The Burden of Hepatitis A Outbreaks in the United States: Health Outcomes, Economic Costs, and Management Strategies

Abstract Background Hepatitis A (HepA) vaccines are recommended for US adults at risk of HepA. Ongoing United States (US) HepA outbreaks since 2016 have primarily spread person-to-person, especially among at-risk groups. We investigated the health outcomes, economic burden, and outbreak management considerations associated with HepA outbreaks from 2016 onwards. Methods A systematic literature review was conducted to assess HepA outbreak-associated health outcomes, health care resource utilization (HCRU), and economic burden. A targeted literature review evaluated HepA outbreak management considerations. Results Across 33 studies reporting on HepA outbreak-associated health outcomes/HCRU, frequently reported HepA-related morbidities included acute liver failure/injury (n = 6 studies of 33 studies) and liver transplantation (n = 5 of 33); reported case fatality rates ranged from 0% to 10.8%. Hospitalization rates reported in studies investigating person-to-person outbreaks ranged from 41.6% to 84.8%. Ten studies reported on outbreak-associated economic burden, with a national study reporting an average cost of over $16 000 per hospitalization. Thirty-four studies reported on outbreak management; challenges included difficulty reaching at-risk groups and vaccination distrust. Successes included targeted interventions and increasing public awareness. Conclusions This review indicates a considerable clinical and economic burden of ongoing US HepA outbreaks. Targeted prevention strategies and increased public awareness and vaccination coverage are needed to reduce HepA burden and prevent future outbreaks.

The ongoing hepatitis A (HepA) virus outbreaks across the United States (US) have spread primarily via person-to-person transmission since 2016, prior to which large outbreaks were often attributable to food contamination [1][2][3].People who use drugs, people experiencing homelessness, people who are or were recently incarcerated, men who have sex with men (MSM), and recent international travelers are at highest risk of HepA infection [1][2][3].While HepA infection typically results in short-term illness, among some, complications may be severe, ranging from relapsing hepatitis to acute liver failure and even death [4,5].
Although treatment of HepA remains limited to symptom management and supportive care, infection is preventable with approved HepA vaccines, which first became available in the United States in 1995 [6,7].Since 2006, the Centers for Disease Control and Prevention's (CDC) Advisory Committee on Immunization Practices (ACIP) has recommended routine HepA vaccination for all children aged ≥1 year [8].The ACIP also recommends HepA vaccination for adults at risk of HepA infection or at increased risk of severe disease from HepA infection, as well as adults who want protection against HepA without known risk factors [9].However, HepA vaccination coverage among US adults remains low [9,10].In 2018, only 11.9% of adults selfreported receiving the full HepA vaccine series (≥2 doses) [11], compared with 79.6% coverage among infants by age 35 months (2019-2021) and 84.8% among adolescents aged 13-17 years (2022), as reported by their vaccination providers [12,13].
Between 2016 and 2023, over 44 000 HepA cases, of which 61% required hospitalization, and over 400 deaths were reported across 37 states [2].However, infections especially in younger children are typically not accompanied by symptoms, likely resulting in underreporting of cases and consequential overestimations of hospitalization and case fatality rates in the overall population [4].Nonetheless, the health outcomes and associated health care resource utilization (HCRU) related to these outbreaks incur a considerable economic cost to health care systems [14].
In light of the recent HepA outbreaks and the wellrecognized gap in adult HepA vaccination, this study aimed to understand current health outcomes, economic burden, and outbreak management considerations associated with US Burden of Hepatitis A Outbreaks in US • JID 2024:230 (15 July) • e199 The Journal of Infectious Diseases R E V I E W HepA outbreaks since 2016 to help inform decision makers on the value of HepA prevention.

Study Design
A systematic literature review (SLR) was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to summarize the evidence regarding the health outcomes, HCRU, and economic burden associated with the ongoing HepA outbreaks [15].A targeted literature review (TLR) was also conducted to evaluate key outbreak management considerations related to the HepA outbreaks.

