Trends in viral hepatitis-related mortality in the United States from 1999 to 2022: A retrospective study

Abstract

BACKGROUND

Viral hepatitis is characterized by a group of hepatotropic viruses that contribute to high rates of liver disease and mortality. It is well-documented that viral hepatitis is the leading cause of liver cancer and liver failure, with Hepatitis B and Hepatitis C being the most common viruses associated with these outcomes.

AIM

To study viral hepatitis-related mortality trends from 1999 to 2022, focusing on gender, race/ethnicity, age, region, and urban/rural classifications.

METHODS

We used the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research database to identify viral hepatitis-related deaths in the United States from 1999 to 2022. Data on demographic and regional information were analyzed and stratified by gender, race/ethnicity, age, regional, and urban rural classifications. Using the Joinpoint Regression Program (version 4.9.0.0 used, available from the National Cancer Institute, Bethesda, Maryland) the annual percentage change (APC) and average APC (AAPC) were calculated with 95%CI for extracted Age Adjusted Mortality Rates (AAMR).

RESULTS

From 1999 to 2022, there were 389916 viral hepatitis-related deaths in the United States. The overall AAMR increased from 1999 to 2013 (APC: 3.20%; 95%CI: 2.54-3.99; P < 0.001), then declined through 2022 (APC: -5.54%; 95%CI: -6.75 to -4.47; P < 0.001). Males accounted for 70.4% of deaths, with steeper declines in females (AAPC: -0.48%; 95%CI: -0.87 to -0.12; P < 0.05). The American Indian/Alaska Native population had the highest AAMR (AAPC: 2.90%; 95%CI: 2.30 to 3.68; P < 0.001). The population of 65-74 years had the largest increase in overall crude mortality rate (AAPC: 3.20%; 95%CI: 2.77 to 3.85; P < 0.001). Mortality was highest in the West (AAPC: –0.78%; 95%CI –1.28 to –0.29; P < 0.05). Rural AAMR exceeded urban rates after 2015.

CONCLUSION

This study found significant racial, ethnic, and geographical disparities in viral hepatitis AAMR. Key factors for mortality reduction include patient education, screening, and access to hepatitis vaccination and treatment.

Key Words: Viral hepatitis; Mortality; Trends; Hepatitis; Center for disease control wonder database

Core Tip: This study examines disparities in viral hepatitis-related mortality across gender, racial/ethnic, age-group and geographical groups in the United States from 1999 to 2022. Various factors have contributed to the decrease in viral hepatitis-related mortality during this time such as direct-acting antivirals in the treatment for hepatitis C virus, and vaccinations in the prevention of hepatitis B virus. However, social determinants of health have contributed to persistent mortality, and in some cases increases in mortality, despite prevention and treatment options, emphasizing the need for targeted public health interventions.

INTRODUCTION

Viral hepatitis is characterized by a group of hepatotropic viruses that contribute to high rates of liver disease and mortality[1]. The five viruses associated with viral hepatitis are hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E. All 5 viruses cause liver damage in some form; however, they are derived from different viral families and can be distinguished by the mechanism and severity of damage they cause[2]. It is well-documented that viral hepatitis is the leading cause of liver cancer [hepatocellular carcinoma (HCC)] and liver failure, with hepatitis B and hepatitis C being the most common viruses associated with these outcomes[3].

In 2016, it was estimated that there were 3.3 million Americans that had chronic viral hepatitis. In 2020, the United States Department of Health and Human Services launched a roadmap toward the elimination of viral hepatitis by 2025. This was initiated because of the current outbreaks of hepatitis A, the lack of adequate prevention for hepatitis B, and the substantial increase in hepatitis C infections from 2011 to 2018[4]. Currently, this plan is in progress and the most recent report was released in 2023 which stated that there have been successes in reducing hepatitis B infections with methods such as “birth dose” vaccinations, however, there are still goals that are yet to be met[5]. Despite the availability of vaccines and highly effective treatments now available, it is clear that there continues to be a substantial morbidity and mortality burden surrounding viral hepatitis.

Our study used the Center for Disease Control (CDC) WONDER database to analyze the variation in age-adjusted mortality rate (AAMR) for deaths attributed to viral hepatitis infections stratified by gender, race, age, region, and urban/rural differences within the United States from 1999-2022. This study seeks to demonstrate trends in viral hepatitis-related mortality, an outcome that is highly preventable through available vaccines and treatments. It highlights the relevance of viral hepatitis-related mortality as a public health issue while identifying disparities that contribute to these deaths.

MATERIALS AND METHODS

This retrospective study used the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database to identify viral hepatitis-related deaths that occurred in the United States from 1999-2022[6,7]. We extracted data from the Multiple Cause-of-Death Data from death certificate records to determine viral hepatitis contribution to death in certificates within the United States. The International Classification of Diseases (ICD), 10^th Revision, Clinical Modification codes B15-B19 were identified for viral hepatitis. This study looked at patients > 25 years of age; this age restriction was selected because ages below 25 were flagged as unreliable on data extracted. This database has served prior studies such as a nationwide study on the trends of HIV-mortality among adults from 1999-2020[8]. Due to the use of anonymized and publicly available data, this study was not subjected to review by the institutional review board.

