Herpes simplex virus and drug resistance-comprehensive update on resistance mutations and implications for clinical...

Antiviral drug resistance in herpes simplex virus 1 and 2 (HSV-1 and 2) is a significant clinical challenge, particularly in immunocompromised patients. Drug susceptibility testing (DST) aids clinical management and can be conducted through genotypic (partial genome sequencing) or phenotypic (cell culture) methods. Both have inherent limitations: genotypic DST is limited by outdated datasets lacking information on new helicase-primase inhibitors and corresponding phenotypic data as well as sparse clinical correlations. Phenotypic DST is mainly hampered by a lack of standardization and timely results.

This study aims to compile an up-to-date and comprehensive HSV drug resistance dataset encompassing all reported drug resistance-associated mutations (DRMs), polymorphisms, and viral phenotypes. This study also aims to aggregate clinical conditions with available DST data.

A PubMed search identified studies (January 2016-September 2024) on DRMs associated with resistance to aciclovir, penciclovir, brivudine, foscarnet, cidofovir, amenamevir, and pritelivir. Data from a previous HSV resistance dataset (pre-2016) were also included.

In this review, we summarize novel mutations in the thymidine kinase, polymerase, and helicase-primase genes of HSV conferring resistance to antiviral drugs. Clinical information was available for 513 mutations. In 90% of these (461 cases), viral phenotype and clinical assessment were congruent. However, 10% of cases not responding to antiviral therapy showed phenotypically susceptible virus isolates. We present a framework for clinical and diagnostic management of cases with drug-resistant HSV infection.

This dataset paves the way to harmonize reporting of DRMs for diagnostic labs and to accelerate genotypic DST interpretation through aggregated data. Ongoing large-scale data collection of genotypic, phenotypic, and clinical data is crucial for evidence-based management of HSV antiviral resistance and clinical guidelines.