Assessing the Cost-Utility of Universal Hepatitis B Vaccination Among Adults 

Abstract

Background

Although effective against hepatitis B virus (HBV) infection, hepatitis B (HepB) vaccination is only recommended for infants, children, and adults at higher risk. We conducted an economic evaluation of universal HepB vaccination among US adults.

Methods

Using a decision analytic model with Markov disease progression, we compared current vaccination recommendations (baseline) with either 3-dose or 2-dose universal HepB vaccination (intervention strategies). In simulated modeling of 1 million adults distributed by age and risk groups, we quantified health benefits (quality-adjusted life years, QALYs) and costs for each strategy. Multivariable probabilistic sensitivity analyses identified key inputs. All costs reported in 2019 US dollars.

Results

With incremental base-case vaccination coverage up to 50% among persons at lower risk and 0% increment among persons at higher risk, each of 2 intervention strategies averted nearly one-quarter of acute HBV infections (3-dose strategy, 24.8%; 2-dose strategy, 24.6%). Societal incremental cost per QALY gained of $152 722 (interquartile range, $119 113–$235 086) and $155 429 (interquartile range, $120 302–$242 226) were estimated for 3-dose and 2-dose strategies, respectively. Risk of acute HBV infection showed the strongest influence.

Conclusions

Universal adult vaccination against HBV may be an appropriate strategy for reducing HBV incidence and improving resulting health outcomes.

In the United States, roughly 2 million persons are estimated to be chronically infected with hepatitis B virus (HBV) [1, 2], a major cause of liver disease and mortality. After declining from 1990 to 2014, acute HBV incidence has remained stable in recent years, with an estimated 21 600 new cases occurring in 2018 alone [3]. Hepatitis B (HepB) vaccination is an effective way to protect against HBV infection for children and adults and was first recommended in the United States in 1982 for high-risk groups [4]. In 1991, universal vaccination of infants was first recommended in a national comprehensive HBV prevention strategy [5–7]. Additionally, at the onset of this analysis, the Advisory Committee on Immunization Practices (ACIP) recommended prevaccination testing and subsequent vaccination of adults deemed at higher risk for HBV infection or resulting health complications. However, the list of risk-based indications for adults recommended to receive vaccination was long and based on behavioral, chronic health, and occupational risk factors [7].

Although most people born in the United States after 1991 received the HepB vaccine as an infant or after 1999 as part of HepB catch-up vaccination, current vaccination coverage among adults remains low [8, 9]. This is particularly concerning because adults are experiencing an increase in acute HBV incidence resulting from increases in injection drug behaviors [3, 10]. Implementation of adult vaccination risk-based recommendations has been suboptimal and could be too complex to consistently implement. Additionally, systematically recording vaccination in US immunization information systems has not been as robust for adults, exacerbating challenges in improving HepB vaccination coverage among risk groups [11]. Simplification of the recommendation and messaging associated with vaccination against HBV could lead to higher uptake and have an impact on transmission. We conducted an economic evaluation of a universal HepB vaccination recommendation among all adults.

METHODS

Study Population and Strategies

We used a decision tree framework with a microsimulation Markov model to compare HepB vaccination strategies among a cohort of 1 000 000 trials representative of the 2017 US adult population. Age heterogeneity was modeled using the single-year age distribution of adults between 19 and 100 years of age from the US Census 2017 intercensal estimates [12]. Baseline strategy represented current levels of vaccination coverage among all US adults (Table 1). Considering vaccination recommendations, vaccination coverage, and risk of infection differed by risk status, our model followed the ACIP recommendations that were in effect at the time of the analysis and explicitly distinguished 2 groups: persons at increased risk of infection and those in the general population (ie, persons at lower risk of infection). In the baseline (or comparator) strategy, only persons considered to be at increased risk have been indicated for adult vaccination and recommended to receive 3 doses of HepB vaccine [7].

The intervention strategies evaluated for this economic analysis were universal HepB vaccination of all US adults using 2 different vaccines: universal HepB vaccination using a 3-dose series and universal HepB vaccination using a 2-dose series (Heplisav-B). Intervention strategies were assumed to be implemented in addition to current existing recommendations. Therefore, current levels of prevaccination testing followed by subsequent vaccination of adults at increased risk were assumed to remain in place in intervention strategies. In the base case scenarios, the intervention strategy modeled 50% HepB vaccination series initiation among adults at lower risk and assumed vaccination coverage among persons at higher risk remained the same as in the baseline strategy. We modeled unnecessary revaccination of persons at lower risk who were not aware that they were previously vaccinated [18] and the unnecessary vaccination of persons with a current chronic HBV infection who were unaware of their infection [1, 16]. Dose-specific compliance was based on data from a cohort study of adult vaccination completion rates [13, 19]. The time frame for the intervention was 1 year.

