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Neurosymptomatic Cerebrospinal Fluid Escape Is a Central Nervous System–Focused Form of Antiretroviral Therapy Treatment Failure

Year: 2025

Type: article

Abstract: Background During antiretroviral therapy, 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 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 with 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) undergoing antiretroviral therapy who met definitions of NSE and systemic treatment failure, and we defined them as having NSE high (NSE-h). Results While plasma viral loads were higher during NSE-h than NSE, the conditions have many shared features, including elevated CSF:plasma viral load ratios, higher 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 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. This suggests that people presenting with neurologic symptoms and treatment failure may be experiencing CNS-focused treatment failure that could require specialized treatment.

Source: Open Forum Infectious Diseases

DOI: 10.1093/ofid/ofaf659