Mitochondrial toxicity before and after combination antiretroviral therapy, a Magnetic Resonance Spectroscopy study

Abstract

The aim of this study was to quantify, via Magnetic Resonance Spectroscopy (MRS), the effect of combination antiretroviral therapy (cART) on brain metabolites and characterize any possible associations between changes in metabolites, age, blood biomarkers of neuronal damage, functional connectivity and cognitive performance. As cART has dramatically increased the life expectancy of HIV-infected (HIV + ) individuals and unmasked an increase in HIV-associated neurocognitive disorders, it is still not clear whether cART neurotoxicity contributes to these disorders. We hypothesized a bimodal effect, with early cART treatment of HIV infection decreasing inflammation as measured by MRS metabolites and improving cognitive performance, and chronic exposure to cART contributing to persistence of cognitive impairment via its effect on mitochondrial function. Basal ganglia metabolites, functional connectivity, cognitive scores, as well as plasma levels of neurofilament light chain (NfL) and tau protein were measured before and after 12 weeks, 1 year and 2 years of cART in a cohort of 50 cART-naïve HIV + subjects and 72 age matched HIV- healthy controls. Glutamate (Glu) levels were lower in the cART naïve patients than in healthy controls and were inversely correlated with plasma levels of NfL. There were no other significant metabolite differences between HIV + and uninfected individuals. Treatment improved Glu levels in HIV+, however, no associations were found between Glu, functional connectivity and cognitive performance. Stable brain metabolites and plasma levels of NfL and Tau over two-years of follow-ups suggest there are no signs of cART neurotoxicity in this relatively young cohort of HIV + individuals.