1. Maurice Cook ( EM Designs Group, Inc.) Pre-Exposure Prophylaxis: How to PrEP with Models of Men and Women Robert M Grant, MD, MPH Sept 24, 2010

2. HIV Prevention 3 new infections for every person starting ART Few Concepts Known –Condoms, Education, Clean Needles, VCT, MTCTp, Circumcision for Heterosexual Men, Treatment –All underutilized, most controversial Multiple Concepts Failed –Acyclovir, Diaphragms, Mass STI Treatment, Intensive Counseling, Polyanion Microbicides No Surrogate Markers Known Adherence can run ½ reported levels Potential Beneficiaries –Would often rather stay in bed then advocate for prevention

3. "We are really groping in the dark" Salim S. Abdool Karim Quoted in the Washington Post, November 1, 2007

4. Finding The Way Out of The Dark: Listen

5. What I Heard (I may have been mistaken) Pills are for sick people –We are not sick HIV is one of many problems –Certainly NOT the most urgent –Violence, Poverty, Isolation are More Urgent If you want to study us –Use our names –Studying sex workers in an era when sex work was a forbidden term was a non-starter

6. Treatment and Prevention Similar Technology Treatment may prevent transmission Prevention enables treatment Both may use pills –Indeed, the same pills Evaluated with Randomized Clinical Trials –Intention to treat is primary

7. Prevention And Treatment Are Different in Respects That Bear Directly on Adherence

8. Prevention is Not Treatment: 1) No Patients Healthy people, notwithstanding… Language That Pathologizes People –risk groups and vulnerable groups vs –gay men, transexuals, sex workers, etc Language that Pathologizes Acts –risk behavior vs –Sex or work or community or procreation

9. Prevention is Not Treatment: 2) No regimens Treatment regimens can be optimized –In vitro activity suggest target level –Pharmacokinetics suggest dosing interval –Phase II studies narrow to few options –Phase IIb/III select the best option –Phase IV explore alternatives Optimization Made possible by –Surrogate markers, small sample size

10. Prevention is Not Treatment: 2) No Regimens No surrogate markers for HIV prevention –Immune correlates not known –Minimum protective level not known –Target cells for activity not known –Safety parameters not always clear Prevention Trials Are Large –few options evaluated

11. Counseling When There is No Regimen Adherence to an optimized regimen –Does not apply to PrEP In Prevention, we do not say –Dont use condoms unless you can use them everytime Also Applies to… –Communication with Partners –Use of HIV Tests May Apply to Pill use as well.

12. Prevention is not Treatment 3) Drug Resistance? In treatment, the virus population has many billions of opportunities to generate resistance –partial adherence to nnRTIs/3TC allows replication to generate drug resistant mutants –Partial adherence to PIs may not be sufficient to select the drug resistant mutants. In Prevention, the virus population clings to a few mls of genital secretions –it is unknown whether new mutations can be generated. –Starting PrEP in the window period of infection will select resistance

13. Daily PrEP Selected M184I/V Resistance in 2/6 Animals Garcia-Lerma et al, 2008 Wild typeNot testedResistent

14. Absence of drug resistance in macaques failing i PrEP with oral Truvada (2 weekly doses) 048121620 0 2 4 6 8 048121620 0 2 4 6 8 Log 10 RNA copies/ml 1800DM91 DM92X Weeks DK40DL6V 048121620 0 2 4 6 8 Log 10 RNA copies/ml 048121620 0 2 4 6 8 Weeks 048121620 0 2 4 6 8 Weeks wt 0 2 4 6 0481216 20 8 Weeks wt Wild type 35032 Not tested Garcia-Lerma et al, 2009

15. Adherence and Resistance Bangsberg et al 2004

16. Resistance and Adherence Concerns For PrEP Starting or Restarting PrEP –during the RNA+/Ab- window –Expected to select resistance Non-adherence to the daily regimen –Unclear effect on resistance –Depends on efficacy, drug levels, selection Fear of resistance drives a high bar –People who miss doses may give up –People who miss doses when highly exposed may be told to give both up (sex and PrEP)

17. Prevention is Not Treatment: 4) We undermine adherence in prevention These messages have been quoted back to us during qualitative research, as reasons for deferring pill use until efficacy is proven.

