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Fixed-dose daily doravirine (100 mg) with islatravir (0⋅25 mg) versus bictegravir, emtricitabine, and tenofovir alafenamide for initial HIV-1 therapy: 48-week results of a phase 3, randomised, controlled, double-blind, non-inferiority trial
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Summary
Background
Doravirine and islatravir is a two-drug regimen being investigated for the treatment of HIV-1. This study evaluated efficacy and safety of once daily doravirine and islatravir versus bictegravir, emtricitabine, and tenofovir alafenamide in adults with HIV-1 who were treatment-naive.
Methods
MK-8591A-053 is a phase 3, randomised, double-blind, active-controlled, non-inferiority study being done at 116 research, community, and hospital-based clinics across 20 countries. Adults aged at least 18 years with HIV-1 RNA of 500 copies per mL or more never previously treated for HIV-1 were randomly assigned (1:1), stratified by screening HIV-1 RNA viral load and CD4-cell count, to received either doravirine (100 mg) and islatravir (0⋅25 mg) or bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) orally once daily. The primary endpoint was percentage of participants with HIV-1 RNA less than 50 copies per mL at week 48 (FDA snapshot; prespecified non-inferiority margin −10%). Participants who received at least one dose of study intervention were analysed for safety. This trial is ongoing and is registered with ClinicalTrials.govNCT05705349.
Findings
We screened 756 participants for eligibility between March 8, 2023, and Oct 11, 2024. 269 participants were treated with doravirine–islatravir and 267 with bictegravir–emtricitabine–tenofovir. The last study visit for this analysis occurred on Oct 13, 2025. Median age was 32 years (IQR 26–40), 134 (25%) participants were assigned female at birth, 225 (42%) were White, 92 (17%) had CD4 counts less than 200 cells per μL, 197 (37%) had an HIV-1 RNA greater than 100 000 copies per mL, and 314 (59%) had pre-existing resistance-associated mutations. At week 48, doravirine–islatravir was non-inferior to bictegravir–emtricitabine–tenofovir: 247 (91⋅8%) of 269 versus 242 (90⋅6%) of 267 had HIV-1 RNA less than 50 copies per mL (estimated difference 1⋅2%, 95% CI –3⋅7 to 6⋅2). Mean increase in CD4 count was 218 cells per μL in the doravirine–islatravir group and 226 cells per μL in the bictegravir–emtricitabine–tenofovir group (estimated difference –6⋅8, 95% CI –35⋅8 to 22⋅2). Two participants in the doravirine–islatravir group and one in the bictegravir–emtricitabine–tenofovir group with pretreatment HIV-1 RNA greater than 1 million copies per mL and CD4 counts less than 200 cells per μL acquired treatment-emergent mutations. Phenotypic analysis revealed resistance to doravirine in two participants treated with doravirine–islatravir. 38 (14%) of 269 participants in the doravirine–islatravir group and 48 (18%) of 267 in the bictegravir–emtricitabine–tenofovir group had treatment-related adverse events: the most common were increased weight (7, 3%), headache (6, 2%), and dizziness (5, 2%) in the doravirine–islatravir group and increased weight (9, 3%), headache (9, 3%), and decreased estimated glomerular filtration rate (8, 3%) in the bictegravir–emtricitabine–tenofovir group.
Interpretation
Doravirine (100 mg) and islatravir (0⋅25 mg) is a two-drug, once daily regimen with efficacy and safety similar to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) for initial treatment of HIV-1, which could provide an option for treatment without an integrase strand transfer inhibitor.
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