The data extracted for viral hepatitis-related mortality ranged from 1999-2022. Data on demographic and regional information were analyzed overall and additionally stratified by gender, race/ethnicity, age, regional, and urban/rural classifications. Race and ethnicity were divided into Hispanic or Latino, and non-Hispanic White, Black, Asian or Pacific Islander, American Indian or Alaskan Native (AI/AN) based on identification on death certificates. This study’s age range was from 25-85+, as data for years 24 and younger were considered unreliable on CDC WONDER database. Ages were divided into 10-year age groups: 25-34, 35-44, 45-54, 55-64, 65-74, 75-84, 85+ years. The population was divided into urban [large metropolitan area (population ≥ 1 million), medium/small metropolitan area (population 50000 to 999999)] and rural (population < 50000) counties with the use of the National Center for Health Statistics Urban-Rural Classification Scheme. Population sizes from the 2013 United States census classification were used to sort counties into these categories[9]. With the use of the Census Bureau definitions, the regions of the United States were classified into Northeast, Midwest, South, and West.

Viral hepatitis-related overall number of deaths were extracted per year, and AAMR were calculated. AAMR was measured using the 2000 United States standard population which is the default and recommended selection for this calculation on the CDC WONDER database[10]. Using the Joinpoint Regression Program (version 4.9.0.0 was used, available from the National Cancer Institute, Bethesda, Maryland) the annual percentage change (APC) and average APC (AAPC) were calculated with 95%CI for extracted AAMRs[11]. Using the Monte Carlo permutation test these calculations were determined by segments joined by connecting Joinpoints. Slopes (change in mortality over the time interval) were used to determine if APCs and AAPCs were increasing or decreasing based on a significant difference from zero using a 2-tailed t-test. Asterisks were used to indicate statistical significance, which was determined by a P ≤ 0.05.

RESULTS

Overall

From 1999 to 2022, there were 389916 deaths due to viral hepatitis in the United States. Overall AAMR increased from 1999 to 2013, followed by a reduction in the subsequent years, reaching the lowest value in 2022 (Table 1 and Figure 1A). The APC in AAMR increased by 3.20% from 1999 to 2013 indicating a rise in viral hepatitis-related mortality. However, from 2013 to 2022, the AAMR decreased by an APC of -5.54% (Figure 2A and Table 2). Overall, the AAPC from 1999 to 2022 showed a slight decline of -0.31% over the study period.

Figure 1 Viral hepatitis age-adjusted mortality rate per 100000 people, 1999-2022. A: Overall and stratified by gender; B: Stratified by race; C: Stratified by region; D: Stratified by urban vs rural.

Figure 2 Joinpoint model of viral hepatitis related Age Adjusted Mortality Rates per 100000 people, 1999-2022. A: Overall and stratified by gender; B: Stratified by race; C: Stratified by region; D: Stratified by urban vs rural. ^aP < 0.05, indicates the annual percentage change is statistically significant. APC: Annual percentage change.

Table 1 Viral hepatitis age-adjusted mortality rate per 100000 people; overall and stratified by gender, 1999-2022.

Year	Overall	Female	Male
1999	5.37	3.24	7.69
2000	5.87	3.55	8.33
2001	6.14	3.65	8.84
2002	6.56	3.87	9.51
2003	6.43	3.77	9.33
2004	6.38	3.69	9.31
2005	6.54	3.74	9.57
2006	7.36	4.26	10.72
2007	7.76	4.44	11.28
2008	7.81	4.46	11.46
2009	7.87	4.43	11.52
2010	7.85	4.44	11.58
2011	8.18	4.60	12.02
2012	8.35	4.72	12.31
2013	8.53	4.82	12.52
2014	8.45	4.77	12.45
2015	8.27	4.59	12.27
2016	7.53	4.32	11.01
2017	7.09	3.99	10.53
2018	6.48	3.66	9.58
2019	5.91	3.25	8.83
2020	6.10	3.46	9.02
2021	5.77	3.36	8.34
2022	5.23	3.09	7.57

Table 2 Viral hepatitis annual percent change and average annual percent change in the age-adjusted mortality rate per 100,000 people; overall and stratified by gender, 1999-2022.

Cohort	Statistic	Segment	Years	Percent change	95%CI	P value
Overall	APC	1	1999-2013	3.20	(2.54, 3.99)	P < 0.001
		2	2013-2022	-5.54	(-6.75, -4.47)	P < 0.001
	AAPC	Full range	1999-2022	-0.31	(-0.69, 0.07)
Female	APC	1	1999-2013	2.64	(2.02, 3.38)	P < 0.001
		2	2013-2022	-5.15	(-6.45, -4.09)	P < 0.001
	AAPC	Full range	1999-2022	-0.48	(-0.87, -0.12)	P < 0.05
Male	APC	1	1999-2008	4.02	(3.10, 7.86)	P < 0.001
		2	2008-2014	1.75	(-6.82, 2.85)
		3	2014-2022	-6.06	(-7.50, -4.84)	P < 0.05
	AAPC	Full range	1999-2022	-0.18	(-0.50, 0.21)

APC: Annual percentage change; AAPC: Average annual percentage change.

