Serum and CSF biomarkers in asymptomatic patients during primary HIV infection: a randomized study

Abstract

It is debated whether CNS involvement begins during acute human immunodeficiency virus (HIV) infection in persons without meningitis/encephalitis and whether specific antiretroviral drugs or combinations would be beneficial. Neurologically asymptomatic participants enrolled in a randomized and controlled study comparing three combination antiretroviral regimens (tenofovir alafenamide/emtricitabine plus dolutegravir; darunavir; or both) during primary HIV infection were enrolled. Serum and CSF were collected at baseline and at 12 and 48 (serum only) weeks after treatment initiation. Single molecule array was used to measure neurofilament light chain (NFL), total tau protein (Tau), brain-derived neurotrophic factor, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase. We assessed the longitudinal change in biomarkers over time, in addition to the change in the prevalence of serum NFL concentrations above previously published age-adjusted cut-offs (7 pg/ml if 5-18 years, 10 pg/ml if 18-51 years, 15 pg/ml if 51-61 years, 20 pg/ml if 61-70 years and 35 pg/ml if >70 years). Serum was available from 47 participants at all time points, and CSF was available from 13 participants at baseline and 7 at Week 12. We observed a significant direct serum-to-CSF correlation for NFL (ρ = 0.692, P = 0.009), GFAP (ρ = 0.659, P = 0.014) and brain-derived neurotrophic factor (ρ = 0.587, P = 0.045). Serum (ρ = 0.560, P = 0.046) and CSF NFL (ρ = 0.582, P = 0.037) concentrations were directly associated with CSF HIV RNA levels. We observed a significant decrease over time in serum NFL (P = 0.006) and GFAP (P = 0.006) but not in the other biomarkers. No significant difference was observed among the treatment arms. At baseline, serum and CSF age-adjusted NFL levels were above age-adjusted cut-offs in 23 (48.9%) and four participants (30.8%), respectively; considering serum NFL, this proportion was lower at Weeks 12 (31.9%, P = 0.057) and 48 (27.7%, P = 0.13). A relevant proportion of neurologically asymptomatic participants had abnormal CSF and serum NFL levels during primary HIV infection. NFL and GFAP decreased in serum following combination antiretroviral therapy without significant differences among the treatment arms.

Keywords: antiretroviral therapy; cerebrospinal fluid; glial fibrillary acidic protein; neurofilament light chain; neurological injury.

Figure 1

Heat map depicting ρ-values for bivariate correlations among serum (s) and CSF biomarkers at baseline. BDNF = brain-derived neurotrophic factor; GFAP = serum glial fibrillary acidic protein; NFL = neurofilament light chain; UCH-L1 = ubiquitin C-terminal hydrolase.

Figure 2

Serum biomarkers at baseline (BL), Week 12 (W12) and Week 48 (W48) according to the treatment arm and in all participants. (A) NFL; (B) Tau; (C) GFAP; (D) BDNF; and (E) UCH-L1. BDNF = brain-derived neurotrophic factor; GFAP = serum glial fibrillary acidic protein; NFL = neurofilament light chain; UCH-L1 = ubiquitin C-terminal hydrolase. Box plots represent interquartile ranges, while horizontal lines are median values.