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PREVENTION OF HIV-1 Myron S. Cohen, MD Institute for Global Health The University of North Carolina Transmission of HIV-1 Biological Requirements Infectious Susceptibility Inoculum (concentration) Phenotypic factors Hereditary resistance Innate resistance Acquired (immune) resistance NSI HIV (M-tropic) SI HIV (T-tropic) semen Lamina Propria Dendritic Cells HIV-1 “SWARM” CD4+ CCR5+ Α4 β7+ CD4 DC-SIGN migration to lymphoid organs CCR5 T cell 99% R5, 82% 1 variant . HIV-1 Transmission Model Cohen et al, NEJM, 2011 Mucosa Recipient Inoculum >106 virions/ml plasma (Most fit virus R0>>1) ~109 infection events Defective virus Less fit virus (R0~1) Defective virus X Less fit, attenuated or stochastic event (R0<<1) 0 3 7 Time (days) 10 14-28 Acute HIV-1 Infection Cohen et al, NEJM, 2011 Onset cytokines apoptosis, Day 7 Virus Concentration in Extracellular Fluid or Plasma (Copies/ml) Acute Phase Reactants Days -5 to-7 Free Antibody, Day 13 Immune Complexes Day 9 Autologous Neutralizing Antibody 108 107 106 105 104 ? Reservoir eclipse 103 102 101 0 CTL Escape CD8 T Cell Responses 10-1 10-2 Transit 10-3 Autologous Neutralizing Antibody Escape T0 10-4 10-5 0 Transmission 5 10 15 20 25 30 35 40 Time Post Exposure (days) 45 50 55 60 65 70 Effect of Acute and Early HIV Infection on Spread Cohen et al, NEJM, 2011 Pinkerton & Abramson 1996** Kretzschmar & Dietz 1998**† Powers et al 2010 Hayes & White 2006* Jacquez et al 1994 Salomon & Hogan 2008* Koopman et al 1997** Xiridou et al 2004 Pinkerton 2007 Prabhu et al 2009 Abu-Raddad & Longini 2008† Hollingsworth et al 2008 * Range of estimates reflects the proportion of all transmissions during an individual’s entire infectious period that occur during EHI. The extent to which this proportion corresponds with the proportion of all transmissions that occur during EHI at the population level will depend on the epidemic phase and the distribution of sexual contact patterns in the population. ** Transmission probabilities were drawn from the population category shown, but the reported estimates result from a range of hypothetical sexual behavior parameters that do not necessarily reflect a specific population. † The range of estimates shown was extracted from the endemic-phase portion of graphs showing the proportion of new infections due to EHI over calendar time. Four Prevention Opportunities Cohen et al, JCI, 2008 Cohen IAS 2008 UNEXPOSED EXPOSED EXPOSED INFECTED (precoital/coital) (postcoital) Behavioral, Structural Structural Circumcision Condoms STDs YEARS Vaccines ART PrEP Microbicides HOURS Vaccines ART PEP 72h Treatment Of HIV Reduced Infectivity YEARS ART to Prevent Sexual Transmission of HIV • Post-exposure Prophylaxis (PEP) • Pre-exposure prophylaxis (PrEP) • Treatment of the infected person Pre-Exposure Prophylaxis • • • • • • • Study CAPRISA (TDF Gel) iPREX (Daily TDF) FEM-PrEP (Daily TDF) Partners (TFV/TDF) Botswana (TDF) Others in Progress Effect 39-50% 44% Stopped >70% >60% TFV/FTC (Truvada®) PO QD Patterson, Cohen, Kashuba et al WAC 2010 Concentration 24 Hours After a Single Dose of Truvada® Concentration 24h After a Single Dose of Truvada AUC over 14 Days After a Single Dose of