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

Abstract

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. This may be due to previously uncontrolled HIV viral replication, immune activation maintained by residual viral replication or activation from other sources, or cART-associated neurotoxicity. The aim of this study was to determine the effect of cART on cognition and neuroimaging biomarkers in PWH before and after initiation of cART compared with that in HIV-negative controls (HCs) and HIV elite controllers (ECs) who remain untreated.

Methods: We recruited 3 groups of participants from the University of Rochester, McGovern Medical School, and SUNY Upstate Medical University: (1) ART treatment-naive PWH; (2) age-matched HCs; and (3) ECs. Participants underwent brain MRI and clinical and neuropsychological assessments at baseline, 1 year, and 2 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 HCs, and 10 ECs. At baseline, PWH had worse cognition and lower cortical volumes than HCs. Cognition improved after 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, ECs had worse cognition, lower cortical thickness, and lower FD in all 4 lobes and caudate than PWH and HCs. Greater cortical thickness, hippocampal volumes, and FD of frontal, temporal, and occipital lobes were associated with better cognition longitudinally.

Discussion: Initiation of cART in PWH is associated with improvement in brain structure and cognition. However, significant differences persist over time when compared with HCs. Similar trends in ECs 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.

Figure 1. Temporal Trends of Cognitive Performance in PWH and HCs in the Large Cohort

Plotted are mean ± SE of total cognitive scores at each time, stratified by HIV status. For PWH, difference between baseline (BSL) (N = 47) and 12 weeks (N = 39) is statistically significant (p < 0.01), but 12 weeks to year 1 (Y1) (N = 33), 12 weeks to year 2 (Y2) (N = 26), and year 1 to year 2 is not statistically significant. For HCs, difference between BSL (N = 58) and Y1 (N = 49) and BSL and Y2 (N = 42) is statistically significant at p < 0.01, whereas difference from Y1 to Y2 is statistically significant at p < 0.05. HC = HIV-negative control; PWH = people with HIV.

Figure 2. Temporal Trends of Cortical Thickness in PWH and HCs in the Large Cohort

Statistical maps showing significant differences between PWH and HCs at baseline (A); 1-year (B); and 2-year (C) follow-up. Greater areas of cortical thinning in PWH are observed in the primary motor cortex and temporal lobe over time. Note warmer colors (yellow and red) indicate lower cortical thickness measurements in the HCs, whereas cooler colors (blue) represent lower cortical thickness measurements in PWH. HC = HIV-negative control; PWH = people with HIV.

Figure 3. Temporal Evolution of MRI Metrics at in PWH and HCs in the Large Cohort

The mean cortical thickness estimates in the left (A) and right (B) postcentral gyrus; the mean volume (percentage of intracranial volume) in the caudate nucleus (C), and hippocampus (D); the mean FD in the caudate nucleus (E) and parietal lobe (F). Error bars indicate the SEM. FD = fractal dimensionality; HC = HIV-negative control; PWH = people with HIV.

Figure 4. Temporal Trends of Cognitive Performance in PWH, HCs, and ECs in the Small Cohort

Plotted are mean ± SE of total cognitive scores at each time, stratified by group status. EC = HIV elite controller; HC = HIV-negative control; PWH = people with HIV.

Figure 5. Temporal Evolution of MRI Metrics in PWH, HCs, and ECs in the Small Cohort

The mean cortical thickness estimates in the left (A) and right (B) postcentral gyrus; the mean volume (percentage of intracranial volume) in the caudate nucleus (C), and hippocampus (D); the mean fractal dimensionality in the caudate nucleus (E), hippocampus (F), frontal lobe (G), parietal lobe (H), temporal lobe (I), and occipital lobe (J). Error bars indicate the SEM. EC = HIV elite controller; HC = HIV-negative control; PWH = people with HIV.