Temporal Trends and Disparities in Hepatitis-B Mortality in the United States Between 1999-2020: A CDC WONDER Study

Temporal Trends and Disparities in Hepatitis-B Mortality in the United States Between 1999-2020: A CDC WONDER Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Temporal Trends and Disparities in Hepatitis-B Mortality in the United States Between 1999-2020: A CDC WONDER Study Dhruv Gandhi, Kinza Raza, Wajdan Ahmad, Ayesha Ahmed Cheema, Mihika Sawale, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7412047/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Aim To determine trends and disparities in hepatitis-B mortality in American adults older than 25 years between 1999–2020. Methods Retrospective analysis of CDC’s WONDER database was performed. For hepatitis-B, ICD-10 codes B16.0-16.2, B16.9, B17.0, B18.0, B18.1 were employed. Age-adjusted mortality rates(AAMR) and crude death rates(CDR) per 100,000 persons were determined. Average annual percentage change(AAPC) was determined using Joinpoint regression. Results 38,845 deaths were reported. AAMRs declined sharply from 1.12–0.87 between 1999–2004(AAPC:-4.45;p < 0.001) followed by a steady decline from 0.87 − 0.69(AAPC:-1.64;p < 0.001), resulting in an overall AAMR of 0.82(AAPC:-2.31;p < 0.001). Males had disproportionately higher AAMR(1.28) than females(0.41) and showed a greater decline(AAPC:-2.62;p < 0.001) than females(AAPC:-2.13;p < 0.001). Among races, non-Hispanic(NH) Asian/Pacific Islanders had disproportionately higher AAMRs(4.04) followed by NH Blacks(1.45), NH American Indians/Alaskan Natives(0.9), Hispanic(0.71), and NH Whites(0.55). All races saw declines in AAMR, with greatest decline seen in Hispanic(AAPC:-6.43;p < 0.001). Geographically, AAMRs were highest in West(1.17) followed by South(0.83). All census regions saw declines in AAMR, with greatest decline seen for Northeast(AAPC:-3.38;p < 0.001). Metropolitan areas had higher AAMR(0.84) than nonmetropolitan areas(0.59) and saw greater decline in AAMR(AAPC:-2.86;p < 0.001) than nonmetropolitan areas(AAPC:-0.55;p = 0.059). Of the 10-year age groups, CDR was highest for 55–64 years(1.46). The age groups of 25–34, 35–44, 45–54, and 55–64 years saw declining AAMRs, with greatest decline seen for 35–44 years(AAPC:-5.64;p < 0.001). However, 65–74, 75–84, and 85 + years saw an increase in AAMRs, with greatest increase seen for 85 + years(AAPC:1.12;p = 0.037). Conclusion We found a significant decline in hepatitis-B mortality, though persistent disparities exist. Elderly males, NH Asian/Pacific Islanders, residents of West and metropolitan areas experienced disproportionately higher mortality rates. sex differences racial disparities geographical variations viral hepatitis mortality hepatocellular carcinoma Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Hepatitis B virus (HBV) infection remains a major global public health concern, with chronic disease leading to significant morbidity and mortality from cirrhosis and hepatocellular carcinoma[ 1 ]. Although improved screening and universal vaccination programs have helped lower the incidence of HBV infections in the United States (US), hepatitis B-related mortality remains a persistent and often overlooked problem[ 2 , 3 ]. Despite the availability of effective antiviral therapies, many individuals with HBV infection remain undiagnosed or untreated, especially in vulnerable and underserved populations[ 4 ]. In the US, disparities in race, ethnicity, and socioeconomic status play a pivotal role in HBV-related outcomes. Immigrant populations, particularly those from Asia and sub-Saharan Africa, still carry a disproportionately excessive burden of chronic HBV infection and its consequent complications[ 4 , 5 ]. Additionally, differences in access to healthcare, insurance coverage, cultural barriers, and stigmatization make it more difficult for some sections of the population to get diagnosed, leading to delayed treatment and ultimately higher mortality rates in these groups[ 4 – 6 ]. While prior data has revealed a decline in the overall HBV-related mortality, it is unclear whether these improvements have been equitably distributed across different demographic groups[ 7 ]. In order to identify differences in mortality by age, sex, race, ethnicity, and geographic distribution, this study examined data from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database from 1999–2020. These insights are essential for advancing equity in HBV care and reducing preventable deaths, particularly in vulnerable populations. Materials and Methods A. Study design and population This retrospective, population-based analysis examined HBV-related mortality among US adults aged > 25 years from 1999–2020. Mortality data was sourced from the CDC WONDER platform, which aggregated death certificate records from all 50 states and the District of Columbia. HBV deaths were identified using the following International Classification of Diseases-10 codes: B16.0, B16.1, B16.2, B16.9, B17.0, B18.0, and B18.1. As the dataset is deidentified and is publicly available, Institutional Review Board approval was not required. The study methodology followed the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines. B. Data extraction and classification We stratified decedents by sex, race/ethnicity, geographical location, urbanization level, and age group. The CDC WONDER database defines race using five categories: American Indian/Alaska Native, Asian/Pacific Islander, Black/African American, White, and Hispanic/Latino. To ensure consistency across datasets and time periods, CDC WONDER employs a bridged-race methodology that assigns individuals of multiple races to a single category[ 8 , 9 ]. This approach also enhances statistical stability when analyzing mortality data across multiple dimensions and geographic areas[ 1 ]. Urbanization classification followed the 2013 National Center for Health Statistics Urban-Rural Scheme, which assigns each US county to one of six categories: Non-core, Micropolitan, Small Metro, Medium Metro, Large Fringe Metro, and Large Central Metro[ 9 ]. For analytical purposes, these were consolidated into two broader tiers: Metropolitan/Urban (comprising all 4 metro categories) and Nonmetropolitan/Rural (including Micropolitan and Noncore categories). Place of death, as recorded on death certificates, was grouped into either medical facility-based or non-medical facility-based settings. Medical facility-based deaths included subcategories such as dead on arrival, inpatient, outpatient or emergency room, and unknown medical status. Non-medical facility-based locations encompassed home, hospice facilities, nursing homes or long-term care, other specified locations, and unknown place of death[ 9 ]. Age-stratification was done using 10-year age group from 25 years onwards till 85 + years age group. C. Statistical analysis We computed both crude death rates (CDRs) and age-adjusted mortality rates (AAMRs) per 100,000 individuals across all population subgroups. Temporal trends were assessed using AAMRs, standardized to the 2000 US population, as defined by the CDC. CDRs can be misleading due to demographic differences, such as age distributions, across states and regions. CDC WONDER database underscores that AAMRs serve as relative indices suitable for subgroup comparisons, rather than indicators of absolute mortality risk[ 10 ]. Our analysis integrated three core indicators: number of deaths, AAMRs from HBV, and geographical location of death. Total deaths provided a foundational measure of HBV-related mortality burden, while AAMRs enabled equitable comparisons across populations and timeframes. Geographical patterns, our principal focus, offered insights into disparities in healthcare access, quality of services, and end-of-life care preferences. Examining these indicators collectively allowed for a