Hepatitis C virus (HCV) infection remains a major global health burden, affecting millions worldwide and contributing significantly to hepatocellular carcinoma (HCC) development. The introduction of direct-acting antivirals (DAAs) has revolutionized HCV treatment, achieving high rates of sustained virologic response (SVR) and reducing HCV-associated morbidity and mortality. Despite these advancements, the risk of HCC persists in certain populations, particularly those with pre-treatment cirrhosis or advanced fibrosis (F3). This review examines the impact of DAAs on HCC risk, explores the underlying mechanisms of hepatocarcinogenesis post-HCV eradication, identifies key risk factors, and discusses optimal HCC surveillance strategies.
DAA Impact on HCC: Turning the Tide on Risk Reduction
DAA therapy has significantly reduced the risk of HCC in HCV-infected patients by eliminating viral replication and decreasing hepatic inflammation. Compared to interferon-based therapy, DAAs achieve superior SVR rates and mitigate fibrosis progression. However, early concerns arose regarding increased HCC recurrence rates in patients treated with DAAs. Subsequent large-scale cohort studies confirmed that DAAs are not associated with higher HCC risk than interferon-based therapy and that achieving SVR remains the most critical factor in reducing HCC incidence. Meta-analyses have further reinforced these findings, demonstrating comparable long-term outcomes between DAA and interferon-treated patients.
Decoding the Pathogenesis of HCC after HCV Eradication: Genetic and Epigenetic Alterations
While HCV eradication significantly reduces hepatic inflammation and fibrosis progression, oncogenic pathways activated during chronic infection may persist post-SVR. Genetic mutations, including alterations in the telomerase reverse transcriptase (TERT) gene and disruptions in pathways such as Wnt/β-catenin, p53, and PI3K/Akt/mTOR, contribute to hepatocarcinogenesis. Additionally, HCV-induced epigenetic modifications, including histone acetylation and DNA methylation, may sustain a pro-carcinogenic environment even after viral clearance. Studies indicate that liver transcriptomic profiles in post-SVR patients retain features associated with increased HCC risk, highlighting the need for ongoing surveillance in high-risk groups.
Risk Factors for HCC after HCV Eradication
Despite SVR, HCC risk remains elevated in patients with pre-treatment cirrhosis, bridging fibrosis (F3), or liver stiffness measurements above 10 kPa. Additional risk factors include metabolic disorders such as diabetes mellitus and hepatic steatosis, which exacerbate fibrosis and promote carcinogenesis. Alcohol consumption is an independent risk factor that synergizes with other comorbidities to heighten HCC risk. Moreover, elevated post-treatment alpha-fetoprotein (AFP) levels and advanced age are associated with increased HCC incidence. A personalized risk assessment approach is crucial to identifying patients who may benefit from continued surveillance despite achieving SVR.
HCC Surveillance after SVR
Professional guidelines offer varying recommendations for HCC surveillance post-SVR, particularly for patients with F3 fibrosis. While there is consensus on lifelong semi-annual surveillance for cirrhotic patients, guidelines differ regarding F3 patients. The European Association for the Study of the Liver (EASL) and the Asian Pacific Association for the Study of the Liver (APASL) recommend semi-annual surveillance for F3 patients, whereas the American Association for the Study of Liver Diseases (AASLD) does not. Given the relatively low annual HCC incidence in F3 patients, routine surveillance may not be cost-effective unless additional risk factors are present. A risk-stratified approach integrating non-invasive fibrosis assessments, AFP measurements, and imaging modalities such as ultrasound or MRI can help optimize HCC detection strategies in post-SVR patients.
Conclusions
DAAs have markedly transformed HCV management, significantly reducing but not eliminating HCC risk. While patients with cirrhosis warrant lifelong surveillance, the necessity of routine monitoring in F3 patients remains debated. A tailored, risk-based approach is essential to balance the benefits of early HCC detection with the cost-effectiveness of surveillance. Future research should focus on refining risk prediction models and optimizing individualized surveillance strategies to improve long-term outcomes for HCV-cured patients.
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The study was recently published in the Journal of Clinical and Translational Hepatology .
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study's novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
