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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.

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

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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



Mucus, secretions


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?

Loss in Anti-HIV Activity (PD) and Drug Recovered (PK) inPostcoitalCVL

} endogenous pre/post sex

28(22, 110) (median(IQR)


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 (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?


  • 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?

Sexual intercourse B (no condom)


intercourse A (no condom)

Study visit 1

Study visit 2

2-6 hrs later

3-5 days later

10-14 hours later


Intercourse C (+condom)


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


Increase immune cells in cervical biopsies observed following sex; Sharkey et al J Imm, 2012

Inflammation is a Double Edged Sword


  • 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


  • Recruit WBC

  • Activates antiviral proteins (IFN, defensins, SLPI

Haase A, Nature 2010

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 mediatorshigh 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


  • 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


  • 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)


  • Funding: NIH and CONRAD

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