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 YEARS Treatment Of HIV Reduced Infectivity INFECTED YEARS UNEXPOSED Behavioral, Structural Circumcision Condoms Cohen et al, JCI, 2008 Cohen IAS 2008 HOURS Vaccines ART PrEP Microbicides EXPOSED (precoital/coital) 72h Vaccines ART PEP EXPOSED (postcoital)

Let’s Accept the Idea that … Coates et al Lancet )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

Why Should Circumcision Prevent HIV Acquisition? Circumcision Mucosa is replaced with epithelium Reduced number of ulcers, Elimination of phimosis Reduced target cells for HIV

Impact of MC on HIV : Evidence from observational studies and RCTs Reduction of risk (95% CI) South Africa (RCT) 60 ( 76, 33) Kenya (RCT) 59 ( 76, 30) Uganda (RCT) 51 ( 82, 14) Overall 58 ( 66, 48) Reduction of risk (0%) Bailey et al. Lancet 2007; 369: 643–56 Weiss et al. AIDS 2000, 14: Auvert et al. PLoS Med 2005(11): e Gray et al. Lancet, 2007, 657–66

But When Primary Prevention Fails… Risk of a Transmission Event Develops InfectiousSusceptible Inoculum (concentration)Hereditary resistance Phenotypic factorsInnate resistance Acquired resistance Cohen and Galvin, Nat Micro Rev 2004

Viral Concentration Really Matters Chakraborty et al., AIDS Log 10 Seminal HIV RNA in one ejaculate Probability of transmission

A Single R5 Virus from “A SWARM” Infects Donor (variable) Mucosa Recipient Abortive Less fit or attenuated Abortive Time (days) Keele et al., PNAS 2008

Estimating HIV Transmission: Have the methods confused the message? HIV Transmission is often estimated as 1/ 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 … Powers et al Lancet ID, 2008

HIV Transmission Efficiency By Cofactor

Amplified Transmission of HIV Acute HIV Infection & STD Co-infection STD Episode AIDS 1/30 or greater odds of transmission to a susceptible partner per coital act HIV RNA In Semen (Log 10 copies/mL)

HSV Suppression to Prevent HIV? Celum et al. Lancet, 371: 1637 vs subjects randomized Acyclovir 400 mg BID 40% reduction in genital ulcers Reduction in HSV reactivation?? 3.6 vs. 3.3/100py acquisition of HIV-1 (NS) The HSV therapy “provided” failed to suppress HIV acquisition…

And treating STDs has a benefit far BEYOND the effects of HIV prevention Gray and Wawers, Lancet 2008 What about…“The STD Paradox”? 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

Four Prevention Opportunities YEARS Treatment Of HIV Reduced Infectivity INFECTED YEARS UNEXPOSED Behavioral, Structural Circumcision Condoms Cohen et al, JCI, 2008 Cohen IAS 2008 HOURS Vaccines ART PrEP Microbicides EXPOSED (precoital/coital) 72h Vaccines ART PEP EXPOSED (postcoital)

Transmission Virus Concentration in Extracellular Fluid or Plasma (Log 10 Copies/ml) Time Post Exposure (days) Set Point Limit of detection for HIV RNA Reservoir Symptoms HIV-1 Integration and Viral Dissemination Window of Opportunity??Established Infection Transit Adapted from Johnston and Fauci, NEJM,2007. eclipse HIV-1 Transmission Event

Biological prevention options at exposure …… When Transmission is Imminent 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 HIV Infection and RNA set point no protection Infection prevented protection against HIV sterilizing immunity! protection against disease A reduced HV peak and “set point” initial infection “controlled” chronic infection with low set point Transmission Vaccine Success Cell-Mediated Immunity

HIV Vaccines: Summary We do not know how to generate neutralizing antibodies Cell mediated (CTL) vaccines lower peak viremia and set point in macaques But, human studies have not yet controlled viremia (STEP Trial) Walker and Burton, Science, 2008 control 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

This CHAVI web site is at

Using Antiretroviral Agents for Prevention?

Pre-Exposure Prophylaxis (PrEP) in Macaques Garcia-Lerma, PLoS Medicine 2008

Current and Proposed PrEP Trials Coitally-dependent TNF GelDaily TNFDaily TruvadaDaily TNF Gel

Efficacy of Oral Truvada PrEP Efficacy of Oral Truvada PrEP Garcia-Lerma & Heneine (in progress) Untreated controls (n=27) - 22h/+2h (n=6); p= h/+2h (n=6); p= h/+22h (n=6); p= Number of rectal exposures % Uninfected animals

Dumond et al. CROI 2008 Maraviroc (CCR5 blockade) as PrEP? protein-free IC 90 = 0.5ng/mL N=12 Blood Plasma Cervicovaginal Fluid Vaginal Tissue

Thinking Ahead Truvada + Maraviroc THE ULTIMATE IN PrEP??? T T …fighting the viral swarm

