Anti-HCV treatment and risk for extrahepatic cancers: evidence of benefits with questions remaining

Hepatitis C virus (HCV) infection impacts tens of millions of people worldwide, remaining a substantial global public health burden. Chronic HCV infection, without effective control, leads to a high incidence of hepatocellular carcinoma (HCC) (1). In addition, epidemiologic associations with non-Hodgkin lymphoma (NHL) and certain solid tumors have been reported in individuals infected with HCV. In the last few decades, remarkable advances have been made in anti-HCV therapies. Between 2014 and 2023, an estimated 13.8 million people living with HCV were treated globally, with the vast majority (12.7 million) receiving highly effective direct-acting antiviral (DAA) therapies, of which 11.1 million utilized sofosbuvir-based regimens, representing approximately 21% of the global viremic population (2). Either oral DAAs or interferon (IFN)-based treatments can fundamentally alter the natural history of chronic HCV, achieving sustained virologic response (SVR) rates that typically exceed 95% (1). While HCC risk drops significantly after SVR, the impact of anti-HCV treatments on long-term extrahepatic malignancies remains poorly defined. However, this information is both clinically and policy relevant, as it would inform the need for potential surveillance strategies.

In a recent study, Tao et al. (3) evaluated the incidence of extrahepatic cancers (including lung cancer, NHL, breast cancer, and prostate cancer) associated with HCV antiviral therapy in a large diverse cohort drawn from four U.S. health systems. They followed 17,485 adults with HCV until cancer diagnosis, death, or last follow-up, identifying 408 incident cancers across up to 15 years. Methodologically, time-varying covariates (including cirrhosis, diabetes, body mass index, and smoking status for lung cancer), and propensity score-based inverse probability of treatment weighting (IPTW) were applied to reduce biases in the treatment selection. Furthermore, the authors modeled discrete time-to-event outcomes using generalized estimating equations (GEEs) with a multinomial link and treated death as a competing risk. Results show that antiviral therapy was associated with significantly lower risk of lung cancer in both SVR-achieving and treatment failure groups compared with no treatment. In contrast, NHL risk reduction was observed only in the SVR group (adjusted hazard ratio: 0.42), whereas treatment failure was not associated with lower NHL risk. No significant associations were observed for breast or prostate cancer incidence (Figure 1). Beyond the conclusions in this study, further considerations are needed.

Figure 1 Risk for extrahepatic cancers in patients treated for chronic HCV infection. The figure summarizes findings from an observational cohort study by Tao et al., reporting distinct effects of anti-HCV treatment by DAAs and/or IFN-based therapies on the subsequent incidence of different extrahepatic cancers. Important conclusions and remaining open questions are discussed in this commentary. The figure was generated using BioRender. DAA, direct-acting antiviral; HCV, hepatitis C virus; IFN, interferon.

The NHL stands as the most biologically relevant extrahepatic cancer type for HCV. Chronic HCV has been known as causally related to B-cell NHL, supporting the concept that viral eradication could reverse key lymphomagenic processes (4). As reported in this study, the “SVR-only” NHL risk reduction in HCV patients can be intuitively consistent with the pathomechanisms. This finding also aligns with prior observational evidence linking SVR to reduced hematologic malignancies (5). Notably, this study combined IFN and DAA effects due to no significant differences observed between therapeutic approaches. However, other cohorts have reported differences between IFN- and DAA-based therapies in relation to hematologic malignancy risk (5-7), suggesting that the limitations of this study in interaction testing and NHL cohort size might compromise the therapeutic differences.

Another remarkable result in this study is the reduced lung cancer risk in both the SVR and treatment failure groups compared with no treatment. Such a finding raises a fundamental question: why does lung cancer risk reduction persist even without achieving viral cure? Tao et al. pointed out evidence that antiviral therapy is associated with improvements in immunologic markers and downregulation of immune checkpoint molecules. Hence, a significant limitation in generalizing the findings from this study to contemporary clinical practice is the high proportion of patients receiving IFN-based regimens (19% IFN vs. 29% DAA vs. 51% no therapy in this study). Owing to potent immunomodulatory properties and enhancement of host tumor surveillance (8), IFN-based regimens may disproportionately account for the observed risk reduction in lung cancer and NHL during the study’s extended post-therapy observational period. However, this study combined therapeutic effects and therefore was unable to assess the effectiveness of DAA on extrahepatic cancer risk. Notably, the authors explicitly acknowledge the absence of lag-time sensitivity analyses to exclude reverse causation due to limited case counts. In addition, patients who receive antiviral therapy may be systematically different from those who remain untreated, reflecting higher levels of health care engagement, treatment tolerance, or lung cancer screening behaviors. Collectively, the study suggests that residual confounding, selection bias or healthcare engagement bias may influence lung cancer risks to some extent, rather than a direct biological effect of HCV or antiviral therapies.

In hormone-driven malignancies (breast cancer in women and prostate cancer in men), no significant associations were revealed between antiviral treatment status. For breast cancer, one detail to note is the association between liver cirrhosis and cancer risk, independent of treatment status. This suggests that, for breast cancer, advanced chronic liver disease may play a role; however, this hypothesis remains speculative and requires further investigation. In clinical practice, antiviral therapy may not (fully) reverse cirrhosis-linked endocrine perturbations in HCV patients with compensated or decompensated cirrhosis. For prostate cancer, the absence of an antiviral association is consistent with some prior cohorts reporting no reduction in prostate cancer risk even after SVR (5), and it may reflect weak causal relationships between HCV and prostate carcinogenesis.

In summary, this study reports real-world, long follow-up, multi-system assessment of extrahepatic cancer outcomes after HCV treatment, supported by time-varying methods and competing-risk modeling. The mixed findings for NHL, lung cancer, and hormone-related cancers indicate that extrahepatic malignancy may not be a single outcome, given variations of the underlying biology and the potential sources of bias across cancer sites and subtypes. Essentially, this study shifts the question from ‘whether HCV is associated with extrahepatic cancers’ to ‘which cancers may truly decline after viral cure’, with an additional focus on the patterns arising from the broader changes in care and prevention.

Looking ahead, future work should leverage larger pooled or federated cohorts that enable lag-time sensitivity analyses and more rigorous time-zero definitions, be adequately powered to distinguish DAA from IFN-era effects (especially for hematologic outcomes) and improve capture of key parameters such as smoking intensity or alcohol consumption. Simultaneously, these findings support integrating extrahepatic cancer prevention into HCV elimination efforts, including but not limited to strengthening smoking cessation, aligning eligible patients with lung cancer screening, and addressing co-morbid risks.

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-2026-1-0223/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0223/coif). F.T.’s lab has received research grants (funding to the institution) from AstraZeneca, MSD, Gilead, and Agomab. F.T. has received honoraria for consulting or lectures from Gilead, Abbvie, Falk, AstraZeneca, Boehringer, Madrigal, MSD, GSK, Ipsen, Pfizer, Mirum, Novo Nordisk, and Sanofi. The other author has 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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