A Retrospective Cohort Study of hepatitis D Virus (HDV) and Hepatitis B Virus (HBV) Co-infection in a Large Healthcare Association
This study investigated the epidemiology and clinical course of Hepatitis D Virus (HDV) infection in individuals with chronic Hepatitis B Virus (HBV) infection within a large healthcare organization, Maccabi Healthcare Services (MHS). The research aimed too determine HDV incidence and prevalence, identify factors associated with HDV diagnosis, and assess disease progression in HDV co-infected versus HBV mono-infected individuals.Methods
Researchers utilized electronic health records from MHS to identify individuals with chronic HBV infection between 2010 and 2021.A retrospective cohort design was employed, comparing those with documented HDV co-infection (HDV cohort) to those with HBV infection alone (HBV-Mono cohort). The index date was defined as the first documented diagnosis of either HDV or HBV.
Data collected included demographic characteristics (age, sex, socioeconomic status), medical history (presence of cancer, cardiovascular disease, diabetes, chronic kidney disease, hypertension, HIV, Hepatitis C Virus (HCV) infection, smoking status, drug dependency, alcohol abuse), body mass index (BMI), and healthcare utilization patterns.The physician specialty initially identifying the HBV or HDV infection was recorded, along with follow-up visits to gastroenterologists and primary care physicians.
Treatment data were gathered based on the dispensation of at least one course of antiviral therapy on or after the index date. Included treatments were pegylated-interferon, adefovir, entecavir, lamivudine, telbivudine, and tenofovir disproxil.
Disease progression was evaluated using a hierarchical classification system: (1) non-cirrhotic (NC), (2) compensated cirrhosis (CC), (3) decompensated cirrhosis (DC), (4) liver cancer (LC), (5) liver transplant (LT), and (6) death. Progression was defined as any movement to a more severe disease state within this hierarchy.
Statistical Analysis
HDV incidence and prevalence rates were calculated for both the chronic HBV population and the entire MHS member population (those enrolled for at least one day during the study period). Incidence calculations excluded individuals with a prior HDV diagnosis. Average annual rates were resolute for the 2010-2021 timeframe.
descriptive statistics were generated for each cohort and by baseline disease state (NC versus CC or more advanced disease/death). Categorical variables were presented as numbers and percentages, with missing data treated as a distinct category. Continuous variables were assessed for normality using the Kolmogorov-Smirnov test and summarized as means and standard deviations (SD) for normally distributed data, or medians and interquartile ranges (IQR) for non-normally distributed data. Group comparisons were performed using the Wilcoxon rank sum test,Pearson’s Chi-squared test,or Fisher’s exact test,with standardized mean differences (SMDs) reported.
Time-to-event analysis of disease progression was conducted using Kaplan-Meier plots and Cox proportional hazards regression models, stratified by baseline disease state. Censoring occurred on December 31,2021,or at the time of patient disenrollment from MHS or death (except when death was the outcome being analyzed). Multivariable Cox models were used to adjust for baseline characteristics including age, sex, socioeconomic status, BMI, pre-existing conditions (cancer, CVD, diabetes, CKD, hypertension, HIV, HCV PCR positivity), and lifestyle factors (smoking, drug dependency, alcohol abuse). A sensitivity analysis was performed, restricting the sample to patients with available HDV PCR results. Due to small sample sizes, stratification by baseline disease state was sometimes aggregated for non-NC states. All statistical analyses were performed using R statistical software version 4.0.2, with statistical meaning defined as P < 0.05. Ethical Considerations
The study protocol was approved by the Institutional Review Board of Maccabi Healthcare Services (protocol number 0037-22-MHS) and adhered to the principles outlined in the Declarations of Helsinki and Istanbul. Due to the anonymized nature of the data, informed consent was waived. The study followed the STROBE statement guidelines for reporting observational studies (checklist available in Supplementary Table S1).