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Safety, tolerability, and systemic absorption of dapivirine vaginal microbicide gel in healthy, HIV-negative women

Nel, Annalene Ma; Coplan, Paulb; van de Wijgert, Janneke Hc,d; Kapiga, Saidi He,f; von Mollendorf, Claireg; Geubbels, Evelinec,d; Vyankandondera, Josephc,h; Rees, Helen Vg; Masenga, Gilearde; Kiwelu, Ireeni; Moyes, Jocelyng; Smythe, Shanique Ca

doi: 10.1097/QAD.0b013e32832c413d
Clinical Science

Objectives: To assess the local and systemic safety of dapivirine vaginal gel vs. placebo gel as well as the systemic absorption of dapivirine in healthy, HIV-negative women.

Methods: Two prospective, randomized, double-blind, placebo-controlled phase I/II studies were conducted at five research centers, four in Africa and one in Belgium. A total of 119 women used dapivirine gel (concentrations of 0.001, 0.002, 0.005, or 0.02%), and 28 used placebo gel twice daily for 42 days. The primary endpoints were colposcopic findings, adverse events, Division of AIDS grade 3 or grade 4 laboratory values, and plasma levels of dapivirine.

Results: Safety data were similar for the dapivirine and placebo gels. None of the adverse events with incidence more than 5% occurred with greater frequency in the dapivirine than placebo groups. Similar percentages of placebo and dapivirine gel users had adverse events that were considered by the investigator to be related to study gel. A total of five serious adverse events occurred in the two studies, and none was assessed as related to study gel. Mean plasma concentrations of dapivirine were approximately dose proportional, and, within each dose group, mean concentrations were similar on days 7, 28, and 42. The maximum observed mean concentration was 474 pg/ml in the 0.02% gel group on day 28. Two weeks after the final application of study gel, mean concentrations decreased to 5 pg/ml or less.

Conclusion: Twice daily administration of dapivirine vaginal gel for 42 days was safe and well tolerated with low systemic absorption in healthy, HIV-negative women suggesting that continued development is warranted.

aInternational Partnership for Microbicides, Silver Spring, Maryland, USA

bWyeth Research, Collegeville, Pennsylvania, USA

cProjet Ubuzima, Kigali, Rwanda

dAcademic Medical Center, Center for Poverty-Related Communicable Diseases, Amsterdam, The Netherlands

eKilimanjaro Reproductive Health Program, Moshi, Tanzania

fLondon School of Hygiene and Tropical Medicine, London, UK

gReproductive Health and HIV Research Unit, University of Witwatersrand, Johannesburg, South Africa

hKigali Teaching Hospital, Kigali, Rwanda

iKCMC Biotechnology Laboratory, Kilimanjaro Reproductive Health Program, Moshi, Tanzania.

Received 13 February, 2009

Revised 26 March, 2009

Accepted 27 March, 2009

Correspondence to Shanique C. Smythe, MS, International Partnership for Microbicides, 8401 Colesville Road, Suite 200, Silver Spring, MD 20910, USA. Tel: +1 301 608 2221; fax: +1 301 2241; e-mail: ssmythe@ipm-microbicides.org

© 2009 Lippincott Williams & Wilkins, Inc.