Working to End the HIV Pandemic: Glimmers of Hope. Transmission of HIV-1 Biological Requirements

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1 Working to End the HIV Pandemic: Glimmers of Hope Myron S. Cohen, MD Director, Institute for Global Health The University of North Carolina Transmission of HIV-1 Biological Requirements Infectious Inoculum (concentration) Phenotypic factors Susceptibility Hereditary resistance Innate resistance Acquired (immune) resistance HIV-1 Transmission Model (CHAVI) Cohen et al, NEJM, 2011 Mucosa Inoculum Recipient >10 6 virions/ml plasma (Most fit virus R 0>>1) ~10 9 infection events Defective virus Less fit virus (R 0~1) Defective virus X Less fit, attenuated or stochastic event (R 0<<1) Time (days) 1

2 Probability of HIV Transmission? ~1/1000 episodes for couples?? (Most recently Hughes et. al. JID) 1/1000 IS AN UNDERESTIMATE?? - exposed uninfected partners - benefits of counseling - missing amplification factors Amplified Transmission of HIV-1 Infectiousness Susceptibility Blood Viral Load Genital Tract Viral Load -Inflammatory STDs Viral clade ACUTE INFECTION (!!) Genital ulcers Inflammatory STDs Cytokine profile Lack of Circumcision Cervical ectopy HLA Haplotype Hormonal Contraception(??) id lu F r la lu e c a tr x E in n tio a tr n e c n o C s u ir V r o Acute Phase Reactants Days -5 to-7 l) /m s ie p o ( C a m s la P Transit Acute HIV-1 Infection Cohen et al, NEJM, 2011 Onset cytokines apoptosis, Day 7 Free Antibody, Day 13 eclipse T0 Immune Complexes Day 9? Reservoir CD8 T Cell Responses CTL Escape Autologous Neutralizing Antibody Autologous Neutralizing Antibody Escape Transmission Time Post Exposure (days) 2

3 Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 UNEXPOSED EXPOSED EXPOSED (precoital/coital) (postcoital) INFECTED Vaccines Behavioral, ART PrEP Structural Structural Microbicides Circumcision Condoms STDs Vaccines ART PEP Treatment Of HIV Reduced Infectivity YEARS HOURS 72h YEARS Behavioral Interventions? No single tool to reduce HIV incidence Padian, AIDS 2010 But HIV incidence has fallen! HPTN 043..Effects of mobile VCT -Cross sectional HIV incidence STAY TUNED ART to Prevent Sexual Transmission of HIV Post-exposure Prophylaxis (PEP)??? Pre-exposure prophylaxis (PrEP)???? Treatment of the infected person??? 3

4 Antiretroviral Exposure at Mucosal Surfaces Rectal Tissue, CVF, Semen Exposure Relative to Blood 1000 CCR5 Receptor Antagonists Integrase Inhibitors Nonnucleoside RT Inhibitors Nucleoside(tide) RT Inhibitors Protease Inhibitors Matrix:Blood Plasma Ratio MRV (27) MRV (4) MRV (0.6) RAL (150) RAL (2) ETR (1.3) EVF (0.6) DLV (0.2) ETR (8) ETR (0.15) EFV (0.03) FTC/ 3TC (4) ZDV (2) DDI (0.21) ABC (0.08) D4T (0.05) TFV (46) 3TC (6) TFV (5) D4T (3.5) ZDV (2) RAL (1) NVP (0.8) NVP (0.7) TFV (1) ABC (1.5) FTC (2.6) CCR5 RA INSTI NNRTI NRTI PI RECTAL CERVICOVAGINAL TISSUE FLUID SEMEN ARV Class IDV (2) APV (0.5) RTV (13) DRV (2.7) IDV (1) RTV (0.3) APV (0.2) ATV (0.18) DRV (0.17) LPV (0.08) LPV/NFV (0.05) SQV & RTV (0.03) SQV (ND) PrEP Utilization Cohen and Baden, NEJM 2012 TDF/FTC (Truvada) PrEP FDA approved - MSM - Discordant Couples - High Risk People (???) Strategy, Infrastructure, Demand? CDC Interim Guidance August 11,2012 Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 UNEXPOSED EXPOSED EXPOSED (precoital/coital) (postcoital) INFECTED Behavioral, Structural Structural Circumcision Condoms Vaccines ART PrEP Microbicides Vaccines ART PEP Treatment Of HIV Reduced Infectivity YEARS HOURS 72h YEARS 4

