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Universal hepatitis B vaccination: The only way to eliminate hepatocellular carcinoma?

Friday, 8th of January 2016

Universal hepatitis B vaccination: The only way to eliminate hepatocellular carcinoma?

Vincent Leroy, Tarik Asselah

See Article, pages 1390–1396

 

DOI: http://dx.doi.org/10.1016/j.jhep.2015.10.001

Chronic hepatitis B infection affects over 240 million people worldwide, with long-term morbidity such as cirrhosis and hepatocellular carcinoma (HCC) accounting for around 600,000 deaths annually [1]. Since the discovery of hepatitis B virus (HBV) by Blumberg in 1965, progress has been impressive with the availability in the 1980 of HBV vaccine and in the 2000 the development of potent antiviral agents resulting in an improved long-term outcome. Despite the fact that the WHO recommends universal vaccination against hepatitis B to ultimately eliminate HBV (this recommendation has been progressively implemented to reach 168 countries), the global burden of HBV-related disease is still substantial. A nationwide hepatitis B vaccination program was implemented in Taiwan in 1984, leading to a rapid decrease in the incidence of hepatocellular carcinoma in children [2].

In the present issue of the Journal, Hung et al. [3] examined and compared the incidence patterns of hepatocellular carcinoma among different age groups in Taiwan between 2003 and 2011, 20 years after the universal HBV immunization program was launched. Moreover, a treatment program against hepatitis B and C was implemented in Taiwan in 2003 and more than 200,000 patients have benefited from an antiviral therapy since then. Data on HCC incidence were collected from the nationwide Taiwan Cancer Registry. Age-standardized incidence rates were calculated to analyse and compare the changes in incidence rates and trends after stratification on age groups. A total of 82,856 patients were diagnosed with HCC over the 2003–2011 period in Taiwan, yielding an age-standardized incidence rate of 32.97 per 100,000 person-years. HCC was mainly (99%) diagnosed in middle-aged adults and elderly people, with a clear male predominance. Taking the whole population, a non-significant trend towards a reduction in HCC incidence over time was observed. Interestingly, most striking declines were found for children and adolescent/young adult groups, with annual percentage changes of −17% and −8%/year, respectively. HCC incidence in children even dropped to zero in 2011. By contrast, only a slight decline in trends occurred for the middle-aged group (−2%/year), and a slight upward trend (+1%/year) was observed for elderly people, more specifically in women.

The main result of this study is that in Taiwan, HBV-related HCC was nearly eliminated in young adults and children in 2011, 30 years after the mass vaccination program against hepatitis B was launched, leading to a current vaccination coverage rate of 97%. A continuous decline in age and sex-adjusted rate ratios of HCC incidence and mortality from 1977 to 2011 has been already reported in the country [4]. In adolescents and young adults born after 1984, incidence regularly declined over time but HCCs related to HBV-infection still occurred in 2011. In a recent study, the prevalence of HBsAg positivity in Taiwan was estimated to be 1.2% in subjects born in 2004, a phenomenon mainly explained by the residual risk of vertical transmission in mothers carrying HBsAg [5]. Many other countries implemented national vaccination programs in the 1980s. In Alaska, a universal newborn immunization program was also initiated in 1984, associated with injection of immuno globulins in newborns of HBsAg positive mothers. McMahon et al. [6] recently reported from following this program, no cases of acute hepatitis B have occurred in children since 1992. Moreover, the annual incidence of HCC in children has dropped to 0/100,000 since 1999. Although the impact of these vaccination programs on HCC risk reduction appears obvious, methodologists could argue that only temporal relationships have been observed and that potential confounders might be involved in the risk reduction. Interestingly, Qu et al. [7]recently published the results of a large population-based cluster-randomized controlled trial of HBV-vaccination in newborns in China, which included 39,292 subjects who were vaccinated at birth and 34,441 who were not. After a median time of 25 years, HCC incidence was significantly lower in the vaccinated group compared to the control group, with a hazard ratio of 0.16. Altogether, these data highlight the strong benefit of national HBV-vaccination programs among neonates in HBV endemic areas. The strategy of universal vaccination against HBV, as recommended by the WHO, with the objective of preventing HCC worldwide should be therefore promoted.