19. Prevention is Not Treatment: 5) Synergies expected Treatment Choices Are Often Exclusionary –TDF/FTC vs AZT/3TC –EFZ vs NVP –Selecting A means not selecting B Prevention Choices Are Typically Complementary –Condom is useful for HIV/ contraception/ STIs –PrEP may protect weak vaccine responses –PrEP may attract people into STI Care

20. Reported Risk Behavior Declined With Open-Label Post-Exposure Prophylaxis and Counseling Martin et al., AIDS 2004

21. Conclusion from SF: PEP and Risk Compensation Martin et al., AIDS 2004

22. Air Bags and Seat Belts Antagonisms assumed initially, but Airbags and seat belt innovations are now motivators for purchase of new cars Safety conscious people demand both. Synergies Prevail

23. How to PrEP? Models of Men and Women

24. IMB I B Information Motivation Skills Behavior Specific IMB for Each Action State People populated by multiple IMB processes Condom use, Test Use, PrEP Use, Reporting IMBot

25. I B A situated IMBot socializing with friends

26. IMBot navigating in stormy waters: poverty, violence, racism, homophobia, addiction, sexuality. I B

27. Oceanic View of Sex and Society Dynamic Complex Unpredictable Mysterious Details matter little IMBots can learn to navigate over rough seas Rough seas are better avoided than studied I B

28. Models of Man Herbert Simon (1916-2001) Published 1956 Bounded Rationality Not Pathological Within Social Context Nobel Prize 1978 APA award 1993

29. Bounded Rationality and Organizational Decision-making Organizations. March and Simon, 1958 Decisions Come From Where People Sit –The Social Situation Governs Information availability Perceptions Motivation and goals Learned Skills and Heuristics

30. Social view of Sex adapted from Gagnon Sexual Conduct 1973 Sex, both desire and control, are social constructs Some safer than others Plans may be lost Behavior constrained, but not determined. Can be studied and understood I B

31. US Traditions in Sex Research Kinsey –Biology, Narratives, Outlets Sociological (Gagnon & Simon) –Social scripts –Shape both desire and control –National surveys Womens studies/LGBT studies Development of ED Drugs AIDS Research

32. On AIDS Research John Gagnon None of these studies has been undertaken to understand sexual phenomena, but rather to measure risk of seroconversion and the effectiveness of prevention efforts… Such purely AIDS-driven work forces researchers to follow outbreaks of the epidemic rather than anticipate them. –Disease and Desire. 1989

33. Where do Prevention Users Sit?

34. In Their Communities Lets Communicate

35. Community Based Prevention Ecuador Constitutional Protections for LGBT Communities Boston Specialized Health Care For LGBT Communities Both Highly Successful iPrEx Sites

36. Successful Prevention Initiatives Condom Use in US Cities Early 1980s Love Carefully Uganda 1990s SeroPos Seroadaptive Behaviors Late 1990s Common Characteristics –Grass Roots Initiatives –The Scripts Changed Love Carefully Be a rubber man –Acknowledge Sexual Goals

37. People Learn What They Need to Know: Will Intermittent PrEP Create a Need to Recognize Exposure and Plan for Sex? (HPTN 067) DailyIntermittent Initiated byInvestigatorsCommunity Locus of ControlExternalInternal Provider asAuthorityConsultant Perception FocusMissed DosesHIV Exposure Desired BehaviorAdherencePill Use Fostered Social RolePatientActivist

38. Culture of Compliance Directly Monitored Essential for Primary Aim ConsentXX HIV TestsXX Safety LabsXX VisitsX Test CounselingX Interview DataX Medical ExaminationsX Pill UseX

39. Toward More Effective Prevention Advocacy for Study Populations –Gay, Lesbian, Transgender –Sex workers –Drug Users –Discordant couples –Abused Focus on Use, not Intention Turn the Oceans into Roadmaps –Sex, society, violence, poverty –NIH NIS and CDC NCS? Focus on Synergies, not Antagonisms

40. iPrEx Presentations on PrEP Pill Use Lorena Vargas, INMENSA, Lima, Peru –Qualitative Research in Andes Albert Liu, SF DPH –Qualitative Research in SF Rivet Amico, U. Conn –Next Step Counseling

41. Many Thanks To IPREX Pill Use Working Group –Rivet Amico –Albert Liu –Ed Wolf –Pedro Goicochea –Lorena Vargas –Vanessa McMahan Social Approaches –Jeff McConnell –John Gagnon –David Halperin HPTN 067 Behavioral Working Group –Frits Von Griensven –Rivet Amico –Kata Chillag –Daniela Marks –Michael Stirrat –Andrew Forsyth –Scott Rose Sponsors/Funders –Division of AIDS, NIMH, Gates, CDC

42. HIV, Risk, Behavior, and Agency 1st Meeting, San Francisco January 16th and 17th, 2008