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Prevention of the Sexual Transmission of HIV-1: A view from the 21st century Myron S Cohen The University of North Carolina Chapel Hill, USA Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 UNEXPOSED EXPOSED EXPOSED INFECTED (precoital/coital) (postcoital) Behavioral, Structural Vaccines ART PrEP Microbicides Vaccines ART PEP Treatment Of HIV Reduced Infectivity Circumcision Condoms YEARS HOURS 72h YEARS Let’s Accept the Idea that … Coates et al Lancet 2008 1) Abstinence or total monagomy in a SERONEGATIVE couple are effective, but difficult to achieve (…and beware concurrency) 2) Barrier Methods Work a) Condoms (serve as a reversible barrier) b) Circumcision ( form an irreversible and imperfect barrier) 3) HIV prevalence has fallen in many communities so some behavioral interventions work 4) Combination multilevel behavioral and structural approaches may ultimately prove very effective, and they certainly need continued effort But When Primary Prevention Fails… Risk of a Transmission Event Develops Cohen and Galvin, Nat Micro Rev 2004 Infectious Susceptible Inoculum (concentration) Phenotypic factors Hereditary resistance Innate resistance Acquired resistance Viral Concentration Really Matters Probability of transmission Chakraborty et al., AIDS 2001 0.016 0.012 0.008 0.004 3 3.5 4 4.5 5 5.5 Log10 Seminal HIV RNA in one ejaculate A Single R5 Virus from “A SWARM” Infects Keele et al., PNAS 2008 Donor Mucosa (variable) Recipient Abortive Abortive Abortive Less fit or attenuated 0 7 14 21 28 Time (days) Estimating HIV Transmission: Have the methods confused the message? Powers et al Lancet ID, 2008 HIV Transmission is often estimated as 1/500-1000 episodes of intercourse but only when… • • • • Acute transmission in couples cannot be measured STDs are RARE in the study population(s) Condom usage cannot be readily measured Anal intercourse is not generally practiced SEXUAL TRANSMISSION MUST ON MANY OCCASIONS BE FAR MORE EFFICIENT … HIV Transmission Efficiency By Cofactor Powers et al Lancet ID, 2008 Amplified Transmission of HIV HIV RNA In Semen (Log10 copies/mL) 10 8 6 4 2 0 1/30 or greater odds of transmission to a susceptible partner per coital act What about…“The STD Paradox”? Gray and Wawers, Lancet 2008 Only 1/7 STD intervention RCTs have led to reduced transmission of HIV So… either STDs do not “amplify” HIV transmission OR (MORE LIKELY) the interventions are inadequate?? BUT Successful intervention requires that….. The “RIGHT” STD(S) are treated At JUST the right time In JUST the right people (HIV positive or negative) With VERY EFFECTIVE drugs(s) For the RIGHT duration of time And treating STDs has a benefit far BEYOND the effects of HIV prevention Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 UNEXPOSED EXPOSED (precoital/coital) Behavioral, Structural Vaccines ART PrEP EXPOSED INFECTED (postcoital) Microbicides Vaccines ART PEP HOURS 72h Treatment Of HIV Reduced Infectivity Circumcision Condoms YEARS YEARS HIV-1 Transmission Event Adapted from Johnston and Fauci, NEJM,2007. Virus Concentration in Extracellular Fluid or Plasma (Log10 Copies/ml) Window of Opportunity?? 8 7 6 5 4 3 eclipse 2 1 0 -1 -2 Transit -3 -4 -5 0 Transmission 5 10 Established Infection Symptoms Set Point Reservoir Limit of detection for HIV RNA HIV-1 Integration and Viral Dissemination 15 20 25 30 35 40 Time Post Exposure (days) 45 50 55 60 65 70 When Transmission is Imminent Biological prevention options at exposure…… 1. Modification of Innate Immunity 2. Acquired Immunity (A VACCINE) a) Neutralizing antibodies b) Cell mediated immunity 3. Antiretroviral therapy Strategies for an HIV Vaccine Transmission Vaccine Success no protection protection against HIV sterilizing immunity! HIV Infection and RNA set point Infection prevented Cell-Mediated Immunity protection against disease A reduced HV peak and “set point” initial infection “controlled” chronic infection with low set point HIV Vaccines: Summary Walker and Burton, Science, 2008 • We do not know how to generate neutralizing antibodies control • Cell mediated (CTL) vaccines lower peak viremia and set point in macaques But, human studies have not yet controlled viremia (STEP Trial) treated Letvin, Science, 2006 WE HAVE ABSOLUTELY NO CHOICE BUT TO CONTINUE TO DEVELOP THE SCIENCE REQUIRED FOR AN HIV VACCINE…NO MATTER HOW LONG IT TAKES Using Antiretroviral Agents for Prevention? Pre-Exposure Prophylaxis (PrEP) in Macaques Garcia-Lerma , PLoS Medicine 2008 % Uninfected animals 100 High-dose Injectable Truvada (n = 6) 75 Oral Truvada (n = 6) 50 Injectable FTC (n = 6) Oral TDF (n = 4) 25 Controls (n = 18) 0 0 2 4 6 8 10 12 14 Number of rectal exposures Current and Proposed PrEP Trials Daily TNF Daily Truvada Daily TNF Gel Coitally-dependent TNF Gel Efficacy of Oral Truvada PrEP % Uninfected animals Garcia-Lerma & Heneine (in progress) 100 -72h/+2h (n=6); p=0.01 -22h/+2h (n=6); p=0.008 75 -2h/+22h (n=6); p=0.04 50 25 0 Untreated controls (n=27) 0 2 4 6 8 10 12 Number of rectal exposures 