The global health landscape has been significantly impacted by the hepatitis C virus (HCV), a condition that contributes to liver cancer development. Direct-acting antivirals (DAAs) have transformed treatment protocols, achieving high success rates in viral elimination and reducing associated health complications. However, despite these advancements, the risk of liver cancer persists, particularly among those with pre-existing liver damage. This article explores how DAAs influence the risk of hepatocellular carcinoma (HCC), delves into the underlying biological processes after HCV eradication, identifies critical risk factors, and outlines effective surveillance strategies.

Hepatocellular carcinoma remains a significant concern even after successful HCV treatment. Although DAAs effectively eliminate the virus, genetic and epigenetic alterations initiated during chronic infection may continue post-treatment. Key risk factors include pre-treatment cirrhosis, metabolic disorders, and alcohol consumption. Furthermore, personalized surveillance approaches are crucial for managing HCC risks in patients who achieve sustained virologic response (SVR).

Evaluating the Impact of DAAs on HCC Risk

Direct-acting antivirals have proven highly effective in diminishing the incidence of liver cancer by halting viral replication and alleviating liver inflammation. Compared to traditional interferon-based therapies, DAAs offer superior outcomes in terms of sustained virologic response and fibrosis stabilization. Despite initial concerns about increased recurrence rates, extensive research confirms that DAAs do not elevate HCC risks compared to interferon treatments. Achieving SVR remains the most influential factor in reducing cancer incidence, as supported by meta-analyses demonstrating comparable long-term benefits between DAA and interferon-treated individuals.

While DAAs have revolutionized HCV management, their impact on HCC risk reduction is multifaceted. By eliminating active viral replication, these medications reduce hepatic inflammation, a key driver of carcinogenesis. Large-scale cohort studies further validate the safety profile of DAAs, showing no heightened HCC risk when compared to interferon-based regimens. Moreover, the effectiveness of DAAs in stabilizing or reversing fibrosis progression underscores their pivotal role in mitigating long-term liver damage. Meta-analytical evidence reinforces the notion that achieving SVR is paramount in minimizing HCC incidence, aligning with broader clinical observations. Consequently, the adoption of DAAs represents a significant advancement in managing HCV-related malignancies, offering improved patient outcomes and enhanced quality of life.

Understanding Mechanisms and Managing Risks Post-Eradication

Even after successful HCV eradication, certain oncogenic pathways activated during chronic infection may persist. Genetic mutations, such as alterations in the telomerase reverse transcriptase gene and disruptions in critical signaling pathways, contribute to liver cancer development. Epigenetic modifications induced by HCV can also maintain a carcinogenic environment post-treatment. These persistent changes necessitate ongoing monitoring, particularly in high-risk groups, highlighting the importance of continued surveillance.

Post-SVR, several mechanisms sustain the risk of hepatocellular carcinoma. Genetic mutations identified in genes like TERT and pathways including Wnt/β-catenin, p53, and PI3K/Akt/mTOR play crucial roles in carcinogenesis. Additionally, epigenetic modifications such as histone acetylation and DNA methylation may perpetuate a pro-carcinogenic state even after viral clearance. Studies reveal that post-SVR patients exhibit liver transcriptomic profiles indicative of elevated HCC risk, emphasizing the need for vigilant surveillance in vulnerable populations. Beyond genetic and epigenetic factors, various clinical indicators heighten HCC susceptibility. Pre-treatment cirrhosis, bridging fibrosis, metabolic disorders, and alcohol consumption represent significant risk factors. Personalized risk assessment becomes imperative in identifying candidates for continued surveillance despite achieving SVR. Professional guidelines vary in their recommendations for HCC surveillance post-SVR, particularly concerning F3 fibrosis patients. While lifelong semi-annual surveillance is universally recommended for cirrhotic patients, consensus on F3 patients remains elusive. Integrating non-invasive fibrosis assessments, alpha-fetoprotein measurements, and imaging techniques such as ultrasound or MRI offers an optimized approach to detecting HCC early in post-SVR patients. A tailored, risk-stratified strategy balances the advantages of early detection with cost-effectiveness, ensuring optimal long-term outcomes for HCV-cured individuals.