptor tropism assay: reanalysis of AIDS clinical trials group A5211. J Infect Dis 12/01/2009; 200(11): 1724-28. PMCID: PMC2783913 [Available on 2010/12/1] (A5211)



Appendix C. Publications and Meeting Abstracts Cont’d *Tsibris A, Korber B, Arnaout R, Russ C, Lo C, Leitner T, Gaschen B, Theiler J, Paredes R, Su Z, Hughes M, Gulick R, Greaves W, Coakley E, Flexner C, Nusbaum C, Kuritzkes D. Quantitative deep sequencing reveals dynamic HIV-1 escape and large population shifts during CCR5 antagonist therapy in vivo. PLoS One 05/25/2009; 4(5):e5683 1-12. PMCID: PMC2682648 (A5211) Tsibris A, Paredes R, Chadburn A, Su Z, Henrich T, Krambrink A, Hughes M, Aberg J, Currier J, Tashima K, Godfrey C, Greaves W, Flexner C, Skolnik P, Wilkin T, Gulick R, Kuritzkes D. Lymphoma diagnosis and plasma Epstein-Barr virus load during vicriviroc therapy: results of the AIDS clinical trials group A5211. Clin Infect Dis 03/01/2009; 48(5):642-9. PMCID: PMC2756462 (A5211) *Wilkin T, McKinnon J, DiRienzo G, Mollan K, Fletcher C, Margolis D, Bastow B, Thal G, Woodward W, Godfrey C, Wiegand A, Maldarelli F, Palmer S, Coffin J, Mellors J, Swindells S. Regimen simplification to atazanavir-ritonavir alone as maintenance antiretroviral therapy: final 48-week clinical and virologic outcomes. J Infect Dis 03/15/2009; 199(6):866-871. PMCID: PMC2680942 (A5201) *Wilkin T, Su Z, Krambrink A, Long J, Greaves W, Gross R, Hughes M. Three-year safety and efficacy of vicriviroc, a CCR5 antagonist, in HIV-1-infected, treatment-experienced patients. J Acquire Immune Defic Syndr. Accepted, 12/07/2009. (A5211) Yeh T, Evans S, Gulick R, Clifford D. Vicriviroc and peripheral neuropathy: results from AIDS clinical trials group 5211. HIV Clin Trials. Accepted, 02/10/2010. (A5211) Optimization of Co-Infection and Co-Morbidity Management (OPMAN) Committee Abstracts Cohn S, Williams P, Jiang H, McCutchan J, Koletar S, Murphy R, Robertson K, de St. Maurice A, Currier J. Ongoing substance use predicts non-adherence to antiretroviral therapy and higher risk of AIDS and death: results from ACTG 362. 4th International Conference on HIV Treatment Adherence, Miami, FL, 04/05/2009 - 04/07/2009. (ACTG 362) Ebenezer G, Evans S, Clifford D, Simpson D, Kitch D, McArthur J. Schwann cell densities in HIV-associated sensory neuropathy. 19th World Congress of Neurology, Bangkok, Thailand, 10/24/2009 - 10/30/2009. (A5117, DACS 254) Kallianpur A, Gerschenson M, Hulgan T, Clifford D, Haas D, Murdock D, McArthur J, Samuels D, Canter J, Simpson D. Hemochromatosis (HFE) gene variants and mitochondrial DNA copy number in chronically treated, HIV-infected persons. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (NWCS 273) Kang M, Cu-Uvin S. Association of HIV viral load and CD4 with HPV infection and clearance in HIV infected women initiating HAART. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (DACS 249)



Appendix C. Publications and Meeting Abstracts Cont’d Sanchez A, Komarow L, Andersen J, Zolopa A, Grant P, Asmuth D, Pollard R, Sattler F. Early antiretroviral therapy (E-ART) compared to deferred ART (D-ART) during acute opportunistic infection (OI) leads to a reduction in the systemic inflammatory response resulting in improved immunologic outcomes. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (A5164) Sax P, Sloan S, Schackman B, Grant P, Devaraj S, Zolopa A, Losina E, Freedberg K. A strategy of early antiretroviral therapy for patients with acute opportunistic infections: A cost-effectiveness analysis of ACTG 5164. 