Absence of Cerebrospinal Fluid Signs of Neuronal Injury Before and After Immediate Antiretroviral Therapy in Acute HIV Infection

Abstract

Background: It is unknown whether neuronal injury begins during acute human immunodeficiency virus (HIV) infection, and whether immediate initiation of combination antiretroviral therapy (cART) prevents neuronal injury.

Methods: Cerebrospinal fluid (CSF) neurofilament light chain (NFL), a measure of axonal injury, was assessed before and after cART initiation in individuals starting treatment during acute or chronic HIV infection. Nonparametric statistics examined relationships between NFL and disease progression, neuroinflammation, and cognitive performance.

Results: Before treatment, subjects with acute infection had lower CSF NFL levels, with elevations for their age in 1 of 32 subjects with acute infection (3.1%) and 10 of 32 with chronic infection (31%) (P = .006). This persisted after cART initiation, with 1 of 25 acute (4%) and 4 of 9 chronic subjects (44%) showing elevated NFL levels (P = .01). In acute infection, pre-cART NFL levels were inversely correlated with proton magnetic resonance spectroscopic findings of N-acetylaspartate/creatine in frontal gray matter (r = -0.40; P = .03), frontal white matter (r = -0.46; P = .01), and parietal gray matter (r = -0.47; P = .01); correlations persisted after treatment in the frontal white matter (r = -0.51; P = .02) and parietal gray matter (r = -0.46; P = .04).

Conclusions: CSF NFL levels are not elevated in untreated acute HIV infection or after 6 months of immediately initiated cART but are abnormal in chronic HIV infection before and after treatment. In acute HIV infection, CSF NFL levels are inversely associated with neuroimaging markers of neuronal health.

Keywords: HIV/AIDS; antiretroviral therapy; magnetic resonance spectroscopy; neurofilament light chain; neuroinflammation; neurological injury.

Figure 1.

Cerebrospinal fluid (CSF) neurofilament light chain (NFL) levels in acute and chronic human immunodeficiency virus infection cohorts at baseline before treatment (A) and at follow-up time points during treatment (B). Horizontal lines represent medians and interquartile ranges. Abbreviation: cART, combination antiretroviral therapy.

Figure 2.

Cerebrospinal fluid (CSF) neurofilament light chain (NFL) levels in subjects with acute or chronic human immunodeficiency virus infection and controls, stratified by age group. Dotted lines represent age-specific upper limits of normal CSF NFL values for each age stratum; points above dotted lines represent individuals with CSF NFL levels elevated for their respective age group. A, Baseline CSF NFL levels before treatment compared with age-specific upper limit of normal for participants aged <30, 30–39, or 40–59 years; 1 of 32 subjects in the acute and 10 of 32 in the chronic infection group had levels above the upper limit of normal for their age (P = .006). B, Follow-up CSF NFL levels at 24 weeks of treatment in the acutely infected cohort and 48 weeks of treatment in the chronically infected cohort; 1 of 25 subjects in the acute and 4 of 9 in the chronic infection group had levels above the upper limit of normal for their age (P = .01). C, CSF NFL levels in control subjects; 2 of 18 controls had elevations relative to the upper limit of normal for their age. Abbreviation: cART, combination antiretroviral therapy.

Figure 3.

Relationship between cerebrospinal fluid (CSF) neurofilament light chain (NFL) and CSF neopterin at baseline and follow-up time points. A, C, Relationship at baseline (before treatment) in the acute (A) and the chronic (C) human immunodeficiency virus infection cohorts. B, D, Relationship at 24 weeks of treatment in the acute infection cohort (B) and at 48 weeks of treatment in the chronic infection cohort (D). Statistical analysis represents Spearman correlation. Abbreviation: cART, combination antiretroviral therapy.

Figure 4.

Relationship between cerebrospinal fluid (CSF) neurofilament light chain (NFL) and the proton magnetic resonance spectroscopy–derived N-acetylaspartate (NAA)/creatine (Cr) ratio, a marker of neuronal health, in the acute human immunodeficiency virus infection cohort. A–D, Relationship at baseline (before treatment). E–H, Relationship after 24 weeks of treatment in the same subjects. There were no correlations between CSF NFL levels and NAA/Cr ratios after 96 weeks of treatment in the acute infection group, nor were there any in the chronically infected group (both not shown). Statistical analysis represents Spearman correlation. Abbreviation: cART, combination antiretroviral therapy.