Novel Dolutegravir and Lenacapavir Resistance Patterns in Human Immunodeficiency Virus Type 2 Infection: A Case Report.

Background: The treatment management of human immunodeficiency virus (HIV)-2 infection presents greater challenges compared to HIV-1 infection, primarily because of inherent resistance against non-nucleoside reverse transcriptase inhibitors. Integrase strand transfer inhibitors, particularly dolutegravir, have improved treatment outcomes for people with HIV-2. Lenacapavir, a novel and potent antiretroviral capsid inhibitor, offers additional therapeutic options. However, limited knowledge exists regarding HIV-2 resistance against dolutegravir and lenacapavir.

Methods: We report the case of a treatment-experienced individual who did not achieve virological suppression with regimens containing dolutegravir and lenacapavir. Clinical monitoring, genotypic and phenotypic resistance assays, and in silico structural modeling were performed.

Results: Lenacapavir was added to a failing regimen of boosted darunavir, twice daily dolutegravir, and 2 nucleoside reverse transcriptase inhibitors. Initially, this addition led to a decline in the viral load and increase in CD4+ T-cell count, despite the identification of a previously unreported combination of integrase resistance mutations. However, virological suppression was not achieved and viral load, although reduced, resumed increasing. This rebound was associated with the development of an N73D capsid substitution in HIV-2, which conferred resistance against lenacapavir. Based on cell-based assays predicting hypersusceptibility to bictegravir, the regimen was adjusted to oral lenacapavir plus bictegravir/emtricitabine/tenofovir alafenamide, resulting in a resumption in viral load decline.

Conclusions: Although lenacapavir demonstrated therapeutic potential, our case underscores the critical need to combine it with other fully active antiretroviral agents to prevent the rapid emergence of resistance and achieve long-term virological control in treatment-experienced individuals with HIV-2.