2Role of antiviral treatment for HCC prevention
Introduction
Prevention of population exposure to the etiologic agents of liver disease stands as the most effective, practical approach to reduce liver-related mortality from hepatocellular carcinoma (HCC), worldwide [1]. This is the clear message conveyed by the program of mass vaccination of newborns against hepatitis B virus (HBV), the dominant risk factor for HCC on a global scale, that was started in early eighties in Taiwan and now is in place in more than 180 WHO nations [2]. Owing to the significant contribution of HBV and hepatitis C virus (HCV) to HCC and the availability of effective antiviral regimens to permanently suppress or remove etiologic agents, antiviral treatments of patients chronically infected by hepatitis viruses stand as a complementary to primary prophylaxis strategy in the prevention of HCC, and this is even more so in the HCV scenario where a sterilizing vaccine is far from being available [1]. However, the evidence that patients with chronic hepatitis B and hepatitis C can effectively be protected against HCC risk by treatment with interferon and/or oral anti-HBV analogues is rather controversial, due to the lack of randomized controlled trials that are ideally needed to establish efficacy, but are logistically and ethically challenging. Reanalysis of studies with antivirals suggest that virus-induced HCC was more likely to be prevented in younger patients with mild liver inflammation rather than in older patients with advanced liver fibrosis or cirrhosis, who in fact are those at higher risk of developing liver cancer [3]. While this calls for a reassessment of current strategies of patient prioritization to antiviral therapies, that are mostly dictated by cost-utility criteria and therefore target the most in need patients with advanced liver disease, we became progressively aware that uncertainty regarding rates and pattern of HCC chemoprevention by antiviral regimens is mainly the consequence of methodological flaws generated by the retrospective scrutiny of the literature. As these studies were originally designed to evaluate the antiviral potency of interferon and oral analogues, treatment outcomes could not properly be weighed for important predictors of liver cancer like hepatitis severity and comorbidities, both common causes of interferon ineligibility, and life style factors like alcohol abuse and tobacco smoking [4]. This was particularly true for patients with chronic hepatitis C, who until a few months ago were bound to receive treatment with interferon-based regimens only, which may suffice to cause permanent virus sterilization in susceptible patients, depending on the infecting genotype, severity of associated liver disease, presence of co-morbidities and genetically determined sensitivity to interferon, but remains of limited applicability and efficacy in patients with cirrhosis and comorbidities who are closest to develop an HCC [4]. As a matter of fact, treatment ineligibility of patients with severe comorbidities and those with advanced or decompensated HCV might have caused two competing risk factors of shortened survival, like HCC and all cause mortality to appear reduced in the selected cohorts of HCV patients who could achieve a sustained virological response (SVR) to interferon therapy [5], [6]. This could no longer be the case once safe, universally applicable and highly effective oral regimens against HCV become available to treat patients not only with decompensated hepatitis but also those at risk of death for extrahepatic complications, provided however that antiviral therapies will reach all the infected population.
Primary prevention of HCC not only means prevention of population exposure to the hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, but it also includes all approaches aiming to interrupt or prevent virus-induced liver damage. There are, however, major differences in the primary prophylaxis of HCC in relation with aetiology, beginning with the lack of a sterilizing vaccine against HCV to finish with differences in the outcome of antiviral therapy which leads to universal virus eradication in hepatitis C responders to interferon and to permanent suppression, but not eradication of the virus, in patients with chronic hepatitis B who successfully respond to either interferon or nucleos(t)ide analogs (NUC) therapy [3], [4]. In the latter patients, in the face of a clinically silent persistence of virus replication leading to tapering down of hepatic inflammation along with reversal of HBV induced hepatic fibrosis, the same virological response does not suffice to prevent cancer, since anti-HBV therapy fails to remove the potentially carcinogenetic sequences of HBVDNA integrated into liver cell chromosomes [7]. Conversely, the virus sterilizing effects of anti-HCV therapy in sustained responders is the consequence of virus inability to integrate into human DNA sequences whereas suppression of intracytoplasmic virus replication allows for the restoration of cell innate immunity resulting in permanent clearance of infection [8]. As a consequence, a proportion of responders experience a substantial reduction of all cause and liver specific mortality, possibly due to interruption of virus induced liver fibrogenesis, with evidence of cirrhosis reversal in some patients [5], [6]. These clinical benefits may not reach those patients with chronic hepatitis C who also suffer co morbidities linked to diabetes, overweight and alcohol abuse.
Section snippets
Hepatitis B
HCC may occur at any clinical stage of HBV infection, yet tumor incidence prevails in patients with higher viremia and those with advanced liver fibrosis compared to low viremic patients and those with an early infection [9], [10]. This notwithstanding, cancer risk appears to be modulated by several other virus and non virus-related factors like genotype C of HBV, mutations of pre-S, enhancer-H and core promoter, increased age, male sex, alcohol abuse and tobacco smoking, which in part account
Hepatitis C
The risk of developing HCC in patients with chronic hepatitis C has been long recognized to be linked to a variety of factors including male sex, increasing age, severity of liver fibrosis, genotype 3 of HCV, diabetes, alcohol abuse and ethnicity [5], [6], both direct and indirect mechanisms being advocated to explain how chronic infection with HCV may lead to HCC [8]. In the direct mechanisms scenario, infected liver cells accumulate mutations that eventually result in cell transformation as a
Conclusions
Circumstantial evidence suggests that effective treatment of chronic viral hepatitis confers substantial survival benefits to both HBV and HCV infected patients, including a reduction (not elimination) of risk of developing a HCC. While the causes for residual HCC risk in responders to antiviral therapy remain elusive in most instances, the observed association of residual HCC risk with advanced liver disease and older age questions the current strategies dictated by cost-utility ratios of
Conflict of interest
None.
Disclosures
Massimo Colombo: Grant and research support: BMS, Gilead Science Advisory committees: Merck, Roche, Novartis, Bayer, BMS, Gilead Science, Tibotec, Vertex, Janssen Cilag, Achillion, Lundbeck, GSK, GenSpera, AbbVie, AlfaWasserman, Jennerex Speaking and teaching: Tibotec, Roche, Novartis, Bayer, BMS, Gilead Science, Vertex, Merck, Janssen, Sanofi.
Massimo Iavarone: Speaking and teaching: Gilead Science, Bayer, Janssen; Travel support: Gilead Science, Bayer.
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