Role of hepatitis B antibody in predicting reactivation of resolved hepatitis B virus infection in leukemia patients

https://doi.org/10.1016/j.antiviral.2020.104765Get rights and content

Highlights

  • Acute lymphoid leukemia is associated with a significantly higher incidence of HBVr than acute myeloid leukemia.

  • Anti-HBe status (positive or negative) does not affect the incidence of HBVr in leukemia patients.

  • Seronegative anti-HBe is a prerequisite for using HBV antibody quantification to predict the risk of HBV reactivation.

Abstract

Background & Aims

Quantification of anti-HBs and anti-HBc predicts the risk of HBV reactivation (HBVr) in lymphoma patients receiving rituximab treatment. However, it remains unclear whether the quantification is predictive of HBVr in leukemia patients undergoing immunosuppression.

Methods

and patients: Clinical and laboratory data of the leukemia patients with resolved HBV infection diagnosed between January 2013 and March 2018 were retrospectively collected. Data series of HBV seromarkers and HBV DNA levels before the patients receiving chemotherapy and/or hematopoietic stem cell transplantation (HSCT) and during follow-up duration were analyzed.

Results

In total, 533 leukemia patients with resolved HBV infection were included. The incidences of HBVr were 5.7% (25/441) and 2.2% (2/92) in patients receiving HSCT and chemotherapy, respectively. In patients receiving HSCT, acute lymphoid leukemia had a significantly higher incidence of HBVr than acute myeloid leukemia (8.9% vs 3.9%, P < 0.05). The incidence varied almost zero to 40% due to the differences in the profiles of HBV antibodies. High anti-HBs (cut-off of 79.2 IU/L) or low anti-HBc levels (cut-off of 4.475, S/CO) at baseline were associated with a low risk of HBVr. Anti-HBe status did not affect the incidence of HBVr. However, the cut-offs were only predictive of HBVr in the patients who had negative anti-HBe.

Conclusion

The baseline profiles of HBV antibodies are predictive of the risk of HBVr in leukemia patients undergoing immunosuppression. However, seronegative anti-HBe is a prerequisite for using baseline anti-HBs and anti-HBc quantification to predict HBVr risk.

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.

Section snippets

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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