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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

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 Acquisition:

FDA Approves Truvada as PrEP


How do we explain the findings
How do we explain the findings? Acquisition:

  • 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 Acquisition:

Impact on HIV risk & PrEP Efficacy

Semen/Sex

FGT

Mucus, secretions

Microbiota

Polarized epithelial barrier


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

Patel et al, JID, 2007


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


Loss in Anti-HIV Activity (PD) and Drug Recovered (PK) in Acquisition:PostcoitalCVL

} 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


Semen Acquisition: 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 Acquisition: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


Semen Acquisition: Induces Inflammatory Response

(in vitro)

NFkB Response


What happens in real life
What Happens in Real Life? Acquisition:

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 Acquisition:

*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 Acquisition: 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


Cervical Dysplasia (HPV) HIV Risk

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).


HIV Risk*

*

*

*

*

Ghartey et al, AJOG, in press


Putting it all together
Putting it all together.. HIV Risk

  • 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 HIV Risk

  • 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


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