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Gene Stollerman Professor of Medicine
Chief, Division of Infectious Diseases
Northwestern University Feinberg School of Medicine
Babafemi Taiwo, MBBS: consultant/advisor/speaker: Gilead Sciences, GlaxoSmithKline, Johnson & Johnson, ViiV Healthcare.
Studies of islatravir, the investigational reverse-transcriptase translocation inhibitor, were placed on clinical hold by the FDA in December 2021 after a decrease in total lymphocyte and CD4+ T‑cell subset counts was uncovered in early clinical trials. Less than 1 year later, in September 2022, it was announced that phase III studies of once-daily oral islatravir plus doravirine will resume, but with a lower dose of islatravir than in the previous phase III trial. There also are plans to resume study of weekly oral islatravir plus lenacapavir, again with a lower dose of islatravir. Two studies presented at HIV Glasgow 2022 indicate that the new dose for once-daily islatravir will be 0.25 mg, which is one third of the 0.75-mg dose that was previously selected for phase III clinical development.
Post Hoc Analysis of P011
In the first report at HIV Glasgow 2022, Correll and colleagues conducted a post hoc analysis of lymphocyte changes with islatravir in the P011 study. The investigators showed that the decline in CD4+ T-cells with islatravir observed in the P011 study was dose dependent, with the largest decline occurring with the 2.25-mg dose, followed by the 0.75-mg dose. Islatravir 0.25 mg once daily was associated with total lymphocyte count and lymphocyte subset changes that were similar to the comparator regimen of doravirine/lamivudine/tenofovir disoproxil fumarate once daily. This dose-dependent effect was observed both in the dose-ranging portion of P011 (Weeks 0-72), when participants were randomized to receive islatravir 0.25 mg, 0.75 mg, or 2.25 mg (each in combination with doravirine) vs doravirine/lamivudine/tenofovir disoproxil fumarate, and after Week 72, when all participants on the islatravir arms received the 0.75-mg dose plus doravirine.
Modeling and Simulation of Optimal Islatravir Dosing
In the second islatravir study presented at HIV Glasgow 2022, Vargo and colleagues reported on a modeling and simulation study to identify optimal dosing of islatravir in treatment-naive and virally suppressed people with HIV. The results showed that islatravir 0.25 mg once daily consistently achieved adequate intracellular levels of the active islatravir triphosphate to provide sufficient activity against wild-type HIV after a single dose. Adequate islatravir triphosphate levels to provide sufficient activity against HIV variants with the M184V/I mutation also were consistently achieved by steady state with islatravir 0.25 mg. The study also predicted comparable changes in total lymphocyte and CD4+ T-cell counts with islatravir 0.25 mg once daily vs standard of care antiretroviral therapy.
Moving Forward With the Islatravir Clinical Study Program
Early identification of potential adverse events of antiretroviral drugs is one of the goals of the rigorous clinical development program for these agents. To me, the dose-dependent adverse effect of islatravir on lymphocytes is reminiscent of the QT prolongation that was seen at the 75-mg and 300-mg daily doses of rilpivirine in early studies, but not at the eventual clinically recommended rilpivirine dose of 25 mg. The safety of rilpivirine 25 mg has since been confirmed over several years of clinical use.
The effect of islatravir on lymphocytes is due to cellular apoptosis caused by accumulation of the active form of islatravir (islatravir triphosphate) in target cells. This effect is not due to mitochondrial toxicity. Now that the effective “lymphocyte-safe” once-daily dose of islatravir has been determined to be 0.25 mg, healthcare professionals can look forward to the results of planned clinical trials. If islatravir 0.25 mg once daily plus doravirine 100 mg proves to be effective and safe in planned clinical trials, this novel regimen would add to the evidence-based options for 2-drug antiretroviral therapy in people with HIV.
What are your thoughts on these new findings with lower-dose islatravir? Join the discussion by posting a comment.