1. Potential role of PEP, PrEP and ART for HIV Prevention among Men who have Sex with Men Frits van Griensven, PhD, MPH Division of HIV/AIDS Prevention US Centers for Disease Control and Prevention and Thailand MOPH - US CDC Collaboration Disclaimer: The views expressed herein are solely the responsibility of the author and do not necessarily represent the official views of the CDC

3. In this presentation 1) Non-occupational (or sexual) post exposure prophylaxis (NPEP) 2) Pre-post exposure prophylaxis or PrEP Oral Topical 3) Antiretroviral treatment for prevention

4. Non-occupational post exposure prophylaxis (NPEP) for MSM Efficacy concerns  No solid data supporting efficacy in MSM; controlled studies are not available  Observational studies in MSM show no clear effect on transmission (Kahn et al, 2001; Schechter et al, 2004; Poynten et al, 2009)  Animal data show no protection against rectal SHIV challenge if started too late (+24 hrs) but some protection if started timely (+2hrs) (Garcia-Lerma et al, 2010)  Men fail to timely recognize high risk exposure, even in the presence of direct access to ARVs (Schechter et al, 2004)  Public health impact of NPEP is considered limited and only cost- effective in very specific situations (MMWR, 2005; Poynten et al, 2007)

5. Non-occupational post exposure prophylaxis (NPEP) In conclusion  NPEP not feasible for programmatic scale-up in MSM  Can be offered as an individual service on a case-by-case basis

6. Non-occupational post exposure prophylaxis (NPEP)  BUT eventually PEP led to PrEP  If you need to take so soon after, why not take it before?  Series of animal studies looking at the timing of drug intake versus exposure, 2 hrs before, 24 hrs after etc, etc.  Particularly relevant are the rectal challenge models  The results of these experiments are driving the PrEP research agenda for MSM today

7. 024681012 0 25 50 75 100 Number of weekly rectal exposures % Uninfected macaques Controls (n = 21) FTC/TFV daily (n=6) FTC/TFV -2h/+22h (n=6) (HR>20, p<0.0001) Efficacy of daily and pre- and post-exposure oral Truvada in preventing SHIV infection following rectal challenge in macaques (HR>20, p<0.0001) Garcia-Lerma et al, PLOS, 2008

8. iPrEx: PrEP Initiative Sponsored by NIH/NIAID/DAIDS With co-funding from the Bill and Melinda Gates Foundation And drug donated by Gilead Sciences Slides, courtesy of Dr Robert Grant

9. Men who have sex with men MSM with a heavy burden In the Americas In Asia In Africa Different from HXY, IDU Differing penetration of virus or drug into rectal tissue iPrEx is the only study of PrEP efficacy in MSM Lima, Peru

11. PrEP Initiative (iPrEx)  Men who have sex with men  Randomized 1:1 FTC/TDF vs Placebo  Daily oral  Followed for: HIV seroconversion Adverse Effects Metabolic Effects HBV exacerbations Risk behavior and STIs (including HSV) Adherence If infected  Drug resistance  Viral load  Immunological responses and CD4 counts

12. Intermittent PrEP (iPrep)  May be more in line with sexual life style  Reduce pill burden  Reduce drug burden  Reduce side-effects  Decrease costs  May increase adherence and coverage  And may be increase safer sex behavior  And is supported by animal models

13. Efficacy of intermittent PrEP with Truvada in the repeat low-dose macaque model: design Garcia-Lerma et al, 2010

14. Risk reduction by i PrEP with oral Truvada Untreated controls (n=32) (9 real time and 23 historical) 02468101214 0 25 50 75 100 Number of rectal exposures % Uninfected macaques +2h/+26h (PEP)HR = 4, p = 0.03 -2h/+22hHR = 4.1, p = 0.02 -22h/+2hHR = 16.7, p = 0.006 -3 days/+2hHR = 15.4, p = 0.008 -7 days/+2hHR = 9.3, p = 0.003 Garcia-Lerma et al, 2010

15. Figure 2 % reporting sex Number of days Sex frequency among 823 HIV negative MSM in Bangkok Thailand (“On how many days in the past week did you have sex?”) van Griensven F, et al. 2010

