Editorial - HCC in HCV patients and the direct acting antivirals: is there really a link?

The onset of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV) patients who achieved the sustained virological response (SVR) after treatment with direct acting antivirals (DAAs) is still a matter of study and debate. Currently, most of the literature is still focusing attention on the assessment of epidemiological data as well as the incidence of HCC during follow-up, compared to the annual mean rate in cirrhotic patients1-9. Globally, among the results of several studies3,4,10-13, a trend towards a progressive reduction or stability of HCC risk with SVR seems to be prevalent. Furthermore, scholars14-17 have shown, especially in the early stages after treatment, the appearance of unexpectedly large HCC lesions. More recently, some preliminary papers are showing a late HCC de novo occurrence in patients after more than 18 months of SVR, suggesting possible other mechanisms subtended to HCC occurrence even in absence of HCV chronic inflammation18. Therefore, these contrasting epidemiological data clearly suggest that mechanisms in carcinogenesis are still unclear, requiring further investigations. Several papers have identified some variables most frequently associated with the appearance of HCC de novo, such as the value of platelets, liver stiffness, portal hypertension, alpha-feto protein value, alcohol consumption, metabolic factors or the most advanced stage of cirrhosis19-25. However, these elements appear to be major risk predictors but are not attributable to direct carcinogenic effect. The possible indirect implication of DAAs was immediately discussed. Our group, in a recent prospective multicenter work26, has highlighted a predominance of HCC de novo in patients who have been treated with sofosbuvir without ribavirin in the 2015-2017 period. Our hypothesis is based on the lack of immunomodulatory protective effect of ribavirin27 and on the possible damage on the mitochondrial RNA of sofosbuvir28. Likewise, some authors focused on the reduced immunosurveillance induced by early and rapid viral clearance, which may partly explain the controversial relationship between eradication and HCC occurrence. Researchers29,30 have highlighted the possible role of some cytokines as carcinogenesis co-factors. To date, there is no direct evidence of an involvement of DAAs in the carcinogenesis. However, it should also be considered that we still do not have details on the new antivirals according to their possible immunomodulatory activity. Indeed, in order to infection disease, the antivirals are well known to exert some immunomodulatory activity. The most interesting immunomodulating activity is for two sub-set of antivirals as the protease inhibitors as, for instance, fosamprenavir or darunavir31,32 and maraviroc33 being involved in the modulation of the angiogenesis, tumor growth and invasion, inflammation, antigen processing and presentation, cell survival. Instead, concerning HCV antivirals, ribavirin has been demonstrated to exert a kind of immunomodulatory activity markedly reducing macrophage activation and diminishing Th2 cytokine production while preserving Th1 cytokine production and stimulating humoral immune response34,35. All these studies and the current literature debate about HCC de novo onset after SVR following new DAAs therapy clearly suggest that most of the drugs, even if to be considered safe, may exert some important effect on host that should be considered. Despite the fact that the DAA therapies are able to remove the HCV from the patients, the epigenetic impact on cells persist also in absence of the virus itself. It is becoming emergent the relationship and European Review for Medical and Pharmacological Sciences 2020; 24: 983-987