the 18 th conference on retroviruses and opportunistic infections boston, ma february 27-march 2,...
TRANSCRIPT
The 18th Conference on Retroviruses and Opportunistic
InfectionsBoston, MA
February 27-March 2, 2011
CME Disclaimer
These slides may not bepublished, posted online, and/or presented
for Continuing Medical Education creditwithout written permission fromRush University Medical Center
and Practice Point Communications
Rush University Medical Center is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Rush University Medical Center designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (UPN #0012-9999-10-150-H02-P). This slide kit is accredited for one hour of continuing education credit. The University of Florida College of Pharmacy will mail Statements of Continuing Education Credit within 30 working days after receiving evidence of successful completion of the course. Successful completion means that you must attend the entire program and complete an evaluation form.
Supported by an independent educational grant from Gilead Sciences Medical Affairs.
Accreditation and Designation
The Association of Nurses in AIDS Care is an approved provider of continuing nursing education by the Virginia Nurses Association Continuing Education Approval Committee, an accredited approver by the American Nurses Credentialing Center’s Commission onAccreditation.
This activity is approved for 1.0 contact hours by the Association of Nurses in AIDS Care.
This program contains .25 hours of pharmacology content.
Faculty:CME Course Director
Harold A. Kessler, MDProfessor of Medicine and Immunology/Microbiology
Associate Director, Section of Infectious DiseasesRush University Medical Center
Chicago, Illinois
Faculty:Content Development and Training
Richard A. Elion, MDDirector of Clinical Research
Walker Whitman ClinicWashington, DC
Graeme J. Moyle, MD, MB BSAssociate Director of HIV Research
Chelsea & Westminster HospitalLondon, England
Jürgen K. Rockstroh, MD, PhDProfessor of Medicine
Department of MedicineHead, HIV Clinic
University of BonnBonn, Germany
Andrew R. Zolopa, MDAssociate Professor of Medicine
Stanford UniversityStanford, California
Faculty:CME Reviewer
David M. Simon, MD, PhDAssistant Professor
Section of Infectious DiseasesRush University Medical Center
Chicago, Illinois
Disclosure Information
• It is the policy of the Rush University Medical Center Office of Continuing Medical Education to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME
• Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships with any commercial interest (including but not limited to pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic) within the preceding 12 months
• If there are relationships that create a conflict of interest, these must be resolved by the CME Course Director in consultation with the Office of Continuing Medical Education prior to the participation of the faculty member in the development or presentation of course content
Disclosure Information:CME Course Director
• Harold A. Kessler, MD− Grants/Research Support
− None− Consultant
− None− Speakers’ Bureau
− None− Stock Shareholder
− Abbott Laboratories, GlaxoSmithKline, Merck− Other Financial or Material Support
− None
Disclosure Information:Content Faculty
• Richard A. Elion, MD− Grant/Research Support:
− Gilead Sciences, Merck, Rapid, Tibotec, ViiV, Wyeth− Consultant:
− Bristol-Myers Squibb, Gilead Sciences, Merck, Tibotec− Speakers’ Bureau:
− Bristol-Myers Squibb, Gilead Sciences, Merck, Tibotec− Stock Shareholder:
− None− Other Financial or Material Support:
− None
Disclosure Information:Content Faculty
• Graeme J. Moyle, MD, MB BS− Grant/Research Support:
− Abbott Laboratories, Ardea Biosciences, Bionor, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Theratechnologies and Tibotec
− Consultant:− Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences,
GlaxoSmithKline, Merck, Prizer, TheraTechnologies, Tibotec, Viiv Healthcare
− Speakers’ Bureau: − Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences,
GlaxoSmithKline, Merck, Prizer, TheraTechnologies, Tibotec, Viiv Healthcare
− Stock Shareholder: − None
− Other Financial or Material Support: − None
Disclosure Information:Content Faculty
• Jürgen K. Rockstroh, MD, PhD− Grant/Research Support:
− Abbott Laboratories, Merck, Roche− Consultant:
− Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche, Tibotec, ViiV
− Speakers’ Bureau: − None
− Stock Shareholder: − None
− Other Financial or Material Support: − None
Disclosure Information:Content Faculty
• Andrew R. Zolopa, MD− Grant/Research Support:
− Bristol-Myers Squibb, Gilead Sciences, Pfizer, VIRxSYS− Consultant:
− Bristol-Myers Squibb, Gilead Sciences, Tibotec− Speakers’ Bureau:
− None− Stock Shareholder:
− None− Other Financial or Material Support:
− None
Disclosure Information:CME Reviewer
• David M. Simon, MD, PhD− Grants/Research Support
− None− Consultant
− None− Speakers’ Bureau
− None− Stock Shareholder
− None− Other Financial or Material Support
− None
Opinions and Off-Label Discussions
The opinions or views expressed in this educational program are those of the participants and do not necessarily reflect the opinions
or recommendations of Gilead Sciences Medical Affairs,Rush University Medical Center, Association of Nurses in AIDS Care,
or the University of Florida College of Pharmacy
The faculty may have included discussion on unlabeled usesof a commercial product or an investigational use of a
product not yet approved for this purpose
Please consult the full prescribing information before usingany medication mentioned in this program
Learning Objectives (CME, CE)
• Upon completion of this activity, the participant intends to incorporate the following objectives into their practice of medicine:− Initiate ARV therapy in ARV-naïve patients based upon the most
current clinical data indicating when the potential benefits of ARV therapy outweigh the potential risks.
− Prescribe ARV therapy in ARV-naïve patients based upon the most current clinical data indicating which ARV regimens are superior regarding efficacy and avoidance of toxicity and adverse events.
− Utilize recent study results regarding the medical management of HIV-positive patients in your clinical practice to improve patient care.
− Utilize the data presented regarding viral hepatitis to improve the health care you provide to HIV-positive patients.
Learning Objectives (CPE)
• Upon completion of this activity, the pharmacist should be able to:− Determine when the most current clinical data indicates the potential
benefits of ARV therapy outweigh the potential risks in ARV-naïve patients.
− Recommend the most superior ARV therapy for ARV-naïve patients based on efficacy and avoidance of toxicity and adverse events according to the most current clinical data.
− Utilize recent study results regarding the medical management of HIV-positive patients in your clinical practice to improve patient care.
− Utilize the data presented regarding viral hepatitis to improve the health care you provide to HIV-positive patients.
Studies in ARV-Naïve PatientsRick Elion, MD
Director of Clinical ResearchWhitman Walker Clinic
Washington, DC
2011 DHHS Guidelines: When to Start ART
Clinical CategoryCD4 Cell Count
(cells/mm3)2011 DHHSGuidelines Strength-Quality
AIDS-defining illness
Any value TreatA-I
Asymptomatic
<350 Treat
350 to 500 Treat A/B-II: 55% A vs. 45% B
>500 Treat/OptionalB/C-III: 50% B
vs. 50% C
Pregnancy, HIV-associated nephropathy, HIV/HBV when HBV treatment indicated
Any value Treat A-III
2011 DHHS Guidelines:When to Start with Active TB
CD4 Count (Cells/mm3) Recommendation
<200Initiate ART within 2–4 weeks of starting TB treatment
200–500
Initiate ART within 2–4 weeks, or at least by 8 weeks, of starting TB therapy
>500Initiate ART within 8 weeks of starting TB therapy
Adapted from US Department of Health and Human Services Guidelines; Revised January 10, 2011.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
Racial Differences in Efficacy of Initial ART Trials
in ACTG (1998-2005)
• 5 clinical trials in ACTG (N=2495)− 1344 non-Hispanic white vs.
