The CAPRISA-004 study represents the only available efficacy data for tenofovir gel in humans. In this study of young South African women, those who were randomized to pericoital use of intravaginal 1% tenofovir gel had a 39% decreased incidence of HIV acquisition compared to those randomized to placebo, after 30 months of follow-up.[3
] The multinational iPrEx trial was the first study to report efficacy data for oral PrEP. In iPrEx, daily oral PrEP with FTC-TDF was associated with a 44% reduction in the risk of HIV acquisition among high-risk MSM and transgender women.[4
] More recently, in July 2011, two additional studies reported preliminary results that support the efficacy of oral PrEP in heterosexual populations. The Partners PrEP study compared the use of daily oral tenofovir, FTC-TDF, or placebo by the HIV-uninfected partner in serodiscordant, heterosexual African couples in which the HIV-infected partner was not medically eligible for antiretroviral therapy. This study demonstrated that tenofovir and FTC-TDF decreased the risk of HIV acquisition compared to placebo by 62% and 73%, respectively, in uninfected partners.[15
] In the TDF2 study, administration of daily oral FTC-TDF to young, sexually active heterosexual men and women in Botswana reduced the risk of HIV acquisition by 63% compared to placebo.[16
These well-designed, randomized controlled trials provide strong evidence that both topical and oral PrEP can protect against HIV acquisition in specific at-risk populations. However, caution is warranted when extrapolating results from these studies into new populations. In April, 2011, a study comparing daily oral FTC-TDF to placebo in 2000 at-risk heterosexual women in Africa (FEM-PrEP) reported equal numbers of new HIV infections in women randomized to FTC-TDF and placebo.[17
] FEM-PrEP investigators have proposed that the absence of demonstrable efficacy may have been due to suboptimal adherence, a lack of biologic efficacy of daily oral FTC-TDF in women, or other unknown causes. Self-reported adherence was over 90% among trial participants, but objective measures of adherence, including pill counts and the presence of drug in blood samples, have yet to be reported and may shed light on study findings.[17
] Importantly, the Partners PrEP study found that oral tenofovir and FTC-TDF were effective in both men and women, and TDF2 reported a trend towards the efficacy of FTC-TDF in women,[15
] offering evidence that oral PrEP can be biologically efficacious in at least some populations of women. The VOICE study is testing the efficacy of daily oral FTC-TDF in young African women, and it will likely offer pivotal additional information about the potential for this regimen to protect at-risk heterosexual women. Results from VOICE are expected in 2012.[12
In terms of safety, in CAPRISA-004, use of tenofovir gel was well-tolerated, though women randomized to tenofovir gel experienced slightly more diarrhea and gastrointestinal symptoms than those randomized to placebo.[3
] In iPrEx, serious adverse events were rare and not different among participants randomized to FTC-TDF or placebo. However, compared to MSM assigned to placebo, those randomized to FTC-TDF experienced increased rates of nausea (9% versus 5%) and unintentional weight loss during the first month of the study, though these symptoms tended to resolve. As tenofovir has been associated with renal injury in HIV-infected patients,[18
] it is important to note that iPrEx participants randomized to FTC-TDF had a trend towards increased creatinine (2% versus 1%; p=0.08) compared to those assigned to placebo. Importantly, renal function generally normalized after discontinuation of study drug, and all except one participant was able to safely resume FTC-TDF.[4
] These results suggest that renal dysfunction due to FTC-TDF administration is rare and transient, though careful monitoring of renal function is recommended.
Tenofovir has also been associated with loss of bone mineral density in patients with HIV-infection.[22
] Rates of bone fracture were no different among participants assigned to receive tenofovir-containing PrEP regimens or placebo in CAPRISA-004 and iPrEx.[3
] However, a substudy within iPrEx and a separate trial of daily oral tenofovir both reported that MSM randomized to use PrEP experienced small but statistically significant decreases in bone mineral density (BMD) of 1% or less compared to placebo.[4
] Future studies will be needed to assess the clinical consequences of these changes. Given these potential adverse effects with antiretroviral chemoprophylaxis, clinicians who prescribe PrEP will need to monitor patients for toxicities.