Antiretroviral regimens containing islatravir and doravirine were found to be efficacious and well tolerated regardless of dose in treatment-naive adults with HIV-1 infection, according to the results of a phase 2b study published in Lancet HIV.

In this randomized, double-blind, comparator-controlled, dose-ranging trial (ClinicalTrials.gov Identifier: NCT03272347), researchers assessed the efficacy and safety of islatravir-based regimens in 121 participants from 24 clinics or hospitals in Chile, France, the United Kingdom, and the United States.

Participants were randomly assigned in a 1:1:1:1 ratio to receive 1 of 3 doses of oral islatravir (0.25 mg, 0.75 mg, or 2.25 mg) in combination with doravirine (100 mg) and lamivudine (300 mg), or a fixed-dose combination of doravirine (100 mg), lamivudine (300 mg), tenofovir disoproxil fumarate (TDF; 300 mg), and matching placebo once daily for 24 weeks. Participants who achieved HIV-1 RNA concentrations lower than 50 copies per mL at week 24 received a 2-drug regimen comprising the 3 initial islatravir doses and doravirine (100 mg) for another 24 weeks, and the doravirine/lamivudine/TDF group continued with the same initial regimen.


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The primary efficacy outcome was the proportion of participants achieving HIV-1 RNA concentrations lower than 50 copies per mL at weeks 24 and 48; the primary safety outcome was the number of participants experiencing adverse events and discontinuing the study drug due to adverse events.

Of the 121 participants included in the study, the majority were men (93%) and White (76%), with a mean age of 31 years. The median baseline HIV-1 RNA concentration was 39,808 copies per mL (interquartile range, 12,949-95,876 copies/mL), with baseline concentrations greater than 100,000 and 500,000 copies per mL reported in 27 and 7 participants, respectively. The median baseline HIV-1 RNA concentration was higher in the 3 islatravir groups compared with the doravirine/lamivudine/TDF group. Demographic and clinical characteristics were similar across all 4 groups. There were 29 participants in the 0.25-mg group, 30 in the 0.75-mg group, 31 in the 2.25-mg group, and 31 in the doravirine/lamivudine/TDF group.

Within the first 24 weeks of treatment, the proportion of participants in the 3 islatravir groups who achieved HIV-1 RNA concentrations lower than 50 copies per mL was similar to that for the doravirine/lamivudine/TDF group:

  • 0.25 mg vs doravirine/lamivudine/TDF: 90% vs 87%; difference 2.8% (95% CI, -14.9 to 20.4)
  • 0.75 mg vs doravirine/lamivudine/TDF: 100% vs 87%; difference 12.9% (95% CI, -1.6 to 27.5)
  • 2.25 mg vs doravirine/lamivudine/TDF: 87% vs 87%; difference 0.3% (95% CI, -17.9 to 18.5)

At week 48, viral suppression remained similar across the treatment groups:

  • 0.25 mg vs doravirine/lamivudine/TDF: 90% vs 84%; difference 6.1% (95% CI, -12.4 to 24.4)
  • 0.75 mg vs doravirine/lamivudine/TDF: 90% vs 84%; difference 6.2% (95% CI, -12.2 to 24.6)
  • 2.25 mg vs doravirine/lamivudine/TDF: 77% vs 84%; difference -6.1% (95% CI -27.1 to 14.8)

Although the 2.25-mg group had a much lower proportion of participants achieving viral suppression, the data were not significantly different from the other islatravir groups, noted the researchers.

There were no deaths at week 48 of treatment. The most frequently reported adverse event was headache in the islatravir groups and diarrhea in the doravirine/lamivudine/TDF group. Although no serious drug-related adverse events were reported in the islatravir groups, 19% of participants (6/31) in the doravirine/lamivudine/TDF group reported experiencing drug-related adverse events. Two participants in the 2.25-mg islatravir group and 1 participant in the doravirine/lamivudine/TDF group discontinued treatment due to adverse events.

A 0.75-mg dose of islatravir has been selected for various phase 3 studies, which will “include trials for treatment-naive participants (ClinicalTrials.gov Identifier: NCT04233879), participants switching regimens (ClinicalTrials.gov Identifier: NCT04223778 and NCT04223791), and a trial for heavily treatment-experienced participants who have multidrug resistance (ClinicalTrials.gov Identifier: NCT04233216),” concluded the researchers.

Disclosure: This study was funded by Merck, Sharp, & Dohme Corp, a subsidiary of Merck & Co., Inc., which was involved in study design, data collection, data analysis, data interpretation, and writing of the report. Several study authors declared affiliations with the pharmaceutical industry including being employees of Merck, Sharp, & Dohme Corp. Please see the original reference for a full list of authors’ disclosures.

Reference

Molina J-M, Yazdanpanah Y, Saud AA, et al. 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. Lancet HIV. Published online May 14, 2021. doi:10.1016/S2352-3018(21)00021-7