Circulating interferon-gamma levels predict liver injury in People with HIV

Background: People with HIV (PWH) are more likely to have maladaptive coping behaviors including alcohol misuse, and liver disease is a leading cause of mortality in PWH. Persistent immune activation, including elevated interferon gamma (IFN-g) has been associated with inflammation and alcohol-associated liver injury. In the New Orleans Alcohol Use and HIV Study, individuals with moderate to severe alcohol use disorder (Alcohol Use Disorder Identification Test (AUDIT) >15) have significantly higher plasma IFN-g levels. Therefore, we hypothesized that IFN-g would independently predict markers of liver injury in PWH. Methods: The present analyses use cross-sectional data from the New Orleans Alcohol Use and HIV study. Adjusted multiple linear regression models were performed in R studio to evaluate whether plasma cytokines predicted markers of liver injury, including AST/ALT ratio and Fibrosis-4 (FIB-4) Index. Analyses were stratified by biologically relevant setpoints (phosphatidyl ethanol (PEth) >250 ng/mL and AST/ALT >1.5, respectively). Models were adjusted for age, gender, race (when applicable), and viral loads. Plasma cytokines, AST/ALT ratio, and FIB-4 index were log-transformed due to non-normal distributions. All models met standard regression assumptions. Results: Among PWH with recent heavy alcohol use (PEth >250 ng/mL; n=57), IFN-g significantly predicted AST/ALT ratio (β=0.06, p=0.003), and the model explained 31% of the variance (adjusted R 2 =0.31). In individuals with evidence of hepatocellular injury (AST/ALT >1.5; n=71), IFN-g also significantly predicted FIB-4 Index (β=0.06, p=0.04), with the model explaining 42% of variance (adjusted R 2 =0.42). Other cytokines tested (IL-10, IL-17A, IL-2, IL-1b) did not significantly predict AST/ALT ratio or FIB-4, highlighting specificity of the association of IFN-g levels to predict markers of liver injury. Conclusions: Higher IFN-g levels were associated with clinically relevant increases in liver injury markers in PWH, supporting its role as a potential immunologic driver and biomarker of alcohol-associated liver disease in this population. Supported by CARC & T32 (P60-AA009803, T32-AA007577). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.