Demographic differences

Gender stratified: From 1999 to 2022, viral hepatitis caused 274383 (70.4%) deaths in males and 115533 (29.6%) deaths in females in the United States.

Among males, the AAMR increased from 1999 to 2013, and subsequently declined until 2022 (Figure 1A and Table 1). The APC in AAMR showed an increase of 4.02% from 1999 to 2008 indicating a rise in male viral hepatitis-related mortality. This was followed by a decline in APC, reaching the steepest decline in AAMR from 2014 to 2022 with -6.06% (Figure 2A and Table 2). During the study period the overall AAPC for males was -0.18%, showing an overall slight decline in mortality.

Among females, the AAMR increased from 1999 to 2013, and then subsequently declined until 2022 (Figure 1A and Table 1). The APC in AAMR for females had a drastic drop from 2013 to 2022 with a change of -5.15%, indicating a notable reduction in mortality for females (Figure 2A and Table 2). Overall, female AAPC demonstrated a sharper decline when compared to males, with -0.48% during this time period.

Race stratified: The American Indian and Alaskan Native population had the highest AAMR over the years. The AAMR primarily increased from 1999 and peaked in 2015, followed by a slight decline after through 2022 (Figure 1B and Table 3). This demographic had an AAPC of 2.90% indicating an overall increase in mortality during this time, with the largest contributor being from 1999 to 2012 with the APC of 5.91% when compared to the remaining study period of -0.88% (Figure 2B and Table 4).

Table 3 Viral hepatitis age-adjusted mortality rate per 100000 people; stratified by race, 1999-2022.

Year	American Indian or Alaska Native	Asian or Pacific Islander	Black or African American	White	Hispanic or Latino
1999	7.77	8.24	9.73	4.28	9.82
2000	8.88	9.40	9.93	4.72	10.16
2001	9.48	9.74	10.83	4.93	10.77
2002	8.50	9.68	11.60	5.37	10.81
2003	11.51	8.34	11.33	5.32	10.11
2004	9.74	8.13	11.33	5.31	9.72
2005	10.02	7.87	11.59	5.44	10.03
2006	13.18	9.21	12.55	6.09	11.76
2007	13.41	9.28	12.71	6.46	12.16
2008	14.03	9.30	12.96	6.58	11.89
2009	14.62	8.96	12.91	6.66	11.67
2010	14.54	9.23	13.04	6.61	11.30
2011	15.10	8.72	13.45	6.92	11.86
2012	17.05	9.21	13.24	7.15	11.78
2013	17.60	8.42	14.23	7.26	11.46
2014	16.39	7.90	13.78	7.34	11.18
2015	18.51	6.99	13.69	7.22	10.54
2016	16.03	6.72	12.50	6.57	9.41
2017	16.60	6.66	11.89	6.22	8.61
2018	14.32	5.43	10.77	5.71	7.73
2019	14.58	5.46	9.55	5.33	6.49
2020	17.01	6.11	9.95	5.45	6.74
2021	16.48	6.05	9.04	5.19	6.23
2022	15.56	5.00	8.33	4.81	5.31

Table 4 Viral hepatitis annual percent change and average annual percent change in the age-adjusted mortality rate per 100000 people; stratified by race, 1999-2022.

Cohort	Statistic	Segment	Years	Percent change	95%CI	P value
American Indian or Alaska Native	APC	1	1999-2012	5.91	(4.66, 7.95)	P < 0.001
		2	2012-2022	-0.88	(-2.61, 0.53)
	AAPC	Full range	1999-2022	2.90	(2.30, 3.68)	P < 0.001
Asian or Pacific Islander	APC	1	1999-2011	0.13	(-1.24, 2.77)
		2	2011-2022	-5.05	(-7.09, -3.76)	P < 0.001
	AAPC	Full range	1999-2022	-2.39	(-3.04, -1.57)	P < 0.001
Black or African American	APC	1	1999-2014	2.23	(1.78, 2.71)	P < 0.001
		2	2014-2022	-6.54	(-7.56, -5.53)	P < 0.001
	AAPC	Full range	1999-2022	-0.91	(-1.18, -0.63)	P < 0.001
White	APC	1	1999-2007	4.52	(3.68, 7.01)	P < 0.001
		2	2007-2014	2.20	(-0.87, 3.06)
		3	2014-2022	-5.31	(-6.26, -4.51)	P < 0.001
	AAPC	Full range	1999-2022	0.30	(0.05, 0.61)	P < 0.05
Hispanic or Latino	APC	1	1999-2013	1.35	(0.61, 2.20)	P < 0.001
		2	2013-2022	-8.48	(-9.79, -7.29)	P < 0.001
	AAPC	Full range	1999-2022	-2.62	(-3.04, -2.20)	P < 0.001

APC: Annual percentage change; AAPC: Average annual percentage change.

The Hispanic or Latino population had the most significant reduction in AAMR over the years, even though the rate increased from 1999 to 2007 before declining until 2022 (Figure 1B and Table 3). The APC significantly decreased from 1.35% from 1999 to 2013, to -8.48% from 2013-2022 (Figure 2B and Table 4). The AAPC for this demographic was -2.62% showing an overall decrease in mortality during this time. Ultimately, the White demographic had the smallest change in AAMR with an AAPC of 0.30% (Figure 2B and Table 4).

