Galantamine for 12 weeks does not improve neurocognition or immune activation in ART-suppressed people with HIV

Area of Science:

• Neuroscience
• Immunology
• Infectious Diseases

Background:

• People with HIV (PWH) on antiretroviral therapy (ART) experience high rates of non-AIDS-related comorbidities, including HIV-associated neurocognitive disorders.
• Persistent monocyte/macrophage activation contributes to neuroinflammation and cognitive impairment in PWH.
• Smoking exacerbates comorbidities in PWH, yet nicotine exhibits anti-inflammatory properties via alpha7-nicotinic acetylcholine receptor (α7-nAChR) activation.

Purpose of the Study:

• To investigate the efficacy of galantamine (GAL), an α7-nAChR potentiator, in improving neurocognition and reducing inflammation in PWH/ART.
• To explore whether GAL's effects differ between smokers and nonsmokers.
• To assess GAL's impact on monocyte and T-cell activation markers and plasma inflammatory mediators.

Main Methods:

• A 12-week, double-blind, randomized, placebo-controlled crossover study involving smoking and nonsmoking PWH/ART.
• Primary outcomes included composite neurocognitive scores, monocyte and CD8 T-cell activation markers (e.g., CD16, CD163, CCR2, CD38, HLA-DR), and plasma biomarkers (e.g., sCD163, CCL2).
• Exploratory analyses utilized Luminex assays for plasma mediators and RNAseq for monocyte transcriptome.

Main Results:

• Galantamine treatment did not significantly improve composite neurocognitive test scores compared to placebo (p=0.82), with no difference observed based on smoking status (p=0.51).
• Monocyte CCR2 expression was significantly increased with GAL (p=0.006), but other immune markers (monocyte CD16, CD163; CD8 T-cell CD38/HLA-DR) and plasma biomarkers (sCD163, CCL2) showed no significant changes.
• Plasma neurofilament light chain (NFL) and high-sensitivity C-reactive protein (hsCRP) remained unchanged; however, several pro-inflammatory cytokines increased with GAL treatment, and monocyte gene expression showed only modest effects.

Conclusions:

• Twelve weeks of galantamine treatment failed to demonstrate cognitive or anti-inflammatory benefits in people with HIV on ART.
• The study findings indicate that GAL is not an effective intervention for HIV-associated neurocognitive disorders or systemic inflammation in this population.
• Smoking status did not alter the lack of efficacy of galantamine in improving neurocognition or reducing inflammation in PWH/ART.