Abstract
Objectives:The objective of this trial was to investigate the safety and preliminary effectiveness of a daily dose of 300 mg of tenofovir disoproxil fumarate (TDF) versus placebo in preventing HIV infection in women.Design:This was a phase 2, randomized, double-blind, placebo-controlled trial.Setting:The study was conducted between June 2004 and March 2006 in Tema, Ghana; Douala, Cameroon; and Ibadan, Nigeria.Participants:We enrolled 936 HIV-negative women at high risk of HIV infection into this study.Intervention:Participants were randomized 1:1 to once daily use of 300 mg of TDF or placebo.Outcome measures:The primary safety endpoints were grade 2 or higher serum creatinine elevations (>2.0 mg/dl) for renal function, grade 3 or 4 aspartate aminotransferase or alanine aminotransferase elevations (>170 U/l) for hepatic function, and grade 3 or 4 phosphorus abnormalities (<1.5 mg/dl). The effectiveness endpoint was infection with HIV-1 or HIV-2.Results:Study participants contributed 428 person-years of laboratory testing to the primary safety analysis. No significant differences emerged between treatment groups in clinical or laboratory safety outcomes. Study participants contributed 476 person-years of HIV testing to the primary effectiveness analysis, during which time eight seroconversions occurred. Two were diagnosed in participants randomized to TDF (0.86 per 100 person-years) and six in participants receiving placebo (2.48 per 100 person-years), yielding a rate ratio of 0.35 (95% confidence interval = 0.03–1.93), which did not achieve statistical significance. Owing to premature closures of the Cameroon and Nigeria study sites, the planned person-years of follow-up and study power could not be achieved.Conclusion:Daily oral use of TDF in HIV-uninfected women was not associated with increased clinical or laboratory adverse events. Effectiveness could not be conclusively evaluated because of the small number of HIV infections observed during the study.
Highlights
The HIV epidemic is continuing to grow worldwide [1]
Safety data were collected throughout the trial, and health problems that arose were classified as adverse events or serious adverse events
Tenofovir disoproxil fumarate (TDF) was selected for clinical development as a treatment for HIV infection because of its (1) potency against wild-type HIV and some nucleoside-resistant strains of HIV [3,4,5,6], (2) low potential of selecting for TDF-resistant mutants [7], (3) low likelihood of metabolic/mitochondrial toxicity [8], and (4) pharmacologic profile supporting daily dosing [2]
Summary
The HIV epidemic is continuing to grow worldwide [1]. Consistent and correct use of condoms is recommended for prevention of sexually transmitted HIV, but often women are unable to negotiate condom use with their male partners. Infection rates seem to be increasing in some countries, and there is an urgent need to find safe and effective ways of preventing HIV from being transmitted from one person to another. Additional strategies for reducing the risk of HIV transmission are needed One of these strategies is called ‘‘pre-exposure prophylaxis.’’ This strategy involves individuals who are at high risk of becoming infected with HIV taking antiviral drugs to prevent HIV infection. Tenofovir disoproxil fumarate, is currently approved as a treatment for HIV infection, and is being investigated as a strong candidate for pre-exposure prophylaxis. The researchers planned to follow up with the women for 12 months, and the primary analysis for efficacy would focus on a comparison of the rate of new HIV infections between the two arms of the trial. Safety data were collected throughout the trial, and health problems that arose were classified as adverse events or serious adverse events
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