Abstract Body

Paroxetine and fluconazole have potent neuroprotective effects in an in vitro model of mitochondrial stress and HIV-protein mediated neural damage.  We studied the safety, tolerability, and efficacy of both paroxetine and fluconazole for the treatment of HIV-associated neurocognitive disorder (HAND).

HIV+ individuals with cognitive impairment were enrolled in a 24 week randomized double-blind, placebo-controlled 2×2 factorial design study.  Participants were randomly assigned to 1 of 4 groups:  1) paroxetine 20mg/day orally, 2) fluconazole 100mg every 12 hours orally, 3) paroxetine 20mg/day and fluconazole 100mg every 12 hours, or 4) placebo.  Safety, tolerability, and efficacy, including neuropsychological testing and cerebrospinal fluid (CSF) lipid markers of oxidative stress, were evaluated.  Change in neuropsychological test performance and oxidative stress markers was modeled using a general linear regression model. 

45 HIV+ individuals were enrolled.  There was no difference in adverse events among the treatment arms.  HIV+ individuals in the paroxetine arms (alone or in combination with fluconazole), compared to the no paroxetine arms (placebo or fluconazole alone) showed a benefit in cognitive performance in the NPZ8 summary measure of 8 neuropsychological tests (NPZ8 mean change = 0.15 vs -0.33, p=0.010), and a computerized test of executive function (Cal Cap sequential mean change = 0.46 vs 0.06, p=0.002), after adjusting for depression symptomatology and baseline NPZ8 in as-treated analyses. There was no difference in change in depression symptomatology or CSF lipid markers of oxidative stress between paroxetine and no-paroxetine arms. HIV+ individuals in the fluconazole arms (alone or in combination with paroxetine) compared to the no fluconazole arms (placebo or paroxetine alone) did not show a benefit in cognitive performance, but fluconazole was associated with a decrease in CSF ceramide 18:0 (p=0.039) after adjustment for baseline ceramide level in intent-to-treat analyses. 

Paroxetine and fluconazole in HIV+ individuals were safe and well tolerated. Paroxetine may be associated with cognitive improvement, even after adjusting for depression symptoms. Fluconazole was associated with a decrease in a lipid marker of oxidative stress.  Studies of additional outcome measures including other CSF markers of oxidative stress and functional neuroimaging are underway to examine specific mechanisms of neuroprotection.