Data Collection
A comprehensive set of search terms was combined to search across MEDLINE and Embase on 12 July 2022 (Supplementary Tables 1 and 2 for the SLR and TLR, respectively).The searches were supplemented by Google, government websites, and grey literature (guidelines, commentaries, press releases, and government agency, health agency, and nongovernmental organization reports) searches.
Eligible articles for the SLR were title-/abstract-and full-text screened by 2 independent reviewers (A.S., B.J.), followed by a third reviewer (E.L.) if consensus could not be reached.Articles included in the TLR were screened and identified by 1 independent reviewer (A.S., B.J., E.L.), with 10% of articles checked by a second reviewer (A.S., B.J., E.L.) for quality control.Assessment of publication bias was not conducted.
Studies included in the SLR reported on health outcomes of interest (morbidity, mortality, and HCRU) and/or economic burden (direct, indirect, and public health intervention costs) among adult populations aged ≥18 years living in an area with a HepA outbreak from 2016 onwards (Supplementary Table 3).While studies reporting outcomes among individuals of all ages were included, this review included data only among those aged ≥18 years.Studies reporting on 1 or more key research questions associated with HepA outbreak management (successes, challenges, and key learnings) were included in the TLR.Characteristics and outcomes of included studies were qualitatively described; no statistical analyses were performed.

RESULTS
Of the 1753 studies identified in the SLR, 1630 were excluded following title/abstract screening.Full texts of the remaining 123 studies were reviewed, and 39 were included (Figure 1).Study characteristics and patient populations of included studies are presented in Supplementary Table 4.

Health Outcomes and Health Care Resource Utilization
The SLR identified 33 studies reporting on HepA outbreakassociated health outcomes and HCRU (Table 1).These studies reported on 1 state or area within a state (n = 18 studies), multistate (n = 7), or national (n = 8) data.Most studies reporting mode of transmission described HepA cases spread solely through person-to-person contact (n = 11), compared with solely food-borne transmission (n = 3) or both (n = 5).
Of the 33 studies, 30 reported on populations affected by outbreaks, including people: who use drugs or with substance use disorder (SUD) (n = 26), experiencing homelessness (n = 19), currently or recently incarcerated (n = 5), with history of hepatitis B or C infection (n = 4), and MSM (n = 4).Other reported populations affected by HepA outbreaks are listed in Supplementary Table 4.

Health Care Resource Utilization
Across the SLR, 30 of 33 studies reported HCRU associated with HepA, including any hospitalization (n = 29), ICU admission (n = 7), 30-day readmission rates (n = 2), outpatient visits (n = 1), and medication/treatment utilization (n = 1).Full HCRU results are listed in Table 1.Of studies reporting any hospitalization in the overall population due to outbreaks that did not solely occur via food-borne transmission (n = 17), the majority (n = 14) reported hospitalization rates greater than 50%, ranging from 41.6% of HepA cases nationally reported to the CDC [22], to 84.8% in a cross-sectional study of HepA cases in Michigan [32].One study found that the large majority of HepA diagnoses were made in the inpatient (84.4%) versus outpatient (15.6%) setting [43].Reichenbach et al (2021) suggested that this was likely due to educational campaigns by the city's health department about the ongoing outbreak, which may have encouraged patients with symptoms to seek out evaluation, while diagnoses in the outpatient setting were likely often among asymptomatic patients [43].
Length of stay, reported in 10 studies, ranged in the overall population from a mean of 2.5 days among hospitalized patients (predominantly people with SUD) in Charleston, West Virginia [18] to 6 days in hospitalized patients (predominantly people with SUD and/or experiencing homelessness) in San Diego, California [38].ICU admission rates ranged from 6.3% in West Virginia in 2016-2019 [32], to 26.5% in Southeast Michigan from 2016-2017 [16].According to a 2016-2019 case-control study in Kentucky, Michigan, and West Virginia, 83.5% of fatal HepA cases were admitted to the ICU, while only 11.1% of HepA survivors were admitted [33].Two studies identified 30-day readmission rates of 4.2% and 23.4% among HepA patients presenting to health systems in Southeast Michigan and San Diego, California, respectively [16,39].No studies were identified that reported on outpatient visit and emergency department visit rates and treatment utilization in the overall population; however, 1 San Diego, California study on treatment utilization in a high-risk (ALF) population found significantly higher rates of treatment utilization in ALF versus non-ALF groups [36].

Economic Burden
In total, 10 studies reported on the economic burden of HepA outbreaks, spanning direct medical costs associated with HCRU and public health intervention costs (Table 2).These studies focused on local or state outbreak data (n = 6) and       national data (n = 4), and 7 reported on populations affected by the outbreaks, including people who use drugs/people with SUD (n = 5), people experiencing homelessness (n = 3), food service workers (n = 2), and MSM (n = 1).One study reported person-to-person transmission, while among the remainder, mode of transmission was not reported or not applicable to the study design.

