Virological failure after switch to long-acting cabotegravir and rilpivirine injectable therapy: an in-depth analysis

BACKGROUND: Long-acting (LA) injectable therapy with cabotegravir (CAB) and rilpivirine (RPV) is currently used as maintenance treatment for HIV-1, and has a low risk for virological failure (VF). Although the risk is low, the circumstances and impact of VF in the real-world setting merits further evaluation.

METHODS: We performed an in-depth clinical, virological and pharmacokinetic analysis on the reasons behind, and the impact of VF during LA CAB/RPV therapy in five cases from the Netherlands. Genotypic resistance testing was performed after the occurrence of VF and drug plasma (trough) concentrations were measured after VF was established and on any other samples to assess on-treatment drug levels. CAB and RPV drug levels that were below the first quartile of the population cut-off (<Q1) were considered to be low.

RESULTS: Five cases who were eligible for LA CAB/RPV experienced VF despite a low predicted risk at baseline. Genotypic resistance testing revealed extensive selection of non-nucleoside reverse transcriptase inhibitor associated mutations in all, and integrase strand transfer inhibitor mutations in four cases. All cases displayed low drug levels of either CAB, RPV or both during the treatment course, likely contributing to the occurrence of VF. In three cases, we were able to identify the potential mechanisms behind these low drug levels.

CONCLUSIONS: This is the first in-depth multiple case analysis of VF on LA CAB/RPV therapy in a real-world setting. Our observations stress the need to be aware for (evolving) risk factors and the yield of a comprehensive clinical, virological and pharmacokinetic approach in case of failure.