Antiviral therapy and the risk of extrahepatic malignancies in chronic hepatitis C: insights from recent evidence

For years, the battle against hepatitis C virus (HCV) has rightly focused on its well-known consequences: liver damage and hepatocellular carcinoma (HCC) (1-3). But a growing body of evidence suggests the virus’s reach is longer than we thought. Extrahepatic manifestations of HCV are important. HCV is also associated with extrahepatic malignancies, as extrahepatic manifestations (4-7). A meta-analysis revealed a 1.94-fold increased risk of developing lung cancer in patients with chronic HCV infection (5). The prevalence of HCV infection was higher in patients with B-cell non-Hodgkin lymphoma (NHL) (8,9). Although inverse associations were observed with prostate cancer, extrahepatic malignancies occur as frequently as HCC (10,11). Thus, despite the previous research gaps, it has been reported that the growing evidence linking HCV with several malignancies.

We would like to congratulate Tao et al. for their recent publication in Cancer Epidemiol Biomarkers Prev, which provides important findings demonstrating that antiviral treatments against HCV reduce the risk of the developing lung cancer and that sustained virologic response (SVR) achieved by antiviral treatments is protective against the development of NHL among patients with chronic HCV infection (12). This commentary explores the clinical implications of these findings and discusses the potential mechanisms that may explain this protective effect of antiviral treatments against HCV.

Tao et al. analyzed data on 17,417 patients with HCV from four United States (U.S.) health systems and investigated the effects of HCV treatment on the incidence of four common extrahepatic cancers—lung cancer, NHL, breast cancer, and prostate cancer—using a novel time-dependent that incorporated time-varying propensity score weighting (12). They reported the incidence of 146 lung cancer, 75 NHL, 89 invasive breast cancer and 124 prostate cancer patients during the follow-up period for the primary incidence of these cancers (12).

Multivariate analysis of incident lung cancer among patients with chronic HCV infection showed that both interferon (IFN)/direct-acting agent (DAA)-treatment failure (TF) [hazard ratio (HR), 0.34; 95% confidence interval (CI): 0.21–0.55; P<0.0001] and IFN/DAA-SVR (HR, 0.35; 95% CI: 0.24–0.52; P<0.0001) compared to no treatment, but there were no significant differences between the two groups (P=0.8754) (12). Thus, antiviral treatment for HCV independently reduced lung cancer risk, irrespective of SVR. This is a fascinating clue. It suggests that the act of treating HCV, even if it does not completely eradicate it, might lower inflammation or other cancer-causing processes enough to protect the lungs.

Multivariate analysis of incident of NHL among patients with chronic HCV infection showed that, compared with no treatment, IFN/DAA-TF (HR, 0.89; 95% CI: 0.54–1.48; P=0.6595) and IFN/DAA-SVR (HR, 0.42; 95% CI: 0.21–0.84; P=0.0140), whereas the IFN/DAA-SVR group had a lower risk of NHL than the IFN/DAA-TF (HR, 0.47; 95% CI: 0.23–0.96; P=0.0388) (12). Thus, SVR achieved through antiviral treatment for HCV independently reduced NHL risk. This makes biological sense. NHL is a malignancy of the immune cells, and it seems that HCV should be completely eradicated from the body to stop it from driving those cells to become malignant.

Multivariate analysis for the risk of incident of breast cancer among female patients with chronic HCV infection revealed cirrhosis (yes vs. no) (HR, 2.63; 95% CI: 1.54–4.50; P=0.0004). There was no antiviral treatment effect on the risk of breast cancer (12). Multivariate analysis for the risk of incident prostate cancer among male patients with chronic HCV infection revealed age (≥60 vs. <60 years) (HR, 2.70; 95% CI: 1.66–4.41; P<0.0001). Moreover, antiviral treatment was not associated with prostate cancer risk (12). It was reported that after antiviral therapy for chronic HCV infection, women seem to have a greater preventive effect against pancreatic, colorectal and lung cancer than men (13). It is possible that the risk factors for breast cancer or those for prostate cancer may be so much stronger that the roles of HCV are negligible.

It has been reported that (I) Compared with hepatocytes, lymphocytes are less efficiently infected by HCV (14-16). (II) HCV protein is associated with anti-apoptosis activity (17). (III) HCV infection enhances metabolic changes (18,19) and androgen receptor signaling (20). (IV) HCV infection induces immunological changes (21,22). (V) HCV infection activates oncogenes, and induces endoplasmic reticulum stress, resulting in carcinogenesis in organs other than the liver (17,23-25). These factors are believed to be associated with extrahepatic malignancies.

Immune checkpoint inhibitors (ICIs) have greatly improved outcomes of patients with several different type of advanced cancers (26,27), and immune-related adverse event increased the overall survivals with certain malignancies treated with ICIs (28). The p53 is one of the frequently mutated gene in human malignancies, and drugs targeting p53 mutations have been approved with U.S. Food and Drug Administration (FDA) and investigated in clinical trials (29,30). RAS (KRAS, NRAS and HRAS) is also one of the frequently mutated gene family in cancer, and the direct RAS inhibitors inhibit RAS-activating pathways or RAS effector pathways, resulting in the improvement of RAS-driven cancers (31). Thus, recent evidence suggests that immunological changes and oncogene activation are deeply involved in oncogenesis.

Although the long-term prognosis remains unclear (Figure 1), after antiviral treatment for chronic HCV infection, screening for extrahepatic malignancy and HCC occurrence is better for older patients (32), resulting in a better prognosis. Clinicians would consider cancer risk reduction as an additional benefit of antiviral therapy. In near future, these findings also may influence screening strategies. From the perspective of public health, widespread antiviral treatment programs could reduce the long-term cancer burden.

Figure 1 Risk of HCC and extrahepatic malignancy before and after DAA against HCV treatment in patients with chronic HCV infection. This figure is original of authors (11-13,25,32,33). (+), positive; (−), negative. DAA, direct-acting agent; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NHL, non-Hodgkin lymphoma; SVR, sustained virologic response.

There are several limitations in their observational study (12). Prospective studies are needed. Potential residual confounding, differences between IFN-based and DAA-based treatments, and racial differences may also exist. Tao et al. did not appear to include patients with HCV and current malignancies (12). Recently, it was reported that DAA treatment could improve overall survival among patients with HCC or other malignancies (11,33).

Long-term follow-up studies evaluating cancer risk after SVR will be needed. Research for the mechanisms linking HCV infection and extrahepatic cancers should be performed. Further studies assessing the effect of antiviral therapy on other malignancy should also be needed.

In conclusion, early antiviral treatment should be performed in patients with HCV infection, and further research into the extrahepatic benefits of HCV eradication is also encouraged.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0381/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0381/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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