hepatitis c virus infection among hematopoietic cell transplant
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Biol Blood Marrow Transplant xxx (2015) 1e13
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Biology of Blood andMarrow Transplantationjournal homepage: www.bbmt.org
Hepatitis C Virus Infection among Hematopoietic CellTransplant Donors and Recipients: American Society for Bloodand Marrow Transplantation Task Force Recommendations
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Harrys A. Torres 1,*, Pearlie P. Chong 2, Marcos De Lima 3, Mark S. Friedman 4,Sergio Giralt 5, Sarah P. Hammond 6, Patrick J. Kiel 7, Henry Masur 8, George B. McDonald 9,John R. Wingard 10, Maya Gambarin-Gelwan 5
1 The University of Texas MD Anderson Cancer Center, Houston, Texas2University of North Carolina at Chapel Hill, Chapel Hill, North Carolina3University Hospitals Case Medical Center and University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, Ohio4Moffitt Cancer Center, Tampa, Florida5Memorial Sloan-Kettering Cancer Center, New York, New York6Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts7 Indiana University Simon Cancer Center, Indianapolis, Indiana8National Institutes of Health Clinical Center, Bethesda, Maryland9University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington10University of Florida, Gainesville, Florida
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Article history:95
Received 28 July 2015Accepted 31 July 2015Financial disclosure: See Acknowl* Correspondence and reprint re
of Texas MD Anderson Cancer CenE-mail address: htorres@mdand
http://dx.doi.org/10.1016/j.bbmt.201083-8791/� 2015 American Socie
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INTRODUCTION preliminary guidance while awaiting the completion of 100101
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In recent years, management of hepatitis C virus (HCV)infection has changed dramatically because of the approvalof new antiviral therapies. The purpose of the American So-ciety for Blood and Marrow Transplantation (ASBMT) TaskForce on HCV infection in hematopoietic cell transplant(HCT) recipients is to provide guidance regarding diagnosisand management of HCV infection in donors and recipientsof hematopoietic cells.
Limited data are available on treating HCV infection inHCT recipients. A group of experts in infectious diseases,hepatology, and HCT worked together to compile thisdocument with 2 goals: to summarize the currently availabledata in the field and to provide evidence-based and expertopinion recommendations regarding early identification andtreatment of HCV-infected donors and recipients to mini-mize barriers to HCT and improve care and outcomes in thispopulation. In preparing this report, the committee recog-nizes that in the absence of data in donors and recipientsof hematopoietic cells, clinicians would benefit from
edgments on page 12.quests: Harrys A. Torres, The Universityter, Houston, TX.erson.org (H.A. Torres).
15.07.033ty for Blood and Marrow Transplantation.
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appropriate studies.The recommendations herein are based on synthesis of
limited evidence, theoretical rationales, practical consider-ations, and author opinion. When appropriate, the level ofthe evidence and the strength of the recommendation havebeen rated by applying the system used for the Hepatitis CGuidance of the American Association for the Study of LiverDisease (AASLD) and Infectious Disease Society of American(IDSA) (http://hcvguidelines.org) (Table 1) [1]. However, forsome individual recommendations, the level of the sup-porting evidence and strength of the recommendation couldnot be rated.
For this report, HCT is defined as transplant of any blood-or marrow-derived hematopoietic progenitor cells,regardless of whether the transplant is allogeneic orautologous and regardless of the cell source (ie, bonemarrow, peripheral blood, or umbilical cord blood). Therecommendations in this document are based on data fromthe following sources: research published in the peer-reviewed literature or presented at major national and in-ternational scientific conferences, safety warnings from theUS Food and Drug Administration (FDA) or other regulatoryagencies or from manufacturers, drug interaction data, andprescribing information for FDA-approved products. Liter-ature searches were conducted using medical subject
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Table 1Grading System used to Rate the Level of the Evidence and Strength of the Recommendation for Each Recommendation
Classification Description
Class I Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure, or treatment isbeneficial, useful, and effective
Class II Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness and efficacy of a diagnosticevaluation, procedure, or treatment
Class IIa Weight of evidence and/or opinion is in favor of usefulness and efficacyClass IIb Usefulness and efficacy are less well established by evidence and/or opinionClass III Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure, or treatment is not useful
and effective or if it in some cases may be harmfulLevel of Evidence Description
Level A* Data derived from multiple randomized clinical trials, meta-analyses, or equivalentLevel B* Data derived from a single randomized trial, nonrandomized studies, or equivalentLevel C Consensus opinion of experts, case studies, or standard of care
Recommendations are based on scientific evidence and expert opinion. Each recommended statement includes a Roman numeral (I, II, or III) that represents thelevel of the evidence that supports the recommendation and a letter (A, B, or C) that represents the strength of the recommendation.
* In some situations, such as for IFN-sparing HCV treatments, randomized clinical trials with an existing standard-of-care arm cannot ethically or practicablybe conducted. The FDA has suggested alternative study designs, including historical control subject or immediate versus deferred, placebo-controlled trials. Foradditional examples and definitions see the FDA link (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM225333.pdf). In those instances for which there was a single predetermined, FDA-approved equivalency established, panel members considered the evi-dence as equivalent to a randomized controlled trial for levels A or B. Adapted from the American College of Cardiology and the American Heart AssociationPractice Guidelines. (American Heart Association, 2011); (Shiffman, 2003Q1 )
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H.A. Torres et al. / Biol Blood Marrow Transplant xxx (2015) 1e132
headings and free text terms combined to maximizeretrieval of relevant citations from the PubMed, Scopus,EMBASE, and Web of Science databases; search termsincluded “HCV and Bone Marrow Cell Transplantation” and“HCV and Hematopoietic Stem Cell Transplantation.” Onlyarticles published in English from 1990 to the present wereconsidered for inclusion. The ASBMT plans to review theserecommendations and update them to include advances inthe published evidence.
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EXECUTIVE SUMMARYFor more than a decade the mainstay of treatment for
HCV infection was a combination regimen of pegylated IFNand ribavirin, but this regimen was associated with a poorrate of sustained virologic response (SVR) and poor tolera-bility, especially in cancer patients and HCT recipients [2,3].Furthermore, almost 30% of infected HCT recipients could notbe treated with pegylated IFN and ribavirin because of con-traindications to the treatment combination [3]. The man-agement of HCV infection in the general population hasrecently changed as a result of FDA approval of several direct-acting antiviral agents (DAAs), which have rendered IFN-containing regimens obsolete for almost all HCV genotypes.
This report, developed by the ASBMT, is specificallydevoted to diagnosis and management of HCV infection indonors and HCT candidates and recipients. There are fewdata that answer important clinical questions for suchdonors or recipients. The online document from the AASLD-IDSA, “Recommendations for Testing, Managing, and Treat-ing Hepatitis C” (http://www.hcvguidelines.org), which isupdated regularly throughout the year, was used as aresource in the development of this report but had no spe-cific recommendations for these populations. Thus, thisdocument was developed to provide expert opinion for cli-nicians who must make management decisions whileawaiting adequately powered trials dealing with donors andHCT recipients.
Evidence is summarized, and, where possible, recom-mendations are provided. This report replaces the 2009
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ASBMT-IDSA guideline [4]. Several topics are new orexpanded from that document (Table 2).
NATURAL HISTORY OF HCV INFECTION IN HCTRECIPIENTS: GEORGE B. MCDONALD AND MARCOSDE LIMARecommendations
� In all HCT survivors with active HCV infection, cofactorsthat can lead to fibrosis should be addressed. Patientsshould be counseled to avoid excessive weight gain,ethanol and medications or herbal supplements thatare hepatotoxic, treatment of other causes of liver dis-ease (nonalcoholic fatty liver disease, hepatitis B virus,HIV, and extrahepatic obstruction) (class I, level C), andmobilization of excess iron (class II, level C).
� All HCV-infected long-term HCT survivors should beevaluated for progression of liver disease every 6 to12 months with a hepatic function panel, completeblood cell count, and evaluation of prothrombin time/international normalized ratio (class I, level C). Iffibrosis is suspected in long-term HCT survivors,noninvasive tests such as serologic panels and transientelastography can be used to evaluate for the presence ofadvanced fibrosis (Scoring System for Histological StageMetavir score � F3) and cirrhosis (Metavir score F4).
� HCV-infected HCT recipients should be vaccinatedagainst hepatitis A virus and hepatitis B virus followingHCT immunization protocols [4].
� Donors and HCT candidates with HCV infection shouldbe counseled to use appropriate precautions to preventtransmission of HCV to others (class I, level C).
� For HCV-infected HCT long-term survivors withadvanced fibrosis (Metavir score � F3), surveillance forhepatocellular carcinoma (HCC) with ultrasonographyevery 6 months is recommended (class I, level C). Forpatients with cirrhosis, endoscopic surveillance foresophageal varices is recommended (class I, level A).
