Global disease burden of viral hepatitis and hepatocellular carcinoma

The most common causes of hepatitis worldwide is a group of viruses known as hepatitis A, B, C, D and E virus. Most deaths from viral hepatitis are due to hepatitis B and hepatitis C. Globally, an estimated 257 million people were living with HBV and 71 million people were living with HCV, which caused 1.34 million deaths in 2015 comparable with deaths from tuberculosis and exceeding deaths from HIV.1

Both liver cancer, mostly hepatocellular carcinoma (HCC), and cirrhosis are end-stage clinical outcomes of chronic hepatitis B (CHB) and chronic hepatitis C (CHC).2 HBV and HCV are the main causes of liver cancer worldwide, and liver cancer was the seventh commonly diagnosed cancer and the second common cause of cancer death as reported in GLOBOCAN 2012.3 There was a significant increase in global deaths from liver cancer and cirrhosis from 1990 to 2013 with a 60% increase for liver cancer and a 45% increase for cirrhosis. Such increases are mostly attributable to the increase in infection of HBV and HCV.4

The incidence of liver cancer and the prevalence of HBV and HCV infection are high in the East, Southeast and Central Asia and the sub-Saharan Africa.1–4 However, the aetiological proportion of liver cancer varies in different countries and regions. HCV is more prevalent in patients with HCC in Japan, North America and Europe, and HBV is more prevalent in patients with HCC in Taiwan, Southeast Asia and China.1 2 Around 75% of global liver cancer cases are caused by chronic HBV and HCV infection,4 and control of viral hepatitis may thus significantly reduce the burden of HCC globally.

Natural history of chronic hepatitis B

The causality of chronic HBV infection to induce HCC was reported in several cross-sectional case-control studies2 and first confirmed by the GECC cohort study in Taiwan,5 the first prospective follow-up study on virus-caused human cancer. There was a wide range of relative risk of developing HCC (5–223 folds) for hepatitis B surface antigen (HBsAg)-seropositives versus HBsAg-seronegatives in these studies.2 In the natural history of CHB, spontaneous seroclearance of hepatitis B e antigen (HBeAg), HBV DNA and even HBsAg, the important milestone biomarkers, may occur in patients with CHB.6 HBeAg seroclearance usually results from a period of elevation of serum level of alanine aminotransferase (ALT), a seromarker of liver inflammation. The serum HBV DNA level (viral load) may remain high or gradually decline in patients who are HBeAg-seronegative. Seroclearance of HBsAg may occur after the serum HBV DNA level becomes undetectable.

Seropositivity of HBeAg was associated with an increased HCC risk in patients with CHB in cross-sectional case-control studies7 8 and longitudinal cohort studies.8 9 The biological gradient of serum HBV DNA level was also associated with an increasing risk of HCC9–11 and cirrhosis12 in the REVEAL-HBV study and other cohort studies. Seroclearance of HBeAg, HBV DNA and HBsAg may lead to a decreased risk of HCC.13 Seroclearance of milestone biomarkers may occur at variable ages in patients with CHB, cirrhosis and HCC occur only in some patients. For patients with CHB in the REVEAL-HBV study, the lifetime (30–78 years old) cumulative risk of cirrhosis was 42.9% for men and 22.8% for women, and the lifetime cumulative HCC risk was 24.8% for men and 8.5% for women.6 In addition to HCC and liver cirrhosis, patients with CHB may also have an increased risk of developing non-Hodgkin’s lymphoma, intrahepatic cholangiocarcinoma and pancreatic cancer.14–16

Multiple cofactors for HBV-related multistage hepatocarcinogenicity

The progression from self-limited HBV infection through chronic hepatitis and cirrhosis to HCC is a multistage pathogenic process driven by viral, host and environmental cofactors.6 In addition to HBeAg serostatus and elevated serum HBV DNA level, HBV genotype and mutant type are also associated with the risk of HCC.10 17 18 Host cofactors include older age, male gender, cirrhosis status, elevated serum ALT level, family history of HCC, diabetes status, elevated serum androgen level as well as genetic polymorphisms of human leucocyte antigens, xenobiotic metabolism enzymes, DNA repairmen enzymes, hormone receptors, oncogenes and tumour suppressor genes.2 6 19 20 Environmental cofactors include alcohol drinking, cigarette smoking, aflatoxin exposure and inadequate intake of antioxidant vitamins and selenium.2 7 21–23

There are gene–environment and gene–gene interactions of HBV-related HCC cofactors. For example, the dose–response relation between HCC and elevated serum level aflatoxin B₁-albumin adducts is modified by genotypes of glutathione S-transferase (GST) M1 and T1.24 The increasing HCC risk with serum aflatoxin B₁-albumin adducts level was observed in patients with CHB with null genotypes of GST M1 or T1 (without detoxification capability), but not in those with non-null genotypes. The increased HCC risk associated with elevated serum testosterone level in male patients with CHB is modified by the genotype of androgen receptor. The increasing HCC risk with serum testosterone level was significant in patients with short trinucleotide CAG repeats of androgen receptor gene (high transactivation capability), but not in those with long CAG repeats.25

Risk calculators for HBV-related HCC and cirrhosis

In the era of precision medicine, it is important to classify patients with CHB into subgroups differing in their susceptibility to particular end-stage liver diseases, in the prognosis of their liver diseases and in their response to specific clinical managements. Preventive or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not.

