Relatioship Between HBV Infection and Haematological Malignancies
Hepatitis B virus is a small 3.2 Kb DNA virus belonging to the Hepadnaviridae family. HBV DNA replicates by reverse transcription of an RNA intermediate.[33] Thus, during viral infection, a relaxed circular, partially double-stranded DNA is converted into a circular covalently closed DNA (cccDNA) which is utilized as the transcriptional template. HBV encodes four overlapping open reading frames (ORFs): the surface, precore/core, polymerase and X. The surface ORF encodes the three related surface antigens small (S), middle (M) and large (L); the precore/core ORF encode for the secreted HBeAg protein and the viral nucleocapsid (HBcAg), respectively. The HBeAg protein is functionally distinct from HBcAg and seems to have a role in evasion of the host immune response. The polymerase ORF encodes for the enzymes needed for replication of viral DNA (reverse transcriptase, RNaseH and a protein primer). Finally, the X ORF encodes the X protein, which modulates many viral and cellular functions.[34] Indeed, it is important for viral infection and replication, activates transcription and upregulates cellular genes involved in oncogenesis, proliferation, inflammation and immune response.[34]
Globally, it is estimated that 293 million people are chronically infected by HBV with a variable geographical prevalence that is highest in sub-Saharan Africa and East Asia.[35] Approximately 2 billion people have evidence of past infection. Worldwide, more than 800 000 people die annually from chronic hepatitis B (CHB) mostly due to complications of cirrhosis and hepatocellular carcinoma (HCC).[16]
The outcome of infection depends on the age at which a person acquires HBV infection. About 80%-90% of infants, and 30%-50% of children infected at age 1–4 years develop a chronic infection. In contrast, only 2%-5% of adults do so. Chronic B hepatitis is characterized by a wide and dynamic spectrum of disease which is partly influenced by host, viral and environmental factors. The course of chronic hepatitis B is often described as four phases based on clinical and serological criteria. However, these phases are not necessarily sequential and stable. The first phase HBeAg-positive chronic HBV infection (previously termed 'immune-tolerant' phase), the second HBeAg-positive chronic hepatitis B (previously termed HBeAg-positive immune-active phase), the third HBeAg-negative chronic HBV infection (previously termed 'inactive carrier' phase), and the fourth HBeAg-negative chronic hepatitis B (previously termed HBeAg-negative immune-active phase).[36–38] The HBeAg-positive chronic HBV infection phase is characterized by HBeAg positivity, high viral replication, normal or minimally elevated ALT levels and a general absence of hepatic inflammation and fibrosis. The next phase is the HBeAg-positive chronic hepatitis B, where HBV replication is still high but lower than the immune-tolerant phase, ALT levels are elevated and fluctuate and varying degrees of liver necroinflammation and fibrosis are present. After several months or decades, this is followed by loss of HBeAg and the inactive phase. In this phase, HBV DNA levels are low or undetectable, ALT levels are normal, necroinflammation is minimal and severity of fibrosis is dependent on the amount of prior liver injury. Patients can progress to liver cirrhosis and hepatocellular carcinoma and rarely clear HBsAg or seroconvert to antibody to HBsAg (anti-HBs). After HBsAg loss, very low level of HBV DNA may persist in the liver and/or in serum. This condition referred to as occult HBV infection (OBI) can reactivate and revert to HBsAg positivity if the host immune system is suppressed.[36–38]
HBV, like HCV can infect lymphatic cells and be associated with lymphoproliferative disorders.[39] Several studies conducted in different regions of the world indicate a higher risk of developing NHL in patients with chronic HBV infection suggesting an oncogenic role of HBV in lymphoid malignancies.[40] A recent meta-analysis of 12 case-control studies strongly supported a causal association of chronic HBV infection with NHL (odds ratio: 1.5–3.6).[41] Similarly, a large cohort study from South Korean found an elevated overall risk of developing NHL (adjusted hazard ratio:1.74 95% CI 1.45–2.09) among HBsAg-positive subjects. Among NHL subtypes, the risk was significantly more elevated for diffuse large B-cell lymphoma (adjusted hazard ratio 2.01, 95% CI 1.48–2.75).[42]
J Viral Hepat. 2019;27(1):4-12. © 2019 Blackwell Publishing
