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Greatest Hits of 2012
Mark Wainberg
McGill AIDS Centre
Jewish General Hospital
Montreal, Quebec
Long-Term Safety and Efficacy of
Raltegravir-Based Versus Efavirenz-Based
Combination Therapy in Treatment-Naïve
HIV-1 Infected Patients:
Final 5-Year Double-Blind Results
From STARTMRK
AIDS 2012
Poster #LBPE19
Copyright © 2012 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All Rights Reserved
Proportion (%) of Patients Achieving HIV RNA
<50 copies/mL (95% CI) Over Time
Non-Completer = Failure Approach
Percent of Patients with
HIV RNA Levels <50 Copies/mL
100
86
81
75
76
69
67
71%
80
82
79
60
61%
40
20
0
0 12 24
48
72
96
120
144
168
192
216
240
Weeks
Number of Contributing Patients
Raltegravir 400 mg bid.
281278279
280
281
281
277
280
281
281
277
279
Efavirenz 600 mg qHS.
282282282
281
282
282
281
281
282
282
282
279
3
Copyright © 2012 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All Rights Reserved
Change From Baseline in CD4-Cell Count
(95% CI) Over Time
374
361
Change from Baseline
CD4 Cell Count (cells/mm3)
400
331
350
300
240
250
189
200
312
301
295
225
150
163
100
50
0
0 12 24
48
72
96
120
144
168
192
216
240
235
228
231
224
235
220
227
218
222
212
Weeks
Number of Contributing Patients
Raltegravir 400 mg bid. 281272266
Efavirenz 600 mg qHS. 281268266
258
251
255
252
250
243
240
234
4
Copyright © 2012 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All Rights Reserved
Adverse-Event Summary
RAL Group
(N=281)
EFV Group
(N=282)
Number (%) of patients:
n (%)
n (%)
% (95% CI)
p-Value
With one or more AEs
271 (96.4)
276 (97.9)
-1.4 (-4.6, 1.5)
0.325
10 (3.6)
6 (2.1)
1.4 (-1.5, 4.6)
0.325
With drug-related AEs
146 (52.0)
226 (80.1)
-28.2 (-35.5, -20.6)
<0.001
With serious AEs
57 (20.3)
57 (20.2)
0.1 (-6.6, 6.7)
1.000
With serious drug-related AEs
8 (2.8)
7 (2.5)
0.4 (-2.6, 3.3)
0.801
Who died
5 (1.8)
5 (1.8)
0.0 (-2.5, 2.6)
1.000
D/C due to AEs
14 (5.0)
25 (8.9)
-3.9 (-8.3, 0.3)
0.096
D/C due to drug-related AEs
3 (1.1)
14 (5.0)
-3.9 (-7.2, -1.2)
----
D/C due to serious AEs
11 (3.9)
10 (3.5)
0.4 (-3.0, 3.8)
----
D/C due to serious drug-related AEs
1 (0.4)
2 (0.7)
-0.4 (-2.2, 1.3)
----
With no AEs
Difference
(RAL – EFV)
5
Copyright © 2012 Merck & Co., Inc., Whitehouse Station, New Jersey, USA, All Rights Reserved
Final 5-Year Results of the BENCHMRK
Studies: Sustained Antiretroviral Effect of
Raltegravir, and Exploratory Analysis of Late
Outcomes based on Early Virologic Response
J. J. Eron1, D. A. Cooper2, R. T. Steigbigel 3, B. Clotet4,
H. Wan5, J. Zhao5, T. Ly5, D. Hepler5, P. Sklar5,
B-Y. Nguyen5, and H. Teppler5
for the BENCHMRK-1 and 2 Study Groups
1University
of North Carolina, Chapel Hill, NC, USA; 2University of New
South Wales, Sydney, Australia; 3SUNY at Stony Brook, Stony Brook,
NY, USA; 4University of Barcelona, Spain; 5Merck Research
Laboratories, North Wales, PA, USA
6
Presented at AIDS 2012, Washington DC, 24-July-2012, Abstract # A-452-0098-12576.
Study Design: BENCHMRK-1&2
• Randomized, double-blind, placebo-controlled with DSMB.
• Total study duration of 240 weeks.
• Double-blind phase completed at Week 156; all patients offered
open-label RAL through Week 240.
