1. A PEP and PrEP Update Jeffrey D. Klausner, MD, MPH Black AIDS Institute-UCLA African-American University September 2014 Special thanks to Raphael Landovitz, MD, MSc

2. Definitions PMTCT –Prevention of Mother-to-Child Transmission of HIV ART during pregnancy, during labor/delivery, and treatment of the infant after birth (x 6 weeks) –AZT alone reduced MTCT from 25% to 8% † –Current ART reduces MTCT to 1% ‡ † Connor et al, NEJM 1994 ‡ Shapiro et al, NEJM 2010

3. Definitions PEP –Post-exposure prophylaxis –Strategy of administering ART to uninfected, at-risk individuals, after they have had a high-risk exposure to someone who is (or might be) HIV-infected –Think of: “Morning after” pill(s) –AZT reduced risk in HCWs by 81% † –Current CDC Guidelines recommend 2- or 3-drug antiretroviral treatment up to 72 hours after exposure for 4 weeks following exposure www.aidsinfo.nih.gov www.aidsinfo.nih.gov † Cardo et al, NEJM 1997

4. Definitions PrEP –Pre-exposure prophylaxis –Strategy of administering ART to uninfected, at-risk individuals –Think of: malaria prevention, birth control pill –MSM: iPrEx study –Women: FEM-PrEP study, VOICE (MTN-003) –Heterosexual Couples: TDF2 and Partners PrEP

7. P RE -E XPOSURE P ROPHYLAXIS (P R EP)

8. P R EP IN MSM: T HE I P R E X S TUDY

9. iPrEx Phase III study of PrEP with fixed dose combination emtricitabine/tenofovir (FTC/TDF) or placebo Study population: HIV uninfected MSM or transgendered women from South America, South Africa, Thailand and U.S. (N=2499) Ten were HIV-infected at enrollment, but inadvertently enrolled anyway Efficacy through study end (mITT): 42% (95% CI: 18% to 60%) P =.002 Placebo FTC/TDF (Truvada) Cumulative Probability of HIV Infection 0.12 0.10 0.08 0.06 0.04 0.02 0 14401224364860728496108120132 Wks Since Randomization Pts at Risk, n Placebo FTC/TDF 12481198115711199327866385284333442391030106 12511190114911099398086515234193452531034116 Grant R, et al. CROI 2011. Abstract 92.

10. 90% % of Visits18%33%49% Efficacy16%34%68% 95% CI-54 - 54-20 - 6436 - 84 Recorded Adherence and Efficacy Grant et al. NEJM 2010

15. Drug Level Correlates of Protection in iPrEx STRAND study determined median levels of TFV in PBMCs after 2x (11 fmol/mL), 4x (32 fmol/mL), and 7x (42 fmol/mL) per week dosing of TDF iPrEx seroconverters had median 11 fmol/mL iPrEx non-seroconverters had median 16 fmol/mL Anderson P. et al, Sci Transl Med, 2012

16. How long do TFV/FTC concentrations last in serum? (Single dose) Patterson, K. Sci Transl Medicine, 2011.

17. iPrEx Drug Level Model Model: 90% reduction in HIV incidence at 16 fmol/mL (IQR 3-28) –2x/week dosing would be predicted to provide 76% efficacy (56-96%) –4x/week dosing would be predicted to provide 96% efficacy (90->99%) –7x/week dosing would be predicted to provide 99% efficacy (96->99%) Anderson P. et al, Sci Transl Med. 2012. Any Drug % Detected100% 8%44% Median:1132421116 OQR:6-1325-3931-474-159-27 STRAND iPrEX (Cases with 1 st evidence HIV) 2/wk4/wk7/wkcasescontrols n:21 2248144 100 10 1

18. 18

19. P R EP IN H ETEROSEXUAL M EN AND W OMEN : TDF2 AND P ARTNERS P R EP

20. Partners PrEP Study: Trial Design Double-Blind Phase 3, Double-Blind Study Kenya, Uganda Serodiscordant, heterosexual couples (n=4758) (HIV-positive partner not yet eligible for ART) Normal liver, renal, hematologic values/function Randomization 1:1 Baeten J et al, CROI 2012, Abstract #29, Seattle, WA. Follow-Up Up to 36 months (7337 person-years) Primary Endpoints HIV infection in HIV-negative partner Safety All patients received comprehensive HIV prevention services. Tenofovir DF qd (n=1845) Emtricitabine/Tenofovir DF qd (n=1579) Placebo (n=1584)

21. Partners PrEP Study: Results Both PrEP treatment arms significantly reduced the risk of HIV acquisition –Similar results between arms and genders, location, VL strata Both PrEP treatment arms were safe and well tolerated –No difference in AEs, labs, SAEs, deaths –No difference in renal function No evidence of risk compensation HIV Incidence (per 100-person-years) 1.99 0.65 67% (44-81%) Reduction (P<0.0001) 0.50 75% (55-87%) Reduction (P<0.0001) PlaceboTenofovir DF Emtricitabine/ Tenofovir DF TDFTDF/FTC Men71% (37-87)84% (54-94) Women63% (20-83)66% (28-84) Baeten J et al, CROI 2012, Abstract #29, Seattle, WA.