Besides children and young adults, only a limited decline – while significant – was reported in the middle-aged group. Since these subjects were born before the vaccination program in newborns, the main factor contributing to risk reduction would be the implementation in 2003 of a national viral hepatitis therapy program delivering reimbursed therapy to patients having the highest risk to develop cirrhosis and HCC. Recently, Chiang et al. [8] reported a significant reduction in liver-related mortality since this program was launched compared to previous periods. We learn from Chiangs paper that 157,570 HBV-infected patients and 61,823 HCV-infected patients have benefited from antiviral therapy over the 2003–2011 period, which represents less than 10% of infected patients in the country. Indeed, stringent eligibility criteria based on ALT serum levels, HBV DNA and/or histology had been used, although extended criteria were implemented after 2009 in order to increase access to treatment. Significant reduction of HCC risk by treating only a minority of HBV-infected patients is clearly encouraging. Although controversies still exist, more and more evidence coming from Asian studies suggest that treatment by second generation analogs result in lower HCC incidence of around 30% in cirrhotic and 80% in non-cirrhotic patients [9]. Thus, a stronger impact on risk reduction could be expected by increasing the number of treated patients and optimizing treatment schedules, with the use of new generation analogs such as entecavir or tenofovir for longer durations. In the largest series published so far comparing 21,595 treated patients with the same number of strictly matched patients, treatment by analogs was associated with a reduced risk of HCC (hazard ratio of 0.37) [10]. However, the residual risk of HCC in treated patients was still substantial, with a cumulative incidence of 7.3% after a follow-up of 7 years. Therefore, even in the context of an ideal scenario where every HBV patient would be screened and treated, elimination of HCC risk thanks to antiviral therapy appears to be very unlikely. However, given the high incidence of HCC in this population, a 30–80% risk reduction would result in a high absolute number of avoided HCC.

A much more disappointing result from Hungs study is that the incidence of HCC increased in elderly people, especially in woman. Aging is a risk factor for HCC development, and HCV-infection constitutes a more predominant part of the etiology of HCC in elderly people. Interestingly, it has been previously reported that the severity of fibrosis was associated with menopause in women [11]. In their paper, the authors state that HCV-infection accounts for 25% of HCC cases in Taiwan. A limitation of the study is that etiologies of HCCs diagnosed during the study period and their evolution over time were not provided. Moreover, the percentage of elderly people eventually treated was not documented. It should be pointed out that anti-HCV therapy was based on dual Peg-IFNα + ribavirin therapy, which is difficult to use in elderly patients. Several studies have suggested that sustained virological response (SVR) is associated with a reduced risk of HCC. Vedt et al. [12]showed that SVR resulted in reduced occurrence of HCC compared to non-SVR patients, with hazard ratios ranging from 0.19 to 0.38 after 7 years of follow-up. The possibility that patients who achieve SVR have a spontaneous more favourable natural history cannot be ruled out. However, the same team recently reported that life expectancy of patients with advanced fibrosis achieving SVR was comparable to that of the general population, whereas not attaining SVR was associated with reduced survival [13]. Therefore, it could be hypothesized that only a few elderly patients from the study achieved SVR, which could be the main factor explaining the absence of HCC reduction in this group. Supporting this hypothesis, Deuffic-Burban et al. [14]have recently shown, using a country-specific Markov model that liver-related mortality depended on the rate of treated patients, the stage of fibrosis considered to treat, and the efficacy of treatments. The recent availability of new generation IFNα-free regimens should have a major impact on HCV-related HCC [15].

Another potential explanation for the increased risk of HCC in the elderly would be the accumulation of comorbidities favouring HCC development. Unfortunately, several details were missing in the study. Alcohol consumption, which is an essential risk factor of HCC, was not documented. For instance, in a study performed in France, deaths related to HBV or HCV-infection occurred at an earlier age in patients with a history of excessive alcohol consumption [16]. Furthermore, obesity and diabetes (metabolic syndromes) were not captured in this registry. Obesity is associated with an increased risk of HCC [17]. Diabetes also increases fibrosis progression [18]. Interestingly, the presence of diabetes was an independent factor of HCC in HBV-infected patients treated by analogs. In the US, HCC mortality tripled from 2001 to 2013, and non-alcoholic fatty liver disease was identified as the second leading cause of HCC after HCV-infection [19]. Besides management of viral hepatitis, the management of metabolic syndrome will be of crucial importance in the future.

In conclusion, we should acknowledge the success of the universal HBV-vaccination program in Taiwan in efficiently preventing HCC. In their important study, Hung et al. also report encouraging data suggesting that antiviral therapy may also decrease HCC occurrence, but to a lesser extent. Improving screening, extending access to treatment with the most potent antiviral agents against HBV and HCV, and preventing and managing metabolic comorbidities will be the next major challenges for hepatologists and health authorities worldwide in order to dramatically reduce the burden of HCC.

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Conflict of interest

The authors declare that the following disclosures: VL: Speaker/Consultant: Roche, AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck.

TA: Speaker/Consultant: Roche, AbbVie, Achillion, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck.

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Acknowledgement

We thank Dr Alison Foote for helpful reading of the mansucript.

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References

© 2015 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.