Role of hepatitis B antibody in predicting reactivation of resolved hepatitis B virus infection in leukemia patients
Introduction
The reactivation of hepatitis B virus (HBV) infection is becoming a challenging issue with the increasing use of immunosuppressive therapy. Particularly in endemic regions, approximately 60% of the adult population has been exposed to HBV infections (Seto et al., 2018). Upon HBV infection, the viral genome is imported into the nucleus to form a covalently closed circular DNA (cccDNA). The cccDNA is quite stable in the infected hepatocytes and can persist in a latent state as a reservoir for HBV reactivation (HBVr) (Allweiss and Dandri, 2017; Sung et al., 2005). Even patients with resolved HBV infection (defined as negative hepatitis B surface antigen [HBsAg], positive hepatitis B core antibody [anti-HBc], with or without positive hepatitis B surface antibody [anti-HBs]) may have low levels of cccDNA in the liver (Caviglia et al., 2018; Raimondo et al., 2019). Since eradicative therapy for HBV cccDNA is not currently available, this population is a large reservoir of individuals at risk for HBVr when they undergo immunosuppression (Werle-Lapostolle et al., 2004; Boyd et al., 2016).
Aggressive chemotherapy and hematopoietic stem cell transplantation (HSCT) are the well-established treatment for hematological malignancies, such as leukemia and lymphoma, which result in an intensive immunosuppression (Craddock, 2000; Sweet and Lancet, 2014; Murawski and Pfreundschuh, 2010). HBVr in these patients can cause chemotherapy interruption, frequent hospitalization, progression to hepatic failure and death. It has been recognized that patients with positive HBsAg are at high risk of HBVr during the treatment, and therefore, prophylactic antiviral therapy is recommended for this population according to clinical practice guidelines (Reddy et al., 2015; Chen et al., 2015; Yeo et al., 2009; Terrault et al., 2018; European Association for the Study of the Liver, 2017). In patients with resolved HBV infection, the risk varies according to the virological profile, underlying disease and the type and duration of immunosuppressive regimen (Terrault et al., 2018; European Association for the Study of the Liver, 2017). Although prophylactic antiviral therapy or followed up regularly by monitoring HBV DNA and preemptive antiviral therapy can be an alternative for these patients (An et al., 2016; Francisci et al., 2010; Buti et al., 2017), these strategies may cause a significant burden on health resource allocation in HBV endemic area or may result in overexposure to antiviral medication. Therefore, identification of risk factors can help optimize the prevention and treatment of HBVr in these patients.
Previous studies have shown that anti-HBc and anti-HBs quantification could be a reliable and useful predictor for managing HBVr in lymphoma patients with resolved infection and rituximab treatment (Hsu et al., 2008; Tang et al., 2017; Matsubara et al., 2017; Yang et al., 2018; Nishida et al., 2019; Kusumoto et al., 2015, 2019). However, whether quantification of HBV antibodies can be used to predict HBVr remains to be evaluated in leukemia patients. China has historically been a highly endemic area for chronic HBV infection and has a high proportion of resolved HBV infection in the population (Wang et al., 2014). In addition, leukemia increasingly afflicts millions of Chinese people in recent years (Wang et al., 2018). In the present study, based on a retrospective analysis of clinical data collected from leukemia patients with resolved HBV infection, we mainly focused on assessing the role of HBV antibodies quantification in predicting HBVr in leukemia patients undergoing immunosuppression.
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Patients and study design
Data of HBV serological examination and HBV DNA quantification from January 2013 to March 2018 were collected from the database of Peking University People's Hospital. In total, 1,345 leukemia patients with HBV serological examination and HBV DNA test more than twice were primarily included. Patients were further excluded according to the following criteria: 1. Without being exposed to HBV infection (Positive anti-HBs only or all HBV serological markers are negative, n = 524); 2. Positive HBsAg
Characteristics of leukemia patients at baseline and reactivation
As shown in Table 1, a total of 533 leukemia patients, including 301 males and 232 females, were included. The diagnoses included acute lymphoid leukemia (ALL, n = 179), acute myeloid leukemia (AML, n = 312), chronic lymphoid leukemia (CLL, n = 12), and chronic myeloid leukemia (CML, n = 24). In addition, six patients were diagnosed as rare types of leukemia including mixed-lineage acute leukemia, aggressive NK-cell leukemia. The median age was 36 (2–77) years and the median duration of
Discussion
Previous prospective studies investigated the role of therapeutic regimen, age, follow-up duration, and HBV DNA load in predicting HBV reactivation in leukemia patients (Mikulska et al., 2014; Seto et al., 2017; Yağci et al., 2010). In the present study, we mainly focused on the impact of baseline characteristics of HBV antibodies on HBVr risk in leukemia patients with resolved HBV infection. We found that seronegative anti-HBe is a prerequisite for using anti-HBs and anti-HBc quantification to
Contributions
TW and NW contributed equally to this work. X–BP designed, interpreted the results and wrote the manuscript. YG provided the clinical data. TW completed the data collection, screening, and statistical analysis. NW helped interpret the results and revise the manuscript. Y-XM and JW completed a part of the data analysis.
Financial support
This study was supported by grants from the National Natural Science Foundation of China (№. 81670530), the Start-up Foundation (2018QDL035), Pandeng Project of Hangzhou Normal University.
Ethics approval statement
This study was approved by the Ethics Committee at Peking University People's Hospital and was conducted in accordance with the ethical guidelines of the Declaration of Helsinki.
Declaration of competing interest
The authors declare that they have no conflict of interest.
Acknowledgments
We would like to thank Dr. Hong-Hu Zhu from hematology department of the First Affiliated Hospital of Zhejiang University for his critical comments on the manuscript.
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