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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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Download the PDF here
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.
Six participants in the doravirine-islatravir group had HIV-1 RNA greater than or equal to 50 copies per mL at week 48 or discontinued the study intervention before week 48 with HIV-1 RNA greater than 50 copies per mL. One participant achieved an HIV-1 RNA less than 200 copies per mL at week 24 but had not suppressed to less than 50 copies per mL; criteria for discontinuation and resistance testing were not met and the participant is continuing in the study. Five participants met criteria for resistance testing: one was lost to follow-up after week 4 and had no treatment-emergent mutations; four discontinued study intervention due to lack of efficacy. Two participants discontinued with virological rebound (one at week 16 and one at week 48). Both participants had plasma doravirine-islatravir concentrations below the limit of quantification at the time of virological rebound, consistent with non-adherence. Resistance testing did not identify treatment-emergent mutations. Two participants (both with pretreatment HIV-1 RNA greater than 1 million copies per mL, baseline CD4-cell count less than 200 cells per μL, and non-exclusionary mutations at baseline in reverse transcriptase) discontinued at week 16 and week 24 without suppressing to less than 50 HIV-1 RNA copies per mL. No history of pre-exposure or post-exposure prophylaxis was reported for either participant. The former participant had relatively low doravirine and islatravir plasma concentrations at week 8, suggesting possible incomplete adherence between weeks 4 and 8, although the reported adherence was 100%. The other participant had quantifiable doravirine and islatravir concentrations at all study visits, supporting adherence at the time of visits (reported adherence 97⋅2%). Both participants acquired treatment-emergent mutations (M184I [Met184Ile], Y188L [Tyr188Leu]; L74I [Leu74Ile], V106A [Val106Ala], M184V [Met184Val], F227L [Phe227Leu]) and phenotypic analysis revealed a 2⋅4-fold to 6⋅7-fold decreased susceptibility to islatravir and resistance to doravirine (appendix p 9). The first participant was started on dolutegravir, emtricitabine, and tenofovir disoproxil fumarate at discontinuation and a 3-log decline in HIV-1 RNA viral load was observed at the last follow-up. No post-study intervention information is available for the latter participant.
Nine participants in the bictegravir-emtricitabine-tenofovir group had HIV-1 RNA greater than or equal to 50 copies per mL at week 48 or at the time of study intervention discontinuation before week 48. Three participants who discontinued the study intervention (one lost to follow-up, one withdrew, and one for personal reasons) did not meet criteria for resistance testing. Six participants met criteria for resistance testing, of which two discontinued the study intervention due to lack of efficacy. One participant had virological rebound at week 48 and no treatment-emergent resistance was identified. The other participant had incomplete virological response at week 24 and acquired minor treatment-emergent mutations that did not result in loss of phenotypic susceptibility to bictegravir-emtricitabine-tenofovir (appendix p 9). This participant had pretreatment HIV-1 RNA greater than 1 million copies per mL and baseline CD4 count less than 200 cells per μL. No history of pre-exposure or post-exposure prophylaxis was reported. The participant reported missing one dose of study intervention. Plasma bictegravir, emtricitabine, and tenofovir concentrations were not measured per protocol. The participant was started on dolutegravir, lamivudine, and tenofovir disoproxil fumarate at discontinuation and HIV-1 RNA was 484 copies per mL at the last follow-up. The four other participants who discontinued the study intervention (three due to non-adherence, one due to a protocol deviation) met the criteria for resistance testing and no treatment-emergent resistance was detected.
16 participants had pretreatment HIV-1 RNA greater than 1 million copies per mL and CD4 counts less than 200 cells per μL, including the three participants above who developed treatment-emergent resistance. Of the other 13 participants, six were in the doravirine-islatravir group and seven were in the bictegravir-emtricitabine-tenofovir group. Four in the doravirine-islatravir group had major non-exclusionary resistance-associated mutations in reverse transcriptase at baseline and two did not; all six achieved HIV-1 RNA less than 50 copies per mL by week 48. No participants in the bictegravir-emtricitabine-tenofovir group had major INSTI resistance-associated mutations at baseline and all had an HIV-1 RNA less than 50 copies per mL by week 48.
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