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ART FOR HIV PREVENTION: PANACEA OR PANDORA’S BOX?

ART FOR HIV PREVENTION: PANACEA OR PANDORA’S BOX?. KENNETH H. MAYER, M.D. HIV TRANSMISSION. SIGNIFICANT, LOW PROBABILITY EVENT (<1/100 AVERAGE) MULTIPLE CO-FACTORS ARE INVOLVED  PLASMA VIRAL LOAD   TRANSMISSION

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ART FOR HIV PREVENTION: PANACEA OR PANDORA’S BOX?

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

  5. HOW HIV INFECTS MUCOSA

  6. HSV control: Rationale for HSV-2 control to reduce HIV transmission Source: Wawer M et al, Lancet 1999

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

  8. 5 4 3 2 AIDS Acute Infection 3 wks STD Episode STD Episode Acute HIV and STD episodes(Cohen and Pilcher, JID, 2005 HIV RNA in Semen (Log10 copies/ml)

  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. Cross-sectional (n=95) and longitudinal (n=35) studies of HIV-1 in semen from HIV+ men. Results: HIV-1 cultured from seminal plasma and semen cells Intermittent shedding HIV with leukocytospermia HIV in advanced disease stage HIV with zidovudine ART

  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. 100 80 60 detectable HIV in semen Patients (%) with 40 20 0 HIV-RNA HIV-DNA Semen HIV in patients with suppressed viral load n=55 Potent ART Controls (drug naive) n=114 p<0.0001 p=0.025 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. 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 Tsai ‘95; Van Rompay ‘99 ‘00 ‘01 ’04 ‘07; Subbarao ’05; Heneine ‘06

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

  18. Example:USDHHSGuidelinesforNon-OccupationalPEP 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+ 3rd drug (n=119) • Mainly MSM, similar between NPEP arms Regimen Completion Rates 87.5% 72.7% Patients (%) 42.1%* 38.8%* ZDV/ 3TC + 3rd Drug TDF + 3TC FTC/ TDF ZDV/ 3TC 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 Adverse Events (%) *P<0.05 and †P<0.01. Mayer KH, et al. JAIDS. 2007

  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. RISK BEHAVIOR IS NOT UNIFORM • Calendar-based retrospective history on newly infected MSM • “Susceptible” period from 3 months before last negative to first HIV positive test • 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 S Buchbinder 2005

  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 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

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

  29. PrEP is not already in wide use 1Had 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

  30. 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

  31. WHERE MICROBICIDES MAY WORK

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

  33. 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)

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

  35. Multivariable analysis of seroconversion risk: Drug use in Explore *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

  36. 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

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