1. ART FOR HIV PREVENTION: PANACEA OR PANDORA’S BOX? KENNETH H. MAYER, M.D.

2. HIV TRANSMISSION SIGNIFICANT, LOW PROBABILITY EVENT (<1/100 AVERAGE) MULTIPLE CO-FACTORS ARE INVOLVED  PLASMA VIRAL LOAD   TRANSMISSION CAN WIDER HAART ACCESS ↓ THE SPREAD OF NEW INFECTIONS? SEXUALLY TRANSMITTED INFECTIONS (STI)  HIV TRANSMISSION AND ACQUISITION: CAN STI CONTROL ↓ HIV SPREAD? BLOOD AND GENITAL HIV MAY CHANGE IN PARALLEL, BUT LOCAL FACTORS, E.G. STI, HAART CONCENTRATIONS MAY ALTER HIV IN DIFFERENT COMPARTMENTS BIOLOGICAL INTERVENTIONS MAY BE INFLUENCED BY BEHAVIORAL ISSUES

3. APPROACHES TO PREVENT HIV TRANSMISSION DECREASE SOURCE OF INFECTION Barrier Protection Treat STI Antiretroviral Therapy Maternal-child transmission  partner’s HIV load Rx of acute infection Blood screening Circumcision DECREASE HOST SUSCEPTIBILITY Barrier protection Treat STI PEP PREP Microbicides Vaccines Infection Control Circumcision ALTER RISK-TAKING BEHAVIOR Condom promotion Individual interventions Couples interventions Community-based interventions Structural interventions (e.g., economic)

4. PLASMA HIV RNA PREDICTS LIKELIHOOD OF TRANSMISSION 0 5 10 15 20 25 30 Viral load (HIV-1 RNA copies/ml) and HIV transmission Transmission rate per 100 Person-Years <400 400-3499 3500-9999 10 000-49 999 >50 000 Source: Quinn N, et al, N Eng J Med 2000 <400 400-3499 3500-9999 10 000-49 999 >50 000 <400 400-3499 3500-9999 10 000-49 999 >50 000 All subjects Male-to-Female Transmission Female-to-Male Transmission

5. HOW HIV INFECTS MUCOSA

6. Probability of HIV infection in the HIV- partner per 10 000 contacts HIV plasma RNA in the HIV+ partner (copies/ml)HSV+HSV- <1700100.4 1700-12,499235 12,500-38,499182 >38,500367 Source: Wawer M et al, Lancet 1999 HSV control: Rationale for HSV-2 control to reduce HIV transmission

7. Syphilis Among Fenway Clients: “The new normal”

8. HIV RNA in Semen (Log 10 copies/ml) Acute Infection 3 wks STD Episode AIDS 2 3 45 Acute HIV and STD episodes (Cohen and Pilcher, JID, 2005

9. WHY ART FOR PREVENTION? HIV is spreading rapidly, more than 5 million new infections in the next year! Behavioral interventions have not resulted in long term changes in most settings Vaccines and Microbicides are years away ART is available now! HOWEVER, ART is relatively expensive, needs to be used repetitively, may result in toxicities, and can select for resistance, and may result in behavioral disinhibition.

10. HOW HAART COULD ALTER HIV TRANSMISSION: NEED TO MONITOR PARTNERS  PVL  SURVIVAL  PLHIV  GENITAL TRACT  DURATION OF HIV INFECTIOUSNESS  TRANSMISSION  TRANSMISSION RELEVANT ISSUES: ACCESS, ADHERENCE, PREVENTION, STI RX.

11. Effects of Disease Stage and Zidovudine Therapy on the Detection of Human Immunodeficiency Virus Type 1 in Semen Deborah J. Anderson, Thomas R. O’Brien, Joseph A. Politch, Adriana Martinez, George R. Seage III, Nancy Padian, Robert Horsburgh, Kenneth H. Mayer JAMA 267:2679-2774, 1992. Results:HIV-1 cultured from seminal plasma and semen cells Intermittent shedding HIV with leukocytospermia HIV in advanced disease stage HIV with zidovudine ART Cross-sectional (n=95) and longitudinal (n=35) studies of HIV-1 in semen from HIV+ men.

12. T Lymphocytes and Macrophages, but not Motile Spermatozoa, are a Significant Source of HIV in Semen Alison J. Quayle, Chong Xu, Kenneth H. Mayer, Deborah J. Anderson Journal of Infectious Diseases 176:960-968, 1997. T lymphocytes and macrophages are principal sources of HIV-1 in semen.

