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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 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 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) 30 Female-to-Male Transmission Male-to-Female Transmission All subjects 25 20 15 10 Viral load (HIV-1 RNA copies/ml) and HIV transmission Source: Quinn N, et al, N Eng J Med 2000 >50 000 10 000-49 999 3500-9999 400-3499 <400 >50 000 10 000-49 999 3500-9999 400-3499 <400 >50 000 10 000-49 999 3500-9999 0 400-3499 5 <400 Transmission rate per 100 Person-Years PLASMA HIV RNA PREDICTS LIKELIHOOD OF TRANSMISSION HOW HIV INFECTS MUCOSA HSV control: Rationale for HSV-2 control to reduce HIV transmission Probability of HIV infection in the HIV- partner per 10 000 contacts HIV plasma RNA in the HIV+ partner (copies/ml) HSV+ HSV- <1700 10 0.4 1700-12,499 23 5 12,500-38,499 18 2 >38,500 36 7 Source: Wawer M et al, Lancet 1999 Syphilis Among Fenway Clients: “The new normal” 60 2.5 50 2 Cases Test + 1.5 30 % No. 40 1 20 0.5 10 0 0 1997 1998 1999 2000 2001 2002 2003 2004 2005 Acute HIV and STD episodes HIV RNA in Semen (Log10 copies/ml) (Cohen and Pilcher, JID, 2005 5 4 3 2 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. HOW HAART COULD ALTER HIV TRANSMISSION: NEED TO MONITOR PARTNERS PVL GENITAL TRACT HIV TRANSMISSION SURVIVAL PLHIV DURATION OF INFECTIOUSNESS TRANSMISSION • RELEVANT ISSUES: ACCESS, ADHERENCE, PREVENTION, STI RX. 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 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. Semen HIV in patients with suppressed viral load Patients (%) with detectable HIV in semen Potent ART Controls (drug naive) 100 n=55 n=114 p<0.0001 80 p=0.025 60 40 20 0 HIV-RNA HIV-DNA Vernazza, Cohen et al., AIDS, 2000 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? 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 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 Male Genital Tract Exposure APV (20%) LPV (5%) NFV (5%) EFV (3%) SQV (3%) RTV (3%) d4T (2%) IDV (100%) ENF (ND) NVP (70%) 0% ABC (150%) ZDV (200%) 100% ddI (100%) SQV (ND) ABC (150%) EFV (0.6%) TDF (500%) 200% 300% IDV (200%) 3TC (400%) ZDV (200%) TDF (400%) 400% 3TC (600%) 500% FTC (600%) d4T (4%) RTV (20%) Female Genital Tract Exposure DLV (20%) ATV (30%) LPV (30%) ABC (40%) APV (50%) NVP (80%) Fusion Inhibitors Nucleoside Reverse Transcriptase Inhibitors Protease Inhibitors Nonnucleoside Reverse Transcriptase Inhibitors (Kashuba et al) Example: US DHHS Guidelines for NonOccupational PEP MMWR 2005 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 Tenofovir DF + Emtricitabine or Lamivudine for Non-Occupational PEP – TDF/FTC (n=68) – TDF/3TC (n=44) – AZT/3TC (n=122) – AZT/3TC+ 3rd drug (n=119) • Mainly MSM, similar between NPEP arms Mayer KH, et al. JAIDS. 2007 Regimen Completion Rates 100 80 87.5% 72.7% Patients (%) Treatment arms 60 42.1%* 38.8%* 40 20 0 FTC/ TDF TDF + 3TC ZDV/ 3TC *P<0.0001 versus TDF-based regimens ZDV/ 3TC + 3rd Drug Tenofovir DF + Emtricitabine or Lamivudine for Non-Occupational PEP • Tenofovir: diarrhea or abdominal discomfort • Zidovudine: nausea and vomiting: AE’s more serious Adverse Events (%) FTC/ TDF TDF + 3TC ZDV/ 3TC ZDV/3TC + 3rd Drug Diarrhea 47.5* 31.3 9.8 58.8 Fatigue 30 28.1 39.3 48.5* Abdominal discomfort 47.5† 20.3† 3.3 2.9 Nausea/ vomiting 22.5 18.8 55.7† 58.8† Headache 22.5 18.8 24.6 11.8 Mayer KH, et al. JAIDS. 2007 *P<0.05 and †P<0.01. Risk Behavior at Time of Incident 60 56.5 Percent 50 40 32.6 26.1 30 20 10 0 Unprotected Anal Sex Alcohol Use Recreational Drug Use Note: TDF/3TC group reported more ua than the AZT/3TC group (30%), and about the same as the AZT/3TC+1 group (52%). 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 • 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 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 Sexual Behavior During PREP Trial in West Africa Screening Follow-up Number of partners (30 days) 21 14 Number of new partners (30 days) Number of sex acts (7 days) 11 6 12 15 52% 94% Condom use (last act) Peterson, XVI AIDS Conference, Toronto, 2006 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 CDC U.S. MSM PrEP Study (Project T; Project PrEPare) 100 TDF 100 Placebo 100 No Pills TDF 100 No Pills Placebo Enrollment 9 months 24 months PrEP is not already in wide use Outcome Overall (n=851) SF Bay Area (n=403) Circuit Party (n=176) STD Clinic (n=272) Heard of PrEP 18% 20% 19% 15% Knew PrEP user 2% 2% 4% 2% 0.12% 0% 0% 0.39%1 68% (n=563) 69% 66% n/a Used PrEP Would use PrEP if safe/effective 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 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 CMPD 167 for 10 days post challenge (inc. day 0) 4/9 CMPD 167 for 4 days prior + 10 days post challenge 6/11 0.47 0.023 0.051 (CMPD 167 +/- 4 days prior + 10 days post challenge 10/20 0.012) Courtesy of John Moore WHERE MICROBICIDES MAY WORK Oral vs. Topical PrEP? (HPTN 050) 1000 PMPA ng/mL 100 10 LLOQ 1 0 4 8 12 Hours 16 20 24 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) HIV incidence among IDUs has been declining in the U.S. Multivariable analysis of seroconversion risk: Drug use in Explore N at baseline No. of infections Hazard ratio* (95% CI) Heavy alcohol** 419 41 1.9 (1.2, 2.8) Amphetamines 527 67 1.9 (1.4, 2.6) Alcohol/drugs before sex 2952 205 1.6 (1.1, 2.3) Drug *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 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