The Impact of Hepatitis B Virus Infection and Vaccination on the Development of Non-hodgkin Lymphoma

C.-E. Huang; Y.-H. Yang; Y.-Y. Chen; J.-J. Chang; K.-J. Chen; C.-H. Lu; K.-D. Lee; P.-C. Chen; C.-C. Chen


J Viral Hepat. 2017;24(10):885-894. 

In This Article

Abstract and Introduction


Hepatitis B virus (HBV) infection has been documented as a risk factor for non-Hodgkin lymphoma (NHL). However, there are few large cohort studies, and there is no report about the impact of HBV vaccination. We conducted this study to evaluate these issues. We used the nationwide cohort of the Taiwan National Health Insurance Research Database for 1997–2013. We compared the incidence and the risk of developing NHL and CD20+ aggressive lymphoma between HBV and non-HBV cohorts. The hazard ratios (HRs) were computed using Cox proportional hazards models. We matched these two large cohorts to reconfirm the data. We also compared the incidence of NHL between cohorts born before and after the inception of universal HBV vaccination. We found that HBV infection increased the risk for developing NHL and CD20+ aggressive lymphoma, with HRs of 4.14 and 5.52, with a higher incidence of 17.07 and 13.9 per 100 000 person-years, respectively, compared to the non-HBV cohort. The incidence of NHL in the cohort born in the era before universal HBV vaccination was higher with 1.85 per 100 000 person-years compared to 0.74 in the cohort born later aged younger than 20. Our study confirms that HBV confers a greater risk for developing NHL, especially CD20+ aggressive lymphoma. The impact of HBV vaccination is protective against lymphoma development in the teenagers in an endemic area, but longer follow-up is needed for older age.


Non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoproliferative diseases originating from variant lymphocytes. NHL is the seventh most common cancer in the United States and the fifth in the United Kingdom.[1,2] The etiology of lymphoma development is complex, including genetic, environmental and infective factors. Some infective agents such as the human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), human T-cell lymphotropic virus (HTLV) and Helicobacter pylori have been proposed as causative factors for specific histological subtypes of NHL.[3] In addition, the hepatitis C virus has been recognized as an etiologic agent for NHL because of the associated increased risk shown by various epidemiological studies and meta-analyses.[4,5] Alternately, this evidence of increased risk for NHL in patients with hepatitis C infection also raises questions about the possible etiologic status of the hepatitis B virus (HBV).

HBV infection is the most common chronic viral infection in the world and is a global health problem. Approximately 30% of the world's population has serological evidence of current or past HBV infection, and it is estimated that more than 350 million people are chronic carriers.[6] The prevalence of HBV infection is higher in Asia, Africa, southern Europe and Latin America.[7] In certain endemic regions, most chronic carriers are infected perinatally or during childhood.[8] In Taiwan, the HBV infection rate was extremely high until universal HBV vaccination of neonates was implemented in July 1984. Twenty-five years after the implementation of universal HBV vaccination, the hepatitis B surface antigen positivity prevalence rate in children less than 15 years of age declined from 9.8% (in 1984) to 0.3% (in 2009).[9] The incidence of hepatocellular carcinoma also decreased over this period.[10] However, HBV infection is still common in adults. These chronic carriers are prone to chronic inflammation and develop various states of liver disease. One hypothesis of lymphomagenesis may be that chronic infection causes chronic stimulation of lymphocytes.[11]

Many epidemiological studies and meta-analyses have demonstrated that hepatitis B infection increases the risk of NHL.[12,13] However, only two large cohort studies have been conducted in high prevalence areas to date.[14,15] In both these studies, the study population was specific: parous women in Taiwan and South Korean workers and their dependents. There has been no study exploring the impact of chronic hepatitis B treatment and universal HBV vaccination on the risk for developing NHL. Therefore, we conducted this study to evaluate the relationship between HBV infection and risk of NHL.