13. HIV-RNAHIV-DNA 0 20 40 60 80 100 Patients (%) with detectable HIV in semen n=55 n=114 Controls (drug naive) Potent ART p<0.0001 p=0.025 Semen HIV in patients with suppressed viral load Vernazza, Cohen et al., AIDS, 2000

14. Acute Infections and HIV Prevention Rakai study: 40% of new transmissions were from acutely infected pts (Wawer, JID, 2005) Quebec study: almost ½ new infections were from recently infected pts (Brenner, JID, 2007) Using discordant HIV rapid tests results and RNA pooling, almost 2% of STD clinic pts in Malawi were identified with acute HIV infection (Pilcher, NEJM, 2005) Could the identification of “hot spots” of newly infected pts present opportunities for early ART and behavioral interventions to slow HIV spread?

15. Can Chronic HAART Decrease HIV Transmission?  HIV INCIDENCE IN BRAZIL AND TAIWAN MULTIPLE REPORTS OF INCREASING TRANSMISSION OF RESISTANT HIV I5-30% OF NEWLY INFECTED PATIENTS HPTN 052: RCT OF HAART TO ASSESS EFFECT ON TRANSMISSION. 1750 HIV discordant couples:India, Brazil, Thailand, Malawi, Zimbabwe, U.S. Early vs. later ART, CD4 >300 Monthly monitoring, couples counseling

16. Tsai ‘95; Van Rompay ‘99 ‘00 ‘01 ’04 ‘07; Subbarao ’05; Heneine ‘06 Preclinical PEP/PrEP Studies NNRTI or NRTI were protective –70% to 100% Effective/exposure Emtricitabine + Tenofovir –The combination was effective –Even after repeated rectal exposures (14) The prophylactic activity probably reflects –Long intracellular half life –Activity in Macrophages –High concentration in genital tissues

17. APV (20%) NVP (80%) APV (50%) ABC (40%) ABC (150%) Female Genital Tract Exposure (Kashuba et al) ZDV (200%) IDV (200%) 0%100% 200% 300% 400% 500% TDF (400%) 3TC (400%) Nonnucleoside Reverse Transcriptase Inhibitors Protease Inhibitors Nucleoside Reverse Transcriptase Inhibitors LPV (30%) ATV (30%) RTV (20%) DLV (20%) FTC (600%) ddI (100%) SQV (ND) EFV (0.6%) d4T (4%) NFV (5%) LPV (5%) SQV (3%) EFV (3%) RTV (3%) d4T (2%) ENF (ND) IDV (100%) NVP (70%) TDF (500%) 3TC (600%) ZDV (200%) ABC (150%) Fusion Inhibitors Male Genital Tract Exposure

18. Example: US DHHS Guidelines for Non- Occupational PEP MMWR 2005

19. NPEP IN BRAZILIAN MSM PEP (AZT/3TC) 4 day starter pack –28 day course N=200 high risk men –Followed over 24.2 months 68 used PEP 109 times HIV incidence 2.9/100py –10 in those who did not use PEP (N=132) –Thought partner was HIV-, –Did not appreciate risk of that contact –1 in a PEP user (N=68) Risk Behavior decreased Schechter M et al (2004) JAIDS 35:519-525

20. Tenofovir DF + Emtricitabine or Lamivudine for Non-Occupational PEP Treatment arms –TDF/FTC (n=68) – TDF/3TC (n=44) –AZT/3TC (n=122) –AZT/3TC+ 3 rd drug (n=119) Mainly MSM, similar between NPEP arms Patients (%) 72.7% Regimen Completion Rates FTC/ TDF 87.5% 42.1%* 38.8%* TDF + 3TC ZDV/ 3TC ZDV/ 3TC + 3 rd Drug Mayer KH, et al. JAIDS. 2007 *P<0.0001 versus TDF-based regimens

21. Tenofovir DF + Emtricitabine or Lamivudine for Non-Occupational PEP Tenofovir: diarrhea or abdominal discomfort Zidovudine: nausea and vomiting: AE’s more serious Mayer KH, et al. JAIDS. 2007 FTC/ TDF TDF + 3TC ZDV/ 3TC ZDV/3TC + 3 rd Drug Diarrhea47.5*31.39.858.8 Fatigue3028.139.348.5* Abdominal discomfort 47.5 † 20.3 † 3.32.9 Nausea/ vomiting 22.518.855.7 † 58.8 † Headache22.518.824.611.8 Adverse Events (%) *P<0.05 and † P<0.01.

22. Risk Behavior at Time of Incident Note: TDF/3TC group reported more ua than the AZT/3TC group (30%), and about the same as the AZT/3TC+1 group (52%).