� HCT recipients who develop end-stage liver disease canbe considered for liver transplant; in rare cases, a living
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Table 2Summary of Changes Compared with the Guidelines Published in 2009 [4]
Major Change Starting Page
Updated background on natural history of HCV infection in HCT recipients 7New recommendations regarding HCV screening:1. Screening of all hematopoietic cell donors within 30 days before cell harvest with FDA-approved HCV antibody and RNA testing in
accordance with the FACT standards and FDA guidance (class I, level C)11
2. Screening of all long-term survivors of HCT, especially those with epidemiologic risk factors including those transplanted in theera before routine donor and blood product screening (class I, level C)
Updated background on impact of HCV infection on eligibility to donate hematopoietic cells or undergo HCT 14 (Table 3)New section regarding monitoring HCV in chronically infected HCT recipients:1. ALT level should be evaluated at entry into care, 2 to 8 weeks after completion of the conditioning regimen, every 2 to 8 weeks
during maintenance chemotherapy or immunosuppressive treatment, and every 3 to 6 months thereafter (class II, level C)17
2. In HCT recipients with chronic HCV infection, routine monitoring of HCV RNA is not recommended. However, viral load should beconsidered for patients who have an unexplained elevation of ALT (class II, level C). HCV RNA should be measured in all patientsat entry into care, andmonitoring of viral load should be performed in patients receiving HCV treatment according to the AASLD-IDSA HCV guidance (http://www.hcvguidelines.org/) (class I, level C).
New section regarding fibrosis assessment in HCV-infected HCT candidates and recipients using serologic markers and ultrasound-based VCTE
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New recommendations regarding antiviral therapy for donors and HCT candidates and recipients:1. Timing of antiviral therapy 242. Treatment interruption is not recommended (class I, level C) 243. IFN-based regimens should be avoided because of their suboptimal efficacy and safety (class I, level B) 254. DAA combinations of potential use in HCV-infected HCT recipients extrapolated from studies in other patient populations 28
New section and table on drugedrug interactions in HCV-infected HCT candidates and recipients receiving DAAs and conditioningregimens or immunosuppressive agents
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donor liver transplant from the original hematopoieticcell donor may be feasible (class I, level C).
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Evidence SummaryCourse of HCV infection to 1 year after HCT
HCV infection has hepatic and extrahepatic manifesta-tions. Hepatic manifestations in HCT recipients in addition tothose seen in immunologically normal hosts include (1) anincreased risk of fatal sinusoidal obstruction syndrome(previously known as veno-occlusive disease) among pa-tients with chronic HCV infection who receive sinusoidalendothelial cell toxins (eg, cyclophosphamide, etoposide,melphalan, thiotepa, total body irradiation�12 Gy) as part ofthe conditioning therapy [5]; (2) hepatic inflammationoccurring 3 to 6 months after HCT, coincident with immunereconstitution and discontinuation of immunosuppressivedrugs [5]; (3) liver decompensation among patients who hadcirrhosis at the time of transplant [6,7]; and (4) rarely, fatalfibrosing cholestatic hepatitis C before day 100 in patientsreceiving mycophenolate mofetil [8]. Fibrosing cholestatichepatitis is an aggressive form of viral hepatitis caused byeither hepatitis B virus or HCV that causes rapid clinicaldeterioration, characterized histologically by extensivefibroblastic portal-to-portal bridging, ductular proliferation,cholestasis, high intrahepatocyte viral load, and inflamma-tion [8].
Extrahepatic manifestations of HCV infection after HCThave been suggested by epidemiologic studies and includegreater 1- to 2-year nonrelapse-related mortality than inHCV-negative control subjects, including an excess of deathsrelated to bacterial infections [6,7]. It is not clear if the highermortality is due to HCV per se, the presence of undetectedhepatic fibrosis and portal hypertension, or chronic viralcoinfections (such as hepatitis B virus infection or HIVinfection) at the time of transplant.
Course of HCV infection between 1 and 10 years after HCTCoincident with immune reconstitution after HCT, serum
alanine aminotransferase (ALT) levels wax and wane in mostHCV-infected patients. The course of this chronic hepatitis is
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usually uncomplicated for 10 years after HCT, but, rarely,patients may progress to cirrhosis. Serum aminotransferaseelevations can be seen in 57% of HCV-infected patients be-tween 5 and 10 years after HCT [5]. In several series no excessmortality was noted in HCV-infected patients up to 10 yearsafter HCT [5,9,10]. In some patients, however, the duration ofHCV infection before HCT can only be estimated, and theextent of fibrosis is unknown at the time of HCT; such pa-tients may experience progressive liver disease that onlybecomes apparent after HCT [6,7].
Course of HCV infection 10 to 40 years after HCTChronic HCV is the leading cause of cirrhosis after HCT,
and the time to cirrhosis is shorter in patients with chronicHCV infection who undergo HCT than in patients withchronic HCV infection who do not undergo HCT [11,12].About one third of HCV-infected 40-year survivors of HCTdevelop end-stage liver disease (cirrhosis, HCC, or diseaserequiring liver transplant). HCT recipients who develop end-stage liver disease can be considered for liver transplant;living donor liver transplant from the original hematopoieticcell donor has been described [13,14].
Knowledge Gaps
� What is the natural history of HCV in HCT in the era ofcurrent immunosuppressive regimens?
� What are the predictors of liver disease progression inHCT recipients?
� Do effective antiviral drugs alter the course of HCV-related fibrosing cholestatic hepatitis, hepatic fibrosis,and cirrhosis in HCV-infected survivors of HCT?
HCV SCREENING IN DONORS OF HEMATOPOIETIC STEMCELLS, HCT CANDIDATES, AND LONG-TERM SURVIVORS:SARAH P. HAMMOND AND JOHN R. WINGARDRecommendations
� All hematopoietic cell donors should be screened forHCV within 30 days before cell harvest with FDA-approved HCV antibody (anti-HCV) and RNA testing in
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accordance with the Foundation for the Accreditationof Cellular Therapies (FACT) standards and FDA guid-ance (class I, level C).
� All HCT candidates should be screened for HCV withFDA-approved anti-HCV testing (class I, level C).
� All long-term survivors of HCT should be screened forHCV infection based on the current recommendationsfor screening in non-HCT recipients, with specialattention to those with epidemiologic risk factors,including those transplanted in the era before routinedonor and blood product screening (class I, level C).
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Evidence SummaryIn the general US population, risk-based screening for
HCV infection with anti-HCV testing (with reflex HCV RNAtesting for individuals with positive results) is recommendedby the Centers for Disease Control and Prevention [15], USPreventive Services Task Force [16], and AASLD, IDSA, andInternational Antiviral SocietyeUSA [1]. Individuals consid-ered at high risk include not only intravenous drug users butalso individuals born between 1945 and 1965 [15].
Transmission of HCV from HCV-infected bone marrowdonors to uninfected recipients was first documented in theearly 1990s [17]. FACT has issued standards for US centersperforming HCT that include HCV screening of allogeneicdonors within 30 days before stem cell harvest using testsrequired by applicable laws and regulations [18]. The FDA hasissued guidelines recommending that such donors bescreened with FDA-licensed antibody and nucleic acid tests[19]. A positive test result for anti-HCV (using third-generation tests) in the setting of undetectable serum HCVRNA indicates past infection (resolved spontaneously ortherapeutically), acute HCV infection during a period of low-level viremia, or a false-positive test result [1,20].
False-positive anti-HCV tests are more common withearlier generation testing, especially if confirmation with therecombinant immunoblot assay was not included in themethod. In such a case the HCV-treating providers shouldretest the donor for anti-HCV and HCV RNA to exclude thepresence of active infection and seek guidance from an in-fectious disease or hepatology expert.
The presence of serum HCV RNA indicates current andactive infection. If the viremia persists for more than6 months postexposure, the infection is considered chronicand is not likely to resolve spontaneously.
FACT and FDA guidance on HCT donor screening does notextend to HCT candidates and recipients. Overall, HCVscreening in HCT candidates establishes a pretransplantbaseline and identifies patients who might benefit from HCVtreatment after transplant. There is usually insufficient timeto complete a course of HCV therapy before HCT. ChronicHCV can be associated with false-negative anti-HCV testresults in immunosuppressed patients [20], including HCTrecipients [21]. Such patients have a positive serum HCV PCRtest.
In a prospective study in allogeneic HCT recipients from15 European transplant centers, data on pretransplant HCVRNA were available for 182 patients, and 11 were found tohave viremia, including 6 anti-HCVenegative patients [21].In HCT candidates and recipients, screening with HCV RNAtesting in addition to anti-HCV serologic testing is advocatedby many experts (class IIb, level C). In 1 study, 13% of HCV-infected patients with a positive anti-HCV test result beforeHCT had a negative anti-HCV test result after HCT [22].
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Knowledge Gap
� How frequently are HCT candidates or HCV recipientsseronegative for HCV with third-generation testsdespite serum nucleic acid evidence of active infection?
� What is the most cost-effective algorithm for screeningHCT candidates and recipients?
IMPACT OF HCV INFECTION ON ELIGIBILITY TO DONATEHEMATOPOIETIC STEM CELLS OR UNDERGO HCT:HARRYS A. TORRES AND JOHN R. WINGARDRecommendations
� HCV infection in donors or potential HCT recipientsshould not be an absolute contraindication for HCT(class I, level C) (Table 3).