Primary analysis:
Week 16
HIV-1-infected
Triple-class resistant
HIV-1 RNA >1000 copies/mL
No CD4 cell cut-off
BENCHMRK-1 (N=352)
(Europe, Asia/Pacific and Peru)
BENCHMRK-2 (N=351)
(North and South America)
Final analysis:
Week 240
RAL/OLRAL Treatment Group
RAL 400 mg BID + OBT
BENCHMRK-1 (n=234)
BENCHMRK-2 (n=232)
RAL 400 mg
BID + OBT
2:1
Pbo/OLRAL Treatment Group
Placebo + OBT
BENCHMRK-1 (n=118)
BENCHMRK-2 (n=119)
RAL 400 mg
BID + OBT
Double-blind (Weeks 0-156)
Open-label
7
Patients Achieving HIV RNA <50 copies/mL
(NC=F†)
For patients who entered Open-Label RAL phase at wk 156, HIV RNA was <50 copies/mL
at wk 240 in 77% (193/251) of RAL group and 81% (38/47) of Pbo group.
8
† Non-completer=failure approach; error bars indicate 95% confidence interval.
Patients Achieving HIV RNA <400 copies/mL
(NC=F†)
For patients who entered Open-Label RAL phase at wk 156, HIV RNA was <400 copies/mL
at wk 240 in 84% (210/251) of RAL group and 85% (40/47) of Pbo group.
9
† Non-completer=failure approach; error bars indicate 95% confidence interval.
Table 5. Number (%) of Patients† with Integrase
Mutations at Time of Virologic Failure
RAL/OLRAL + OBT
N = 148
Mutation at AA 143, 148 and/or 155
89
(60.1)
Mutation at AA 143
18
(12.2)
Mutation at AA 148
36
(24.3)
Mutation at AA 155
58
(39.2)
59
(39.9)
6
(4.1)
No mutation at AA 143, 148 or 155
Other known RAL resistance mutations‡
Virologic failure: (1) <1 log10 ↓ in HIV RNA from baseline and HIV RNA >400 c/mL at wk 16, OR (2)
virologic relapse: >1 log10 ↑ in HIV RNA above nadir or >400 c/mL from nadir (on 2 consecutive
measurements at least 1 wk apart) after response <400 c/mL . After week 48, VF = HIV RNA > 50 c/mL
on 2 consecutive measurements at least 1 week apart.
† over the entire study period; among patients who received RAL in DB phase followed by OLRAL.
‡ Included L74M, E92Q, T97A, E138A, E138K, G140A, G140S, G163R, S230R.
•
Mutations detected in patients with virologic failure during OLRAL phase
(Week 156-240)
 RAL group: 3 patients (1 with Q148Q/H/R, 2 with N155H)
 PBO group: 1 patient (with Q148H)
10
Change From Baseline in CD4 Cell Count (OF†)
For patients who entered Open-Label RAL phase at wk 156, CD4 count change from
baseline to Week 240 was +293 cells/µL in RAL group and +267 cells/µL in Pbo group.
11
† Observed Failure Approach: only discontinuations for lack of efficacy are counted as failures.
XIX International AIDS Conference 2012
Washington DC, USA, 22-27 July, 2012
B40: Clinical trials and antiretroviral therapy in children and adolescents
IMPAACT P1066: Raltegravir (RAL) safety
and efficacy in HIV infected (+) youth 2 to 18
years of age through week 48
S. Nachman1, E. Acosta2, N. Zheng3, H. Teppler4, B. Homony4, X. Xu4,
C. Alvero3, E. Handelsman5, C. Worrell6, B. Graham7, M. Toye8,
E. Petzold9, A. Wiznia10, and the P1066 Group
1SUNY
Stony Brook, Pediatrics, Stony Brook, United States;
2University of Alabama at Birmingham, Birmingham, United States;
3Harvard School of Public Health, Boston, United States;
4Merck, North Wales, United States;
5Division of AIDS, NIAID, NIH, Bethesda, United States;
6Natl Inst of Child Hlth and Human Devt, Bethesda, United States;
7Frontier Science Inc, Buffalo, United States;
8Baystate Medical Center, Springfield, United States;
9Social and Scientific Systems, Durham, United States;
10Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, United States
Background


New antiretrovirals are needed for HIV+
children.