Age group stratified

The population of 65-74 years had the largest increase in overall crude mortality rate, rising from 1999 to 2022, with an AAPC of 3.20% over this period indicating the increasing trend of viral hepatitis-related mortality in this age group (Figure 3 and Table 5). The population of 55-64 years had the highest overall crude mortality rate during this time. Overall crude mortality rate for this group peaked in 2013 with the highest number of deaths out of all age groups, before declining through 2022. The AAPC of 2.79% (Figure 4 and Table 6) reflected an overall increase in mortality throughout the study period despite the decrease after 2013.

Figure 3  Viral hepatitis overall crude mortality rate per 100000 people; stratified by ten-year age groups, 1999-2022.

Figure 4 Joinpoint model of viral hepatitis related overall crude mortality rate per 100000 people stratified by ten-year age groups, 1999-2022. ^aP < 0.05, indicates the annual percentage change is statistically significant. APC: Annual percentage change.

Table 5 Viral hepatitis overall crude mortality rate per 100000 people; stratified by ten-year age groups, 1999-2022.

Year	25-34	35-44	45-54	55-64	65-74	75-84	85+
1999	0.59	4.01	8.70	6.23	7.89	8.65	7.46
2000	0.47	3.67	10.27	7.46	8.4	9.38	6.70
2001	0.44	3.86	11.14	8.17	8.61	8.69	7.42
2002	0.52	3.91	12.55	9.00	8.35	9.00	7.12
2003	0.44	3.65	12.77	9.19	7.99	8.42	5.49
2004	0.45	3.35	12.56	10.25	7.64	7.68	6.42
2005	0.41	3.05	12.85	10.98	7.94	8.15	6.61
2006	0.40	2.84	14.17	14.14	9.13	8.89	6.76
2007	0.42	2.65	14.31	16.7	9.50	8.86	7.08
2008	0.35	2.35	13.72	18.53	9.54	9.43	7.22
2009	0.36	2.28	12.92	19.96	9.69	9.47	6.86
2010	0.36	2.02	12.17	21.57	10.02	8.83	7.32
2011	0.36	2.02	12.11	23.16	10.73	9.60	7.62
2012	0.39	1.83	11.52	25.21	11.80	9.13	7.61
2013	0.35	1.76	10.69	26.54	13.25	9.53	7.73
2014	0.44	1.64	10.23	26.27	14.22	9.15	8.16
2015	0.47	1.73	9.21	24.91	15.96	9.28	7.49
2016	0.44	1.58	7.75	22.94	15.54	8.36	6.91
2017	0.45	1.49	6.72	20.91	16.21	8.23	7.93
2018	0.53	1.51	5.55	18.45	16.01	7.70	6.86
2019	0.47	1.44	4.81	16.17	16.04	6.88	6.27
2020	0.54	1.58	4.52	15.59	17.83	7.97	7.22
2021	0.46	1.68	4.29	13.87	16.98	7.86	7.58
2022	0.44	1.47	3.42	12.13	16.76	7.98	6.48

Table 6 Viral hepatitis annual percent change and average annual percent change in the overall crude mortality rate per 100000 people; stratified by ten-year age groups, 1999-2022.

Cohort	Statistic	Segment	Years	Percent change	95%CI	P value
25-34 years	APC	1	1999-2010	-3.57	(-5.81, -1.66)	P < 0.05
		2	2010-2020	4.24	(-1.05, 11.38)
		3	2020-2022	-10.14	(-18.83, 2.22)
	AAPC	Full range	1999-2022	-0.86	(-1.68, -0.03)	P < 0.05
35-44 years	APC	1	1999-2002	-0.18	(-3.32, 4.84)
		2	2002-2013	-7.34	(-8.64, -6.69)	P < 0.001
		3	2013-2022	-1.12	(-2.38, 0.83)
	AAPC	Full range	1999-2022	-4.03	(-4.41, -3.67)	P <0.001
45-54 years	APC	1	1999-2002	11.25	(7.38, 17.86)	P < 0.001
		2	2002 -2007	2.95	(-0.03, 4.62)
		3	2007-2014	-4.51	(-6.07, -3.44)	P < 0.001
		4	2014-2022	-12.90	(-14.28, -11.81)	P < 0.001
	AAPC	Full range	1999-2022	-4.10	(-4.52, -3.71)	P < 0.001
55-64 years	APC	1	1999-2005	9.64	(0.95, 13.63)	P < 0.05
		2	2005-2008	18.69	(6.24, 22.34)	P < 0.001
		3	2008-2014	6.28	(-10.65, 7.45)
		4	2014-2022	-9.50	(-10.56, -7.65)	P < 0.001
	AAPC	Full range	1999-2022	2.79	(2.29, 3.48)	P < 0.001
65-74 years	APC	1	1999-2004	-0.76	(-7.82, 3.34)
		2	2004-2011	4.25	(0.40, 10.89)	P < 0.05
		3	2011-2015	10.01	(-1.47, 13.73)
		4	2015-2022	1.27	(-0.89, 4.60)
	AAPC	Full range	1999-2022	3.20	(2.77, 3.85)	P < 0.001
75-84 years	APC	1	1999-2015	0.51	(-0.78, 1.36)
		2	2015-2019	-6.22	(-10.56, 2.02)
		3	2019-2022	4.24	(-2.43, 12.36)
	AAPC	Full range	1999-2022	-0.22	(-0.80, 0.20)
85+ years	APC	1	1999-2022	0.20	(-0.35, 0.83)
	AAPC	Full range	1999-2022	0.20	(-0.35, 0.83)

APC: Annual percentage change; AAPC: Average annual percentage change.

