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“Some things old, Some things new Most slides borrowed, Some in blue” \

STDs Amplify Transmission of HIV: Where Do WE Go From Here?. “Some things old, Some things new Most slides borrowed, Some in blue” . Myron S. Cohen, MD Yeargan-Bate Eminent Professor of Medicine, Microbiology and Epidemiology Director, Institute for Global Health and Infectious Diseases

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“Some things old, Some things new Most slides borrowed, Some in blue” \

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  1. STDs Amplify Transmission of HIV: Where Do WE Go From Here? “Some things old, Some things newMost slides borrowed, Some in blue” \ Myron S. Cohen, MD Yeargan-Bate Eminent Professor of Medicine, Microbiology and Epidemiology Director, Institute for Global Health and Infectious Diseases Associate Vice Chancellor for Global Health The University of North Carolina-Chapel Hill

  2. Myron S. Cohen, MD Yeargan-Bate Eminent Professor of Medicine, Microbiology and Epidemiology Director, Institute for Global Health and Infectious Diseases Associate Vice Chancellor for Global Health The University of North Carolina-Chapel Hill

  3. Transmission of HIV Josephs et al, Nature Micro Reviews 13:415, 2015

  4. Epidemiological Synergy Interrelationships between Human Immunodeficiency Virus Infection And Other Sexually Transmitted Diseases JUDITH N. WASSERHEIT, MD, MPH From the Sexually Transmitted Diseases Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland Sex Transm Dis. 1992 Mar-Apr;19(2):61-77

  5. What could possibly go wrong?

  6. Amplified Transmission of HIV Cohen MS. Tran Am ClinClimatol. Assoc. 117:213-225, 2006 Infectiousness Blood Viral Load Genital Tract Viral Load -Inflammatory STDs Viral clade ACUTE INFECTION Susceptibility Genital ulcers Inflammatory STDs Cytokine profile Lack of circumcision Cervical ectopy HLA Haplotype Hormonal contraception? “Dysbiosis”?

  7. Volume 74 . Number 3 WWW.JAIDS.COM March 1, 2017 Genital—Systemic Chemokine Gradients and the Risk of HIV Acquisition in Women Liebenberg, Lenine J. P. PhD; Masson, LindiPhD; Arnold, Kelly B. PhD; Mckinnon, Lyle R. PhD; Werner, Lise MSc; Proctor, Elizabeth PhD; Archary, Derseree PhD; Mansoor, Leila E. PhD; Lauffenburger, Douglas A. PhD; Abdool Karim, Quarraisha PhD; Abdool Karim, Salim S. MD, PhD; Passmore, Jo-Ann S. PhD J Acquir Immune Defic Syndr. 2017 Mar 1;74(3):318-325.

  8. Corpus cavernosum Corpus spongiosum Urethra Corona suculus Foreskin Sub-preputial space Glans penis Fossa Does HIV Exploit the Inflammatory Milieu of the Male Genital Tract for Successful Infection? navicularis Stratum Corneum Stratum Lucidum Stratum Granulosum Stratum Spinosum Stratum Basale Stratum Corneum Stratum Lucidum Stratum Granulosum Stratum Spinosum Stratum Basale EPIDERMIS EPIDERMIS Rachel T. Esra, Abraham J. Olivier, Jo-Ann S. Passmore, Heather B. Jaspan, Rushil Harryparsad and Clive M. Gray DERMIS DERMIS SUBCUTANEOUS TISSUE Esra, et al. Front Immunol. 2016; 7: 245.

  9. Langerhans cells STI- STI+

  10. Viral Fitness and HIV Transmission Carlson et al, Science 2014 137 Transmission Pairs Examination of amino acid sequences encode by non-envelope genes in the “founder” viruses Transmission probability reflects viral “fitness” Reduced fitness requirements for men with STDs (genital inflammation) and in women generally

  11. A Vicious Cycle: STDs predict future HIV Risk Rectal GC or CT 1 in 15 MSM were diagnosed with HIV within 1 year.* Primary or Secondary Syphilis 1 in 18 MSM were diagnosed with HIV within 1 year.** No rectal STD or syphilis infection 1 in 53 MSM were diagnosed with HIV within 1 year.* *STD Clinic Patients, New York City. Pathela, CID 2013:57; **Matched STD/HIV Surveillance Data, New York City. Pathela, CID 2015:61

  12. 0 5 10 15 20 25 30 35 40 Acute HIV-1 Infection 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

  13. Amplified Transmission of HIVCohen MS. Tran Am ClinClimatol. Assoc. 117:213-225, 2006 Infectiousness Blood Viral Load Genital ulcers Genital Tract Viral Load -Inflammatory STDs Viral clade Acute HIV infection Susceptibility Genital ulcers Inflammatory STDs Cytokine profile Lack of circumcision Cervical ectopy HLA Haplotype Hormonal contraception? “Dysbiosis”?

