Published online January 2, 2007
PEDIATRICS Vol. 119 No. 1 January 2007, pp. e12-e21 (doi:10.1542/peds.2006-1573)
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ARTICLE

Cost-Effectiveness of Routine Childhood Vaccination for Hepatitis A in the United States

David B. Rein, PhDa, Katherine A. Hicks, MSa, Kathleen E. Wirth, BAa, Kaafee Billah, PhDb,{dagger}, Lyn Finelli, DrPHb, Anthony E. Fiore, MD, MPHb, Thomas J. Hoerger, PhDa, Beth P. Bell, MD, MPHb and Gregory L. Armstrong, MDb

a RTI International, Atlanta, Georgia
b Centers for Disease Control and Prevention, National Center for Infectious Diseases, Division of Viral Hepatitis, Atlanta, Georgia


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVES. Economic analysis is an important component in formulating national policy. We evaluated the economic impact of hepatitis A vaccination of all US children ages 12 to 23 months as compared with no vaccination and with current implementation of the preexisting (issued in 1999), regional policy.

METHODS. We developed a Markov model of hepatitis A that followed a single cohort from birth in 2005 through death or age 95 years. From the societal perspective, the model compared the outcomes that resulted from routine vaccination at age 1 year to 2 scenarios: no hepatitis A vaccination and hepatitis A vaccination at levels observed in 2003 under the preexisting policy. We evaluated the economic impact of vaccination nationwide, in areas where vaccination was already recommended, and in areas where no previous recommendation existed.

RESULTS. Without childhood vaccination, the ~4 million children in the 2005 birth cohort would be expected over their lifetimes to have 199000 hepatitis A virus infections, including 74000 cases of acute hepatitis A and 82 deaths, resulting in $134 million in hepatitis A–related medical costs and productivity losses. Compared with no vaccination, routine vaccination at age 1 year would prevent 172000 infections, at a cost of $28000 per quality-adjusted life year saved. Compared with maintaining the levels of hepatitis A vaccination under the preexisting regional policy, routine vaccination at age 1 year would prevent an additional 112000 infections, at a cost of $45000 per quality-adjusted life year saved.

CONCLUSIONS. The cost-effectiveness of nationwide hepatitis A vaccination compared with no vaccination, and the incremental cost-effectiveness of this recommendation compared with preexisting recommendations, is similar to that of other accepted public health interventions. In October 2005, the Advisory Committee on Immunization Practices recommended extending hepatitis A immunization to all US children ages 12 to 23 months.

Key Words: cost-effectiveness • hepatitis A • vaccination • public policy • economics • ACIP

Abbreviations: FLF—fulminant liver failure • HAV—hepatitis A virus • ACIP—Advisory Committee on Immunization Practices • QALY—quality-adjusted life year • NNDSS—National Notifiable Disease Surveillance System • CDC—Centers for Disease Control and Prevention

Hepatitis A is characterized by abrupt onset of symptoms such as fever, malaise, anorexia, nausea, abdominal discomfort, dark urine, and jaundice. The syndrome generally lasts 10 to 33 days1,2 followed by a full recovery, often after a prolonged convalescence. Severe cases can lead to fulminant liver failure (FLF) and death.3 Infection with hepatitis A virus (HAV), particularly among children, can also result in less severe disease, including a relatively mild, anicteric (without jaundice) illness or asymptomatic infection.

In the United States, an average of 26000 hepatitis A cases were reported annually during the 1980s and 1990s, representing an estimated 270000 infections per year after accounting for unreported cases, anicteric illness, and asymptomatic infections.4 In 1995, highly effective hepatitis A vaccines were licensed in the United States for use in adults and in children ≥2 years old. In 2005, the Food and Drug Administration approved lowering the minimum age for immunization to 12 months.5,6