1151 black• Black race associated with 40%
increased risk of viral failure after adjustment for covariates: 1.4 (1.2 to 1.6), p<0.001.
• Black race associated with greater improvement in CD4 count over 96 wks, but not shorter time periods (ITT: p=0.05)
Adjusted for sex, disease status co-morbidities, mode of HIV transmission, depression, education level, alcohol use, self-efficacy and perceived social support.
Ribaudo H, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 50.
Time to Virologic failure (Multivariable)
Black race 1.4 (1.2-1.6)
Gender (Female) 0.9 (0.8-1.1)
Age (per 10 yrs) 0.8 (0.8-0.9)
Baseline CD4 (per 50 cells/mm3) 1.0 (1.0-1.0)
Baseline VL (per log10 copies/ml)
For VF in 0-6 months 1.4 (1.2-1.7)
For VF in 6-12 months 1.1 (1.0-1.2)
For VF >12 months 1.1 (0.9-1.3)
Ever Hepatitis C positive 1.4 (1.1-1.8)
Ever Hepatitis B positive 1.1 (0.9-1.3)
Education (No high school diploma or GED) 1.2 (1.0-1.5)
Satisfied with support? (Not very satisfied) 1.2 (1.0-1.4)
Will ART have a positive effect? (Not sure) 1.1 (0.9-1.3)
Recent adherence (<100%) 2.6 (2.3-3.1)
Adjusted HR
1.0 3.0
A5202: Study Design
Multicenter, randomized, placebo-controlled, 96-week, non-inferiority studyEnrolled 2005-2007 and followed through Sept 2009
Stratified by screening HIV-1 RNA (< or ≥ 100,000 c/mL)
ART-naïve patients
(N = 1857)
≥ 16 years oldHIV RNA ≥ 1000 c/mL
3TC/ABC placebo (QD)
TDF/FTC FDC (QD) EFV (QD)
TDF/FTC placebo (QD)
3TC/ABC FDC (QD) EFV (QD)
3TC/ABC placebo (QD)
TDF/FTC FDC (QD) ATV/r(QD)
TDF/FTC placebo (QD)
3TC/ABC FDC (QD) ATV/r(QD)
Primary endpoint: Time to virologic failure, first grade 3-4 AE, or modification
of randomized regimenGrant P, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 535.
ACTG 5202 Differences Between Gender and Race
• Evaluated 1857 subjects in ACTG 5202− 40% White, 33% Black, 23% Hispanic− Blacks with lower baseline CD4 (24%
vs. 13% <50 cells/mL, p≤0.01) and VL (63% vs. 46% <50,000 cps/mL, p ≤0.01) than whites
• Results− Blacks had higher rates of VF,
nonadherence and 3rd agent intolerability
− Women had higher risk of virologic failure on ATV/r compared to EFV
• Conclusion: Results suggest certain interventions and regimens may be helpful in some populations with HIV
ABC/3TC P value TDF/FTC P value
Race(ref to W)*
B1.53
(1.02, 2.29)0.02
2.42 (1.52, 3.83)
<0.001
H0.81
(0.49, 1.32)0.96
(0.54, 1.70)
Sex (ref to M)*
F-EFV0.52
(0.26, 1.04)0.006
0.86(0.41, 1.80)
0.03
F-ATV/r1.72
(0.99, 2.98)2.35
(1.30, 4.26)
3rd agent(EFV ref)
F-ATV/r2.55
(1.20, 5.41)0.02
2.16(0.97, 4.80)
0.03
M-ATV/r0.94
(0.66, 1.34)0.80
(0.52, 1.23)
*Multivariable adjusted for sex, R/E, age at baseline, CD4, VL, h/o AIDS, Hep B/C, IVDU, scr HIV genotype
Time to Virologic Failure (ITT: HR, 95% CI)
Smith K, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 536.
Current DHHS Guidelines Regimens for Treatment-Naïve Patients
Preferred Regimens
• EFV• ATV/r • DRV/r (QD)• RAL[Pregnant Women Only: LPV/r (twice daily) + ZDV/3TC]
AlternativeRegimens
• EFV + (ABC or ZDV)/3TC• NVP + ZDV/3TC• ATV/r + (ABC or ZDV)/3TC• FPV/r (once or twice daily) + either [(ABC or ZDV)/3TC1] or TDF/FTC• LPV/r (once or twice daily) + either [(ABC or ZDV)/3TC1] or TDF/FTC
AcceptableRegimens
• EFV + ddI + (3TC or FTC)• ATV + (ABC or ZDV)/3TC• MVC + ZDV/3TC
InsufficientData
• MVC + either ABC/3TC or TDF/FTC• RAL + (ABC or ZDV)/3TC• (DRV/r or SQV/r) + (ABC or ZDV)/3TC
Adapted from US Department of Health and Human Services Guidelines; Revised January 10, 2011.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
+ TDF/FTC
A5202: Time to Virologic Failure by Baseline Viral Load and CD4 Count
ABC/3TC TDF/FTC
Pro
bab
ility
of
Rem
ain
ing
Fre
e o
f V
iro
log
ic F
ailu
re
Grant P, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 535.
• Increased risk of VF with baseline lower CD4 or higher VL in those assigned ABC/3TC
• Results confirm previously reported analysis based on screening viral load
n=9835 VF
n=7823 VF
n=8019 VF
n=15310 VF
n=396 VF
n=27328 VF
n=235 VF
n=18429 VF
Week 192 from Randomization
n=806 VF
n=8317 VF
n=709 VF
n=15819 VF
n=558 VF
n=28929 VF
n=202 VF
n=17324 VF
QDMRK:Raltegravir QD vs. BID in Initial ART
Raltegravir 800 mg QD + TDF/FTC n=382
Raltegravir 400 mg BID + TDF/FTCn=388
Treatment naiveHIV-1 RNA >5000 copies/mL
Primary endpointWeek 48
Secondary endpointWeek 96
Double-blind, randomized, multi-center studyAnalysis: Non-inferiority design (10% margin)
Eron J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 150LB.
QDMRK: Baseline Characteristics
Eron J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 150LB.
RAL
QD + TDF/FTCRAL
BID + TDF/FTC
Age (median, years) 38 38
Male 82% 77%
Non-White 28% 30%
vRNA copies/mL (geometric mean)
67,968 70,942
HIV RNA >105 copies/mL 40% 39%
Mean CD4 count (cells/mm3)
291 279
QDMRK: HIV RNA <50 copies/mL (NC=F)
Eron J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 150LB.
