Longitudinal Effects of Combination Antiretroviral Therapy on Cognition and Neuroimaging Biomarkers in Treatment-Naïve People with HIV

Background and Objectives: While combination antiretroviral therapy (cART) has dramatically increased the life expectancy of people with HIV (PWH), nearly 50% develop HIV-associated neurocognitive disorders (HAND) 1 . This may be due to previously uncontrolled HIV viral replication, immune activation maintained by residual viral replication 2 or activation from other sources 3, 4 , or cART-associated neurotoxicity 5 . The aim of this study was to determine the effect of cART on cognition and neuroimaging biomarkers markers in people with HIV (PWH) before and after initiation of cART compared to HIV negative controls (HC) and HIV elite controllers (EC) who remain untreated. Methods: We recruited three groups of participants from the University of Rochester, McGovern Medical School and SUNY Upstate Medical University: 1) ART-treatment-naïve PWH; 2) age-matched HC; and 3) EC. Participants underwent brain MRI and clinical and neuropsychological assessments at baseline, one year, and two years. PWH were also assessed 12 weeks after initiating cART. Volumetric analysis and fractal dimensionality (FD) were calculated for cortical and subcortical regions. Mixed effect regressions examined the effect of group and imaging variables on cognition. Results: We enrolled 47 PWH, 58 HC, and 10 EC. At baseline, PWH had worse cognition and lower cortical volumes than HC. Cognition improved following initiation of cART and remained stable over time. Greater cortical thickness was associated with better cognition at baseline; greater FD of parietal, temporal and occipital lobes was associated with better cognition at baseline and longitudinally. At baseline, EC had worse cognition, lower cortical thickness and lower FD in all four lobes and caudate than PWH and HC. Greater cortical thickness, hippocampal volumes and FD of frontal, temporal and occipital lobes were associated with better cognition longitudinally. Conclusions: Initiation of cART in PWH is associated with improvement in brain structure and cognition. However, significant differences persist over time compared to HC. Similar trends in EC suggest that results are due to HIV infection rather than treatment. Stronger associations between cognition and FD suggest this imaging metric may be a more sensitive marker of neuronal injury than cortical thickness and volumetric measures.