We sincerely appreciate the insightful comments regarding our study on the impact of metabolic dysfunction on fibrosis regression following direct-acting antiviral (DAA) therapy in patients with chronic hepatitis C (CHC) [1]. The editorial highlights critical issues in understanding fibrosis regression in the context of viral eradication and metabolic dysfunction [2]. We would like to take the opportunity to address the major points raised and provide additional context for our findings.

We acknowledge the concerns regarding the interpretation of fibrosis regression based on non-invasive tests (NITs), such as the Fibrosis-4 index and liver stiffness measurement (LSM) using vibration-controlled transient elastography. Rapid changes in these tests after DAA therapy might reflect a decrease in necroinflammation, rather than true fibrosis regression [3,4]. Nevertheless, we believe our study adds to the evidence that metabolic dysfunction, particularly type 2 diabetes mellitus (T2D) and hypercholesterolemia, negatively affects the likelihood of fibrosis regression after DAA treatment, independent of achieving a sustained virologic response (SVR). Persistent metabolic risks prolong the fibrotic burden, despite hepatitis C virus eradication, emphasizing the requirement for precise patient monitoring beyond SVR. Although this improvement is often attributed to reduced necroinflammation, rather than to true fibrosis regression, our findings indicate that serum-based biomarkers and LSM changes reflect fibrosis regression more sensitively in the early post-SVR period. The differences between histological and NIT-based fibrosis regression measurements highlight the need for further research to elucidate their distinct implications for liver health.

An important point was raised regarding dynamic changes in steatotic liver disease (SLD) post-SVR. We noticed that more patients were diagnosed with SLD after SVR, possibly because of the changes in metabolism following viral clearance. The mechanisms explaining this phenomenon remain incompletely understood, but may involve alterations in lipid metabolism and insulin sensitivity post-SVR. A previous study showed that DAA therapy leads to increased total cholesterol and low-density lipoprotein (LDL) cholesterol levels [5]. Similar findings were reported with various DAA combinations, showing increased insulin resistance, serum total cholesterol levels, and LDL cholesterol levels during treatment [6]. Furthermore, our findings suggest that patients with pre-existing metabolic risk factors are more likely to have persistent fibrosis, presenting the interplay between metabolic dysfunction and liver fibrosis in the DAA era.

Our study also examined long-term liver-related outcomes, including hepatic decompensation and the incidence of hepatocellular carcinoma (HCC), following DAA therapy. We observed that patients with T2D and hypercholesterolemia presented an increased risk of adverse liver-related outcomes, despite achieving SVR, supporting previous studies that demonstrated a link between metabolic dysfunction and liver disease progression [7,8]. While some studies have suggested that metabolic dysfunction does not play a dominant role in hepatic decompensation after SVR, the association between cardiometabolic risk factors and HCC development remains evident [9,10]. Given these findings, further research is needed to clarify the specific pathways through which metabolic dysfunction contributes to the risk of liver disease progression in patients with CHC. Additionally, investigating whether targeted interventions, such as lipid-lowering or insulin-sensitizing therapies, could reduce this risk is essential. Future studies should also incorporate generalized patient populations and use advanced imaging and biomarker analyses for risk prediction models and the optimization of post-SVR management strategies.

Although fibrosis regression is a key indicator of liver disease, identifying other metabolic risk factors that contribute to adverse liver-related outcomes is equally important. Lifestyle modifications, including dietary changes, weight management, and increased physical activity, should be emphasized as part of post-DAA care. Another critical aspect that warrants further investigation is the potential effect of genetic predisposition on post-SVR fibrosis regression. Genetic polymorphisms related to lipid metabolism, insulin resistance, and inflammatory pathways may influence the variability observed in fibrosis outcomes among different patient populations [11]. Understanding these genetic factors may facilitate the development of personalized therapeutic approaches that enhance fibrosis regression.

Future studies should focus on distinguishing true fibrotic regression from reduced inflammation. Longitudinal data incorporating histological confirmation or magnetic resonance elastography may provide a more precise assessment of fibrosis dynamics. Further research should explore whether targeted metabolic interventions, such as lipid-lowering or insulin-sensitizing therapies, can enhance fibrosis regression in this high-risk population.

We appreciate the opportunity to discuss our findings further in response to the editorial comments. Our study highlights the impact of metabolic dysfunction on liver fibrosis regression after SVR and the requirement for comprehensive metabolic management in this patient population. By integrating metabolic interventions, personalized medicine approaches, and long-term monitoring, we optimized outcomes and improved the overall prognosis of patients with CHC after DAA therapy. We hope that our research contributes to a broader discussion on optimizing post-DAA care to improve long-term liver health.