I read with interest the case report presented by Tapia-Sosa et al.1 The authors’ contribution has undoubtedly benefited the global discussion regarding the correlations between direct-acting antiviral therapy (DAA) in the treatment of chronic hepatitis C (HCV) infection, and the disease course of hepatocellular carcinoma (HCC). However, the authors may have risked oversimplifying the link between DAA therapy and HCC pathogenesis by raising the possibility of a causal relationship. Although the 2 patients in the paper presented with cirrhosis pursuant to HCV infection, this only serves to strengthen the argument that irreversible changes might have been induced by HCV in the cellular architecture in the liver. Hence, although HCV is eradicated through DAA, such changes remain and influence the disease course of HCC.
Chronic HCV infection is capable of eliciting various epigenetic changes to hepatocytes during the course of infection. According to recent studies,2,3 chronic HCV infection is conducive to epigenetic modifications to histone H3, a DNA packaging protein. The epigenetic change, H3K27ac, which involves the acetylation of the lysine residue at N-terminal position 27 of the protein, is found to be associated with an increase in HCC risk, where there is altered expression of the genes associated with HCC pathogenesis. Eight genetic signatures are identified (WNT10A, JUNB, FOSL2, MYCN, TNFAIP3, KLF4, EDN1, and PCSK9). Moreover, such epigenetic modifications persist after HCV cure through DAA therapy. The fact that these changes precede hepatocellular carcinogenesis strengthens the argument. H3K27ac is also associated with greater risk of hepatic fibrosis, which is a major risk factor of HCC progression.4
Secondly, I would recommend that the authors provide a more comprehensive picture of the patients they presented, since nuances in the medical history can suggest alternative explanations towards the observed development of HCC after the administration of DAA therapy. It is uncertain whether the two patients had any concurrent etiologies for hepatocellular carcinogenesis. For instance, if a patient were co-infected by HCV and chronic hepatitis B (HBV), the implementation of DAA therapy would lead to the eradication of HCV, but also a simultaneous increase in HBV disease activity afterwards. This increase can be associated with de novo hepatocellular carcinogenesis or cancer progression. In this case, being cognizant of the time interval between the attainment of sustained virologic response (SVR) and hepatocellular carcinogenesis is key.
Thirdly, such results have to be interpreted in light of the socio-epidemiological landscape in Mexico. Since the proportion of people who inject drugs is relatively high in the region, coupled with the risk of viral transmission via blood transfusion, the two patients reported may have experienced human immunodeficiency virus (HIV) co-infection, which carries a substantially higher risk of HCV recurrence than that in patients who are mono-infected with HCV (summary 5-year risk: 15.02%; 95% CI: 0.00-48.26%, versus 0.95%; 95% CI: 0.35-1.69%).5 There is also a risk of de novo contraction of hepatitis C through established transmission routes, as mentioned above. This is particularly relevant if the patient has a continuing history of injection drug use and coagulopathies that require regular blood transfusions.
Ethical considerationsInformed consent from patients is not required. This manuscript is a response to a published article and requires no approval from an ethics committee. The author also declares that this article does not contain personal information that enables patient identification.
Financial disclosureNo financial support was received in relation to this article.
Conflict of interestThe author declares that there is no conflict of interest.
Please cite this article as: Ng A, ¿Sobresimplificación de la conexión entre el tratamiento de la hepatitis C y la carcinogénesis hepatocelular? Rev Gastroenterol Méx. 2022;87:125–126.
In response to: Tapia-Sosa R, Hernández-Cabral F, Gabutti A, et al. Hepatocellular carcinoma associated with direct-acting antiviral therapy for hepatitis C virus: a report of two cases. Rev Gastroenterol Mex (Engl Ed). 2021;86:197–199.