Direct Medical Costs Associated With Health Care Resource Utilization
Five studies reported on direct medical costs associated with HCRU, such as hospitalization, outpatient, vaccination, and Medicaid-specific direct clinical costs.In a 2017 national cohort study, the estimated nationwide average cost per HepA-related hospitalization was $16 232 (ranging from $12 921 to $19 680 by region; 2017 USD) [14].Another study in a local health department area reported that estimated inpatient and outpatient costs per HepA case in 2016 were $15 562 and $474, respectively (2016 USD) [48].A national database review reporting on acute HepA cases from 2011-2017 reported estimated inpatient costs stratified by survival status, which ranged from $48 611 per surviving patient to $155 523 per deceased patient (USD, currency year not reported [NR]) [40].One study in West Virginia identified the economic burden related to direct clinical and inpatient costs of the HepA outbreaks among people with SUD, reporting that people with SUD incurred higher costs than people without SUD (ie, 77% of Medicaid direct clinical costs; 71% of total inpatient costs) from 2018-2019 [47].Total HepA-related hospitalization costs from 2016-2020 were estimated to be approximately $306.8 million (USD, currency year NR) [14].

Public Health Intervention Costs
Six studies reported public health intervention costs, centered around prevention (vaccination costs, as well as advertising, administrative, staffing, and equipment costs).In 2017, the cost of the New York City Department of Health and Mental Hygiene's emergency activation collaboration, offering HepA testing and vaccines to food service workers, was $50 914 ($253 per restaurant employee evaluated; 2017 USD) [51].
One national study also evaluated public health intervention costs in a high-risk population (MSM), in addition to food service workers, reporting the cost of a 2019 8-day national Facebook advertising campaign that reached 53 422 users, with an average cost-per-link-click of $0.92 and total amount spent of $445.68 (USD, currency year NR) [54].Two cost-effectiveness analyses reporting HepA outbreakrelated public health intervention costs were also identified, 1 of which modeled total costs of a 2015-2016 HepA vaccination program at $10 188 000 per 100 000 clients (2016 USD, currency year NR) [48].The other national model found that a universal HepA vaccination policy in the United States was cost-effective at $55 778 per quality-adjusted life year gained (USD, currency year NR), compared to a willingness-to-pay threshold of $100 000/quality-adjusted life year gained, and resulted in lower HepA incidence [53].

Outbreak Management
The TLR included 34 studies reporting on the successes (n = 25), challenges (n = 28), and key learnings (n = 24) of outbreak management efforts related to ongoing HepA outbreaks (Supplementary Table 5 and Figure 2).No studies reporting cost drivers of outbreak management were identified.
Most of these studies reported on HepA cases at the local or state level (n = 21), rather than multistate (n = 5) or national or global level (n = 8), and many reported on some form of vaccination-related intervention, followed by education and hygiene interventions.Overall, 27 of 34 studies reported on populations affected by the HepA outbreak, including people experiencing homelessness (n = 20), people who use drugs or with SUD (n = 15), people currently or recently incarcerated (n = 6), MSM (n = 5), and people who ate contaminated food (n = 3).Study design and patient populations included in the TLR are summarized in Supplementary Table 6.

Successes
Early detection, early preparation, and prompt response were all found to have a considerable positive impact on HepA outbreak management, as evidenced in California's early outbreak detection efforts, which led to increased vaccination in vulnerable populations [55], Tennessee's allocation of vaccination funds during early outbreak stages [56], and Massachusetts' integration of surveillance data to expedite outbreak response [57].
Partnerships between organizations were also a key success.Coordination between public health agencies, hospitals, and pharmacies aided in containing a San Diego, California outbreak by increasing vaccination [38,52].In Michigan, partnerships expanded the reach of vaccine and education materials to at-risk populations in locations such as bars, prisons, and shelters [58].
Outbreak management tools that used an individualized approach to target at-risk populations were also successful, especially in reducing barriers to vaccination uptake.These tools included targeted computerized alerts [59]; efforts to engage medically underserved populations, implementing innovative vaccine delivery strategies, vaccine tracking, repeat community vaccination events, and vaccination safety informational materials [60]; and offering vaccines in nontraditional settings such as jails, SUD treatment programs, and homeless services [61,62].For example, one 2017 San Diego, California outbreak response reported success in adopting a highly individualized approach using vaccination events, educational outreach, and sanitation campaigns (eg, handwashing stations, increased access to public restrooms/hygiene kits) targeted towards people experiencing homelessness [63].
Finally, increasing overall public awareness (eg, through social media) was found to be an effective measure mitigating further HepA outbreak spread (Supplementary Table 5 and Figure 2) [54,55,64].

