Switching from antiretroviral therapy (ART) combinations to single-tablet doravirine plus islatravir is noninferior for HIV virologic suppression but may lead to reductions in CD4+ cell and total lymphocyte counts. These findings, from 2 phase 3 companion trials, were published in The Lancet HIV.
Two- and 3-drug ART regimens have been the standard of care for HIV management. However, given the need for life-long treatment in patients with HIV infection, there are concerns about costs and long-term safety. The development of single-tablet formulations of ART may help to address some of these concerns. Therefore, in 2 phase 3 trials, researchers assessed 48-week outcomes among patients with HIV infection who switched to fixed-dose ART with single-tablet doravirine plus islatravir.
The first phase 3 trial was a multicenter, randomized, active-controlled, open-label, noninferiority trial (ClinicalTrials.gov Identifier: NCT04223778) conducted in 2020 at 77 sites across 15 countries. Patients (N=672) on at least 3 months of continuous 2- or 3-drug regimens of oral ART with no history of virologic failure or resistance to doravirine were randomly assigned 1:1 to either switch to single-tablet doravirine (100 mg) plus islatravir (0.75 mg) once daily (n=336) or continue their current ART regimens (n=336).
The second phase 3 trial was a multicenter, randomized, active-controlled, double-blind, double-dummy, noninferiority trial (ClinicalTrials.gov Identifier: NCT04223791) conducted in 2020 at 89 sites across 11 countries. Patients (N=643) on bictegravir, emtricitabine, and tenofovir alafenamide for at least 3 months with no history of virologic failure or resistance to doravirine were randomly assigned 1:1 to either switch to single-tablet doravirine (100 mg) plus islatravir (0.75 mg) once daily (n=322) or continue their current regimen plus corresponding placebo (n=321).
The primary efficacy outcome in both trials was the percentage of patients with HIV-1 RNA measurements at or above 50 copies/mL at week 48. Noninferiority was defined as less than 4% of the upper 95% CI.
Demographic and clinical characteristics were well balanced between the groups in both trials. Among patients in the first trial who switched to single-tablet ART and those who continued their current regimen, the median ages were 46.0 and 45.0 years, 63.4% and 62.5% were male patients, 62.5% and 58.9% were White, the median time since HIV diagnosis was 9.9 and 8.8 years, and the median duration of ART prior to enrollment was 32.8 and 34.1 months, respectively. Among patients in the second trial who switched to single-tablet ART and those who continued their current regimen, the median ages were 48 and 48 years, 67.4% and 75.9% were male patients, 74.5% and 74.9% were White, the median time since HIV diagnosis was 10.2 and 9.4 years, and the median duration of ART prior to enrollment was 14.4 and 15.3 months, respectively.
At week 48, the researchers of the first trial observed HIV-1 RNA measurements at or above 50 copies/mL among 0% of patients who switched regimens and 1.5% of those who continued their baseline regimens (mean difference [MD], -1.5%; 95% CI, -3.4 to -0.3), indicating noninferiority. The researchers also observed noninferiority between the groups in the second trial, with HIV-1 RNA measurements at or above 50 copies/mL in 0.6% of those who switched regimens and 0.3% of those who continued their baseline regimen (MD, 0.3%; 95% CI, -1.2 to 2.0).
Overall, most patients in the first (range, 94.3%-94.6%) and second (range, 93.2%-94.0%) trials showed HIV-1 RNA measurements below 40 copies/mL for the duration of the study.
In both trials, the single-tablet ART recipients exhibited reduced counts of CD4+ (MD, -30.3 cells/µL for trial 1 and -19.7 cells/µL for trial 2) and total lymphocytes (MD, -0.26×109/L for trial 1 and -0.20×109/L for trial 2) counts from baseline to week 48.
In the first trial, between-group analysis indicated that the mean rate of adverse events (AEs) and treatment-related AEs was 9.8% and 10.7% higher, respectively, among single-tablet ART recipients. A total of 7 patients who switched to single-tablet ART discontinued treatment, primarily due to treatment-related AEs (n=5), severe AEs (n=2), and severe treatment-related AEs (n=1). The most common treatment-related AEs were insomnia (2.1%), abnormal dreams (1.8%), headache (1.8%), nausea (1.5%), pruritus (1.5%), and weight gain (1.5%).
In the second trial, there were no significant between-group differences in the rate of AEs. A total of 8 single-tablet ART recipients discontinued treatment, primarily due to treatment-related AEs (n=6) and severe AEs (n=1). The most common treatment-related AEs were nausea (2.5%), headache (1.2%), and dizziness (0.3%).
Study limitations include the open-label design of the first trial and the exclusion of patients with active hepatitis B virus infection or a history of virologic failure in both trials.
“[D]ecreases in CD4 cell and total lymphocyte counts do not support further development of once-daily doravirine (100 mg) and islatravir (0.75 mg),” the researchers noted. “Phase 3 clinical trials are underway investigating the fixed combination of doravirine (100 mg) with islatravir (0.25 mg) in adults who are virologically suppressed or naive to HIV-1 treatment,” they concluded.
Disclosure: These studies were supported by Merck Sharp & Dohme, a subsidiary of Merck & Co. Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
By Jessica Nye, PhD
References:
- Molina J-M, Rizzardini G, Orrell C, et al. Switch to fixed-dose doravirine (100 mg) with islatravir (0.75 mg) once daily in virologically suppressed adults with HIV-1 on antiretroviral therapy: 48-week results of a phase 3, randomised, open-label, non-inferiority trial. Lancet HIV. Published online May 8, 2024. doi:10.1016/S2352-3018(24)00031-6
- Mills AM, Rizzardini G, Ramgopal MN, et al. Switch to fixed-dose doravirine (100 mg) with islatravir (0.75 mg) once daily in virologically suppressed adults with HIV-1 on bictegravir, emtricitabine, and tenofovir alafenamide: 48-week results of a phase 3, randomised, controlled, double-blind, non-inferiority trial. Lancet HIV. Published online May 8, 2024. doi:10.1016/S2352-3018(24)00030-4
Source : Infectious Disease Advisor
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