382 382 377 381 379 380 381 382388 388 386 387 386 387 386 386
RAL 800 mg QDRAL 400 mg BID
Number of Contributing Patients
BID 88.9%
QD 83.2%
Δ (QD-BID) [95% CI] = -5.7 [-10.7, -0.83]
0 4 8 12 16 24 36 48
Study Week
0
20
40
60
80
100P
erc
en
t o
f P
ati
en
ts w
ith
HIV
RN
A <
50
Co
pie
s/m
L
QDMRK: Virologic Efficacy Stratified by Baseline
Viral Load and CD4 Count
HIV RNA <50 copies/mL at Week 48 by Subgroup (NC=F)
Difference
RAL QD RAL BID% (95% CI)
n/N % n/N %
Baseline HIV RNA (copies/mL)
>100,000 copies/mL
113/152
74.3128/152
84.2
-9.9(-19.0, -0.8)
≤100,000 copies/mL
205/230
89.1215/234
91.9
-2.7(-8.3, 2.7)
Baseline CD4 (cells/mm3)
≤200 cells/mm3
63/89 70.8 80/99 80.8 -10.0
(-22.3, 2.2)
>200 cells/mm3
254/292
87.0262/286
91.6
-4.6(-9.8, 0.4)
Eron J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 150LB.
QDMRK: Resistance at 48 Weeks
• Majority of pts failed with 2 or more mutations associated with RAL resistance
• Signature mutations : N155H (4 pts in QD arm) and Y143C/R (3 pts in QD, 1 pt in BID)
• No cases of TDF resistance
Eron J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 150LB.
Raltegravir
QDRaltegravir
BID
Virologic Failures 53/382 (13.9%) 35/388 (9.0%)
VF >400 c/mL, (data available)
30 (27 with IN data)
16 (12 with IN data)
No Evidence of Resistance 7 7
Integrase Resistance and FTC Resistance
9 2
FTC Resistance Alone 11 4
QDMRK: Histograms for GM Ctrough and % with HIV RNA <50 copies/mL (Observed Failure)
Eron J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 150LB.
GM C12hr (nM) GM C24hr (nM)
RangeMedian
RangeMedian
STARTMRK: 3 Year Results
281 Patients Treated with
RAL + TDF/FTC
282 Patients Treated with
EFV + TDF/FTC
Enrolled Patients Randomized 1:1
To RAL:EFV Arms
227 Patients (80.8%)
Completed156 Weeks
211 Patients (74.8%)
Completed156 Weeks
54 Patients (19.2%)Discontinued5 – lack of efficacy
12 – AEs8 – lost to follow-up29 – miscellaneous
71 Patients (25.2%)Discontinued7 – lack of efficacy
22 – AEs14 – lost to follow-up28 – miscellaneous
Rockstroh J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 542.
STARTMRK: HIV RNA <50 c/mL Through 156 Weeks (NC = F)
Rockstroh J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 542.
Δ (RAL-EFV) [95% CI] = +7.3 [-0.2, +14.7]
Non-Inferiority P-Value <0.001
281 281 278 280 281 281 280 281 281 277 279 280 281282 281 280 281 282 282 281 282 279 281 281 281 282
Raltegravir groupEfavirenz group
0 16 32 48 60 72 84 96 108 120 132 144 156
Weeks
0
20
40
60
80
100P
erc
en
t o
f P
ati
en
ts w
ith
HIV
RN
A <
50
Co
pie
s/m
L
Number of Contributing Patients
86
82
81
79
75
68
Darunavir/r + Raltegravir:NRTI Sparing Regimen for ARV-naïve Patients
Taiwo B, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 551.
DRV/r + RAL associated with high failure rate and should not be used
Single arm study of DRV/r (800/100 mg) QD + RAL (400 mg BID) (N=112)Age (years) Median (Q1,Q3) 36 (27, 45)
Sex Male 98 (88%)
Race White 49 (44%)
CD4 cell count (cells/mm3) <200200<350≥350
40 (36%)32 (29%)40 (36%)
HIV-1 RNA (copies/mL) ≤100,000≥100,000
63 (56%)49 (44%)
Proportion Of Subjects With HIV-1 RNA <200 and <50 copies/mL (ITT analysis, missing/off study= ignored
Mma Bana Study: Influence of ART on Premature Birth
• HIV-infected pregnant women with CD4 > 200 (n=530) in Botswana randomized to ZDV/3TC/ABC or ZDV/3TC + LPV/r− ART started at 26-34 wks
gestation− Rate of HIV transmission to
newborn low as previously reported
− Pre-term delivery analysis limited to women with singleton births
• After adjustment for maternal income, initiation of PI-based ART in late pregnancy was associated with a 2-fold increase in preterm delivery (AOR 2.02; 95% CI 1.25 – 3.27)
• Results confirm similar results reported in French observational study
Powis K, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 746; Sibiude J, et al. ibid., Abst. 743; N Engl J Med. 2010;362(24):2282-94.
Gestational Age at HAART Initiation
TZV(n)
% PretermCBV-KAL
(n)% Preterm
26 to 28 Weeks 177 10.2% 180 21.7%
29 to 31 Weeks 44 13.6% 63 19.1%
32 to 34 Weeks 42 16.7% 24 25.0%
Total 263 11.8% 267 21.4%
Efficacy and Safety of EFVwith ZDV/3TC or TDF/FTC
• Randomized, prospective, open-label study of EFV + TDF/FTC or ZDV/3TC (N=1045) in patients with CD4 <300 cells/mm3
• Results− Significantly fewer patients in
TDF/FTC arm met primary safety endpoint (P<0.0001)
− Significantly more treatment modifications for in ZDV/3TC arm vs. TDF/FTC arm (59 for neutropenia/anemia vs. 0)
− Significantly more metabolic complications with ZDV/3TC (19 vs. 3, P<0.001)
• Conclusion: Similar efficacy, but TDF/FTC safer
Comparison of Safety Endpoints
Campbell T, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 149LB.
Number of Events
Relative Hazard
TDF/ FTC EFV (N=526)
3TC/ ZDV EFV
(N=519)
EFV+TDF/FTC vs.
EFV+3TC/ZDV (95% CI)
P
Primary Safety (composite endpoint)
243 3130.64
(0.54, 0.76)<0.0001
All initial dose modification
140 2220.54
(0.44, 0.67)<0.0001
All initial Grade 3 or 4 lab abnormality
98 1540.55
(0.43, 0.71)<0.0001
Studies of Investigational Compounds and Resistance
Andrew Zolopa, MDAssociate ProfessorStanford University
Palo Alto, CA
VIKING Study: Dolutegravir (572) Following RAL Failure
RAL-failures with evidence of RAL-resistance andat least 3 ART-class resistant (includes INI)
*Q148H/K/R plus changes in L74 and/or E138 and/or G140**N155H and Y143H pathways or Q148H/K/R single mutants
Allocated to one of two groups based on genotype at screen to ensure broad sensitivity range
Functional Monotherapy Phase
Replace RAL with DTG or
add, if RAL already stopped
Continuation Phase
DTG + OBR
Day 1 Day 11 Week 24
Q148H/K/R + one or more secondary resistance mutations*
N~ 10 (cohort II)
All other mutations (including codon 148 single mutation)**
N~ 10 (cohort II)
Eron J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 151LB.
