Evaluation of hepatitis B virus reactivation prevention measures in immunosuppressed patients: current status and effectiveness
Toru Ishikawa1#
, Mitsuyuki Suzuki2#, Terasu Honma1, Toshiaki Yoshida1
Contributions: (I) Conception and design: T Ishikawa, M Suzuki; (II) Administrative support: T Honma, T Yoshida; (III) Provision of study materials or patients: T Ishikawa, M Suzuki; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of the manuscript: All authors.
#These authors contributed equally to this work as co-first authors.
Background: Prevention of hepatitis B virus (HBV) reactivation is a very important issue, but there is still no clear strategy. This study aimd to develop and evaluate an in-hospital collaboration flow to prevent HBV reactivation, guided by the Japanese Society of Hepatology (JSH) guidelines.
Methods: We have strengthened and implemented a screening system and for HBV reactivation from February 2022 to January 2023. We assessed the administration of nucleic acid analogs (NAs) in hepatitis B surface antigen (HBsAg) or HBV DNA-positive cases, the detection rate of HBs or hepatitis B core (HBc) antibodies in HBsAg or HBV DNA-negative cases, and the follow-up status of HBV DNA testing. A total of 1,195 patients were included, with exclusions based on the judgement of no need for testing by the attending physician.
Results: Among 1,172 tested patients, 1.88% (n=22) were HBsAg or HBV DNA-positive, all of whom received NA therapy. Among 1,150 HBsAg or HBV DNA-negative cases, 9.91% (n=114) were HBs or HBc antibody-positive, with 82.5% (n=94) undergoing HBV DNA testing. Over the years, the HBV DNA measurement rates increased significantly to 82.5% in 2022.
Conclusions: The implemented screening regimen resulted in high and improving testing rates over time. Most HBsAg or HBV DNA-positive cases were treated with tenofovir alafenamide (TAF), highlighting its potential benefits in terms of safety and adherence. Continued validation and adaptation of the screening system are necessary to further prevent HBV reactivation.
Keywords: Hepatitis B virus reactivation (HBV reactivation); screening system; nucleic acid analogs (NAs); chemotherapy; tenofovir alafenamide (TAF)
Received: 08 August 2024; Accepted: 27 October 2024; Published online: 09 January 2025.
doi: 10.21037/tgh-24-103
Highlight box
Key findings
• This study investigates the effectiveness of hepatitis B virus (HBV) screening and reactivation prevention protocols in a clinical setting, focusing on patients undergoing immunosuppressive treatment and chemotherapy over a 1-year period.
What is known and what is new?
• HBV screening and reactivation prevention protocols in a clinical setting, focusing on patients undergoing immunosuppressive treatment and chemotherapy is very important issue.
• The current study concludes highly relevant to healthcare providers managing patients who require immunosuppressive treatments, offering valuable guidance on optimizing HBV screening and prevention strategies.
What is the implication, and what should change now?
• The importance of rigorous HBV screening and monitoring practices in immunosuppressed patients significantly contribute to preventing HBV reactivation.
Introduction
Recent advances in chemotherapy, immunotherapy, and transplantation have significantly increased the use of anticancer drugs and immunosuppressive agents. Traditionally, patients negative for hepatitis B surface (HBs) antigen and positive for HBs and hepatitis B core (HBc) antibodies were considered clinically cured, assuming the hepatitis B virus (HBV) had been eliminated (1,2). However, it is now evident that even in these previously infected patients, small amounts of HBV DNA remain in hepatocyte nuclei (3,4). Strong immunosuppression and chemotherapy can reactivate HBV, inducing severe hepatitis.
Despite being HBs antigen-negative, HBc or HBs antibody-positive patients may harbor low levels of HBV in their liver and peripheral blood mononuclear cells (5). The presence of glucocorticoid enhancement elements in the HBV gene, along with immunosuppressive effects of chemotherapy (6), can disrupt the immune balance and lead to severe hepatitis through extensive hepatocyte destruction and HBV proliferation.
