Hepatitis C virus (HCV) infection remains a major contributor to the global burden of liver disease, driving the progression from chronic hepatitis to cirrhosis and, ultimately, hepatocellular carcinoma (HCC) [
1]. Although the advent of direct-acting antivirals (DAAs) enabled high rates of sustained virologic response (SVR), long-term outcomes after SVR continue to raise clinical concerns [
2]. This is particularly relevant for individuals with pre-existing hepatic fibrosis or cirrhosis, who continue to exhibit an increased risk of HCC and other liver-related complications [
3-
5]. Persistent immune dysregulation within the hepatic microenvironment, which is characterized by low-grade inflammation and aberrant immune cell activation, is thought to underlie this residual risk. Recent studies have demonstrated that levels of soluble immune mediators (SIMs), which reflect systemic inflammatory activity, often remain altered for prolonged periods following SVR [
6]. However, comprehensive data on the long-term trajectories and clinical significance of alterations in SIMs remain limited, particularly in the context of liver cirrhosis. Understanding the temporal dynamics of SIMs following SVR in relation to underlying liver pathology is essential for refining long-term patient management.
The study by Witte et al. provides timely and robust insights into how SIM levels are changed in patients with chronic HCV infection who achieved SVR following DAA treatment [
7]. Profiling SIMs in 102 patients with and without cirrhosis at treatment initiation, end-of-treatment, and longterm follow-up (median 96 weeks), the authors demonstrated that cirrhosis is associated with a distinct and more persistent inflammatory signature. At baseline, they observed significant alterations in SIM levels in both cirrhotic and non-cirrhotic patients compared to healthy controls, but individuals with cirrhosis exhibited a greater number and magnitude of changes. Several inflammatory mediators, including CXCL10, IL-8, hepatocyte growth factor (HGF), CASP-8, PD-L1, and IL-18R, were elevated, uniquely dysregulated in the cirrhotic cohort. Although longitudinal anal-yses revealed a general decline in inflammatory markers following SVR, persistent immune alterations remained evident at the long-term follow-up, particularly among patients with cirrhosis. Compared to non-cirrhotic individuals, patients with cirrhosis exhibited more pronounced and sustained immune dysregulation following antiviral therapy, with a greater number of inflammatory mediators remaining altered.
SIM profiling provides a valuable perspective on systemic inflammation, which is closely influenced by the cellular activity of the immune system. Chronic HCV infection is known to induce long-lasting alterations in both innate and adaptive immune compartments. Importantly, previous studies demonstrated that many of these immune perturbations fail to fully resolve even after DAA-induced viral clearance [
8]. A recent study reported an elevated frequency of activated regulatory T cells (Tregs) in peripheral blood during chronic HCV infection, and the expansion was sustained following SVR. The expanded Treg population acquired inflammatory features at the phenotypic and transcriptomic levels, which were maintained even after successful viral elimination by DAA treatment [
9]. Comprehensive interpretation of post-SVR SIM profiles requires detailed insights into sustained immune alterations that may perpetuate or amplify inflammatory signaling despite viral clearance.
Emerging evidence indicates that the persistent immune alterations observed after HCV clearance may stem, at least in part, from sustained epigenetic modifications. Recent studies have demonstrated that prolonged viral exposure induces epigenetic reprogramming in hepatic and immune cell subsets, effectively locking them into altered states that persist beyond SVR [
9-
11]. These modifications may play a role in the maintenance of pro-inflammatory signaling, fibrogenic activity, and establishment of a prooncogenic hepatic milieu. Thus, the concept of a viral cure must be reframed to encompass both the elimination of viral RNA and the resolution of virus-induced cellular reprogramming in the immune system, particularly at the epigenetic level.
Crucially, the study by Witte et al. linked these persistent alterations to liver stiffness and HCC development. Patients who had sustained high elastography values (≥14 kPa) exhibited minimal normalization of SIMs, whereas those with improvements in liver stiffness demonstrated partial restoration of the inflammatory milieu. Correlation analyses revealed that the levels of many SIMs were positively associated with liver stiffness, implicating structural hepatic damage in the persistence of immune activation. To further assess the clinical relevance, the authors examined SIM profiles in relation to HCC occurrence. Cirrhotic patients who subsequently developed HCC exhibited consistently elevated levels of IL-6, IL-8, HGF, and urokinasetype plasminogen activator (uPA). A composite score based on these mediators effectively stratified patients by HCC risk, suggesting the potential for prognostic biomarker development. The persistence of inflammatory SIMs, particularly those associated with oncogenic pathways, may help explain the residual risk of HCC and other complications despite viral eradication. These findings reinforce the value of SIM profiling for risk stratification and underscore the importance of continued surveillance in patients with chronic HCV infection following DAA-induced SVR.
Taken together, Witte et al.’s findings demonstrate a close relationship between persistent systemic inflammation and liver cirrhosis even after successful viral eradication, emphasizing early antiviral intervention to prevent irreversible immunological imprinting and structural liver damage. Integrating SIM profiling with elastography and additional clinical parameters may improve risk stratification and inform long-term surveillance strategies. Future research should aim to elucidate the mechanisms through which persistent inflammation, cirrhosis, and oncogenesis converge, particularly in patients with chronic HCV infection and incomplete immunological recovery following SVR. A clearer understanding of these intersecting pathways may facilitate the development of targeted therapies and predictive biomarkers, ultimately improving long-term outcomes in patients with chronic HCV infection who achieved SVR following DAA treatment.
FOOTNOTES
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Authors’ contributions
All authors reviewed the literature and drafted the manuscript.
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Acknowledgements
This work was supported by the Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (RS-2024-00439160); a grant (RS-2025-02213409) from Ministry of Food and Drug Safety; and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (RS-2024-00512914).
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Conflicts of Interest
The authors have no conflicts of interest to report.
Figure 1.In patients with chronic HCV infection, the immune system is altered, and various soluble inflammatory mediators (SIMs) increased (A). After achieving SVR by DAA treatment, these immune alterations are not completely normalized, and upregulation of SIMs persists (B). Persistently increased SIM levels are more prominent in patients with cirrhosis and HCC (C). Further studies are needed to evaluate SIMs as potential biomarkers and to elucidate the mechanisms by which persistent immune alterations and SIM upregulation contribute to the development of cirrhosis and HCC in patients with chronic HCV infection who achieved SVR following DAA treatment. HCV, Hepatitis C virus; SVR, Sustained virologic response; DAA, Direct-acting antiviral; HCC, Hepatocellular carcinoma.
Abbreviations
Sustained virologic response
Urokinase-type plasminogen activator
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