Greatest Hits of 2012

1. Greatest Hits of 2012 Mark Wainberg McGill AIDS Centre Jewish General Hospital Montreal, Quebec

2. 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

3. Proportion (%) of Patients Achieving HIV RNA <50 copies/mL (95% CI) Over Time 100 86 81 76 75 71% 80 82 79 60 69 67 61% HIV RNA Levels <50 Copies/mL Percent of Patients with 40 20 0 0 12 24 48 72 96 120 144 168 192 216 240 Weeks Number of Contributing Patients Raltegravir 400 mg bid. 281 278 279 280 281 281 277 280 281 281 277 279 Efavirenz 600 mg qHS. 282 282 282 281 282 282 281 281 282 282 282 279 Non-Completer = Failure Approach

4. Change From Baseline in CD4-Cell Count (95% CI) Over Time 374 361 400 331 350 300 240 312 301 295 250 189 200 225 CD4 Cell Count (cells/mm3) Change from Baseline 150 163 100 50 0 0 12 24 48 72 96 120 144 168 192 216 240 Weeks Number of Contributing Patients Raltegravir 400 mg bid. 281 272 266 258 255 250 240 235 231 235 227 222 Efavirenz 600 mg qHS. 281 268 266 251 252 243 234 228 224 220 218 212

5. Adverse-Event Summary

6. 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 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. Final analysis: 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) RAL/OLRAL Treatment Group RAL 400 mg BID + OBT RAL 400 mg BID + OBT BENCHMRK-1 (n=234) BENCHMRK-2 (n=232) 2:1 Pbo/OLRAL Treatment Group RAL 400 mg BID + OBT Placebo + OBT BENCHMRK-1 (n=118) BENCHMRK-2 (n=119) Double-blind (Weeks 0-156) Open-label

8. 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. † Non-completer=failure approach; error bars indicate 95% confidence interval.

9. 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. † Non-completer=failure approach; error bars indicate 95% confidence interval.

10. Table 5. Number (%) of Patients† with Integrase Mutations at Time of Virologic Failure 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)

11. 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. † Observed Failure Approach: only discontinuations for lack of efficacy are counted as failures.

12. 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 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 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

13. 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

14. Efficacy: Percent of Patients (95% CI) with vRNA<50 c/mL (Final Dose)

15. 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

16. TDF/FTC 1 pill/day (n=1251) • HIV uninfected MSM at high risk of sexual acquisition of HIV Placebo 1 pill/day(n=1248) iPREX Study Design Proof of concept double-blinded, randomized, placebo-controlled trial • 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.

17. 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.

18. 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.

19. 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

20. 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.

21. Unlike M184V and L74V, there is not a single case of transmitted K65R on record

22. Full prevention services* TDF/FTC before and after sex (n=950) • High risk MSM • Condomless anal sex with > 2 partners Full prevention services* placebo before and after sex (n=950) IPERGAY Study Design Proof of concept of “on demand” Prep Randomized placebo-controlled trial • *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

23. HPTN 052 Study Design Stable, healthy, serodiscordant couples, sexually active CD4 count: 350 to 550 cells/mm3 Randomization Delayed ART CD4 <250 Immediate ART CD4 350-550 Primary Transmission Endpoint Virally linked transmission events Primary Clinical Endpoint WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death

24. 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

38. Thank you Merci