Once-weekly oral ART with ulonivirine plus islatravir: 24-week phase 2 results

20 July 2025. Related: Conference reports, Antiretrovirals, .


Jean-Michel Molina at IAS 2025.

Simon Collins, HIV i-Base

Several pipeline compounds are in development for once-weekly oral ART and IAS 2025 included several studies on ulonivirine (ULO, MK-8507) and islatravir (ISL).

Ulonivirine is a once-weekly NNRTI that retains activity against drug resistance to early NNRTIs (including K103N, Y181C and G190A) – with a resistance profile similar to doravirine. It is being developed as a partner to one-weekly islatravir and both compounds were put on development hold in 2021 due islatravir-induced reductions in lymphocyte and CD4 counts.

Week-24 results (from until the study was stopped in 2021) of a phase 2b dose-ranging study of ULO+ISL were presented at IAS 2025 by Jean-Michel Molina from the University of Paris.

This double-blind (placebo-matched) study randomised (1:1:1:1) 161 adults on stable bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) for >6 months to switch to one of three once-weekly doses of ULU (100, 200, or 400 mg) plus islatravir (20 mg) or remain on B/F/TAF.

However, use of ULO+ISL was stopped early in 2021 due to side effects linked to accumulation of intracellular islatravir triphosphates, which has been overcome by reducing the daily dose to 0.75 mg and the weekly dose to 2 mg.

Baseline characteristics included 80% male and 64% white, with a mean age of 45 years and baseline CD4 count of 748 cells/mm3. When dosing of ISL+ULO was discontinued, 113 participants had reached week 24 when viral load remained <50 copies/mL in all participants.

Adverse events were broadly similar in the pooled investigational vs control arm respectively: any (76% vs 67%), drug-related (17% vs 10%), and related to discontinuation (2.5% vs 0%).

Mean changes in total lymphocyte and CD4 counts were –26% and –23% with ULU vs –2.5% and –0.8% with B/F/TAF but returned to baseline in all arms after a further 24 weeks.

Three pharmacokinetic studies were included as e-posters at IAS. Two phase 1 studies in HIV-negative participants reported (i) no drug-drug interactions between ulonivirine and islatravir and (ii) a phase 1 multiple dose safety study of ulonivirine alone that reported similar events to the placebo arm with no signal of lymphocyte toxicity. The third poster was a phase 2 dose-finding study of ulonivirine that selected the 200 mg dose to take forward into phase 3 studies. [2, 3, 4]

Both compounds are being developed by Merck/MSD.

Comment

Once-weekly combinations could dramatically simplify oral ART and likely improve quality of life, similar to previous advances that reduced pill count over the last 25 years.

Concerns about weekly dosing bringing new adherence challenges are actually likely to be easily overcome. Needing only 52 tablets a year will also simplify distribution and delivery.

A phase 2b switch study of ULO/ISL 200 mg/2 mg is already ongoing, with sites in Australia, Puerto Rico, Switzerland and the US. [5]

Although other once-weekly oral compounds are in development, two of the compounds with Gilead were put on clinical hold in June 2025. [6]

References

Unless stated otherwise, all references are to the programme and abstracts of the 13th IAS Conference on HIV Science (IAS 2025), 14 to 17 July 2025, Kigali, Rwanda.

  1. Molina J-M et al. A double-blind, active-controlled, phase 2b study to evaluate the efficacy and safety of ulonivirine in combination with islatravir in virologically suppressed adults living with HIV-1. IAS 2025, Kigali. Oral abstract OAB0102.
    https://programme.ias2025.org/Abstract/Abstract/?abstractid=1663
  2. Nussbaum J et al. An open-label Phase 1 study to evaluate drug interactions between multiple weekly doses of ulonivirine (MK-8507) and single doses of islatravir in adults without HIV. IAS 2025, Kigali. E-poster P0175.
    https://programme.ias2025.org/Abstract/Abstract/?abstractid=2061
  3. Nussbaum J et al. A double-blind, placebo-controlled, Phase 1 study to evaluate extended multiple dosing of ulonivirine (MK-8507) in adults without HIV. IAS 2025, Kigali. E-poster EP0176.
    https://programme.ias2025.org/Abstract/Abstract/?abstractid=2065
  4. Pham M et al. Phase 2 once-weekly dose optimization for ulonivirine in combination with Islatravir 2 mg. IAS 2025, Kigali. E-poster EP0193.
    https://programme.ias2025.org/Abstract/Abstract/?abstractid=4169
  5. ClinicalTrials.gov. A Study of Islatravir (ISL) and Ulonivirine (ULO) Once Weekly (QW) in Virologically Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) (MK-8591B-060).
    https://clinicaltrials.gov/study/NCT06891066

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