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Islatravir in combination with doravirine for treatment-naive adults with HIV-1 infection receiving initial treatment with islatravir, doravirine, and lamivudine: a phase 2b, randomised, double-blind, dose-ranging trial
 
 
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Lancet HIV June 6 2021
 
Summary
 
Background

 
Islatravir is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1 infection. We aimed to assess the efficacy and safety of islatravir-based regimens for the treatment of HIV-1.
 
Methods
 
We did a phase 2b, randomised, double-blind, comparator-controlled, dose-ranging trial at 24 clinics or hospitals in four countries (Chile, France, the UK, and the USA). Treatment-naive adults (≥18 years) with plasma HIV-1 RNA concentrations of at least 1000 copies per mL, CD4 T-cell counts of at least 200 cells per mL, and a calculated creatinine clearance of at least 50 mL/min (all within 60 days before study treatment) were eligible for inclusion. Participants were randomly assigned (1:1:1:1) with a block size of four via an interactive voice and web response system to receive oral treatment with one of three doses of islatravir (0⋅25 mg, 0⋅75 mg, or 2⋅25 mg) plus doravirine (100 mg) and lamivudine (300 mg) or to doravirine (100 mg) plus lamivudine (300 mg) plus tenofovir disoproxil fumarate(TDF; 300 mg) once daily with placebo (part 1). Treatment groups were stratified according to screening HIV-1 RNA concentration (≤100 000 copies per mL or >100 000 copies per mL). After at least 24 weeks of treatment, participants taking islatravir who achieved an HIV-1 RNA concentration lower than 50 copies per mL switched to a two-drug regimen of islatravir and doravirine (part 2). All participants and study investigators were masked to treatment in part 1; in part 2, the islatravir dose was masked to all participants and investigators, but the other drugs were given open label. The primary efficacy outcomes were the proportions of participants with an HIV-1 RNA concentration lower than 50 copies per mL at weeks 24 and 48 (US Food and Drug Administration snapshot approach). The primary safety outcomes were the number of participants experiencing adverse events and the number of participants discontinuing study drug owing to adverse events. All participants who received at least one dose of any study drug were included in the analyses. This trial is ongoing, but closed to enrolment of new participants; herein, we report study findings through 48 weeks of treatment. This trial is registered with ClinicalTrials.gov, NCT03272347.
 
Findings
 
Between Nov 27, 2017, and April 25, 2019, 121 participants (mean age 31 years [SD 10⋅9], 112 [93%] male, 92 [76%] white, 27 [22%] with HIV-1 RNA concentration >100 000 copies per mL) were randomly assigned: 29 to the 0⋅25 mg, 30 to the 0⋅75 mg, and 31 to the 2⋅25 mg islatravir groups, and 31 to the doravirine, lamivudine, and TDF group. At week 24, 26 (90%) of 29 participants in the 0⋅25 mg islatravir group, 30 (100%) of 30 in the 0⋅75 mg islatravir group, and 27 (87%) of 31 in the 2⋅25 mg islatravir group achieved HIV-1 RNA concentrations lower than 50 copies per mL compared with 27 (87%) of 31 in the doravirine plus lamivudine plus TDF group (difference 2⋅8%, 95% CI -14⋅9 to 20⋅4, for the 0⋅25 mg islatravir group; 12⋅9%, -1⋅6 to 27⋅5, for the 0⋅75 mg islatravir group; and 0⋅3%, -17⋅9 to 18⋅5, for the 2⋅25 mg islatravir group). At week 48, these data were 26 (90%) of 29 in the 0⋅25 mg islatravir group, 27 (90%) of 30 in the 0⋅75 mg islatravir group, and 24 (77%) of 31 in the 2⋅25 mg islatravir group compared with 26 (84%) of 31 in the doravirine plus lamivudine plus TDF group (difference 6⋅1%, 95% CI -12⋅4 to 24⋅4, for the 0⋅25 mg islatravir group; 6⋅2%, -12⋅2 to 24⋅6, for the 0⋅75 mg islatravir group; and -6⋅1%, -27⋅1 to 14⋅8, for the 2⋅75 mg islatravir group). 66 (73%) of participants in the islatravir groups combined and 24 (77%) of those in the doravirine plus lamivudine plus TDF group reported at least one adverse event. Two participants in the 2⋅25 mg islatravir group and one participant in the doravirine plus lamivudine plus TDF group discontinued owing to an adverse event. No deaths were reported up to week 48.
 
Interpretation
 
Treatment regimens containing islatravir and doravirine showed antiviral efficacy and were well tolerated regardless of dose. Doravirine in combination with islatravir has the potential to be a potent two-drug regimen that warrants further clinical development. No deaths were reported in the study up to week 48. Overall rates of drug-related adverse events, and discontinuations owing to adverse events up to week 48 were low (table 4). No serious drug-related adverse events were reported by islatravir participants. A higher proportion of participants in the doravirine plus lamivudine plus TDF group reported drug-related adverse events (six [19%] of 31) compared with any of the islatravir groups (seven [8%] of 90 overall; table 4). We report the adverse events with incidences greater than 10% in one or more treatment groups in table 5 and all adverse events in the appendix (pp 8-16). Of the most frequently reported adverse events, diarrhoea was more frequently reported in the doravirine plus lamivudine plus TDF group than in the combined islatravir group, whereas headache was more common in the combined islatravir group compared with the doravirine plus lamivudine plus TDF group (table 5). The frequency of DAIDS grade 3 or 4 laboratory abnormalities was low and similar between treatment groups (appendix p 7). No islatravir dose-dependent difference was observed in reported adverse events or grade 3 or 4 laboratory abnormalities.
 
