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Protection of Rhesus Macaques from Vaginal Infection by Maraviroc (solution), an Inhibitor of HIV-1 Entry via the CCR5 Co-receptor
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Reported by Jules Levin
CROI 2010
R Veazey1, T Ketas2, J Dufour1, P Klasse2, and John Moore*2
1Tulane Natl Primate Res Ctr, Covington, LA, US and 2Weill Cornell Med Coll, New York, NY, US
Background: An effective vaginal microbicide could reduce human immunodeficiency virus type 1 (HIV-1) transmission to women. The detergent- or polyanion-based microbicide candidates have all failed to demonstrate efficacy in clinical trials, so the emphasis has finally switched to anti-retroviral drugs. Among microbicide candidates now in clinical development is Maraviroc (MVC), an FDA-approved small molecule drug that binds the CCR5 co-receptor and impedes HIV-1 entry into cells.
Methods: Delivered systemically, MVC reduces viral load in HIV-1-infected people, but its ability to prevent transmission is untested. We have now evaluated MVC as a vaginal microbicide, using a stringent model involving challenge of rhesus macaques with a high-dose of a CCR5-using virus, SHIV-162P3.
Results: Gel-formulated MVC derived from prescription-grade tablets provided dose-dependent protection, half-maximally at 0.5 mM (0.25 mg/mL) and fully at 6 mM (3 mg/mL). The duration of protection was transient; the longer the delay between MVC application and virus challenge, the less protection (T1/2 ∼ 4 h). As expected, MVC did not protect against vaginal challenge with a CXCR4-using virus, SHIV-KU1, but its presence also did not exacerbate post-infection viremia in animals infected with this virus.
Conclusions: These findings validate MVC development as a vaginal microbicide for women, and should guide clinical programs. Of note is that a single 300 mg tablet of prescription-grade MVC, which retails for ∼$15 in the USA, contains enough active drug to fully protect about 25 macaques, and by implication a similar number of women, if applied vaginally in a gel.
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