Current evidence on islatravir drug resistance and implications for future HIV treatment

Islatravir (ISL; MK-8591; 4'-ethynyl-2-fluoro-2'-deoxyadenosine; EFdA) is the first antiviral drug that acts as a nucleoside reverse transcriptase translocation inhibitor (NRTTI). Unlike classic nucleoside and nucleotide analogue reverse transcriptase inhibitors (nRTIs) that terminate viral DNA chain extension upon incorporation because they lack the 3'-hydroxyl group, ISL primarily interferes with reverse transcriptase (RT) translocation. After ISL-triphosphate (ISL-TP) is incorporated into viral DNA, RT has a reduced ability to shift along the template to effectively position the subsequent nucleotide for incorporation, thereby inhibiting further DNA synthesis. In addition, ISL is frequently misincorporated by RT, leading to mismatched primer termini that further reduces productive DNA elongation. ISL has highly potent antiviral activity against both wildtype HIV-1 (50% effective concentration [EC₅₀], ∼0.07-0.20 nM) and a broad panel of nRTI-resistant clinical isolates in vitro. It is also active against HIV-2, with an EC50 on average 4.8-fold more potent than observed for HIV-1. In late 2025, a fixed-dose combination of the nonnucleoside reverse transcriptase inhibitor (NNRTI) doravirine (DOR) and ISL (DOR/ISL 100/0.25 mg once daily) was filed with the US Food and Drug Administration for therapy in adults with HIV who are virologically suppressed on their antiretroviral (ARV) regimens and have no known resistance to either drug. In parallel, a once-weekly oral regimen combining ISL with the capsid inhibitor lenacapavir is currently undergoing phase III clinical investigation as maintenance therapy for people with HIV-1 who are virologically suppressed. People with HIV who are expected to be eligible for combinations with ISL may have been previously exposed to ARV therapy or preexposure prophylaxis, during which resistance mutations may have emerged. In addition, some individuals may have acquired virus containing resistance mutations through the transmission of a resistant strain.