14 Maraviroc (CCR5 blockade) as PrEP? Dumond et al. CROI 2008 Day 7-10 Mean/SD Profile Plasma 1000 Maraviroc Concentration (ng/mL) CVF Vaginal Tissue 100 10 protein-free IC90 = 0.5ng/mL 1 0 N=12 12 24 36 Time (hr) 48 60 72 Thinking Ahead Truvada + Maraviroc T …fighting the viral swarm THE ULTIMATE IN PrEP??? Topical Approaches for HIV-1 Prevention Klasse et al Annu Rev Med 2008 Current Microbicide Candidates Tenofovir Gel Reservoir and Matrix Vaginal Rings (listed in latest stage of development) Candidate Status - Phase PRO 2000 Ongoing – Phase 3 Tenofovir gel Ongoing – Phase 2B PRO 2000/BufferGel® Ongoing – Phase 2/2B Dapivirine Ongoing – Phase I Ethanol in Emollient Gel Ongoing – Phase I UC-781 Ongoing – Phase I VivaGel® Paused – Phase I ACIDFORM ™ Planned – Phase 3 Invisible Condom™ Planned – Phase 2/3 CAP vaginal soft tablet Planned – Phase I Duet® Planned – Phase I PC-815 Planned – Phase I www.microbicide.org, July 2008 Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 UNEXPOSED EXPOSED (precoital/coital) Behavioral, Structural Vaccines ART PrEP EXPOSED INFECTED (postcoital) Microbicides Vaccines ART PEP HOURS 72h Treatment Of HIV Reduced Infectivity Circumcision Condoms YEARS YEARS Post Exposure Prophylaxis Roland, 2008 • A clinical trial to PROVE that PEP works cannot be developed • PEP requires emergent usage and a full 28 days of therapy, and multiple agents • Human failures have occurred, especially after anal exposure and with delayed initiation of ART • In several reports health care providers seem to demonstrate ambivalence about the PEP strategy Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 UNEXPOSED EXPOSED EXPOSED INFECTED (precoital/coital) (postcoital) Behavioral, Structural Vaccines ART PrEP Microbicides Vaccines ART PEP HOURS 72h Treatment Of HIV Reduced Infectivity Circumcision Condoms YEARS YEARS Secondary HIV Prevention • Transmission from those who do not know their status is important (Marks, AIDS 2006) • Transmission in HIV discordant couples represents an ongoing challenge (Dunkle, Lancet 2008) HIV TESTING REMAINS A CRITICAL LINK!! The Hierarchy of Transmission Risk.. from ~36-39 Million People with HIV Acute HIV Infection ? INCREASING RISK ? ? 30,000,000 people (Fraser et al, PNAS, 2007) 2.5 million people (only 8 weeks) AIDS (untreated) Established infection (untreated + STDs) Established infection (unrecognized) Established infection (on ART) ART for Secondary Prevention • Strong biological plausibility for men and women • Retrospective clinical studies • Observational studies of couples • Ecological population studies Patients (%) with detectable HIV in genital secretions Cohen et al. Annals Int Med 2006 100 Not on ART On ART 80 60 40 20 0 Men Women Vernazza, al., AIDS, 2000 Cu-Uvin et al., JAIDS, 2006 BUT WE DO NOT KNOW THE DEGREE OR DURABILITY OF BENEFIT FROM ART AS AN HIV-1 PREVENTION WITHIN A COUPLE (Wilson et al. Lancet, 2008) HPTN 052…AN RCT UNDERWAY (www.hptn.org/research_studies/hptn052.asp) HIV-infected subjects with 350 to 550 CD4 T cells Randomization Immediate ART 350-550cells/uL AZT+3TC+EFV Deferred ART CD4 <250>200 Endpoints: i) Transmission Events ii) OIs and Clinical Events iii) ART Toxicity Prevention of the Sexual Transmission of HIV-1: Results from Randomized Controlled Trials Wasserheit, WHO, 2007 Intervention Behavior change Circumcision Diaphragms Microbicides PrEP STD Treatment Vaccines RCTs Completed RCTs Effective 9 0 4 3 1 0 9.5 0 1 0 7 1 2 0 1) RCT results are one measure of success 2) 15 RCTs in progress: new results each year HIV Prevention and Public Health Potts et al. Science, 2008 • Resources must match opportunities? • Failure to implement ideas that work? • Failure to undertake combined multipronged and multilevel approaches? Highly Active HIV Prevention Coates, Richter et al., 2008 The Big Challenge NOW Great HIV treatment success… – 22 antiretroviral agents available – More than 2 million people receiving ART But 2.5 million new HIV infections/yr HIV prevention lags behind and has not married treatment except for MTCT!! HIV prevention MUST marry treatment NOW: With the community…a unified strategy Integrating HIV Prevention and Treatment Salomon at al. PLoS Medicine, 2005 Modeling Interventions in Sub-Saharan Africa, 2004-2020 Scenario Millions of Total New Adult Infections Millions of Infections Averted vs. Baseline Millions of Total Adult Deaths Millions of Deaths Averted vs. Baseline Baseline 52.3 NA 37.4 NA Treatment-centered (optimal effects) 49.2 3.0 (6%) 32.4 5.0 (13%) Treatment-centered (mixed effects) 57.4 -5.1 (-10%) 33.9 3.5 (9%) Prevention-centered 33.2 19.1 (36%) 32.6 4.8 (13%) Combined response (optimistic) 23.4 28.8 (55%) 27.3 10.1 (27%) Combined response (pessimistic) 43.6 8.7 (17%) 31.6 5.8 (16%) THANK YOU • To the organizers • To many collaborators over 25 years • To faculty and staff at UNC-CH, and UNC Projects in Malawi, China, Madagascar and other countries • To patients and volunteers who participated in many clinical trials • To NIH, CDC, USAID, and others for funding