Challenges
Vaccine hesitancy due to fear and distrust, and difficulty accessing at-risk populations, were both challenges of implementing outbreak management tools.In multiple studies, individuals who hesitated or refused HepA vaccination expressed beliefs including danger or uselessness of the vaccine and mistrust of vaccinators or manufacturers [52,65], as well as of public officials and health care providers (HCPs) [66].Limited access to medical care or vaccination sites [38,62], geographic constraints [61], limited resources within correctional facilities [31], and gender discrepancies in social media usage also contributed to difficulty reaching at-risk groups [54].
Other challenges included strains in vaccination supply and resource requirements during periods of high demand and monopolization, and/or scarcity of available resources [52,[67][68][69][70][71].One San Diego, California study found that because media coverage tends to better reach populations who are not at high risk for HepA, those populations might seek resources that should be preserved for at-risk individuals [52].
Incomplete data on HepA vaccination rates was described as a challenge, as reporting HepA vaccination in immunization information systems is not required in some states [72].Limited funding was also commonly reported, with supplies, vaccines, and storage equipment further constrained during the coronavirus disease 2019 (COVID-19) pandemic [26,56,57,66,73,74].Additional challenges in outbreak management among at-risk populations were observed at a more systemic level.For example, poor sanitation and/or homelessness have been identified as root causes of outbreaks that need to be addressed (Supplementary Table 5 and Figure 2) [37,55,63,75].

Key Learnings
Formal incidence management plans were found to improve coordination and communication across affected agencies, especially when collaborations were established in advance of outbreaks [55,60,61,66,68].Proactive control strategies, particularly vaccination among high-risk groups before or in early stages of outbreaks, were also effective [17,75].
Key learnings also included the importance of understanding the root causes of disparities in HepA vaccination among different groups.A retrospective cohort study in Illinois and Wisconsin found that among HepA vaccine recipients, people who were insured with Medicare, Hispanic, non-Asian, or who had a history of incarceration were significantly less likely to be vaccinated [76].Furthermore, directly addressing root causes [75], such as barriers to sanitation and vaccination among people experiencing homelessness [65,77], is necessary.Alternative routes, such as needle exchange programs [17], and improving hygiene facility and supply accessibility [52], could also be utilized to decrease HepA spread.
Due to distrust of vaccination and government health policies among high-risk groups, developing strategic, nontraditional ways of reaching these groups and communicating HepA vaccination safety and importance were necessary.This included targeted, accessible outreach on social media platforms and word-of-mouth via community leaders [68].Collaborations, especially those strengthening partnerships between organizations with existing trusted relationships with vulnerable populations, could also improve vaccination uptake [60].Implementing nontraditional vaccine delivery locations that might be more convenient for higher-risk groups, such as jails and SUD facilities, could also increase vaccination access for these groups [31,73].
Other key learnings included the importance of building upon preexisting materials or data [26,78], as well as using informatics tools in increasing vaccination efforts [59], positive public perception of public health efforts [67], formal record keeping [45,72], and improved social media messaging [54] (Supplementary Table 5 and Figure 2).

DISCUSSION
This review demonstrates the considerable burden of HepA on health and economic outcomes, particularly among at-risk populations.By implementing the successes and addressing the challenges of past HepA outbreak responses, the morbidity, mortality, associated HCRU, and economic burden of these outbreaks can be reduced.Increased vaccine awareness, education, and uptake through targeted efforts of HCPs, public health department leaders, and community organizations are key in preventing future HepA outbreaks.
National and international initiatives have been enacted to prevent and eliminate HepA, including the Viral Hepatitis National Strategic Plan (2021-2025) in the United States and the World Health Organization's Global Health Sector Strategy on Viral Hepatitis [79,80].However, vaccination coverage in the United States remains low, especially among populations at highest risk of HepA infection, such as injection drug users and MSM [81].Therefore, it is critical to address key challenges that remain around vaccination distrust, knowledge gaps, and disease misinformation, via education strategies targeting high-risk groups.
In addition, although HepA and HepA & HepB combination vaccines are available and recommended for adults by the ACIP, adherence to and knowledge of ACIP guidelines vary, and some HCPs still report not recommending vaccination against HepA for reasons including low perceived risk of certain patient populations and uncertainty of guidelines [82,83].Focusing on prevention, including targeted efforts in HCP education, could be beneficial in increasing vaccine uptake and reducing HepA disease burden.For example, educating HCPs on risk factors, and making HCPs aware that the ACIP recommends that any person who was not vaccinated previously may be vaccinated, may help to prevent infection among at-risk populations who experience stigma (eg, persons experiencing homelessness, drug users, MSM) [81].Given the risk of hospitalization and associated direct medical and indirect costs of HepA infection, vaccinating patients without confirmed risk factors may help to further decrease the HCRU and economic burden of HepA.Ultimately, the key outbreak management considerations identified in this study can be used to inform future outbreaks across diverse disease areas outside of HepA, especially other vaccine-preventable diseases.

