Novel once-weekly oral ART regimen scores high for viral suppression maintenance

A once-weekly oral antiretroviral therapy (ART) regimen combining the nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir with the non-nucleoside reverse transcriptase inhibitor (NNRTI) ulonivirine helps maintain viral suppression in adults living with HIV-1, according to a phase IIb study.

All participants who switched from the three-drug regimen of bictegravir/emtricitabine/tenofovir alafenamide fumarate (BIC/FTC/TAF) to the combination of islatravir 20 mg plus ulonivirine at 100, 200, or 400 mg remained virologically suppressed through 24 weeks of treatment, reported lead investigator Dr Jean-Michel Molina from the University of Paris Cité in Paris, France. [IAS 2025, abstract 1663]

Molina emphasized the absence of confirmed virologic failure, defined as two consecutive occurrences (2–4 weeks apart) of HIV-1 RNA ≥200 copies/mL at any time during the study, across all treatment arms.

However, the study was discontinued prematurely due to a 26.6-percent decline in total lymphocyte counts and a 23.9-percent decrease in CD4 counts in islatravir–ulonivirine-treated participants as opposed to a drop of only 2.5 percent and 0.8 percent, respectively, in those who continued with BIC/FTC/TAF.

“On-treatment declines in total lymphocyte and CD4 counts were evident in all islatravir plus ulonivirine arms by 8–12 weeks,” Molina noted. He pointed out that these declines were reversed over 132 weeks following a switch to a different ART regimen at week 24.

In terms of safety, islatravir plus ulonivirine was generally well tolerated, with similar adverse event (AE) profile to BIC/FTC/TAF, he said.

AEs occurred in 76.9 percent of participants across the islatravir–ulonivirine arms vs 67.5 percent in the BIC/FTC/TAF arm. Drug-related AEs were documented in 17.4 percent vs 10.0 percent, and AEs led to study discontinuation in 2.5 percent vs 0 percent, respectively.

The most common AEs in the islatravir–ulonivirine arms were COVID-19 (11.6 percent), fatigue (9.9 percent), diarrhoea (8.3 percent), headache (8.3 percent), and nausea (6.6 percent).

These findings demonstrate that the combination of islatravir 20 mg plus ulonivirine at three different doses, given orally once weekly, was efficacious at maintaining viral suppression (HIV-1 RNA <50 copies/mL) through week 24, Molina concluded.

He shared that they are currently enrolling participants in a new phase IIb study evaluating the same once-weekly combination, but using a lower islatravir dose at 2 mg and ulonivirine at 200 mg. This islatravir dose has been previously shown to have no negative effect on total lymphocyte and CD4 counts. [IDWeek 2024, abstract 577]

Islatravir and ulonivirine have complementary pharmacokinetic and pharmacodynamic profiles, and their combination seems to be a promising long-acting two-drug regimen against HIV-1 variants with common resistance mutations, Molina said. He believed that a regimen that can be taken orally once a week has the potential to improve lifelong adherence to ARTs.

The present study included 161 adults (average age 45 years, 80.7 percent men, 65 percent White) with HIV-1 who were virologically suppressed for at least 6 months on BIC/FTC/TAF. None of them had a history of treatment failure on any regimen, any known virologic resistance to NNRTI, or active hepatitis B or C coinfection.

The participants were randomly assigned to receive islatravir 20 mg with ulonivirine 100 mg (n=40), 200 mg (n=41), or 400 mg (n=40) or to continue with BIC/FTC/TAF (n=40).

At baseline, the average CD4 count was 748 cells/mm³, and around 94 percent of participants had a CD4 count above 350 cells/mm³. The median duration of ART ranged between 64.5 and 116.8 months across the treatment arms, and prior BIC/FTC/TAF duration was a median of 21.1–23.4 months.