Postmortem Analysis of Dolutegravir, Tenofovir, Lamivudine, and Efavirenz Penetration in Multiple Central Nervous System Compartments

Abstract

Abstract Background Central nervous system (CNS) compartmentalization provides opportunity for human immunodeficiency virus (HIV) persistence and resistance development. Differences between cerebrospinal fluid (CSF) and cerebral matter regarding HIV persistence are well described. However, CSF is often used as surrogate for CNS drug exposure, and knowledge from solid brain tissue is rare. Methods Dolutegravir, tenofovir, lamivudine, and efavirenz concentrations were measured across 13 CNS regions plus plasma in samples collected during autopsy in 49 Ugandan decedents. Median time from death to autopsy was 8 hours (interquartile range, 5–15 hours). To evaluate postmortem redistribution, a time course study was performed in a mouse model. Results Regions with the highest penetration ratios were choroid plexus/arachnoid (dolutegravir and tenofovir), CSF (lamivudine), and cervical spinal cord/meninges (efavirenz); the lowest were corpus callosum (dolutegravir and tenofovir), frontal lobe (lamivudine), and parietal lobe (efavirenz). On average, brain concentrations were 84%, 87%, and 76% of CSF for dolutegravir, tenofovir, and lamivudine, respectively. Postmortem redistribution was observed in the mouse model, with tenofovir and lamivudine concentration increased by 350% and efavirenz concentration decreased by 24% at 24 hours postmortem. Conclusions Analysis of postmortem tissue provides a unique opportunity to investigate CNS antiretroviral penetration. Regional differences were observed paving the way to identify mechanisms of viral compartmentalization and/or neurotoxicity.