Hepatitis B and C Virus Infection and Risk of Haematological Malignancies

Aldo Marrone; Marco Ciotti; Luca Rinaldi; Luigi Elio Adinolfi; Marc Ghany


J Viral Hepat. 2019;27(1):4-12. 

In This Article

Occult HBV Infection and Haematological Malignancies Association

In a meeting held in Taormina nearly a decade ago, a panel of experts defined occult HBV infection (OBI) as the presence of HBV DNA in the liver (with detectable or undetectable HBV DNA in the serum) of individuals testing negative for HBsAg.[43] This is considered a 'fifth phase' of HBV infection, and its clinical relevance is still unclear.[38] Persons with OBI may be infectious with reports of transmission occurring through blood transfusion and liver transplantation. OBI may worsen the progression of liver fibrosis, in patients with chronic HCV infection and can reactivate in patients under immunosuppression. Finally, because of the ability of HBV to integrate in the host genome and to synthesize pro-oncogenic proteins, OBI can contribute to the development of hepatocellular carcinoma.[44] Furthermore, a role of OBI in the development of intrahepatic cholangiocarcinoma and non-Hodgkin lymphoma has been hypothesized.[45–47] Almost two billion people have evidence of past HBV infection and can potentially be considered OBI carriers. The association of OBI with increased risk of developing lymphoproliferative disorders has been recently emphasized. Marcucci et al[48] reported among patients with a diagnosis of NHL, a significantly higher proportion were anti-HBc–positive, anti-HBs–negative patients, compared with serologically negative controls (adjusted OR, 2.05; CI, 1.24–3.37). OBI was observed in about 10% of patients with chronic lymphocytic leukaemia (CLL) and 6% of those with B-cell lymphoma.[47,49] Sinha et al reported detection of HBV DNA positivity in 21% of 110 HBsAg negative NHL patients, 79% of them with Bcell NHL.[50] Laurenti et al[51] found an 8.6% prevalence of OBI in a population of 387 patients with chronic lymphocytic leukaemia.

HBV has been shown to replicate in lymphocytes[52] and persists during chronic infection. However, there are no data which demonstrate the presence of HBV-DNA in lymphocytes of patients with NHL. In a Korean study, Park and colleagues found HBV S, X and C genes in DNA extracted from peripheral blood mononuclear cells but did not detect HBV-DNA in lymphoma tissues, suggesting an indirect effect on the pathogenesis.[49,53] In another study conducted on 240 subjects (80 diagnosed with multiple myeloma, 80 with CLL and 80 healthy controls) a significant association was found between CLL and OBI but not with the other two conditions. Indeed, chronic lymphocytic leukaemia had an odds ratio of 4.6 (95% CI 1.5–13.9) for the presence of OBI compared with multiple myeloma and controls.[54] Interestingly, 55% (44/80) of the patients with CLL group had evidence of HBV DNA in PBMC.[54] This study suggests that HBV may have a causative role in the development of B-cell lymphoma and strengthens the hypothesis that chronic HBV infection may be associated with lymphoid malignancies.[42]