Chih-Lin Lin1,2 , Jia-Horng Kao3,4,5
1Department of Gastroenterology, Renai Branch, Taipei City Hospital, Taipei 10629, Taiwan.
2Department of Psychology, National Chengchi University, Taipei 116011, Taiwan.
3Graduate Institute of Clinical Medicine, National Taiwan University, College of Medicine, Taipei 10002, Taiwan.
4Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan.
5Hepatitis Research Center, and Department of Medical Research, National Taiwan University, National Taiwan University Hospital, Taipei 10002, Taiwan.
Correspondence Address: Prof. Jia-Horng Kao, Graduate Institute of Clinical Medicine, National Taiwan University, College of Medicine, 1 Chang-Te St., Taipei 10002, Taiwan.
E-mail: kaojh@ntu.edu.tw
Abstract
Hepatocellular carcinoma (HCC), especially hepatitis B virus (HBV)-related, remains a major cause of cancer-related mortality worldwide. Unless there is early detection with curative treatment, the 5-year survival rate of advanced HCC is less than 15%. The preventive strategies for HBV-related HCC are thus urgently needed to reduce the global burden of this disastrous cancer. Primary prevention involves the avoidance of viral infection through hepatitis B vaccination and interruption of viral transmission from patients with chronic HBV infection. The universal neonatal hepatitis B vaccination program has successfully reduced the prevalence of HBV carriage rate as well as HCC incidence in vaccinated cohorts. However, HBV elimination is still difficult to achieve. Regarding secondary prevention, long-term treatment with nucleos(t)ide analogues has been proven to reduce the risk of HBV-related HCC. Individual risk stratification and periodic HCC surveillance in these patients could facilitate early HCC diagnosis. Finally, tertiary prevention can also be achieved by life-long treatment with NAs to reduce the risk of HCC recurrence after curative treatment of primary HCC. Challenges ahead include the fact that HBV is not yet curable by current antiviral agents. Combination therapy with direct anti-HBV agents and host-targeting immunomodulatory agents is under active development. In addition, HCC risk cannot be eliminated even in patients with HBsAg seroclearance or functional cure. Therefore, HCC surveillance is strongly recommended for every patient with chronic HBV infection.
Keywords
Anti-HBV therapy, hepatitis B vaccination, hepatitis B virus, hepatocellular carcinoma
Introduction
Hepatocellular carcinoma (HCC) is one of the most prevalent solid tumours and leading causes of cancer-related death worldwide. In 2018, the estimated annual incidence and mortality increased to 841,000 cases and 782,000 deaths, respectively1. The highest HCC incidence rates are found in East and Southeast Asia and Northern Africa as well, but the incidence rates of HCC also increased in North America and Europe over the past few decades2. Although early detection by HCC surveillance provides the opportunity for curative treatment for early-stage HCC, the worldwide 5-year survival rate of HCC has been unsatisfactory over the past two decades3. In the last 10 years, emerging molecular target therapy and immunotherapy has constituted a major breakthrough for advanced HCC. However, overall survival has improved marginally4. The major reasons for the poor prognosis of HCC include the heterogeneous nature of HCC affecting treatment outcomes and the majority of HCC occurring in countries where medical resources are limited5. Therefore, we urgently need effective measures to prevent the occurrence of HCC in the populations at risk. The current exploration of HCC risk factors provides us with a good opportunity to develop preventive strategies. It is known that the etiologies of HCC include virological factors (such as hepatitis virus infection), chemical factors (such as aflatoxin B1 and alcohol) and genetic as well as metabolic factors [such as hereditary hemochromatosis, metabolic associated fatty liver disease (MAFLD) or non-alcoholic steatohepatitis (NASH)6,7. The contribution of different risk factors to HCC varies widely by country and region. Among them, chronic hepatitis B virus (HBV) infection is one of the most important risk factors. The global burden of HCC in 2015 revealed that the contribution of HBV to HCC mortality was geographically related. From highest (up to 40%-60%) in most areas of Asia and Sub-Saharan Africa to the less common cause of HCC death, approximately 9% in North America8.
Since 1981, the development of hepatitis B vaccines has successfully prevented the spread of HBV across the world. In addition, the development of anti-HBV agents has led to a delay or block of the progression of chronic hepatitis B (CHB). As a consequence, prevention of HBV-related HCC in this setting should be expected by the early 2050s. In this review, the mechanisms of HBV-induced HCC and individual prevention of HBV-related HCC will be summarized and discussed.
Factors associated with HBV-related HCC
Thanks to the advances in the molecular biology of HBV, the pathogenesis of HBV-related HCC is largely clarified [Figure 1]. The pathogenesis of HCC in patients with CHB can be divided according to HBV-related direct and indirect mechanisms. Direct oncogenic effects of HBV include HBV-host genome integration and HBV-encoded oncogenic protein. The integration of HBV DNA into the host genome induces both host chromosomal instability and insertional mutagenesis of HCC-related genes9. This integration in the host genome most frequently happens in the telomerase reverse transcriptase region and myeloid/ lymphoid or mixed-lineage leukaemia 4 genes. Dysregulation of telomerase and histone methyltransferase expression subsequently increase the risk of hepatocarcinogenesis10. Truncated HBV pre-S/S mutation induces surface protein synthesis imbalance and may increase endoplasmic reticulum stress and decrease tumour suppressor gene expression, and thus, it may play a primary role in oncogenesis11. Among HBV-encoded proteins, HBV X protein has the most oncogenic effect in hepatocarcinogenesis. HBV X protein is a multifunctional regulator, and it is involved in several cancer-related molecular mechanisms, including alteration of signal pathways (e.g., inhibition of P53 and activation of the Jak1/STAT pathway), DNA repair (e.g., alteration of p53/ERCC3), apoptosis (inhibition of P53), mitochondrial function (e.g., activation of calcium-dependent kinase pathway, epigenetic modification (e.g., epigenetic silencing of ASPP gene), and expression of non-co