Analytic Model and Primary Outcomes

We analyzed the costs and outcomes of all strategies using a decision-tree model (Figure 1) with a nested Markov HBV-disease progression component (Supplementary Figure 1) in TreeAge Pro 2019 [29]. Age-specific vaccine coverage and vaccine efficacy estimates were applied according to the following age groups: 19–29 years, 30–39 years, 40–49 years, 50–59 years, and ≥ 60 years old. We modeled trials that represent individual people and each trial resulted in either being currently infected, having vaccine-induced protection (anti-HBs > 10 mIU/mL) against HBV infection, or not protected (mutually exclusive) prior to entering the Markov stages.

Trials who were protected against infection entered a “healthy life” Markov process in which they were not at risk of acquiring an HBV infection and experienced an age-specific annual probability of death defined by the National Vital Statistics System 2015 US Life Tables [30], resulting in a life expectancy of 82.4 years. All trials not seroprotected entered the “susceptible to infection” Markov process, which was adapted from a previously published model [31, 32], described in detail in Supplementary Methods. Trials that became infected then passed through a series of health states that represented acute and chronic HBV infection, potential treatment, and resulting advanced liver disease (Supplementary Tables 1–3).

The time step for the Markov processes was 1 year and individual trials accumulated costs and quality-adjusted life years (QALYs) for every time step spent in each health state. The analytic horizon was the age-specific life expectancy in the cohort. We estimated the average cost and average QALYs per trial for each strategy. Incremental cost-effectiveness ratios (ICERs) were calculated by dividing the difference in average cost by the difference in average QALYs. The number needed to vaccinate to prevent 1 acute HBV infection was calculated by dividing the difference in number of persons vaccinated and protected against infection by the difference in total number of acute infections (ie, prevented infections) among strategies [33]. Due to stochastic variability in the Markov processes, we present base case results as the median values of 100 model runs with the same inputs.

Epidemiologic Inputs

The risk of acute HBV infection differed by risk group and age group and represented the risk of acquiring HBV infection among unvaccinated, uninfected US adults. To estimate the risk of infection parameter, we adjusted the reported 2017 HBV incidence from the Centers for Disease Control and Prevention (CDC) Viral Hepatitis Surveillance Report [13] to account for underreporting of new HBV cases [34], current HBV prevalence [1], and current levels of HepB vaccination coverage [8, 9]. A full description of these calculations is included in Supplementary Methods and Supplementary Table 4.

Data for current vaccine coverage differed by age group and was from national surveys. Data from the 2016 National Health Interview Survey (NHIS) indicated 32.9% of adults aged 30–49 years and 15.9% of adults aged ≥ 50 years had received 3 doses of HepB vaccine [9] (Table 1). Considering adults aged > 30 years were born after the universal infant vaccination recommendation [7], these coverage estimates were applied to the group of persons at higher risk and coverage among adults > 30 years in the group of persons at lower risk was assumed to be 0%. As a result of the 1991 recommendation to provide HepB vaccination for all infants, coverage in 2018 among the cohort of adults younger than 30 years was much higher than coverage among older adults. However, the NHIS survey is based on participant recall, and adults younger than 30 years may not be able to accurately report vaccinations received as an infant. To mitigate potential recall error from NHIS data, we used data from the National Immunization Survey-Teen (NIS-Teen) for current vaccine coverage among adults aged 19–29 years. NIS-Teen includes data collection from parents/guardians and vaccine providers [8]. For adults 19–29 years of age, we used the coverage estimate from 2013 because it reflected individuals who would have been 19–23 years old in 2019. We assumed vaccine-induced protection did not wane over time because protection has been shown to last for at least 3 decades, regardless of waning anti-HBs levels [35, 36].

