The open-label MK-8591A-051 (NCT05631093) trial and the double-blind MK-8591A-052 (NCT05630755) trial, both from Merck, are evaluating the efficacy and safety of 100-mg doravirine (DOR) and 0.25-mg islatravir (ISL) as a once-daily 2-drug regimen for virologically suppressed people living with HIV-1. Their primary and secondary outcomes of interest, respectively, are proportions of participants maintaining HIV-1 RNA levels at 50 copies/mL or below at week 48 and maintaining viral suppression at week 48.
New data from both trials were presented today at the 2025 Conference on Retroviruses and Opportunistic Infections (CROI) by Amy Colson, MD, MPH, director of research at Community Resource Initiative in Boston, which operates the Massachusetts AIDS Drug Assistance Program, the state’s tuberculosis drug assistance program, and an HIV clinical trials unit. Colson is also an instructor at Harvard Medical School and has worked for 25 years as an HIV clinician at the Zinberg Clinic in Cambridge.
Amy Colson, MD, MPH | Image Credit: © Community Resource Initiative
This interview has been lightly edited for clarity and length.
The American Journal of Managed Care® (AJMC®): Can you summarize what the ongoing MK-8591A-051 and MK-8591A-052 trials are investigating, including their primary and key secondary outcomes of interest and the patient populations?
Colson: The goal of these 2 phase 3 trials is to investigate the efficacy and safety of the once-daily fixed-dose combination of DOR 100 mg and ISL 0.25 mg in virologically suppressed individuals as a potential new daily switch option for the treatment of HIV-1.
The open-label 051 trial enrolled adults with virologic suppression on multiple antiretroviral regimens, and the double-blind 052 trial enrolled adults with virologic suppression on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). Both trials randomized participants in a 2:1 ratio to either switch to DOR/ISL or to continue their current therapy.
The primary efficacy end point is the proportion of individuals with a viral load not exceeding 50 copies/mL at week 48. A secondary efficacy end point is the proportion of individuals who maintained viral suppression at week 48 (viral load < 50 copies/mL). Safety is also being evaluated in both studies, including monitoring of adverse events and labs.
AJMC: Were there unmet patient needs or treatment gaps that Merck identified that led to the initiation of these studies?
Colson: There remains a need for novel antiretroviral regimens that have high potency and low risk of long-term toxicity, particularly as people living with HIV are aging. There are many people who are well controlled on their current regimen but who need or are interested in switching their HIV treatment, perhaps due to an issue with tolerability or a drug interaction with a new medication. DOR/ISL is a simple regimen, containing less drugs from different families and/or with different mechanisms of action from the current available ones, and has potential to be a highly efficacious and safe regimen for people living with HIV infection who may need or want an integrase strand transfer inhibitor (InSTI)–sparing regimen.
AJMC: In December, Merck announced topline results from these phase 3 studies showing success in participants with HIV-1 RNA levels of 50 copies/mL or below at week 48. Can you break down the key data presented at CROI 2025 for each study?
Colson: In both trials, switching to DOR/ISL was found to be noninferior—or, statistically similar—to continuing current suppressive therapy, and the primary efficacy objectives were achieved. In the 051 trial, 1.4% of patients on DOR/ISL had a viral load measurement of 50 copies/mL or less at week 48 compared with 4.9% who continued baseline therapy. In the 052 trial, 1.5% on DOR/ISL had a viral load measurement of 50 copies/mL or less at week 48 compared with 0.6% who continued BIC/FTC/TAF. Trial 052 is the first phase 3 trial to demonstrate that a 2-drug regimen without an InSTI is noninferior to BIC/FTC/TAF. Importantly, in both studies, no treatment-emergent resistance to doravirine or islatravir was detected in either trial.
AJMC: How do these results build on the data you already have?
Colson: There are considerable data from earlier studies with ISL, including efficacy and safety data from earlier phase 3 trials with DOR/ISL that used a higher dose of ISL (0.75 mg). In these studies, ISL was efficacious; however, this higher daily dose was associated with declines in total lymphocyte and CD4 counts.
