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

Implications for PrEP

Betsy C. Herold, M.D.Albert Einstein College of MedicineChildren’s Hospital at Montefiore

Bronx, New York, USA

Progress in Prevention ResearchFDA 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 EpidemicImpact on HIV risk & PrEP Efficacy

FGT Mucus, secretions

Semen/Sex

MicrobiotaPolarized epithelial barrier

Patel et al, JID, 2007

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

Visit 1 Visit 2 Visit 3 Visit 4No drug

No coitusNo drugCoitus

DrugNo Coitus

DrugCoitus

EndogenousActivity

Endogenous ActivityAfter Sex

PK/PDAbsence of Sex

PK/PDAfter Sex

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

Keller, et al, PLoSOne, 2010

1.0×103 1.0×104 1.0×105 1.0×106

PRO 2000/Post-coital

PRO 2000

Post-coital

Endogenous

Control Buffer

RLU

14(3,27)

28(22, 110) (median(IQR)

} endogenous pre/post sex

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

Barrier unprotected sex associated with decrease in PK/PD of PRO 2000 Drug may leak out or be redistributed following sexSeminal proteins interfere with antiviral activity of PRO 2000

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?

•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

GEL

Semen Induces Inflammatory Response(in vitro)

NFkB Response

What Happens in Real Life?

– 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

Study visit 1 Study visit 2Sexual intercourse A

(no condom)

Study visit 3

Sexual intercourse B

(no condom)3-5 days

later2-6 hrs

later

Study visit 4Sexual Intercourse C

(+condom)

3-5 days later

10-14 hours later

2-6 hrs later

3-5 days later

Sexual Intercourse D

(+condom)3-5 days later

10-14 hours later

Study visit 5

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 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 WBCActivates 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 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

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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