ArticlesSingle-agent tenofovir versus combination emtricitabine plus tenofovir for pre-exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial
Introduction
Combination antiretroviral treatment is vital for individuals with HIV-1 infection, and antiretroviral medications are essential for the prevention of mother-to-child HIV-1 transmission. According to recent evidence, antiretroviral medications can also prevent HIV-1 transmission between adults, through the reduction of the infectiousness in people who are infected and as oral or topical pre-exposure prophylaxis (PrEP) in individuals who are at high risk of becoming infected with HIV-1.1, 2, 3, 4, 5, 6, 7
The results of four randomised trials3, 4, 5, 7 in diverse geographic and at-risk populations have shown that oral antiretroviral PrEP is efficacious in protecting individuals against HIV-1 infection. The efficacy of oral PrEP with tenofovir disoproxil fumarate in combination with emtricitabine has been assessed in two trials (in heterosexual men and women in Botswana and men who have sex with men from four continents),4, 5 and as single-agent therapy in one trial (in injection drug users in Thailand).7 Results of animal model studies provided early evidence that antiretroviral PrEP might be an efficacious intervention for HIV-1 prevention,8 and in subsequent studies in animals various antiretroviral agents, delivery approaches, and dosing strategies for PrEP were assessed.9, 10, 11 Data from studies of animal models with rectal viral challenge suggested that emtricitabine plus tenofovir disoproxil fumarate might provide greater HIV-1 protection than does tenofovir disoproxil fumarate alone.9 Both tenofovir disoproxil fumarate alone and emtricitabine plus tenofovir disoproxil fumarate were assessed in our trial to provide a direct comparison of these approaches, with the rationale that dual-agent versus single-agent therapy might differ in efficacy, tolerability, antiretroviral resistance in breakthrough HIV-1 seroconverters, and in costs.
In our previous report from our multisite, randomised, double-blind, three-group, placebo-controlled phase 3 trial, we compared daily oral tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate as PrEP in African heterosexual men and women who were at high risk of HIV-1 acquisition because they had an HIV-1 infected sexual partner (the Partners PrEP Study).3 An interim review showed that PrEP afforded protection against HIV-1 transmission, as assessed with prespecified efficacy thresholds. The trial's placebo group was discontinued and the results were reported: the efficacy for prevention of HIV-1 transmission with tenofovir disoproxil fumarate was 67% and that with the coformulation was 75%, but the difference between tenofovir disoproxil fumarate alone versus in combination with emtricitabine was not significant (p=0·23).3 The active groups were continued thereafter, and the participants who were initially randomly assigned to placebo were offered rerandomisation to tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate as PrEP to gather additional comparative safety and efficacy data related to single-agent versus dual-agent PrEP. We report the efficacy of single-agent tenofovir disoproxil fumarate in relation to dual-agent emtricitabine plus tenofovir disoproxil fumarate as PrEP for HIV-1.
Section snippets
Study design and participants
Between July 3, 2008, and Nov 30, 2010, heterosexual couples who were HIV-1 serodiscordant (ie, one member was HIV-1 infected and the other was not infected) were enrolled from nine research clinics in Kenya and Uganda, as described previously.3, 12 Eligible couples were sexually active and intending to remain as a couple. HIV-1 seronegative partners had normal renal function, were not infected with hepatitis B virus, and the women were not pregnant or breastfeeding.
An independent data and
Results
At the initial randomisation, 4747 couples were enrolled: 1584 assigned to tenofovir disoproxil fumarate, 1579 to emtricitabine plus tenofovir disoproxil fumarate, and 1584 to placebo. Of the 1584 HIV-1 uninfected individuals initially randomly assigned to placebo, 1502 were alive and had not seroconverted to HIV-1 and of these 84 (6%) were deemed ineligible to receive active PrEP—77 pregnant and breastfeeding women (which were exclusion criteria for provision of PrEP in the study protocol) and
Discussion
The results of this study suggest that once-daily oral tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate have comparable HIV-1 protective efficacy and safety. HIV-1 protective efficacy in intention-to-treat analyses compared with placebo in previous studies ranged from 44% to 75%, with no clear differentiation in efficacy estimates for tenofovir disoproxil fumarate compared with emtricitabine plus tenofovir disoproxil fumarate.3, 4, 5, 7 Notably, the protective
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2020, Cell Reports MedicineCitation Excerpt :Complete sample size information is listed in Table 1. Tenofovir levels were measured in the serum for the GMS A and GMS B studies as previously described.57 Samples from the treatment arm without detectable tenofovir were removed, as was one post-treatment sample, where drug was unexpectedly detected.