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Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings: A Double-Blind Randomized Trial

Chen, Beatrice A. MD, MPH*,†; Panther, Lori MD, MPH; Marzinke, Mark A. PhD§; Hendrix, Craig W. MD§; Hoesley, Craig J. MD; van der Straten, Ariane PhD, MPH¶,#; Husnik, Marla J. MS**; Soto-Torres, Lydia MD, MPH††; Nel, Annalene MD, PhD‡‡; Johnson, Sherri MPH§§; Richardson-Harman, Nicola PhD‖‖; Rabe, Lorna K. BS; Dezzutti, Charlene S. PhD*,†; On behalf of the MTN-013IPM 026 Protocol Team for the Microbicide Trials Network

JAIDS Journal of Acquired Immune Deficiency Syndromes: 1 November 2015 - Volume 70 - Issue 3 - p 242–249
doi: 10.1097/QAI.0000000000000702
Clinical Science

Background: Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one approach to improve adherence and drug delivery.

Methods: MTN-013/IPM 026, a multisite, double-blind, randomized, placebo-controlled trial in 48 HIV-negative US women, evaluated vaginal rings containing dapivirine (DPV) (25 mg) and maraviroc (MVC) (100 mg), DPV only, MVC only, and placebo used continuously for 28 days. Safety was assessed by adverse events. Drug concentrations were quantified in plasma, cervicovaginal fluid (CVF), and cervical tissue. Cervical biopsy explants were challenged with HIV ex vivo to evaluate pharmacodynamics.

Results: There was no difference in related genitourinary adverse events between treatment arms compared with placebo. DPV and MVC concentrations rose higher initially before falling more rapidly with the combination ring compared with relatively stable concentrations with the single-drug rings. DPV concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. MVC was consistently detected only in CVF. DPV and MVC CVF and DPV tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and DPV levels.

Conclusions: In this first study of a combination microbicide vaginal ring, all 4 rings were safe and well tolerated. Tissue DPV concentrations were 1000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. DPV, but not MVC, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Because MVC concentrations were consistently detectable only in CVF and not in plasma, improved drug release of MVC rings is needed.

*Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA;

Magee-Womens Research Institute, Pittsburgh, PA;

Department of Medicine and Infectious Disease, Fenway Institute, Boston, MA;

§Department of Pathology and Medicine, Johns Hopkins University, Baltimore, MD;

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL;

Women's Global Health Imperative (WGHI) RTI International, San Francisco, CA;

#Center for AIDS Prevention Studies, University of California San Francisco, Department of Medicine, San Francisco, CA;

**Statistical Center for HIV/AIDS Research & Prevention/Fred Hutchinson Cancer Research Center, Seattle, WA;

††NIAID/DAIDS, Bethesda, MD;

‡‡International Partnership for Microbicides, Silver Spring, MD;

§§FHI 360, Durham, NC; and

‖‖Alpha StatConsult, Damascus, MD.

Correspondence to: Beatrice A. Chen, MD, MPH, 300 Halket Street, Magee-Womens Hospital, Pittsburgh, PA 15213 (e-mail: chenba@upmc.edu).

The study was designed and implemented by the Microbicide Trials Network (MTN). The MTN is funded by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, UM1AI106707), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. The vaginal rings used in this study were supplied by the IND sponsor, International Partnership for Microbicides (IPM).

Meetings at which data were presented: oral presentation at Conference on Retroviruses and Opportunistic Infections 2014, March 3–6, 2014, Boston, MA, and at AIDS Impact Conference, September 29 to October 2, 2013, Barcelona, Spain. Poster presentation at HIV Research for Prevention, October 28–31, 2014, Cape Town, South Africa.

N.R.-H. was a paid consultant for the pharmacodynamic data analysis. C.W.H. has received research support from Gilead Sciences managed through Johns Hopkins University. The remaining authors have no conflicts of interest to disclose.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Trial registration: ClinicalTrials.gov identifier: NCT01363037.

Received November 24, 2014

Accepted April 20, 2015

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