Neurosymptomatic CSF escape is a CNS-focused form of ART treatment failure

Background

While on antiretroviral therapy (ART), people with HIV-1 (PWH) occasionally present with new symptoms and signs of central nervous system (CNS) injury accompanied by higher HIV-1 RNA levels in cerebrospinal fluid (CSF) than in blood, a condition defined as neurosymptomatic HIV CSF escape (NSE). PWH meeting these general criteria but with plasma HIV-1 RNA levels > 500 copies/ml have typically been assumed to be experiencing systemic treatment failure without special consideration for HIV-1 dynamics in the CNS. Thus, people experiencing CNS-focused treatment failure may receive suboptimal treatment, targeted at controlling replication in the periphery, not the CNS.

Methods

We genetically and phenotypically characterized HIV-1 RNA in the CSF and blood of PWH (N = 9) on ART who met definitions of both NSE and systemic treatment failure and defined them as having NSE high (NSE-h).

Results

While plasma viral loads were higher during NSE-h than during NSE, the conditions have many shared features including elevated CSF:plasma viral load ratios, elevated CSF white blood cell counts and drug-resistant, T-tropic HIV-1 replicating in the CNS. During NSE-h, HIV-1 populations in blood and CSF were genetically equilibrated, indicating that they were not independently replicating in both compartments.

Conclusions

Both NSE and NSE-h are driven by replication of drug-resistant HIV-1 in CD4+ T cells in the CNS with NSE-h having higher CSF viral loads reflecting more HIV-1 replication in the CNS. This suggests that people presenting with neurologic symptoms and treatment failure may be experiencing CNS-focused treatment failure that could require specialized treatment.