VIKING Study: Resistance at Baseline
DTG 50mg QD
(N=27)
DTG 50mg BID
(N=24)
Q148+≥1* All 9 (33%) 11(46%)
Q148+2 3 (11%) 2 (8%)
Q148+1 4 (15%) 8 (33%)
Mixture** 2 (7%) 1 (4%)
Other All 18 (67%) 13 (54%)
N155 4 (15%) 6 (25%)
Y143 12 (44%) 6 (25%)
Other 2 (7%) 1 (4%)
* Q148H/K/R + ≥1 Q148 associated mutations at L74,E138 or G140** for 50mg BID: N=1 Q148H + G140S / Y143Y/H/R/C for 50mg QD: N=1 Q148H + G140S / Y143H
N=1 Q148H + E138A+G140S / Y143H
Ba
se
lin
e F
old
Ch
an
ge
64
32
16
8
4
2
1
0.5DTG 50mg QD
Cohort IDTG 50mg BID
Cohort II
5.9
2.5
1.51.0
5.4
2.7
1.4
Eron J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 151LB.
*Primary endpoint: <400c/mL and/or ≥0.7log decline in HIV RNA
VIKING Study: Virologic Results
DTG 50mg QD
(n=27)DTG 50mg BID
(n=24)
All subjects: 1o endpoint*
21/27 (78%) 23/24 (96%)
With Q148 +≥1 3/9 (33%) 11/11 (100%)
With other pathways 18/18 (100%) 12/13 (92%)
All subjects: <400 c/mL
11/27 (41%) 13/24 (54%)
Eron J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 151LB.
Phase I/II Study of GS 7340: Novel Tenofovir Pro-drug
• Amidate Prodrug that is designed to target lymphoid cells− Results in lower systemic exposures of TDF
• 14 day monotherapy study in HIV adults• ART naïve subjects randomized, double blinded
− TDF 300mg (n=10)− GS-7340 – 50 mg (n=10)− GS-7340 – 150 mg (n=10)
• PK in plasma AUC 24− GS-7340 50mg – 88% lower than TDF− GS-7340 150mg – 56% lower than TDF
• No safety issues over 14 days no resistance
Markowitz M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 152LB.
Phase I/II Study of GS 7340: Viral Dynamics
Treatment (10 pts/arm)
Mean ΔVLDay 14
[log10 c/mL]
p-value of mean ΔVL vs.TDF 300 mg
TDF 300 mg - 0.94 0.49 -
GS-7340 50 mg - 1.57 0.53 0.0257
GS-7340 150 mg - 1.71 0.24 0.0010
Markowitz M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 152LB.
-2
-1.5
-1
-0.5
0
0.5
0 7 14 21 28
∆V
iral
Lo
ad f
rom
Bas
elin
e(l
og
10 c
/mL
)
Day
BMS 663068: Pro-drug of an Attachment Inhibitor
No safety signal or concern regarding AEs based on data presentedSummary: Evidence of activity in once daily unboosted dosing; phase IIb planned
Nowicka-Sans B, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 518.
Median Maximum Change in HIV-1 RNA From Baseline with Monotherapy
• Novel attachment inhibitor• Study in pts either ARV-naïve or off ARVs: 8 day treatment period
DART: Second Line Therapy Following 3 NRTI Failure
• Patients failing first-line 3 NRTI therapy randomized to LPV/r + NNRTI (EFV/NVP) alone (n=67) or plus ddI (n=67) or 3TC (n=68)
Exact (3 randomized groups X 4 VL groups) P=0.24
Viral Load at Switch
Per
cen
t o
f P
ati
en
ts
Viral Load
Mambule I, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 541.
DART: Virologic Response at 24 Weeks
Exact (3 randomized groups X 5 VL groups) P=0.83VL < vs ≥50 c/ml P=0.42VL ≤ vs >1,000 c/ml P=0.44
Mambule I, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 541.
ACTG 5230: LPV/r Monotherapy Following Failure of First-line NNRTI
• Patients failing first-line NNRTI-containing combinations started LPV/r 400/100mg monotherapy (N=123)− NNRTI-regimen ≥6 months− HIV RNA 1,000-200,000 copies/mL− Resistance:
− 98% ≥1 NNRTI mutation− 95% ≥1 NRTI mutation
• At week 24, 107 subjects (87%) remained on LPV/r monotherapy without VF
• 13 subjects intensified ART with FTC/TDF− 85% suppressed to <400 copies/mL
• New major mutations: A71T (n=2), V82F (n=2)
Bartlett J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 583.
STAR Study: LPV/r With or Without TDF + 3TC Following
Failure of First-line NNRTI200 Patients who failed first-line NNRTI-containing randomized to
LPV/r BID monotherapy or LPV/r BID + TDF + 3TCResistance: M184V (82.1%, K65R (6.7%), ≥3 TAMS (33.3%), ≥4 TAMS (11.3%)
Proportion of Patients with Virological Suppression at 48 Weeks (M=F)
Bunupuradah T, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 584.
TRIO: Treatment of Heavily-Experienced Patients
• Single arm trial of combination of DRV/r, ETR and RAL (+/- nRTIs, ENF) in Heavily-Experienced Patients (Week 96 update)
Baseline Characteristics (n=100)
Years of ARV Use (Median) 13
CD4+ Nadir (Cells/mm3, Median) 80
# Mutations at ScreeningMajor PINRTIsNNRTIs
451
Fagard C, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 549.
88% HIV-1 RNA <50 copies/ml at Week 96
HIV RNA Suppression and CD4 Change
HIV
RN
A (
log
10 c
p/m
l) D
elt
a f
rom
We
ek
0M
ea
n a
nd
Sta
nd
ard
De
via
tio
nC
D4
(Ce
lls/m
m3) D
elta
from
We
ek
0 M
ea
n a
nd
Sta
nd
ard
De
via
tion
HIV RNA Delta from Week 0 (Log10 cp/ml)CD4 Cells per mm3 Delta from Week 0
Weeks
MONOI:Switch to DRV/r ± NRTIs
Valantin M-A, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 534.
Randomized study of DRV/r or DRV/r + NRTIs in Patients with HIV RNA <50 c/mL on ART and No Prior PI Failure and Naïve to DRV
P=0.07
71%
59%
Proportion with HIV RNA < 50 copies/ml (ITT)
Proportion with HIV RNA < 50 copies/ml at All Points from Baseline to Week 96
88%
84%
P=NS
MONOI: Response Predictors
• Conclusion: Favorable indicators for PI/r monotherapy include patient with undetectable HIV RNA when monotherapy begun, strict adherence to ART, and on ART for a long time before switching to monotherapy
All Patients (Week 96) Univariate Analysis Multivariate Analysis
Variables Associated with Rebound by W96 OR (95%CI) P OR (95%CI) P
Difficulty in Adherence (< 100% vs. 100% adherence) 2.04 (0.97, 4.32) 0.06
Randomized Group (Monotherapy vs. HAART) 3.15 (1.39, 7.13) 0.004 4.81 (1.91, 13.7) 0.002
Baseline US HIV-1 RNA (<1 copy/mL vs. Others) 0.47 (0.21, 1.04) 0.053
HIV-1 DNA at D 0 (per 1 log10 copies/106 cells increase) 1.70 (1.02, 2.84) 0.044 1.97 (1.10, 3.57) 0.02
HIV-1 RNA at D 0 (Blip vs. <50 copies/mL) 3.74 (0.85, 16.47) 0.010 0.023
Duration of Prior ART (per 5 years decrease) 1.74 (1.11, 2.73) 0.013 2.11 (1.23, 3.8) 0.009
Patients Randomized in the DRV/r Monotherapy ARM Univariate Analysis Multivariate Analysis
Variables Associated with Rebound by W96 OR (95%CI) P OR (95%CI) P
Difficulty in Adherence (< 100% vs. 100% adherence) 2.36 (0.94, 5.92) 0.07 3.84 (1.29, 12.49) 0.02
Randomized Group (Monotherapy vs. HAART) 2.38 (1.30, 4.38) 0.003 2.93 (1.43, 6.66) 0.006
Baseline US HIV-1 RNA ( <1 copy/mL vs. Others) 0.41 (0.16, 1.05) 0.06
HIV-1 DNA at D 0 (per 1 log10 copies/106 cells increase) 2.45 (1.07, 5.61) 0.03 2.66 (1.11, 7.48) 0.04
HIV-1 RNA at D 0 (Blip vs. <50 copies/mL) 4.05 (0.76, 21.5) 0.11
Valantin M-A, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 534.
