Hepatitis B Virus and Risk of Non-Hodgkin Lymphoma

An Updated Meta-analysis of 58 Studies

M. Li; Y. Gan; C. Fan; H. Yuan; X. Zhang; Y. Shen; Q. Wang; Z. Meng; D. Xu; H. Tu


J Viral Hepat. 2018;25(8):894-903. 

In This Article

Abstract and Introduction


Previous studies have focused on the relationship between hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL). However, the results remain inconsistent and somehow conflicting in different subgroups. The aim of this study was to combine the findings of independent studies to comprehensively assess the association between HBV and NHL using a meta-analysis. Relevant studies were identified through structured keyword searches in PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) database, and 58 studies with a total of 53 714 NHL cases and 1 778 591 controls were finally included. Pooled estimates indicated a significantly increased NHL risk in HBV-infected individuals (summary odds ratio [sOR]: 2.50; 95% confidence interval [CI]: 2.20–2.83) regardless of the study design (case-control studies: sOR: 2.47; 95% CI: 2.16–2.82; cohort studies: sOR: 2.64; 95% CI: 1.78–3.91). Considerable heterogeneity was observed across studies that was primarily attributed to the NHL subtypes (meta-regression: P < .05). Overall, B-cell NHL (sOR: 2.46; 95% CI: 1.97–3.07) presented a stronger association with HBV infection than T-cell NHL (sOR: 1.67; 95% CI: 1.34–2.10). Within the B-cell NHL subtypes, HBV infection was significantly associated with diffuse large B-cell lymphoma (DLBCL, sOR: 2.06; 95% CI: 1.48–2.88) and follicular lymphoma (FL, sOR: 1.54; 95% CI: 1.11–2.12), but not with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) and Burkitt lymphoma. The results of this meta-analysis support a positive link between HBV infection and NHL development. Further investigations for the mechanisms underlying HBV-induced NHL are warranted.


Hepatitis B virus (HBV) is a hepatotropic DNA virus. However, it also exhibits a significant capacity to infect and replicate in peripheral blood mononuclear cells, including lymphocytes.[1,2] Currently, approximately 248 million individuals worldwide were chronically infected with HBV.[3] HBV has a high level (>8%) of endemicity in African and the Western Pacific region, an intermediate level (2%–7%) in European and Asia, and a low level (< 2%) in America. Although China has changed from highly endemic into intermediate endemic with an overall HBV prevalence of 6%,[4] HBV infection remains a major public health problem due to the large absolute number of individuals infected with HBV.

non-Hodgkin lymphoma (NHL) is the main subtype of lymphoma that originated from the lymphatic hematopoietic system. Recent data from the International Agency for Research on Cancer (ICRC) showed that NHL represents 3% of all new cancer cases worldwide, making NHL as an increasingly crucial contributor to the whole cancer burden.[5] Studies on the aetiology of lymphoma have indicated that virus infection is the primary risk factor for NHL. The Epstein-Barr virus (EBV), human herpes virus 8, human immunodeficiency virus (HIV) and Human T-cell lymphoma viruses I and II have been regarded as causative agents of the development of NHL.[6] Recently, etiologic studies have increased their focus on the association between chronic HBV infection and NHL.

Several epidemiologic studies have suggested that chronic HBV infection can increase the risk of NHL. However, analyses of specific subtypes of NHL have yielded inconsistent results. A population-based cohort study in Taiwan showed that HBV infection was significantly associated with an increased risk of diffuse large B-cell lymphoma (DLBCL) but not with the risk of T-cell NHL and follicular lymphoma (FL).[7] However, other studies have shown that HBV infection was significantly associated with T-cell NHL and FL.[8,9] HBV-infected individuals had an overall odds ratio (OR) of 2.24 of developing NHL according to a meta-analysis performed in 2013 that involved 22 studies.[10] However, there was high heterogeneity in their analysis and the source of heterogeneity was not defined by the authors. In this study, we conducted an updated meta-analysis combining 58 original studies, and additional subset analyses were performed to improve the accuracy of summary estimate of the relationship between HBV infection and NHL risk.