Polygenic risk score and risk of drug-induced liver injury after initiating antiretroviral therapy in people living with HIV

Résumé fourni par la source

Drug-induced liver injury affects some people living with HIV (PWH) during antiretroviral therapy (ART). We examined associations of polygenic risk scores (PRS) with liver injury during ART. We derived PRS using summary statistics from the Veterans Affairs Million Veteran Program (MVP) and the Penn Medicine BioBank (PMBB). We constructed PRS for individuals of African (AFR) and European (EUR) ancestry in 3,619 treatment-naïve participants from ART-naive studies of the Advancing Clinical Therapeutics Globally (ACTG) network. Liver injury was defined as incident grade 3 or greater alanine aminotransferase (ALT) within 48 weeks. Associations were evaluated by multivariable regression models. Clinical variables associated with higher baseline ALT values included hepatitis B or C virus infection, increasing BMI and age, and male sex. In analyses of liver injury among 1,897 EUR participants (28 cases, 1869 controls) and 1722 AFR participants (21 cases, 1701 controls), HBV was associated with liver injury in both EUR and AFR participants, and HCV in EUR participants (p < 0.001 for each). PRSALT was not independently associated with incident liver injury in either EUR or AFR participants. No association was observed between baseline PRSALT and subsequent liver injury following initiation of ART. Some people living with HIV (PWH) experience liver injury after starting antiretroviral therapy (ART). Liver injury causes liver enzymes in the blood to increase. Differences in liver enzyme levels between people may be inherited. We hypothesized that an individual’s genetic underpinnings may identify who is at most risk for liver injury after starting ART. We tested whether a polygenic risk score, for alanine aminotransferase (ALT) and metabolic dysfunction-associated steatotic liver disease (MASLD), which is a way to classify each person’s cumulative genetic risk for a condition, identified who is more likely to have liver injury after starting ART. We generated polygenic scores for ALT from the Penn Medicine BioBank and MASLD from the VA Million Veteran Program, and then tested these on past participants from large, randomized ART clinical trials. We found that polygenic scores of ALT and MASLD did not help to identify who was more likely to develop liver injury.

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