Poor User Adherence May Explain Lack of Efficacy In HIV Prophylaxis Trial

Abstract

Daily prophylactic treatment with one of three tenofovir-based regimens did not reduce the risk of HIV acquisition among women at high risk for the infection, according to a randomized, placebo-controlled trial conducted in South Africa, Uganda and Zimbabwe. (1) Failure to follow the treatment protocol may have contributed to the lack of efficacy: Although the mean rate of adherence was 86-90% (depending on the method of assessment), tenofovir was detected in only 25-30% of plasma samples from a random sample of participants assigned to one of the intervention regimens. Several randomized trials have found pre-exposure prophylaxis with oral or topical tenofovir to be effective in reducing the risk of HIV acquisition, though none of them focused on women of reproductive age. While those studies were in progress, researchers initiated a randomized, placebo-controlled trial to compare the effectiveness of oral tenofovir with that of topical tenofovir in preventing HIV infection and to assess the safety of the treatments. Women aged 18-45 at 15 sites in the three study countries were eligible for the trial if they had had vaginal intercourse in the prior three months; were using an effective contraceptive (hormonal method, IUD or sterilization); had normal kidney, hematologic and liver function; and were neither pregnant (or planning to become pregnant in the next two years) nor breast-feeding. Participants were randomly assigned to one of five regimens: 300 mg oral tenofovir and a placebo; oral tenofovir-emtricitabine (300 mg tenofovir and 200 mg emtricitabine) and a placebo; two placebos; vaginal 1% tenofovir gel; or vaginal placebo gel. Participants were instructed to use the products every day, and were provided with HIV risk-reduction counseling, adherence counseling, hepatitis B immunization and condoms. HIV testing was performed monthly, and testing for other STIs was done at enrollment and annually thereafter (or if necessary). Other monitoring included monthly interviews and pregnancy testing, quarterly tenofovir plasma testing and biannual pelvic examinations. Adherence was assessed monthly through interviews and in-clinic counts of empty pill bottles, unused pills or unused vaginal applicators, and every three months via audio computer-assisted self-interview (ACASI); the latter was also used to assess participants' condom use and sexual practices. Study products were withheld (temporarily or permanently) if women became pregnant, started breast-feeding, or had adverse effects or a positive HIV test. Women were followed for 12-36 months. However, mean follow-up was only slightly more than a year, as the trial was terminated ahead of schedule (in 2012) because of lack of intervention efficacy. Analyses included Cox proportional-hazard models (to assess time to HIV seroconversion), Kaplan-Meier plots (to estimate the cumulative probability of infection), generalized-estimating-equation models (to identify characteristics associated with tenofovir detection) and Cox regression analyses (to identify characteristics associated with HIV acquisition and assess the association between tenofovir detection and HIV acquisition). In all, 5,029 women enrolled in the trial. Participants were similar across the five study groups: Their mean age was 25, 21% were married, 92% had at least some secondary education, 85% reported condom use at last sex and 71% used an injectable for contraception. …