nuanced understanding of Hepatitis B outcomes and associated inequities. Results A. Overall Trends Between 1999-2020, a total of 38,845 adult deaths attributed to HBV were reported in the US. AAMRs showed an initial significant decline from 1999-2004, with an AAPC of -4.45 (95% CI:-6.70 to -2.15) (p<0.001). However, from 2004-2020, the rate of decline slowed with an AAPC of -1.64 (95% CI:-2.10 to -1.17) (p<0.001). The overall trend from 1999-2020 showed a statistically significant decline with an AAPC of -2.31 (95% CI:-2.92 to -1.70) (p<0.001) (Figure 1). B. Trends s tratified by s ex From 1999-2020, males consistently demonstrated a significantly higher AAMR (1.28) for HBV compared to females (0.41). Among males, AAMR declined markedly from 1.74 in 1999 to 1.39 in 2003, with an AAPC of -5.18 (95% CI:-7.60 to -2,69) (p<0.001). This downward trend continued, reaching 1.02 in 2020, corresponding to an AAPC of -2.01 (95% CI:-2.31 to -1.70) (p<0.001). Overall, male AAMRs showed a significant reduction over the study period, with an AAPC of -2.62 (95% CI:-3.12 to -2.12) (p<0.001). In contrast, females exhibited a more modest decline in AAMR, decreasing from 0.56 in 1999 to 0.34 in 2020, with an AAPC of -2.13 (95% CI:-2.65 to -1.59) (p<0.001). C. T rends s tratified by r ace/ e thnicity Throughout the study period, non-Hispanic (NH) Asian/Pacific Islander adults consistently exhibited the highest AAMRs (4.04), followed by NH Black/African American adults (1.45), NH American Indians/Alaskan Natives adults (0.9), Hispanic/Latino adults (0.71), and NH White adults (0.55). Figure 2 shows the trends stratified by race/ethnicity for HBV mortality from 1999-2020. For NH Asian/Pacific Islander adults, AAMRs declined from 4.38 in 1999 to 3.81 in 2020, corresponding to an AAPC of -1.5 (95% CT:-2.03 to -0.97) (p<0.001). Similarly, NH Black/African American adults saw a marked decline in AAMRs from 2.25 in 1999 to 1.04 in 2020, reflecting an AAPC of -3.31 (95% CI:-3.78 to -2.84) (p<0.001). Among Hispanic/Latino adults, the AAMRs showed a substantial decrease from 1.72 in 1999 to 0.43 in 2020, with an AAPC of -6.43 (95% CI:-7.02 to -5.84) (p<0.001). NH White adults also saw a decline in AAMRs from 0.77 in 1999 to 0.42 in 2020, with an AAPC of -2.91 (95% CI:-3.29 to -2.54) (p<0.001), indicating a relatively slower but consistent declining trend. Trends for NH American Indians/Alaskan Natives were not reported due to unreliable data. D. Trends s tratified by g eographical l ocation 1. Census r egion s Between 1999-2020, the average AAMR for HBV remained highest in the West (1.17), followed by the South (0.83), Northeast (0.77), and Midwest (0.53) regions. Figure 3 shows the census region-stratified trends in HBV mortality from 1999-2020. For the West, an initial decline was observed from 1.58 in 1999 to 1.29 in 2003, with an AAPC of -5.06 (95% CI:-8.48 to -1.51) (p=0.01). This was followed by a gradual decrease from 1.23 in 2003 to 1.15 in 2014, with an AAPC of -1.20 (95% CI:-2.11 to -0.28) (p=0.015). A more pronounced decline occured between 2014-2018, with AAMRs dropping from 1.15 to 0.80 (AAPC:-7.80; 95% CI:-13.06 to -2.21) (p=0.011). However, a subsequent increase was observed from 0.80 in 2018 to 0.92 in 2020, with an AAPC of 7.56 (95% CI:-4.89 to 21.63) (p=0.22), though this change was not statistically significant. Overall, the West showed a declining mortality trend with an AAPC of -2.44 (95% CI:-4.02 to -0.84) (p=0.003). In the South, the AAMR significantly decreased from 1.18 in 1999 to 0.84 in 2004, with an AAPC of -6.01 (95% CI:-9.02 to -2.91) (p<0.001). This was followed by a slower but consistent decline from 0.84 in 2004 to 0.68 in 2020 (AAPC:-1.37%; 95% CI:-1.95 to -0.79) (p<0.001). The overall AAPC was -2.5 (95% CI:-3.31 to -1.68) (p<0.001). The Northeast also showed a substantial decline in AAMR, from 1.06 in 1999 to 0.52 in 2020, with an AAPC of -3.38 (95% CI:-4.00 to -2.75) (p<0.001). The Midwest observed a modest decline over the study period, from 0.62 in 1999 to 0.52 in 2020, with an AAPC of -1.19 (95% CI:-1.76 to -0.62) (p=0.001). 2. State s Significant variations in AAMRs were observed across US states throughout the study period. From 1999-2020, the District of Columbia (2.44), Hawaii (1.95), California (1.5), Oklahoma (1.33), and Rhode Island (1.21) ranked among the top five states with the highest AAMRs. In contrast, states such as North Dakota (0.26), South Dakota (0.27), Montana (0.32), and Wisconsin (0.36) reported some of the lowest AAMRs nationwide (Figure 4). 3 . Urban ization Between 1999-2020, urban areas exhibited slightly higher AAMRs for HBV (0.84) compared to rural areas (0.59). In urban regions, the AAMR declined from 1.20 in 1999 to 0.89 in 2005, corresponding to an AAPC of -4.53 (95% CI:-5.87 to -3.16) (p<0.001). This was followed by a period of gradual decline with minor fluctuations from 2005-2013, during which the AAMR decreased from 0.89 to 0.85, yielding an AAPC of -1.08 (95% CI:-2.18 to 0.03) (p=0.055). A more pronounced decrease occurred between 2013-2020, with the AAMR falling from 0.85 to 0.68, resulting in an AAPC of -3.42 (95% CI:-4.69 to -2.13) (p<0.001). Overall, urban areas demonstrated a consistent decline in mortality across the study period, with an AAPC of -2.86 (95% CI:-3.51 to -2.2) (p<0.001). In rural areas, the AAMR decreased modestly from 0.69 in 1999 to 0.56 in 2020, with an AAPC of -0.55 (95% CI:-1.13 to 0.02) (p=0.059), indicating a non-significant trend. Figure 5 shows the urbanization-stratified trends in HBV mortality from 1999-2020. E. Place of death Figure 6 shows the distribution of the places of death for adults with HBV from 1999-2020. Most patients died at inpatient medical facilities (54.02%), followed by at their homes (22.92%), and at nursing homes/long-term care facilities (8.25%). F. Trend stratified by age All 10-year age groups except 65-74 years, 75-84 years, and 85+ years saw declines in HBV-related mortality from 1999-2020. For the 25-34 years age group, an AAPC of -4.27 (95% CI:-5.43 to -3.09) (p<0.001) was reported. The greatest decline in mortality was seen for 35-44 years age group, with an AAPC of -5.64 (95% CI:-6.67 to -4.59) (p<0.001). For the 45-54 years and 55-64 years age groups, AAPCs of -4.84 (95% CI:-5.15 to -4.54) (p<0.001) and -1.43 (95% CI:-2.56 to -0.28) (p=0.015) were reported. For 65-74 years and 75-84 years, increase in AAMRs were reported although they were not significant (p=0.85 and p=0.76, respectively). For 85+ years, an AAPC of 1.12 (95% CI:0.08 to 2.18) (p=0.037) was reported. Figure 7 shows the age-stratified trends in hepatitis-B mortality from 1999-2020. Data tables are available within the supplementary file. Discussion In this 20-year analysis of mortality data from the CDC, we report several key findings. Firstly, HBV-related AAMRs declined rapidly in the early years upto 2004, followed by a slower, more gradual decrease through 2020, suggesting diminishing returns in the impact of existing public health strategies. Secondly, men consistently exhibited markedly higher AAMRs than women throughout the study period. Thirdly, NH Asian/Pacific Islanders bore the highest HBV-related mortality burden, with AAMRs nearly five times greater than the combined average of every other major racial and/or ethnic group. Fourth, marked variation by region and urbanicity was observed, with the West and metropolitan areas consistently demonstrating the highest AAMRs, whereas the Midwest and nonmetropolitan areas reported the lowest rates over the two-decade period. Lastly, despite the overall decline, substantial differences persisted at the state level, with states in the upper 90th percentile including the District of Columbia, Hawaii, California, Oklahoma, and Rhode Island exhibiting over five times higher mortality than those in the lower 10th percentile such as North Dakota, South Dakota, Montana, Wisconsin, and Illinois. HBV remains a major global public health concern, with an estimated 296 million individuals living with a chronic infection, many of whom are at risk of progressing to severe complications such as cirrhosis and hepatocellular carcinoma[ 11 ]. In 2022, HBV caused approximately 1.1 million deaths globally, making it the second leading infectious cause of mortality and accounting for 83–87% of hepatitis-related deaths worldwide. However, the Global Hepatitis Report 2024 revealed major gaps in care, with only 13% of HBV-infected individuals being diagnosed and just 3% having received antiviral treatment in low- and middle-income countries[ 12 ]. Our analysis revealed a sex-specific disparity in HBV-related mortality, with men consistently exhibiting higher death rates than women, despite an overall decline in mortality for both sexes. This pattern may be partially explained by the higher prevalence of hepatitis B surface antigen (HBsAg) in males across all age groups, as reported by Tsay et al.