� The risk of HCV transmission is extremely low whenseronegative and HCV RNAenegative HCT candidatesreceive HCT from donors of hematopoietic stem cellswith positive anti-HCV and undetectable HCV RNA(class I, level C).
� HCV-infected donors should be assessed for advancedchronic liver disease and other extrahepatic manifes-tations of HCV to recommend an optimal managementof their disease (class I, level C).
� HCV-infected donors should be screened for othercoinfections (eg, HIV). HIV-HCVecoinfected individualsshould not be considered as donors for HIV-seronegative recipients, according to standard HCTguidelines [4].
� HCV-infected HCT candidates requiring HCT and forwhom there is no alternative donor can proceed withHCT from a donor also infected with HCV provided therecipient has full understanding of the potential con-sequences given the viral characteristics of the donors’HCV infections (class IIa, level C).
� If the donor is HCV RNA positive and transplantation toan HCV-infected or -uninfected recipient is considered,the donor should start antiviral therapy immediatelywith the goal of reducing the infectious potential of thedonor, ideally attaining undetectable plasma HCV RNAin the donor before stem cell harvest (class I, level C).
� Selection of HCV-infected candidates for HCT should bebased on the extent of liver fibrosis and degree of portalhypertension (class I, level C).
Evidence SummaryDonors with positive HCV screening test results
As recommended for the general population [1], donors(or HCT recipients) found to have positive results for anti-HCV and negative results for HCV RNA by PCR using anFDA-approved sensitive HCV RNA test should be informedthey do not have evidence of current (active) HCV infection.Repeat HCV RNA testing at a later date (eg, 1 to 2 months) istypically unnecessary but can be performed when there isstrong suspicion of acute infection or in patients withongoing risk factors for HCV infection [1].
Up to 100% of infected donors transmit HCV to uninfectedHCT recipients [17]. If no alternative donor is available and iftime does not permit treatment of the infected donor toeliminate HCV from the infusion product, the use of HCV-infected hematopoietic cells for an HCV-uninfected recip-ient is not contraindicated. New DAAs could potentiallyprovide a virologic cure after HCT in most patients and may
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Table 3Eligibility to Donate Hematopoietic Stem Cells or Undergo HCT according to Different Clinical Scenarios
ClinicalScenario
DonorAnti-HCV
DonorHCV RNA
HCT Candidate/Recipient Anti-HCV
HCT Candidate/RecipientHCV RNA
Recommendation for Donor Recommendation for HCT Candidate/Recipient
1 Negative Negative Negative Negative Proceed with stem cell harvest. Proceed with HCT.2 Negative Positive Negative Negative Proceed with stem cell harvest. When possible, start antivirals
and proceed with cell harvest once HCV PCR is undetectable.*Proceed with HCT. Monitor HCV RNA managing acute infectionper HCV guidance.y
3 Negative Positive Positive Negative Proceed with stem cell harvest. When possible, start antiviralsand proceed with cell harvest once HCV PCR is undetectable.*
Proceed with HCT. Monitor HCV RNA managing acute infectionper HCV guidance.y
4 Negative Positive Positive Positive Proceed with stem cell harvest.z Proceed with HCT.z Start antiviral therapy, when possible.x
5 Negative Positive Negative Positive Proceed with stem cell harvest.z Proceed with HCT.z Start antiviral therapy, when possible.x
6 Negative Negative Positive Negative Proceed with stem cell harvest. Proceed with HCT.jj
7 Negative Negative Positive Positive Proceed with stem cell harvest. Proceed with HCT. Start antivirals, when possible.x
8 Negative Negative Negative Positive Proceed with stem cell harvest. Proceed with HCT. Start antivirals, when possible.x
9 Positive Negative Negative Negative Proceed with stem cell harvest.jj Proceed with HCT.10 Positive Positive Negative Negative Proceed with stem cell harvest. When possible, start antivirals
and proceed with cell harvest once HCV PCR is undetectable.*Proceed with HCT. Monitor HCV RNA managing acute infectionper HCV guidance.y
11 Positive Positive Positive Negative Proceed with stem cell harvest. When possible, start antiviralsand proceed with cell harvest once HCV PCR is undetectable.*,jj
Proceed with HCT.y Monitor HCV RNA managing acute infectionper HCV guidance.y
12 Positive Positive Negative Positive Proceed with stem cell harvest.cManage infection per HCVguidance.
Proceed with HCT.z Start antivirals, when possible.x
13 Positive Positive Positive Positive Proceed with stem cell harvest.z Manage infection perHCV guidance.
Proceed with HCT.z Start antivirals, when possible.x
14 Positive Negative Positive Positive Proceed with stem cell harvest.jj Proceed with HCT. Start antivirals, when possible.x
15 Positive Negative Negative Positive Proceed with stem cell harvest.jj Proceed with HCT. Start antivirals, when possible.z,x
16 Positive Negative Positive Negative Proceed with stem cell harvest.jj Proceed with HCT.jj
* When possible, start antiviral therapy immediately, attaining viral clearance before stem cell harvest to reduce the risk of HCV transmission. If HCT must be done urgently, stem cell harvest from a viremic donor should beconsidered.
y Per HCV guidance, monitor HCV RNA (eg, every 4 to 8weeks) for 6 to 12months after the time of infection to determine spontaneous viral clearance versus active HCV. Detectable HCV RNA at 6months after onset of infectionwill identify most persons who need HCV therapy (http://hcvguidelines.org/full-report/management-acute-hcv-infection).
z HCV-infected HCT candidates requiring HCT and for whom there is no alternative donor can proceed with HCT from a donor also infected with HCV (see text for details).x HCV-infected HCT candidates should be started on therapy and should complete HCV therapy before transplant, when possible.jj HCT donors and candidates with positive anti-HCV in the setting of undetectable HCV RNA should have repeat HCV RNA testing when there is strong suspicion of acute infection or in patients with ongoing risk factors for HCV
infection (see text for details).
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halt liver disease progression in HCT survivors. The risk ofdying from the underlying hematologic malignancy withoutthe transplant outweighs the risk of acquiring potentiallycurable HCV. However, the donor should be assessed foradvanced chronic liver disease per current HCV guidance [1]as well as extrahepatic manifestations of HCV (eg, lympho-proliferative diseases) and coinfections (eg, HIV) that mightcontraindicate donation (class I, level C) [4].
The risk of transmission of HCV was decreased to nearly0 if HCV RNA was undetectable at the time of hematopoieticcell donation [17]. In viremic donors, viral clearance withDAAs before cell harvest may be attempted if feasible toreduce the risk of HCV transmission, because most donorswill attain undetectable HCV PCR within 4 weeks of startingcurrently available DAAs [4,23,24]. The timing of HCV ther-apy is further discussed below (see When to Treat HCVInfection in Donors and Autologous or Allogeneic HCT Can-didates and Recipients).
HCT candidates with positive HCV screening test resultsSimilar to what is recommended for donors, HCT candi-
dates with positive test results for anti-HCV in the setting ofundetectable HCV RNA should be evaluated to exclude acuteinfection by repeating HCV RNA. HCV-infected HCT candi-dates requiring HCT and for whom there is no alternativedonor can proceed with HCT from a donor also infected withHCV, provided the recipient has full understanding of thepotential consequences (class IIa, level C) [5]. The potentialconsequences include infections with different genotypes(eg, genotype 3) or resistance-associated variants (such asNS5A variants) potentially associated with a higher rate ofvirologic failure. Treatment recommendations in HCT can-didates are further discussed below (see When to Treat HCVInfection in Donors and Autologous or Allogeneic HCT Can-didates and Recipients). All individuals (donors and re-cipients) with HCV infection should be referred to apractitioner able to provide comprehensive management ofHCV [1].
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Knowledge Gaps
� Studies are needed to determine the magnitude of riskfor HCV transmission when HCV-infected donors haveachieved undetectable HCV RNA but have notcompleted their recommended treatment course.
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MONITORING HCV IN HCT RECIPIENTS WITH CHRONICHCV INFECTION: HARRYS A. TORRES AND MARCOS DELIMARecommendations
� In HCT recipients with chronic HCV infection, ALT levelshould be evaluated at entry into care, 2 to 8 weeksafter completion of the conditioning regimen, every 2to 8 weeks during maintenance chemotherapy orimmunosuppressive treatment, and every 3 to6 months thereafter (class II, level C).
� In HCT recipients with chronic HCV infection, routinemonitoring of HCV RNA is not recommended. However,viral load should be considered for patients who havean unexplained elevation of ALT (class II, level C). HCVRNA should be measured in all patients at entry intocare, and monitoring of viral load should be performedin patients receiving HCV treatment according to the
REV 5.4.0 DTD � YBBMT53933_proof � 24 Aug
AASLD-IDSA HCV guidance (http://www.hcvguidelines.org/) (class I, level C).