Soon after hepatitis A vaccines became available, the Advisory Committee on Immunization Practices (ACIP) adopted a strategy of incremental implementation of recommendations for childhood hepatitis A vaccination. The ACIP first issued recommendations in 1996,7 directed at children living in areas with the highest disease rates and periodic outbreaks. In 1999, the next incremental step was taken when recommendations were expanded8 to include routine childhood immunization in 11 states where hepatitis A rates were historically at least twice the national average. At that time, the ACIP also recommended that providers consider immunizing children in 6 additional states where hepatitis A rates were historically between 1 and 2 times the national average. No recommendation was made for the remaining 33 states where rates were historically below the national average. Subsequently, national hepatitis A incidence declined to historically low levels, with the largest declines observed in the areas in which routine vaccination of children was recommended.9,10 Despite these successes, hepatitis A vaccine coverage among children living in states covered by the recommendations has lagged behind the coverage of childhood vaccines for which there is a single nationwide recommendation, and little childhood vaccination has occurred in areas where there were no recommendations for statewide vaccination of children.11

In October 2005, the ACIP voted unanimously to take the final step in the incremental strategy by recommending routine hepatitis A vaccination for all children aged 12 to 23 months nationwide.12 The ACIP was concerned about the long-term sustainability of the previous policy and the fact that the overwhelming majority of remaining US cases of hepatitis A were occurring in parts of the country where no hepatitis A vaccination of children was recommended. In this article we describe the cost-effectiveness of hepatitis A immunization in the United States in terms of the cost per year of life saved and the cost per quality-adjusted life year (QALY) saved.13 This analysis, provided to the ACIP as the updated policy was being considered, evaluates the direct (ie, excluding herd immunity) economic impacts of the vaccine, and finds that the economics of nationwide immunization against hepatitis A are favorable when compared both with no immunization and with immunization at current levels.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Design
We developed a Markov model (a technical report outlining the details of this model can be accessed on the internet at www.rti.org/pubs/hepa-model_report_rein.pdf) of hepatitis A that simulated clinical and economic outcomes among a single US birth cohort from birth in 2005 through age 95 years. We compared outcomes resulting from routine nationwide vaccination at age 1 to either no hepatitis A vaccination or hepatitis A vaccination at levels observed in 2003. The analysis was run nationwide and separately by region. Region 1 was defined as the 11 states where hepatitis A vaccination was recommended under the 1999 ACIP policy. Region 2 was defined as the 6 additional states in which the 1999 ACIP policy advised that vaccination should be considered. Finally, region 3 was defined as the remaining 33 states for which no recommendation was made by the 1999 ACIP policy.

All of the cohort members were born susceptible to hepatitis A (Fig 1). In each subsequent time period without vaccination, cohort members could be uninfected and susceptible to future infection, actively infected with hepatitis A, recovered and thereby immune to infection, or dead from hepatitis A or other causes. The model incorporated the full range of potential hepatitis A symptomatic states from asymptomatic infection to FLF. With vaccination, patients would immediately develop immunity that would wane slowly over time.


Figure 1
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  		FIGURE 1 Model structure diagram. Death from non-hepatitis A–related causes occurs at the same rate in all states (arrows for this transition not drawn). Dotted lines indicate death from hepatitis A–related causes. Hospitalization includes additional outpatient visits.

 
Data and Assumptions
The probabilities of the model were derived from published studies, notifiable disease data, previously unpublished vaccine efficacy data, proprietary adult vaccine sales data, expert opinion, and assumptions (Table 1). Costs, life years, and QALYs were considered from the societal perspective and discounted on a present-value basis using a 3% annual rate. Costs were measured in 2005 dollars.


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  		TABLE 1 Summary of Input Parameters for the Model

 
Incidence of Infection
US hepatitis A incidence trends have been characterized by ~5- to 15-year cycles and by an overall decline. To account for this long-term decline, we estimated the future rate of hepatitis A using a linear regression of the logarithm of reported hepatitis A rates against year, from 1966 to 2001, with incidence after 1994 adjusted to compensate for the effects of immunization.9 This regression showed an annual rate of decline of 1.4% after 1990. The model assumed that without immunization this rate of decline would have continued indefinitely from 1990. Historically, incidence also varied regionally and by age.14 Regional age-specific incidence was estimated by multiplying the estimated average incidence for each region by the ratio of age-specific incidence to overall incidence during 1990–1995, the years immediately preceding the licensing of hepatitis A vaccine.14 Across all of the regions, we assumed 3.28 unreported cases for each reported case of hepatitis A.4 All of the reported cases were assumed to be icteric. The number of additional anicteric cases (asymptomatic or mildly symptomatic without jaundice) was estimated by applying an age-specific ratio, also determined by regression.4