16. Figure 4 % reporting planned sex Day of the week Sex planning among 823 HIV negative MSM in Bangkok Thailand (“On the last day you had sex, was the first sex on that day planned?”) van Griensven F, et al. 2010

17. Multivariate analysis of sex planning among 823 HIV negative MSM in Bangkok, Thailand (first sex on last sex day was planned) Multivariate OR(95% CI) Younger age (<30 years old)1.671.12 – 2.48 Lower education (<high school)2.971.51 – 5.83 Not indentifying as gay1.581.04 – 2.38 Receptive in anal sex1.671.16 – 2.40 Group sex (ever)0.540.34 – 0.85 van Griensven F, et al. 2010

18. Intermitent PrEP (iPrep)  Post IPREX generation of studies will be comparing continuous versus intermittent PrEP Non-inferiority or equivalency studies (costly, large N) Daily vs pre-post exposure Daily vs standing doses plus post exposure dose Daily vs standing doses  HPTN 067: the “ADAPT Study” “Alternative Dosing to Augment Pill Taking Study” Phase II, Randomized, Open-Label, Pharmacokinetic and Behavioral Study of the Use of Intermittent Truvada 3-armed study: daily, vs pre-post, vs bi-weekly standing plus post exposure dose N=360, MSM n=180 Bangkok; HW n=180, Capetown Adherence, coverage, PK and risk behavior Start January 2011

19. Safety and adherence to intermittent Emtricitabine/Tenofovir for HIV pre-exposure prophylaxis (PrEP) in Kenya and Uganda. Mutua et al. IAC 2010, MOPE0369

20. In the shadow of Caprisa Figure: Courtesy of Dr Ian McGowan Strong push for evaluation of rectal microbicides, e.g., TDF gel, possibly in combination with oral formulations

21. Rectal Specific Products  CHARM Program Combination HIV Antiretroviral Rectal Microbicide Program DAIDS IPCP Program Tenofovir, UC781, tenofovir + UC781 Consortium University of Pittsburgh UCLA Johns Hopkins CONRAD PI: Ian McGowan MD PhD Courtesy of Dr Ian McGowan

22. In the shadow of Caprisa

23. Where Would We Conduct Phase 2/3 Studies?  Phase 2 studies RAI sexually active men and women Higher risk populations  Phase 2B studies 3% sero-incidence MSM populations North America Latin America (Peru, Brazil) Asia Pacific (Thailand) Africa (South Africa) Courtesy of Dr Ian McGowan

24. MTN 017  Phase II, multi-site, randomized, six sequence, three period, open label crossover study of adherence and pharmacokinetics of oral and rectal formulations of tenofovir  120 MSM  Bangkok, Thailand; Lima, Peru; 2 US Sites  Possibly roll-over into Phase IIB, III efficacy trial

25. Rectal Microbicide Timeline* 201020112012201320142015201620172018 Phase 1 Phase 2 Phase 2B Review Available Vaginal microbicides *An approximation based on 1% tenofovir Courtesy of Dr Ian McGowan

26. ART as prevention  Test and link  Test and treat

27. HPTN 065 – Wash DC and Bronx: Test-Link-Care-Plus Study Test HIV Positive Adopt safer behaviors Enroll in Care Treat Maintain viral suppression Positive Prevention Testing Initiation of ART Linkage to care sites Adherence to ART Decrease in HIV Transmission

28. Treatment as Prevention for MSM Rationale: lower viral load reduces transmission; ART reduces viral load, thus ART reduces transmission Dr Myron Cohen will give an excellent review and summary on this However: No transmission studies in discordant MSM couples No information about the reduction in transmission probability in discordant MSM couples in the presence of ART We need scientific evidence to support this intervention in MSM Study of 350 discordant couples is being prepared in Sydney, Australia (Prof Andrew Grulich); behavior, transmission events, phylogenetic analysis

29. Treatment as Prevention for MSM  In the mean time:  April 2010 - San Francisco guidelines issued: offer treatment to all HIV positives, regardless of CD4 and VL  Strong association between mean community viral load, total community viral load and reduction in newly identified HIV cases from 798 in 2008 to 434 in 2008  Very special situation with good surveillance data on HIV infection and viral load, almost universal access to ART