We are pleased to see that in the 051 and 052 trials, ISL at a lower daily dose of 0.25 mg did not adversely affect total CD4 or lymphocyte counts, demonstrating that the lower ISL dose resolved the prior safety concern from earlier studies while maintaining high efficacy. In both studies, DOR/ISL had an overall safety profile comparable to that of the other regimens in the trial.
AJMC: How do the mechanisms of action and resistance profiles of DOR and ISL complement each other in the treatment of HIV?
Colson: DOR is an approved non-nucleoside reverse transcriptase inhibitor (NNRTI), and ISL is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI). ISL has considerable potency due to its high binding affinity for the reverse transcriptase enzyme and its ability to inhibit reverse transcription through multiple mechanisms, including translocation. DOR/ISL is a promising combination because the 2 drugs have complementary mechanisms of action and resistance profiles. In particular, a key DOR resistance mutation hypersensitizes HIV to ISL, which results in a high barrier to resistance for the combination.
AJMC: What are the advantages of these complementary mechanisms of action and resistance profiles compared with existing HIV treatment regimens?
Colson: DOR/ISL is a 2-drug complete regimen consisting of an NNRTI and an NRTTI and is distinct from many existing HIV treatment regimens, which may include 3 drugs and an InSTI.
AJMC: What factors might contribute to the difference in virologic suppression between DOR/ISL and BIC/FTC/TAF?
Colson: In both trials, switching to DOR/ISL was found to be noninferior (statistically similar) to continuing current suppressive therapy, including BIC/FTC/TAF, and the primary efficacy objectives were achieved.
AJMC: How do the study results address prior concerns about CD4 and total lymphocyte declines observed with higher doses of ISL?
Colson: Prior phase 3 trials of the DOR/ISL combination using a higher daily ISL dose (0.75 mg) showed declines in the total lymphocyte and CD4 counts. A previous phase 2b dose-finding trial supported the efficacy of a lower daily ISL dose of 0.25 mg, and population pharmacokinetic modeling indicated that the lower ISL dose would not adversely affect total lymphocyte or CD4 counts.
In both trials, lymphocytes and CD4 counts were closely monitored. DOR with ISL at a daily dose of 0.25 mg did not adversely affect total CD4 or lymphocyte counts, demonstrating that the lower ISL dose resolved the prior safety concern from earlier studies while maintaining high efficacy.
AJMC: Given that drug-related adverse events (AEs) were more common with DOR/ISL than with baseline antiretroviral therapy, what considerations should clinicians keep in mind when recommending this regimen?
Colson: Trial 051 was an open-label trial. The rate of drug-related AEs for the DOR/ISL group was 12% compared with 5% in the baseline antiretroviral therapy group. It is not uncommon to have more treatment-related AEs reported for the investigational agent in open label trials. Importantly, the frequencies of total AEs, grade 3 or 4 AEs, serious AEs, and AEs leading to discontinuation between groups was similar. In the blinded 052 trial, the rates of treatment-related AEs were similar (10.2% in the DOR/ISL group vs 9.4% in the BIC/FTC/TAF group). Overall, the safety profile of DOR/ISL was comparable to the comparator.
AJMC: What are the next steps for investigating DOR/ISL, and how might these findings influence future treatment strategies for diverse populations of patients living with HIV?
Colson: The current data through 48 weeks support the use of DOR/ISL as a switch option for people living with HIV who are currently virologically suppressed. Merck plans to begin submitting applications for marketing authorization to regulatory agencies in the next few months. Trials 051 and 052 will continue to assess efficacy and safety through week 144.
In addition to 051 and 052, there is an ongoing phase 3 trial of DOR/ISL, MK-8591A-053 (NCT05705349), in people living with HIV who have not previously received treatment. This study is fully enrolled and has the potential to support broader use of DOR/ISL.
The trials with daily DOR/ISL further support ongoing development of ISL as a component of long-acting 2-drug regimens, including weekly oral regimens with it at the 2-mg weekly dose, and ulonivirine (Merck’s investigational NNRTI, currently in phase 2) and lenacapavir (in collaboration with Gilead, currently in phase 3).