[ 13 ], who attributed the difference to both biological and behavioral factors. Further compounding this disparity, a meta-analysis in chronically infected Chinese populations identified male sex, alcohol use, and family history of hepatocellular carcinoma (HCC) as key risk factors, collectively associated with a two- to fourfold increase in HCC, which remains a major cause of HBV-related deaths[ 14 ]. Biological mechanisms, particularly hormonal influences, may further underlie this trend. Yu and Chen (1993) demonstrated that elevated serum testosterone levels significantly increased HCC risk in HBV-infected men[ 15 ]. In contrast, estrogen signaling appears protective; Wang et al.[ 16 ] showed that estrogen receptor-α suppresses HBV gene transcription by inhibiting hepatocyte nuclear factor 4α activity, thereby reducing viral replication and potentially contributing to the lower disease burden observed in women. In addition to sex-based disparities, our study highlights persistent racial differences in HBV mortality, with NH Asians/Pacific Islanders experiencing disproportionately higher mortality rates compared to other racial groups. In contrast, previous studies examining all types of viral hepatitis had identified American Indian populations as having the highest overall mortality[ 17 ]. This distinction underscores the need to analyze viral hepatitis subtypes separately, as different racial groups bear different disease burdens. Such understanding can inform targeted vaccination and prevention efforts in affected populations. Notably, the racial disparity observed in our retrospective analysis is consistent with findings by Kim et al.[ 18 ], who reported that Asians had the highest prevalence of chronic hepatitis B infection at 2.74% (n = 47/1,740), nearly 18 times higher than that seen for NH Whites, further highlighting significant racial disparities in HBV burden and awareness in the US. Prior epidemiologic studies indicate that Asian immigrants have the highest prevalence of HBV in the US[ 19 , 20 ]. Limited HBV-related knowledge within these communities has been shown to significantly reduce screening frequencies, leading to delayed diagnosis and missed opportunities for early intervention, which in turn contribute to increased morbidity and mortality[ 21 – 23 ]. In response, the US Preventive Services Task Force in 2014 classified individuals born in Asia as a high-risk group and recommended routine HBV screening for this population[ 24 ]. In addition, we observed marked geographical disparities in HBV-related mortality, with the West carrying the highest burden among all US regions. Western States, including California, Oregon, and Washington consistently reported mortality rates well above the national average of 0.47 per 100,000 population, demonstrating a distinct regional concentration. This elevated burden may be partly attributable to the larger Asian and Pacific Islander populations in these states, demographic groups historically documented to have higher prevalence of chronic HBV infection[ 25 , 26 ]. Supporting this observation, a modeling study by Razavi-Shearer et al.[ 27 ] estimated that, as of 2020, approximately 76% of chronic HBV cases among U.S. immigrants originated from Asia, emphasizing the clustering of infections among foreign-born individuals. The study also highlighted that national surveys likely underestimate true HBV prevalence due to underrepresentation of immigrant populations, underscoring the need for targeted interventions in high-risk regions[ 27 ]. Our analysis additionally identified concentrated HBV-related mortality in states within the top 90th percentile, notably the District of Columbia, Hawaii, and California. This geographical pattern correlates with states hosting the largest foreign-born populations, including California (27.3%), New Jersey (24.2%), New York (23.1%), Florida (22.1%), and Nevada (19.3%)[ 26 ]. This strong correlation between elevated HBV mortality rates and higher immigrant population densities in these states reflects persistent geographical disparities and emphasizes the urgent need for region-specific public health interventions. Despite higher average mortality, urban areas experienced more consistent and significant declines over time, while rural areas showed minimal improvement. This disparity may reflect underdiagnosis and limited access to care, as recent US data showed that the vast majority of HBV/Hepatitis-D virus diagnoses originated from urban providers, with rural providers contributing only a small proportion of cases[ 28 ]. Corroborating these findings, Wong et al.[ 29 ] documented a rising incidence of HCC in rural populations, highlighting the downstream consequences of delayed diagnosis and inadequate management of chronic liver disease. Further evidence indicates that rural patients are significantly less likely to undergo liver cancer screening or receive specialist consultation, reflecting structural barriers to early detection and care delivery[ 30 ]. Collectively, these studies highlight the role of geographic inequities in perpetuating stagnant HBV-related outcomes in rural settings. Whether acquired at birth or later, all individuals with chronic HBV need lifelong medical care to monitor disease progression, assess antiviral treatment necessity, and undergo regular HCC screening as appropriate[ 31 ]. These clinical practices align with CDC guidelines, which stress on protecting household contacts through timely screening and vaccination[ 32 ]. However, despite these recommendations, notable gaps remain in hepatitis B management across the United States, including uneven screening, limited provider awareness, and systemic obstacles to treatment access[ 33 ]. Addressing these gaps requires improved provider and patient education, expanded access to rapid testing, simplified treatment protocols, and coordinated efforts from healthcare systems and policymakers. Such strategies are vital to reducing disparities and advancing hepatitis B elimination. Declarations Competing Interests: The authors have no conflicts of interest to report. Funding Declaration: The authors report no financial sources of support. Clinical Trial Number: Not applicable. Ethics, Consent to Participate, and Consent to Publish declarations: Not applicable. Author Contribution WA and AAC extracted and analysed the data. DG, KR, WA, AAC, MI wrote the main manuscript text. SG prepared the tables and SF prepared the figures. DG critically reviewed and edited the manuscript. All authors reviewed the manuscript. Data Availability Data is provided within the supplementary information files References World Health Organization. Hepatitis B [Internet]. Geneva: WHO; 2024 Feb [cited 2025 Jun 20]. Available from:https://www.who.int/news-room/fact-sheets/detail/hepatitis-b Kim WR, Loomba R, Berg T, Jonas MM, Flisiak R, Yi Q, et al. Prevalence of chronic hepatitis B virus infection in the United States. Am J Gastroenterol. 