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Immediate Antiretroviral Therapy Mitigates the Development of Neuronal Injury in Acute HIV
Michael J. Peluso, Victor Valcour, Jintanat Ananworanich, Pasiri Sithinamsuwan, Thep Chalermchai, Nitiya Chomchey, Bonnie Slike, Magnus Gisslen, Henrik Zetterberg, Serena Spudich, on behalf of the RV/SEARCH 010 and 011 Study Teams Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States, Memory and Aging Center, University of California San Francisco, San Francisco, CA, United States, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, SEARCH, The Thai Red Cross AIDS Research Center, Bangkok, Thailand, Phramongkutklao Hospital, Bangkok, Thailand, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States, University of Gothenburg, Gothenburg, Sweden, Yale University School of Medicine, New Haven, CT, United States
Background: Neurofilament light chain (NFL) in cerebrospinal fluid (CSF) is a sensitive marker of axonal injury that is elevated in neurodegenerative disorders, HIV-associated dementia, and some neuroasymptomatic subjects during the early and late stages of HIV infection. We sought to determine whether axonal injury can be detected acutely after HIV transmission, and if initiation of combination antiretroviral therapy (cART) during acute HIV is associated with lower levels of CSF NFL compared to cART initiated during chronic HIV. Methodology: Acute (n=32) and chronic (n=33) HIV infected Thai subjects naive to cART underwent blood and CSF sampling, followed by immediate cART initiation. CSF was then sampled at 24 (n=26) and 96 weeks (n= 15) in the acute and at 48 weeks (n=10) in the chronic subjects. HIV RNA levels and soluble immune biomarkers were measured in CSF and blood at each visit. CSF NFL was analyzed using a highly sensitive, two-site enzymatic quantitative immunoassay with a lower limit of detection of 50 ng/L. Cross-sectional analyses employed the Mann-Whitney test and Spearman correlations; paired analyses were used to compare subjects across time points. Results: At baseline (median 18 days post infection in acute subjects), median CD4 T cell count was 401 and 228 cells/uL in the acute and chronic groups, respectively (p<0.0001). Baseline CSF NFL was lower in acute than in chronic subjects (median, 234 versus 327 ng/L; p=0.003), and only 1/32 (3.1%) acute subjects had NFL above the upper limit of normal for age, compared to 10/33 (30.3%) chronic subjects. Baseline CSF NFL did not correlate with blood or CSF HIV RNA or soluble immune biomarkers in acute subjects, and modestly correlated only with the macrophage activation marker CSF neopterin in chronic subjects (r=0.35, p=0.049). In acute subjects, there was no change in NFL from baseline values to 24 and 96 weeks after cART. After at least 6 months of sustained cART (24 weeks duration of cART in acute cases and 48 weeks duration of cART in chronic cases), the acute group had a lower median CSF NFL than chronic subjects (216 vs 490 ng/L; p=0.015), and only 1/26 (3.9%) of acute subjects had CSF NFL above the upper limit of normal for age, compared to 5/10 (50%) in the chronic group. Conclusions: Neuronal injury as measured by CSF NFL was not detected during very acute HIV infection. Immediate initiation of cART may mitigate development of neuronal injury, which may be more difficult to reverse during later stages of infection.