MVC Intensification
• Randomized, placebo controlled, 24 week study (N=45)− Virologically suppressed pts, on ART for >1 yr with CD4 <350
• Primary outcome – change in activated CD8 T cells in peripheral blood
• Conclusions:− T cell activation increased in gut and blood− Lower LPS levels (p=0.41)− No impact on CD4 cell counts
Rectal lymph cells CD4 activation CD8 activation
Placebo No change No change
Maraviroc +22% (p<0.001) +9% (p<0.001)
Hunt P, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 153LB.
ACTG 5244: RAL Intensification
• Randomized Cross-over Study− Chronic patients on ART with full suppression (N=50)
• Results: No impact on 2-LTR levels, VL by U/S, HIV DNA levels, T cell activation
Gandhi R, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 51
Arm A: RAL first (immediate intensification)Arm B: Placebo first (deferred intensification)
% CD4+ CD38+HLA-DR+ % CD8+ CD38+HLA-DR+
More M184V When 3TC is Used with TDF Compared to FTC
French clinic cohort
• Evaluated resistance at failure with EFV or PI/r + TDF + 3TC or FTC
• Conclusion: Findings similar to those in clinical trials and suggests PK profile of the
whole regimen is an important factor in limiting failure and
drug resistance
Marcelin A-G, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 617.
Percentage of M184V
Role of NRTIs in RAL-based Salvage ART
Swiss Cohort• Patients who received RAL
as part of new ART regimen • Compared those with 2
NRTIs vs. <2 NRTIs and suppression rates at 24 wks
• Based on GT activity of background ART was higher in the <2 NRTI group (GSS=2.5 vs. 2.0)
• Median GSS for NRTI was 0.5 in both groups
• Multivariate analysis showed better response with 2 NRTI’s
Scherrer A, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 550.
0.01 0.1 1 10
Viral Suppression at Week 24
Per Protocol (n=83)
2 NRTIs better <2 NRTIs betterITT m=f (n=130)
Metabolics, Body Shape Changes and Adverse Events
Graeme J. Moyle, MD, MB, BSAssociate Director of HIV Research
Chelsea & Westminster HospitalLondon, England
ECHO/THRIVE: Grade of Psychiatric AEs by Randomized Group
Mills A, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 420.
RPV
EFV
RPV
EFV
RPV
EFV
RPV
EFV
RPV
EFV
RPV
EFV
Anx
iety
Dep
ress
ion
Inso
mni
aSl
eep
Dis
orde
rs
Abn
orm
alD
ream
s/ni
ghtm
ares
(com
bine
d)
All
slee
pdi
sord
ers
(com
bine
d)
Grade 1Grade 2Grade 3
Proportion of Patients (%)0 5 10 15 20
p<0.001
p<0.0001
ECHO/THRIVE: Mean Changeto Week 48 in Lipid Parameters
by Regimen
Mean lipid parameter, mg/dL
ABC/3TC ZDV/3TC TDF/FTC
RPVn=31
EFVn=30
RPVn=95
EFVn=86
RPVn=472
EFVn=459
Total Cholesterol 16.9 40 8.7 32.2 -0.4 25.7
LDL-C 5.8 22.3 1.7 17.4 -2.1 13.3
HDL-C 7.2 10.7 4.9 11.4 2.9 9.5
Triglycerides 13.2 43.3 11.8 9.4 -12.4 11.7
Change from baseline to Week 48 in 10-year Framingham CHD risk was the same in both treatment groups (–0.09)
Arribas J, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 819.
Week 96 Cardiovascular Factors
Shaffer D, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 818.
OCTANE : LPV/r vs. NVP + TDF/FTCin Women Initiating ART in Sub-Saharan Africa
NVP(n=370)
LPV(n=371)
Adjusted Analysis
Mean Change Mean Change P value
TC (mg/dl) 26.6 34.3 0.014
HDL (mg/dl) 18.8 13.0 <0.001
TC/HDL ratio -1.6 -0.6 0.006
SBP (mm hg) 6.8 3.5 0.007
DBP (mm hg) 4.1 0.2 <0.001
BMI (kg/m²) 2.7 1.8 0.003
ATV/r N = 24
DRV/rN = 25
Male, n (%) 22 (92%) 23 (92%)
Age, mean 46 48
CD4 Count cells/mm3 mean (range)
554 (31-1066) 584 (249-996)
Viral Load copies/mL, median
< 50 < 50
LPV/r 23 23
FPV/r 1 2
TDF/FTC 17 15
ABC/3TC 5 5
LARD: Changing PI/r for Hypertriglyceridemia
• Similar % on ATV/r (55%) and DRV/r (48%) achieved a TG <200 mg/dL by week 24 • Changes in other lipid fractions were also similar• Virologic suppression was maintained in both arms
Tri
gly
ceri
des
, mg
/dL
Replace LPV/r (n=46) or FPV/r (n=3) with ATV/r or DRV/r for Hypertriglyceridemia
Skiest D, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 817.