Cost and Utility Inputs

We used a limited societal perspective [37, 38] that included all direct medical costs related to HBV infection and resulting sequelae as well as time and travel costs related to HepB vaccination in 2019 US dollars (USDs). All annual health state costs related to the medical management of HBV infection and resulting sequelae were abstracted from a previously published model [31] and converted to 2019 USDs using the Medical Care Consumer Price Index (CPI) [25] (Supplementary Table 5). Effectiveness of each strategy was quantified using the QALYs, a summary measure that incorporates both the quantity and quality of life [39] by using previously published utility weights for time in each health state (Supplementary Table 5) [31]. All costs and utilities were discounted at 3% per year.

Public and private prices for HepB vaccines were obtained from the CDC Vaccine Price List 2019 [24]. Cost of vaccine administration ($25.80 per dose in 2016) was previously published as the mean reimbursement for routine vaccine administration [26]. This was adjusted to 2019 USD using the 2019 Medical Care CPI [25]. The cost of time for receiving 1 dose was calculated by multiplying the average hourly wages from all nonfarm workers ($27.55) by 3 hours of work [28].

In both the baseline and intervention strategy, adults at increased risk received prevaccination screening and testing (PVST) to determine previous vaccination or infection. A single PVST visit included costs associated with a hepatitis B surface antibody (anti-HBs) test, a hepatitis B core antibody (anti-HBc) test, a hepatitis B surface antigen (HBsAg) test, 3 hours of time and travel. All costs for PVST came from the Centers for Medicare and Medicaid Services 2020 Clinical Diagnostic Laboratory Fee [27]. Individuals at increased risk that were eligible to receive vaccination were assumed to receive the first dose of vaccine at the same visit as their PVST.

Sensitivity Analyses

We conducted 3 types of sensitivity analyses. First, 1-way and 2-way interval sensitivity analyses were conducted to probe epidemiologic scenarios of interest. For example, a 1-way interval sensitivity analysis was conducted on the proportion of adults at lower risk that initiate vaccination in the intervention strategy. Additionally, we conducted a stepwise sensitivity analysis in which a proportion of unvaccinated persons at higher risk (0%, 20%, 40%, 60%, 80%) also initiated vaccination as an indirect result of change from a risk-based to universal approach. As an extension of these 2 sensitivity analyses, we calculated results at varying levels of reported acute HBV incidence under both favorable and unfavorable vaccination coverage assumptions. We defined the favorable coverage scenario as the intervention strategy achieving vaccination coverage of 70% in the general population and resulting in 60% additional vaccination among persons at higher risk. In contrast, the unfavorable coverage assumption was defined as 30% coverage in the general population and no additional vaccination among persons at higher risk. Additionally, we conducted a scenario sensitivity analysis that utilized the lowest reported seroprotection rates for each dose-specific efficacy input of the 3-dose vaccination series [20].

Second, 1-way sensitivity analyses were conducted to determine the potential individual impact of each input’s uncertainty on base case results. Third, we conducted a probabilistic sensitivity analysis (PSA) to assess the combined stochastic uncertainty of all model inputs. A triangle distribution was defined for each input parameter, with the base case value set as the distribution mean and the upper and lower limits set as the upper and lower bounds of the distribution, respectively. We sampled 100 input parameter sets and ran 1 000 000 microsimulation Monte Carlo trials with each parameter set. For all outcomes of interest, we report the median result and the 95% interval (2.5th and 97.5th percentile) from the PSA results.

RESULTS

Each of the intervention (ie, universal vaccination) strategies resulted in increased costs and QALYs gained compared to the current (ie, baseline) strategy. Achieving 50% vaccination initiation with a 3-dose universal vaccination strategy increased costs per individual by $130 (interquartile range [IQR], $126–$132) and increased QALYs by 0.0008 (IQR, 0.0005–0.0011) per individual, resulting in a societal ICER of $152 722 per QALY gained (IQR, $119 113–$235 086; Table 2). Similarly, 50% initiation with a 2-dose strategy resulted in a cost increase of $129 (IQR, $125–$131) per person and increased QALYS by 0.0008 per person (IQR, 0.0005–0.0010), resulting in a societal ICER of $155 429 per QALY gained (IQR, $120 302–$242 226). Compared to the current strategy, the intervention strategies averted nearly one-quarter of acute HBV infections (24.8% in the 3-dose strategy and 24.6% in the 2-dose strategy) and HBV-related deaths (22.8% in the 3-dose strategy and 22.2% in 2-dose strategy). When stratifying these estimates by age group (Supplementary Table 6), the ICERs were the lowest among persons aged 30–39 years for both intervention strategies.

