1 / 18

The Role of Semen & Genital Tract inflammation on HIV Acquisition: Implications for PrEP

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.

danika
Télécharger la présentation

The Role of Semen & Genital Tract inflammation on HIV Acquisition: Implications for PrEP

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 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

  2. Progress in Prevention Research FDA Approves Truvada as PrEP

  3. 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

  4. Sex and Semen Fuel the HIV Epidemic Impact on HIV risk & PrEP Efficacy Semen/Sex FGT Mucus, secretions Microbiota Polarized epithelial barrier

  5. Antiviral Activity of PRO 2000 Reduced if Virus Introduced in Seminal Plasma Patel et al, JID, 2007

  6. Sex Study: What happens to drug PK/PD following sex?

  7. Loss in Anti-HIV Activity (PD) and Drug Recovered (PK) inPostcoitalCVL } endogenous pre/post sex 28(22, 110) (median(IQR) 14(3,27) 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

  8. 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 (cervicovaginallavage) Challenged with HIV in buffer (white) or in 25% semen (black) TFV retained antiviral activity Keller, Madan; PLoS one 2011

  9. Could Sex/Semen Impact Tenofovir Based PrEP? GEL • 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

  10. Semen Induces Inflammatory Response (in vitro) NFkB Response

  11. What Happens in Real Life? Sexual intercourse B (no condom) Sexual intercourse A (no condom) Study visit 1 Study visit 2 2-6 hrs later 3-5 days later 10-14 hours later Sexual Intercourse C (+condom) Sexual Intercourse D (+condom) Study visit 4 Study visit 3 Study visit 5 2-6 hrs later 3-5 days later 3-5 days later 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 3-5 days later

  12. 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

  13. Inflammation is a Double Edged Sword • INFLAMMATION PROMOTES HIV INFECTION: • Increase immune target cells in genital tract(#; 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 Haase A, Nature 2010

  14. Clinical Conditions Associated with Inflammation & Increased HIV Risk • Sex/semen • STI • HSV shedding • Bacterial vaginosis • Cervical dysplasia (HPV) • ? Hormonal contraception • ? Adolescents • ? Pregnancy

  15. Cervical Dysplasia (HPV) Compared CVL concentrations of mediatorshigh risk HPV positive (HRHPV+) CIN-3 (n=37), CIN-1 (n=12), or PAP negative controls (n=57) (Mhatre, STD, 2012).

  16. * * * * * Ghartey et al, AJOG, in press

  17. 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

  18. Acknowledgments • Niall Buckley • Natalia Cheshenko • Colleen Carpenter • EsraFakioglu • JenyGhartey • 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. AbdoolKarim (South Africa and Columbia U.) • Joanne Passmore (South Africa) • MTN BSWG • Funding: NIH and CONRAD

More Related