Study ABC Non-ABC Risk Difference
(95% CI)
Non-ABC Worse ABC Worse
ACTG 368 xii 0/140 (0%) 0/143 (0%) 0 (-2.73, 2.87)
COL30305 0/58 (0%) 0/29 (0%) 0(-13.79, 6.38)
ACTG 372A xiii 4/116 (3.45%) 3/113 (2.65%) 0.79 (-4.77, 6.54)
ACTG A5202 xiv 2/923 (0.22%) 5/925 (0.54%) -0.32 (-1.08, 0.33)
ABCDE xv 0/115 (0%) 2/122 (1.64%) -1.64 (-6.17, 1.64)
FIRST xvi 0/93 (0%) 0/89 (0%) 0(-4.49, 4.13)
ACTG 5095 xvii 6/758 (0.79%) 1/376 (0.27%) 0.53 (-0.75, 1.5)
ACTG A5110 xviii 0/48 (0%) 0/53 (0%) 0 (-7.01, 8.34)
STEAL xix 4/178 (2.25%) 1/175 (0.57%) 1.68 (-1.27, 5.17)
NEFA xx 1/149 (0.67%) 0/311 (0%) 0.67 (-0.55, 4.04)
CNAF3007 1/96 (1.04%) 1/91 (1.1%) -0.06 (-5.23, 4.9)
CNA30017 0/80 (0%) 2/127 (1.57%) -1.57 (-5.61, 3.38)
ESS 40003 0/51 (0%) 0/44 (0%) 0 (-9.09, 7.08)
CNAA3006 0/102 (0%) 0/103 (0%) 0 (-3.79, 3.88)
NZTA4002 0/150 (0%) 3/152 (1.97%) -1.97 (-5.94, 0.58)
CNA109586 0/192 (0%) 1/193 (0.52%) -0.52 (-3.12, 1.55)
CNAB3014 0/165 (0%) 0/164 (0%) 0 (-2.42, 2.4)
ESS40002 1/85 (1.18%) 0/166 (0%) 1.18 (-1.14, 7.08)
BIOCOMBO xxi 1/167 (0.6%) 1/166 (0.6%) 0 (-3.15, 3.11)
CNAB3002 0/91 (0%) 0/93 (0%) 0 (-4.35, 4.19)
EPZ104057 1/343 (0.29%) 0/345 (0%) 0.29 (0.86, 1.75)
CNA30024 1/324 (0.31%) 0/325 (0%) 0.31 (0.91, 1.86)
CNAC3005 1/262 (0.38%) 0/264 (0%) 0.38 (-1.13, 2.29)
ESS100327 0/137 (0%) 1/141 (0.71%) -0.71 (-4.27, 2.21)
CNAC3003 1/156 (0.54%) 0/80 (0%) 0.64 (-4.21, 3.6)
CNAB3001 0/49 (0%) 1/50 (2%) -2(-11.05, 5.37)
Mantel-Haenszel 0.01 (-0.26, 0.27)
FDA Meta-AnalysisNo Association Between ABC and MI
• 26 RCTs involving ABC− 5028 subjects on
ABC, 4840 controls− Average 1.62 person/years of
F/U
• Overall events/subjects: 28/5628 ABC vs. 22/4840 controls (OR 1.02 95%CI 0.56, 1.84)
• Authors conclude that the findings ‘raise significant uncertainty about the likelihood of an ABC-MI risk association’
Forest Plot of Meta Analysis Results: Trials Sorted Based on Duration of Person –Years of Follow-up
Ding X, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 808.
-5.0% -2.5% 0.0% 2.5% 5.0%
PREPARE: Change in Limb Fat, Fat Mass and mtDNA
with ZDV/3TC to TDF/FTC• Design: On ZDV/3TC ≥2 years VL<50 c/ml randomized to continue or switch to TDF/FTC• Results: Subjects switched to TDF had significantly increase in both subcutaneous adipose tissue
and limb fat at week 48• Switch to TDF resulted in significantly greater increases in mtDNA content and mtDNA quality at
weeks 24 and 48 and adipocyte volume
Feeney E, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 846.
P<0.05 (W48 TDF vs W0 TDF)P=0.50 (W48 TDF vs ZDV)
P<0.01 (TDF W48 vs TDF W0)P=0.01 (TDF vs ZDV at W48)
ACTG 5224s: Visceral Fat Change by Regimen in A5202
• ATV/r led to greater gains in weight (1.1kg more), trunk fat and a trend to greater gain in VAT than EFV. There were no differences between NRTIs
• Changes in VAT correlated with changes in limb fat (r=0.48; p<0.001)• Age, sex, race/ethnicity, baseline HIV-1 RNA, CD4 count, and BMI were not associated
with week 96 absolute or percent change in VAT
0 10 20 30 40 50
ATV/rEFVABC/3TCTDF/FTC
NRTI ComponentSecondary Analysis
NNRTI/PI ComponentSecondary Analysis
VAT change from week 0 (%)
P=0.55
P=0.090
CT Results: Mean percent change in VAT (ITT, Week 96)
McComsey, G, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 77.
FRAM: Low Limb Muscle Massand Central Adiposity Associated with
5 Year Mortality
Arm SM:
LegSM:
VAT:
Tertile 1
Tertile 2
Tertile 3
Tertile 1
Tertile 2
Tertile 3
Tertile 1
Tertile 2
Tertile 3
reference
0.59 (0.35, 0.99)
0.51 (0.25, 1.04)
reference
0.92 (0.54, 1.57)
0.42 (0.21, 0.84)
reference
1.77 (1.03, 3.03)
2.12 (1.13, 3.98)
Lower Odds of Death Higher Odds of Death
0.10 1.00 10.00Odds Ratio (95% CI)
Odds Ratio (95% CI)
Scherzer R, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 76.a
Bone Resorption as an IRIS Event
• TDF/FTC+LPV/r (n=20) • Bone resorption markers (CTx, RANKL) increase from week 2.
Maximal change for CTx +93% at week 12, and RANKL +162% at week 24 (both p<0.01)
• In T-cell null mice undergoing T cell reconstitution with similar changes in RANKL
Change in Bone Resorption with HAART
C-T
erm
inal
Tel
op
epti
de
(% C
han
ge
fro
m B
ase
lin
e)
HAART(LPV/r + TDF/FTC)
-100
0
100
200
300
400
0 2 12 24 Time (Weeks)
P<0.001 P<0.001
Ofotokun I, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 78.
iPrEX: PrEP in HIV-Negative IndividualsMean Change in BMD Through Week 72
FTC/TDF(n=247)
Placebo(n=256) Difference (95% CI) P-value
Total hip
Wk 24 -0.33 (0.13) +0.36 (0.13) -0.69 (-1.06 to -0.33) < 0.001
Wk 48 -0.02 (0.21) +0.91 (0.21) -0.94 (-1.53 to -0.35) 0.002
Wk 72 +0.25 (0.27) +0.59 (0.27) -0.34 (-1.10 to 0.42) 0.38
Spine
Wk 24 -0.65 (0.20) +0.30 (0.20) -0.94 (-1.50 to -0.39) 0.001
Wk 48 -0.38 (0.24) +0.20 (0.24) -0.58 (-1.24 to 0.07) 0.081
Wk 72 -0.96 (0.31) +0.07 (0.30) -1.03 (-1.88 to -0.19) 0.017
• There were no differences in bone fractures between the groups (p=0.56)
Mulligan K, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 94LB.
ECHO: Severe Vitamin D Deficiency with Rilpiverine vs. Efavirenz
P <0.05P <0.05
Deficient at BL Deficient or Insufficient at BL
Per
cen
tag
e D
evel
op
ing
Sev
ere
Vit
amin
D D
efic
ien
cy
• Change in 25(OH)D levels over 48wks: RPV -0.6 nmol/l (p=0.57) vs. EFV -6.2 nmol/l (p<0.05)
• Baseline insufficiency or deficiency had significantly greater risk of developing severe deficiency with EFV vs. RPV
Wohl D, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 79LB.
Vitamin D TherapyEffect on PTH
• Randomized trial of Vit D 50,000 IU/wk x 12 weeks vs. PBO in patients on (n=118) or not on (n=85) TDF
• Higher baseline PTH levels at baseline in TDF group• Vitamin D had no impact on PTH levels in patients not on TDF
TDF No TDF
Day 0
ChangeDay
0Change
Vit D 47 -6 26 -2
PBO 37 +2 25 0
Changes in PTH on study
Havens P, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 80.