Additionally, the only other group that had an increase in mortality rate over this time period was the 85+ age group with an AAPC of 0.20%, although the overall crude mortality rate demonstrated a decline from 1999 to 2022, the positive AAPC indicates there were intervals of increase during this time period (Figure 4 and Table 6). In comparison, 25-34, 35-44, 45-54, and 75-84 age groups showed decreases in overall crude mortality rate, with AAPCs of -0.86%, -4.03%, -4.10% and -0.22% respectively, with those in the 45-54 group having the most remarkable reduction in crude mortality rate throughout the study period (Figure 4 and Table 6).

Regional variation

Census region-based differences: All four regions had a similar overall trend in AAMR, increasing from 1999 to the early to mid 2010s and then subsequently decreasing through 2022. Of the four regions, the West consistently had the highest mortality rate with its AAMR rising from 1999, peaking in 2012, and subsequently decreasing until 2022 (Figure 1C and Table 7). The change in APC of 3.53% from 1999 to 2013 to -7.13% from 2013 to 2022 shows the drastic decline in mortality post-2013 for the West (Figure 2C and Table 8). The West’s AAPC from 1999 to 2022 was –0.78%, indicating an overall decline in mortality during this study period.

Table 7 Viral hepatitis age-adjusted mortality rate per 100000 people; stratified by region, 1999-2022.

Year	Northeast	Midwest	South	West
1999	4.83	3.42	5.61	7.64
2000	5.43	3.68	6.01	8.27
2001	5.75	4.00	6.28	8.58
2002	6.23	4.20	6.75	9.15
2003	5.82	4.19	6.87	8.70
2004	5.87	3.91	6.77	8.92
2005	5.68	4.12	7.07	8.97
2006	6.05	4.82	7.59	10.82
2007	6.50	5.32	7.74	11.35
2008	6.46	5.29	7.91	11.45
2009	6.24	5.06	7.93	11.88
2010	6.55	5.22	7.77	11.67
2011	6.87	5.46	8.33	11.72
2012	6.95	5.45	8.38	12.45
2013	6.89	5.70	8.67	12.44
2014	6.83	5.64	8.71	12.09
2015	6.61	5.69	8.72	11.36
2016	5.44	5.21	8.21	10.33
2017	5.03	4.76	8.04	9.50
2018	4.40	4.60	7.32	8.50
2019	3.93	4.25	6.75	7.66
2020	4.04	4.54	6.78	8.06
2021	3.69	4.20	6.53	7.53
2022	3.51	3.87	5.99	6.64

Table 8 Viral hepatitis annual percent change and average annual percent change in the age-adjusted mortality rate per 100000 people; stratified by region, 1999-2022.

Cohort	Statistic	Segment	Years	Percent change	95%CI	P value
Northeast	APC	1	1999-2014	1.86	(0.67, 3.82)	P < 0.05
		2	2014-2019	-10.84	(-14.67, 2.90)
		3	2019-2022	-3.64	(-9.44, 3.40)
	AAPC	Full range	1999-2022	-1.76	(-2.39, -1.33)	P < 0.001
Midwest	APC	1	1999-2013	3.53	(2.77, 4.53)	P < 0.001
		2	2013-2022	-4.38	(-5.90, -3.15)	P < 0.001
	AAPC	Full range	1999-2022	0.36	(-0.10, 0.84)
South	APC	1	1999-2006	3.92	(3.06, 6.01)	P < 0.001
		2	2006-2015	1.67	(0.46, 2.21)	P < 0.05
		3	2015-2022	-5.26	(-6.10, -4.48)	P < 0.001
	AAPC	Full range	1999-2022	0.18	(-0.03, 0.43)
West	APC	1	1999-2013	3.53	(2.69, 4.53)	P < 0.001
		2	2013-2022	-7.13	(-8.69, -5.75)	P < 0.001
	AAPC	Full range	1999-2022	-0.78	(-1.28, -0.29)	P < 0.05

APC: Annual percentage change; AAPC: Average annual percentage change.

The Midwest had the lowest AAMR of all the regions until 2018, when its AAMR surpassed that of the Northeast and remained higher through 2022. Similar to the West, the Midwest’s AAMR increased from 1999 to 2013 and subsequently decreased until 2022 with APCs of 3.53% and –4.38% respectively (Figure 2C and Table 8). The later APC depicts the decline in viral-hepatitis related mortality in this region after 2013.

Rural vs urban: When comparing populated regions, AAMRs were initially highest in urban areas when compared to rural areas. In 2015, the AAMR in rural areas surpassed that of urban areas and remained higher than that of urban areas through 2020 (Figure 1D and Table 9).

Table 9 Viral hepatitis age-adjusted mortality rate per 100000 people; stratified by urban vs rural, 1999-2022.