Funding
 
Merck, Sharp, & Dohme Corp, a subsidiary of Merck & Co., Inc.
 
Research in context
 
Evidence before this study

 
We searched the US National Library of Medicine PubMed database without language restrictions for research articles published between database inception and April 20, 2020, for the terms "islatravir", "MK-8591", and "EFdA". We identified studies from the reference lists of the articles returned using these search terms and our knowledge of the literature. Previous publications have focused on in-vitro and preclinical studies of islatravir and have shown that islatravir is a nucleoside reverse transcriptase translocation inhibitor with potent activity in vitro against HIV-1 replication and a high genetic barrier to the development of drug resistance. In preclinical studies, islatravir suppressed HIV-1 viraemia in mice and rhesus macaques and showed pharmacokinetics amenable to extended-duration dosing. In a phase 1b trial, islatravir had robust antiviral activity with single doses as low as 0⋅5 mg causing a more than 1⋅0 log decline in HIV-1 RNA concentrations over 7-10 days of follow-up, and islatravir was well tolerated by participants in this trial.
 
Added value of this study
 
Here, we present, to our knowledge, the first clinical data showing the efficacy and safety of antiretroviral regimens containing islatravir and doravirine in a phase 2b dose-ranging study. A high proportion of participants who initiated islatravir plus doravirine in combination with lamivudine and switched to islatravir plus doravirine had HIV-1 RNA concentrations lower than 50 copies per mL at week 48. Regimens containing islatravir and doravirine were generally well tolerated regardless of islatravir dose.
 
Implications of all the available evidence
 
Collective data support the further development of islatravir as a novel antiretroviral agent for the treatment of HIV-1. The promising efficacy and safety profile of doravirine plus islatravir create the potential for an efficacious two-drug regimen that would have a high barrier to resistance and would be an important milestone in the evolving treatment options for people living with HIV.
 
Introduction
 
Islatravir is the first-in-class nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1 infection.
 
Islatravir inhibits reverse transcriptase through several mechanisms of action.
 
Unlike currently approved nucleoside reverse transcriptase inhibitors, islatravir contains the 3'-hydroxyl group found in endogenous nucleosides, which is associated with high affinity for reverse transcriptase. After intracellular phosphorylation to islatravir triphosphate, islatravir triphosphate inhibits reverse transcriptase translocation with the interaction of the 4'-ethynyl group with a conserved hydrophobic pocket near the active site of HIV-1 reverse transcriptase, which results in immediate chain termination and prevention of nucleotide incorporation to the viral DNA chain. In some instances, translocation might still occur, in which case islatravir causes delayed chain termination by preventing incorporation of further nucleotides owing to additional steric interactions of the 4'-ethynyl group. Additionally, islatravir inhibits reverse transcriptase via misincorporation into viral DNA, which occurs more efficiently than with deoxyadenosine triphosphate, resulting in mismatched bp that are difficult to extend.
 
In in-vitro studies,islatravir had more than ten-times greater potency than all other approved antiretroviral agents and has a high barrier to the development of resistance. Islatravir had robust antiviral activity in preclinical animal models of HIV-1 infection, including HIV infection in humanised mice and simian immunodeficiency virus infection in rhesus macaques. In a phase 1b clinical trial, islatravir showed robust antiviral activity with single doses as low as 0⋅5 mg causing a more than 1⋅0 log decline in HIV-1 RNA concentrations over 7-10 days of follow-up; islatravir was well tolerated by participants, and these results supported its further clinical development.
 
Doravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) approved in more than 30 countries for the treatment of HIV-1. Doravirine is active in vitro against both wild-type HIV-1 and most common NNRTI-resistant variants (reverse transcriptase Lys103Asn, Tyr181Cys, Gly190Ala, Lys103Asn/Tyr181Cys, and Glu138Lys) at concentrations achieved with 100 mg once-daily dosing. The in-vitro resistance profile of doravirine is unique among NNRTIs, with lower half-maximal inhibitory concentration values against NNRTI-resistant variants compared with other NNRTIs. Additionally, doravirine has a low potential for drug-drug interactions, including with acid-reducing agents, statins, and metformin. In phase 2 and 3 studies, Doravirine also has a superior neuropsychiatric profile compared with efavirenz. The potent antiviral activity and complimentary in-vitro resistance profile of doravirine and islatravir create the potential for an efficacious two-drug regimen that would have a high barrier to resistance and a favourable safety profile. In this study, we aimed to assess the efficacy and safety of antiretroviral regimens containing islatravir and doravirine.

 
 
 
 
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