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Evaluating Associations Between Cumulative Use of Chronic Liver Injury-Inducing Antiretroviral Therapy and Hepatocellular Carcinoma, By Chronic Liver Disease Status
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JAIDS June 26, 2026.
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Despite the benefits of antiretroviral therapy (ART), antiretrovirals may be associated with drug toxicity and adverse effects. People with HIV (PWH) can develop liver enzyme elevations following ART initiation,1 and prolonged exposure to hepatotoxic ART could lead to chronic liver injury and promote hepatic fibrosis.2,3 Dideoxynucleoside analogues have been associated with mitochondrial dysfunction and chronic hepatic changes such as noncirrhotic portal hypertension.4,5 Protease inhibitors might contribute to chronic liver injury though production and accumulation of toxic intermediates via cytochrome P450 pathways.6 The chronic hepatic changes that develop due to exposure to these drug classes may increase risk of hepatocellular carcinoma (HCC).7
Background:
Prolonged exposure to hepatotoxic antiretroviral therapy (ART) could lead to chronic liver injury, which might increase risk of hepatocellular carcinoma (HCC). We used causal inference methods to evaluate if cumulative exposure to ART with known mechanisms of chronic liver injury is associated with HCC among people with HIV (PWH), by chronic liver disease (CLD) status.
Methods:
We conducted a cohort study of antiretroviral-naïve PWH with and without diagnosed CLD who initiated ART in the Veterans Affairs (VA) between 1999-2023. Exposure to ART with known mechanism of chronic liver injury (mitochondrial toxicity or accumulation of toxic intermediates) was determined monthly via prescription fills. Incident HCC was identified by VA National Cancer Registry and/or recorded diagnoses. Marginal structural models estimated odds ratios (ORs) with 95% confidence intervals (CIs) of HCC associated with cumulative exposure to chronic liver injury-inducing ART compared to ART without chronic liver injury mechanisms, by CLD status.
Results:
Among 11,854 PWH without CLD and 6,771 PWH with CLD, we observed 112 and 378 HCC events, respectively. Among PWH without CLD, ≥4 years of exposure to chronic liver injury-inducing ART was associated with HCC when compared to ≥4 years of use of ART without chronic liver injury mechanisms (OR=4.02 [95% CI, 1.00-16.24]). Among PWH with CLD, ≥4 years of exposure to chronic liver injury-inducing ART was not associated with HCC (OR=1.36; 95% CI, 0.68-2.72).
Conclusion:
Four or more years of ART with a chronic liver injury mechanism was associated with HCC among PWH without CLD, but not those with CLD.
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