The role of semen genital tract inflammation on hiv acquisition implications for prep
This presentation is the property of its rightful owner.
Sponsored Links
1 / 18

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


  • 64 Views
  • Uploaded on
  • Presentation posted in: General

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.

Download Presentation

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.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


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

Progress in Prevention Research

FDA Approves Truvada as PrEP


How do we explain the findings

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


The role of semen genital tract inflammation on hiv acquisition implications for prep

Sex and Semen Fuel the HIV Epidemic

Impact on HIV risk & PrEP Efficacy

Semen/Sex

FGT

Mucus, secretions

Microbiota

Polarized epithelial barrier


The role of semen genital tract inflammation on hiv acquisition implications for prep

Antiviral Activity of PRO 2000 Reduced if Virus Introduced in Seminal Plasma

Patel et al, JID, 2007


The role of semen genital tract inflammation on hiv acquisition implications for prep

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


The role of semen genital tract inflammation on hiv acquisition implications for prep

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


The role of semen genital tract inflammation on hiv acquisition implications for prep

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


Could sex semen impact tenofovir based prep

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


The role of semen genital tract inflammation on hiv acquisition implications for prep

Semen Induces Inflammatory Response

(in vitro)

NFkB Response


What happens in real life

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


Influx of cd3 cells after sexual intercourse

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

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


Clinical conditions associated with inflammation increased hiv risk

Clinical Conditions Associated with Inflammation & Increased HIV Risk

  • Sex/semen

  • STI

  • HSV shedding

  • Bacterial vaginosis

  • Cervical dysplasia (HPV)

  • ? Hormonal contraception

  • ? Adolescents

  • ? Pregnancy


The role of semen genital tract inflammation on hiv acquisition implications for prep

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).


The role of semen genital tract inflammation on hiv acquisition implications for prep

*

*

*

*

*

Ghartey et al, AJOG, in press


Putting it all together

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

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


  • Login