
==== Front
J Infect Dis
J Infect Dis
jid
The Journal of Infectious Diseases
0022-1899
1537-6613
Oxford University Press US

38457349
10.1093/infdis/jiae023
jiae023
Brief Report
Viruses
AcademicSubjects/MED00290
Growing Awareness: Limited Testing and Screening Bias for Hepatitis Delta Virus in Utah 2000–2021
https://orcid.org/0000-0003-3715-0670
Hesterman Matthew C School of Dentistry, University of Utah, Salt Lake City, Utah, USA

https://orcid.org/0000-0001-8308-418X
Fallon Braden S School of Dentistry, University of Utah, Salt Lake City, Utah, USA

Lynch Keisa M Department of Gastroenterology and Hepatology, University of Utah, Salt Lake City, Utah, USA

https://orcid.org/0000-0002-6646-1403
Weller Melodie L School of Dentistry, University of Utah, Salt Lake City, Utah, USA
Division of Pathology, Department of Microbiology and Immunology, School of Medicine, University of Utah, Salt Lake City, Utah, USA

Presented in part: IDWeek 2022, Washington, DC, 19–23 October 2022. Poster Presentation. Hesterman MC, Fallon BS, Wilson PA, Weller ML. Hepatitis D virus and hepatitis B virus epidemiology in Utah.

Correspondence: Melodie L. Weller, PhD, School of Dentistry, University of Utah, 383 Colorow Drive, Salt Lake City, UT 84108 (Melodie.Weller@hsc.utah.edu).
Potential conflicts of interest. M. L. W. and K. M. L. have current funding from Gilead Sciences, Inc. All other authors report no potential conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

15 9 2024
08 3 2024
08 3 2024
230 3 e679e683
18 8 2023
17 1 2024
08 3 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Abstract

Background

This study assessed the epidemiology of hepatitis delta virus (HDV) within the University of Utah UHealth health care system (2000–2021).

Methods

Analysis of HDV/HBV testing, diagnostic codes, liver enzymes, and comorbidities was performed.

Results

Among the 1962 HBV patients, only 22.2% underwent HDV testing, revealing an 8.3% positivity rate for HDV coinfections. This study observed a consistent increase in HBV and HDV cases, with higher HDV detection rates linked to increased testing. Limited HDV testing and potential screening biases were evident.

Discussion

Improved HDV testing and surveillance are crucial for early detection and implementation of targeted therapies.

This 22-year study at University of Utah UHealth reveals only 22.2% of HBV patients were tested for HDV, with an 8.3% HDV positivity rate. Findings underscore the need for enhanced HDV testing to increase the early detection of HDV.

hepatitis delta virus
hepatitis D virus
hepatitis B virus
Sjögren's Foundation 10.13039/100003392 National Institutes of Health 10.13039/100000002 National Institute of Dental and Craniofacial Research 10.13039/100000072 R00/DE021745 University of Utah 10.13039/100009963 University of Utah 10.13039/100007747
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pmcHepatitis delta virus (HDV) is a rare infectious disease that occurs as a coinfection with hepatitis B virus (HBV) [1, 2]. Concurrent HDV/HBV coinfection is linked to a more aggressive progression of hepatic disease. Despite its potential impact on human health, few studies have been conducted on HDV epidemiology in the United States [3–6]. The Centers for Disease Control and Prevention currently do not classify HDV as a notifiable infectious disease, resulting in a lack of tracking of the incidence and prevalence of this infection [7]. Limited surveillance makes it difficult to define the epidemiology of HDV and to implement effective prevention and treatment strategies.

HDV is the only known satellite RNA that infects humans and can occur either as a coinfection with HBV or as a superinfection in patients with chronic HBV infection [1]. Testing for HDV involves detection of HDV antibodies (HDVAb), HDV RNA, and/or HDV antigen (HDAg). However, previous studies have demonstrated limited testing for HDV in HBV patient populations, making it difficult to fully understand the epidemiology and impact of this infection [4, 5, 8–10]. Increased testing of HDV is crucial to better understand its transmission, epidemiology, and impact on human health.

