Ulonivirine Shows Promise for Once-Weekly HIV Treatment Despite Early Trial Setback
核心洞察
Ulonivirine, a novel non-nucleoside reverse transcriptase (搜索) inhibitor from Merck (搜索), demonstrated efficacy in maintaining viral suppression when combined with islatravir in a Phase IIb trial.
The original study was halted due to lymphocyte and CD4 count declines attributed to high-dose islatravir, but these effects were reversible and not linked to ulonivirine itself.
A new Phase IIb trial is underway using ulonivirine with a significantly lower 2 mg dose of islatravir to address the safety concerns.
Ulonivirine (MK-8507), an experimental non-nucleoside reverse transcriptase (搜索) inhibitor from Merck (搜索), has demonstrated promising efficacy for once-weekly oral HIV (搜索) treatment, according to Phase II study results presented at the International AIDS Society Conference on HIV Science (IAS 2025) in Rwanda. Despite early safety concerns that led to trial suspension, the novel compound maintains potential as a component of simplified HIV therapy regimens.
Trial Design and Patient Population
The Phase IIb double-blind study enrolled 161 adults currently receiving daily Biktarvy (bictegravir/tenofovir alafenamide/emtricitabine) with viral suppression for at least six months. Participants were randomly assigned to continue their daily regimen or switch to once-weekly dosing with islatravir (20 mg) plus one of three ulonivirine doses (100, 200, or 400 mg).
The study population was predominantly male (80%) and white (64%), with a median age of 45 years and baseline CD4 count of 748 cells/mm³. All participants had no history of treatment failure and lacked known NNRTI resistance mutations, with more than 90% maintaining CD4 counts above 350 at baseline.
Efficacy Results Demonstrate Viral Suppression
Lead investigator Jean-Michel Molina, MD, of University of Paris Cité, reported that switching to ulonivirine/islatravir matched the efficacy of continuing on Biktarvy. All participants maintained viral loads below 50 copies/mL through the 24-week analysis period, with no cases of confirmed virologic failure in any treatment group.
"A once-weekly oral regimen will likely improve lifelong adherence to treatment over a daily oral regimen," Molina suggested, highlighting the potential impact on patient compliance and quality of life.
Safety Profile and Lymphocyte Concerns
While overall adverse event rates were similar across treatment groups, participants receiving ulonivirine/islatravir experienced higher rates of drug-related adverse events (17.4% versus 10.0%) and treatment discontinuation (2.5% versus 0%) compared to those continuing Biktarvy.
The most significant safety concern involved substantial decreases in lymphocyte and CD4 counts. Those on the experimental combination showed mean decreases of 26.6% in total lymphocytes and 23.9% in CD4 counts, compared to 2.5% and 0.8% respectively in the Biktarvy group. However, these declines were reversible, with counts returning toward baseline levels within 24 weeks after stopping the regimen.
Importantly, rates of infections—a potential consequence of white blood cell deficiencies—remained similar across all groups, suggesting the clinical impact of these laboratory changes was limited.
Islatravir Implicated in Safety Issues
The lymphocyte and CD4 count declines were attributed to the high 20 mg dose of islatravir rather than ulonivirine itself. According to Molina, ulonivirine does not inhibit DNA polymerase alpha (搜索) and showed no effect on lymphocyte or CD4 counts in laboratory studies or animal models, unlike islatravir.
The Food and Drug Administration had placed a clinical hold on islatravir trials in late 2021 after participants experienced similar declines in lymphocyte counts. Further investigation confirmed that the doses used in these studies were too high, leading to the development of lower-dose formulations.
Development Continues with Lower Islatravir Dose
A new Phase IIb trial using ulonivirine with a significantly reduced 2 mg dose of islatravir is currently underway (NCT06891066), with sites in Australia, Puerto Rico, Switzerland, and the United States. This dramatic dose reduction—from 20 mg to 2 mg weekly—aims to maintain efficacy while eliminating the lymphocyte toxicity observed in earlier studies.
Novel Mechanism and Resistance Profile
Ulonivirine represents a novel potent NNRTI with activity against HIV (搜索) strains resistant to older drugs in its class, including those with K103N, Y181C, and G190A mutations. Early monotherapy studies demonstrated that a single dose could suppress HIV in treatment-naive patients, with pharmacokinetics supporting once-weekly dosing.
The compound is being developed alongside islatravir (MK-8591), the first nucleoside reverse transcriptase (搜索) translocation inhibitor, as HIV (搜索) rapidly develops resistance to single-drug therapy.
Addressing Treatment Adherence Challenges
Daily antiretroviral treatment remains highly effective, but adherence challenges persist for some patients experiencing "pill fatigue." Once-weekly oral medications could provide an alternative for those who prefer not to use long-acting injectable drugs while maintaining the convenience of oral administration.
The potential impact extends beyond individual patient benefits, as once-weekly dosing would require only 52 tablets annually, potentially simplifying drug distribution and delivery systems.
Competitive Landscape
Merck (搜索) and Gilead Sciences are also collaborating on a weekly oral regimen combining low-dose islatravir with Gilead's HIV (搜索) capsid inhibitor lenacapavir (Sunlenca), which has shown promising 48-week results. However, other once-weekly oral compounds in development faced setbacks when two Gilead compounds were placed on clinical hold in June 2025.