HIV This Week

Maraviroc Concentrates in the Cervicovaginal Fluid and Vaginal Tissue of HIV-Negative Women.

Dumond JB, Patterson KB, Pecha AL, Werner RE, Andrews E, Damle B, Tressler R, Worsley J, Kashuba AD. J Acquir Immune Defic Syndr. 2009; 51:546-53.

The authors compared single- and multiple-dose maraviroc exposures in cervicovaginal fluid (CVF) and vaginal tissue (VT) with blood plasma (BP) and quantified maraviroc protein binding in cervicovaginal fluid. In this open-label pharmacokinetic study of 12 HIV-negative women, 7 paired CVF and BP samples were collected over 12 hours after 1 maraviroc dose. Subjects then received maraviroc twice daily for 7 days. After the last dose, subjects underwent cervicovaginal fluid and blood plasma sampling as on day 1, with additional sampling during terminal elimination. Vaginal tissue biopsies were obtained at steady state. Day 1 and day 7 median maraviroc cervicovaginal fluid AUCtau were 1.9- and 2.7-fold higher, respectively, than blood plasma. On day 1, 6 of 12 subjects had detectable maraviroc cervicovaginal fluid concentrations within 1 hour; 12 of 12 were detectable within 2 hours, and all exceeded the protein-free IC90. On day 7, maraviroc cervicovaginal fluid protein binding was 7.6% and the VT AUCtau was 1.9-fold higher than blood plasma. Maraviroc cervicovaginal fluid concentrations 72 hours after dose and blood plasma concentrations 12 hours after dose were similar. Higher maraviroc exposure in the female genital tract provides a pharmacologic basis for further evaluation of chemokine receptor 5 antagonists in HIV infection prophylaxis. This is the first study to report antiretroviral vaginal tissue concentrations, cervicovaginal fluid protein binding, and cervicovaginal fluid terminal elimination.

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Editors’ note: Discordance between antiretroviral concentrations in the blood plasma and genital tract compartments may result in ongoing HIV genital shedding in the presence of undetectable viral load in blood plasma. This has implications for onward HIV transmission and could lead to harbouring of resistant virus which could reseed systemically producing treatment failure. Thus the degree to which antiretroviral drugs concentrate in the genital tract is important both for public health and for individual treatment outcome. Since viruses that use CCR5 chemokine receptors predominate in the early stages of mucosal transmission, this team studied the pharmacokinetics of the CCR5 inhibitor maraviroc in the genital tract. It achieved not only high cervicovaginal fluid concentrations but also high vaginal tissue concentrations – about twice as high as in blood plasma. These results were a surprise because maraviroc has high protein-binding affinity which reduces its activity. Interestingly this study found protein-binding to be 10 times less in the cervicovaginal fluid than in blood plasma, meaning that the drug is active where we need it to be. A number of questions remain unanswered but maraviroc deserves further study for the prevention of heterosexual transmission.

Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women.

Nel A, Smythe S, Young K, Malcolm K, McCoy C, Rosenberg Z, Romano J. J Acquir Immune Defic Syndr. 2009; 51:416-23.

Vaginal microbicides for the prevention of HIV transmission may be an important option for protecting women from infection. Incorporation of dapivirine, a lead candidate nonnucleoside reverse transcriptase inhibitor, into intravaginal rings (IVRs) for sustained mucosal deliverymay increase microbicide product adherence and efficacy compared with conventional vaginal formulations. Twenty-four healthy HIV-negative women 18-35 years of age were randomly assigned (1:1:1) to dapivirine matrix intravaginal ring, dapivirine reservoir intravaginal ring, or placebo intravaginal ring. Dapivirine concentrations were measured in plasma and vaginal fluid samples collected at sequential time points over the 33-day study period (28 days of intravaginal ring use, 5 days of follow-up). Safety was assessed by pelvic/colposcopic examinations, clinical laboratory tests, and adverse events. Both intravaginal ring types were safe and well tolerated with similar adverse events observed in the placebo and dapivirine groups. Dapivirine from both intravaginal ring types was successfully distributed throughout the lower genital tract at concentrations over 4 logs greater than the EC50 against wild-type HIV-1 (LAI) in MT4 cells. Maximum concentration (Cmax) and area under the concentration-time curve (AUC) values were significantly higher with the matrix than reservoir intravaginal ring. Mean plasma concentrations of dapivirine were <2 ng/mL. These findings suggest that intravaginal ring delivery of microbicides is a viable option meriting further study.

For abstract access click here: 1

Editors’ note: The idea of an intravaginal ring carrying an antiretroviral for HIV prevention and needing replacement once a month or less is attractive. This study found that such rings, carrying the nonnucleoside reverse transcriptase inhibitor dapivirine, were safe, well-tolerated, and produced high levels of dapirivine in cervicovaginal secretions. The rings tested released drug through different mechanisms but pharmacokinetic studies found that systemic exposure of dapivirine in the blood was low with both of them. Now it’s on to the next stage!