Mechanism of Action: Microbicide; non-nucleoside reverse transcriptase inhibitor (NNRTI). HIV-specific topical microbicides formulated with antiretroviral (ARV) drugs, such as dapivirine, are being developed as a pre-exposure prophylaxis (PrEP) strategy to prevent the sexual transmission of HIV. ARV-based topical microbicides are designed to inhibit the infection process at the vaginal or rectal mucosa and directly interfere with the HIV replication cycle.4,5,6,7
Dapivirine, a substituted diarylpyrimidine derivative, irreversibly binds to and inhibits HIV reverse transcriptase, preventing the conversion of viral RNA to proviral DNA. Because of dapivirine’s tight binding and lipophilic characteristics, it may be active against both cell-free and cell-associated HIV.8,9
In a pharmacokinetic and safety study of two formulations of dapivirine vaginal gel (0.05%) applied once daily over 11 days, plasma concentrations of dapivirine did not exceed 1.1 ng/mL. Dapivirine cervicovaginal fluid concentrations were at least 5 logs greater than dapivirine’s in vitro inhibitory concentrations for wild type HIV-1 virus.7,10 In a study comparing matrix- and reservoir-type dapivirine intravaginal rings (IVRs) used over 28 days by HIV-uninfected women, both rings successfully delivered dapivirine throughout the lower genital tract at concentrations over 4 logs greater than the in vitro 50% effective concentration value for dapivirine against wild type virus. Mean plasma concentrations of dapivirine were less than 2 ng/mL.11
T½: In a study of two formulations of dapivirine vaginal gel (0.05%) used once daily over 11 days, the dapivirine terminal half-life was 72 to 73 hours in plasma and 15 to 17 hours in vaginal fluids.10
Metabolism/Elimination: Cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes were found locally expressed in vaginal and colorectal tissues and may have a role in the metabolism of dapivirine in these tissue compartments.12
Resistance: In an in vitro study, primary cells were infected with HIV-1 of varying subtypes and resistance profiles and then exposed to increasing, suboptimal concentrations of dapivirine, tenofovir, or dapivirine in combination with tenofovir. Results indicated that suboptimal doses of dapivirine alone permitted the emergence of more reverse transcriptase mutations than did suboptimal doses of dapivirine in combination with tenofovir and tenofovir alone. Suboptimal concentrations of tenofovir alone resulted in the development of one NRTI mutation, K65R. In this study, the drug-resistant virus selected with suboptimal doses of dapivirine in combination with tenofovir demonstrated resistance to nevirapine, but it remained susceptible to lamivudine and stavudine.13
Additional studies of dapivirine IVR have been completed or are ongoing or planned, including a Phase I study of a combination IVR containing dapivirine and maraviroc. Dapivirine forms of a vaginal gel and film are also being studied in early- or mid-phase clinical trials.7,19
6. Balzarini J, Van Damme L. Intravaginal and intrarectal microbicides to prevent HIV infection. CMAJ. 2005 Feb 15;172(4):461-4. Last accessed on January 8, 2014.
7. Adams JL, Kashuba AD. Formulation, pharmacokinetics and pharmacodynamics of topical microbicides. Best Pract Res Clin Obstet Gynaecol. 2012 Aug;26(4):451-62. Last accessed on January 8, 2014.
8. Garg AB, Nuttall J, Romano J. The future of HIV microbicides: challenges and opportunities. Antivir Chem Chemother. 2009;19(4):143-50. Last accessed on January 8, 2014.
9. Nuttall JP, Thake DC, Lewis MG, Ferkany JW, Romano JW, Mitchnick MA. Concentrations of Dapivirine in the Rhesus Macaque and Rabbit following Once Daily Intravaginal Administration of a Gel Formulation of [14C] Dapivirine for 7 Days. Antimicrob Agents Chemother. 2008 Mar;52(3):909-14. Last accessed on January 8, 2014.
10. Nel AM, Smythe SC, Habibi S, Kaptur PE, Romano JW. Pharmacokinetics of 2 dapivirine vaginal microbicide gels and their safety vs. Hydroxyethyl cellulose-based universal placebo gel. J Acquir Immune Defic Syndr. 2010 Oct;55(2):161-9. Last accessed on January 8, 2014.
11. Nel A, Smythe S, Young K, et al. Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women. J Acquir Immune Defic Syndr. 2009 Aug 1;51(4):416-23. Last accessed on January 8, 2014.
12. To EE, Hendrix CW, Bumpus NN. Dissimilarities in the metabolism of antiretroviral drugs used in HIV pre-exposure prophylaxis in colon and vagina tissues. Biochem Pharmacol. 2013 Oct 1;86(7):979-90. Last accessed on January 8, 2014.
13. Schader SM, Oliveira M, Ibanescu RI, Moisi D, Colby-Germinario SP, Wainberg MA. In Vitro Resistance Profile of the Candidate HIV-1 Microbicide Drug Dapivirine. Antimicrob Agents Chemother. 2012 Feb;56(2):751-6. Last accessed on January 8, 2014.
14. International Partnership for Microbicides, Inc. A Double-Blind, Randomized, Placebo-Controlled Phase I/II Study to Evaluate the Safety of an Intravaginal Matrix Ring With Dapivirine in Healthy, HIV-Negative Women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 17, 2010. NLM Identifier: NCT01071174. Last accessed on January 8, 2014.
15. International Partnership for Microbicides, Inc. A Multi-Centre, Randomised, Double-Blind, Placebo-Controlled Safety and Efficacy Trial of a Dapivirine Vaginal Matrix Ring in Healthy HIV-Negative Women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 21, 2012. NLM Identifier: NCT01539226. Last accessed on January 8, 2014.
16. International Partnership for Microbicides, Inc. A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Phase 3 Safety and Effectiveness Trial of a Vaginal Matrix Ring Containing Dapivirine for the Prevention of HIV-1 Infection in Women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 8, 2012. NLM Identifier: NCT01617096. Last accessed on January 8, 2014.
17. Nel A, Kamupira M, Woodsong C, et al. Safety, Acceptibility and Pharmacokinetic Assessment (Adherence) of Monthly Dapivirine Vaginal Microbicide Rings (Ring-004) for HIV Prevention. 19th Conference on Retroviruses and Opportunistic Infections (CROI); March 5-8, 2012; Seattle, WA. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2012. Last accessed on January 8, 2014.
18. Rosenberg Z. Expanding the Method Mix: Current and planned trials of different ARV-based approaches for women. Powerpoint presented at: 19th International AIDS Conference; July 22-27, 2012; Washington DC. Last accessed on January 8, 2014.
19. International Partnership for Microbicides, Inc. Assessing the Safety of Dapivirine Gel and Film Formulations. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 1, 2012. NLM Identifier: NCT01548560. Last accessed on January 8, 2014.
20. International Partnership for Microbicides, Inc. An Open-label, Randomized, Three-period Crossover Trial in Healthy HIV-negative Women to Assess the Drug-drug Interaction Between Dapivirine Vaginal Ring-004 and Miconazole Nitrate. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 14, 2012. NLM Identifier: NCT01731574. Last accessed on January 8, 2014.
Last Reviewed: January 8, 2014
Last Updated: January 8, 2014