Evidence SummaryAcute exacerbation of chronic HCV infection, indicated by
a significant elevation of serum aminotransferase levels overthe baseline level in the absence of other potential causes ofacute hepatitis, can occur in both immunocompetent [25]and immunocompromised cancer patients [26]. However,there are no standard definitions for this phenomenon. In aretrospective study of 308 patients with cancer and chronicHCV infection, 11% were identified as having acute exacer-bation of chronic HCV infection, defined as a 3-fold or greaterincrease in serum ALT level from baseline in the absence of(1) infiltration of the liver by cancer, (2) use of hepatotoxicmedications, (3) blood transfusion within 1 month ofelevation of ALT level, or (4) other systemic infectionsaffecting the liver (including hepatitis A virus, hepatitis Bvirus, cytomegalovirus, adenovirus, herpes simplex virus,varicella-zoster virus, and HIV infections) [26]. In that study,acute exacerbation (significant ALT elevation) of HCV infec-tion during chemotherapy prompted clinicians to discon-tinue chemotherapy in nearly half of affected patients [26].
Enhanced HCV replication (also known as HCV reac-tivation [26]) has been defined as an increase in HCV RNAviral load of at least 1 log10 IU/mL over baseline afterchemotherapy or immunosuppressive therapy [26] becausechronically infected patients have stable HCV RNA levels thatmay vary by approximately .5 log10 IU/mL [27]. The increasedreplication of HCV appears to be associated with a moreindolent course than hepatitis B virus reactivation [28]; onlya few reports of deaths have been associated with increasedHCV replication [8,29]. Regrettably, the published data onsimultaneous changes in ALT levels and HCV viral load arelimited and not sufficient for examination of whether acorrelation exists between enhanced viral replication andhepatocellular injury [26], as has been described for patientswith chemotherapy-induced hepatitis B virus reactivation.
Little is known about acute exacerbation of HCV infectionin HCT recipients, with emerging data after autologous andallogeneic HCT recently presented [22,30]. However, suchstudies should be considered preliminary becausemost wereretrospective analyses of small numbers of patients. In 1prospective study, aspartate aminotransferase (AST) levelswere compared between HCV-infected and HCV-negativeHCT recipients [5]. A severe acute flare of hepatitis(AST >10 times the upper limit of normal) developed in 11 of36 HCV-infected patients (31%) who survived at least 1 yearafter HCT but only 6 of 115 HCV-negative patients (5%)(P < .0001). Data on HCV RNA were not presented; thus, itwas not possible to determine whether the increase in ASTlevel in patients receiving chemotherapy resulted fromcoinfections, drugs, or enhanced HCV replication in thesetting of immunosuppression.
Patients with significant ALT elevations (eg, �3-fold in-crease from the upper limit of normal) should be carefullyevaluated for signs and symptoms of liver insufficiency andfor alternative causes of liver injury. HCV-treating physiciansshould participate in the diagnostic workup of acute exac-erbation of HCV to exclude other potential explanations forALT increase (eg, infiltration of the liver by cancer, hepato-toxic medications, blood transfusion within 1 month, thehepatitic presentation of liver graft-versus-host disease[GVHD], or other systemic infections affecting the liver).
ust 2015 � 2:01 pm � ce PT
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Knowledge Gaps
� Prospective studies are needed to determine the inci-dence, clinical implications, and outcome of acuteexacerbation of chronic HCV infection in HCTrecipients.
� What is the best strategy for monitoring HCV infectionaround the time of HCT?
FIBROSIS ASSESSMENT IN HCV-INFECTED HCTCANDIDATES AND RECIPIENTS: MAYA GAMBARIN-GELWAN AND MARK S. FRIEDMANRecommendations
� All HCV-infected HCT candidates should undergoassessment of the stage of liver fibrosis and the pres-ence of cirrhosis (class I, level C).
� The presence of cirrhosis may affect duration and typeof HCV therapy and will identify patients who need tobe screened for HCC and the presence of esophagealvarices (class I, level C).
� The decision to perform a liver biopsy should be madeonly after careful consideration of the risks and benefitsof the procedure (class I, level B).
� Serologic marker panels for detection of fibrosis havenot been studied in HCV-infected HCT candidates, andtheir use is not recommended (class IIb, level C).
� Ultrasound-based vibration-controlled transient elas-tography (FibroScan VCTE; Echosens) has not beenstudied in HCT recipients, and thus results should beinterpreted with caution (class II, level C).
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Evidence SummaryAll HCV-infected HCT candidates should undergo assess-
ment of the stage of liver fibrosis and the presence ofcirrhosis (class I, level C). The presence of advanced fibrosis(Metavir � F3) or cirrhosis (Metavir F4) may have a signifi-cant impact on HCT eligibility, the choice of conditioningregimen, HCV therapy, and risk of HCC.
Liver biopsyLiver biopsy has been the criterion standard for histo-
pathologic assessment of fibrosis in patients with chronicHCV infection, particularly when the stage of fibrosis andpresence or absence of cirrhosis may guide subsequentmanagement. However, liver biopsy is an imperfect criterionstandard because it is associated with sampling limitationsand error, is invasive, and carries a risk of complications.Individuals with hematologic malignancies requiring HCTmay be at particular risk for complications [31] and oftenrequire a transjugular approach because of severe throm-bocytopenia [32]. The decision to perform a liver biopsyshould be made only after careful consideration of the risksand benefits of the procedure (class I, level B) [33].
Serologic marker panels for detection of fibrosisTests for serologic markers of fibrosis have becomewidely
available in the past several years and are used extensively inpatients with chronic HCV infection. The AST-to-plateletsratio and FIB-4 are easy to calculate using data available onroutine laboratory testing. Four commercial serum markerpanels have been validated in the general population of pa-tients with chronic HCV infection: FibroTest/FibroSure(LabCorp), Hepascore (Quest Diagnostics), FibroSpect
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(Prometheus Corp), and the European Liver Fibrosis StudyGroup panel (not available in the United States). No panel hasyet emerged as standard of care or is FDA approved; how-ever, all 4 panels have demonstrated accuracy in dis-tinguishing patients with significant fibrosis (Metavir scoreF2 to F4) from those without significant fibrosis (Metavirscore F0 or F1) [34]. Because individual markers in thesepanels include aminotransferases, platelets, coagulation pa-rameters, g-glutamyl transferase, total bilirubin, hapto-globin, gamma globulins, and so on, the results might beunreliable in HCT candidates and recipients because ofcytopenias, ongoing systemic inflammation, drug-relatedliver damage, and infection. These panels have not beenstudied in candidates for HCT or in HCT recipients, and theiruse is not recommended in either population.
Vibration-controlled transient elastographyUltrasound-based elastography in the form of FibroScan
VCTE was approved by the FDA in April 2013. This procedurehas been endorsed by the AASLD “to be used by cliniciansproviding care for patients with liver disease to evaluate liverfibrosis at the point of care” [35]. VCTE is quick, is done at thetime of the clinic visit, is noninvasive, has good reproduc-ibility, is relatively inexpensive, and provides informationabout a large area of the liver. VCTE has been extensivelystudied in patients with chronic HCV infection. In a recent USmulticenter study, VCTE demonstrated a positive predictivevalue of 75.6% to 80.8% and a negative predictive value of55.0% to 84.7% for diagnosis of significant fibrosis (F � 2) andan estimated positive predictive value of 41.6% to 60.4% andnegative predictive value of 95.6% to 97.6% for diagnosis ofcirrhosis [36]. VCTE would plausibly be useful for assessmentof advanced fibrosis, particularly to rule out cirrhosis in HCTcandidates and recipients, although these patient pop-ulations have not been extensively studied [37,38].
Knowledge Gaps
� Reliability of serologic markers of fibrosis and FibroScanVCTE in predicting the presence of advanced fibrosisand cirrhosis in HCT candidates and recipients.
� Effect of leukemic infiltration of hepatic sinusoids,lymphoma of the liver, or extramedullary hematopoi-esis with sinusoidal fibrosis on the accuracy of VCTE.
� Role of VCTE as a predictor of hepatotoxicity in HCTrecipients.
WHEN TO TREAT HCV INFECTION IN DONORS ANDAUTOLOGOUS OR ALLOGENEIC HCT CANDIDATES ANDHCT SURVIVORS: MAYA GAMBARIN-GELWAN, SERGIOGIRALT, AND GEORGE B. MCDONALDRecommendations
� HCV-infected donors should be evaluated for HCVtherapy and treated before cell harvest to preventtransmission of HCV to uninfected recipients, if possible(class I, level C).
� All HCT candidates with HCV infection should be eval-uated for HCV therapy before the start of conditioningtherapy; after transplant, HCV-infected survivorsshould also be evaluated for therapy (class I, level B).
� When possible, HCV-infected HCT candidates should bestarted on therapy and should complete therapy forHCV before transplant (class IIa, level C).
24 August 2015 � 2:01 pm � ce PT
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H.A. Torres et al. / Biol Blood Marrow Transplant xxx (2015) 1e138
� After HCT, the following patients should be treated forHCVwithout delay: HCV-infected patients who developfibrosing cholestatic hepatitis C, patients with cirrhosiswhose condition is deteriorating, and patients whounderwent HCT for HCV-related lymphoproliferativedisorders (class I, level C).
� After HCT, treatment for HCV can be deferred until afterimmune reconstitution for patients not meeting thecriteria above (class I, level C).
