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Low Virologic Failure Rate at 48 Weeks
With Islatravir/Doravirine in Phase 2 Trial
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AIDS 2020: 23rd International AIDS Conference Virtual, July 6-10, 2020
Mark Mascolini
Only 5 of 90 previously untreated adults (5.5%) randomized to islatravir/doravirine (ISL/DOR) had protocol-defined virologic failure through 48 weeks in the international P011 trial [1]. All 5 participants had a confirmed viral load below 80 copies after failure, and no participant had a viral load above 400 copies.
Islatravir is the first antiretroviral in a novel class, the nucleoside reverse transcriptase translocation inhibitors, being developed by Merck for prevention and treatment of HIV infection. Researchers have been testing islatravir in combination with the licensed nonnucleoside doravirine as a potential two-drug regimen with a good safety profile.
P011 is a phase 2 dose-ranging trial of ISL/DOR involving previously untreated people randomized to once-daily ISL/DOR (with ISL at 0.25, 0.75, or 2.25 mg) or to DOR/lamivudine (3TC)/tenofovir disoproxil fumarate (TDF) for 48 weeks [2,3]. Participants randomized to ISL/DOR took those drugs with 3TC for the first 24 weeks, then dropped 3TC during weeks 24 through 48 if they had reached a viral load below 50 copies. Each of the four study arms had about 30 participants.
Protocol-defined virologic failure meant (1) viral rebound above 50 copies or a viral load at least 10-fold higher after more than a 10-fold drop on treatment, or (2) nonresponse, a viral load at or above 200 copies any time from week 24 through week 48 or a confirmed viral load at or above 50 copies at week 48. Protocol-defined virologic failure had to be confirmed by another viral load measure within 2 weeks of the first.
At week 48 an FDA snapshot analysis determined that a slightly higher proportion of participants in the 2.25-mg ISL arm (4 of 31, 12.9%) had a viral load at or above 50 copies than in the 0.25-mg arm (2 of 29, 6.9%), the 0.75-mg arm (2 of 30, 6.7%), or the control arm (2 of 31, 6.5%). But protocol-defined virologic failure rates were similar across the four study arms (2 of 29, 6.9%, on 0.25-mg ISL; 2 of 30, 6.7%, on 0.75-mg ISL; 1 of 31, 3.2%, on 2.25-mg ISL; 1 of 31, 3.2%, on the control regimen). There were two rebounders in each of the lower-dose ISL arms and one in the control arm; there was one nonresponder in the 2.25-mg ISL arm.
No one in any treatment arm had a viral load high enough to trigger resistance testing (400 copies), and everyone who quit the study with protocol-defined virologic failure had a load below 200 copies. Among the 6 people with protocol-defined virologic failure, initial viral failure and later confirmation values were 51 and 79, 93 and 55, 87 and 58, 77 and 53, 93 and 50, and (in the control arm) 59 and 55.
Three people discontinued the study early, all in the 2.25-mg ISL arm. One of these 3 withdrew from the study and 2 were lost to follow-up (failed to keep study visits).
Five trials are evaluating DOR plus ISL at the 0.75-mg dose. Two phase 3 trials in adults enroll virologically suppressed people taking another regimen (ClinicalTrials.gov NCT04223778 and NCT04223791), one phase 3 trial in adults enrolls antiretroviral-naive people (NCT04233879), and one phase 3 trial enrolls heavily treatment-experienced adults (NCT04233216). A phase 2 trial enrolls antiretroviral-naive or virologically suppressed adolescents (NCT04295772).
References
1. Orkin C, Molina JM, Yazdanpanah Y, et al. Analysis of protocol defined virologic failure through week 48 from a phase 2 trial (P011) of islatravir and doravirine in treatment-naive adults with HIV-1 infection. AIDS 2020: 23rd International AIDS Conference Virtual. July 6-10, 2020. Abstract OAB0302.
2. ClinicalTrials.gov. Islatravir (MK-8591) with doravirine and lamivudine in participants infected with human immunodeficiency virus type 1 (MK-8591-011). ClinicalTrials.gov identifier NCT03272347.
3. Molina JM, Yazdanpanah Y, Saud A, et al. MK-8591 at doses of 0.25 to 2.25 mg QD, in combination with doravirine establishes and maintains viral suppression through 48 weeks in treatment-naive adults with HIV-1 infection. Tenth International AIDS Society Conference on HIV Science, Mexico City. 2019. Abstract WEAB0402LB. http://www.natap.org/2019/IAS/IAS_15.htm
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