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Gilead Sciences Truvada

Gilead Sciences has submitted an sNDA application for the approval of once-daily Truvada (emtricitabine/tenofovir disoproxil fumarate) for pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection among uninfected adults. Truvada was approved by the FDA in 2004 for the treatment of HIV-1 infection and is currently the most-prescribed antiretroviral treatment in the US.

If the sNDA is approved, Truvada would be the first agent indicated for uninfected individuals to reduce the risk of acquiring HIV through sex, a prevention approach called PrEP. The application is based on the results of two large placebo-controlled trials of Truvada as PrEP, sponsored by the National Institutes of Health (NIH) and the University of Washington.

The first trial providing data to support the Truvada sNDA is a Phase III, randomised, double-blind, placebo-controlled trial known as the Pre-Exposure Prophylaxis Initiative (iPrEx), which was sponsored by the NIH and conducted among 2,499 high-risk HIV-negative adult homosexuals in the US and countries in Africa, Asia and South America. Results from the trial, published in the New England Journal of Medicine in November 2010, showed that once-daily use of Truvada for PrEP reduced the risk of acquiring HIV overall by 44 per cent compared with placebo and by up to 73 per cent among men who reported taking the drug consistently (defined as at least 90 per cent of days). Among men who took the drug consistently enough to have detectable drug in their body, the risk was reduced by more than 90 per cent.

The Truvada sNDA submission is also supported by data from Partners PrEP, a Phase III, randomised, double-blind, placebo-controlled trial conducted among 4,758 heterosexual couples in Kenya and Uganda, in which one partner was infected with HIV and the other was not. The trial, sponsored by the University of Washington, showed that once-daily use of oral Truvada by the HIV-negative participants reduced their risk of acquiring HIV by 73 per cent compared with placebo.

Additional supportive data come from two studies sponsored by the Centers for Disease Control (CDC). The first trial, known as TDF2, was a Phase III, randomised, double-blind, placebo-controlled trial conducted in Botswana among 1,200 HIV-negative heterosexual men and women. Participants taking once-daily oral Truvada for PrEP had 63 per cent fewer HIV infections compared with those receiving placebo. The second trial, known as CDC 4323, was a Phase II, randomised, placebo-controlled, double-blind study of homosexual men in the US primarily designed to assess the safety, adherence and acceptability of PrEP.

Although full details are not yet available, another separate Phase III study of Truvada for PrEP known as FEM-PrEP was stopped in April 2011 based on a recommendation by the study’s Independent Data Monitoring Committee that the trial would not be able to establish the efficacy of Truvada among HIV-negative women in sub-Saharan Africa. The reason for this outcome is not yet understood and a complete detailed analysis of the data is currently under way.

In all studies, side-effects included nausea, weight loss and serum creatinine elevations. The incidence of side effects was consistent with Truvada’s safety and tolerability profile when used as HIV treatment, which is supported by more than 1.8 million years of patient use. Overall, there have been more than 4.4 million patient years of experience with tenofovir-containing regimens. Three cases of resistance to emtricitabine were reported in the iPrEx trial among participants who tested negative for HIV infection by serology at enrollment, but were later found to have been infected with HIV prior to enrolment using a different assay. Two of these cases occurred in the active drug arm, and one case occurred in the placebo arm.

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