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Role of antiviral treatment for HCC prevention

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Abstract

Chemoprevention of hepatocellular carcinoma (HCC) is listed as a yet highly debated long-term benefit of a successful treatment of patients with chronic viral hepatitis. In the hepatitis B virus (HBV) arena, the retrospective scrutiny of both interferon and nucleos(t)ide analogues (NUC) studies failed to provide robust evidence for HCC chemoprevention, due to a number of confoundings in the studies that were originally designed to assess the antiviral activity of interferon therapy. However, the reanalysis of outcomes following patients stratification for risk factors of HCC, provided a clue to find an association between NUC therapy and a reduced risk of liver cancer in non cirrhotic patients, only. In the hepatitis C scenario, a meta analysis of 30 observational studies of patients treated with interferon demonstrated a more than 70% reduction of HCC risk occurring independently of severity of underlying liver fibrosis which was less pronounced in aged patients and those with more advanced liver fibrosis. While the reasons for the residual risk of HCC in virological responders remain largely unexplained, international societies recommend surveillance for HCC of both HBV and HCV responders to antiviral therapy.

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.

References (51)

  • H.L. Chan

    Identifying hepatitis B carriers at low risk for hepatocellular carcinoma

    Gastroenterology

    (2012)
  • G.L. Wong et al.

    Accuracy of risk scores for patients with chronic hepatitis B receiving entecavir treatment

    Gastroenterology

    (2013)
  • Y.S. Lim et al.

    Mortality, liver transplantation, and hepatocellular carcinoma among patients with chronic hepatitis B treated with entecavir vs lamivudine

    Gastroenterology

    (2014)
  • S.C. Gordon et al.

    Antiviral therapy for chronic hepatitis B virus infection and development of hepatocellular carcinoma in a US population

    Clin Gastroenterol Hepatol

    (2014)
  • G. Fattovich et al.

    Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors

    J Hepatol

    (2008)
  • C. Cammà et al.

    Treatment of hepatocellular carcinoma in compensated cirrhosis with radio-frequency thermal ablation (RFTA): a prospective study

    J Hepatol

    (2005)
  • A.C. Cardoso et al.

    Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis

    J Hepatol

    (2010)
  • C.F. Huang et al.

    Baseline gamma-glutamyl transferase levels strongly correlate with hepatocellular carcinoma development in non-cirrhotic patients with successful hepatitis C virus eradication

    J Hepatol

    (2014)
  • J. Bruix et al.

    Management of hepatocellular carcinoma: an update

    Hepatology

    (2011)
  • M.H. Chang et al.

    Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group

    N Engl J Med

    (1997)
  • M.H. Lee et al.

    Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study

    J Infect Dis

    (2012)
  • J. McCombs et al.

    The risk of long-term morbidity and mortality in patients with chronic hepatitis C: results from an analysis of data from a Department of Veterans Affairs Clinical Registry

    JAMA Intern Med

    (2014)
  • S.N. Zaman et al.

    Silent cirrhosis in patients with hepatocellular carcinoma. Implications for screening in high incidence and low-incidence areas

    Cancer

    (1990)
  • C.J. Chen et al.

    Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level

    JAMA

    (2006)
  • W.S. Yang et al.

    The role of pre-existing diabetes mellitus on hepatocellular carcinoma occurrence and prognosis: a meta-analysis of prospective cohort studies

    PLoS One

    (2011)
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