The American Association for the Study of Liver Diseases (AASLD) currently recommends testing for HDV only in HBV patients with known risk factors [11]. Recommended tests include total HDVAb and, if positive, subsequent testing for HDV RNA. These risk factors include patients born in regions with high HDV prevalence, men who have sex with men, intravenous drug use, patients with a history of hepatitis C virus (HCV) and human immunodeficiency virus (HIV), multiple sexual partners, or elevated liver enzymes with limited detectable HBV DNA [11]. These guidelines are in place to identify individuals at a higher risk of HDV infection, ensure that they are tested, and receive appropriate treatment. However, a prior study noted that a risk-based assessment for determining who is tested for HDV may not be adequate [10].

The lack of comprehensive data on HDV, combined with the limitations of current testing protocols highlighted by the AASLD, emphasizes the critical need for our study. We conducted a retrospective analysis to explore the incidence of HDV and HBV cases from 2000 to 2021 in Utah, specifically within the University of Utah UHealth system.

METHODS

This retrospective cross-sectional study, spanning 2000–2021, evaluated the HBV and HDV patient populations within the University of Utah UHealth health care system electronic medical records. The collected information included patient demographics (sex, age, race, and ethnicity), diagnosis codes (International Classification of Diseases-Ninth Revision [ICD-9] and ICD-10 codes and subcodes), and associated laboratory test results (aspartate aminotransferase [AST], alanine aminotransferase [ALT], albumin, bilirubin, alkaline phosphatase [ALP], hepatitis B surface antigen [HBsAg], hepatitis B core antibody [HBcAb], HBV DNA, hepatitis B e antigen [HBeAg], hepatitis B e antibody [HBeAb], HDVAb, HDV RNA, HDAg), as outlined in Supplementary Figure 1 and Supplementary Table 1. The inclusion criteria for HBV and HDV case definitions are detailed in Supplementary Figure 1, including using ICD diagnosis codes and laboratory tests for HDV or HBV. The examination of variables such as sex, ethnicity, and age group utilized the χ2 test, while the analysis of continuous variables such as age and liver enzyme levels were performed using the Kruskal-Wallis test and Welch t test. Descriptive statistics, including the mean, median, standard deviation, and interquartile range, were calculated. The study was conducted in accordance with the ethical standards set by the University of Utah's Institutional Review Board (IRB) program, which is managed by the Office of Research Integrity and Compliance (IRB 00157695).

RESULTS

A total of 1962 patients with HBV were identified in the UHealth system over a 22-year period (2000–2021) (Table 1). The average age of the HBV patient cohort was 43.2 (SD 14.9) years, with the highest representation in the 20–39 age group (43%). Men accounted for 55% (1079) of the cohort, while women accounted for 45% (883) (Table 1). Among the HBV patients, 62 met the inclusion criteria for HDV coinfection, with an average age of 41.3 (SD 5.0) years and the most prominent age group was 40–59 (45%) in this population. HDV-coinfected patients consisted of 47% (29) men and 53% (33) women.

Table 1. HBV and HDV Cohort and Testing Characteristics

Characteristic	HBV Total Cases (n = 1962)	HBV Not Tested for HDV (n = 1527)	HBV Tested for HDV (n = 435)	HDV Coinfection Cases (n = 62)	P	
Sex		.55	
 Male	1079 (55)	846 (55)	233 (54)	29 (47)		
 Female	883 (45)	681 (45)	202 (46)	33 (53)		
Race/ethnicity					<.001	
 Native American	12 (1)	10 (0.7)	2 (0.5)	1 (2)		
 Asian	423 (22)	275 (8)	148 (34)	24 (39)		
 Black	223 (11)	141 (9)	82 (19)	8 (13)		
 Hispanic/Latino	128 (7)	110 (7)	18 (4)	2 (3)		
 Hawaiian/PI	124 (6)	85 (6)	39 (9)	2 (3)		
 White	736 (38)	640 (42)	96 (22)	20 (32)		
 Other	134 (7)	102 (7)	32 (7)	3 (5)		
 Unknown	182 (9)	164 (11)	18 (4)	2 (3)		
Age, y, mean ± SD	43.2 ± 14.9	44.0 ± 15.2	42.2 ± 13.7	41.3 ± 5.0	<.001	
Age group, y					.17	
 0–19	59 (5)	56 (4)	17 (4)	1 (2)		
 20–39	843 (43)	649 (43)	194 (45)	26 (42)		
 40–59	734 (37)	570 (37)	176 (40)	28 (45)		
 60+	326 (17)	252 (17)	48 (11)	7 (11)		
Liver enzymes, median (IQR)						
 Albumin, g/dL	4.4 (4.1–4.7)	4.5 (4.3–4.7)	4.4 (4.1–4.7)	4.6 (4.2–4.7)	<.001	
 Bilirubin, mg/dL	0.9 (0.6–1.7)	1.0 (0.7–1.7)	0.9 (0.6–1.7)	1.2 (0.7–3.7)	<.001	
 ALT, U/L	54 (30–130)	52.0 (30–153)	55.0 (30–126)	83.0 (39.8–247.3)	.03	
 AST, U/L	52 (31–123)	46.0 (30–120)	54.0 (32–125)	97.5 (38.5–234.5)	.06	
 ALP, U/L	104 (77–158)	99.0 (74–148)	106.0 (78–159)	116.5 (88.3–193.5)	.09	
Data are No. (%) except where indicated.