2020 Sep;115(9):1370–7. Cohen C, Evans AA, London WT, Block JM, Conti M, Block TM. 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Available from: https://usafacts.org/articles/where-are-immigrants-moving-to-in-the-us/ Razavi-Shearer, D., Gamkrelidze, I., Pan, C. Q., Razavi-Shearer, K., Blach, S., Estes, C., Mooneyhan, E., & Razavi, H. (2023). The impact of immigration on hepatitis B burden in the United States: a modelling study. Lancet regional health. Americas , 22 , 100516. https://doi.org/10.1016/j.lana.2023.100516 Gish, R. G., Jacobson, I. M., Lim, J. K., Waters-Banker, C., Kaushik, A., Kim, C., Cyhaniuk, A., & Wong, R. J. (2024). Prevalence and characteristics of hepatitis delta virus infection in patients with hepatitis B in the United States: An analysis of the All-Payer Claims Database. Hepatology (Baltimore, Md.) , 79 (5), 1117–1128. https://doi.org/10.1097/HEP.0000000000000687 Wong, R. J., Saab, S., Konyn, P., Sundaram, V., & Khalili, M. (2021). Rural-Urban Geographical Disparities in Hepatocellular Carcinoma Incidence Among US Adults, 2004-2017. The American journal of gastroenterology , 116 (2), 401–406. https://doi.org/10.14309/ajg.0000000000000948 Rongey, C., Shen, H., Hamilton, N., Backus, L. I., Asch, S. M., & Knight, S. (2013). Impact of rural residence and health system structure on quality of liver care. PloS one , 8 (12), e84826. https://doi.org/10.1371/journal.pone.0084826 McMahon B. J. (2010). Natural history of chronic hepatitis B. Clinics in liver disease , 14 (3), 381–396. https://doi.org/10.1016/j.cld.2010.05.007 Centers for Disease Control and Prevention (CDC) When Someone Close To You Has Chronic Hepatitis B. CDC.gov; Updated June 2010. Accessed July 18, 2025. https://www.cdc.gov/hepatitis/hbv/pdfs/hepbwhensomeoneclose.pdf Wong R. J. (2025). Gaps and disparities in the treatment of chronic hepatitis B infection in the USA. Gastroenterology report , 13 , goaf016. https://doi.org/10.1093/gastro/goaf016 Additional Declarations No competing interests reported. Supplementary Files HepBTablesfinal.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Gandhi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCUlEQVRIiWNgGAWjYDCCG3AGY+ODDwYSciD2gQdEamk2nFFgYwzWkkCcFgY2aY4PaYkNIA4+LXy3e59J8/yyy+O73dwgzWBwOH1+2OGHQFvs5HQbsGuRvHPcTJq3L7lY8s7BBuMCg8O5G2+nGQC1JBubHcCuxeBGGpvkzB7mxA03EhuSZ4C0zE4AaTmQuA2/lnqwlsM8QIcZzk7/QFCLxIcfh0FaGpt5DNIS5KVz8NsieSON2eJjw/HEmTcSmxlnGNgYbpDOKTiQYIDbL3w30hhvJPypTuy7kf78x4c/EvLys9M3f/hQYSeHSwsYMLYhOxWs0gCPcjD4g8SWbyCkehSMglEwCkYaAABX2m/q3Sf2nAAAAABJRU5ErkJggg==","orcid":"","institution":"St Francis Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Dhruv","middleName":"","lastName":"Gandhi","suffix":""},{"id":514285058,"identity":"a4feb2e0-07f7-4a8b-885f-48612c4cb141","order_by":1,"name":"Kinza Raza","email":"","orcid":"","institution":"Bakhtawar Amin Medical \u0026 Dental College","correspondingAuthor":false,"prefix":"","firstName":"Kinza","middleName":"","lastName":"Raza","suffix":""},{"id":514285059,"identity":"cc3ecb67-a6c3-48a3-a958-83707ba9b387","order_by":2,"name":"Wajdan Ahmad","email":"","orcid":"","institution":"Al Tibri Medical College","correspondingAuthor":false,"prefix":"","firstName":"Wajdan","middleName":"","lastName":"Ahmad","suffix":""},{"id":514285060,"identity":"cd6eaa52-0ca3-4e68-b9ff-574a3626f29d","order_by":3,"name":"Ayesha Ahmed Cheema","email":"","orcid":"","institution":"Al Tibri Medical College","correspondingAuthor":false,"prefix":"","firstName":"Ayesha","middleName":"Ahmed","lastName":"Cheema","suffix":""},{"id":514285061,"identity":"e2d39412-a355-4837-8398-41c9e61208e1","order_by":4,"name":"Mihika Sawale","email":"","orcid":"","institution":"KJ Somaiya Medical College and Research Centre","correspondingAuthor":false,"prefix":"","firstName":"Mihika","middleName":"","lastName":"Sawale","suffix":""},{"id":514285062,"identity":"2c33ec10-94e6-4b5d-9197-f5fae6797d58","order_by":5,"name":"Sadia Ghafur","email":"","orcid":"","institution":"United Medical and Dental College","correspondingAuthor":false,"prefix":"","firstName":"Sadia","middleName":"","lastName":"Ghafur","suffix":""},{"id":514285063,"identity":"415444ed-ac44-49d5-bd92-8b3288fdba4b","order_by":6,"name":"Saamin Farooq","email":"","orcid":"","institution":"Al-Nafees Medical College","correspondingAuthor":false,"prefix":"","firstName":"Saamin","middleName":"","lastName":"Farooq","suffix":""}],"badges":[],"createdAt":"2025-08-19 23:23:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7412047/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7412047/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91456686,"identity":"a528eac5-8a5e-4f87-a787-29c9dbef09bc","added_by":"auto","created_at":"2025-09-16 16:25:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":115253,"visible":true,"origin":"","legend":"\u003cp\u003eOverall and sex-stratified trends in hepatitis-B mortality from 1999-2020.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7412047/v1/11dd201be4dab3e91748a115.png"},{"id":91456687,"identity":"6bb69801-fb83-40f2-9463-7886e58722ec","added_by":"auto","created_at":"2025-09-16 16:25:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":107541,"visible":true,"origin":"","legend":"\u003cp\u003eRace/ethnicity-stratified trends in hepatitis-B mortality from 1999-2020.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7412047/v1/1eedb7a61ed07a49d0f8b255.png"},{"id":91456688,"identity":"acb7df2c-7473-41ba-892a-5877459d397a","added_by":"auto","created_at":"2025-09-16 16:25:16","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":116967,"visible":true,"origin":"","legend":"\u003cp\u003eCensus region-stratified trends in hepatitis-B mortality from 1999-2020.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7412047/v1/f0fc693842c3c81eba9b2663.png"},{"id":91459993,"identity":"b1dc1e34-b472-43d1-89be-fe5031432787","added_by":"auto","created_at":"2025-09-16 16:57:16","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":146244,"visible":true,"origin":"","legend":"\u003cp\u003eMap of the United States showing states-wise stratification of hepatitis-B mortality from 1999-2020.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7412047/v1/441ef15796f27cde2add5044.png"},{"id":91457184,"identity":"aff98835-6f20-4592-95ea-482d1a31b2fc","added_by":"auto","created_at":"2025-09-16 16:33:16","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":63871,"visible":true,"origin":"","legend":"\u003cp\u003eUrbanization-stratified trends in hepatitis-B mortality from 1999-2020.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7412047/v1/1759c6698afbc3e17f0ed2d4.png"},{"id":91457188,"identity":"60c2b761-1c8f-4df1-9845-047bbdb20ff9","added_by":"auto","created_at":"2025-09-16 16:33:16","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":81264,"visible":true,"origin":"","legend":"\u003cp\u003ePie chart showing the distribution of the places of death in hepatitis-B mortality from 1999-2020.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7412047/v1/c95155c0f7ee745abb4aed17.png"},{"id":91456701,"identity":"ba0f890d-9b45-4525-b794-7d3128edf9f7","added_by":"auto","created_at":"2025-09-16 16:25:16","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":176427,"visible":true,"origin":"","legend":"\u003cp\u003eAge-stratified trends in hepatitis-B mortality from 1999-2020.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-7412047/v1/62f37585f16b17fb6c0f84d4.png"},{"id":95193808,"identity":"064b7db8-aa93-48c9-9773-bd3ea27de59e","added_by":"auto","created_at":"2025-11-05 10:54:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1260389,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7412047/v1/6a14453d-37da-4aa5-a5e4-919d2a960186.pdf"},{"id":91457192,"identity":"9aede869-ba2c-461d-bca5-9057aa558903","added_by":"auto","created_at":"2025-09-16 16:33:17","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":2344087,"visible":true,"origin":"","legend":"","description":"","filename":"HepBTablesfinal.docx","url":"https://assets-eu.researchsquare.com/files/rs-7412047/v1/0903fea6db1004cf6fdd5b19.