5th IAS Conference on HIV Pathogenesis, Treatment & Prevention, Cape Town, South Africa, 07/19/2009 - 07/22/2009. (A5164) Sax P, Komarow L, Finkelman M, Grant P, Andersen J, Zolopa A. (1,3)-beta-glucan is a promising non-invasive diagnostic test for HIV-related pneumocystis jirovecii pneumonia. 49th Interscience Conference on Antimicrobial Agents & Chemotherapy, San Francisco, CA, 09/12/2009 - 09/15/2009. (A5164, NWCS 299) Manuscripts Alonzo T, Nakas C, Yiannoutsos C, Bucher S. A comparison of tests for restricted orderings in the three-class case. Stat Med 03/30/2009; 28(7):1144-58. (ACTG 700) (PMCID number is pending.) *Andrews E, Seaman W, Webster-Cyriaque J. Oropharyngeal carcinoma in non-smokers and non-drinkers: A role for HPV. Oral Oncology 06/01/2009; 45(6):486-91. (PMCID number is pending.) Canter J, Robbins G, Selph D, Clifford D, Kallianpur A, Shafer R, Levy S, Murdock D, Ritchie M, Haas D, Hulgan T. African mitochondrial DNA subhaplogroups and peripheral neuropathy during antiretroviral therapy. J Infect Dis. Accepted, 12/14/2009. (NWCS 723, ACTG 384, A5117, A5128) Chow D, Chen H, Glesby M, Busti A, Souza S, Andersen J, Kohrs S, Wu J, Koletar S. Short-term ezetimibe is well tolerated and effective in combination with statin therapy to treat elevated LDL cholesterol in HIV-infected patients. AIDS 10/23/2009; 23(16): 2133-41. PMCID: PMC2782438 (A5209) *Clifford DB, Evans S, Yang Y, Acosta EP, Ribaudo H, Gulick RM. Long-term impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals (ACTG 5097s). HIV Clin Trials Nov-Dec 2009; 10(6):343-55. (A5097s) (PMCID number is pending.) Clifford D, Smurzynski M, Park L, Yeh T, Zhao Y, Blair L, Arens M, Evans S. Effects of active HCV replication on neurological status in HIV RNA virally suppressed patients. Neurology 07/28/2009; 73(4): 309-14. PMCID: PMC2715213 (NWCS 270R) Fife K, Wu J, Squires K, Watts H, Andersen J, Brown D. Prevalence and persistence of cervical human papillomavirus infection in HIV-positive women initiating highly active antiretroviral therapy. J Acquir Immune Defic Syndr 07/01/2009; 51(3):274-282. PMCID: PMC2742168 (A5029)



Appendix C. Publications and Meeting Abstracts Cont’d Haas D, Koletar S, Laughlin L, Kendall M, Suckow C, Gerber J, Zolopa A, Bertz R, Child M, Hosey L, Alston-Smith B, Acosta E. Hepatotoxicity and gastrointestinal intolerance when healthy volunteers taking rifampin add twice-daily atazanavir and ritonavir. J Acquir Immune Defic Syndr 03/01/2009; 50(3):290-293. PMCID: PMC2653210 (A5213) *Jacobson M, Dittmer D, Sinclair E, Martin J, Deeks S, Hunt P, Mocarski E, Shiboski C. Human herpesvirus replication and abnormal CD8+ T cell activation and low CD4+ T cell counts in antiretroviral-suppressed HIV-infected patients. PLoS One 04/17/2009; 4(4):1-6. PMCID: PMC2667217 (non-protocol related) *Marra C, Zhao Y, Clifford D, Letendre S, Evans S, Henry K, Ellis R, Rodriguez B, Coombs R, Schifitto G, McArthur J, Robertson K. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 07/17/2009; 23(11): 1359-66. PMCID: PMC2706549 (ACTG 736) Robertson K, Su Z, Margolis DM, Krambrink A, Havlir DV, Evans SR, Skiest DJ, Neurocognitive function before and after antiretroviral treatment discontinuation in patients with immunological preservation: Neurological Substudy of ACTG 5170. Neurology. Accepted, 02/02/2010. (A5170) Schifitto G, Yiannoutsos C, Ernst T, Navia B, Nath A, Sacktor N, Anderson C, Marra C, Clifford D. Selegiline and oxidative stress in HIV-associated cognitive impairment. Neurology 12/08/2009; 73(23):1975-81. PMCID: PMC2790227 [Available on 2010/12/8] (A5114s) *Shiboski C, Patton L, Webster-Cyriaque J, Greenspan D, Traboulsi R, Ghannoum M, Jurevic R, Phelan j, Reznik D, Greenspan J. The oral HIV/AIDS research alliance: updated case definitions for oral mucosal disease endpoints. J Oral Pathol Med 07/01/2009; 38(6):481-8. (non-protocol related) (PMCID number is pending.) Tebas P, Zhang J, Hafner R, Tashima K, Shevitz A, Yarasheski K, Berzins B, Owens S, Forand J, Evans S, Murphy R. Peripheral and visceral fat changes following a treatment switch to a non-thymidine analog or nucleoside-sparing regimen in HIV-subjects with peripheral lipoatrophy: results of ACTG A5110. J Antimicrob Chemother 05/01/2009; 63(5):998-1005. PMCID: PMC2721697 (A5110) Williams P, Wu J, Cohn S, Koletar S, McCutchan J, Murphy R, Currier J. Improvement in lipid profiles over 6 years of follow-up in adults with AIDS and immune reconstitution. HIV Med 05/01/2009; 10(5):290-301. PMCID: PMC2778216 [Available on 2010/5/1] (ACTG 362) Wohl D, Kendall M, Andersen J, Crumpacker C, Spector S, Feinberg J, Alston-Smith B, Owens S, Chafey S, Marco M, Maxwell-Henkel S, Lurain N, Jabs D, Benson C, Keiser P. Low rate of CMV end-organ disease in HIV-infected patients despite low CD4+ cell counts and CMV viremia: results of ACTG protocol A5030. HIV Clin Trials May-June 2009; 10(3): 143-152. PMCID: PMC2754189 (A5030)



Appendix C. Publications and Meeting Abstracts Cont’d Yeh T, Evans S, Gulick R, Clifford D. Vicriviroc and peripheral neuropathy: results from AIDS Clinical Trials Group 5211. HIV Clin Trials. Accepted, 02/10/2010. (A5211). Zhao Y, Navia B, Marra C, Singer E, Chang L, Berger J, Ellis R, Kolson D, Simpson D, Miller E, Lipton S, Evans S, Schifitto G. Memantine for AIDS dementia complex: open-label report of ACTG 301. HIV Clin Trials. Accepted, 2010. (ACTG 301) Zolopa A, Andersen J, Komarow L, Sanne I, Sanchez A, Hogg E, Suckow C, Powderly W. Early antiretroviral therapy reduces AIDS progression/death in HIV-infected individuals with acute opportunistic infections: a randomized phase IV strategy trial. PLoS One 05/18/2009; 4(5):e5575: 1-10. PMCID: PMC2680972 (A5164) Translational Research and Drug Development Committee (TRADD) Abstracts Andrade A, Rosenkranz S, Daar E, Jacobson J, Acosta E, Lederman M, Touw J, Campbell T, Mellors J, Kuritzkes D. Longer phase I viral decay in treatment-naive patients receiving raltegravir (RAL)-based antiretroviral therapy (ART): preliminary results from ACTG A5248. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (A5248) Bosch R, Aga E, Volberding P, Connick E. Correlates of CD4 and CD8 activation in primary HIV infection: baseline results from ACTG 371. HIV Acute Infection Meeting, Boston, MA, 09/22/2009 - 09/23/2009. (ACTG 371) Gandhi R, Zheng L, Bosch R, Chan E, Margolis D, Read S, Kallungal B, Sprenger H, Janik J, Jacobson J, Wiegand A, Kearney M, Palmer S, Coffin J, Mellors J, Eron J. Raltegravir (RAL) intensification does not reduce low-level residual viremia in HIV-1-infected patients on antiretroviral therapy (ART): results from ACTG A5244. 