Doravirine/Islatravir Combination Maintains Virologic Suppression Through 96 Weeks

A double-blind phase 3 study evaluated the long-term efficacy and safety of switching adults with HIV-1 with virological suppression from bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) to the 2-drug regimen of doravirine (DOR) and the investigational agent islatravir (ISL). The trial enrolled adults with HIV-1 RNA of less than 50 copies/mL for at least 3 months, adequate CD4-positive T-cell counts, and no history of treatment failure or known DOR resistance.

Participants were randomly assigned 2:1 to switch to DOR/ISL 100 mg/0.25 mg or to continue BIC/FTC/TAF, with week 96 virologic and safety outcomes assessed as secondary end points following previously reported noninferior results at week 48.

At week 96, virologic suppression was well maintained in both treatment arms. Confirmed HIV-1 RNA of 50 copies/mL or more occurred in 1.5% of participants who switched to DOR/ISL and 1.2% of those who continued BIC/FTC/TAF, a difference that was not statistically meaningful. Discontinuations due to lack of efficacy were uncommon, and overall rates of HIV-1 RNA of less than 50 copies/mL and less than 200 copies/mL remained high across both groups. These findings indicate durable viral control through nearly 2 years of follow-up after switching therapy.

Safety and tolerability outcomes through week 96 were similar between regimens. The adverse event profile for DOR/ISL was consistent with earlier results and revealed no new safety signals. Importantly, there were no meaningful differences between groups in CD4-positive T-cell or total lymphocyte count changes over time, and protocol-specified discontinuations related to lymphocyte declines were rare and balanced between arms.

Contagion spoke with the study’s lead investigator, Amy Colson, MD, MPH, medical director of the Zinberg Clinic at Cambridge Health Alliance and research director at Community Resource Initiative, about the findings.

Contagion: What do the week 96 results from the MK-8591A-052 study tell us about the long-term durability of virologic suppression when switching to the combination therapy?

Colson: This was a double-blind study [that] enrolled over 500 people in a 2:1 randomization ratio. So we're now looking, at this conference, at week 96 data on the DOR/ISL combination vs the participants who were on bictegravir/emtricitabine/tenofovir alafenamide. And what we saw at week 96 is that the efficacies of the 2 treatments were very comparable. At week 96, there were 1.5% of participants on DOR/ISL who had a viral load greater than or equal to 50 [copies/mL] compared with 1.2% of participants who continued BIC/FTC/TAF.

Contagion: Safety has been a consideration with islatravir. How should clinicians interpret the lymphocyte and CD4-positive T-cell findings through week 96, particularly given the protocol-specified discontinuation criteria?

Colson: There was an earlier version of this study that used a higher dose of islatravir. It used a 0.75-mg daily islatravir dose, as opposed to this trial, which used a 0.25-mg daily islatravir dose. And what was seen in the 2 phase 3 trials that used the higher islatravir doses is that there were some dose-related declines in both the total lymphocyte count and the CD4 count. So those trials were held, and there were some modeling studies that were done, which predicted that the 0.25-mg dose of islatravir, which was used in this trial, would have effective exposure without impacting CD4 count and lymphocyte count. So the phase 3 program was then resumed with the lower 0.25-mg daily dose. And what we saw at the time of the primary analysis [at] week 48 and also at week 96 was that [in] the 2 treatments, so BIC/FTC/TAF vs DOR/ISL, there was no difference in change in CD4 count or change in lymphocyte count. So I think, particularly, the week 96 data have really put to rest this question.

Contagion: With comparable adverse event rates and no new safety signals emerging after week 48, how does the overall tolerability profile of this combination shape its potential role as a switch option for virologically suppressed patients?

Colson: The week 96 data showed very similar safety profiles between the 2 arms of the trial, between the BIC/FTC/TAF arm and the DOR/ISL arm. There were no new safety signals during the second year between week 48 and week 96. So overall, [it was a] super well-tolerated regimen, and the trial looked at a number of metabolic parameters. It looked at insulin resistance, lipids, weight, renal function, [and] bone mineral density, and on all these measures, the 2 regimens were highly comparable, so no real tolerability signals.

Contagion: From a treatment strategy perspective, which patient populations might benefit most from a switch to this combination therapy, based on its complementary mechanism of action and resistance profile demonstrated in this study?

Colson: I think what is nice about this combination is that it's just 2 therapies. The drugs don't have a lot of interactions, so I would imagine that it would be attractive to patients who have multimorbidity and they're on lots of medications. They want to reduce the number of drugs they're exposed to, [especially] older patients.

Often, I have a number of older patients, so I can imagine that a lot of these folks on lots of medicines would really benefit. And then I have patients as well in my practice who don't tolerate integrase inhibitors well. So they have insomnia, which they attribute to the drug, or they have some nausea, and this would be a welcome alternative to try in those patients as well.

The conversation has been edited for grammar and clarity.