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Temporal Trends and Disparities in Hepatitis-B Mortality in the United States Between 1999-2020: A CDC WONDER Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHepatitis B virus (HBV) infection remains a major global public health concern, with chronic disease leading to significant morbidity and mortality from cirrhosis and hepatocellular carcinoma[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although improved screening and universal vaccination programs have helped lower the incidence of HBV infections in the United States (US), hepatitis B-related mortality remains a persistent and often overlooked problem[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Despite the availability of effective antiviral therapies, many individuals with HBV infection remain undiagnosed or untreated, especially in vulnerable and underserved populations[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In the US, disparities in race, ethnicity, and socioeconomic status play a pivotal role in HBV-related outcomes. Immigrant populations, particularly those from Asia and sub-Saharan Africa, still carry a disproportionately excessive burden of chronic HBV infection and its consequent complications[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Additionally, differences in access to healthcare, insurance coverage, cultural barriers, and stigmatization make it more difficult for some sections of the population to get diagnosed, leading to delayed treatment and ultimately higher mortality rates in these groups[\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. While prior data has revealed a decline in the overall HBV-related mortality, it is unclear whether these improvements have been equitably distributed across different demographic groups[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In order to identify differences in mortality by age, sex, race, ethnicity, and geographic distribution, this study examined data from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) database from 1999\u0026ndash;2020. These insights are essential for advancing equity in HBV care and reducing preventable deaths, particularly in vulnerable populations.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eA. Study design and population\u003c/h2\u003e\u003cp\u003eThis retrospective, population-based analysis examined HBV-related mortality among US adults aged\u0026thinsp;\u0026gt;\u0026thinsp;25 years from 1999\u0026ndash;2020. Mortality data was sourced from the CDC WONDER platform, which aggregated death certificate records from all 50 states and the District of Columbia. HBV deaths were identified using the following International Classification of Diseases-10 codes: B16.0, B16.1, B16.2, B16.9, B17.0, B18.0, and B18.1. As the dataset is deidentified and is publicly available, Institutional Review Board approval was not required. The study methodology followed the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eB. Data extraction and classification\u003c/h3\u003e\n\u003cp\u003eWe stratified decedents by sex, race/ethnicity, geographical location, urbanization level, and age group. The CDC WONDER database defines race using five categories: American Indian/Alaska Native, Asian/Pacific Islander, Black/African American, White, and Hispanic/Latino. To ensure consistency across datasets and time periods, CDC WONDER employs a bridged-race methodology that assigns individuals of multiple races to a single category[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. This approach also enhances statistical stability when analyzing mortality data across multiple dimensions and geographic areas[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Urbanization classification followed the 2013 National Center for Health Statistics Urban-Rural Scheme, which assigns each US county to one of six categories: Non-core, Micropolitan, Small Metro, Medium Metro, Large Fringe Metro, and Large Central Metro[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. For analytical purposes, these were consolidated into two broader tiers: Metropolitan/Urban (comprising all 4 metro categories) and Nonmetropolitan/Rural (including Micropolitan and Noncore categories). Place of death, as recorded on death certificates, was grouped into either medical facility-based or non-medical facility-based settings. Medical facility-based deaths included subcategories such as dead on arrival, inpatient, outpatient or emergency room, and unknown medical status. Non-medical facility-based locations encompassed home, hospice facilities, nursing homes or long-term care, other specified locations, and unknown place of death[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Age-stratification was done using 10-year age group from 25 years onwards till 85\u0026thinsp;+\u0026thinsp;years age group.\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eC. Statistical analysis\u003c/h2\u003e\u003cp\u003eWe computed both crude death rates (CDRs) and age-adjusted mortality rates (AAMRs) per 100,000 individuals across all population subgroups. Temporal trends were assessed using AAMRs, standardized to the 2000 US population, as defined by the CDC. CDRs can be misleading due to demographic differences, such as age distributions, across states and regions. CDC WONDER database underscores that AAMRs serve as relative indices suitable for subgroup comparisons, rather than indicators of absolute mortality risk[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Our analysis integrated three core indicators: number of deaths, AAMRs from HBV, and geographical location of death. Total deaths provided a foundational measure of HBV-related mortality burden, while AAMRs enabled equitable comparisons across populations and timeframes. Geographical patterns, our principal focus, offered insights into disparities in healthcare access, quality of services, and end-of-life care preferences. Examining these indicators collectively allowed for a nuanced understanding of Hepatitis B outcomes and associated inequities.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eA.\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eOverall Trends\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween 1999-2020, a total of 38,845 adult deaths attributed to HBV were reported in the US. AAMRs showed an initial significant decline from 1999-2004, with an AAPC of -4.45 (95% CI:-6.70 to -2.15) (p\u0026lt;0.001). However, from 2004-2020, the rate of decline slowed with an AAPC of -1.64 (95% CI:-2.10 to -1.17) (p\u0026lt;0.001). The overall trend from 1999-2020 showed a statistically significant decline with an AAPC of\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e-2.31 (95% CI:-2.92 to -1.70) (p\u0026lt;0.001) (Figure 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB.\u0026nbsp;\u0026nbsp;Trends\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003cstrong\u003etratified by\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003cstrong\u003eex\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrom 1999-2020, males consistently demonstrated a significantly higher AAMR (1.28) for HBV compared to females (0.41). Among males, AAMR declined markedly from 1.74 in 1999 to 1.39 in 2003, with an AAPC of -5.18 (95% CI:-7.60 to -2,69) (p\u0026lt;0.001). This downward trend continued, reaching 1.02 in 2020, corresponding to an AAPC of -2.01 (95% CI:-2.31 to -1.70) (p\u0026lt;0.001). Overall, male AAMRs showed a significant reduction over the study period, with an AAPC of \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e-2.62 (95% CI:-3.12 to -2.12) (p\u0026lt;0.001). In contrast, females exhibited a more modest decline in AAMR, decreasing from 0.56 in 1999 to 0.34 in 2020, with an AAPC of\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e-2.13 (95% CI:-2.65 to -1.59) (p\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC.\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eT\u003c/strong\u003e\u003cstrong\u003erends\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003cstrong\u003etratified by\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003er\u003c/strong\u003e\u003cstrong\u003eace/\u003c/strong\u003e\u003cstrong\u003ee\u003c/strong\u003e\u003cstrong\u003ethnicity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThroughout the study period, non-Hispanic (NH) Asian/Pacific Islander adults consistently exhibited the highest AAMRs (4.04), followed by NH Black/African American adults (1.45), \u0026nbsp;NH American Indians/Alaskan Natives adults (0.9), Hispanic/Latino adults (0.71), and NH White adults (0.55). Figure 2 shows the trends stratified by race/ethnicity for HBV mortality from 1999-2020.\u003c/p\u003e\n\u003cp\u003eFor NH Asian/Pacific Islander adults, AAMRs declined from 4.38 in 1999 to 3.81 in 2020, corresponding to an AAPC of -1.5 (95% CT:-2.03 to -0.97) (p\u0026lt;0.001). Similarly, NH Black/African American adults saw a marked decline in AAMRs from 2.25 in 1999 to 1.04 in 2020, reflecting an AAPC of -3.31 (95% CI:-3.78 to -2.84) (p\u0026lt;0.001). Among Hispanic/Latino adults, the AAMRs showed a substantial decrease from 1.72 in 1999 to 0.43 in 2020, with an AAPC of -6.43 (95% CI:-7.02 to -5.84) (p\u0026lt;0.001). NH White adults also saw a decline in AAMRs from 0.77 in 1999 to 0.42 in 2020, with an AAPC of -2.91 (95% CI:-3.29 to -2.54) (p\u0026lt;0.001), indicating a relatively slower but consistent declining trend. Trends for NH American Indians/Alaskan Natives were not reported due to unreliable data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD.\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eTrends\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003cstrong\u003etratified by\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eg\u003c/strong\u003e\u003cstrong\u003eeographical\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003el\u003c/strong\u003e\u003cstrong\u003eocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCensus\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003er\u003c/strong\u003e\u003cstrong\u003eegion\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween 1999-2020, the average AAMR for HBV remained highest in the West (1.17), followed by the South (0.83), Northeast (0.77), and Midwest (0.53) regions. Figure 3 shows the census region-stratified trends in HBV mortality from 1999-2020.\u003c/p\u003e\n\u003cp\u003eFor the West, an initial decline was observed from 1.58 in 1999 to 1.29 in 2003, with an AAPC of -5.06 (95% CI:-8.48 to -1.51) (p=0.01). This was followed by a gradual decrease from 1.23 in 2003 to 1.15 in 2014, with an AAPC of -1.20 (95% CI:-2.11 to\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e-0.28) (p=0.015). A more pronounced decline occured between 2014-2018, with AAMRs dropping from 1.15 to 0.80 (AAPC:-7.80; 95% CI:-13.06 to -2.21) (p=0.011). However, a subsequent increase was observed from 0.80 in 2018 to 0.92 in 2020, with an AAPC of 7.56 (95% CI:-4.89 to 21.63) (p=0.22), though this change was not statistically significant. Overall, the West showed a declining mortality trend with an AAPC of -2.44 (95% CI:-4.02 to -0.84) (p=0.003).\u003c/p\u003e\n\u003cp\u003eIn the South, the AAMR significantly decreased from 1.18 in 1999 to 0.84 in 2004,\u003c/p\u003e\n\u003cp\u003ewith an AAPC of -6.01 (95% CI:-9.02 to -2.91) (p\u0026lt;0.001). This was followed by a slower but consistent decline from 0.84 in 2004 to 0.68 in 2020 (AAPC:-1.37%; 95% CI:-1.95 to -0.79) (p\u0026lt;0.001). The overall AAPC was -2.5 (95% CI:-3.31 to -1.68) (p\u0026lt;0.001). The Northeast also showed a substantial decline in AAMR, from 1.06 in 1999 to 0.52 in 2020, with an AAPC of -3.38 (95% CI:-4.00 to -2.75) (p\u0026lt;0.001). The Midwest observed a modest decline over the study period, from 0.62 in 1999 to 0.52 in 2020, with an AAPC of -1.19 (95% CI:-1.76 to -0.62) (p=0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eState\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSignificant variations in AAMRs were observed across US states throughout the study period. From 1999-2020, the District of Columbia (2.44), Hawaii (1.95), California (1.5), Oklahoma (1.33), and Rhode Island (1.21) ranked among the top five states with the highest AAMRs. In contrast, states such as North Dakota (0.26), South Dakota (0.27), Montana (0.32), and Wisconsin (0.36) reported some of the lowest AAMRs nationwide (Figure 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003cstrong\u003e.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eUrban\u003c/strong\u003e\u003cstrong\u003eization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween 1999-2020, urban areas exhibited slightly higher AAMRs for HBV (0.84) compared to rural areas (0.59). In urban regions, the AAMR declined from 1.20 in 1999 to 0.89 in 2005, corresponding to an AAPC of -4.53 (95% CI:-5.87 to -3.16) (p\u0026lt;0.001). This was followed by a period of gradual decline with minor fluctuations from 2005-2013, during which the AAMR decreased from 0.89 to 0.85, yielding an AAPC of -1.08 (95% CI:-2.18 to 0.03) (p=0.055). A more pronounced decrease occurred between 2013-2020, with the AAMR falling from 0.85 to 0.68, resulting in an AAPC of -3.42 (95% CI:-4.69 to -2.13) (p\u0026lt;0.001). Overall, urban areas demonstrated a consistent decline in mortality across the study period, with an AAPC of -2.86 (95% CI:-3.51 to -2.2) (p\u0026lt;0.001). In rural areas, the AAMR decreased modestly from 0.69 in 1999 to 0.56 in 2020, with an AAPC of -0.55 (95% CI:-1.13 to 0.02) (p=0.059), indicating a non-significant trend. Figure 5 shows the urbanization-stratified trends in HBV mortality from 1999-2020.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eE.\u0026nbsp;\u0026nbsp;Place of death\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 6 shows the distribution of the places of death for adults with HBV from 1999-2020. Most patients died at inpatient medical facilities (54.02%), followed by at their homes (22.92%), and at nursing homes/long-term care facilities (8.25%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eF.\u0026nbsp; \u0026nbsp;Trend stratified by age\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll 10-year age groups except 65-74 years, 75-84 years, and 85+ years saw declines in HBV-related mortality from 1999-2020. For the 25-34 years age group, an AAPC of -4.27 (95% CI:-5.43 to -3.09) (p\u0026lt;0.001) was reported. The greatest decline in mortality was seen for 35-44 years age group, with an AAPC of -5.64 (95% CI:-6.67 to -4.59) (p\u0026lt;0.001). For the 45-54 years and 55-64 years age groups, AAPCs of -4.84 (95% CI:-5.15 to -4.54) (p\u0026lt;0.001) and -1.43 (95% CI:-2.56 to -0.28) (p=0.015) were reported. For 65-74 years and 75-84 years, increase in AAMRs were reported although they were not significant (p=0.85 and p=0.76, respectively). For 85+ years, an AAPC of 1.12 (95% CI:0.08 to 2.18) (p=0.037) was reported. Figure 7 shows the age-stratified trends in hepatitis-B mortality from 1999-2020.\u003c/p\u003e\n\u003cp\u003eData tables are available within the supplementary file.