Disease Severity, Service Use, and Costs of Care
The probability of receiving health care given icteric infection was taken from published studies.15 The probability of hospitalization given reported icteric infection was set equal to the average probability of hospitalization from 1990 through 1995 as reported by the National Notifiable Disease Surveillance System (NNDSS)14 and the National Hospital Discharge Survey.16 Icteric patients treated as outpatients were assumed to have more severe illness and to consume more health resources if their cases were reported to the health department; all hepatitis A hospitalizations were assumed to be reported. Half of anicteric infections were assumed to be asymptomatic and the other half to have mild, nonspecific symptoms of short duration requiring a single outpatient visit 50% of the time.

The number of deaths resulting from hepatitis A was estimated from NNDSS data. We assumed that death could occur only from hepatitis A after FLF and that all patients with FLF would be treated as inpatients. Values for the probability of death given FLF and no transplant and the probability of transplant given FLF were taken from published studies.17 The probability of death after transplant was based on data from the United Network for Organ Sharing.18 The age-specific probability of FLF was then calculated based on the known probabilities of inpatient admissions, transplants, and death from FLF with or without transplant and the total number of hepatitis A–related deaths identified in the NNDSS data.

Medical costs of outpatient care, inpatient care, FLF, and liver transplants were taken from published studies.2,19,20 The costs of unreported outpatient icteric cases were assumed to be one third those of reported cases. We assumed that patients with symptomatic anicteric infections who used medical services used only 1 outpatient visit and that the cost of that visit was the same as that for a visit for fever and malaise associated with influenza.21 Productivity losses, based on the expected duration of the episode of illness and the expected wage of the patient or caretaker, were included in the model to account for the work loss incurred by caregivers of cohort members infected during childhood and by cohort members themselves when infected as adults.2,22 Only work losses incurred by caregivers of cohort members who were infected while children were included in the numerator used to calculate the cost per QALY saved ratio, whereas all of the productivity losses were included in the numerator used to calculate the cost-per-life-year-saved ratio. This is because patients were asked to consider work losses that they would experience as adults in the survey used to determine QALY values.

Public Health Costs
As a reportable infectious disease, hepatitis A cases create public health costs associated with surveillance, contact tracing, and outbreak response that would be largely eliminated through routine childhood vaccination. We estimated the cost and probability of hepatitis A–related physician and patient interviews, contact tracing, immune globulin distribution, and public notification from expert opinion and published reports.23

Health Utilities
Relative quality-of-life values were taken directly from the tables found in a published time tradeoff estimation of utility losses associated with hepatitis A.24,25 Full-year QALY values were then adjusted for partial-year disease duration, with different durations for different symptomatic states.2 These adjusted QALY weights were multiplied by age-specific background QALYs to account for the background prevalence of chronic disease and disability in the population.

For vaccine studies, cost-effectiveness ratios based on traditional time tradeoff utility estimates are directly comparable to the majority of other vaccine cost-effectiveness studies. However, more recently, some economists have been concerned about the accuracy of traditional QALY estimation methods.26 To account for uncertainty in the precise value of QALYs associated with hepatitis A, we used a low and high method to calculate QALYs in our sensitivity analysis. Our low estimate simply divided the QALY losses for each hepatitis A health state in half compared with the baseline. Our high estimate assumed no loss of background QALYs with age, a method commonly used in earlier vaccination cost-effectiveness studies.

