AIDS in Developing Countries. Blood Semen/genital secretions Vertical MODES OF TRANSMISSION.
The Role of Semen & Genital Tract inflammation on HIV Acquisition: Implications for PrEP
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Transcript of 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 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