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this 20-year analysis of mortality data from the CDC, we report several key findings. Firstly, HBV-related AAMRs declined rapidly in the early years upto 2004, followed by a slower, more gradual decrease through 2020, suggesting diminishing returns in the impact of existing public health strategies. Secondly, men consistently exhibited markedly higher AAMRs than women throughout the study period. Thirdly, NH Asian/Pacific Islanders bore the highest HBV-related mortality burden, with AAMRs nearly five times greater than the combined average of every other major racial and/or ethnic group. Fourth, marked variation by region and urbanicity was observed, with the West and metropolitan areas consistently demonstrating the highest AAMRs, whereas the Midwest and nonmetropolitan areas reported the lowest rates over the two-decade period. Lastly, despite the overall decline, substantial differences persisted at the state level, with states in the upper 90th percentile including the District of Columbia, Hawaii, California, Oklahoma, and Rhode Island exhibiting over five times higher mortality than those in the lower 10th percentile such as North Dakota, South Dakota, Montana, Wisconsin, and Illinois.\u003c/p\u003e\u003cp\u003eHBV remains a major global public health concern, with an estimated 296\u0026nbsp;million individuals living with a chronic infection, many of whom are at risk of progressing to severe complications such as cirrhosis and hepatocellular carcinoma[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In 2022, HBV caused approximately 1.1\u0026nbsp;million deaths globally, making it the second leading infectious cause of mortality and accounting for 83\u0026ndash;87% of hepatitis-related deaths worldwide. However, the Global Hepatitis Report 2024 revealed major gaps in care, with only 13% of HBV-infected individuals being diagnosed and just 3% having received antiviral treatment in low- and middle-income countries[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur analysis revealed a sex-specific disparity in HBV-related mortality, with men consistently exhibiting higher death rates than women, despite an overall decline in mortality for both sexes. This pattern may be partially explained by the higher prevalence of hepatitis B surface antigen (HBsAg) in males across all age groups, as reported by Tsay et al.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], who attributed the difference to both biological and behavioral factors. Further compounding this disparity, a meta-analysis in chronically infected Chinese populations identified male sex, alcohol use, and family history of hepatocellular carcinoma (HCC) as key risk factors, collectively associated with a two- to fourfold increase in HCC, which remains a major cause of HBV-related deaths[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Biological mechanisms, particularly hormonal influences, may further underlie this trend. Yu and Chen (1993) demonstrated that elevated serum testosterone levels significantly increased HCC risk in HBV-infected men[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In contrast, estrogen signaling appears protective; Wang et al.[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] showed that estrogen receptor-α suppresses HBV gene transcription by inhibiting hepatocyte nuclear factor 4α activity, thereby reducing viral replication and potentially contributing to the lower disease burden observed in women.\u003c/p\u003e\u003cp\u003eIn addition to sex-based disparities, our study highlights persistent racial differences in HBV mortality, with NH Asians/Pacific Islanders experiencing disproportionately higher mortality rates compared to other racial groups. In contrast, previous studies examining all types of viral hepatitis had identified American Indian populations as having the highest overall mortality[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This distinction underscores the need to analyze viral hepatitis subtypes separately, as different racial groups bear different disease burdens. Such understanding can inform targeted vaccination and prevention efforts in affected populations. Notably, the racial disparity observed in our retrospective analysis is consistent with findings by Kim et al.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], who reported that Asians had the highest prevalence of chronic hepatitis B infection at 2.74% (n\u0026thinsp;=\u0026thinsp;47/1,740), nearly 18 times higher than that seen for NH Whites, further highlighting significant racial disparities in HBV burden and awareness in the US. Prior epidemiologic studies indicate that Asian immigrants have the highest prevalence of HBV in the US[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Limited HBV-related knowledge within these communities has been shown to significantly reduce screening frequencies, leading to delayed diagnosis and missed opportunities for early intervention, which in turn contribute to increased morbidity and mortality[\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In response, the US Preventive Services Task Force in 2014 classified individuals born in Asia as a high-risk group and recommended routine HBV screening for this population[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn addition, we observed marked geographical disparities in HBV-related mortality, with the West carrying the highest burden among all US regions. Western States, including California, Oregon, and Washington consistently reported mortality rates well above the national average of 0.47 per 100,000 population, demonstrating a distinct regional concentration. This elevated burden may be partly attributable to the larger Asian and Pacific Islander populations in these states, demographic groups historically documented to have higher prevalence of chronic HBV infection[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Supporting this observation, a modeling study by Razavi-Shearer et al.[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] estimated that, as of 2020, approximately 76% of chronic HBV cases among U.S. immigrants originated from Asia, emphasizing the clustering of infections among foreign-born individuals. The study also highlighted that national surveys likely underestimate true HBV prevalence due to underrepresentation of immigrant populations, underscoring the need for targeted interventions in high-risk regions[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Our analysis additionally identified concentrated HBV-related mortality in states within the top 90th percentile, notably the District of Columbia, Hawaii, and California. This geographical pattern correlates with states hosting the largest foreign-born populations, including California (27.3%), New Jersey (24.2%), New York (23.1%), Florida (22.1%), and Nevada (19.3%)[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. This strong correlation between elevated HBV mortality rates and higher immigrant population densities in these states reflects persistent geographical disparities and emphasizes the urgent need for region-specific public health interventions.\u003c/p\u003e\u003cp\u003eDespite higher average mortality, urban areas experienced more consistent and significant declines over time, while rural areas showed minimal improvement. This disparity may reflect underdiagnosis and limited access to care, as recent US data showed that the vast majority of HBV/Hepatitis-D virus diagnoses originated from urban providers, with rural providers contributing only a small proportion of cases[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Corroborating these findings, Wong et al.[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] documented a rising incidence of HCC in rural populations, highlighting the downstream consequences of delayed diagnosis and inadequate management of chronic liver disease. Further evidence indicates that rural patients are significantly less likely to undergo liver cancer screening or receive specialist consultation, reflecting structural barriers to early detection and care delivery[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Collectively, these studies highlight the role of geographic inequities in perpetuating stagnant HBV-related outcomes in rural settings.