On a population level, the 3-dose intervention strategy required 176 021 559 additional HepB vaccination doses and resulted in 52 526 738 additional persons with vaccine-induced protection compared to the baseline strategy, whereas the 2-dose strategy required 134 584 881 additional vaccine doses and resulted in 54 499 654 additional persons with vaccine-induced protection compared to the baseline strategy (Table 3). The 3-dose and 2-dose intervention strategies averted 142 250 and 142 002 acute HBV infections, respectively.

One-way interval sensitivity analyses on vaccination coverage indicated that higher levels of vaccination coverage among the general (persons at lower risk) population averted a higher proportion of infections and yields lower ICERs. Achieving 70% vaccination initiation averted 33.4% of incident acute HBV infections (ICER = $155 009) in the 3-dose strategy and 34.1% of acute HBV infections in the 2-dose strategy (ICER = $154 290; Supplementary Table 7). Importantly, scenarios in which additional persons at higher risk received vaccination as a result of change in approach from risk-based to universal also resulted in increased costs and increased QALYs compared to the current strategy. In general, as the proportion of additional persons at higher risk who received vaccination increased, the cost per person increased and health outcomes improved. For example, in scenarios when 60% of additional persons at higher risk sough vaccination, the 3-dose strategy averted 41.8% of HBV infections (ICER = 117 062) and the 2-dose strategy averted 39.4% of HBV infections (ICER = $118 736) (Supplementary Table 8).

Results from a scenario sensitivity analysis that utilized the lowest reported dose specific efficacy inputs for the 3-dose vaccination series are reported in Supplementary Table 9. The inputs with the largest individual impact on the resulting ICER were related to the risk of infection (Supplementary Figure 2). As the assumed risk of acute HBV infection increased, the resulting ICER decreased for both vaccination strategies under a variety of assumed vaccination coverage scenarios (Figure 2). Results from the probabilistic sensitivity analysis on all model inputs are displayed in Supplementary Table 10. The resulting median ICER across all PSA model runs was $105 898 (95% interval, $64 560 to $276 552) and $101 489 (95% interval, $57 130 to $253 554) for the 3-dose and 2-dose strategies, respectively.

DISCUSSION

The findings from this analysis indicate that a universal adult HepB vaccination strategy would result in additional costs and additional QALYs gained, compared to the current strategy. The results were very similar for a strategy that utilizes either a 3-dose series or a 2-dose series. The similarity of these results is driven by similar levels of protection against infection and the difference in cost per dose being offset by the number of required doses for each strategy. Furthermore, results remain relatively stable across a range of vaccination coverage scenarios and are relatively robust against the influence of any single model assumption or input. Higher vaccination coverage in the intervention strategies resulted in better health outcomes—the average QALYs gained, life-years gained, number of acute HBV infections averted, and number of HBV-related deaths averted all increased as vaccination coverage increased.

Because vaccination was previously recommended for persons at higher risk, the primary analysis relied on a conservative base case scenario without changes in the current vaccination coverage among persons at higher risk. However, the actual implementation of a universal adult vaccination recommendation would likely result in an increase in vaccination among persons at higher risk, in addition to the intended effects among the general population. As expected, scenarios in which vaccination coverage increase among adults at higher risk resulted in an increase in incremental costs and a notable increase in health outcomes gained and more favorable ICERs.

Previous economic analyses of HepB vaccination among adults have focused on providing vaccination to specific populations (eg, adults with diabetes [40], injection drug users [31, 41], homeless persons) or in specific settings (eg, clinics for sexually transmitted infections [42], human immunodeficiency virus [HIV] testing sites [43]). To our knowledge, this is the only economic analysis of recommending vaccination for all adults, although the framework and approach used in this analysis are relatively standard to most economic evaluations of adult vaccination [44]. This analysis differs from the HBV studies included in that review because they only focused on indication-based recommendations. Unlike those in the review, the results from this analysis support expansion to a universal HepB vaccination recommendation to simplify and improve the implementation of adult HepB vaccination guidelines.