5 Treatment as Prevention The Four Questions 1) Do ART drugs prevent HIV transmission? 2) What do we tell infected people? 3) Can we reduce population HIV incidence? 4) Barriers to Treatment as Prevention? HPTN 052 Study Design Stable, healthy, serodiscordant couples, sexually active CD4 count: 350 to 550 cells/mm 3 Randomization Immediate ART CD Delayed ART CD4 <250 Primary Transmission Endpoint Virally linked transmission events Primary Clinical Endpoint WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death HPTN 052 Timeline: The Fast Track? ART for prevention of HIV 1993-THE PRESENT HPTN 052 ACTG 5175 Protocol Requirement Development HPTN 052 Drug Procurement HPTN 052 Pilot HPTN 052 Enrollment HPTN 052 DSMB (#10) April 28,

6 HPTN 052 Recognition U.S. Sponsors: National Institutes of Health (NIH) Division of AIDS (DAIDS), U.S. National Institute of Allergy and Infectious Diseases (NIAID) HIV Prevention Trials Network (HPTN): Network Laboratory, Johns Hopkins University Statistical Center for HIV/AIDS Research & Prevention (SCHARP) and University of Washington Coordinating and Operations Center, Family Health International (FHI) HPTN Leadership AIDS Clinical Trials Group (ACTG): ACTG Leadership and Investigators Pharmaceutical Companies: Abbott Laboratories Boehringer Ingelheim Pharmaceuticals, Inc. Bristol-Myers Squibb Gilead Sciences, Inc. GlaxoSmithKline Merck & Co., Inc. Sites (Investigators of Record): Porto Alegre, Brazil (Breno Santos) Rio de Janeiro, Brazil (Beatriz Grinsztejn) Boston, United States (Kenneth Mayer) Chennai, India (N. Kumarasamy) Pune, India (Sheela Godbole) Chiang Mai, Thailand (Suwat Chariyalertsak) Gaborone, Botswana (Joseph Makhema) Kisumu, Kenya (Lisa Mills) Blantyre, Malawi (Johnstone Kumwenda) Lilongwe, Malawi (Mina Hosseinipour) Johannesburg, South Africa (Ian Sanne) Soweto, South Africa (Guy De Bruyn) Harare, Zimbabwe (James Hakim) Study Participants UNC and 22 Years in Lilongwe, Malawi 12.5 million people Half live on less than $1/day Life expectancy: 39 years 2 physicians per 100,000 people 6

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10 HPTN 052 Enrollment 10,838 Individuals Screened 1763 Couples (3526 Individuals) Randomized Major reasons for exclusion: 3058 HIV+ but CD4 count out of range 2565 HIV- but HIV+ partner ineligible 308 Seroconcordant couples 155 Ineligible due to sexual history Immediate Arm 886 Couples Delayed Arm 877 Couples HPTN 052 Enrollment (Total Enrollment: 1763 couples) U.S. Americas 278 Brazil Botswana South Africa India Kenya Malawi Zimbabwe Africa 954 Thailand Asia 531 DSMB Recommendation April 28, 2011 (DSMB 10 th Biannual Review) The Board recommends that the results of the trial be announced as soon as possible 10

