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Islatravir Plus Doravirine Maintains HIV Control Through 96 Weeks
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HIV Drug Therapy/Glasgow 2020, October 5-8, 2020
Mark Mascolini
In a 121-person dose-ranging study of the novel antiretroviral islatravir, this nucleoside reverse transcriptase translocation inhibitor (NRTTI) plus the nonnucleoside doravirine controlled HIV replication well through 96 weeks after participants stopped taking a third drug, lamivudine (3TC), at week 20 or later [1]. Protocol-defined virologic failure was infrequent but twice as common in the three combined islatravir arms as in the doravirine/3TC/tenofovir disoproxil fumarate (TDF) control arm.
Islatravir inhibits HIV replication at two steps in viral reverse transcription: translocation (stopping the reverse transcriptase nucleotide binding site from opening) and delayed chain termination (preventing nucleotides from linking onto the growing viral DNA chain). This double mechanism may heighten islatravir's barrier to resistance and boost its antiviral potency [2].
This phase 2 dose-ranging trial included antiretroviral-naive people with a viral load at or above 1000 copies, a CD4 count at or above 200, no resistance to antiretrovirals, and no HCV infection or active HBV infection. In the first 24 weeks researchers randomized participants to 0.25, 0.75, or 2.25 mg of islatravir daily plus doravirine and 3TC or to the single-tablet combination doravirine/3TC/TDF. People taking islatravir who reached a viral load below 50 copies at week 20 or later dropped 3TC from their combination and continued islatravir and doravirine. Participants continued their assigned dose of islatravir for at least 24 weeks. When researchers decided 0.75 mg would be the best dose for continued study, everyone taking islatravir switched to that dose.
The trial randomized about 30 people to each of the four study arms. About 90% in all treatment arms were men. In the islatravir arms 21% were black, 76% white, and 50% Hispanic. Those proportions in the control arm were 16%, 77%, and 48%. Median age stood at 28.5 years with islatravir and 27.0 years with doravirine/3TC/TDF. Respective median pretreatment viral loads were 4.6 and 4.2 log10 copies (about 40,000 and 16,000 copies).
At week 96 FDA snapshot analysis determined that 86.2% randomized to 0.25 mg islatravir, 90% randomized to 0.75 mg, 67.7% randomized to 2.25 mg, 81.1% in any islatravir arm, and 80.6% in the control arm had a viral load below 50 copies.
The lower response rate in the 2.25-mg islatravir arm could be traced to more discontinuations through week 48. In this arm 21 of 31 people had a viral load below 50 copies at week 96, 5 had a viral load above 50 copies, and 5 had no virologic data in the week-96 window. Among the 5 people with no data, 2 stopped treatment because of death or an adverse event and 3 stopped for other reasons.
A week-96 observed failure analysis dropped data missing at week 96 if the last on-treatment viral load lay below 50 copies. By this approach 25 of 27 (92.6%) in the 0.25-mg islatravir arm, 27 of 29 (93.1%) in the 0.75-mg arm, 21 of 26 (80.8%) in the 2.25-mg arm, and 25 of 27 (92.6%) in the control arm had a week-96 viral load below 50 copies.
Six of 90 people (6.7%) in the combined islatravir arms had protocol-defined virologic failure at week 96, compared with 1 of 31 (3.2%) in the doravirine/3TC/TDF control arm. Each islatravir arm had 2 protocol-defined virologic failures. Everyone who dropped out because of protocol-defined virologic failure had a viral load below 200 copies at that point [3]. Only 1 protocol-defined failure happened during weeks 48 to 96.
Drug-related adverse events affected no one taking 0.25 mg of islatravir, 3 (10%) taking 0.75 mg, 4 (12.9%) taking 2.25 mg, and 7 (22.6%) taking the control regimen. Respective rates of serious adverse events were 3.4%, 10%, 3.2%, and 9.7%. No one stopped 0.25-mg or 0.75-mg of islatravir because of a drug-related adverse event. Two (6.5%) stopped 2.25 mg of islatravir and 1 (3.2%) stopped the control regimen for that reason.
In the combined islatravir arms, 3.4% had grade 3 triglyceride elevations (vs 0 in the control arm), 3.3% had grade 3 alanine aminotransferase elevations (vs 3.2% in the control arm), 4.4% and 6.7% had grade 3 and 4 creatine kinase elevations (vs 3.2% and 3.2% in the control arm), and 4.4% had grade 3 creatinine elevations (vs 6.5% in the control arm). All grade 3 or 4 creatinine kinase abnormalities resolved while on study drug, as did all grade 3 creatinine abnormalities.
Islatravir/doravirine as a two-drug 0.75/100-mg once-daily regimen is in phase 3 trials.
References
1. Molina J, Yazdanpanah Y, Afani Saud A, et al. Islatravir in combination with doravirine maintains HIV-1 viral suppression through 96 weeks. HIV Drug Therapy/Glasgow 2020, October 5-8, 2020. Abstract O415.
2. Schurmann D, Rudd DJ, Zhang S, et al. Safety, pharmacokinetics, and antiretroviral activity of islatravir (ISL, MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor, following single-dose administration to treatment-naive adults infected with HIV-1: an open-label, phase 1b, consecutive-panel trial. Lancet HIV;7:e164-e172. 2020. DOI: https://doi.org/10.1016/S2352-3018(20)30046-1
3. Orkin C, Molina J, Yazdanpanah Y, et al. Analysis of protocol-defined virologic failure through 96 weeks from a phase II trial (P011) of islatravir and doravirine in treatment-naive adults with HIV-1. HIV Drug Therapy/Glasgow 2020, October 5-8, 2020. Abstract P047.
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