Cerebral metabolite changes prior to and after antiretroviral therapy in primary HIV infection

Abstract

Objective: We examined the longitudinal effects of primary HIV infection (PHI) and responses to early antiretroviral therapy (ART) on the brain using high-field magnetic resonance spectroscopy (MRS).

Methods: Cerebral metabolites were measured longitudinally with 4T proton MRS and assessed for ART effects in participants with PHI. Levels of glutamate (Glu), N-acetylaspartate (NAA), myo-inositol (MI), and choline-containing metabolites (Cho) were measured relative to creatine + phosphocreatine (Cr) in anterior cingulate, basal ganglia, frontal white matter, and parietal gray matter.

Results: Fifty-three participants recruited at median 3.7 months post HIV transmission were followed a median 6.0 months. A total of 23 participants initiated ART during follow-up. Prior to ART, increases per month were observed in Cho/Cr (slope = 0.0012, p = 0.005) and MI/Cr (slope = 0.0041, p = 0.005) in frontal white matter as well as increases in MI/Cr (slope = 0.0041, p < 0.001) and NAA/Cr (slope = 0.0024, p = 0.030) in parietal gray matter. After initiation of ART, prior positive slopes were no longer significantly different from zero, while Glu/Cr in basal ganglia decreased (slope = -0.0038, p = 0.031).

Conclusions: Early in HIV infection, increases of Cho/Cr and MI/Cr in treatment-naive participants suggest progressive inflammation and gliosis in the frontal white matter and parietal gray matter, which is attenuated after initiation of ART. Elevated baseline Glu/Cr in basal ganglia may signal excitotoxicity; its subsequent stabilization and downward trajectory with ART may lend further support for early ART initiation.

Figure 1. Cross-sectional magnetic resonance spectroscopy comparisons

Kruskal-Wallis comparison among cross-sectional groups: HIV-uninfected (HIV−), primary HIV infection (PHI), and chronic HIV infection (CHI) in frontal white matter (FWM), parietal gray matter (PGM), basal ganglia (BG), and anterior cingulate (AC). Kruskal-Wallis post-test results are not adjusted for multiple comparisons. Box and whiskers plot with whiskers at 10th–90th percentile.

Figure 2. Longitudinal cerebral metabolite ratios and results of linear mixed model analysis

Left column displays cerebral metabolite measurements in relationship to date of infection for all participants with primary HIV infection (PHI) and the right column displays measurements centered on date of antiretroviral therapy (ART) initiation for 23 ART participants. (A) Choline/creatine ART-naive slopes increase in the frontal white matter. ART-initiated slope is not significantly different from zero. A similar pattern was seen in myo-inositol/creatine in the frontal white matter (B) and parietal gray matter (C). (D) N-acetylaspartate/creatine ART-naive slope increases in the parietal gray matter; ART-initiated slope is not significantly different from zero. (E) Glutamate/creatine ART-naive slope is not significantly different from zero in the basal ganglia. However, ART-initiated slope is significantly negative. For all graphs, red circles represent ART-naive measurements, black lines ART-naive slope, green squares post-ART measurements, and blue lines connect participants' metabolite ratios longitudinally. Gray lines represent ART-initiated slope beginning at 6.4 months (median time of ART initiation) in the left column and begin at 0.0 months in the right column.