IMPACT OF VAGINAL MICROBIOTA ON GENITAL TISSUE AND PLASMA CONCENTRATIONS OF DAPIVIRINE - PowerPoint Presentation

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IMPACT OF VAGINAL MICROBIOTA ON GENITAL TISSUE AND PLASMA CONCENTRATIONS OF DAPIVIRINE

Sharon L Hillier, Leslie A Meyn, Katherine Bunge, Michele Austin, Bernard J Moncla, Charlene S. Dezzutti, Brid Devlin, Mark Marzinke, Craig Hendrix and Lisa Rohan for the FAME Team

University of Pittsburgh and Magee-

Womens

Research Institute, Pittsburgh, PA; the International Partnership for Microbicides, Silver Springs, MD and Johns Hopkins University, Baltimore, MD

International AIDS Conference

Paris, France

July 25, 2017

Tenofovir gel effective against HIV with Lactobacillus dominance

Klatt

, et al. Science Volume 356(6341):938-945. June 2, 2017

What does the microbiota do to tenofovir

in vitro

? Klatt, et al. Science Volume 356(6341):938-945. June 2, 2017

Limitations of Published Data

Women having greater numbers of partners and more frequent sexual activity at greater risk of BV and HIV; association between BV and apparent decreased efficacy in CAPRISA-04 trial could be attributed to unmeasured differences in behavior

Degradation of tenofovir in presence of G vaginalis was demonstrated within hours in vitro, but this may not replicate in vivo conditions.Klatt, et al. Science Volume 356(6341):938-945. June 2, 2017

Connecting the Dots

Results from the trial

In vitro studies of microbes and drugs

Klatt, et al. Science Volume 356(6341):938-945. June 2, 2017

Klatt, et al. Science Volume 356(6341):938-945. June 2, 2017

FAME trials:

Timed in vivo exposure with direct measurement of drug in plasma and tissues after accounting for differences in the microbiome

Hillier et al, CROI 2017

Objective and HypothesisObjective: To evaluate whether vaginal microbiota associated with BV impact

dapivirine

concentrations in genital tract tissues and plasma following vaginal application. Hypothesis: Vaginal microbiota associated with BV will not decrease genital tract tissue and plasma levels of dapivirine

Study Population

66 healthy, nonpregnant women from Pittsburgh, PA, USA using effective contraception

Asymptomatic, HIV-, negative for chlamydia, gonorrhea, trichomoniasisCharacteristics: 76% unmarried 67% White, 27% Black

Tenofovir or

dapivirine

(film or gel) applied in clinic

Collect

:

vaginal swabs for qPCR for microbiota

Collect plasma, CVL and vaginal fluid for drug levels

Insert 7

th

dose in clinic

2 hours

Collect:

Plasma

Cervical biopsy

drug applied

daily at home

Study Design

Bunge, et al, CROI 2016 and Hillier et al, CROI 2017

Methods

qPCR performed from vaginal swab samples collected at baseline

Gardnerella vaginalisLactobacillus crispatus, L jensenii, L gasseri, Bacterial vaginosis detected using Nugent criteria from a Gram stained vaginal smear collected at baselineStatistics:

Relationship between vaginal microbiota and TFV or dapivirine concentrations was assessed using linear regression models

A quadratic term was included in the tenofovir models with G.

vaginalis

to improve model fit.

Reported P-values are from the global F-test. 

Vaginal administration of tenofovir or dapivirine

Tenofovir and Dapivirine:

Tissue and Plasma

Plasma

Genital epithelium

BV

LB dominant

Drug Level in Plasma

vs Nugent Score

(Score of 0-3 Lactobacillus dominant)

Hillier et al, CROI 2017

Drug Level in Plasma

vs Concentration of

G vaginalis Hillier et al, CROI 2017

Drug Level in Plasma vs quantity of

L

crispatus, L jensenii or L gasseri

Hillier et al, CROI 2017

Drug Levels in Cervical Tissue vs Nugent Score

Drug Levels in Cervical Tissuevs Concentration of

G vaginalis

Hillier et al, CROI 2017

Drug Levels in Cervical Tissue vs

L

crispatus, L jensenii or L gasseri

Hillier et al, CROI 2017

Conclusions

In contrast to tenofovir, genital and plasma concentrations of

dapivirine were not decreased by bacteria associated with BV. These data suggest that the levels of dapivirine following vaginal application should not be impacted by the microbiota associated with bacterial vaginosis. This is supportive of the ASPIRE study results 40% of women had bacterial vaginosis at baseline. No difference in the efficacy of the dapivirine ring in women with bacterial vaginosis and in those without bacterial vaginosis at baseline (39% vs. 21%, P=0.4 for interaction). (NEJM 2017 Mar 9;376: 995-6This emphasizes the need for HIV-1 prevention products that work in women with vaginal dysbiosis.

Acknowledgements

Study participants

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Grant AI082639 and UL1 TR000005. CONRAD was the regulatory sponsor of the tenofovir trial and donated tenofovir drug substance and some study product.IPM was the regulatory sponsor for the dapivirine trial and donated drug substance and study product.