Several risk predictors for HBV-related HCC and cirrhosis have been identified in several long-term follow-up studies including REVEAL-HBV study.2 6 26 Some can accurately predict the HCC occurred in a short period after enrolment such as cirrhosis status and elevated serum level of alpha-fetoprotein; some are long-term predictors of HCC and cirrhosis including age, gender, habitual alcohol consumption, family history of HCC, serum ALT level and HBV biomarkers such as HBeAg and serum levels of HBV DNA and HBsAg.5 26

Risk nomograms and calculators incorporating host, viral and environmental biomarkers for precise prediction of personal long-term risk of HCC and cirrhosis in patients with CHB have recently been developed by REVEAL-HBV study and other studies.27–29 The REACH-B and REACH-B-II scores were HCC risk calculators derived from the community cohort of REVEAL-HBV study and internationally validated by hospital cohorts in Hong Kong, Korea and Taiwan.30 31 These risk calculators are helpful for the triage of patients with CHB who need intensive liver surveillance and/or antiviral therapy and for the efficacy evaluation of clinical managements of CHB.29

Natural history of chronic hepatitis C

HCV is mostly transmitted through blood or blood-derived products. The iatrogenic infection including blood transfusion, medical injection and acupuncture as well as the needle-sharing among drug misusers are major transmission routes of HCV.1 32 HCV infection is infrequently diagnosed during the acute phase because a majority of infected persons have no or mild symptoms. Most asymptomatic infections progress to CHC not being aware until end-stage liver diseases occur. The cumulative lifetime (30–80 years old) HCC risk of patients with CHC was 19.7% for men and 17.2% for women in the REVEAL-HCV study.32 Coinfection with HBV may increase the lifetime cumulative HCC risk up to 38.4% for men and 27.4% for women.33 In addition to HCC and cirrhosis, patients with CHC may also have an increased risk of extrahepatic cancers including cholangiocarcinoma and non-Hodgkin’s lymphoma, circulatory diseases and renal diseases.14 34

Cofactors and risk calculator for HCV-related HCC

The risk of developing HCC in patients with CHC was significantly associated with increasing age, detectable serum level of HCV RNA, elevated serum ALT level, HCV genotype, obesity, diabetes status and coinfection with HBV.20 33 35 The dose–response relation between serum HCV RNA level and HCC risk needs to be further validated by other long-term follow-up studies. A risk calculator for HCV-related HCC was derived from REVEAL-HCV cohort and validated by another community cohort in southern Taiwan.29 36 The risk calculator was composed of six biomarkers including age, cirrhosis status, serum ALT level, serum aspartate aminotransferase (AST)/ALT ratio, serum HCV RNA level and HCV genotype. It may be used to triage patients with CHC for various clinical managements more precisely to assure the efficacy and cost-effectiveness of the antiviral therapy.

Global elimination of viral hepatitis and hepatocellular carcinoma

As HBV and HCV are major aetiological factors of HCC, effective control of them may reduce the disease burden of HCC. Viral hepatitis B may be eliminated by immunisation, interruption of mother-to-child transmission, early diagnosis and treatment of eligible patients with CHB. Viral hepatitis C may be eliminated by injection safety using engineered devices, blood safety by donation screening, harm reduction for people who inject drugs, early diagnosis and treatment of eligible patients with CHC. All these prevention, diagnosis and treatment measures are currently available. Several national programmes for successful control of viral hepatitis and HCC have also been demonstrated.

Hepatitis B immunisation reduces burden of liver diseases and hepatocellular carcinoma

Immediately after the efficacy of the hepatitis B immunisation to prevent HBV infection in infants born to HBeAg-seropositive mothers was reported, a national immunisation programme was launched in Taiwan in 1984.37 All newborns received vaccines, but only newborns of high-risk mothers with HBeAg-seropositivity or a high titre of HBsAg received hepatitis B immunoglobulin with the first dose of vaccine at birth. The immunisation rate of eligible infants was more than 90%. The HBsAg-seropositive rate at the age of 6 years decreased significantly from more than 10% in unimmunized birth cohorts to less than 1% in the immunised.