5th IAS Conference on HIV Pathogenesis, Treatment & Prevention, Cape Town, South Africa, 07/19/2009 - 07/22/2009. (A5244) Li J, Brumme C, Brumme Z, Wang H, Spritzler J, Robertson M, Lederman M, Walker B, Schooley R, Kuritzkes D. Factors associated with viral rebound in HIV-positive subjects receiving a therapeutic HIV-1 gag vaccine. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (A5197) White E, Balamane M, Henry W, Katzenstein D. Prediction of X4-tropic human immunodeficiency virus from proviral envelope sequence in patients with suppressed viral load on antiretroviral therapy (ART). 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (A5102) Wilkin T, Goetz M, Leduc R, Skowron G, Su Z, Chan E, Heera J, Chapman D, Gulick R, Coakley E. Reanalysis of coreceptor tropism in HIV-1-infected adults using a phenotypic assay with enhanced sensitivity. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (ACTG 384, A5211, NWCS 261R)



Appendix C. Publications and Meeting Abstracts Cont’d *Wilkin T, Lalama C, Tenorio A, Landay A, Ribaudo H, McKinnon J, Gandhi R, Mellors J, Currier J, Gulick R. Maraviroc (MVC) intensification for suboptimal CD4+ cell response despite sustained virologic suppression: ACTG5256. 17th Conference on Retroviruses & Opportunistic Infections, San Francisco, CA, 02/16/2010 - 02/19/2010. (A5256) Manuscripts Asmuth D, Murphy R, Rosenkranz S, Lertora J, Kottilil S, Cramer Y, Chan E, Schooley R, Rinaldo C, Thielman N, Li X, Wahl S, Shore J, Janik J, Lempicki R, Simpson Y, Pollard R. Safety, tolerability and mechanisms of antiretroviral activity of peginterferon alfa-2a in HIV-1-mono-infected subjects: A phase II clinical trial. J Infect Dis. Accepted, 12/15/2009. (NWCS 283R, A5192) *Crawford K, Spritzler J, Kalayjian R, Parsons T, Landay A, Pollard R, Stocker V, Lederman M, Flexner C. Age-related changes in pharmacokinetic parameters of the HIV protease inhibitor lopinavir. AIDS Res Human Retrovir. Accepted, 12/28/2009. (A5015) *Eron J, Park J, Haubrich R, Aweeka F, Bastow B, Pakes G, Yu S, Wu H, Richman D. Predictive value of pharmacokinetics-adjusted phenotypic susceptibility on response to ritonavir-enhanced protease inhibitors (PIs) in human immunodeficiency virus-infected subjects failing prior PI therapy. Antimicrob Agents Chemother 06/23/2009; 53(6):2335-41. PMCID: PMC2687257 (A5126) Gandhi R, Bosch R, Aga E, Albrecht M, Demeter L, Dykes C, Bastow B, Para M, Lai J, Siliciano R, Siliciano J, Eron J. No evidence for decay of the latent reservoir in HIV-1-infected patients receiving intensive enfuvirtide-containing antiretroviral therapy. J Infect Dis 01/15/2010; 201(2):293-6. (A5173) (PMCID number is pending.) Gandhi R, O'Neill D, Bosch R, Chan E, Bucy R, Shopis J, Baglyos L, Adams E, Fox L, Purdue L, Marshak A, Flynn T, Masih R, Schock B, Mildvan D, Schlesinger S, Marovich M, Bhardwaj N, Jacobson JM. A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV alone in HIV-1-infected patients on antiretroviral therapy. Vaccine 10/09/2009; 27(43):6088-94. PMCID: PMC2820102 (A5130) Hulgan T, Donahue J, Smeaton L, Pu M, Wang H, Lederman M, Smith K, Valdez H, Pilcher C, Haas D. Oral cyclosporin A inhibits CD4 T cell P-glycoprotein activity in HIV-infected adults initiating treatment with nucleoside reverse transcriptase inhibitors. Eur J Clin Pharmacol 11/01/2009; 65(11): 1081-8. (A5138) (PMCID number is pending.) *Jiang W, Lederman M, Hunt P, Sieg S, Haley K, Rodriguez B, Landay A, Martin J, Sinclair E, Asher A, Deeks S, Douek D, Brenchley J. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis 04/15/2009; 199(8):1177-1185. PMCID: PMC2728622 (A5014) Jordan P, Poon A, Eron J, Squires K, Ignacio C, Richman D, Smith D. A novel codon insert in protease of Clade B HIV type 1. AIDS Res Hum Retroviruses 05/01/2009; 25(5): 547-30. PMCID: PMC2749665 (A5126)