Reactivation of HBV due to immunosuppression and chemotherapy is a significant medical concern. Guidelines for the prevention of immunosuppression and chemotherapy-induced hepatitis B were published to mitigate severe hepatitis caused by HBV reactivation (7). However, many years after these guidelines, the issue remains critical. Preventing HBV reactivation is paramount as it not only complicates the treatment of the underlying disease but also exacerbates the severity of hepatitis. The cornerstone prevention involves identifying high-risk groups through HBV screening before initiating immunosuppression or chemotherapy and administering prophylactic nucleic acid analogs (NAs) (8-10).
In response to this challenge, we have implemented a screening protocol based on the Japan Society of Hepatology guidelines and developed an in-hospital collaborative workflow led by the Medical Safety Management Office. This report examines the effectiveness of our current screening system and discusses the outcomes. We present this article in accordance with the STROBE reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-103/rc).
Methods
Study design and population
This retrospective study included 1,195 patients treated with drugs for which caution is advised regarding HBV reactivation in the Japanese Society of Hepatology (JSH) HBV treatment guideline (7). The study period was from February 2022 to January 2023. Inclusion criteria were patients who received immunosuppressive or chemotherapeutic drugs and had available HBV screening data.
HBV screening and follow-up
Patients were screened for HBs antigen (HBsAg) and HBV DNA to identify those at risk for HBV reactivation. Additionally, the presence of HBs and HBc antibodies was determined in patients who tested negative for HBsAg and HBV DNA. The screening protocol followed the guidelines established by the JSH.
Data collection
Data collected at receiving immunosuppressive or chemotherapeutic drugs and had available HBV screening data. The proportion of HBs or HBc antibody-positive cases among HBsAg or HBV DNA-negative patients was also recorded. Follow-up data included the status of HBV DNA testing and reasons for any missing measurements.
Changes in screening over time
To assess changes in screening practices, we analyzed data from three different years: 2015, 2019, and 2022. This included the rate of HBV DNA measurement in antibody-positive individuals and the subsequent administration of NAs.
Ethical approval and compliance
This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Institutional Review Board of Saiseikai Niigata Hospital (No. 06-222). Informed consent was obtained from all patients or their legal guardians.
Statistical analysis
Descriptive statistics were used to summarize the data. Proportions of positive cases and rates of NA administration were calculated. Differences in HBV DNA measurement rates over the years were analyzed using Chi-squared tests. A P value of <0.05 was considered statistically significant. All statistical analyses were performed using EZR (Saitama Medical Centre, Jichi Medical University, Shimotsuke, Japan), a graphical user interface for R version 3.2.2 (The R Foundation for Statistical Computing, Vienna, Austria) (11).
Results
Target drugs and screening flow
The target drugs used in this study are listed in Table 1. The hepatitis B reactivation prevention flow is shown in Figure 1.
Table 1
| Drug classification | n (%) (total =1,195) |
|---|---|
| Corticosteroid | 568 (47.5) |
| Immunosuppressant | 447 (37.4) |
| Anticancer drugs | 176 (14.7) |
| Antiviral drugs | 4 (0.3) |
HBV, hepatitis B virus.
Screening and follow-up
Out of 1,195 patients included in the study, 23 patients had no measurement of HBs antigen or HBV DNA. These cases were predominantly pediatric patients or involved single-dose steroid administration, and the attending physician deemed these measurements unnecessary (Table 2).
Table 2
| Drug classification | n (%) (total =23) |
|---|---|
| Methylprednisolone sodium succinate | 14 (60.9) |
| Dexamethasone | 3 (13.0) |
| Prednisolone sodium succinate | 2 (8.7) |
| Prednisolone | 2 (8.7) |
| Sodium hydrocortisone succinate | 1 (4.3) |
| Methotrexate | 1 (4.3) |
HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.
The characteristics of the 1,195 patients in the study population were as follows: male, n=671; female, n=524, median age is 71 years (range, 12–87 years), The treatments of the patients were as follows: corticosteroid (n=568, 47.5%), immunosuppressant (n=447, 37.4%), anticancer drugs (n=176, 14.7%) and antiviral drugs (n=4, 0.3%) (Table 1).
