Differential Impact of Interferon-Based and Direct-Acting Antiviral Therapies on Bone Metabolism in Chronic Hepatitis C: Insights from Transcriptomic and Clinical Analyses.

Abstract

Chronic hepatitis C (CHC) is a risk factor for hepatic osteodystrophy, increasing osteoporosis and fracture risks. While historical pegylated interferon/ribavirin (PEG-IFN/RBV) showed variable bone effects, the newer direct-acting antivirals' (DAAs) impact is less clear. This study compared these antiviral strategies' effects on bone metabolism in CHC patients through two separate analyses. First, we conducted a retrospective analysis of a prospectively collected observational cohort (n = 73) to assess longitudinal bone mineral density (BMD) and bone turnover marker (BTM) changes following PEG-IFN/RBV or DAA therapies. Second, to explore mechanisms, we analyzed two independent, publicly available peripheral blood mononuclear cell (PBMC) transcriptomic cohorts from CHC patients treated with PEG-IFN/RBV (GSE7123, n = 69) or an IFN-free DAA regimen (GSE51699, n = 8). Clinically, PEG-IFN/RBV induced a temporary lumbar spine BMD increase, then a post-treatment decline, and modulated BTMs. DAAs showed minimal BMD/BTM effects. PBMC transcriptomics revealed PEG-IFN/RBV responders showed downregulation of osteoclast precursor (OCP)-related gene sets and concurrent upregulation of osteoblast-related gene sets. DAAs had a minimal impact on these PBMC pathways. These findings demonstrate distinct effects of PEG-IFN/RBV and DAA therapies. PEG-IFN/RBV significantly modulates PBMC gene expression related to bone remodeling, potentially contributing to the complex clinical BMD changes, while DAAs appear largely bone-neutral. This highlights treatment-specific osteoporosis risk and surveillance needs in CHC survivors.