What type of drug is Islatravir? A Deep Dive into the First-in-Class NRTTI

October 6, 2025 •

3 min read

With lifelong antiretroviral therapy, the life expectancy for people living with HIV now approaches that of the general population. A key question in ongoing research is, what type of drug is Islatravir? It is a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI).

Quick Summary

Islatravir (MK-8591) is a new type of investigational antiretroviral medication known as a nucleoside reverse transcriptase translocation inhibitor (NRTTI) for treating HIV-1.

Key Points

Drug Class: Islatravir is a first-in-class Nucleoside Reverse Transcriptase Translocation Inhibitor (NRTTI).
Mechanism of Action: It works by blocking the HIV reverse transcriptase enzyme through multiple mechanisms, including immediate and delayed DNA chain termination.
Developer: Islatravir (MK-8591) was developed by the pharmaceutical company Merck.
Primary Indication: It is being studied for the treatment of HIV-1 infection, typically in combination with other antiretroviral drugs.
Clinical Hold: In 2021, development was paused due to findings of decreased lymphocyte and CD4 cell counts in trial participants.
Development Status: Trials for HIV treatment resumed with a lower dose; development for PrEP has been discontinued.
Current Formulations: It's being actively developed as part of a once-daily oral tablet with doravirine and an investigational once-weekly tablet with lenacapavir.
FDA Application: As of July 2025, the FDA has accepted a New Drug Application for the doravirine/islatravir combination tablet for review.

Introduction to Islatravir

Islatravir, known as MK-8591 and developed by Merck, is a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI). This makes it distinct from existing HIV medications by offering a new approach to combat the virus. Its potent activity and extended intracellular half-life initially suggested potential for various dosing regimens, including daily and weekly oral options and a possible yearly implant, though some long-acting formulations are no longer being pursued. The development of Islatravir has involved both promising results and challenges.

How Islatravir Works: A Novel Mechanism of Action

Islatravir's unique mechanism as an NRTTI targets the HIV-1 reverse transcriptase (RT) enzyme, which is vital for viral replication. Once in the cell, it is converted to its active form, Islatravir-triphosphate (ISL-TP).

ISL-TP inhibits the RT enzyme through multiple actions:

Chain Termination and Translocation Inhibition: ISL-TP is incorporated into the growing viral DNA chain and primarily prevents the RT enzyme from moving along the RNA template, immediately stopping DNA synthesis.
Delayed Chain Termination: In some cases, translocation still occurs, but ISL-TP causes structural changes that prevent further nucleotide addition, terminating the chain later.
Misincorporation: ISL-TP can also be mistakenly incorporated, creating faulty DNA primers.

This multi-targeting mechanism distinguishes Islatravir from traditional NRTIs and contributes to its high potency against various HIV strains, including those resistant to other drugs.

The Development Journey: Trials, Holds, and Relaunches

Islatravir's clinical development saw early excitement, particularly for long-acting formulations like a monthly oral pill for PrEP and a yearly implant. However, in December 2021, the FDA placed clinical holds on several Islatravir studies.

The Clinical Hold

The holds were due to observed dose-dependent decreases in total lymphocyte and CD4 T-cell counts in some study participants. CD4 cells are critical for immune function and are targeted by HIV. While significant, these declines were not generally linked to increased infections, but the safety signal warranted investigation. The issue was more pronounced at higher doses intended for less frequent administration. As a result, Merck stopped developing once-monthly oral Islatravir for PrEP.

Relaunch with Lower Doses

Following analysis, Merck announced in September 2022 a restart of the Phase 3 program for Islatravir for HIV treatment using a lower dose. Research indicated a lower daily dose of 0.25 mg resulted in lymphocyte changes comparable to standard regimens. Development shifted to a once-daily oral combination tablet with doravirine. As of July 2025, the FDA has accepted a New Drug Application for the doravirine/islatravir (DOR/ISL) combination, with a decision expected in April 2026. Islatravir is also being studied in a once-weekly combination with lenacapavir.

Islatravir vs. Other Antiretrovirals

Islatravir's properties differentiate it from many existing antiretroviral drugs. The table below compares it with a standard NRTI (Tenofovir) and a common single-tablet regimen (Biktarvy).


Feature	Islatravir	Tenofovir (TDF/TAF)	Biktarvy
Drug Class	NRTTI	NRTI	INSTI + 2 NRTIs
Mechanism	Inhibits RT translocation and acts as an immediate/delayed chain terminator	Acts as a chain terminator	Inhibits integrase enzyme and acts as chain terminators
Primary Use	Investigational for HIV treatment	HIV treatment and PrEP	HIV treatment
Dosing Potential	Once-daily, investigational once-weekly	Once-daily	Once-daily
Key Feature	High potency, long intracellular half-life	Well-established efficacy and safety profile	Complete single-tablet regimen
Developer	Merck	Gilead Sciences	Gilead Sciences
Status	In Phase 3 trials; NDA under review by FDA as of July 2025	Widely approved and used	Widely approved and used

Conclusion: The Future of Islatravir

Islatravir remains a promising, complex investigational drug for HIV treatment. Its novel NRTTI mechanism offers high potency and a strong barrier to resistance. The journey through clinical holds and restarts highlights the rigorous safety evaluations of new medications. While development for long-acting PrEP was discontinued, its future in once-daily or once-weekly treatment regimens is ongoing. The ongoing Phase 3 trials and the FDA's review of the doravirine/islatravir combination will be crucial in determining Islatravir's role in future HIV care.

For more information on Islatravir's clinical development, visit Clinical Info HIV.gov.

Frequently Asked Questions

Islatravir is in a novel drug class called nucleoside reverse transcriptase translocation inhibitors (NRTTIs).

Unlike traditional NRTIs that only terminate the viral DNA chain, Islatravir has a dual mechanism. It primarily inhibits the 'translocation' or movement of the reverse transcriptase enzyme and also acts as a chain terminator.

Islatravir, also known as MK-8591, is developed by Merck.

No, Islatravir is still an investigational drug. However, as of July 2025, the FDA has accepted a New Drug Application for a combination tablet of doravirine and islatravir, with a decision expected in 2026.

The FDA placed a clinical hold on Islatravir studies in December 2021 due to reports of decreases in total lymphocyte and CD4 T-cell counts in some participants, which raised safety concerns.

No, the development of once-monthly oral Islatravir for PrEP has been discontinued due to safety concerns at the higher doses required for long-acting prevention.

Islatravir is currently in late-stage development as part of a once-daily oral regimen with doravirine. It is also being investigated in Phase 3 trials as part of a once-weekly oral regimen with lenacapavir.