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PrEP Trial Unable to Meet Efficacy Endpoints

A Phase III trial originally designed to test the safety and efficacy of Truvada—a combination of the antiretroviral (ARV) drugs tenofovir and emtricitabine—in reducing the risk of HIV infection among 1,200 HIV-uninfected heterosexual men and women in Botswana will not be able to determine the efficacy of this drug combination because the HIV incidence rate among volunteers was lower than anticipated. To meet the pre-specified efficacy endpoint for this trial, investigators would have had to double enrollment. However, the clinical research centers participating in the trial had also encountered unanticipated problems in retaining volunteers, so instead trial investigators have decided to modify the protocol and collect only safety and behavioral data.

The study, known as TDF2, is among several large clinical trials investigating whether the delivery of ARVs prior to HIV exposure, an idea known as pre-exposure prophylaxis (PrEP), can prevent HIV transmission among individuals at risk of HIV infection. The trial began in 2005, testing tenofovir alone, but then switched to testing Truvada in early 2007. TDF2 is being conducted by BOTUSA, a partnership between the Botswana Ministry of Health and the US Centers for Disease Control and Prevention (CDC) in Atlanta. The amended trial protocol will be submitted for approval to the scientific and ethical review boards in Botswana and the US in January.

Lynn Paxton, team leader for the PrEP and Microbicides Team for the CDC’s Division of HIV/AIDS Prevention, says the incidence data for men and women ages 18-29 in Botswana was initially estimated at around 10%. “We were conservative and halved that number but we subsequently found, over the course of the study, that the incidence was likely much lower than that.” Paxton said researchers are still analyzing data collected from the trial and are unable to say what the observed HIV incidence rate was during the three-year study.

Paxton attributes the lower-than-anticipated HIV incidence to a number of factors, including government-sponsored education and prevention programs that target younger men and women. She says the availability of ARVs among HIV-infected people in Botswana may also play a role in driving down HIV incidence rates in the country.

The low retention rates in TDF2 were also due to many factors. Some enrollees moved out of the area or became pregnant, which made them ineligible to continue in the trial, while others found the time requirements for participation too great. Paxton says BOTUSA took steps to overcome these challenges, including expanding weekend clinic hours, increasing participant reimbursements, and strengthening participant education and retention procedures. While these improvements have made a difference, the trial organizers still weren’t sure a valid efficacy endpoint could be determined.

Proposed plans are being discussed and finalized with the Botswana Ministry of Health, as well as with the trial’s community advisory boards. —Regina McEnery