The classification of anticancer treatment is shown in Table 3, 40.3% (71/176) was for hematological malignancy, and 31.3% (55/176) was for malignant tumors of the digestive system.
Table 3
| Cancer classification | N (total =176) |
|---|---|
| Malignant lymphoma | 27 |
| Chronic myeloid leukemia | 17 |
| Multiple myeloma | 13 |
| Chronic lymphocytic leukemia | 5 |
| Acute lymphoblastic leukemia | 3 |
| Primary myelofibrosis | 2 |
| Myelodysplastic syndrome | 2 |
| Polycythemia vera | 1 |
| Idiopathic thrombocytopenic purpura | 1 |
| Breast cancer | 9 |
| Gastric cancer | 15 |
| Cholangiocarcinoma | 9 |
| Pancreatic cancer | 9 |
| Colorectal cancer | 7 |
| Esophageal cancer | 3 |
| Gastrointestinal stromal tumor | 3 |
| Neuroendocrine tumor | 2 |
| Duodenal cancer | 2 |
| Gallbladder cancer | 1 |
| Hepatocellular carcinoma | 4 |
| Lung cancer | 4 |
| Malignant rheumatoid arthritis | 37 |
HBV screening proportion and practice patterns
A total of 1,195 patients were identified for the baseline period (24 months) and on the first prescription date for between April 2016 and August 2022 (Figure 1).
Positive cases and treatment
In the 1,172 patients that were followed up, 1.88% (22/1,172) tested positive for HBs or HBV DNA, and all received NAs (Figure 2).
Antibody-positive cases
Among the 1,150 patients who were HBsAg or HBV DNA-negative, 9.91% (114/1,150) were positive for HBs or HBc antibodies. Of these antibody-positive patients, 82.5% (94/114) underwent HBV DNA testing, and 1 patient (1.1%) (1/94) tested positive (Figure 2).
Reasons for missing HBV DNA measurements
For the 20 patients without HBV DNA measurements, the reasons were as follows: temporary steroid administration: 5 patients, planned quarterly HBV DNA measurement in the future: 11 patients, patient transfer: 1 patient, completion of treatment: 1 patient, low risk: 1 patient, and HBV vaccination: 1 patient. This resulted in an HBV DNA unmeasured rate of 17.5% (20/114) (Figure 2).
Nucleic acid analog administration
Regarding the choice of NAs for HBsAg or HBV DNA-positive cases, the distribution was as follows: 1 patient received lamivudine (LAM), 7 patients received entecavir (ETV), and 14 patients received tenofovir alafenamide (TAF), with TAF being used in 64% of the cases (Figure 2).
Clinical outcomes after each antiviral preventive treatment
One LAM case was a pancreatic cancer case and continued to be HBV DNA-negative. Two of the seven cases treated with ETV were hepatocarcinoma cases, both with HBV DNA <+1.0 and variable negative status. All TAF cases continued to be HBV DNA-negative.
Screening trends over time
The rates of HBsAg or HBV DNA positivity were 1.65% in 2015, 2.16% in 2019, and 1.88% in 2022, showing no significant difference over time. However, the rates of HBV DNA testing among HBs or HBc antibody-positive individuals increased significantly over time, from 55.2% in 2015, to 77.3% in 2019, and 82.5% in 2022 (Figure 3).
Discussion
In this study, we presented the current status of HBV reactivation measures in Japanese community hospitals. Although the measurement rate of HBV reactivation measures has improved over time by improving adherence to screening protocols, but further efforts are needed to achieve 100% compliance. Outcome of NA treatment includes some cases of ETV that do not continue to be HBV DNA-negative, considering TAF’s advantages in terms of renal and bone safety, it is likely to become more widely used in the future (12,13). Additionally, TAF’s lack of dietary influence may contribute to better patient adherence (13).
Previous studies have shown that HBV reactivation due to chemotherapy is always preceded by an increase in HBV DNA levels (14). This underscores the importance of regular monitoring for previously infected patients. It has been reported that immediate administration of NAs can prevent hepatitis in cases of reactivation during conventional chemotherapy for solid tumors. The frequency of monitoring in cases of malignant lymphoma treated with rituximab plus steroid combination chemotherapy, as well as in cases of solid tumors treated with conventional chemotherapy, has been reported (15,16).