22. Partners PrEP Resistance –2 of 8 acute seroconverters on therapy 1 K65R (TDF) 1 M184V (TDF/FTC) –0 of 27 seroconversions ON STUDY had treatment emergent resistance –4 with NNRTI resistance (2 TDF, 1 TDF/FTC, 1 PBO) Baeten J et al, CROI 2012, Abstract #29, Seattle, WA. Baeten J et al, NEJM 2012.

23. Partners PrEP Adherence/Drug levels –Case cohort: 30 seroconverter cases, 200 controls in active arms (randomly selected) –TDF testing at mos 1, 3, 6, 12, 24, 36 + seroconversion (if applicable) If detectable drug (@ 0.3 ng/mL): TDF efficacy 86% TDF/FTC efficacy 90% Cases (TDF 17, TDF/FTC 12) Cohort (N=198) Visits prior to seroconversion Visit at seroconversion All Visits TDF56%31%83% TDF/FTC56%25%81% Donnell D et al, CROI 2012, Abstract #30, Seattle, WA. Baeten J et al, NEJM 2012.

24. Partners PrEP 9 seroconverters had detectable drug –4 had drug levels > 40 ng/mL –4 had lower, but consistently detectable levels 3 adherence patterns noted –70% stayed > 40 ng/mL at most time points –10% had low but detectable levels –20% had undetectable levels – consistently Self-report, pill count, and drug levels well correlated (!) Donnell D et al, CROI 2012, Abstract #30, Seattle, WA.

25. TDF2 Study: PrEP in Heterosexual Adults Phase 2 trial in heterosexual men and women (n=1200) in Botswana –Women: 45% –Married: 94% –Completed study: 67% Primary results –HIV seroconversion (n=33) Daily oral emtricitabine/tenofovir DF (n=9 [2 males/7 females]) Placebo (n=24 [10 males/14 females]) Thigpen MC, et al. NEJM 2012. Proportion 0 1 2 3 HIV Seroconversion (ITT) Emtricitabine/ Tenofovir DF (n=601) Placebo (n=599) 63% Reduction (P=0.013) Years

26. Murnane et al, CROI 2013, Abstract #1000 Summary of Oral PrEP Efficacy Data

27. Adherence and Efficacy in PrEP Trials % of blood samples with tenofovir detected HIV protection efficacy in randomized comparison Partners PrEP FTC/TDF arm 81%75% TDF279%62% iPrEx51%44% FEM-PrEP26%6% Donnell et al CROI 2012 Grant et al N Engl J Med 2010 Van Damme et al CROI 2012 Paxton et al FDA 2012

28. W HAT ARE THE C ONCERNS ?

29. Risk Compensation PrEP trials have not seen risk compensation But …. –These were trials in which participants knew they might be getting a “placebo” –People were counseled REPEATEDLY that the pill had not been shown to “work” yet, so condoms MUST be used all the time What will happen now that we know it works, and there are no more placebos?

30. Implementation Who should be delivering PrEP? What services should be co-packaged with PrEP? Where should PrEP be delivered? When should people/laboratory testing be done (at what interval)? How will PrEP and its services be paid for? Will the people most at risk use it and adhere to it?

31. CDC Guidance for PrEP for MSM: (Interim: 1/27/11) Before starting: –Document HIV Antibody- and r/o acute infection –CrCl >60, screen for STIs and HBV Prescribe FTC/TDF daily X 90 days –Provide risk reduction, adherence counseling, condoms On treatment: –Check HIV Antibody every 2-3 months –Check kidney function at 3 months and yearly –Risk reduction, condoms, STI assessments/rx http://www.cdc.gov/hiv/prep/index.htm

32. http://www.cdc.gov/hiv/pdf/PrEPguidelines2014.pdf

33. CDC PrEP Guidance 2014 Daily oral PrEP with the fixed-dose combination of tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine (FTC) 200 mg has been shown to be safe and effective in reducing the risk of sexual HIV acquisition in adults; therefore, PrEP is recommended as one prevention option for sexually-active adult MSM (men who have sex with men) at substantial risk of HIV acquisition (IA) PrEP is recommended as one prevention option for adult heterosexually active men and women who are at substantial risk of HIV acquisition. (IA) PrEP is recommended as one prevention option for adult injection drug users (IDU) at substantial risk of HIV acquisition. (IA) PrEP should be discussed with heterosexually-active women and men whose partners are known to have HIV infection (i.e., HIV-discordant couples) as one of several options to protect the uninfected partner during conception and pregnancy so that an informed decision can be made in awareness of what is known and unknown about benefits and risks of PrEP for mother and fetus (IIB)

34. Community Discussion What will be the adverse effects profile in other populations? Who will pay for it? If it is effective in demonstration projects, will it be made available to those most at risk? Will biomedical prevention increase health disparities? What will the real world risk-compensation consequences be? Resistance

35. What’s next? Open label “demonstration projects” of daily FTC/TDF Intermittent FTC/TDF dosing (HPTN 066, 067, ANRS Study in France/Quebec) Daily dosing of alternative agents (HPTN 069) Long(er) acting preparations (TMC278LA and S/GSK1265744), Topical patches, vaginal rings (Dapivirine, TDF, others) Daily FTC/TDF in IDUs

36. Thank you! Questions?