Year	Urban	Rural
1999	5.69	3.80
2000	6.20	4.12
2001	6.46	4.71
2002	6.84	5.19
2003	6.70	5.30
2004	6.67	5.28
2005	6.81	5.44
2006	7.65	6.10
2007	8.01	6.55
2008	8.06	6.86
2009	8.06	6.87
2010	8.08	6.64
2011	8.33	7.50
2012	8.54	7.73
2013	8.66	7.94
2014	8.63	7.82
2015	8.31	8.34
2016	7.57	7.60
2017	7.09	7.43
2018	6.43	6.94
2019	5.80	6.72
2020	6.02	6.83

Urban zones saw the AAMR increase from 1999 to 2013 and then decline until 2020 with APCs of 2.98% and –6.13% (Figure 2D and Table 10). This indicates a sharp decline in AAMR after 2013. The AAPC of –0.15% shows an overall decline in mortality during this study period.

Table 10 Viral hepatitis annual percent change and average annual percent change in the age-adjusted mortality rate per 100000 people; stratified by urban vs rural, 1999-2022.

Cohort	Statistic	Segment	Years	Percent change	95%CI	P value
Urban	APC	1	1999-2013	2.98	(2.28, 3.80)	P < 0.001
		2	2013-2022	-6.13	(-7.97, -4.62)	P < 0.001
	AAPC	Full range	1999-2022	-0.15	(-0.59, 0.29)
Rural	APC	1	1999-2002	10.66	(5.48, 19.12)	P < 0.001
		2	2002-2014	4.05	(2.19, 4.67)	P < 0.05
		3	2014-2022	-3.60	(-5.44, -2.14)	P < 0.05
	AAPC	Full range	1999-2022	2.71	(2.22, 3.29)	P <0.001

APC: Annual percentage change; AAPC: Average annual percentage change.

In rural zones the AAMR peaked in 2015 and subsequently declined until 2020 (Figure 1D and Table 9). The APC from 1999 to 2002 of 10.66% reflects a significant increase in AAMR during this period, followed by an APC of 4.05% from 2002 to 2014 indicating a slower rise during this time. The APC for the remaining time period of –3.60% depicts the decrease in AAMR following the peak in 2015 (Figure 2D and Table 10). The positive AAPC of 2.71% indicates an overall increase in mortality during the study period.

DISCUSSION

This study of viral hepatitis-related mortality trends in the United States from 1999 to 2022 revealed significant differences among demographic groups and geographic regions. Overall, mortality rates increased from 1999 to 2013, before declining from 2014 to 2022. This trend was also seen in both male and female demographics; however, males experienced higher mortality rates than females during the study period. Additionally, the racial/ethnic group that demonstrated the highest mortality in this period was the AI/AN. Regional data showed that the West had the highest mortality rate. Interestingly, urban areas initially had the highest mortality but then were surpassed by rural areas in 2015.

The increase in viral hepatitis-related mortality from 1999 to 2013 is multifactorial, with Hepatitis C and Hepatitis B being the viruses with the largest disease burden[12]. Hepatitis C virus (HCV) is the most common bloodborne pathogen in the United States, as well as a leading cause of liver-related mortality, therefore making it the major contributor to the increase in viral hepatitis-related mortality during this period[13]. Despite the availability of treatments for HCV, the number of infected patients and mortality increased from 1999-2013 which can be partially attributed to increases in injection drug use throughout the United States and the long disease course it carries[14].

Approximately, 75% of people acutely infected with HCV progress to live with a chronic infection. The disease course for HCV takes decades to progress to cirrhosis, with 15%-35% of individuals with chronic HCV developing it after 30 years of infection[15]. This long disease course suggests that the mortality increase during this time may be strongly linked to long-standing infection of HCV among individuals born between 1945-1965 (baby boomers); a population that has a significantly higher incidence of HCV infection when compared to non-baby boomer populations[16]. This can be highly attributed to unscreened blood transfusions before the discovery of the virus[17]. Additionally, studies suggest that many populations infected with HCV were not receiving or completing antiviral treatments. A study released in 2016 that examined rising mortality in HCV infections from 2003-2013 found that less than 20% of patients with HCV were starting antiviral therapy and even fewer were completing the treatment[18].

Furthermore, hepatitis B virus (HBV) is a significant contributor to liver disease deaths and poses the risk for both acute and chronic infections. HBV can be transmitted via blood borne contact, sexual transmission, and vertical transmission[19]. It is estimated that 15%-40% of individuals with chronic HBV will progress to cirrhosis, liver failure or HCC, indicating a pronounced risk of mortality[20]. One population that is significantly impacted is the immigrant population. A study found that 76% of HBV infections in the United States are attributed to immigrants, and 96% of chronic HBV cases were imported[21]. Given this data, it is reasonable to infer that there is significant underreporting of HBV cases among undocumented immigrant populations. These disparities call to action increasing public funding for immigrant health, with increased accessibility to treatments for those found infected and access to vaccinations for those not infected. Most HCV and HBV infections can remain asymptomatic for extended periods of time, which leads to underdiagnosis and predisposition to increased viral hepatitis-related mortality[13,22].

