This retrospective cohort study utilized the Japanese administrative claims database provided by JMDC Inc. [19]. This nationwide database consolidates annual health check-up results along with claims data on insured employees and their dependents and encompasses information related to hospitalization and outpatient treatments. As of February 2022, the number of patients in the database was approximately 14 million. This database includes patient’s attributes (i.e., age and gender), medical facilities where they are treated, diagnoses, procedures and medications they received. Although data have been anonymized, individuals can be tracked across different hospitals using personal IDs if the same insurance covers them. While the database contains records of laboratory tests, it does not contain specific test results such as that for HBs antigen or a numerical value for HBV DNA levels.

The current study utilized data on patients diagnosed with HBV-related diseases between April 2011 and June 2021. It also required records of procedures for HBV-DNA tests available daily; however, in the JMDC database, it was only accessible from April 2012 onward. In this context, the start of the study period was set as April 2011, accounting for a 1-year look-back period to assess eligibility and covariates (as shown in the supplementary material, Figure S1).

The study population consisted of patients with chronic HBV infections of HBsAg who received ISTs or patients who had resolved HBV infections who received ISTs. The study selected the population based on the records of the HBV-DNA tests. According to the JSH guidelines [15], prophylactic administration of NUCs is recommended after testing of HBs antigen and HBc or HBs antibodies prior to induction of IST, followed by HBVDNA testing if HBs antigen is positive (chronic HBV infections of HBsAg). In cases where HBc or HBs antibody tested positive (resolved HBV infections) when HBs antigen was negative, HBVDNA testing should be performed and prophylactic administration of NUCs is recommended when HBVDNA is ≥ 20 IU/ml. Monitoring of HBVDNA every 1–3 months is recommended when HBVDNA is < 20 IU/ml. Since the JMDC database lacks the results of laboratory tests for HBs antigen and HBs and HBc antibody, it was not possible to apply these criteria to identify the target population. However, patients with HBVDNA test history are expected to be positive for either HBs antigen or HBc antibody because HBV treatment and management in Japanese clinical practice strongly follows the JSH guidelines; the subjects in this study can consequently be selected based on the HBV-DNA test history. The study selected patients who were diagnosed with HBV-related diseases, had two or more HBV-DNA tests and underwent ISTs with immunosuppressive drugs, corticosteroids, anti-tumor drugs, anti-rheumatic drugs and antiviral drugs within the study period (April 2011–June 2021). The index date (Day 0) was defined as the first prescription date of an IST. Study patients were required to have data for at least 365 days before the index date to assess eligibility and covariates for the analyses. Relevant disease names, procedure names and drug names are described in the supplementary materials.

In the Japanese healthcare reimbursement system, claims for HBV-DNA tests are exclusive to patients previously confirmed as having chronic HBV infection of HBsAg, those who have recovered from HBV infections and those who were newly diagnosed with HBV infections. Because of the low incidence rate of new HBV infections in Japan, this test can be used as a proxy for the identification of patients who have either chronic HBV infections of HBsAg or have resolved HBV infections. For further enhancement of this specificity, the study included only patients who had two or more records of undergoing the HBV-DNA test.

This study excluded patients who met any of the following criteria: (1) diagnosed with HBV-related acute diseases (such as complicated acute hepatitis B, hepatic coma, fulminant hepatitis B, acute hepatitis B, subacute hepatitis, acute hepatitis, hepatitis B cirrhosis and fulminant hepatitis) between 365 days before the index date and the index date, (2) received NUC treatments between 365 and 90 days before the index date or (3) were < 18 years old at the index date. The design diagram of this study, list of diseases and IST are shown in the supplementary material (Figure S1, Table S1 and Table S2).

The eligible patients were evaluated for appropriate management to prevent HBV reactivation during the IST. The JSH guidelines suggest that patients are appropriately managed if they either: (1) undergo prophylactic NUC therapy or (2) have their HBV DNA levels regularly monitored [15]. This study defined recipients of prophylactic NUC treatments as those who received a prescription for any NUC medication, such as entecavir, tenofovir disoproxil, tenofovir alafenamide, lamivudine and adefovir pivoxil, between 90 days before the index and the index date. This definition is relevant for patients initiating an IST with non-steroid medications. However, for those starting IST that includes steroids, the time frame extends from 90 days before the index date to 7 days after the index date. Patients who received regular monitoring of HBV DNA levels were defined as those who had at least one HBV-DNA test in each quarter of a 360-day period, specifically during the intervals of days 0–90, 91–180, 181–270 and 271–360 (visual images are shown in the supplementary material, Figure S2).

The follow-up of the patients ended on the earliest of the following dates: 360 days after the index date, the date of death or departure from the insurance or the end of the study period (as of June 30, 2021).

Patients with a follow-up period < 360 days were deemed to have been regularly monitored for their HBV DNA levels if they underwent at least one HBV-DNA test per quarter during the period. Patients were considered censored if they did not receive prophylactic NUC therapy, had a follow-up period < 90 days and did not undergo an HBV DNA test until the end of the follow-up.

The IST at the index date was classified according to the risk level of HBV reactivation (high risk, intermediate risk, low risk and risk uncertain) regarding the Asian Pacific Association for the Study of the Liver (APASL) guideline [13]. The risk associated with ISTs using steroid medications was categorized based on the total dosage within a 30-day period from the index date. The therapies were considered high risk when patients received ≥ 560 mg steroids in total, intermediate risk when they received ≥ 300 mg but < 560 mg and low risk when they received < 300 mg within 30 days from the index date.

Furthermore, this study identified patient groups that received particularly high-risk ISTs. One group received treatments with rituximab and steroids within a week of the index date, and the other group was on the R-CHOP regimen, which administered rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (Oncovin) and prednisolone.

This study also collected information on the medical institutions that the patients visited. This encompassed the institutions' management organizations (e.g., university hospitals, national and public hospitals, clinics and other hospitals) at index date, their classifications as either hospital (HP) or general practice (GP), whether they are hub hospital for cancer treatment and the number of beds. Furthermore, the study obtained information on the patient's age at the index date and gender diagnosed within a year preceding the index date.

The study estimated the number and proportion of patients who received appropriate management to prevent HBV reactivation. The results were stratified based on the HBV reactivation risk classification associated with IST. For the sensitivity analysis, the evaluation period for the outcome calculation was shortened from 360 to 180 days. Additionally, the proportion was assessed for patient groups that received particularly high-risk ISTs, specifically the rituximab + steroid combination and the R-CHOP regimen.

This study calculated the odds ratios and 95% confidence intervals for each characteristic variable using the univariate logistic regression model to identify the characteristics of patients with appropriate management to prevent HBV reactivation across each risk level of IST.

The study examined the annual trends in the proportion of patients who received appropriate management to prevent HBV reactivation from 2012 to 2021. Using an interrupted time series (ITS) analysis, it assessed whether the trend in the proportion of appropriate management shifted before and after the guideline revision in January 2013. The regression model was used to estimate the level change and trend change. The dependent variable was the proportion of appropriate management. The independent variables included an indicator representing before and after the guideline revision in January 2013, the time elapsed since April 2012, time elapsed since the January 2013 guideline revision and a quadratic term for the time elapsed (to account for non–linear time trend).

Data processing was executed using the Amazon Athena engine, version 3 (Amazon.com, Inc.), and statistical analyses were conducted using R, version 4.2.1 (The R Project for Statistical Computing).

This study was conducted following the World Medical Association’s Declaration of Helsinki, respecting the ethical standards for research involving human participants.

This study did not require patient consent or approval from an institutional review board and independent ethics committee because the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects do not apply to studies exclusively on de-identified data.