Postexposure Protection of Macaques from Vaginal SHIV Infection by Topical Integrase Inhibitors

Postexposure protection of macaques from SHIV infection by a gel containing integrase inhibitors. An After-Sex Gel to Protect Against HIV Vaginal gels containing antiretroviral (ARV) drugs are important for HIV prevention but are all designed to be applied by women before sex, which can interfere with sex practices and limit their use. A gel that can be applied after sex would be more desirable because it will have more user control and less need for sex anticipation and partner acceptance. However, all ARV-based gels in development contain ARV drugs that block the early steps in virus infection and thus require application before sex. Dobard et al. in their new study reasoned that HIV integrase inhibitors, which belong to a different ARV class that blocks later steps in virus infection, may be more suitable for application after HIV exposure during sex. They first confirmed that HIV integration into cellular DNA begins about 6 hours after virus infection, providing a wide window for dosing with integrase inhibitors after sex. Using a macaque model to assess efficacy, the authors further showed that a vaginal gel containing an integrase inhibitor protected macaques when applied 30 min before or 3 hours after vaginal challenge with simian HIV. The study supports evaluation of topical integrase inhibitors for HIV prevention and the assessment of after-sex use for improved acceptability by women. Coitally delivered microbicide gels containing antiretroviral drugs are important for HIV prevention. However, to date, microbicides have contained entry or reverse transcriptase inhibitors that block early steps in virus infection and thus need to be given as a preexposure dose that interferes with sexual practices and may limit compliance. Integrase inhibitors block late steps after virus infection and therefore are more suitable for post-coital dosing. We first determined the kinetics of strand transfer in vitro and confirmed that integration begins about 6 hours after infection. We then used a repeat-challenge macaque model to assess efficacy of vaginal gels containing integrase strand transfer inhibitors when applied before or after simian/human immunodeficiency virus (SHIV) challenge. We showed that gel containing the strand transfer inhibitor L-870812 protected two of three macaques when applied 30 min before SHIV challenge. We next evaluated the efficacy of 1% raltegravir gel and demonstrated its ability to protect macaques when applied 3 hours after SHIV exposure (five of six protected; P < 0.05, Fisher’s exact test). Breakthrough infections showed no evidence of drug resistance in plasma or vaginal secretions despite continued gel dosing after infection. We documented rapid vaginal absorption reflecting a short pharmacological lag time and noted that vaginal, but not plasma, virus load was substantially reduced in the breakthrough infection after raltegravir gel treatment. We provide a proof of concept that topically applied integrase inhibitors protect against vaginal SHIV infection when administered shortly before or 3 hours after virus exposure.