  14. HIV Infected Patients Acquire STDsKalichman et al. STI, 2011 • 37 studies of co-infection after diagnosis • POINT PREVALENCE STIs 19.6% (!!) • STD reinfection SOON after diagnosis

  15. Volume 349 . Number 9069 . Pages 1851-1922 . June 28, 1997 www.thelancet.com Reduction of concentration of HIV-1 in semen after treatment of urethritis: implications for prevention of sexual transmission of HIV-1 Myron S. Cohen, Irving F. Hoffman, Rachel A. Royce, Peter Kazembe, John R. Dyer, Celine Costello Daly, Dick Zimba, Pietro L. Vernazza, Martin Maida, Susan A. Fiscus, Joseph J. Eron Jr, and the AIDSCAP Malawi Research Group* Lancet. 1997 Jun 28;349(9069):1868-73.

  16. 140 120 100 80 60 40 0 Effect of STD Treatment on HIV-1 RNA in Semen of Urethritis Patients (median values) RNA copies / ml (in thousands) 20 Wk1 Wk1 Wk2 Wk2 Wk3 Wk3

  17. STI Treatment for HIV Prevention“The Disappointing Confusion”

  18. Clinical Trial Results Caused “Confusion” • Mwanza, 1996: Treating STDs reduced HIV • Rakai, 1999: No benefit treating STDs? • Masaka, 2002: No benefit treating STDs? (And… 4 more negative studies later) Reviewed by Padian et al. AIDS 2010.

  19. For STD Treatment to Prevent HIV You must treat the correct STD • AT JUST THE RIGHT TIME! • IN JUST THE RIGHT PEOPLE (POPULATION)! • WITH THE CORRECT DRUGS (THAT WORK)! • FOR THE APPROPRIATE DURATION Only Mwanza met these criteria Incomplete HSV-2 treatment compromises benefit

  20. What Happens with ART?

  21. STIs and ART and Prevention? TASP and Discordant Couples • HPTN052 (Cohen) • Partner Study (Rodger) • Opposites Attract (Bavinton) PrEP and Discordant Couples • Partners in Prevention (Baeten) Other PrEP iPREX (Grant) IPERGAY (Molina) Proud (McCormick) Kaiser Observational (Volk)

  22. Genital Tract Shedding during ART • Cross-sectional studies estimate prevalence of women with detectable cervical or vaginal at a single point in time1-6: • HAART: 15% - 50% prevalence of shedding • Non-HAART: 31% - 79% prevalence of shedding • Longitudinal studies estimate “break-through” shedding: • 65% of women on treatment with viremia in cervicovaginalsecretions at least once over median follow-up of 21 months7 • 64% of women with detectable viremia at least once during pregnancy8 1 Cu-Uvin et al. (2000), 2 Fiore et al. (2003), 3 Kovacs et al. (2001), 4 Si-Mohammed et al. (2000), 5 Vettore et al. (2006), 6 Neely et al. (2007), 7 DeBiaggi et al. (2001), 8 Tuomola et al. (2002)

  23. Where Do We Go From Here? • STDS have their own serious consequences • TDF/FTC TASP and PrEP overwhelm STDs • HIV shed is either below concentration needed or NOT replication competent or bathed ART • Anticipate detection of AHI in STD clinics • Gonorrhoea and syphilis are SPECIAL

  24. HIV/STD Synergy Focus Gonorrhoea • Remarkable incidence • Common extragenital infections, generally unmeasured • Increasing resistance..even to ceftriaxone Syphilis • Remarkable incidence • A harbinger (precursor?) to HIV • Prophylaxis to prevent infection or HIV (??)

  25. THANK YOU

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