\u003c/p\u003e\u003cp\u003eWhether acquired at birth or later, all individuals with chronic HBV need lifelong medical care to monitor disease progression, assess antiviral treatment necessity, and undergo regular HCC screening as appropriate[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. These clinical practices align with CDC guidelines, which stress on protecting household contacts through timely screening and vaccination[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. However, despite these recommendations, notable gaps remain in hepatitis B management across the United States, including uneven screening, limited provider awareness, and systemic obstacles to treatment access[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Addressing these gaps requires improved provider and patient education, expanded access to rapid testing, simplified treatment protocols, and coordinated efforts from healthcare systems and policymakers. Such strategies are vital to reducing disparities and advancing hepatitis B elimination.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003eThe authors have no conflicts of interest to report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Declaration:\u0026nbsp;\u003c/strong\u003eThe authors report no financial sources of support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics, Consent to Participate, and Consent to Publish declarations:\u003c/strong\u003e Not applicable.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eWA and AAC extracted and analysed the data. DG, KR, WA, AAC, MI wrote the main manuscript text. SG prepared the tables and SF prepared the figures. DG critically reviewed and edited the manuscript. All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData is provided within the supplementary information files\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWorld Health Organization. Hepatitis B [Internet]. Geneva: WHO; 2024 Feb [cited 2025 Jun 20]. Available from:https://www.who.int/news-room/fact-sheets/detail/hepatitis-b\u003cbr\u003e \u003c/li\u003e\n\u003cli\u003eKim WR, Loomba R, Berg T, Jonas MM, Flisiak R, Yi Q, et al. Prevalence of chronic hepatitis B virus infection in the United States. Am J Gastroenterol. 2020 Sep;115(9):1370\u0026ndash;7.\u003cbr\u003e \u003c/li\u003e\n\u003cli\u003eCohen C, Evans AA, London WT, Block JM, Conti M, Block TM. Underestimated burden of chronic hepatitis B virus infection in the United States: a simulation study. J Viral Hepat. 2008 Jan;15(1):12\u0026ndash;3.\u003cbr\u003e \u003c/li\u003e\n\u003cli\u003eWong RJ, Brosgart CL, Welch S, Block TM, Chen MS. 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Q., Razavi-Shearer, K., Blach, S., Estes, C., Mooneyhan, E., \u0026amp; Razavi, H. (2023). The impact of immigration on hepatitis B burden in the United States: a modelling study. \u003cem\u003eLancet regional health. Americas\u003c/em\u003e, \u003cem\u003e22\u003c/em\u003e, 100516. https://doi.org/10.1016/j.lana.2023.100516\u003c/li\u003e\n\u003cli\u003eGish, R. G., Jacobson, I. M., Lim, J. K., Waters-Banker, C., Kaushik, A., Kim, C., Cyhaniuk, A., \u0026amp; Wong, R. J. (2024). Prevalence and characteristics of hepatitis delta virus infection in patients with hepatitis B in the United States: An analysis of the All-Payer Claims Database. \u003cem\u003eHepatology (Baltimore, Md.)\u003c/em\u003e, \u003cem\u003e79\u003c/em\u003e(5), 1117\u0026ndash;1128. https://doi.org/10.1097/HEP.0000000000000687\u003c/li\u003e\n\u003cli\u003eWong, R. J., Saab, S., Konyn, P., Sundaram, V., \u0026amp; Khalili, M. (2021). 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Gaps and disparities in the treatment of chronic hepatitis B infection in the USA. \u003cem\u003eGastroenterology report\u003c/em\u003e, \u003cem\u003e13\u003c/em\u003e, goaf016. https://doi.org/10.1093/gastro/goaf016\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"sex differences, racial disparities, geographical variations, viral hepatitis mortality, hepatocellular carcinoma","lastPublishedDoi":"10.21203/rs.3.rs-7412047/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7412047/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eAim\u003c/h2\u003e\u003cp\u003eTo determine trends and disparities in hepatitis-B mortality in American adults older than 25 years between 1999\u0026ndash;2020.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eRetrospective analysis of CDC\u0026rsquo;s WONDER database was performed. For hepatitis-B, ICD-10 codes B16.0-16.2, B16.9, B17.0, B18.0, B18.1 were employed. Age-adjusted mortality rates(AAMR) and crude death rates(CDR) per 100,000 persons were determined. Average annual percentage change(AAPC) was determined using Joinpoint regression.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003e38,845 deaths were reported. AAMRs declined sharply from 1.12\u0026ndash;0.87 between 1999\u0026ndash;2004(AAPC:-4.45;p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) followed by a steady decline from 0.87\u0026thinsp;\u0026minus;\u0026thinsp;0.69(AAPC:-1.64;p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), resulting in an overall AAMR of 0.82(AAPC:-2.31;p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Males had disproportionately higher AAMR(1.28) than females(0.41) and showed a greater decline(AAPC:-2.62;p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) than females(AAPC:-2.13;p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Among races, non-Hispanic(NH) Asian/Pacific Islanders had disproportionately higher AAMRs(4.04) followed by NH Blacks(1.45), NH American Indians/Alaskan Natives(0.9), Hispanic(0.71), and NH Whites(0.55). All races saw declines in AAMR, with greatest decline seen in Hispanic(AAPC:-6.43;p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Geographically, AAMRs were highest in West(1.17) followed by South(0.83). All census regions saw declines in AAMR, with greatest decline seen for Northeast(AAPC:-3.38;p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Metropolitan areas had higher AAMR(0.84) than nonmetropolitan areas(0.59) and saw greater decline in AAMR(AAPC:-2.86;p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) than nonmetropolitan areas(AAPC:-0.55;p\u0026thinsp;=\u0026thinsp;0.059). Of the 10-year age groups, CDR was highest for 55\u0026ndash;64 years(1.46). The age groups of 25\u0026ndash;34, 35\u0026ndash;44, 45\u0026ndash;54, and 55\u0026ndash;64 years saw declining AAMRs, with greatest decline seen for 35\u0026ndash;44 years(AAPC:-5.64;p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, 65\u0026ndash;74, 75\u0026ndash;84, and 85\u0026thinsp;+\u0026thinsp;years saw an increase in AAMRs, with greatest increase seen for 85\u0026thinsp;+\u0026thinsp;years(AAPC:1.12;p\u0026thinsp;=\u0026thinsp;0.037).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eWe found a significant decline in hepatitis-B mortality, though persistent disparities exist. Elderly males, NH Asian/Pacific Islanders, residents of West and metropolitan areas experienced disproportionately higher mortality rates.\u003c/p\u003e","manuscriptTitle":"Temporal Trends and Disparities in Hepatitis-B Mortality in the United States Between 1999-2020: A CDC WONDER Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-16 16:25:12","doi":"10.21203/rs.3.rs-7412047/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2967ed68-8e93-40ed-9e0d-d582adc4d9d6","owner":[],"postedDate":"September 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-05T10:54:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-16 16:25:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7412047","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7412047","identity":"rs-7412047","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}