Islatravir: a first-in-class nucleoside reverse transcriptase translocation inhibitor for HIV treatment

Islatravir is a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI) characterized by high antiviral potency and a long intracellular half-life. Recent clinical developments, including dose optimization following previously observed lymphocyte reductions, phase 3 evaluation of once-daily doravirine/islatravir, and development of once-weekly islatravir/lenacapavir combination therapy, warrant reassessment of its potential role in HIV treatment.

Recent phase 3 studies show that doravirine/islatravir 100/0.25 mg maintains virologic suppression after switching from established antiretroviral therapy, without clinically meaningful reductions in total lymphocyte or CD4+ T-cell counts. These findings support the efficacy and safety of reduced islatravir exposure. The regimen was also noninferior to bictegravir/emtricitabine/tenofovir alafenamide in treatment-naïve individuals. Two phase 3 switch trials further showed that investigational islatravir/lenacapavir (2 mg/300 mg) can maintain virologic suppression with once-weekly oral dosing. Resistance studies identify M184I/V as the principal pathway affecting islatravir susceptibility.

Islatravir combines a novel mechanism of action with pharmacologic properties enabling simplified and extended-interval treatment. Its future importance may extend beyond daily therapy by facilitating effective once-weekly oral antiretroviral treatment.