Mean Baseline PTH by Vitamin D status and Tenofovir Use PTH Differs by Tenofovir use, not Vitamin D status
52
35
43
27
P=0.001P=0.001 P<0.001P<0.001
Treatment Effects of Vitamin D
• Goal: Evaluate effect of vitamin D on flow mediated dilitation (FMD)1
• Design: Placebo-controlled trial of vitamin D 4000 mg daily in patients with HIV RNA <50 c/mL and 25(OH)D ≤20 ng/mL− 2:1 randomization, n=45
• Results− No impact of vitamin D on
FMD compared to placebo− In vitamin D group:
− Non-HDL cholesterol fell 7.0 mg/dL
− No impact on markers of coagulation
− HOMA-IR and insulin levels rose
• Goal: Evaluate effect of vitamin D therapy on Incidence of DM II2
• Design: Non-randomized cohort (n=1574) study comparing vitamin D
(30,000 IU weekly) treated and non-treated patients
1. Longenecker C, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 829; 2. Guaraldi G, et al. ibid., Abst. 827.
Inci
de
nce
(%
)
• Tesamorelin 2mg in HIV+ persons with excess abdominal fat increases bone turnover markers over 26 weeks
• Relative to placebo, increases in osteocalcin (bone formation) were greater than NTx (bone resorption); Changes correlated with IGF-1 levels
Tesamorelin Increases Markers of Bone Formation
Mean changes from baseline to Week 26 in osteocalcin by treatment group
p<0.001 vs.placebo and baseline
211 Completed the Study (77%)
211 Completed the Study (77%)
115 Completed the Study (84%)
115 Completed the Study (84%)
273 Tesamorelin273 Tesamorelin 137 Placebo137 Placebo
412 Patients Randomized412 Patients Randomized
2 patients did not receive study drug
Mamputu J-C, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 834.
ManagementJürgen Rockstroh, MD
Professor, University of BonnBonn, Germany
Changing Patterns of the Causes of Death in a Swiss Cohort (SHCS)
• SHCS is a prospective observational cohort• Characteristics of participants that died from 2005-2009• 459 deaths/9,053 participants (5.1%)
Ruppik M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 789.
Causes of Death in Participants in the Swiss HIV Cohort Study in 3 different Time Periods, and in the Swiss Population in 2007
Years of Death of HIV+ Persons Versus Swiss Population
Study of immediate vs. early ART to reduce AIDS and death in HIV+ patients
with CD4+ cells <250 cells/mm3 and confirmed or suspected TB48 weeks analysis
N=405 TMP/SMX + TDF/FTC/EFV at 2 weeks post TB Tx
Arm 1 Immediate ART
(2 weeks after TB treatment)
N=401 TMP/SMX + TDF/FTC/EFV at 8-12 weeks post TB Tx
Arm 2 Early ART
(8-12 weeks after TB treatment)
Havlir D, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 38.
ACTG 5221: Starting ART in Patients on TB Therapy
ACTG 5221: Results
Immediate ART
Early ART p value
TB diagnosis confirmed 46% 54%
Median ART Start Time 10 days 70 days
Experienced AIDS or death by week 48
12.9% 16.1% p=0.45
Experienced AIDS or death by W48 with ≤ 50 cells/mm3 (n=285)
15.5% 26.6% p=0.02
>50cells/mm3 (n=521) 11.5% 10.3% p=0.67
Havlir D, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 38.
SAPiT: Reduced Survival ProbabilityWith Sequential vs Integrated
TB Therapy
N Engl J Med. 2010;362:697-706.
Su
rviv
al
Pro
ba
bil
ity
Mos after Randomization
0
0.70
0.75
0.80
0.85
0.90
0.95
1.00
0 2 4 6 8 10 12 14 16 18 20 22 24
Sequential therapy
Integrated therapy
SAPiT: Optimal Timing of ART Relative to TB Treatment
in Coinfected Patients
Early TreatmentInitiate ART within first 2 months of
starting TB treatment (n = 214)
Patients enrolled in the Integrated Treatment Arm of the SAPiT Trial:•HIV-infected patients •CD4+ < 500 cells/mm3
•Smear-positive TB(n=642)
Late TreatmentInitiate ART as soon as possible after 2 months
of intensive TB treatment phase completed(n = 215)
Karim S, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 39LB.
No discernable differences in AIDS/death
Early - Events / # at risk
Late - Events / # at risk
Karim S, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 39LB.
SAPiT: Kaplan-Meier Curve for AIDS or Death in Patients
with CD4 ≥50 cells/mm3
68% reduction of AIDS/death by starting ART Early (p=0.06)
Early - Events / # at risk
Late - Events / # at risk
Karim S, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 39LB.
SAPiT: Kaplan-Meier Curvefor AIDS or Death in Patients
with CD4 <50 cells/mm3
Treatment Outcome in Acute HCV in HIV-coinfection: RVR & EVR
• Prospective study of HIV-positive patients with acute HCV treated early with PegIFN alone (N=31) or with PegIFN/RBV (N=207)
Boesecke C, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 113.
Boesecke C, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 113.
Treatment Outcome in Acute HCV in HIV-coinfection: ETR & SVR
Boesecke C, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 113.
Treatment Outcome in AcuteHCV in HIV-coinfection:
Uni- and Multivariate AnalysisSVR n=161
no SVR n=77
Univariate p-value
Multivariate p-value
Multivariate Odds-Ratio
(95% CI)
RVR 65.4% 28.3% ≤0.0001 ≤0.00014.600
(2.336-9.059)
GT 2/3 21.7% 10.4% 0.046 0.0432.945
(1.034-8.385)
IL28B CC genotype 55.3% 34.8% 0.271
Median baseline CD4-cells [/µl] (95% range)
484 (368-632)
433 (347-602)
0.164
Baseline HIV-RNA <50 copies/ml
61.3% 56.7% 0.551
Baseline HCV-RNA >800,000 IU/ml
44% 58.1% 0.069
Median maximum ALT [U/l] (95% range)
398 (195-761)
325 (168-706)
0.227
Clinical symptoms 27% 22.4% 0.523
peg IFN/RBV 85.7% 88.3% 0.714
HAART 67.7% 63.6% 0.559
TW 8-24 HCV-RNA UndetectableTW 8-24 HCV-RNA Undetectable
TW 8-24 HCV-RNA DetectableTW 8-24 HCV-RNA Detectable
PR + Placebo PR + Placebo Follow-up
Follow-upFollow-up
BOCRGT
(N=368)
PR + Boceprevir PR + BoceprevirPRlead-in
BOC/PR48
(N=366)
PR + BoceprevirPR + Boceprevir Follow-upPRlead-in
SPRINT 2: Boceprevir in HCV Mono-infected Patients
Week 4 Week 48
PR + Placebo PR + Placebo Follow-upPRlead-in
Week 28 Week 72
Control48 P/R(N=363)
Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 115.
SPRINT-2: SVR and Relapse Rates (ITT)
Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 115.
p < 0.0001
p <0.0001
Non-Black Patients
p = 0.044
p =0.004
Black Patients
SVR
Relapse Rate
48 PR BOC RGT BOC/PR48
Median treatment duration (days) 203 197 335
Deaths (N) 4 1 1
Serious AEs 9% 11% 12%
Discontinued due to AEs 16% 12% 16%
Dose modification due to AEs 26% 40% 35%
Hematologic parameters
Neutrophil count (<750 to 500/mm3 / <500/mm3)
14% / 4% 24% / 6% 25% / 8%
Hemoglobin (<10 to 8.5 g/dL / <8.5 g/dL)
Discontinuation due to anemia
Dose reductions due to anemia
Erythropoietin use
Mean (median) days of use
26% / 4%
1%
13%
24%
121 (109)
45% / 5%
2%
20%
43%
94 (85)
41% / 9%
2%
21%
43%
156 (149)
SPRINT-2: Safety Profile Over Entire Course of Therapy
Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 115.