In cases of reactivation of preexisting infections during conventional chemotherapy for solid tumors, hepatitis was reportedly not observed if a nucleic acid analog was administered immediately. It has also been reported that patients with B-cell lymphoma with HBs antibody titers of less than 100 mIU/mL become HBs antibody negative when treated with rituximab (17).
If HBV screening is not completed before the start of chemotherapy, it is crucial to perform the missing laboratory tests as early as possible (18). The HBV-related testing status of patients remains on the list even if their chemotherapy is changed, suspended, or discontinued. This ensures continuous monitoring and regular HBV DNA quantification.
Using this flow, HBV screening can be performed in almost all cases. However, our system has ensured that required test items can be identified and screened effectively.
On the other hand, the Asia Pacific Association for the Study of the Liver (APASL), American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) guidelines are somewhat different from the JSH HBV reactivation guidelines in Japan (19), although the general concept is similar.
AASLD guideline recommends monitoring of HBV DNA, HBsAg, and alanine transaminase (ALT) levels every 1–3 months for HBV reactivation or on demand therapy and up to 12 months after withdrawing NA therapy (20). APASL guideline recommends monitoring ALT and HBV DNA every 1–3 months with undetectable HBV DNA receiving on-demand therapy for resolved HBV (21). Finally, EASL guideline recommends monitoring HBsAg and/or HBV DNA every 1–3 months in moderate or low risk resolved HBV and on-demand therapy to treat if DNA is positive (22).
In Japan, the guidelines for preventing HBV reactivation during immunosuppressive therapy were first introduced in 2009 and have subsequently been revised. The JSH guidelines recommend monitoring HBV DNA levels during immunosuppressive therapy and for at least 6 months including discontinuation.
In the present study, it was considered that the JSH guidelines were sufficient for HBV reactivation prophylaxis, but further studies on the validity of other guidelines are needed.
In the future, the validity of the target population should be re-examined. More appropriate HBV screening and monitoring protocols should be considered to ensure the prevention of reactivation.
However, there are several limitations in this study. Firstly, it is a single-center analysis in this study. Secondary, there is only an evaluation of the implementation of primary screening for the prevention of HBV reactivation in immunosuppressed patients. Third, it is not a screening based on the duration or amount of steroids. Finally, the HBV DNA unmeasured rate of 17.5% (20/114) in antibody-positive cases is a significant issue, primarily due to temporary steroid administration and future planned measurements. This gap highlights the need for more stringent guidelines to ensure complete screening before starting chemotherapy. Additionally, the exclusion of certain patient groups, such as pediatric patients or those receiving single-dose steroids, might have influenced our results. Therefore, it is necessary to consider the evaluation of the implementation of follow-up in the future.
Our study validates the current HBV screening system but also identifies areas for improvement, particularly in ensuring complete pre-chemotherapy screening. Future studies should focus on refining the target population for screening and enhancing adherence to monitoring protocols to prevent HBV reactivation effectively. Continued evaluation and adaptation of screening practices will be crucial in managing HBV reactivation risk in immunocompromised patients.
Conclusions
Although the HBV reactivation prophylaxis at Saiseikai Niigata Hospital contributed to good screening and therapeutic intervention, further research with multiple institutions and long-term follow-up are needed to determine whether further utilization of each guideline can contribute to perfect screening and reactivation prophylaxis.
Acknowledgments
We would like to thank Editage (www.editage.com) for English language editing.
Funding: None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-103/rc
Data Sharing Statement: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-103/dss
Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-103/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-103/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Institutional Review Board of Saiseikai Niigata Hospital (No. 06-222). Informed consent was obtained from all patients or their legal guardians.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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Cite this article as: Ishikawa T, Suzuki M, Honma T, Yoshida T. Evaluation of hepatitis B virus reactivation prevention measures in immunosuppressed patients: current status and effectiveness. Transl Gastroenterol Hepatol 2025;10:5.
