Date of Award

January 2018

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Serena Spudich

Abstract

Neuroinflammation has been implicated as a major contributor to neuronal injury in HIV-associated neurocognitive disorders (HAND). Previous in vitro and animal studies have shown that drugs of abuse can create a pro-inflammatory environment in the CNS that can potentiate HAND; however, clinical research studies are lacking, especially during the early years of HIV infection when therapeutic intervention would likely make the greatest difference in disease progression. A total of 82 male participants with variable drug use history (no drug use: n=17, occasional drug use: n=25, heavy drug use: n= 40) were enrolled within one year of HIV infection and followed longitudinally. All participants were enrolled when antiretroviral therapy (ART)-naïve, and initiated ART during follow up outside of the study. Paired plasma and cerebrospinal fluid (CSF) samples and neuropsychological testing data were collected from participants at baseline, 6 weeks, and every 6 months thereafter for up to four years. Mixed model analyses were conducted to compare the effect of drug use on levels of CSF and plasma neopterin, a marker of macrophage activation, and neuropsychological testing performance. Pre-ART, both plasma and CSF neopterin levels were elevated in the heavy drug use group compared to the no drug use group (plasma: β = +7.1, SE = 2.4, p = 0.003; CSF: β = +7.4, SE = 1.9, p <0.001). The difference in neopterin levels was attenuated post-ART in plasma (β = +3.6, SE = 2.2, p = 0.10), but persisted in CSF (β = +4.4, SE =1.9, p = .019). Neuropsychological assessment showed that participants with heavy drug use had the greatest impairments both pre- and post- ART (pre-ART heavy vs. none: β = -0.32, SE = 1.1, p = .006; post-ART heavy vs. none β = -0.46, SE = 1.2, p <0.001). We conclude that drug use potentiates neuroinflammation in HIV infection and exacerbate neurocognitive impairment in this early HIV infection study.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 06/25/2100

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