� All HCV-infected long-term survivors of HCT should beoffered antiviral therapy (class I, level C).
� HCV therapy should be undertaken only with theintention of completion of the full course of therapy asdefined in the AASLD-IDSA Hepatitis C Guidance(http://www.hcvguidelines.org/). Treatment interrup-tion is not recommended (class I, level C).
� IFN-based regimens should be avoided in donors andHCT candidates/recipients with HCV infection becauseof their suboptimal efficacy and safety (class I, level B).
� HCV therapy should be undertaken by providersexperienced in management of HCV in HCT recipientsin close collaboration with transplant teams (class I,level B).
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Evidence SummaryTreatment of HCV-infected donors before HCT
Several case reports have described successful preventionof HCV transmission through treatment of HCV-infecteddonors before cell harvest [5,24,39,40]. When there areoncologic imperatives for moving quickly to transplant, DAAsshould be able to clear extrahepatic HCV from donors morequickly than IFN and ribavirin can without significant toxiceffects on the donor marrow. Once initiated, a full course ofantiviral therapy should be completed in donors based onthe current treatment recommendations for individuals withHCV infection [1].
The risk of HCV transmission at various time points dur-ing HCV therapy has not been studied. Plausibly the risk oftransmission should be sharply reduced if serum HCV RNAlevels are below the level of detection for the assay.
Treatment of HCV-infected candidates before HCT andrecipients after HCT
Data are lacking regarding treatment of HCV-infected HCTcandidates. DAA therapy before HCT should be considered.
Prompt treatment of HCV infection after transplant isurgent for 3 groups: patients with fibrosing cholestatic HCV[8], patients with cirrhosis whose condition is deteriorating[41], and patients who underwent HCT for HCV-relatedlymphoproliferative disorders [22,42]. It is not known,however, whether the efficacy of DAA therapy is affected bydysfunctional immunity after therapy for cancer. It is also notknown whether eliminating HCV before HCT improves theoutcome of transplant by, for example, reducing the risks ofpost-HCT fatal sinusoidal obstruction syndrome, liverdecompensation, fibrosing cholestatic hepatitis, or recurrentlymphoma [43,44]. Once HCV therapy is started in either HCTcandidates or recipients, treatment interruption is not rec-ommended, because it is associated with increased risk oftreatment failure [2].
The alternative to pre-HCT therapy for HCV is to treatafter HCT using DAAs after immune reconstitution [22].Although published data are limited on outcomes of DAAtherapy in HCT recipients, SVR rates of 70% to 96% have been
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observed in patients who received DAAs during immuno-suppressive therapy after liver transplant [43,44].
A preliminary observational study suggested that IFN-sparing regimens were well tolerated and effective in 10HCT recipients and have potential to improve patient out-comes [22]. Combination DAA therapy appears to be safe andeffective in HCV-infected allogeneic and autologous HCT re-cipients after a follow-up period of 6 months after transplant[22]. Some experts advocate waiting for 6 months after thetransplant to allow tapering of immunosuppression agentsand GVHD prophylaxis, which might result in higher SVRrates and reduction of drugedrug interactions.
Flare of GVHD that occurs after tapering immunosup-pressive therapy could be confused for HCV exacerbationand/or medication toxicity in those receiving antivirals.Some clinicians may still choose to defer DAA therapy untilimmunosuppressive treatment has been discontinued toavoid drugedrug interactions.
IFN-based regimens should be avoided in donors and HCTcandidates with HCV infection because of their suboptimalefficacy and safety (class I, level B). Data are not availableregarding the impact of treatment regimens consisting ofribavirin plus DAA in HCV-infected HCT recipients.
Treatment of HCV-infected long-term HCT survivorsAbout one third of HCV-infected long-term HCT survivors
develop end-stage liver disease or HCC [11,12]. Thus, all HCV-infected long-term HCT survivors should be offered DAAtherapy. The rationale for universal treatment of infectedsurvivors is that it can prevent transmission of HCV, delay thedevelopment of cirrhosis, and reduce long-term conse-quences of chronic HCV infection, including development ofHCC, extrahepatic manifestations of HCV, and possible needfor liver transplantation.
Knowledge Gaps
� Should all HCV-infected donors and HCT candidates betreated with antivirals before HCT?
� What is the optimal timing of antiviral therapy for HCTcandidates?
� How effective and safe are DAAs given to HCT candi-dates or recipients?
� What is the effect of virologic cure of HCV on the risk ofsinusoidal obstruction syndrome and other liver-related complications of HCT in HCV-infectedindividuals?
� Does antiviral therapy prevent post-HCT liver diseaseprogression and relapse of HCV-associated non-Hodg-kin lymphoma?
� Does recovery of a full immunologic repertoire afterHCT affect the efficacy of antiviral treatment?
ROLE OF DAA COMBINATIONS IN HCV-INFECTED HCTRECIPIENTS: PEARLIE P. CHONG, MARK S. FRIEDMAN,AND HENRY MASURRecommendationsRecommendations by HCV genotype as of July 2015
� For infection with genotype 1a, 1b, or 4 HCV, treatmentwith 1 of the following 3 DAA combinations isrecommended:
ugus
BDaily fixed-dose combination of ledipasvir andsofosbuvir.
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H.A. Torres et al. / Biol Blood Marrow Transplant xxx (2015) 1e13 9
BTwice-daily fixed-dose combination of ombitasvir,paritaprevir, ritonavir, and dasabuvir with or withoutribavirin.
BDaily sofosbuvir plus simeprevir.
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The choice of regimen should be individualized on thebasis of patient-specific data, including potential druginteractions.
� For infection with genotypes 2, 3, or 5 HCV, thepreferred regimen is sofosbuvir plus weight-basedribavirin.
� Monotherapy with a DAA is not recommended for anypatient with HCV infection (class III, level A).
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Treatment considerations in specific patient populations
� HCT recipients often receive multiple drugs that couldhave pharmacologic interactions with DAAs or toxiceffects that overlap with those of DAAs. Treating phy-sicians should be mindful of potential drug interactionsand/or side effects, although this has not been exten-sively studied in HCT recipients.
� In patients with mild (creatinine clearance 60 to89 mL/min) to moderate (creatinine clearance 30 to59 mL/min) renal impairment, no dosage adjustment isrequired for sofosbuvir plus simeprevir, ledipasvir plussofosbuvir, or ombitasvir, paritaprevir, ritonavir, anddasabuvir (class I, level A). The total daily dose ofribavirin should be reduced for patients with creatinineclearance �50 mL/min [45].
� In patients with severe renal impairment (creatinineclearance 15 to 29 mL/min) or with end-stage renaldisease, safety and efficacy data for DAAs are notavailable; treatment can be contemplated afterconsultationwith an expert (class IIb, level C) or as newdata in this patient population become available. Ifribavirin used, dose should be reduced [45].
� Patients coinfected with HIV and HCV should be treatedlike HCV-monoinfected patients, except that in-teractions with antiretroviral medications must berecognized and managed (class I, level B).
Evidence SummaryDAAs are oral agents that target various HCV-encoded
proteins vital to the replication of the virus. When used incombination, DAAs are capable of curing HCV infection;DAAs have demonstrated excellent rates of SVR and favorablesafety profiles in multiple phase III clinical trials [46-51].
Unfortunately, the efficacy and safety of DAAs in HCV-infected HCT recipients have not been extensively studiedor documented. The recommendations above are extrapo-lated from studies in other patient populations. The optimaltherapy for HCV is evolving rapidly and will continue toevolve as multiple new drugs are approved and as morestudies are reported. The recommendations above should becompared with the online AASLD-IDSA Hepatitis C Guidancefor the management of HCV infection, which are updatedfrequently as new data emerge (http://www.hcvguidelines.org/news/hcv-guidance).
The choice of DAA regimen and duration of DAA treat-ment for HCV-infected HCT recipients should be informed by
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prior treatment experience, HCV genotype, and the degree offibrosis. The combination of sofosbuvir and daclatasvir isapproved by the FDA for use in the United States in patientswith genotype 3 HCV infection [52].
Knowledge Gaps
� Efficacy and safety of various DAA regimens in HCTrecipients.
� Optimal duration of DAA regimens in HCT recipients.
DRUGeDRUG INTERACTIONS IN HCV-INFECTED HCTCANDIDATES AND RECIPIENTS RECEIVING DAAS ANDCONDITIONING REGIMENS OR IMMUNOSUPPRESSIVEAGENTS: PATRICK J. KIELRecommendations
� Physicians should frequently assess for drugedruginteractions in HCV-infected HCT recipients (class I,level C).
� HCT candidates should not receive DAAs concomitantlywith the chemotherapy preparative regimen if thepotential for drugedrug interactions exists (class I,level C).
� In patients receiving tacrolimus concomitantly withparitaprevir and ritonavir, increased therapeutic drugmonitoring and a 50% to 75% decrease in the tacrolimusdose may be required (class IIb, level B).
� In patients receiving cyclosporine concomitantly withparitaprevir and ritonavir, increased therapeutic drugmonitoring and a 35% to 50% decrease in the cyclo-sporine dose may be required (class IIb, level B).Sofosbuvir should not be administered concomitantlywith cyclosporine.