The decline in viral hepatitis-related mortality from 2014-2022 follows improvement in treatment, diagnosis, and prevention. The decline can largely be attributed to the development and use of direct-acting antivirals (DAAs) to treat HCV, which were approved by the FDA in 2011[23]. A 2017 study found that patients who achieved sustained virological response (SVR) through DAAs showed a 76% reduction in risk of HCC when compared to those who did not achieve SVR[24]. This represents a significant relative reduction in one of the leading causes of mortality in viral hepatitis infected patients[24]. Additionally, widespread vaccination campaign efforts for HBV have shown significant reduction in infections and adverse outcomes such as viral hepatitis-related mortality[25]. HBV vaccination has risen from 30% in 2000 to 85% in 2019 worldwide. These effective and affordable vaccinations have allowed for a substantial decrease in HBV morbidity and mortality[26].

Furthermore, increased testing and screening mechanisms for viral hepatitis leads to reductions in morbidity and mortality. These screening tests are inexpensive and can detect infections before the development of severe liver disease[27]. Through time diagnostic testing and screening recommendations have evolved. In 2012, the CDC recommended a one-time HCV test for the baby boomer population and in 2023 expanded their recommendation to all adults over the age of 18[28]. In 2008, the CDC expanded their recommendations for HBV testing to cover at risk populations, and in 2023 recommendations expanded to include screening for all adults above the age of 18 at least once in their lifetime[29].

Males demonstrated a higher AAMR when compared to females. Moreover, the male demographic showed a smaller decline in viral hepatitis-related mortality when compared to females. For HCV, the infection spreads most commonly through contact with blood, such as using contaminated syringes and needles in the healthcare and injection drug use setting, and transfusion of unscreened blood products[30]. Women are more likely to engaged in receptive needle sharing than men, however, men are more likely to be incarcerated and participate in this activity in prison[31]. Incarcerated persons are about 10 times more likely to have HCV infections than the regular population, suggesting an increased risk for infection in this setting[32]. HBV primarily infects both males and females through blood, semen, or other bodily fluids[33]. Chronic HBV infection is more common in males than females, with the demographic of men who have sex with men at greater risks[34].

Studies have shown that females have a more rapid elimination of HCV with treatment and a slower rate of disease progression[35]. Estrogen’s antifibrogenic effects may contribute to this slower disease progression, in comparison to androgens which have pro-fibrogenic properties, potentially explaining the lower AAMR in females when compared to males[36,37]. Similarly, HBV antigen clearance is achieved faster in females than males who exhibit androgen stimulated viral transcription. Male sex is considered a major risk factor for progression to HCC with HBV infection[38]. This illustrates that sex, and genetics contribute to disease progression for viral hepatitis. However, environmental factors can have significant contributions to morbidity and mortality experienced with viral hepatitis.

One of the most significant environmental contributions to worsening of liver disease is alcohol intake. Alcohol has been shown to increase oxidative stress and viral replication, while downregulating immune system regulation, therefore contributing to the development of liver fibrosis, end stage liver disease, and HCC[39]. Interestingly, the female sex has been found to be more vulnerable to alcohol’s effects on the liver with higher mortality in females[40]. However, excessive alcohol intake exacerbates and accelerates liver disease in both sexes[41]. This is an important point to consider, as alcohol use disorders have significant prevalence in today’s society.

The AI/AN demographic had the highest AAMR across all races. This can be attributed to socioeconomic and geographical reasons. AI/AN have a higher rate of being uninsured when compared to the rest of the population[42]. This demographic often experiences the negative effects from lack of adequate funding for their health facilities, lack of pharmaceuticals and technology, and a shortage of providers. There is a significant shortage of specialty providers for these populations which further exacerbate morbidity and mortality. Furthermore, rural AI/AN faces significant disadvantages when accessing healthcare due to geographical isolation[42,43]. Comparatively, the AAMRs for Hispanic/Latino, Asian or Pacific Islanders, Black or African American, and White populations were much lower than AI/AN. This significant difference shows the critical need for improvements in healthcare access, and increased aid for AI/AN demographics.

The age group of 55-64 was consistently the age group with the highest viral hepatitis mortality rate until 2019 when the age group of 65-74 overtook them. The 55-64 group’s mortality rate increased from 1999 to 2013 after which it steadily decreases. The 65-74 group on the other hand steadily increased over the entire time period of interest. These findings are consistent with the significant burden of HCV infection among baby boomers and aging of this demographic during these years. The age groups 25-34 and 35-44 had low viral hepatitis mortality rates that steadily declined over the entire period of interest. These differences in mortality rates between the age groups can partially be explained by low rates of HCV infection of individuals under the age of 20 and over the age of 60 as reported by the CDC. Additionally, it is possible that advancements in the treatment of viral hepatitis, liver failure, and HCC have extended the lifespan of individuals with viral hepatitis thus leading to the 65-74 age group overtaking the 55-64 age group after 2019.