30. Mean community viral load in San Francisco, by neighborhood, 2005-8 Das, et al, 2010

31. Total community viral load in San Francisco, by neighborhood, 2005-8

32. Reductions in VL, newly diagnosed and reported cases and estimated HIV incidence in San Francisco 2004-8 Das, et al, 2010

33. Challenges for ARV prevention in MSM  Adherance  Risk compensation and behavioral disinhibition, individually and at the community level  Targeting and duration of programs  Programming outside the Western world  Implementation and programming in low HIV prevalence communities  Costs and competition with curation  Pill burden, drug burden, side-effects, toxicity, resistance  How to monitor impact

34. In conclusion  PEP not ready for programmatic scale up, but good as an individual service on a case by case basis  Daily PrEP results expected soon; if efficacious, studies will try to identify non-inferior alternative regimens  Many implementation issues  Rectal PrEP – promising, but still long way to go  ART for prevention, seems reasonable, ecological evidence available, MSM transmission studies are urgently needed

35. Acknowledgements Ian McGowanUniversity of Pittsburgh Lynn PaxtonUS CDC Peter KilmarxUS CDC Tim MastroFamily Health International Bob GrantUniversity of California, San Francisco Eduard SandersUniversity of Oxford/KEMRI/IAVI Susan BuchbinderSFDPH/UCSF Anchalee Varangrat Thailand MOPH–US CDC Collaboration Kathie McCarthyASPH/CDC Global Public Health Fellow Disclaimer: the results and conclusions presented in this presentation are those of the author, and do not necessarily represent those of the US Centers for Disease Control and Prevention

36. fav1@cdc.gov

37. StudyProductN, PopulationCountriesEnrollment Started Status as of Jan 2010 Expected Results West Africa Tenofovir Trial TDF oral936 Women Ghana, Cameroon, Nigeria 2004, Q2CompletedPublished 2007 US Extended TDF Safety Trial TDF oral400 MSM US2005, Q1Fully enrolled2010, Q2 Bangkok Tenofovir Study (BTS) TDF oral2400 M&F IDU Thailand2005, Q22364 (99%) enrolled 2010 TDF-2TDF/FTC oral 1200 M&F, heterosexuals Botswana2007, Q1Fully enrolled - Changed to safety study, 2009 2010 iPREX, UCSF TDF/FTC oral 3000 MSM Peru, Ecuador, Brazil, US, Thailand, SA 2007, Q12451 (82%) enrolled 2010 CAPRISA 004 Trial TFV 1% gel900 Women South Africa2007, Q2Completed, Released 2010 Partners PrEPTDF oral, TDF/FTCoral 3900 Disco Heterocouples Kenya, Uganda2008, Q23100 (79%) couples enrolled 2011 FEM-PrEPTDF/FTC oral 3900 Women Kenya, Malawi, South Africa, Tanzania Expected: 2009, Q2 461 (12%) enrolled 2012 VOICE, MTN-003 TDF oral, TDF/FTC oral, TFV 1% gel 4950 Women Malawi, Uganda, South Africa, Zambia, Zimbabwe Expected: 2009, Q2 137 (3%) enrolled 2013 Status of Completed, Ongoing and Planned Advanced Stage Clinical Trials of Antiretrovirals for Prevention (Oral and Topical), 2010

38. Non-occupational post exposure prophylaxis (NPEP)  Concern about negative behavioral side-effects In some studies NPEP recipients were at higher subsequent risk for HIV seroconversion due to continued exposure or re- exposure (Poynten et al, 2009) No increases in high risk behavior after NPEP were observed (Schechter et al, 2004; Martin et al, 2004), but no decreases were observed either (Poynten et al, 2007)

39. Non-occupational post exposure prophylaxis (NPEP)  Drug side-effects uncommon with current generation of ARVs available for NPEP  ARV resistance unlikely, because HIV infection after NPEP is uncommon current ARV’s less likely to cause resistance  Public health impact of NPEP is considered limited and only cost- effective in very specific situations (MMWR, 2005; Poynten et al, 2007) In conclusion  NPEP not feasible for programmatic scale-up in MSM  Can be offered as an individual service on a case-by-case basis