# Real-world Prevalence of Nonintegrase INSTI Resistance-Associated Mutations and Virological Outcomes in People Who Have Recently Acquired HIV-1 in the United Kingdom

## TL;DR

This study examines the prevalence of nonintegrase resistance mutations in recently acquired HIV-1 cases in the UK and finds they do not significantly impact virological outcomes.

## Contribution

The study identifies common nonintegrase INSTI resistance mutations in newly diagnosed HIV patients and evaluates their clinical relevance for the first time in a real-world setting.

## Key findings

- Nonintegrase mutations like Env Y61H and A539V were commonly observed but did not affect virological outcomes.
- Accessory INSTI mutations were more frequent in individuals with the Env A539V mutation.
- No significant association was found between nonintegrase mutations and time to viral suppression or blips.

## Abstract

Integrase strand transfer inhibitors (INSTIs) are the mainstay of antiretroviral therapy (ART) globally. Virological breakthrough is uncommon but often manifests as low-level viremia, and only 50% of cases have identified drug resistance mutations in the integrase gene. Nonintegrase mutations in the Gag-nucleocapsid protein (NC), envelope glycoprotein (Env), and 3′ polypurine tract (3′PPT) have been identified in vitro.

Between 2015 and 2021, human immunodeficiency virus type 1 (HIV-1) whole genome sequencing was performed on samples from people with recently acquired HIV-1 in the United Kingdom. Sequences were linked to demographic and clinical data within the UK Health Security Agency's HIV and AIDS Reporting System. The relationship between nonintegrase enzyme mutations and virological outcomes was assessed. Of 1106 participants, 375 (34%) started an INSTI-based regimen. Of these, 337 (90%) were men and 196 (52%) were living with subtype B. The median age was 33 years and number of viral loads within 24 months of starting ART was 4.

Overall, Env Y61H (33 [10%]), A539V (16 [5.0%]), 3′PPT c9053t (17 [5.0%]), and NC N8S (16 [4.8%]) were the most prevalent nonintegrase enzyme mutations. Univariable and multivariable Cox regression did not identify significant associations between the presence of these mutations individually and time to viral suppression, or to viral blip. Interestingly, accessory INSTI mutations were found significantly more frequently in people whose virus also harbored the Env mutation A539V (P = .002).

Several nonintegrase mutations were prevalent, but we found no evidence of an impact upon virological outcomes within treatment-naive individuals on INSTI-based regimens who had recently acquired HIV.

Common transmitted nonenzyme integrase strand transfer inhibitor mutations were not found to affect virological outcomes in isolation. The effect of accumulation of multiple such mutations alone or in combination with enzyme mutations should be the focus of future research.

Graphical abstract