Demographic differences between regions likely played a large role in the marked differences of AAMR between the four regions of the United States. The West consistently had the largest AAMR from 1999 to 2022 followed by the South. It’s possible that the higher proportion of AI/AN individuals in the West and Black individuals in the South contributed to these regions having consistently higher AAMRs when compared to the Northeast and Midwest regions. According to the United States Department of Commerce, the West had 49.5% of the nation’s population of AI/AN individuals in 2006 while the South, Midwest, and Northeast had 15.9%, 28.9%, and 5.7% of the nation’s AI/AN individuals, respectively[44]. This disproportionate representation of AI/AN individuals in the West could have contributed to this region having consistently higher AAMRs than the other regions. According to the U.S. Census Bureau, 55% of Blacks living in the United States lived in the South in 2010, while only 17.1%, 18.1%, and 9.8% of the country’s black population lived in the Northeast, Midwest, and West, respectively[45].

Additionally, the CDC has found that, while overall Hepatitis B vaccination rates increased from 2017 to 2021, disparities in vaccination rates between urban and rural regions of the United States persisted in children born in these years[46,47]. It is possible that the increase in total vaccination rates has contributed to the downtrend in age-adjusted mortality seen in both rural and urban areas. The widening in the disparity of AAMR between urban and rural areas could be partly due to widening in the disparity of Hepatitis B vaccination between these two groups. Addressing these regional disparities will take targeted and comprehensive public health interventions. These include increasing public awareness, enhancing patient education, and improving access to viral hepatitis screening and treatment[13]. Effort should also be made to further improve rates of viral hepatitis vaccination in these areas.

The viral hepatitis AAMR has been trending down in both urban and rural areas since 2015. The AAMR has decreased more significantly in urban areas compared to rural areas, so much so that the AAMR in urban areas fell below that of rural areas in 2015. It was shown that DAA use gradually increased in both urban and rural areas from 2014 to 2017, however, the increase was greater in patients from urban areas than in patients from rural areas[48]. This likely contributed the greater decrease in AAMR in urban areas compared to rural areas. Future studies could look further into the use of and access to DAAs in rural areas compared to urban areas. In fact, universal HCV screening of all adults with rapid subsequent treatment has been proposed due to current screening guidelines missing young patients who are exposed to viral hepatitis[49].

CONCLUSION

In this study, we found that there are marked racial, ethnic, and geographical disparities in viral hepatitis AAMR. Overall, mortality trends increased from 1999 to 2013, however, data shows a decline starting in 2014. Males experienced higher mortality rates than females during this study period, however, both males and females have recent downward trends in mortality. AI/AN population demonstrated the highest mortality rate during this period, while the Hispanic and Latino population had the most significant reduction in mortality rate. The 65-74 age group had the largest increase in overall crude mortality rate. Regional data demonstrated that the West consistently had the highest mortality rate during this study period. Urban areas initially showed higher mortality rates that were eventually surpassed by rural areas in 2015.

Social determinants of health are highly implicated in these disparities. Our findings align with prior research that demonstrates AI/AN and rural population face disproportionate disparities. Factors that are particularly significant with respect to viral hepatitis mortality reduction include patient education, viral hepatitis screening, and access to vaccination and treatment. In nearly all of the demographic groups that we looked at, viral hepatitis AAMR has been trending down since the mid to late 2010s. This is promising information, and it underscores the significance of the introduction of DAAs, the commitment to widespread vaccination campaigns, and the improvement of viral hepatitis testing and screening methods.

The generalizability of these findings is due to several factors. The use of national mortality data allows for broader applicability across the United States, while the specific regional and population data allows for targeted approaches aimed at reducing viral hepatitis-related mortality within subgroups. However, access to DAAs and vaccinations may vary by state which may impact the applicability of these findings. Future research aimed at healthcare access metrics within individual states can contribute to a better understanding of regional differences and aid in more effective public interventions.

This study has some limitations due to the use of the CDC WONDER database. Due to this being a public health database we cannot be certain that there are no flaws in the data. Something to consider is misclassification on death certificates and possible coding errors that may affect results. Furthermore, social determinants of health which contribute to mortality is not reported on the death certificates or in the data. Additionally, data is coded by the location where the death took place and does not account for possible travel for treatment, potentially leading to misrepresentation of regional mortality trends.

The database itself holds several limitations including lack of robust information available for individual viral hepatitis ICD codes; making it difficult to report on specific viral hepatitis and their trends over time. Therefore, this study used the overarching viral hepatitis ICD code to examine the collective trends of viral-hepatitis related mortality rather than focusing on individual viruses. This limitation may lead to incomplete interpretations. Another significant limitation is found in the lack of sufficient data for individuals under the age of 24, which discouraged further analysis of this cohort. The data sets downloaded from the CDC WONDER database showcased “unreliable” readings, indicating that there was not enough data to derive accurate conclusions from individuals under the age of 24. Additionally, CDC WONDER does not offer rural vs urban demographic information past 2020, therefore analysis for these demographics ends in 2020.

Further limitations can also be seen with the limited information provided for diagnostics availability and diagnosis rates and how these have evolved over time. The dataset did not provide sufficient data for individual viral hepatitis types as mentioned above, preventing thorough exploration of which diagnostic methods contributed most to detecting infections. However, the discussion section contains reasonable inferences on diagnostic mechanisms that have contributed substantially to this landscape. Additionally, information on year-banding and age ranges for the baby boomer demographic was discussed briefly, as many studies have already concisely explored this significant difference.