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B. Wang et al.
able HBV DNA levels depending on the balance between HBV replication and immune control.7 Up-dated nomen- clature regarding the phases of HBV infection reflect this and broadly classify patients into hepatitis B e antigen (HBeAg) positive or negative, and whether or not there is evidence of a chronic hepatitis (Table 1).4 Those with resolved HBV infection are HBsAg negative and have cir- culating anti-core antibody (anti-HBc), and often anti-sur- face antibody (anti-HBs). Although such patients are con- sidered to have past HBV infection, HBV DNA persists within the liver in the form of highly stable covalently closed circular DNA (cccDNA) and integrated DNA.8 Active replication is controlled by both innate and adap- tive immune responses, including HBV-specific T-cell responses and neutralizing antibodies produced by acti- vated B cells. However, these responses are not sufficient to eradicate all latent forms of HBV DNA and a reservoir of persistent HBV exists. With immunosuppression due to any cause, immune-mediated control of HBV replication is lost and reactivation can occur.9
Hepatitis B virus reactivation includes both exacerbation of chronic hepatitis B infection in an HBsAg-positive patient (with ≥2 log10 rise in HBV DNA level) and true reactivation of resolved hepatitis B infection, which can either be reverse HBsAg seroconversion (reappearance of HBsAg) or detec- tion of HBV DNA with negative HBsAg. These virological events are often followed by a reactivation-related hepatitis (increase in ALT or AST ≥3 x baseline). In severe cases, or where reactivation is not recognized and there is a delay in treatment, hepatitis may progress to jaundice and potential- ly fulminant hepatic failure. More commonly, however, HBV DNA falls again either due to immune control or antiviral therapy, and the patient recovers.10
Studies of HBV reactivation during chemotherapy for lymphoma have demonstrated that viral reactivation itself can occur at any time during or after immunosuppression, but the hepatitis and clinical manifestations related to reactivation typically occur after treatment has ended when immune reconstitution takes place.11 In B-cell deple- tive therapies, such as rituximab, risk of reactivation is protracted, with cases reported up to two years after the last dose.12 Furthermore, HBV reactivation after hematopoietic stem cell transplantation (HSCT) may occur several years after transplantation because of the potential long delay in immune reconstitution.13 Therefore, reactivation may be ongoing over an extended period of time before therapy can be implemented, and requires long-term follow up and surveillance.
Risk factors
Factors pertaining to the host, the virus, the immuno- suppressive regimen, and the underlying disease itself can all impact on the risk of HBV reactivation. Male sex and older age (≥50 years) have been associated with increased risk. One study of more than 600 HBsAg-positive patients receiving chemotherapy for a range of cancers showed an almost 3-fold increased incidence in men, although the reason for this was not clear.14 Older patients are more likely to have HBsAg seroclearance but persistent levels of total HBV DNA and cccDNA in the liver, hence increasing the risk of reactivation.15 Viral factors associated with reac- tivation have been shown to include HBsAg positivity, HBeAg positivity, and elevated HBV DNA levels prior to commencing immunosuppressive therapy, all of which reflect a state of poor HBV-specific immune control prior to immunosuppression.16,17 Conversely, possessing anti- HBs antibodies has been suggested to be protective against reactivation, although it has not been determined whether the specific titer has any effect.18 More recently, co-infection of HBV with other viruses such as HIV and hepatitis C virus (HCV) has been highlighted as a risk fac- tor for reactivation even without the influence of immunosuppression. Treatment of HBV/HCV co-infected individuals with direct acting antivirals against HCV can result in HBV reactivation, although the clinical signifi- cance of this may be minimal.19,20 The mechanism of this observation is thought to be either a direct inhibitory effect of HCV replication on HBV or that immune responses against HCV also suppress HBV replication.21
The risk of HBV reactivation may be determined in part by the underlying disease, although studies comparing similar treatments in different hematologic diseases are lacking. Lymphoma has been the most common underly- ing condition in reports of reactivation; whether this is a reflection of the disease itself or the treatments given is not clear. An association between chronic HBV infection and non-Hodgkin lymphoma (NHL) has long been postu- lated and several studies have accumulated evidence to support this; a meta-analysis of more than 3000 patients with NHL and over 1 million controls showed an overall odds ratio of 2.56 for detecting HBsAg positivity in patients with NHL.22 A higher prevalence of anti-HBc pos- itivity alone in NHL patients has also been demonstrated. Possible mechanisms to explain the association include direct HBV infection of lymphocytes, and chronic anti- genic stimulation and associated B-cell proliferation.23,24
Table 1. Up-dated nomenclature for natural history phases of chronic hepatitis B virus (HBV) infection, adapted from the 2017 EASL Clinical Practice Guidelines.
HBeAg
HBV DNA
ALT
Liver disease Old terminology
Chronic infection
Positive
>107 IU/mL Normal None/minimal Immune tolerant
Chronic hepatitis
Positive
104 – 107 IU/mL Elevated Moderate/severe Immune reactive
Chronic infection
Negative
<2000 IU/mL* Normal None Inactive carrier
HBeAg positive
HBeAg negative
Chronic hepatitis
Negative
>2000 IU/mL Elevated** Moderate/severe
HBeAg negative chronic hepatitis
EASL: European Association for the Study of the Liver; HBeAg: hepatitis B e antigen; ALT: alanine transaminase. *Can be 2000-20000 IU/mL in some patients without signs of chronic hepatitis. **Either persistently or intermittently.
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haematologica | 2019; 104(3)