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Neurocognitive Dysfunction With Neuronal Injury in People With HIV on Long-Duration Antiretroviral Therapy
Cynthia McMahan1, Devon K Dietrich1, Elizabeth F Horne1
1From the Section of Infections of the Nervous System (C.M., D.K.D., E.F.H., E.K., K.G., P.S.S.J., A.N., B.R.S.), Office of the Clinical Director (T.W.),, and Translational Neuroradiology Section (D.S.R., G.N.), National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD; University of Pittsburgh School of Medicine (C.M.), PA; Duke University School of Medicine (E.F.H.), Durham, NC; Virginia Commonwealth University School of Medicine (E.K.), Richmond; Department of Neurology (K.G.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; Department of Psychiatry (P.S.S.J.), Washington University School of Medicine, St. Louis, MO; Office of the Clinical Director (L.H., J.S.), National Institute of Mental Health, NIH, Bethesda, MD; San Diego State University/University of California San Diego Joint Doctoral Program in Clinical Psychology (L.H.); Leidos Biomedical Research (U.S.), Frederick, MD; HIV Dynamics and Replication Program (C.-Y.L.), NCI, NIH, Bethesda, Infectious Diseases Clinical Research Program (H.-C.H., A.G., B.K.A.), Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda,; The Henry M. Jackson Foundation for the Advancement of Military Medicine (H.-C.H., A.G., B.K.A.), Bethesda,; Department of Medicine (A.G., B.K.A.), Uniformed Services University, Bethesda, MD; Division of Infectious Diseases (C.B.), Naval Medical Center San Diego, CA; and Department of Psychiatry and the Behavioral Sciences (S.K.), University of Southern California Keck School of Medicine, Los Angeles.
Background And Objectives:
Neurologic outcomes in people with HIV (PWH) on long-duration antiretroviral therapy (ART) are not fully understood, and the underlying pathophysiology is unclear. To address this, we established a cohort of such individuals and compared them with HIV-negative controls using a novel matching technique. Both groups underwent extensive cognitive testing, evaluation for psychiatric measures, and MRI and CSF analyses.
Methods:
Participants underwent comprehensive neuropsychological testing and completed standardized questionnaires measuring depressive symptoms, perceptions of own functioning, and activities of daily living as part of an observational study. Brain MRI and lumbar puncture were optional. Coarsened Exact Matching was used to reduce between-group differences in age and sex, and weighted linear/logistic regression models were used to assess the effect of HIV on outcomes.
Results:
Data were analyzed from 155 PWH on ART for at least 15 years and 100 HIV-negative controls. Compared with controls, PWH scored lower in the domains of attention/working memory (PWH least square mean [LSM] = 50.4 vs controls LSM = 53.1, p = 0.008) and motor function (44.6 vs 47.7, p = 0.009) and a test of information processing speed (symbol search 30.3 vs 32.2, p = 0.003). They were more likely to self-report a higher number of cognitive difficulties in everyday life (p = 0.011). PWH also reported more depressive symptoms, general anxiety, and use of psychiatric medications (all with p < 0.05). PWH had reduced proportions of subcortical gray matter on MRI (β = -0.001, p < 0.001), and CSF showed elevated levels of neurofilament light chain (664 vs 529 pg/mL, p = 0.01) and tumor necrosis factor α (0.229 vs 0.156 ng/mL, p = 0.0008).
Discussion:
PWH, despite effective ART for over a decade, displayed neurocognitive deficits and mood abnormalities. MRI and CSF analyses revealed reduced brain volume and signs of ongoing neuronal injury and neuroinflammation. As the already large proportion of virologically controlled PWH continues to grow, longitudinal studies should be conducted to elucidate the implications of cognitive, psychiatric, MRI, and CSF abnormalities in this group.
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