� In patients receiving sirolimus concomitantly withparitaprevir and ritonavir, increased therapeutic drugmonitoring and a decrease of up to 90% in the sirolimusdose may be required (class IIb, level C).
Evidence SummaryThe introduction of novel antiviral agents in the treat-
ment of HCV has not eliminated the risk of drug interactions.Physicians should frequently assess for drugedrug in-teractions in HCV-infected HCT recipients. Many interactionsmay not be adequately documented but rather may have tobe inferred on the basis of the isoenzymes responsible fordrug metabolism. Current databases (eg, http://www.hep-druginteractions.org) should be consulted along with theproduct prescribing information to ensure the safety ofconcomitantly prescribed medications such as acid reducers,antidepressants, antihypertensives, phosphodiesterase in-hibitors, novel oral anticoagulants, macrolide antibiotics,triazoles, and HMG CoA inhibitors [1]. However, these da-tabases lack documentation of potential interactions be-tween DAAs, commonly prescribed immunosuppressiveagents, and chemotherapy. The pharmacology of DAAs andpotential drugedrug interactions between DAAs andchemotherapy or immunosuppressive agents used in pa-tients undergoing HCT are summarized in Table 4 [53-58].
Drugedrug interactions can be pharmacokinetic, result-ing in changes in drug concentrations, or pharmacodynamic,resulting in additive, synergistic, or antagonistic effects onefficacy or toxicity. Metabolism by CYP450 enzyme, specif-ically the CYP3A4 isoform, is the major metabolic pathway of
24 August 2015 � 2:01 pm � ce PT
Table 4DAA Pharmacology and Potential Interactions with Drugs Used in HCT
Antiviral Agent* Metabolism/Elimination Metabolism Effects Transporter Substrate Transporter Effects Drugs with Which DAA Does or May Interact
Protease inhibitorsBoceprevir CYP3A4, aldoreductase Inhibits CYP3A4 P-gp Potentially inhibits P-gp Increase azoles, CSA, tacrolimus, sirolimus,
etoposide, Cy levelsParitaprevir (ABT-450)
with ritonaviryCYP3A4, CYP3A5 Inhibits CYP3A4,
UGT1A1ABCG2, OATP1B1/3, P-gp Inhibits ABCG2, OATPB1/3 Increase azoles, CSA, tacrolimus, sirolimus,
etoposide, Cy levelsSimeprevir CYP3A4 Inhibits CYP1A2,
intestinal CYP3A4OATP1B1/3, P-gp Inhibits OATP1B1/3, P-gp Increase azoles, CSA, tacrolimus, sirolimus,
etoposide, Cy levelsTelaprevir CYP3A4 Inhibits CYP3A4 OATP1B1, OATP2B1, P-gp Inhibits OATP1B1, OATP2B1, P-gp Increase azoles, CSA, tacrolimus, sirolimus,
etoposide, Cy levelsRitonaviry CYP3A4, CYP2D6 Inhibits CYP3A4 P-gp Inhibits ABCG2 Increase azoles, CSA, tacrolimus, sirolimus,
etoposide, Cy levelsNS5A inhibitorDaclatasvir CYP3A4 No data P-gp Inhibitor of ABCG2, OATP1B1, P-gp Increase CSA, tacrolimus levelsz
Ledipasvir Oxidized by unknown mechanisms N/A ABCG2, P-gp inhibits ABCG2, P-gp Increase CSA, tacrolimus levelsOmbitasvir (ABT-267) Amide hydrolysis, then oxidation Inhibits UGT1A1 ABCG2, P-gp substrate only Unknown
Nonnucleos(t)ide polymeraseinhibitor
Dasabuvir (ABT-333) CYP2C8 (primary), CYP3A4, CYP2D6 Inhibits UGT1A1 ABCG2, P-gp Inhibit ABCG2 CYP2D6 inhibitors increase dasabuvirNucleos(t)ide polymerase
inhibitorSofosbuvir Extensive hepatic metabolismx to
active moiety GS-461203, then mostis renally eliminated
N/A ABCG2, P-gp Substrate only Unknown
Nucleoside analogRibavirin Unknown metabolism, 60% renal
eliminationN/A N/A N/A Increase myelotoxicity with azathioprine
P-gp indicates P-glycoprotein; OATP1B1/3, organic anion-transporting polypeptides 1B1 and 1B3; OATP2B1, organic anion-transporting polypeptides 2B1; ABCG2, ATP-binding cassette subfamily Gmember 2; CSA, cyclosporineA; Cy, cyclophosphamide; N/A, not applicable.
* Boceprevir and telaprevir are no longer available in the United States but are still in use in other countries. Ombitasvir, paritaprevir, ritonavir, and dasabuvir are copackaged under the brand name Viekira Pak. Ledipasvir andsofosbuvir are copackaged under the brand name Harvoni.
y Ritonavir is used to boost plasma concentrations of paritaprevir.z Based on the results of drug interaction trials, no clinically relevant changes in exposure were observed for cyclosporine or tacrolimus with concomitant use of daclatasvir [52].x Metabolic pathway involves hydrolysis of carboxyl ester moiety catalyzed by human cathepsin A or carboxylesterase 1 and phosphoramidate cleavage by histidine triad nucleotide-binding protein 1 followed by phos-
phorylation by the pyrimidine nucleotide biosynthesis pathway.
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H.A.Torres
etal./
BiolBlood
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H.A. Torres et al. / Biol Blood Marrow Transplant xxx (2015) 1e13 11
approved HCV therapies, including DAAs. Membrane trans-porters are also implicated in clinically relevant drugedruginteractions and may include P-glycoprotein, organic aniontransporting polypeptides, and the ATP-binding cassettesubfamily G member 2. Membrane transporters and the CYPisoenzymes can be induced or inhibited.
The pharmacologic targets of the novel DAAs include NS3/NS4A protease inhibitors, NS5A inhibitors, and NS5B poly-merase inhibitors. The protease inhibitors (paritaprevir,simeprevir, telaprevir, and boceprevir) prevent the NS3 viralprotease from cleaving the enzymes responsible for viralreplication. All 5 agents undergo CYP3A4metabolism and areaffected by inducers (ie, phenytoin, rifampin, carbamazepine,and phenobarbital) and inhibitors (ie, posaconazole andvoriconazole) [18,54-58].
The protease inhibitors may also increase serum con-centrations of chemotherapy or immunosuppressive agentscommonly used for HCT that are substrates of CYP3A4,including cyclophosphamide, etoposide, tacrolimus, cyclo-sporine, and sirolimus. Paritaprevir is administeredconcomitantly with ritonavir, a potent CYP3A4 inhibitor, as a“boosting” agent and will also interfere with other CYP3A4and CYP2D6 metabolized medications. Thiotepa is an in-hibitor of CYP2B6 and has no interactions with DAAs.
The NS5A inhibitors (daclatasvir, ledipasvir, and ombi-tasvir) inhibit NS5A viral RNA replication and virion assem-bly. Daclatasvir is metabolized via CYP3A4, whereasledipasvir and ombitasvir undergo oxidative metabolism[52,55,58]. Ledipasvir is an inhibitor and a substrate of in-testinal P-glycoprotein; inducers of P-glycoprotein (ie, St.John’s wort, rifabutin, phenobarbital) that are coadminis-tered may lead to reduced plasma concentrations and ther-apeutic effects of ledipasvir [58].
The polymerase inhibitor sofosbuvir is renally eliminated,whereas dasabuvir is metabolized via CYP2C8 (majorpathway), 3A4, and 2D6 [55]. Sofosbuvir is a substrate ofintestinal P-glycoprotein, and inducers of P-glycoprotein (ie,St. John’s wort, rifabutin, phenobarbital) that are coad-ministered may lead to reduced plasma concentrations andtherapeutic effects of sofosbuvir [58].
Immunosuppression with cyclosporine, tacrolimus, andsirolimus is common after HCT. Cyclosporine has beenobserved to increase sofosbuvir area under the curve (AUC)by 353% [59]. Simeprevir can increase cyclosporine andtacrolimus AUC by 19% and 17%, respectively [60]. Telaprevirincreases the dose-normalized exposure AUC0-N values ofcyclosporine and tacrolimus approximately 4-fold and 70-fold, respectively [61]. The mean half-life of cyclosporinewas increased from 12 hours to 42.1 hours, and the meanhalf-life of tacrolimus was increased from 40.7 hours to195 hours. Boceprevir increases the AUC0-N values of cyclo-sporine and tacrolimus approximately 3-fold and 17-fold,respectively [62]. Experience with dosing of immunosup-pressive agents after liver transplant concomitantly withtelaprevir or boceprevir plus IFN and ribavirin suggests anempiric dose reduction of approximately 75% for tacrolimusand 35% for cyclosporine [63,64]. Telaprevir and boceprevirare no longer available in the United States. Sirolimus plasmaconcentrations with the use of DAAs have not been pro-spectively evaluated, but case reports in patients with livertransplant would suggest a 90% dose decrease [64].