23. Calendar-based retrospective history on newly infected MSM Calendar-based retrospective history on newly infected MSM “Susceptible” period from 3 months before last negative to first HIV positive test “Susceptible” period from 3 months before last negative to first HIV positive test Each row represents a newly infected MSM Each row represents a newly infected MSM Each dot represents a report of at least one unprotected anal or oral sex contact with HIV positive or unknown partner Each dot represents a report of at least one unprotected anal or oral sex contact with HIV positive or unknown partner S Buchbinder 2005 RISK BEHAVIOR IS NOT UNIFORM

24. Phase 2, Randomized, Double Blinded, Placebo Controlled Trial Conducted between June 2004 and March 2006 Cameroon; Nigeria; Ghana Objective: Determine the safety and preliminary effectiveness of a daily dose of 300 mg oral TDF vs Placebo for HIV prevention among high risk women also receiving HIV testing, counseling, and condoms Safety Evaluated in N=936 including 428 Person Years

25. HIV Seroconversions 8 on-product seroconversions –2 TDF : 6 placebo Difference is not statistically significant –95% confidence interval = 0.03-1.93 –p = 0.24 On TDF seroconversions occurred after 1 and 2 months on product, neither TDF-R –Baseline Specimens were not available Peterson, Plos Clinical Trials, 2007

26. Sexual Behavior During PREP Trial in West Africa ScreeningFollow-up Number of partners (30 days) 2114 Number of new partners (30 days) 116 Number of sex acts (7 days) 1215 Condom use (last act) 52%94% Peterson, XVI AIDS Conference, Toronto, 2006

27. PREP and Drug Resistance? TDF/FTC resistance comes with a high fitness cost Monotherapy with TDF –No resistance detected after 28d in people (Barditch-Crovo 2001) –Resistant minor variants enriched in monkeys (Van Rampay 2007) Non-human primate studies –TDF PEP partially effective vs drug resistant SIV (Van Rompay 2000) –No TDF resistance after TDF or FTC/TDF failure (Subbarao 2006) –FTC resistance intermittently detected (Garcia Lerma 2007) TDF and FTC resistance –Makes AZT more active, but diminishes activity of other nRTIs –Has no effect on other classes of drugs

29. TDF Placebo Enrollment 9 months 24 months 100 TDF Placebo 100 No Pills CDC U.S. MSM PrEP Study (Project T; Project PrEPare) 100

30. PrEP is not already in wide use OutcomeOverall (n=851) SF Bay Area (n=403) Circuit Party (n=176) STD Clinic (n=272) Heard of PrEP18%20%19%15% Knew PrEP user2% 4%2% Used PrEP0.12%0% 0.39% 1 Would use PrEP if safe/effective 68% (n=563) 69%66%n/a 1 Had not heard of PrEP and received 30 days of medication from clinician → may have been post-exposure prophylaxis (1 month of antiretroviral therapy started shortly after high-risk exposure) Liu, IAS, 2006

31. An orally delivered CCR5 inhibitor Provided partial protection of macaques from SHIV-162P3 vaginal transmission Condition Infected p-value Controls (no inhibitor, including historic controls) 16/18 CMPD 167 for 4 days prior to challenge 3/4 0.47 CMPD 167 for 10 days post challenge (inc. day 0) 4/9 0.023 CMPD 167 for 4 days prior + 10 days post challenge 6/11 0.051 (CMPD 167 +/- 4 days prior + 10 days post challenge 10/20 0.012) Courtesy of John Moore

32. WHERE MICROBICIDES MAY WORK

33. LLOQ Oral vs. Topical PrEP? (HPTN 050)

34. NEW ART FOR PREVENTION STUDIES: DRUGS, FREQUENCY, & ROUTE Karim: TDF Vaginal Gel dose just before and just after intercourse MTN: Oral vs. topical chemoprophylaxis; design challenges, double randomization New agents, combinations? Important to have sufficient studies to understand dosing regimens/trade offs using combinations (e.g. cost, AEs, efficacy, adherence)

35. HIV incidence among IDUs has been declining in the U.S.

36. Multivariable analysis of seroconversion risk: Drug use in Explore Drug N at baseline No. of infections Hazard ratio* ( 95% CI) Heavy alcohol** 419411.9 (1.2, 2.8) Amphetamines 527671.9 ( 1.4, 2.6) Alcohol/drugs before sex 29522051.6 ( 1.1, 2.3) *REF = no/light/moderate use of alcohol; no speed use; no use before sex ** 4+ drinks every day or 6+ drinks on a typical day

37. CONCLUSIONS Vaccines are years away, antiretrovirals are available now However, because they will need to be used recurrently and are not expected to be 100% protective, further studies of pharmacology, virology and behavioral sciences will be needed to best understand their intended and unintended consequences. They may become part of HAARP: highly active antiretroviral prevention