Galantamine showed no cognitive benefit in people with HIV-associated neurocognitive disorders.

OBJECTIVE: People with HIV on ART are highly vulnerable to non-AIDS-related comorbidities, including HIV-associated neurocognitive disorders, which are linked to persistently activated monocytes/macrophages. Smoking is a major contributor to HIV-related comorbidities. However, nicotine alone has anti-inflammatory effects, mainly through α7-nicotinic receptor (nAChR) activation. Galantamine (GAL) is an FDA-approved pro-cognitive medication that increases endogenous acetylcholine and also directly potentiates the α7-nAChR. We hypothesized that GAL would improve neurocognition in PWH, both by direct pro-cognitive effects and by reducing inflammation. We also explored whether effects differed by smoking status. DESIGN/METHODS: Smoking and nonsmoking PWH/ART participated in a double-blind, randomized, placebo-controlled crossover study of 12 weeks of GAL treatment. Primary outcomes were composite neurocognitive test score; monocyte CD16, CD163 and CCR2, and CD8 T-cell CD38/HLA-DR; and plasma sCD16, sCD163 and CCL2. Plasma hsCRP and neurofilament light chain (NFL) were also measured. Exploratory analyses included plasma mediators by Luminex and monocyte transcriptome by RNAseq. RESULTS: Neurocognition did not differ between GAL and placebo treatment (adjusted standardized difference (95% CI) -0.02 (-0.2, 0.2); P  = 0.82), with no difference by smoking status ( P  = 0.51). Monocyte CCR2 expression was 15.2% (5, 25.1) greater with GAL than placebo ( P  = 0.006). No differences were seen in monocyte CD16 ( P  = 0.76) or CD163 ( P  = 0.8), CD8 + T-cell CD38/HLA-DR ( P  = 0.54), or plasma sCD163 ( P  = 0.36), sCD14 ( P  = 0.46), or CCL2 ( P  = 0.34). NFL and hsCRP were not different, but several pro-inflammatory cytokines increased with GAL. Only modest effects were seen on monocyte gene expression. CONCLUSIONS: Galantamine for 12 weeks did not improve cognition or reduce inflammation in PWH/ART regardless of smoking status.