When a calcineurin inhibitor or sirolimus is used with aprotease inhibitor, it is reasonable to empirically reduce thedose of the immunosuppressive agents and monitor their
REV 5.4.0 DTD � YBBMT53933_proof �
levels more frequently because of major CYP3A4 andP-glycoprotein drugedrug interactions. Formal dosing rec-ommendations and the degree of dose adjustments in HCTrecipients are conservatively estimated because pharmaco-kinetic studies have not evaluated dosage changes; studiesare limited to healthy volunteers or solid organ transplantrecipients.
Knowledge Gap
� Studies are needed on the potential interactions be-tween DAAs, immunosuppressive agents, and chemo-therapy used in HCT candidates.
OVERLAP BETWEEN TOXIC EFFECTS OF DAAS AND OFCONDITIONING REGIMENS AND SYMPTOMS OF GVHD INHCV-INFECTED HCT CANDIDATES AND RECIPIENTS:SARAH P. HAMMOND AND SERGIO GIRALTRecommendations
� No recommendations can be made regarding overlapbetween the toxic effects of DAAs and the toxic effectsof HCT conditioning regimens or symptoms of GVHDbecause evidence is lacking.
Evidence SummaryHistorically, treatment of HCV with IFN and ribavirin in
allogeneic HCT recipients was carried out with some trepi-dation because of concerns about exacerbation of GVHD,anemia, and neutropenia. However, a relatively large cohortstudy showed no overall increase in GVHD among allogeneicHCT recipients treated with IFN with or without ribavirinafter transplant, and there was a trend toward a decrease inthe risk of severe liver complications after transplant withHCV treatment [65].
Because DAAs have been approved by the FDA for treat-ment of HCV only since 2011, information about the use ofthese agents in allogeneic HCT candidates and recipients islargely anecdotal [1]. This paucity of data limits under-standing of the overlap between the toxic effects of DAAs andthe toxic effects of HCTconditioning regimens and symptomsof GVHD.
The first DAAs approved to treat genotype 1 HCV infec-tion, telaprevir and boceprevir, were both associated withtoxic effects that could bemistakenly attributed to GVHD (eg,rash) or HCT conditioning regimens (eg, anemia) in theappropriate clinical context [66,67]. However, the availabilityof potent alternatives with fewer side effects to treat geno-type 1 HCV has made telaprevir and boceprevir less desirablethan other agents (both telaprevir and boceprevir have beenremoved from the US market) [47,48]. Simeprevir, a morerecently approved protease inhibitor, can cause mild hyper-bilirubinemia, which could also be mistakenly attributed toGVHD in the appropriate clinical context, but this effect istypically transient [68].
In general, the observed toxic effects of newer DAAsapproved for clinical use outside of clinical trials are minimalcompared with the toxic effects of IFN, ribavirin, and eventelaprevir and boceprevir. Further studies and more post-marketing experiencewith these medications, particularly inpatients with hematologic disorders and patients who haveundergone HCT, will be crucial for predicting potential toxiceffects unique to HCT recipients.
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H.A. Torres et al. / Biol Blood Marrow Transplant xxx (2015) 1e1312
Knowledge Gap
� The toxicity profile of DAAs in HCT recipients, includingthe toxic effects on progenitor cells.
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ACKNOWLEDGMENTSThe authors thank Stephanie Deming, The University of
Texas MD Anderson Cancer Center, for editorial assistance.The Executive Committee comprises the following
individuals: Maya Gambarin-Gelwan (Co-Chair), Harrys A.Torres (Co-Chair), Pearlie P. Chong, Marcos De Lima, Mark S.Friedman, Sergio Giralt, Sarah P. Hammond, Patrick J. Kiel,Henry Masur, George B. McDonald, and John R. Wingard.
Financial disclosure: The authors have nothing to disclose.Conflict of interest statement: H.A.T. is a consultant for
Janssen Pharmaceuticals, Inc., Gilead Sciences, Merck & Co.,Inc., Vertex Pharmaceuticals, Novartis, Genentech, Astellas,Pfizer, and Theravance, Inc. and has received research grantsfrom The University of Texas MD Anderson Cancer Center,Gilead Sciences, Merck & Co., Inc., and Vertex Pharmaceuti-cals. S.P.H. has received research grants fromMerck & Co., Inc.and Ansun Biopharma. J.R.W. is a consultant for Ansun,Gilead Sciences, Merck & Co, and Astellas; speaker for Pfizer;and has received royalties from UpToDate Inc. The remainingauthors have no conflicts of interest to declare.
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REFERENCES1. AASLD/IDSA/IASeUSA. Recommendations for testing, managing, and
treating hepatitis C. Available at: http://hcvguidelines.org/. AccessedJuly 27, 2015.
2. Torres HA, Mahale P, Blechacz B, et al. Effect of hepatitis C virusinfection in patients with cancer: addressing a neglected population.J Natl Comprehen Cancer Netw. 2015;13:41-50.
3. Peffault de Latour R, Asselah T, Levy V, et al. Treatment of chronichepatitis C virus in allogeneic bone marrow transplant recipients. BoneMarrow Transplant. 2005;36:709-713.
4. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventinginfectious complications among hematopoietic cell transplantationrecipients: a global perspective. Biol Blood Marrow Transplant. 2009;15:1143-1238.
5. Strasser SI, Myerson D, Spurgeon CL, et al. Hepatitis C virus infectionand bone marrow transplantation: a cohort study with 10-year follow-up. Hepatology. 1999;29:1893-1899.
6. Ramos CA, Saliba RM, de Padua L, et al. Impact of hepatitis C virusseropositivity on survival after allogeneic hematopoietic stem celltransplantation for hematologic malignancies. Haematologica. 2009;94:249-257.
7. Nakasone H, Kurosawa S, Yakushijin K, et al. Impact of hepatitis C virusinfection on clinical outcome in recipients after allogeneic hemato-poietic cell transplantation. Am J Hematol. 2013;88:477-484.
8. Evans AT, Loeb KR, Shulman HM, et al. Fibrosing cholestatic hepatitis Cafter hematopoietic cell transplantation: report of 3 fatal cases. Am JSurg Pathol. 2015;39:212-220.
9. Ljungman P, Johansson N, Aschan J, et al. Long-term effects of hepatitisC virus infection in allogeneic bone marrow transplant recipients.Blood. 1995;86:1614-1618.
10. Tomas JF, Pinilla I, Garcia-Buey ML, et al. Long-term liver dysfunctionafter allogeneic bone marrow transplantation: Clinical features andcourse in 61 patients. Bone Marrow Transplant. 2000;26:649-655.
11. Strasser SI, Sullivan KM, Myerson D, et al. Cirrhosis of the liver in long-term marrow transplant survivors. Blood. 1999;93:3259-3266.
12. Peffault de Latour R, Levy V, Asselah T, et al. Long-term outcome ofhepatitis C infection after bone marrow transplantation. Blood. 2004;103:1618-1624.
13. Shimizu T, Kasahara M, Tanaka K. Living-donor liver transplantation forchronic hepatic graft-versus-host disease. N Engl J Med. 2006;354:1536-1537.
14. Andreoni KA, Lin JI, Groben PA. Liver transplantation 27 years afterbone marrow transplantation from the same living donor. N Engl J Med.2004;350:2624-2625.
15. Smith BD, Morgan RL, Beckett GA, et al. Recommendations for theidentification of chronic hepatitis C virus infection among persons bornduring 1945-1965. Morbid Mortal Wkly Rep. 2012;61:1-32.
REV 5.4.0 DTD � YBBMT53933_proof � 24 A
16. Moyer VA. US Preventive Services Task Force. Screening for hepatitis Cvirus infection in adults: U.S. Preventive Services Task Force recom-mendation statement. Ann Intern Med. 2013;159:349-357.
17. Shuhart MC, Myerson D, Childs BH, et al. Marrow transplantation fromhepatitis C virus seropositive donors: transmission rate and clinicalcourse. Blood. 1994;84:3229-3235.
18. Foundation for the Accreditation of Cellular Therapies. Internationalstandards for cellular therapy, product collection, processing, andadministration. 5th ed. 2012.
19. US Food and Drug Administration. Tissues and cellular and tissue-based products. 2007.
20. Ghany MG, Strader DB, Thomas DL, Seeff LB, American Association forthe Study of Liver D. Diagnosis, management, and treatment of hepa-titis C: an update. Hepatology. 2009;49:1335-1374.
21. Locasciulli A, Testa M, Valsecchi MG, et al. The role of hepatitis C and Bvirus infections as risk factors for severe liver complications followingallogeneic BMT: a prospective study by the Infectious Disease WorkingParty of the European Blood and Marrow Transplantation Group.Transplantation. 1999;68:1486-1491.
22. Kyvernitakis A, Mahale P, Popat UR, et al. Hepatitis C virus infection inpatients undergoing hematopoietic cell transplantation in the era ofdirect-acting antiviral agents. Presented at the annual meeting of theAmerican Society of Clinical Oncology, May 29 to June 2, 2015, Chicago.
23. Hsiao HH, Liu YC, Wang HC, et al. Hepatitis C transmission from viremicdonors in hematopoietic stem cell transplant. Transplant Infect Dis.2014;16:1003-1006.
