Baseline Neurofilament Light Chain and Neurocognitive Disorders in Patients With HIV: A Systematic Review and Meta-analysis
Alejandra Gutierrez1, Erick Barrientos-Ventura2, Mael Ayala-Alban3, Leonarp Ghiamaroj Ordinola Llontop1, sebastian Vargas Bayona1, Christoper A. Alarcon Ruiz4, Monica Diaz5
1Facultad de Ciencias de la Salud, Universidad Cesar Vallejo, 2Facultad de Ciencias de la Salud, Universidad San Ignacio de Loyola, 3School of medicine, Universidad Nacional de Piura (UNP), 4Instituto Nacional de Ciencias Neurológicas, 5University of North Carolina at Chapel Hill
Objective:
To evaluate the association between baseline levels of neurofilament light chain (NfL), measured in cerebrospinal fluid (CSF) or plasma, and HIV-associated neurocognitive disorders (HAND) among people living with HIV (PWH) in the combination antiretroviral therapy (cART) era.
Background:
HAND remains one of the most relevant HIV-related neurological complications despite viral suppression with cART. NfL, a structural protein released in response to axonal injury and a marker of neuronal degeneration, has emerged as a potential sensitive biomarker of neurocognitive disorders.
Design/Methods:
We conducted a systematic review and meta-analysis, searching five databases through September 15, 2025. Inclusion criteria were observational studies of PWH that measured NfL in CSF or plasma, using ELISA or Simoa assays and assessed cognitive status with any validated cognitive screening tool or neuropsychological testing. The primary outcome was the mean difference (MD) in log10 NfL levels between participants with and without HAND, calculated using a random-effects model. PROSPERO ID: CRD420251131664.
Results:
Of the 354 articles initially identified, 13 observational studies, comprising 2 case-control and 11 cross-sectional designs, were included for final extraction. Ten studies reported significantly higher both NfL plasma and CSF levels in the HAND group with very high heterogeneity among HAND definition and NfL assays. While, one study found significantly modest levels (difference of 0.05), and other two reported no significant difference. Of these, only three studies provided analyzable CSF log10 NfL data for meta-analysis (HAND n=190; non-HAND n=122). The pooled MD was 0.08 (95% CI, -3.29 to 3.46) and substantial heterogeneity (I² = 97%).
Conclusions:
Baseline CSF NfL may be a relevant biomarker of neurocognitive disorder in PWH. However, evidence from observational studies is inconsistent and limited by substantial between-study heterogeneity. Standardization of cognitive assessment in PWH, HAND definition, and NfL assays, alongside adequately powered longitudinal cohorts, are required to establish prognostic validity and clinical utility.
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