Single-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

Abstract

Background: Antiretroviral pre-exposure prophylaxis (PrEP), with daily oral tenofovir disoproxil fumarate or tenofovir disoproxil fumarate in combination with emtricitabine, has been shown to be efficacious for HIV-1 prevention. Although the use of more than one antiretroviral agent is essential for effective HIV-1 treatment, more than one agent might not be required for effective prophylaxis. We assessed the efficacy of single-agent tenofovir disoproxil fumarate relative to combination emtricitabine plus tenofovir disoproxil fumarate as PrEP.

Methods: We did a randomised, double-blind, placebo-controlled three-group phase 3 trial of daily oral tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate PrEP in HIV-1 uninfected individuals in heterosexual HIV-1 serodiscordant couples from Kenya and Uganda. After an interim review, the trial's placebo group was discontinued and thereafter the active groups were continued, and participants initially randomly assigned to placebo were offered rerandomisation in a 1:1 ratio to tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate as PrEP. The primary endpoints were HIV-1 seroconversion and safety. This trial is registered with ClinicalTrials.gov, number NCT00557245.

Findings: 4410 (99·6%) of 4427 couples received tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate and were followed up for HIV-1 acquisition. Of 52 incident HIV-1 infections, 31 occurred in individuals assigned tenofovir disoproxil fumarate (incidence 0·71 cases per 100 person-years) and 21 were in those assigned emtricitabine plus tenofovir disoproxil fumarate (0·48 cases per 100 person-years); HIV-1 incidence in the placebo group until discontinuation was two cases per 100 person-years. HIV-1 prevention efficacy with emtricitabine plus tenofovir disoproxil fumarate was not significantly different from that of tenofovir disoproxil fumarate alone (hazard ratio [HR] 0·67, 95% CI 0·39-1·17; p=0·16). Detection of tenofovir in plasma samples, compared with no detection and as measured in seroconverters and a subset of non-seroconverters, was associated with an 85% relative risk reduction in HIV-1 acquisition for the tenofovir disoproxil fumarate group (HR 0·15, 95% CI 0·06-0·37; p<0·0001) and 93% for the emtricitabine plus tenofovir disoproxil fumarate group (0·07, 0·02-0·23; p<0·0001). No significant differences were noted in the frequency of deaths, serious adverse events, or serum creatinine and phosphorus abnormalities between the two groups.

Interpretation: These results do not rule out the potential for a slight difference in HIV-1 protection with tenofovir disoproxil fumarate compared with emtricitabine plus tenofovir disoproxil fumarate, but show that once-daily oral tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate regimens both provide high protection against HIV-1 acquisition in heterosexual men and women.

Funding: Bill & Melinda Gates Foundation and US National Institutes of Health.

Conflict of interest statement

Declaration of Interests

We declare that we have no conflicts of interest.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Initial randomization, re-randomization, and follow-up

A total of 4758 HIV-1 serodiscordant couples were initially randomized. In July 2011, the trial’s Data and Safety Monitoring Board recommended discontinuation of the placebo arm and re-randomization of eligible placebo arm participants to the remaining active PrEP arms. Of 1584 participants initially randomized to placebo, 1502 were alive and had not seroconverted to HIV-1, of whom 84 (5.6%) were deemed ineligible to receive active PrEP, primarily due to pregnancy and breastfeeding (which were exclusion criteria for PrEP provision in the study protocol), with 7 (0.5%) determined to be ineligible due to clinical safety reasons or investigator decision. Thus, 1418 were clinically eligible to receive PrEP, of whom 1264 (89.1% of those considered for re-randomization) agreed to receive PrEP and continue in the study, 100 declined further study participation, and 54 had been lost to follow-up. Participants originally assigned to the active PrEP arms were eligible for up to 36 months of follow-up from the time of randomization, including up to 12 months after July 2011; those re-randomized from the placebo arm were eligible for up to 12 months of active PrEP after July 2011.

Figure 2. PrEP drug detection in blood over time

Panel A depicts the proportion of participants from the randomly-selected cohort with tenofovir detected in plasma samples collected during study follow-up. Individuals are grouped based on tenofovir detection at the first month after randomization (blue = tenofovir detected at Month 1, orange = tenofovir not detected at Month 1). Panel B depicts the proportion of subjects who acquired HIV-1 with tenofovir detected in plasma samples, with the time axis aligned to the visit at which HIV-1 seroconversion was observed. Individuals are grouped based on tenofovir detection at the HIV-1 seroconversion visit (blue = tenofovir detected at the HIV-1 seroconversion visit, orange = tenofovir not detected at the HIV-1 seroconversion visit).

Figure 2. PrEP drug detection in blood over time

Panel A depicts the proportion of participants from the randomly-selected cohort with tenofovir detected in plasma samples collected during study follow-up. Individuals are grouped based on tenofovir detection at the first month after randomization (blue = tenofovir detected at Month 1, orange = tenofovir not detected at Month 1). Panel B depicts the proportion of subjects who acquired HIV-1 with tenofovir detected in plasma samples, with the time axis aligned to the visit at which HIV-1 seroconversion was observed. Individuals are grouped based on tenofovir detection at the HIV-1 seroconversion visit (blue = tenofovir detected at the HIV-1 seroconversion visit, orange = tenofovir not detected at the HIV-1 seroconversion visit).