Microbicides in Product Development Free virus Lactin-V Invisible Condom NCp7’s GM Biotics (Osel) Attachment Fusion Reverse Transcription Protein synthesis and assembly Budding Maturation PRO2000 SPL7013 (VivaGel) RANTES analogs Cyanovirin-N S-DABO Dapivirine UC781 Tenofovir PC-815 Next-generation compounds Early-generation compounds Pyrimidinediones (Samjin) BufferGel Integration DS007 (Merck L’644) DS003 (BMS 793) DS001 (Merck 167) Maraviroc (Pfizer)

Topical Approaches for HIV-1 Prevention Klasse et al Annu Rev Med July 2008 Tenofovir Gel Reservoir and Matrix Vaginal Rings CandidateStatus - Phase PRO 2000Ongoing – Phase 3 Tenofovir gel Ongoing – Phase 2B PRO 2000/BufferGel® Ongoing – Phase 2/2B DapivirineOngoing – 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 tabletPlanned – Phase I Duet®Planned – Phase I PC-815Planned – Phase I Current Microbicide Candidates (listed in latest stage of development)

Topical ART and New Results Garcia Lerma et al, US CDC 1% tenofovir gel or 1% tenofovir/ 5%FTC gel tested in a vaginal pig tail macaque model… 1% tenofovir gel or 1% tenofovir/ 5%FTC gel tested in a vaginal pig tail macaque model… IAS Late Breaker Abstract and other unpublished results (n=6 animals)... IAS Late Breaker Abstract and other unpublished results (n=6 animals)... COMPLETE protection with episodic usage 30 minutes before HIV exposure COMPLETE protection with episodic usage 30 minutes before HIV exposure

Four Prevention Opportunities YEARS Treatment Of HIV Reduced Infectivity INFECTED YEARS UNEXPOSED Behavioral, Structural Circumcision Condoms Cohen et al, JCI, 2008 Cohen IAS 2008 HOURS Vaccines ART PrEP Microbicides EXPOSED (precoital/coital) 72h Vaccines ART PEP EXPOSED (postcoital)

Post Exposure Prophylaxis 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 Roland, 2008

Four Prevention Opportunities YEARS Treatment Of HIV Reduced Infectivity INFECTED YEARS UNEXPOSED Behavioral, Structural Circumcision Condoms Cohen et al, JCI, 2008 Cohen IAS 2008 HOURS Vaccines ART PrEP Microbicides EXPOSED (precoital/coital) 72h Vaccines ART PEP EXPOSED (postcoital)

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 Established infection (on ART) Established infection (unrecognized) Established infection (untreated + STDs) Acute HIV Infection (only 8 weeks) INCREASING RISK 2.5 million people 30,000,000 people ( Fraser et al, PNAS, 2007) ? ? ? AIDS (untreated)

.. Location of Bushenyi District

Uganda Summary findings Indicator N (%) Male Female Total Number Eligible for HIV Testing147,664148,767296,431 Number Tested for HIV123,501141,465264,966 (89.4) Number who received HIV Test Results 123,491141,462264,953 (99.9) Number HIV Positive4,042 (3.4)7,317 (5.2)11,359 (4.3) Individuals in Discordant Partnerships ,785

ART for Secondary Prevention Strong biological plausibility for men and women Retrospective clinical studies Observational studies of couples Ecological population studies 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)…and “THE SWISS DECLARATION” Cohen et al. Annals Int Med 2006 Vernazza, al., AIDS, 2000 Cu-Uvin et al., JAIDS, 2006 Men Women Patients (%) with detectable HIV in genital secretions Not on ART On ART

HPTN 052…AN RCT UNDERWAY ( HIV-infected subjects with 350 to 550 CD4 T cells Immediate ART cells/uL Deferred ART CD4 200 AZT+3TC+EFV Endpoints: i) Transmission Events ii) OIs and Clinical Events ii) OIs and Clinical Events iii) ART Toxicity iii) ART Toxicity Randomization

Prevention of the Sexual Transmission of HIV-1: Results from Randomized Controlled Trials InterventionRCTs CompletedRCTs Effective Behavior change Circumcision Diaphragms Microbicides PrEP STD Treatment Vaccines Wasserheit, WHO, ) RCT results are one measure of success 2) 15 RCTs in progress: new results each year

HIV Prevention and Public Health Resources must match opportunities? Failure to implement ideas that work? Failure to undertake combined multi- pronged and multilevel approaches? Potts et al. Science, 2008

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

Scenario Millions of Total New Adult Infections Millions of Infections Averted vs. Baseline Millions of Total Adult Deaths Millions of Deaths Averted vs. Baseline Baseline52.3NA37.4NA Treatment-centered (optimal effects) (6%) (13%) Treatment-centered (mixed effects) (-10%) (9%) Prevention-centered (36%) (13%) Combined response (optimistic) (55%) (27%) Combined response (pessimistic) (17%) (16%) Integrating HIV Prevention and Treatment Salomon at al. PLoS Medicine, 2005 Modeling Interventions in Sub-Saharan Africa,

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