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PREVENTION OF HIV-1

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) Hereditary resistance Phenotypic factors Innate resistance

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PREVENTION OF HIV-1

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  1. PREVENTION OF HIV-1 Myron S. Cohen, MD Institute for Global Health The University of North Carolina

  2. Transmission of HIV-1Biological Requirements Infectious Susceptibility Inoculum (concentration) Hereditary resistance Phenotypic factors Innate resistance Acquired (immune) resistance

  3. NSI HIV (M-tropic) SI HIV (T-tropic) semen Lamina Propria Dendritic Cells CD4+ CCR5+ Α4 β7+ HIV-1 “SWARM” CD4 DC-SIGN CCR5 T cell migration to lymphoid organs 99% R5, 82% 1 variant .

  4. 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) 3 0 7 10 14-28 Time (days)

  5. 0 5 10 15 20 25 30 35 40 Acute HIV-1 Infection Cohen et al, NEJM, 2011 Onset cytokines apoptosis, Day 7 Free Antibody, Day 13 Immune Complexes Day 9 Acute Phase Reactants Days -5 to-7 Autologous Neutralizing Antibody 108 107 106 ? 105 104 eclipse Reservoir 103 102 Virus Concentration in Extracellular Fluid or Plasma (Copies/ml) 101 Virus dissemination CTL Escape 0 CD8 T Cell Responses 10-1 Autologous Neutralizing Antibody Escape Transit 10-2 T0 10-3 10-4 10-5 45 50 55 60 65 70 Time Post Exposure (days) Transmission

  6. Effect of Acute and Early HIV Infection on Spread Cohen et al, NEJM, 2011 Pinkerton & Abramson 1996** Kretzschmar & Dietz 1998**† Powers et al 2010 Jacquez et al 1994 Salomon & Hogan 2008* Hayes & White 2006* Koopman et al 1997** Xiridou et al 2004 Pinkerton 2007 Prabhu et al 2009 Hollingsworth et al 2008 Abu-Raddad & Longini 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.

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

  8. ART to Prevent Sexual Transmission of HIV • Post-exposure Prophylaxis (PEP) • Pre-exposure prophylaxis (PrEP) • Treatment of the infected person

  9. Pre-Exposure Prophylaxis • Study Effect • CAPRISA (TDF Gel) 39-50% • iPREX (Daily TDF) 44% • FEM-PrEP (Daily TDF) Stopped • Partners (TFV/TDF) >70% • Botswana (TDF) >60% • Others in Progress

  10. ART Concentrations Rectal vs. Female Genital Tract TFV/FTC (Truvada®) PO QD Patterson, Cohen, Kashuba et al WAC 2010 Concentration 24 Hours After a Single Dose of Truvada® FTC TFV FTC-TP TFV-DP Not Detected

  11. CAPRISA 004: TFV 1% Gel BAT24 Extracellular Tenofovir Concentrations Gel Cervicovaginal Fluid Gel Vaginal Tissue Tablet Cervicovaginal Fluid Tablet Blood Plasma Gel Blood Plasma Dumond, Kashuba et al 2007; Schwartz, Kashuba et al IAS 2009

  12. Pre-Exposure Prophylaxis? • Differerences in studies -Gels vs. Pills? -Adherence? • PrEP next steps -Infrastructure (testing requirements)? -Dosage schedules? -Different agents? -PrEPfor whom?

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

  14. 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? POSITIVE RESULTS: Bunnell (JAIDS, 2007) Sullivan (IAS 2008) Donnell (Lancet, 2010) Romero (BMJ, 2010) NEGATIVE RESULTS: Wang (IAS, JAIDS, 2010)

  15. HPTN 052 1763 discordant heterosexual couples 9 countries, 13 sites Randomization Immediate ART 350-550cells/uL Deferred ART CD4 <250 AZT+3TC+EFV Endpoints: i) HIV Transmission to partners ii) OIs and clinical Events iii) ART toxicity

  16. 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

  17. HPTN 052 Prevention Results • 39 total infections, 35 in the delayed arm (p<.0001) • 28 linked infections (by 3 independent methods) • 27 delayed arm • 1 immediate arm • 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 p<0.001

  18. 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

  19. HPTN 052 Implications • For discordant couples? • For the Test and Treat Movement?

  20. The Economist June 4, 2011

  21. Treatment as PreventionThe “Test and Treat” MovementTHE 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

  22. HIV Prevention ARV TOPICAL PrEP COUNSELING ARV ORAL PrEP CIRCUMCISION VACCINE ACUTE HIV INFECTION? STD TREATMENT? ARV TREATMENT

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