Truvada Concentration 24h After a Single Dose of Truvada 10000 FTC TFV 1000 10 1 RECTAL VAGINAL 100 10 10 1 1 106 106 10 Not Detected 102 RECTAL VAGINAL CERVICAL 105 5 104 FTC-TP C24 (fmol/g) 10 10 3 1 FTC-TP TFV-DP AUC (d*fmol/g) TFV-DP C24 (fmol/g) 104 10 105 TFV-DP 10 100 RECTAL RECTAL VAGINAL VAGINAL CERVICALCERVICAL CERVICAL 5 FTC AUC (d*ng/g) 100 1000 1000 FTC C24h (ng/g) TFV AUC (d*ng/g) TFV C24h (ng/g) 1000 100 10000 10000 FTC-TP AUC (d*fmol/g) 10000 104 103 104 103 3 102 102 102 RECTAL RECTAL VAGINALVAGINAL CERVICAL CERVICAL CAPRISA 004: TFV 1% Gel BAT24 107 Tenofovir Concentrations Extracellular Tenofovir Concentrations single dose oral and topical administration Tenofovir Concentration (ng/mL) 106 105 Gel Cervicovaginal Fluid 104 Gel Vaginal Tissue 103 102 Tablet Cervicovaginal Fluid Tablet Blood Plasma 101 100 0 4 8 12 Gel Blood Plasma 16 20 24 Time Post-Dose (hr) Dumond, Kashuba et al 2007; Schwartz, Kashuba et al IAS 2009 Pre-Exposure Prophylaxis? • Differerences in studies -Gels vs. Pills? -Adherence? • PrEP next steps -Infrastructure (testing requirements)? -Dosage schedules? -Different agents? -PrEP for whom? 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 Structural Circumcision Condoms YEARS HOURS 72h YEARS HIV “Treatment as Prevention”? • Compelling biological plausibility: ART reduces HIV in genital secretions • Five observational reports What is the magnitude and durability of ART for prevention? Does early ART (for prevention) benefit an HIV infected person? HPTN 052 1763 discordant heterosexual couples 9 countries, 13 sites Randomization Immediate ART 350-550cells/uL AZT+3TC+EFV Deferred ART CD4 <250 Endpoints: i) HIV Transmission to partners ii) OIs and clinical Events iii) ART toxicity HPTN 052 Modified • April 28, 2011 (DSMB meeting #11) Recommendation: “Make the results available to the public (and study subjects) as soon as possible” HPTN 052 is ongoing with all HIV infected subjects offered ART, regardless of CD4 count HPTN 052 Prevention Results 39 total infections, 35 in the delayed arm (p<.0001) – 28 linked infections (by 3 independent methods) • 27 delayed arm p<0.001 • 1 immediate arm o 17 of 27 infections in delayed arm occurred when the index participants’ CD4 was >350 – 7 unlinked infections • 4 delayed arm (ALL NOW PROVEN UNLINKED) • 3 immediate arm (ALL PROVEN UNLINKED) – 4 infections still being analyzed (ALL IN THE DELAYED ARM) – The details of 1/27 transmissions are being evaluated HPTN 052 Clinical Results 105 morbidity and mortality events (p<.01) – 65 in delayed arm – 40 in immediate arm 20 cases of extrapulmonary TB (p= 0.0013) – 17 in delayed arm – 3 in immediate arm 23 deaths (NS) – 13 in delayed arm – 10 in immediate arm HPTN 052 Implications • For discordant couples? • For the Test and Treat Movement? The Economist June 4, 2011 Treatment as Prevention The “Test and Treat” Movement THE HORSE IS OUT OF THE GATE • • • • Botswana cohort study (Essex, MP3) US HPTN 065 in NYC, DC, (El-Sadr) ANRS South Africa (Newell, Dabas) Combination Prevention Competition: – CDC September, 2011 – HPTN August, 2011 HIV Prevention ARV TOPICAL PrEP COUNSELING ARV TREATMENT CIRCUMCISION ARV ORAL PrEP VACCINE ACUTE HIV INFECTION? STD TREATMENT?