This immunisation programme has been well documented to prevent HBV infection, fulminant hepatitis in infants, chronic liver diseases and cirrhosis and HCC in immunised birth cohorts in Taiwan, showing a very high efficacy even 30 years after the immunisation in infancy.38 Hepatitis B vaccine has become the first vaccine to prevent human cancer. By now, the HBV vaccine has been incorporated in national immunisation programmes of 184 countries. The number of children under five living with chronic HBV infection in the world was significantly reduced to 1.3% in 2015 from 4.7% before vaccines were introduced. Hepatitis B vaccine is preventing 4.5 million HBV infections per year in children worldwide.1

Antiviral therapy reduces burden of hepatocellular carcinoma

Several antivirals have been approved for CHB therapy.39 Lamivudine was first approved in 1998 for the treatment of CHB, it may decrease the HCC risk of treated patients significantly with a large proportion developed antiviral-resistant mutants. Newly developed antivirals for CHB therapy have higher genetic barriers to induce antiviral-resistant HBV. The interferon-based therapy was the standard for CHC treatment before the direct acting agent (DAA) was launched in 2013.40 HCV genotypes 1 and 4 are less responsive to interferon-based treatment than other genotypes. IL28 variants were found to be associated with the efficacy of interferon-based CHC therapy, showing the Asia-Pacific ethnicities have a high frequency of favourable genotypes. DAAs are highly effective for all HCV genotypes without ethnic variation, with low side effects and convenient with oral intake.

Several recent international studies has shown the decrease in incidence of HCC in patients with CHB treated with oral nucleoside/nucleotide analogues and in patients with CHC who cleared HCV with DAAs.41 42 A national programme of antiviral therapy on patients with high-risk CHB and CHC was launched in October 2003 in Taiwan.43 A significant reduction in the burden of end-stage liver diseases through this programme has recently been documented. A total of 157 570 patients with CHB and 61 823 patients with CHC were treated with reimbursed antiviral therapy from 2004 to 2011. There was 22% reduction in mortality from chronic liver diseases and cirrhosis, 24% reduction in HCC mortality and 14% reduction in HCC incidence in 2008–2011 compared with the 4-year period before the programme launch, that is, 2000–2003.

Opportunities and challenges for successful elimination

Both hepatitis B and hepatitis C may be prevented, diagnosed early and treated using currently available medical technology and public health infrastructure. The strategies to eliminate HBV of HCV are different. HBV infection may be prevented by both immunisation and suppressive treatment of patients with CHB. Although there is no HCV vaccine, the fact that curative treatments exist would allow eradication of HCV if the treatments became more affordable and accessible to patients with CHC. The high efficacy and cost-effectiveness of hepatitis B immunisation and antiviral therapy for CHB and CHC have also been demonstrated.

Viral hepatitis control has been identified as a sustainable development goal by the United Nations. The global targets for 2030 set by WHO include 90% hepatitis B vaccination coverage, 90% prevention of mother-to-child HBV transmission, 100% blood transfusion and injection safety, 90% diagnosis of HBV and HCV infections and 80% treatment of eligible patients.1 In 2015, the global coverage was 84% for hepatitis B vaccination and 97% for blood safety, but only 9% HBV and 20% HCV infections were diagnosed and only 8% CHB and 7% CHC eligible patients were treated.1

Different strategies are required in different regions or countries to achieve the global elimination of viral hepatitis and HCC. The policy-makers have to take the prevalence and major transmission routes of HBV and HCV, the content and schedule of hepatitis B immunisation, the availability and accessibility of diagnosis and treatment of CHB and CHC, the healthcare infrastructure and manpower to deliver preventive and therapeutic interventions, the domestic and international resources for elimination programmes, as well as the assessment of efficacy and cost-effectiveness of the programmes into consideration.

Clinical guidelines for prevention, diagnosis and treatment of CHB and CHC have been published by many national and international organisations including American Association for the Study of Liver Diseases, Asian-Pacific Association for the Study of the Liver and European Association for the Study of the Liver. Regional characteristics in HBV and HCV epidemiology, clinical practice and healthcare system and availability and accessibility of diagnostic and treatment methods are specifically considered. WHO has also published the guidelines with specific recommendations for low-income and middle-income countries.

Strategies for elimination of viral hepatitis and HCC should be tailored to meet the needs in different regions or nations in order to achieve high efficacy and cost-effectiveness. For example, the screening of patients with CHB and CHC is considered appropriate only for high-risk rather than general population in countries such as Canada and USA, where the prevalence of the viral infection is low in the general population. The hepatitis B immunoglobulin is recommended to give with the first dose of hepatitis B vaccine to newborns of mothers with high HBV viral load within 24 hours after delivery in countries such as Taiwan, where the HBV infection is hyperendemic.44 While aspartate aminotransferase-to-platelet ratio index is recommended as the preferred non-invasive test to assess the presence of cirrhosis in resource-limited settings, transient elastography may be preferred in settings where they are available and cost is not a major constraint.

In order to achieve the WHO’s goals for HBV and HCV elimination in 2030, concerted national and international efforts are in urgent need. The diagnosis and treatment coverage has to be rapidly scaled up through a public health approach to benefit all. Sustainable financing and innovation are also required for the development and delivery of vaccines, diagnostics and treatments to transform global hepatitis response.