Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial

Summary

Background

Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and tenofovir disoproxil fumarate for HIV prevention.

Methods

This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02842086, and is no longer recruiting.

Findings

Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19–1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06–0·33]), and 15 participants in the emtricitabine and tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19–0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and tenofovir disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints.

Interpretation

Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and tenofovir disoproxil fumarate.

Funding

Gilead Sciences.

Introduction

When taken as directed, pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir disoproxil fumarate is safe and highly effective in preventing HIV acquisition in diverse, at-risk populations with rare seroconversions or drug resistance.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 Increasing population-level uptake of PrEP is associated with declining HIV incidence, particularly in jurisdictions with high access to health care, robust HIV prevention programmes, and where a high proportion of people with HIV are virologically suppressed.12, 13, 14, 15, 16, 17

Tenofovir, a nucleotide reverse transcriptase inhibitor of HIV, inhibits viral replication in cells. Although tenofovir alafenamide and tenofovir disoproxil fumarate are both prodrugs of tenofovir, tenofovir alafenamide transports the active metabolite, tenofovir diphosphate, more rapidly into peripheral blood mononuclear cells (PBMCs) than tenofovir disoproxil fumarate, with at least four times higher concentrations, resulting in increased antiviral activity.¹⁸ At 1–2 h after a single dose of tenofovir alafenamide, median tenofovir diphosphate concentrations exceed the 90% effective concentration (EC₉₀) associated with HIV prevention efficacy in PBMCs, whereas tenofovir disoproxil fumarate does not surpass this threshold until after 3 days of daily dosing.19, 20 Emtricitabine and tenofovir alafenamide has been shown to prevent rectal simian-human immunodeficiency virus in macaques.²¹ In HIV and hepatitis B virus (HBV) treatment trials, tenofovir alafenamide was shown to be non-inferior to tenofovir disoproxil fumarate, and bone and renal safety biomarkers were significantly improved, which was most likely to have been caused by the 90% reduction in plasma tenofovir exposure with tenofovir alafenamide compared with tenofovir disoproxil fumarate.22, 23, 24, 25, 26, 27, 28, 29, 30, 31 Regimens that include emtricitabine and tenofovir alafenamide are recommended by HIV treatment guidelines.32, 33, 34

We did this active-controlled study to compare the efficacy and safety of emtricitabine and tenofovir alafenamide with emtricitabine and tenofovir disoproxil fumarate for the prevention of HIV among cisgender men who have sex with men (MSM) and transgender women who have sex with men.

Research in context

Evidence before this study

We searched PubMed for clinical trials of HIV pre-exposure prophylaxis (PrEP) with tenofovir between database inception to Nov 3, 2019, using the title or abstract search term “HIV” AND (“prevention” OR “prophylaxis”). The search was limited to trials published in English. Our search yielded 174 articles published between 2007 and 2018, 16 of which reported efficacy outcomes. Oral emtricitabine and tenofovir disoproxil fumarate is highly effective for PrEP when adherence is adequate. The identified studies showed that emtricitabine and tenofovir disoproxil fumarate was well tolerated and safe, but was associated with modest and generally reversible declines in renal function and bone mineral density. A systematic review of nine trials of PrEP with emtricitabine and tenofovir disoproxil fumarate by the US Preventive Services Task Force confirmed the high efficacy of this drug combination and the strong positive association between adherence and efficacy, and showed that the use of this drug combination was associated with an increased risk of mild, generally reversible renal and gastrointestinal adverse events, but was not associated with an increased risk of fractures.

Added value of this study

The efficacy and safety of tenofovir alafenamide in HIV treatment has been well documented; however, the efficacy and safety of this drug in HIV prevention is unknown. To our knowledge, our study is the first active-controlled trial comparing a new regimen for PrEP (emtricitabine and tenofovir alafenamide) with the current standard-of-care regimen (emtricitabine and tenofovir disoproxil fumarate). Compared with emtricitabine and tenofovir disoproxil fumarate, we show that emtricitabine and tenofovir alafenamide has non-inferior efficacy and has more favourable effects on bone mineral density and biomarkers of renal safety when used as PrEP in HIV prevention. Therefore, the emtricitabine and tenofovir alafenamide combination shows similar effects when used for HIV prevention as it does for HIV treatment.

Implications of all the available evidence

The results of our study show that daily emtricitabine and tenofovir alafenamide is effective for HIV prevention and leads to favourable bone density and renal biomarker profiles in people without HIV, as it does in HIV treatment, when used as part of a complete HIV treatment regimen. These results establish emtricitabine and tenofovir alafenamide as an additional option for PrEP in cisgender men who have sex with men and transgender women who have sex with men, both at risk of acquiring HIV, particularly in those with risk factors for, or pre-existing, renal or bone disease. Whether PrEP with emtricitabine and tenofovir alafenamide shows efficacy in cisgender women who have sex with men is being investigated.