IMPAACT P1066 is an international Phase
I/II open label multicenter trial to evaluate
pharmacokinetics (PK), safety, tolerability,
and efficacy of multiple RAL formulations
in treatment experienced HIV+ youth
Percent of Patients with HIV RNA <50 Copies/mL
Efficacy: Percent of Patients (95% CI) with
vRNA<50 c/mL (Final Dose)
Week 24 Week 48
Cohort I
55.2%
57.1%
50.0%
Cohort IIA 50.0%
54.5%
Cohort IIB 53.8%
50.0%
57.9%
Cohort III
53.7%
56.7%
Total
100
80
60
40
20
0
0
4
8
12
24
96
91
90
95
48
94
90
Weeks
Number of Contributing Patients
Total
36
95
mk518p22.foffd50c July 10, 2012
Conclusions (2)



Data from this study has been used in
obtaining US FDA approval for use of
raltegravir in HIV+ youth ages 2-18 yrs
RAL film-coated tablet: 400 mg BID
 Ages 12 to 18 yrs
 Ages 6 to <12 yrs, weight ≥ 25kg
RAL chewable tablet
 Ages 2 to <12 yrs, weight ≥10kg: weight
based dosing (75-300mg) BID
iPREX
Study Design
Proof of concept double-blinded, randomized, placebo-controlled trial
TDF/FTC 1 pill/day
• HIV uninfected MSM at
high risk of sexual
acquisition of HIV
(n=1251)
Placebo 1 pill/day
(n=1248)
 High risk defined as having in the 6 months prior to screening : anal sex with > 4
partners, STI, transactional sex, condomless anal sex (HIV prevalence at
screening : 8%)
 Events driven trial : 85 events yield a power of 80% to reject the null hypothesis
of efficacy of < 30% if the true efficacy is > 60%
 Rapid HIV testing at every 4 weeks visit, with drug dispensation and adherence
counseling
Grant RM et al N Engl J Med, Nov 23, 2010.
iPREX : KM Estimates of Time to HIV Infection (mITT Population)
After a median follow-up of 14 months, 100 subjects became infected, 36 in
the TDF/FTC arm and 64 in the placebo arm :
44% reduction in the incidence of HIV (95% CI : 15-63, p=0.005)
Update at CROI 2011 : 42% at 144 weeks
Grant RM et al N Engl J Med, Nov 23, 2010.
Iprex : Levels of Study-Drugs in Blood of Subjects Receiving TDF/FTC
 The study drug was
detected in 22/43 (51%) of
seronegative subjects and
3/34 (9%) of HIV-infected
subjects
 In the TDF/FTC group
among those with detectable
level, odds of HIV lower by a
factor 12.9, corresponding to
a relative protection of 92%
Detectable levels strongly
correlated with prophylactic
effect
TDF/FTC Limit of detection in plasma : 10 ng/ml
Grant RM et al. N Engl J Med 2010.
Inconsistency of Prep Results
 Iprex : 44% reduction in the incidence of HIV (95% CI : 15-63 ) after a
median follow-up of 14 months, and 42% afer 144 weeks
 Failure to reach the primary endpoint : trial was designed to exclude a
strategy with < 30% of protection
 5 trials using oral Prep have reported results : 2/5 could not show a
benefit
 Oral TDF and TDF/FTC failed to prevent HIV-infection in heterosexual
women in Sub-Saharan Africa (VOICE, Fem-Prep)
 Oral TDF and TDF/FTC prevented new HIV-infections in heterosexual
individuals (TDF-2 : 62.6%) and discordant couples (Partners Prep :
75% TDF/FTC and 67% TDF)
 Will efficacy be better/worse outside placebo-controlled trials ?
 Efficacy of Prep could be different from its effectiveness
 Open-label extension if Iprex (Iprex-OLE) could answer this question
The occurrence of drug
resistance to either FTC
(M184I/V) or TDF (K65R)
does not appear to be a
problem in all the studies
conducted until now.
Unlike M184V and L74V,
there is not a single case of
transmitted K65R on record
IPERGAY
Study Design
Proof of concept of “on demand” Prep
Randomized placebo-controlled trial
• High risk MSM
• Condomless anal sex with > 2
partners
Full prevention services*
TDF/FTC before and after sex
(n=950)
Full prevention services*
placebo before and after sex
(n=950)
 *Counseling, testing for STI, condoms, HBV and HAV vaccination, PEP
 Primary endpoint : HIV infection, 64 events expected
 Incidence of HIV-infection: 3% / yr in the control arm, assessing a 50% efficacy of Prep
and a two-year follow-up : need to enroll ~ 2000 individuals
HPTN 052 Study Design
Stable, healthy, serodiscordant couples, sexually active
CD4 count: 350 to 550 cells/mm3
Randomization
Immediate ART
CD4 350-550
Delayed ART
CD4 <250
Primary Transmission Endpoint
Virally linked transmission events
Primary Clinical Endpoint
WHO stage 4 clinical events, pulmonary tuberculosis,
severe bacterial infection and/or death
96%
Results of the HPTN052 trial
announced on 12 May 2011
show that if an HIV-positive
person adheres to an effective
antiretroviral therapy regimen,
the risk of transmitting the virus
to their uninfected sexual
partner can be reduced by 96%
UNAIDS 2011 AIDS at 30
SMARTER , FASTER , BETTER CAMPAIGN
“Treatment
for
prevention
is a game
changer”.
Michel Sidibe
Executive
Director of
UNAIDS
Thank you
Merci