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A long-acting integrase inhibitor protects female macaques from repeated high-dose intravaginal SHIV challenge

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Science Translational Medicine  14 Jan 2015:
Vol. 7, Issue 270, pp. 270ra4
DOI: 10.1126/scitranslmed.3010298

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Taking a Shot at HIV

HIV-1 transmission during vaginal intercourse remains a major public health issue. Antiretrovirals can prevent HIV-1 transmission when used as preexposure prophylaxis, but results are highly dependent on patient adherence to prescribed therapy. One possible solution to this limitation is the use of long-acting injectable agents. Andrews et al. used an animal model that simulates the heterosexual transmission of HIV-1 to women and found that GSK744 LA, a long-acting integrase inhibitor amenable to dosing every 3 months in humans, is highly protective against viral transmission. These results support further clinical trials in women at risk for HIV-1 infection.


Long-acting GSK1265744 (GSK744 LA) is a strand transfer inhibitor of the HIV/SIV (simian immunodeficiency virus) integrase and was shown to be an effective preexposure prophylaxis (PrEP) agent in a low-dose intrarectal SHIV (simian-human immunodeficiency virus) rhesus macaque challenge model. We examined the pharmacokinetics and efficacy of GSK744 LA as PrEP against repeat high-dose intravaginal SHIV challenge in female rhesus macaques treated with Depo-Provera (depot medroxyprogesterone acetate), which promotes viral transmission vaginally. When Depo-Provera–treated female rhesus macaques were dosed with GSK744 LA (50 mg/kg) monthly, systemic and tissue drug concentrations were lower than previously observed in male rhesus macaques. GSK744 concentrations were fivefold lower on average in cervical tissues than in rectal tissues. Eight female rhesus macaques were treated with GSK744 LA at week 0, and four female rhesus macaques served as controls. All animals received a high-dose challenge of SHIV162P3 at week 1. No infection was detected in GSK744 LA–treated rhesus macaques, whereas viremia was detected 1 to 2 weeks after SHIV challenge in all control animals. The GSK744 LA–treated rhesus macaques were given a second administration of drug at week 4 and further challenged at weeks 5 and 7. GSK744 LA treatment protected six of eight female rhesus macaques against three high-dose SHIV challenges, whereas all control animals became infected after the first challenge (P = 0.0003, log-rank test). These results support further clinical development of GSK744 LA for PrEP.

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