Transcript Powerpoint
The Role of Semen & Genital Tract inflammation on HIV Acquisition: Implications for PrEP Betsy C. Herold, M.D. Albert Einstein College of Medicine Children’s Hospital at Montefiore Bronx, New York, USA Progress in Prevention Research FDA Approves Truvada as PrEP How do we explain the findings? • Preclinical vs. clinical trial outcomes • CAPRISA 004 versus VOICE • Dosing schedule • Adherence • Sexual practices • Hormonal contraception • Hidden toxicities Sex, semen, mucosal inflammation Sex and Semen Fuel the HIV Epidemic Impact on HIV risk & PrEP Efficacy Semen/Sex FGT Mucus, secretions Microbiota Polarized epithelial barrier Antiviral Activity of PRO 2000 Reduced if Virus Introduced in Seminal Plasma Patel et al, JID, 2007 Sex Study: What happens to drug PK/PD following sex? Visit 1 Visit 2 Visit 3 Visit 4 No drug No coitus No drug Coitus Drug No Coitus Drug Coitus Endogenous Activity Endogenous Activity After Sex PK/PD Absence of Sex PK/PD After Sex Loss in Anti-HIV Activity (PD) and Drug Recovered (PK) in Postcoital CVL Control Buffer } endogenous pre/post sex Endogenous Post-coital PRO 2000 28(22, 110) (median(IQR) PRO 2000/Post-coital 14(3,27) 1.0×10 3 1.0×10 4 1.0×10 5 1.0×10 6 RLU Barrier unprotected sex associated with decrease in PK/PD of PRO 2000 Drug may leak out or be redistributed following sex Seminal proteins interfere with antiviral activity of PRO 2000 Keller, et al, PLoSOne, 2010 Semen No Effect on Antiviral Activity of TFV in vitro/ex vivo Women applied TFV gel x 14 days (no sex!) Cells exposed to D7 secretions (cervicovaginal lavage) Challenged with HIV in buffer (white) or in 25% semen (black) TFV retained antiviral activity Keller, Madan; PLoS one 2011 Could Sex/Semen Impact Tenofovir Based PrEP? GE L •Reduce dose leakage/dilution •Drug permeability & transport •Metabolism of drug •Increase immune target cells •Increase activation status of targets dNTP : TFV-DP ratio Post coital PK/PD studies MTN011 & CONRAD113 Semen Induces Inflammatory Response (in vitro) NFkB Response What Happens in Real Life? Study visit 1 3-5 days later Study visit 3 3-5 days later Sexual intercourse A (no condom) Sexual Intercourse C (+condom) Study visit 2 2-6 hrs later 3-5 days later Study visit 4 2-6 hrs later 3-5 days later Sexual intercourse B (no condom) Sexual Intercourse D (+condom) 10-14 hours later Study visit 5 10-14 hours later – Each woman presents for 5 visits • 1 visit in the absence of sexual intercourse (>72 hours) • 2 visits after sexual intercourse without a condom • 2 visits after sexual intercourse with a condom – Women are randomized as to the order in which they complete the condom and non-condom visits – Male partner presents for first visit Influx of CD3+ cells after sexual intercourse *p=0.03 Increase immune cells in cervical biopsies observed following sex; Sharkey et al J Imm, 2012 Inflammation is a Double Edged Sword Haase A, Nature 2010 INFLAMMATION PROMOTES HIV INFECTION: Increase immune target cells in genital trac t(#; activation) Disrupt epithelial barrier (TNFα, IL-1 disrupt tight junctions) Activate NF-κB, binds viral LTR, promotes HIV replication INFLAMMATION AUGMENTS HOST INNATE DEFENSE: Recruit WBC Activates antiviral proteins (IFN, defensins, SLPI Clinical Conditions Associated with Inflammation & Increased HIV Risk • • • • • • • • Sex/semen STI HSV shedding Bacterial vaginosis Cervical dysplasia (HPV) ? Hormonal contraception ? Adolescents ? Pregnancy Cervical Dysplasia (HPV) Compared CVL concentrations of mediators high risk HPV positive (HRHPV+) CIN-3 (n=37), CIN-1 (n=12), or PAP negative controls (n=57) (Mhatre, STD, 2012). * * * * * Ghartey et al, AJOG, in press Putting it all together.. • Factors associated with HIV risk characterized by • • • • • Increased inflammatory cytokines Increase in immune targets Disruption of epithelial barrier Altered vaginal microbiota ? Lower levels of protective mediators • Sex/semen induce similar response • Comparable mucosal immune environment could adversely impact PrEP efficacy • e.g. TFV transport, metabolism, +/or [dNTP] • Suggested by data from CAPRISA 004 and MTN001 • Interventions must be fine-tuned & not disrupt ability of host to respond to pathogens Acknowledgments • • • • • • • • • • • • • • Niall Buckley Natalia Cheshenko Colleen Carpenter Esra Fakioglu Jeny Ghartey Susan Irvin Rebecca Madan Pedro Mesquita Natasha Nakra Briana Nixon Chris Petro Martha Stefanidou Ekaterina Taneva Merna Torres EINSTEIN COLLABORATORS • Marla Keller (AECOM) • Lilia Espinoza • Jennifer Walsh • Mark Einstein (AECOM) • Kathy Anastos (AECOM) • Harris Goldstein COLLABORATORS: • Patrick Kiser (U. of Utah) • Robert and Karen Buckheit (ImQuest) • Mark Mitchnick (Particle Sciences) • James Smith (CDC) • Tom Hope (Northwestern U.) • Gustavo Doncel (CONRAD, Eastern Virginia U.) • Craig Hendrix (Johns Hopkins University) • Salim S. Abdool Karim (South Africa and Columbia U.) • Joanne Passmore (South Africa) • MTN BSWG Funding: NIH and CONRAD