24. Beckerich F, Hezode C, Robin C, et al. New nucleotide polymerase in-hibitors to rapidly permit hematopoietic stem cell donation from apositive HCV-RNA donor. Blood. 2014;124:2613-2614.
25. Sagnelli E, Pisaturo M, Stanzione M, et al. Clinical presentation,outcome, and response to therapy among patients with acute exacer-bation of chronic hepatitis C. Clin Gastroenterol Hepatol. 2013;11:1174-1180.
26. Mahale P, Kontoyiannis DP, Chemaly RF, et al. Acute exacerbation andreactivation of chronic hepatitis C virus infection in cancer patients.J Hepatol. 2012;57:1177-1185.
27. McGovern BH, Birch CE, Bowen MJ, et al. Improving the diagnosis ofacute hepatitis C virus infection with expanded viral load criteria. ClinInfect Dis. 2009;49:1051-1060.
28. Torres HA, Davila M. Reactivation of hepatitis B virus and hepatitis Cvirus in patients with cancer. Nat Rev Clin Oncol. 2012;9:156-166.
29. Vento S, Cainelli F, Mirandola F, et al. Fulminant hepatitis on with-drawal of chemotherapy in carriers of hepatitis C virus. Lancet. 1996;347:92-93.
30. Varma A, Saliba RM, Torres HA, et al. Outcomes and survival in hepa-titis C virus seropositive lymphoma and myeloma patients afterautologous stem cell transplantation. The 79th Annual Meeting of theAmerican College of Gastroenterology. Am J Gastroenterol. 2014;109(Suppl 2). abstr 2075.
31. Chahal P, Levy C, Litzow MR, Lindor KD. Utility of liver biopsy in bonemarrow transplant patients. J Gastroenterol Hepatol. 2008;23:222-225.
32. Wallace MJ, Narvios A, Lichtiger B, et al. Transjugular liver biopsy inpatients with hematologic malignancy and severe thrombocytopenia.J Vasc Intervent Radiol. 2003;14:323-327.
33. Rockey DC, Caldwell SH, Goodman ZD, et al. Liver biopsy. Hepatology.2009;49:1017-1044.
34. Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in pa-tients with chronic hepatitis C virus infection: a systematic review. AnnIntern Med. 2013;158:807-820.
35. Available at: http://theliverlab.com/downloads/AASLD_Endorses_FibroScan.pdf. Accessed March 19, 2015.
36. Afdhal NH, Bacon BR, Patel K, et al. Accuracy of FibroScan, comparedwith histology, in analysis of liver fibrosis in patients with hepatitis Bor C: a United States multicenter study. Clin Gastroenterol Hepatol.2015;13:772-779.
37. Hamidieh AA, Shazad B, Ostovaneh MR, et al. Noninvasive measure-ment of liver fibrosis using transient elastography in pediatric patientswith major thalassemia who are candidates for hematopoietic stemcell transplantation. Biol Blood Marrow Transplant. 2014;20:1912-1917.
38. Auberger J, Graziadei I, Clausen J, et al. Non-invasive transient elas-tography for the prediction of liver toxicity following hematopoieticSCT. Bone Marrow Transplant. 2013;48:159-160.
39. Vance EA, Soiffer RJ, McDonald GB, et al. Prevention of transmission ofhepatitis C virus in bone marrow transplantation by treating the donorwith alpha-interferon. Transplantation. 1996;62:1358-1360.
40. Surapaneni SN, Hari P, Knox J, et al. Suppressive anti-HCV therapy forprevention of donor to recipient transmission in stem cell trans-plantation. Am J Gastroenterol. 2007;102:449-451.
41. Hogan WJ, Maris M, Storer B, et al. Hepatic injury after non-myeloablative conditioning followed by allogeneic hematopoietic celltransplantation: a study of 193 patients. Blood. 2004;103:78-84.
42. Arcaini L, Vallisa D, Rattotti S, et al. Antiviral treatment in patients withindolent B-cell lymphomas associated with HCV infection: a study ofthe Fondazione Italiana Linfomi. Ann Oncol. 2014;25:1404-1410.
1556
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H.A. Torres et al. / Biol Blood Marrow Transplant xxx (2015) 1e13 13
43. Charlton M, Gane E, Manns MP, et al. Sofosbuvir and ribavirin fortreatment of compensated recurrent hepatitis C virus infection afterliver transplantation. Gastroenterology. 2015;148:108-117.
44. Reddy KR, Everson GT, Flamm SL, et al. Ledipasvir/sofosbuvir withribavirin for the treatment of hcv in patients with post transplantrecurrence: preliminary results of a prospective, multicenter study. The65th Annual Meeting of the American Association for the Study of LiverDiseases: The Liver Meeting 2014. Hepatology. 2014;60(Suppl).
45. Product information: Copegus� (ribavirin) otG, Inc. South San Fran-cisco, CA. 2011.
46. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir forpreviously treated HCV genotype 1 infection. N Engl J Med. 2014;370:1483-1493.
47. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for un-treated HCV genotype 1 infection. N Engl J Med. 2014;370:1889-1898.
48. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370:1594-1603.
49. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir anddasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370:1983-1992.
50. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir,with or without ribavirin, to treat chronic infection with hepatitis Cvirus genotype 1 in non-responders to pegylated interferon and riba-virin and treatment-naive patients: the COSMOS randomised study.Lancet. 2014;384:1756-1765.
51. Osinusi A, Kohli A, Marti MM, et al. Re-treatment of chronic hepatitis Cvirus genotype 1 infection after relapse: an open-label pilot study. AnnIntern Med. 2014;161:634-638.
52. Product information: Daklinza oral film-coated tablets, daclatasvir oralfilm-coated tablets. Bristol-Myers Squibb Company, Princeton, NJ. 2015.
53. Peyrin-Biroulet L, Cadranel JF, Nousbaum JB, et al. Interaction of riba-virin with azathioprine metabolism potentially induces myelosup-pression. Aliment Pharmacol Therap. 2008;28:984-993.
54. Product information: Victrelis� oral capsules, boceprevir oral capsules.Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ. 2014.
55. Product information: Viekira Pak oral tablets, ombitasvir paritaprevirritonavir oral tablets and dasabuvir oral tablets. AbbVie Inc. (permanufacturer), North Chicago, IL. 2014.
56. Product information: Incivek� oral tablets, telaprevir oral tablets.Vertex Pharmaceuticals Incorporated (per FDA), Cambridge, MA. 2013.
REV 5.4.0 DTD � YBBMT53933_proof �
57. Product information: Olysio� oral capsules, simeprevir oral capsules.Janssen Therapeutics (per manufacturer), Titusville, NJ. 2014.
58. Product information: Harvoni� oral tablets, ledipasvir sofosbuvir oraltablets. Gilead Sciences, Inc. (per manufacturer), Foster City, CA. 2014.
59. Mathias A, Cornpropst M, Clemons D, et al. No clinically significantpharmacokinetic drug-drug interactions between sofosbuvir (GS-7977)and the immunosuppressants, cyclosporine A or tacrolimus in healthyvolunteers. The 63rd Annual Meeting of the American Association forthe Study of Liver Diseases: The Liver Meeting 2012 [abstract 1869].Hepatology. 2012;56(Suppl 1):1063A-1064A.
60. Ouwerkerk-Mahadevan S, Simion A, Mortier S, et al. No clinically sig-nificant interaction between the investigational HCV protease inhibitorTMC435 and the immunosuppressives cyclosporine and tacrolimus.The 63rd Annual Meeting of the American Association for the Study ofLiver Diseases: The Liver Meeting 2012 [abstract 80]. Hepatology. 2012;56(Suppl 1):213A.
61. Garg V, van Heeswijk R, Lee JE, et al. Effect of telaprevir on the phar-macokinetics of cyclosporine and tacrolimus. Hepatology. 2011;54:20-27.
62. Hulskotte E, Gupta S, Xuan F, et al. Pharmacokinetic interaction be-tween the hepatitis C virus protease inhibitor boceprevir and cyclo-sporine and tacrolimus in healthy volunteers. Hepatology. 2012;56:1622-1630.
63. Coilly A, Roche B, Dumortier J, et al. Safety and efficacy of proteaseinhibitors to treat hepatitis C after liver transplantation: a multicenterexperience. J Hepatol. 2014;60:78-86.
64. Tischer S, Fontana RJ. Drug-drug interactions with oral anti-HCV agentsand idiosyncratic hepatotoxicity in the liver transplant setting.J Hepatol. 2014;60:872-884.
65. Ljungman P, Locasciulli A, de Soria VG, et al. Long-term follow-up ofHCV-infected hematopoietic SCT patients and effects of antiviraltherapy. Bone Marrow Transplant. 2012;47:1217-1221.
66. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previ-ously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416.
67. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreatedchronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.
68. Jacobson IM, Dore GJ, Foster GR, et al. Simeprevir with pegylatedinterferon alfa 2a plus ribavirin in treatment-naive patients with chronichepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised,double-blind, placebo-controlled trial. Lancet. 2014;384:403-413.
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24 August 2015 � 2:01 pm � ce PT