Figure 1 .
Figure 1.PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow chart.

Figure 2 .
Figure 2. Successes, challenges, and key learnings associated with US hepatitis A (HepA) outbreak management.

Table 1 . Health Outcomes and Health Care Resource Utilization Associated With the US HepA Outbreaks
NR NR NR e202 • JID 2024:230 (15 July) • Horn et al

Table 1 . Continued
who died of HepA-associated causes, 19 (95.0%) had underlying factors (eg, cirrhosis, diabetes, or cardiomyopathy) that may have contributed to increased risk of severe outcomes.Two patients (10.0%) had relapsing HAV infection (defined as recurrent disease within 6 months of last recovery).The first patient died and the second patient improved with supportive care.
Abbreviations: ACLF, acute on chronic liver failure; ALF, acute liver failure; ALT, alanine transaminase; AR, Arkansas; AST, aspartate aminotransferase; AZ, Arizona; Bup, buprenorphine; CA, California; CDC, Centers for Disease Control and Prevention; CLD; chronic liver disease; CLIF-C, Chronic Liver Failure Consortium; CO, Colorado; DE, Delaware; ED, emergency department; EMR, electronic medical records; FDA, Food and Drug Administration; FL, Florida; GA, Georgia; GI, gastrointestinal; HAV, hepatitis A virus; HCRU, health care resource utilization; HE, hepatic encephalopathy; HepA, hepatitis A; HI, Hawaii; ICU, intensive care unit; IgM, immunoglobin M; IL, Illinois; IN, Indiana; IV, intravenous; KY, Kentucky; LA, Louisiana; LMPHW, Louisville Metro Department of Public Health and Wellness; MA, Massachusetts; MD, Maryland; MDSS, Michigan Disease Surveillance System, MI, Michigan; MI, myocardial infarction; MN, Minnesota; MS, Mississippi; MSM, men who have sex with men; N, overall population size; n, sample population size; NAC, N-acetylcysteine; NAFLD, nonalcoholic fatty liver disease; NC, North Carolina; ND, North Dakota; NIS, National Inpatient Sample; NNDSS, National Notifiable Diseases Surveillance System; NR, not reported; NV, Nevada; NX, naloxone; NY, New York; OH, Ohio; PA, Pennsylvania; SD, standard deviation; SE, standard error; TN, Tennessee; UT, Utah; VA, Virginia; VT, Vermont; WA, Washington; WI, Wisconsin; WV, West Virginia.a Unless otherwise stated.b Unfavorable outcome, defined as occurrence of one or more of the following during hospitalization: death, intensive care admission, acute or chronic liver failure, renal failure, respiratory failure, or shock.c Outbreak(s) occurred solely via food-borne transmission.d National surveillance acute hepatitis A case definition in 2018: acute illness with discrete onset of symptoms consistent with acute viral hepatitis, jaundice, or elevated ALT or aspartate aminotransferase, and IgM antibody to hepatitis A virus (anti-HAV) positive.e Compared with recent incarceration.f HepA outbreak-associated patients who died and whose deaths were determined to be associated with HepA by the respective state health departments.g HepA outbreak-associated patients who had not died.h Of 20 patients i One patient with underlying alcoholic cirrhosis-developed GI bleeding and hepatorenal syndrome; 1 had underlying NAFLD; both were considered for transplant.Burden of Hepatitis A Outbreaks in US • JID 2024:230 (15 July) • e209

Table 2 . Continued
: CA, California; CDC, Centers for Disease Control and Prevention; CI, confidence interval; DOHMH, Department of Health and Mental Hygiene; ED, emergency department; FHCSD, Family Health Centers of San Diego; FSW; food service workers; HAV, hepatitis A virus; HepA, hepatitis A; IgM, immunoglobin M; KY, Kentucky; LMPHW, Louisville Metro Public Health and Wellness; MSM, men who have sex with men; NA, not applicable; NIS, National Inpatient Sample; NR, not reported; NY, New York; PA, Pennsylvania; SD, standard deviation; SUD, substance use disorder; WV, West Virginia.