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HBV, hepatitis B virus; HDV, hepatitis delta virus; IQR, interquartile range; PI, Pacific Islander.

Limited testing for HDV has been observed among patients with HBV. Only 22.2% (435) of the 1962 HBV patients underwent HDV testing and 8.3% (36) tested positive for HDV (Table 1 and Supplementary Table 2). The positivity rates for HDV among those tested were 6.4% for men and 10.4% for women. Among patients who tested positive for HDVAb, 53.9% underwent further testing for HDV RNA, resulting in a positivity rate of 21.4%. Analysis of HBV and HDV testing history showed that 77.8% of HBV patients were not tested for HDV, and more than half of those who tested positive for HDVAb did not undergo evaluation for active HDV infection by HDV RNA testing.

There was a consistent increase in the number of HBV and HDV cases in the Utah cohort between 2000 and 2021. The number of HBV cases steadily increased over the 22-year period (Mann-Kendall test = 133, P < .0001; Figure 1A), as did the number of HDV coinfections (Mann-Kendall test = 79, P < .05; Figure 1B). This increase in HDV coinfections can be attributed to increased HDV testing, as reflected by the growing number of HBV patients tested for HDV during the study period (Figure 1C). These data indicate an upward trend in HBV and HDV coinfections in Utah, with increased HDV testing observed over the study period.

Figure 1. HBV and HDV cases and testing overview, 2000–2021. Yearly distribution of HBV cases (A) and HDV cases (B) according to the defined cohort criteria (see “Methods” section). Yearly HDV tests (C) incorporate any patient tested for HDV antigen, HDV antibody, or HDV RNA. Race/ethnicity associations with HDV testing (D) and HDV positivity (E). Abbreviations: CI, confidence interval; HBV, hepatitis B virus; HDV, hepatitis delta virus; OR, odds ratio; PI, Pacific Islander. *P < 0.05, ***P < 0.001.

There were significant differences noted in patient demographics, particularly age, race, and ethnicity, between the HBV and HDV coinfection patient cohorts (Table 1). The average age did not differ significantly between the HBV and HDV coinfected patients. However, HBV patients who underwent HDV testing (42.4 [SD 13.7] years of age) were, on average, younger than those who were not tested for HDV (44.0 [SD 15.2] years of age, P < 00001), suggesting that patients with HDV coinfections are diagnosed at a younger age than those with HBV monoinfection. The results showed that patient sex was not a significant factor in determining HDV testing rates (odds ratio [OR], 0.9; 95% confidence interval [CI], .7–1.1).

Patients who underwent HBV testing for specific markers (HBcAb, HBV DNA, HBeAg, and HBeAb) were more likely to be tested for HDV (Supplementary Table 3). For example, patients who tested positive for HBV DNA were 40.5 times more likely to be tested for HDV (95% CI, 20.0–82.2). Patients who tested positive for HBcAb were 2.6 times more likely to be tested for HDV (95% CI, 1.9–3.6). However, a positive HBeAg test was not found to be associated with an increased HDV testing rate (OR, 1.3; 95% CI, .97–1.7).