Study 110: Telaprevir in HIV/HCV Patients
Part A: no ARTPart A: no ART
240 48 72Weeks 12 36
PR PR
PR PR
T/PR TVR + PR Follow-upSVR
Follow-upPR48
(control)
SVRPbo + PR
PR PR
PR PR
Follow-upPR48
(control)
SVRPbo + PR
T/PR TVR + PR Follow-upSVR
Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC)Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC)
Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 146LB
Study 110: Demographics and Baseline Characteristics
Part A Part B
No ART EFV/TDF/FTCATV/r + TDF +
FTC/3TC
T/PRN=7
PRN=6
T/PRN=16
PRN=8
T/PRN=14
PRN=8
Gender, n (%): Male6 (86) 4 (67)
16(100)
7(88)
12(86)
7(88)
Race†, n(%) Caucasian Black/African American
2 (29)4 (57)
3 (50)3 (50)
12 (75)3 (19)
5 (62)3 (38)
12 (86)2 (14)
7 (88)1 (12)
Ethnicity†, n (%) Hispanic
3(43)
2(33)
5(31)
1(12)
3(21)
3(38)
Age, median years (range) 39(34-51)
48(43-65)
48(31-57)
47(31-53)
54(37-60)
39(26-53)
BMI, median kg/m2 (range) 29(22-37)
31(26-37)
24(21-32)
23(19-29)
24(23-33)
25(22-30)
HCV RNA ≥ 800,000 IU/mL**, n (%) 7(100)
5(83)
13(81)
7(88)
10(71)
7(88)
HCV Genotype Subtype*, n (%) 1a 1b
3 (43)4 (57)
3 (50)2 (33)
12 (75)4 (25)
6 (75)1 (12)
11 (79)3 (21)
5 (62)3 (38)
HIV RNA median copies/mL (range) 1495(155-53,450)
267 (25-21,950)
<50 <50 <50 <50
CD4+ median cells/mm3 (range) 604 (496-759)
672 (518-1189)
533 (299-1075)
514 (323-1034)
492(279-874)
535 (302-772)
Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 146LB
Study 110: Undetectable HCV RNA at Week 4 (RVR)
No ARTNo ART
EFV/TDF/FTCEFV/TDF/FTC
ATV/r + TDF + FTC/3TCATV/r + TDF + FTC/3TC
5/75/7 12/1612/16 9/149/14 0/80/81/81/80/60/6
71717575
00
6464
1313
00
Per
cen
t o
f p
atie
nts
w
ith
HC
V R
NA
Un
det
ecta
ble
Per
cen
t o
f p
atie
nts
w
ith
HC
V R
NA
Un
det
ecta
ble
TVR + PRTVR + PR
n/N =n/N =
PRPR
0
10
20
30
40
50
60
70
80
90
100
Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 146LB
Study 110: Undetectable HCV RNA at Week 12 (cEVR)
Per
cen
t o
f p
atie
nts
w
ith
HC
V R
NA
Un
det
ecta
ble
Per
cen
t o
f p
atie
nts
w
ith
HC
V R
NA
Un
det
ecta
ble
TVR + PRTVR + PR
n/N =n/N =
PRPR
0
10
20
30
40
50
60
70
80
90
100
71717575
1717
5757
1212 1212
5/75/7 12/1612/16 8/148/14 1/81/81/81/81/61/6
Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 146LB
No ARTNo ART
EFV/TDF/FTCEFV/TDF/FTC
ATV/r + TDF + FTC/3TCATV/r + TDF + FTC/3TC
Part A Part B
No ART EFV/TDF/FTC ATV/r + TDF + FTC/3TC
T/PR(N=7)
PR(N=6)
T/PR(N=16)
PR(N=8)
T/PR(N=14)
PR(N=8)
Any AE 100% 83% 94% 88% 100% 100%
Serious AE 14% 0 0 0 21% 0
Discontinuation of all study drugs
Due to AE
Due to anemia
Due to rash
0
0
0
0
0
0
0
0
0
0
0
0
14%
7%
0
0
0
0
Study 110: Serious Events and Treatment Discontinuation
• Mild and moderate rash events occurred in 16% and 11% of T/PR patients, respectively and in 14% and <1% of PR patients
Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 146LB
Pharmacokinetic Interactions Between ARVs and Telaprevir
TVR Dose ARV TVR AUC TVR Cmin ARV AUC ARVCmin
TVR 750 mg tid ATV/r0.80
(0.76-0.98)0.85
(0.75-0.98)1.17
(0.97-1.43)1.85
(1.40-2.44)
DRV/r0.65
(0.61-0.69)0.68
(0.63-0.74)0.60
(0.57-0.63)0.58
(0.52-0.63)
FPV/r0.68
(0.63-0.72)0.70
(0.64-0.77)0.53
(0.49-0.58)0.44
(0.40-0.50)
LPV/r0.46
(0.41-0.52)0.48
(0.40-0.56)1.06
(0.96-1.17)1.14
(0.96-1.36)
TVR 1250 mg tid EFV
0.82 (0.73-0.92)
0.75 (0.66-0.86)
0.82 (0.74-0.90)
0.90 (0.81-1.01)
TDF1.10
(1.03-1.18)1.17
(1.06-1.28)
TVR 1500 mg bid EFV
0.80 (0.73-0.88)
0.52 (0.42-0.64)
0.85 (0.79-0.91)
0.89 (0.82-0.96)
TDF1.10
(1.03-1.17)1.06
(0.98-1.15)
Van Heeswijk R, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 119.
PK of Rilpivirine Following EFV
• EFV is an inducer of Cyp3A; it can increase the metabolism of RPV
• 20 healthy volunteers treated sequentially− Part A: RPV x 2 wks, plus 2 wks washout
(control)− Part B: EFV X 2 weeks followed by C− Part C: RPV x 4 weeks (Switch)
• To compare RPV PKs during Part A andPart C
• Results:− RPV exposures lower after switch from EFV− Differences were very significant on day 1− RPV PK gradually improved over 4 weeks − Levels of EFV were detectable for
3 weeks post dose
• Concentrations of RPV may be affected after a switch from an EFV containing regimen
Crauwels H, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 630.
Outcomes Measurement Reminder
• CME providers are required to assess “changes in learners competence, performance or patient outcomes achieved as a result of their participation in a CME sponsored educational activity”
• As a result of this requirement you will receive via e-mail a short 1-page survey 2 to 3 months after completing this course− We consider the survey to be an additional component of your overall
participation in this educational activity and would urge you to reflect on what you learned in the activity and then complete this survey
• Please be certain that you have correctly written your e-mail address on the CME evaluation form that you complete at the end of today’s activity
The 18th Conference on Retroviruses and Opportunistic
InfectionsBoston, MA
February 27-March 2, 2011