Recent trends in HBV incidence further highlight the importance of HepB vaccination among adults. From 2011 to 2018, estimated national acute HBV incidence increased 14% [3], with much larger increases reported in specific states in Appalachia (ie, Kentucky, Tennessee and West Virginia) [45]. The increase in infectious transmission is likely being driven by an increase in injection drug use as a result of the opioid crisis [10, 46, 47]. Considering that HepB vaccination coverage is low among the general population, it is likely to also be low among injection drug users under current recommendations.

This analysis had some limitations. First, the epidemiologic model was a static model that assumed risk of infection does not change over time. Compared to a dynamic epidemiological model, this approach results in a conservative estimate of benefits because it does not include indirect effects (eg, herd immunity) that would result in indirect protection of persons that never seek or complete vaccination or confer protection. Because we did not model individuals aging into the cohort, the economic value of universal vaccination would likely decline over time because of high existing vaccination coverage among persons that would age into the cohort. Therefore, a static model is justified because the intervention being considered represents a single point in time vaccination strategy, the analytic horizon is the lifetime of the cohort, and the intervention strategy projects to be cost-effective [48].

As part of the estimation of risk of infection for each age group, we adjusted reported acute HBV infection rates to account for underreporting with a commonly used multiplier [34], which has not been estimated for different age groups. The 1-way sensitivity analyses on acute HBV incidence within each age group provide additional understanding of how this assumption may impact results. Furthermore, the uncertainty around the input used to estimate risk of infection was the motivation for the extensive sensitivity analysis presented in Figure 2. Although we present results for a variety of scenarios, if the risk of infection decreases over time (either as a result of declines in acute HBV infections, improved prevention strategies, or changes in the population composition), and conclusions around the resulting cost-effectiveness of the intervention will change as well. Additionally, the adapted model of HBV disease progression does not include coinfections with HIV, hepatitis C, or other infections, which could alter quality (and length) of life, progression of HBV infection, and associated medical costs [31]. We explicitly modeled a group of persons at higher risk of infection and a group at lower risk of infection but assumed homogeneity of risk by age within each group and assumed risk group status did not change for the duration of the individual’s life. We did not explicitly model individual high-risk groups, such as incarcerated persons. Although HBV risk factors likely differ by geographic region [45], we only used national data. Finally, this study focused only on the recommendation of universal vaccination and did not model implementation costs of a universal vaccination program. As vaccination coverage increased, it may become more costly to identify and vaccinate the remaining susceptible adults. These assumptions may have resulted in an underestimation of the complete cost of the intervention strategies.

CONCLUSION

Universal adult vaccination against HBV may be an appropriate strategy for reducing HBV incidence and improving resulting health outcomes, particularly in scenarios that result in additional vaccination coverage among adults at higher risk. Although the use of a willingness-to-pay threshold alone as a decision rule should be taken cautiously, our ICER estimate of a universal adult vaccination against HBV may be cost-effective if the willingness-to-pay threshold used is $180 000, namely, 3 times the US gross domestic product per capita (ie, GDP per capita in 2020) as suggested by the World Health Organization [49]. These results support a need to quantify and increase communication of the economic value of adult vaccinations [44]. ACIP already recommends the vaccination of infants at birth and any unvaccinated persons < 19 years of age [7]. In February 2021, the results of this economic analysis were presented to ACIP as evidence to consider for recommending universal adult HepB vaccination. In November 2021, ACIP voted to recommended HepB vaccination for all adults 19 through 59 years of age and adults 60 years and older with risk factors for hepatitis B infection, while adults 60 years and older without known risk factors may be vaccinated as well.

Supplementary Data

Supplementary materials are available at The Journal of Infectious Diseases online. 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.

Notes

Acknowledgment. The authors acknowledge the Advisory Committee of Immunization Practices Viral Hepatitis Work Group for their contributions to the development and review of this analysis.

Disclaimer. The findings and conclusions in this report are those of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the Department of Health and Human Services. Use of trade names and commercial sources is for identification only and does not imply endorsement by the National Center for HIV, Viral Hepatitis, STD, and TB Prevention, the Centers for Disease Control and Prevention, the Public Health Service, or the US Department of Health and Human Services.

Financial support. This work was supported by the National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention (NCHHSTP), Centers for Disease Control and Prevention, as part of the NCHHSTP Epidemiologic and Economic Modeling Cooperative Agreement (grant numbers 5U38PS004646 and 5U38PS004650).

Presented in part: Advisory Committee on Immunization Practices at Centers for Disease Control and Prevention, Atlanta, GA, 24 February 2021.

References

Author notes