Islatravir: evaluation of clinical development for HIV and HBV

ABSTRACT

Introduction

Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that inhibits HIV RT through multiple mechanisms. Contrary to all approved NtRTIs, islatravir retains a 3’OH group. In vitro and clinical data show that ISL is an ultrapotent investigational drug with high tolerability.

Areas covered

The historical development of islatravir and its mechanisms of HIV and HBV inhibition and resistance are covered. Additionally, the outcomes of Phase I and Phase II clinical trials are discussed.

Expert opinion

Current first-line antiretroviral therapy, preexposure, and postexposure prophylactic interventions are highly effective in maintaining low or undetectable viral load. Despite these measures, an unusually high rate of new infections every year warrants developing novel antivirals that can suppress drug-resistant HIV and improve compliance. ISL, an NRTTI once deemed a long-acting drug, was placed on a clinical hold. The outcome of ongoing clinical trials with a reduced ISL dose will decide its future clinical application. Additionally, MK-8527, which inhibits HIV via same mechanism as that of ISL may supersede ISL. Data on ISL inhibition of HBV are scarce, and preclinical data show dramatically lower ISL efficacy against HBV than currently preferred nucleos(t)ide drugs, indicating that ISL may not be a potent anti-HBV drug.

KEYWORDS:

• HIV
• HBV
• islatravir
• clinical trials
• resistance
• natural polymorphism
• long-acting
• NtRTI

Article highlights

• Islatravir (ISL) is an ultrapotent antiviral with good tolerability. ISL was developed by a series of modifications with structure-guided design involving HIV-1 reverse transcriptase (HIV-1 RT) in complex with DNA and dNTPs. Despite the availability of combination antiretroviral therapies (cARTs) that can improve life expectancy of an HIV-infected patient to be similar to uninfected individuals, complementary resistance profiles are still needed.

• ISL inhibits HIV-1 RT by multiple mechanisms including defects in the translocation of RT along the template-primer. Biochemical characterization, early molecular modeling, and subsequent structure determination provided the detailed mechanism of ISL inhibition of HIV.

• The emergence of resistance mutations identified through in vitro assays and their prevalence as natural polymorphisms as well as transmitted drug resistance remains a concern for widespread use of ISL. However, a complementary profile with doravirine may result in a two-drug regimen, although more robust clinical trials are needed.

• It is likely that ISL may not be an anti-HBV drug for two reasons: (a) the antiviral activity of ISL against HBV is lower than approved nucleos(t)ide analogs (NAs), and (b) (II) the group who developed ISL as a potent anti-HIV compound has also developed compounds with better efficacy against HBV than ISL.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. CLL is co-founder and Chief Scientific Officer of Shift Pharmaceuticals, Overland Park, KS, USA. KS is chief scientific officer for Sanctum Therapeutics Corporation, Sunnyvale, CA.

Acknowledgement

K. Singh acknowledges the computation facilities of the Molecular Interactions Core at the University of Missouri, Columbia, MO 65211. We also thank numerous laboratories that have enormously contributed to HIV research, but we could not cite their work.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

K Singh was partially funded by the Bond Life Sciences Center (Early Concept grant), and the University of Missouri startup support.