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. Eron 1, D. A. Cooper 2, R. T. Steigbigel 3, B. Clotet 4, H. Wan 5, J. Zhao 5, T. Ly 5, D. Hepler 5, P. Sklar 5, B-Y. Nguyen 5, and H. Teppler 5 for the BENCHMRK-1 and 2 Study Groups 1 University of North Carolina, Chapel Hill, NC, USA; 2 University of New South Wales, Sydney, Australia; 3 SUNY at Stony Brook, Stony Brook, NY, USA; 4 University of Barcelona, Spain; 5 Merck Research Laboratories, North Wales, PA, USA 6 Presented at AIDS 2012, Washington DC, 24-July-2012, Abstract # A-452-0098-12576.
7 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. RAL 400 mg BID + OBT BENCHMRK-1 (n=234) BENCHMRK-2 (n=232) Placebo + OBT BENCHMRK-1 (n=118) BENCHMRK-2 (n=119) 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) 2:1 Primary analysis: Week 16 Final analysis: Week 240 RAL 400 mg BID + OBT RAL 400 mg BID + OBT Double-blind (Weeks 0-156) Open-label Pbo/OLRAL Treatment Group RAL/OLRAL Treatment Group
Patients Achieving HIV RNA <50 copies/mL ( NC=F † ) 8 † Non-completer=failure approach; error bars indicate 95% confidence interval. 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.
Patients Achieving HIV RNA <400 copies/mL ( NC=F † ) 9 † Non-completer=failure approach; error bars indicate 95% confidence interval. 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.
10 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 15589(60.1) Mutation at AA 14318(12.2) Mutation at AA 14836(24.3) Mutation at AA 15558(39.2) No mutation at AA 143, 148 or 15559(39.9) Other known RAL resistance mutations ‡ 6(4.1) 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) Virologic failure: (1) 400 c/mL at wk 16, OR (2) virologic relapse: >1 log 10 ↑ in HIV RNA above nadir or >400 c/mL from nadir (on 2 consecutive measurements at least 1 wk apart) after response 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.
Change From Baseline in CD4 Cell Count (OF † ) 11 † Observed Failure Approach: only discontinuations for lack of efficacy are counted as failures. 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.
IMPAACT P1066: Raltegravir (RAL) safety and efficacy in HIV infected (+) youth 2 to 18 years of age through week 48 S. Nachman 1, E. Acosta 2, N. Zheng 3, H. Teppler 4, B. Homony 4, X. Xu 4, C. Alvero 3, E. Handelsman 5, C. Worrell 6, B. Graham 7, M. Toye 8, E. Petzold 9, A. Wiznia 10, and the P1066 Group XIX International AIDS Conference 2012 Washington DC, USA, 22-27 July, 2012 B40: Clinical trials and antiretroviral therapy in children and adolescents 1 SUNY Stony Brook, Pediatrics, Stony Brook, United States; 2 University of Alabama at Birmingham, Birmingham, United States; 3 Harvard School of Public Health, Boston, United States; 4 Merck, North Wales, United States; 5 Division of AIDS, NIAID, NIH, Bethesda, United States; 6 Natl Inst of Child Hlth and Human Devt, Bethesda, United States; 7 Frontier Science Inc, Buffalo, United States; 8 Baystate Medical Center, Springfield, United States; 9 Social and Scientific Systems, Durham, United States; 10 Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, United States
Background New antiretrovirals are needed for HIV+ children. 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 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
Efficacy: Percent of Patients (95% CI) with vRNA<50 c/mL (Final Dose)
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 Grant RM et al N Engl J Med, Nov 23, 2010. HIV uninfected MSM at high risk of sexual acquisition of HIV TDF/FTC 1 pill/day (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 60% Rapid HIV testing at every 4 weeks visit, with drug dispensation and adherence counseling Proof of concept double-blinded, randomized, placebo-controlled trial
iPREX : KM Estimates of Time to HIV Infection (mITT Population) Grant RM et al N Engl J Med, Nov 23, 2010. 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
Iprex : Levels of Study-Drugs in Blood of Subjects Receiving TDF/FTC Grant RM et al. N Engl J Med 2010. 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
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 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 Proof of concept of “on demand” Prep Randomized placebo-controlled trial
Stable, healthy, serodiscordant couples, sexually active CD4 count: 350 to 550 cells/mm 3 Primary Transmission Endpoint Virally linked transmission events Primary Clinical Endpoint WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death HPTN 052 Study Design Immediate ART CD4 350-550 Delayed ART CD4 <250 Randomization
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