Race and ethnicity played a significant role in determining HDV testing rates among patients with HBV (Table 1 and Figure 1D and 1E). White patients were less likely to be tested for HDV (OR, 0.4; 95% CI, .3–.5), and Hispanic/Latino patients were also found to be less likely to be tested for HDV (OR, 0.6; 95% CI, .3–.9). Conversely, Asian patients were significantly more likely to be tested (OR, 2.3; 95% CI, 1.9–3.0), as were black patients (OR, 1.7; 95% CI, 1.7–3.1) and Hawaiian/Pacific Islander patients (OR, 1.7; 95% CI, 1.1–2.5).

Evaluation of liver function tests demonstrated significant differences between patients with HBV and HDV coinfections. HDV coinfected patients exhibited higher levels of albumin, bilirubin, and ALT than those with only HBV (Table 1). Although AST and ALP levels were higher in HDV coinfected patients, the differences were not statistically significant.

Patients with HDV coinfection were at a heightened risk of developing hepatocellular carcinoma and HCV infections (Supplementary Table 4). Among the cohort, there was a higher incidence of liver and intrahepatic bile duct neoplasms in HDV coinfected patients than in HBV monoinfected patients (OR, 2.2; 95% CI, 1.1–4.6; P < .05). Of 134 HBV patients diagnosed with hepatocellular carcinoma, 39 (29.1%) were tested for HDV. Furthermore, 28 of the 39 patients underwent HDV testing before receiving a neoplasm diagnostic code. Additionally, the study revealed a significant increase in the risk of HCV coinfection among patients with HDV. No significant difference was observed in the incidence of HIV infection between the HBV monoinfected and HDV coinfected patient groups.

DISCUSSION

This 22-year study in the UHealth system found that of 1962 HBV patients, only 435 (22.2%) were tested for HDV. Of those tested, 36 (8.3%) were positive for HDVAb and 21.4% of HDVAb positive cases had active HDV coinfection (indicated by a positive HDV RNA test). The number of HBV and HDV cases in Utah increased steadily during the study, along with an increase in the number of HBV patients being tested for HDV. Race and ethnicity significantly influenced HDV testing rates, with Asian, black, and Hawaiian/Pacific Islander populations being overrepresented and white and Hispanic/Latino populations being underrepresented. HDV coinfected patients had a higher risk of hepatocellular carcinoma than the HBV patient population. These findings highlight the need to reconsider the current testing paradigm for HDV.

Studies evaluating HDV testing among patients with HBV in the United States have shown similar deficiencies. International organizations, such as the European Association for the Study of the Liver (EASL) and the Asian Pacific Association for the Study of the Liver (APASL), recommend testing all HBV patients for HDV. Implementing the EASL guidelines led to a 5-fold increase in HDV detection [12]. Therefore, increased HDV testing in the HBV patient community in the United States is necessary to detect HDV early and provide targeted therapies for HDV coinfection.

This study also identified an increased risk of hepatocellular carcinoma and HCV in the HDV coinfected population. Early detection of HDV would facilitate the early monitoring and treatment of both hepatocellular carcinoma and HCV.

The limitations of the study include incomplete medical records, limited documentation of risk factors, and changes in testing during the coronavirus disease 2019 (COVID-19) pandemic. The study focused on the UHealth health care system; therefore, it may not be representative of the entire state. Larger prospective studies are needed to better understand the epidemiology of HDV and HBV infections in Utah.

In conclusion, this 22-year study revealed limited HDV testing among patients with HBV, particularly in certain racial and ethnic groups. Increased testing has led to higher HDV detection rates. It is crucial to expand the study to include other health care systems in Utah and to increase HDV testing and tracking at the state and federal levels. Re-evaluation of the AASLD guidelines to test all HBV patients for HDV is necessary to increase the early detection of HDV.

Supplementary Data

Supplementary materials are available at The Journal of Infectious Diseases online (http://jid.oxfordjournals.org/). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.

Supplementary Material

jiae023_Supplementary_Data

Notes

Author contributions. M. C. H. and M. L. W. designed the study, collected, and analyzed the data, and wrote the manuscript. All authors critically revised the manuscript.

Financial support. This work was supported by the Sjögren's Foundation; the National Institute of Dental and Craniofacial Research (grant number R00/DE021745); the University of Utah School of Dentistry; and the Office of Undergraduate Research, Undergraduate Research Opportunities Program (UROP) at the University of Utah. Data requests for electronic medical records were made through Data Science Services at the University of Utah.
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