Appendix C. Publications and Meeting Abstracts Cont’d *Kalayjian R, Machekano R, Rizk N, Robbins G, Gandhi R, Rodriguez B, Pollard R, Lederman M, Landay A. Pre-treatment levels of soluble cellular receptors and Interleukin-6 are associated with HIV disease progression in HAART-treated subjects. J Infect Dis. Accepted, 12/18/2009. (NWCS 287, A5015) Para M, Schouten J, Rosenkranz S, Yu S, Weiner D, Tebas P, White C, Reeds D, Lertora J, Patterson K, Daar E, Cavert W, Brizz B. Phase I/II trial of the anti-HIV activity of mifepristone in HIV-infected subjects. ACTG 5200. J Acquire Immune Defic Syndr. 02/03/2010. [Epub ahead of print] (A5200) (PMCID number is pending.) *Sereti I, Dunham R, Spritzler J, Aga E, Proschan M, Medvik K, Battaglia C, Landay A, Pahwa S, Fischl M, Asmuth D, Tenorio A, Altman J, Fox L, Moir S, Malaspina A, Morre M, Buffet R, Silvestri G, Lederman M. IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection. Blood 06/18/2009; 113(25): 6304-14. PMCID: PMC2710926 (A5214) *Skowron G, Spritzler J, Weidler J, Robbins G, Johnson V, Chan E, Asmuth D, Gandhi R, Lie Y, Bates M, Pollard R. Replication capacity in relation to immunologic and virologic outcomes in HIV-1-infected treatment-naive subjects. J Acquir Immune Defic Syndr 03/01/2009; 50(3):250-8. (NWCS 261R) (PMCID number is pending.) *Smith K, Zheng L, Bosch R, Margolis D, Tenorio A, Napolitano L, Saag M, Connick E, Lawrence J, Gross B, Francis I, Valdez H, Wang R, Muurahainen N, Stocker V, Pollard R. Treatment with recombinant growth hormone is associated with enhanced CD4 lymphocyte reconstitution in HIV-infected subjects with incomplete immune reconstitution on HAART - results of adult AIDS clinical trial group protocol (AACTG) 5174. AIDS Res Hum Retroviruses. Accepted, 11/23/2009. (A5174, A5198s) *Stapleton J, Chaloner K, Zhang J, Klinzman D, Souza I, Xiang J, Landay A, Fahey J, Pollard R, Mitsuyasu R. GBV-C viremia is associated with reduced CD4 expansion in HIV-infected people receiving HAART and interleukin-2 therapy. AIDS 03/13/2009; 23(5):605-610. PMCID: PMC2739595 (NWCS 223, ACTG 328, A5046s) Tenorio A, Spritzler J, Martinson J, Gichinga C, Pollard R, Lederman M, Kalayjian R, Landay A. The effect of aging on T-regulatory cell frequency in HIV infection. Clin Immunol 03/01/2009; 130(3):298-303. PMCID: PMC2662473 (NWCS 263R) Twigg H, Schnizlein Bick C, Weiden M, Valentine F, Wheat L, Day R, Rominger-Grubbs H, Zheng L, Collman R, Coombs R, Bucy R, Rezk N, Kashuba A. Measurement of antiretroviral drugs into the lungs of HIV-infected patients. J HIV Ther. Accepted, 01/26/2010. (NWCS 211) Volberding P, Demeter L, Bosch R, Aga E, Pettinelli C, Hirsch M, Vogler M, Martinez A, Little S, Connick E. Antiretroviral therapy in acute and recent HIV infection: a prospective, multicenter stratified trial of intentionally interrupted treatment. AIDS 09/24/2009; 23(15): 1987-95. (ACTG 371) (PMCID number is pending.) *ACTG Network Laboratory contributed to this study.

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