Novel non-invasive markers for monitoring hepatic steatosis, liver fibrosis, and mortality risk in people with HCV and HIV: exploring the impact of antiviral therapy and metabolic transitions

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Background. In the era of curative antivirals for hepatitis C virus (HCV) and potent antiretroviral therapy (ART) for human immunodeficiency virus (HIV), liver disease remains a leading cause of morbidity and mortality for people with HCV, HIV, and especially those living with both viruses. Much of this residual burden now arises from metabolic dysfunction–associated steatotic liver disease (MASLD), the most common liver condition worldwide. MASLD progresses silently and is poorly captured by sporadic, biopsy-based assessment. People with HCV, HIV, or both are often underserved, facing barriers to timely diagnosis and ongoing liver care. To address these gaps, we applied an integrated, non-invasive framework combining established markers, FibroScan® (liver stiffness measurement [LSM] for fibrosis and controlled attenuation parameter [CAP] for hepatic steatosis [HS]) and the fibrosis-4 (FIB-4) index, alongside exploratory biomarkers of injury and systemic stress (cytokeratin 18 [CK18] and fibroblast growth factor 23 [FGF23]). Objectives. This thesis aims to improve liver care through non-invasive detection, on-treatment monitoring, and long-term risk stratification in people with HCV and/or HIV by: (1) defining the burden and trajectory of HS and fibrosis following HCV cure; (2) evaluating hepatic safety of switching to integrase inhibitors-based ART in people with HIV and MASLD; (3) determining the prognostic value of FGF23 in people with HIV/HCV co-infection. Methods. Three complementary studies were conducted among a total of 460 individuals with HCV and/or HIV. First, a longitudinal cohort of 108 individuals with HCV who achieved sustained virologic response (SVR) following direct-acting antiviral therapy was evaluated for HS and fibrosis using CAP and LSM at baseline and 24 weeks post-SVR. Second, a 24-month, randomized controlled trial enrolled 31 adults with HIV and HS to compare continued ART not containing integrase inhibitors versus a switch to raltegravir. Changes in CAP, CK18, LSM, and FIB-4 were evaluated to assess hepatic safety. Third, a prospective study of 321 participants with HIV/HCV co-infection in the Canadian Co-infection Cohort (mean follow-up 8.4 years) examined the prognostic value of FGF23, with fibrosis staged using FIB-4 and mortality risk assessed through Cox regression and causal mediation analysis.Results. In the longitudinal study, follow-up after HCV cure revealed a distinct divergence: liver fibrosis improved significantly, whereas HS worsened, consistent with metabolic “unmasking” following viral eradication. This pattern, driven by higher body mass index and rising lipids, underscores the importance of continued post-SVR surveillance using simple, repeatable non-invasive tests. Among individuals with HIV and HS, switching to a raltegravir-based regimen was hepatically safe, leading to improvements in liver enzymes and stability of the metabolic profile. These findings support the use of non-invasive monitoring to guide ART optimization. In the third study, elevated circulating FGF23 levels in individuals with HIV/HCV co-infection identified those at markedly higher risk of mortality. Although part of this excess risk was mediated through liver fibrosis, the majority was independent, underscoring the prognostic value of FGF23 beyond conventional fibrosis staging. Conclusions. These studies show that scalable, non-invasive tools can enhance liver care to track post-cure and on-treatment dynamics, complemented by biomarkers for long-term risk. This integrated approach could guide more personalized follow-up and support early identification of patients at increased risk. Overall, the findings advance a precision model of liver health in underserved populations, replacing episodic biopsies with longitudinal, patient-friendly measurements to enable earlier intervention and better outcome.

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