Longitudinal profiling of blood-tissue HIV-1 reservoirs reveals the mechanism of failure to long-acting cabotegravir / rilpivirine

This case illustrates that virological failure on long acting cabotegravir/rilpivirine can occur despite optimal eligibility, correct injection timing and adequate drug exposure. Longitudinal analyses showed that an archived NNRTI-resistant variant was already present years before long-acting therapy, highlighting the potential value of proviral DNA genotyping in both patient selection and the stratification of individual failure risk. This archived clone likely reflects either transmitted resistance or selection during prior rilpivirine exposure. Using provirus-aware bioinformatic tools also proved essential to filter out mutations supported by reads showing hallmarks of defective genomes, thereby improving clinical interpretability. Finally, this case underscores the practical benefit of prospective biobanking of PBMCs or buffy coat, which can enable retrospective resistance profiling when clinical decisions depend on it and may support a more personalized and preventive approach to long acting therapy.