The role of the central nervous system as a sanctuary site for HIV due to limited penetration of antiretroviral drugs

Introduction. HIV-associated neurocognitive disorders appear to remain common despite access to antiretroviral therapy (ART). Penetration of ART into the central nervous system (CNS) is highly variable between drugs and between individuals. Cerebrospinal fluid (CSF) concentrations of many antiretroviral medications fall below the minimum inhibitory concentration for wild type virus. HIV-1 RNA can be detected in the CSF at greater levels than in plasma (CSF/plasma discordance), however the clinical significance of this is unclear, and the degree of difference considered pathological varies. Whether the CNS can act as a sanctuary site leading to persistent HIV detection in plasma is not known. Methods. The PARTITION study recruited HIV positive adults from 13 UK clinical sites. Paired CSF and plasma was collected from patients undergoing LP for clinical indication (group A) and subjects with unexplained viraemia despite ART (group B). The study aimed to determine a) the prevalence of CSF/plasma discordance and factors associated with this occurrence, and b) the prevalence of HIV-1 RNA detection in CSF in those with HIV-1 RNA persistence in plasma. A sensitive assay detected HIV-1 RNA below 50 copies/ml in a subgroup and a cytometric bead array determined CSF biomarkers. A matrix of clinical features and CSF/plasma biomarkers was related to cognitive decline in subjects from the CHARTER study. Drug concentrations in CSF and plasma were measured by mass spectrometry assays and related to host genetic factors in subjects in the PARTITION study and a Vietnamese cohort with tuberculous meningitis. Results. CSF/plasma HIV discordance occurred in 13% of this cohort and was associated with nadir, but not current, CD4 cell count. CSF/plasma discordance occurred in 7 of 40 (18%) of subjects with ongoing viral detection in plasma vs. 0 of 39 of those without. Residual HIV-1 RNA detection below 50 copies/ml was also associated with CSF HIV-1 RNA detection. Resistance associated HIV mutations were detected in CSF of subjects with CSF/plasma discordance. CSF/plasma discordance above 0.5log10 was associated with raised profiles of inflammatory CSF proteomic biomarkers compared to those without discordance. In the CHARTER cohort, cognitive decline over 18 months was associated with lower concentrations of CSF TNFa and plasma IGF1/2. CSF concentrations of efavirenz were associated with the CYP2B6 c.516G>T single nucleotide polymorphism. Efavirenz metabolites were mainly glucuronidated in CSF, were present at neurotoxic levels, and were related to degree of blood brain barrier permeability. Host genetic factors were did not relate to CSF DRV concentrations. Conclusions. CSF/plasma discordance is a frequent occurrence, likely related to processes established during advanced immunosuppression not fully reversed by ART. It is associated with CSF HIV resistance and raised CSF biomarkers, even at levels 0.5-1log10 which have been considered non-significant in some studies. Potentially neurotoxic CSF concentrations of efavirenz relate to host genetic factors