Islatravir (MK-8591): A Comprehensive Analysis of a First-in-Class NRTTI from Clinical Promise to Regulatory Relaunch

I. Executive Summary

Islatravir (MK-8591, DB15653) is a first-in-class, investigational small molecule antiretroviral agent developed by Merck (known as MSD outside the U.S. and Canada) for the treatment and prevention of Human Immunodeficiency Virus Type 1 (HIV-1) infection.[1] It is classified as a Nucleoside Reverse Transcriptase Translocation Inhibitor (NRTTI), a novel class of drug that distinguishes it from all currently approved antiretrovirals. The development of Islatravir represents a significant narrative in modern pharmacology, characterized by immense initial promise, a critical safety-related setback, and a subsequent strategic realignment. The drug's unique mechanism of action and exceptionally long intracellular half-life positioned it as a potential cornerstone for future long-acting HIV treatment and prevention regimens. However, its development was fundamentally reshaped by the discovery of a dose-dependent safety signal—decreases in lymphocyte and CD4+ T-cell counts—which compelled a strategic pivot away from ambitious long-acting applications toward a more conservative once-daily oral treatment regimen.

Islatravir exerts its potent antiviral activity through a multi-pronged mechanism that includes both immediate and delayed termination of viral DNA synthesis, a process distinct from conventional nucleoside reverse transcriptase inhibitors (NRTIs).[4] This unique mechanism confers a high barrier to the development of drug resistance.[7] In extensive clinical trials, Islatravir, in a fixed-dose combination with the non-nucleoside reverse transcriptase inhibitor (NNRTI) doravirine (DOR/ISL), demonstrated non-inferior efficacy in maintaining viral suppression compared to standard-of-care three-drug regimens.[9]