11 HPTN 052: HIV-1 Transmission Total HIV-1 Transmission Events: 39 Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 Immediate Arm: 1 p < Delayed Arm: 27 18/28 (64%) transmissions from infected participants with CD4 >350 cells/mm 3, and VL >50,000 copies/ml at transmission 23/28 (82%) transmissions in sub-saharan Africa 18/28 (64%) transmissions from female to male partners HPTN 052: ADHERENCE MATTERS Proportion of participants with VL<400 at each visit Immediate Arm Delayed Arm (not on ART) Delayed Arm (on ART) Months One Transmission Event on ART Index begins ART AZT/3TC/EFV Index VL<400 Partner HIV+ (WB) Enrollment Screening Days Partner VL < 400 Index VL = 87,202 Single Genome Analysis: 1-2 viruses transmitted Analysis of Transmission: >50 days earlier ( days) 11

12 HIV-1 RNA and CD4 Over Time (ITT) Immediate Delayed HPTN 052: We Are Not Done Yet The HPTN 052 study is ongoing All HIV infected subjects offered ART 93% index cases are now on ART Retention is 96% among the index cases and 85% for the discordant couples Questions remain: Durability of the prevention benefit? Consequences of delayed ART? PEPFAR, WHO AND HPTN ART for heterosexual discordant couples Treat HIV before CD4 count falls below 350 Does ART prevent HIV transmission in MSM couples? IDU transmission? 12

13 The Economist TnT: Aspiration Meets Reality Smith, Cohen et al. PLOS MED, July Acute Infection? 2. THE CASCADE 3. Ecological and observational studies HIV Rx Cascade Aspiration Meets Reality 80% 77% 66% 89% 77% Multiplies to 28% 850,000 HIV+ Americans (72%) lack viral control Refs: MMWR 2011; see also Gardner CID 2011; Burns CID

14 The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may Black MSM Undiagnosed HIV OR, 6.38 ( ) HIV Detection Diagnosed HIV+ OR, 3.00 ( ) Health insurance coverage OR,0.47 ( ) 15 X risk for HIV Policies that criminalize homosexuality associated with increased HIV prevalence Safe and culturally competent access to care lacking for black MSM ART utilization/ access OR, 0.56 ( ) >200 CD4 cells/mm 3 before ART initiation OR, 0.40 ( ) ART adherence OR, 0.50 ( ) HIV suppression OR, 0.51 ( ) Viral Suppression Millett AIDS 2012, Lancet HPTN 065 (TLC-Plus) Provider Survey Study Population and Participants ART-prescribing providers at 38 participating HPTN 065 care sites in Bronx, NY and Washington, DC Internet-based survey (anonymous) Kurth et al, TASP 2012 Glimmers of Hope 14

15 The Test and Treat Movement US HPTN 065 Linkage in NYC, DC ANRS PILOT in South Africa THE PEPFAR Combination Prevention Trials: CDC-BOTSWANA NIH HPTN 071 -South Africa, Zambia USAID JHU-Tanzania HPTN 071 Intervention Package Community HIV Care Providers (CHiPs team): Counselling, condom provision, syndromic STI Rx Referral of pregnant women for ANC/PMTCT services Universal voluntary HIV testing house-to-house HIV-uninfected men offered circumcision HIV-infected persons Arm A: Immediate ART (analogous to HPTN 052) Arm B: Enhanced Standard of Care (CD4<350) Arm C: Standard of Care (CD4<350) 15

16 Personal Conclusions 34,000,000 people with HIV to treat -for health, and transmission prevention Mass treatment of HIV is a bridge -to simpler, modified intervention -to a cure -to a vaccine Wishful, magical or aspirational thinking? Clinton Speech November 8,

17 PPEFAR ROADMAP Saving Lives: Scale up combination prevention and treatment Smart Investments: Going where the virus is Shared Responsibility: Creating an AIDS-Free Generation requires a global effort Driving Results with Science: Science must continue to guide our efforts HIV Prevention 2012 COUNSELING ARV TOPICAL PrEP CIRCUMCISION ARV ORAL PrEP ARV TREATMENT VACCINE PMTCT ACUTE HIV INFECTION 17