Childhood Vaccine Coverage and Costs
Vaccine coverage for 1 and 2 doses was set equal to the average coverage in 2003 for Haemophilus influenzae type b vaccine and pneumococcal conjugate vaccine, both of which are routinely administered between ages 1 and 2 years.27 For the scenario comparing routine vaccination to vaccination at current levels, current coverage levels were taken from a 2003 survey.11 Vaccine costs were based on the reported public and private prices paid for childhood vaccine by the Vaccines for Children program,28 assuming that 59% of the vaccine would be purchased at the lower public contract price (Centers for Disease Control and Prevention [CDC], unpublished data, 1995–2003). Excise taxes were excluded. For each vaccine dose, patients had a 1 in 200 chance29 of a mild adverse reaction that imposed only slight productivity costs and a 1 in 1000000 chance of a severe adverse reaction requiring some medical attention.

Vaccine Efficacy and Duration of Vaccine-Acquired Immunity
Not all patients develop immunity from vaccination and in those that do, vaccine-acquired immunity wanes over time. In the model, the establishment of initial immunity and the years of duration of immunity after vaccination was estimated from the mean and distribution of geometric mean titers after 1 and 2 doses of vaccine observed in published studies30,31 and in primary data. Using these data, our model predicted that 91% of those vaccinated would develop immunity for ≥1 year after 1 dose of vaccine, and 100% of those vaccinated would develop immunity for ≥1 year after 2 doses. Subsequently, the model used an estimated 20% annual decline in antibody concentrations for the first 5 years after vaccination,30 a 5% annual decline in the years thereafter (P. Van Damme, MD, PhD, written communication, 2005), and a threshold for immunity of 20 mIU/mL31 to calculate the duration of immunity among those who exhibited an initial response. After vaccination with 1 or 2 doses, the vaccinated patient cohort was distributed according to the estimated number of years of vaccine-acquired immunity remaining. For patients who received 1 dose of vaccine that developed an initial immune response, the model estimated that 37% maintained immunity for 1 to 10 years, 20% for 11 to 20 years, 30% for 21 to 40 years, and 13% for ≥41 years. The model estimated that all of the patients who received 2 doses of vaccine developed an immunity for ≥20 years: 10% for between 21 and 40 years and 90% for ≥41 years. The model assumed that patients who lost vaccine-acquired immunity had the same risk of infection as those who were susceptible and never vaccinated.

Adult Vaccination
Based on vaccine sales data,9 unvaccinated adults in the model aged >18 years were vaccinated at a rate of 1.3% per year in regions 1 and 2 and a rate of 0.8% per year in region 3. Most of this adult vaccination would be unnecessary if routine childhood immunization were implemented.

Sensitivity Analyses
In univariate sensitivity analyses, we tested the sensitivity of our model to changes in the discount rate, the baseline and annual rates of decline of hepatitis A incidence, the long-term decline in antibody to HAV after immunization, the rate of adult vaccination, the value of QALY decrements associated with illness, public health costs, and symptomatic adverse events. In a multivariate probabilistic sensitivity analysis, we tested the sensitivity of the model to the combined uncertainty of all of the model parameters. This was done by randomly and independently altering all of the model parameters within their margin of error in each of 10000 iterations of the model and then evaluating the range of cost-effectiveness ratios that were generated.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Disease Burden and Costs of Hepatitis A
Our model estimated that without childhood vaccination, 198751 members (4.9%) of the 2005 birth cohort would be infected with HAV during their lifetimes. Of these infections, 124939 would be asymptomatic or involve mild nonspecific symptoms and 73812 would result in acute hepatitis A with jaundice. Of the jaundiced cases, 222 would progress to FLF, resulting in 33 liver transplants and 82 deaths (Table 2). These cases would produce $133.5 million in total economic costs, including $86.8 million in health care and adult vaccination costs, $31.6 million in productivity losses among parents of infected children, and $15.3 million in productivity losses among adults with hepatitis A.


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  		TABLE 2 Expected Hepatitis A Disease Outcomes and Costs with No Immunization

 
Compared with no childhood vaccination, routine vaccination at age 1 year would result in 172334 fewer infections and 32 fewer deaths nationwide. This reduction would produce a gain of 247 discounted life years or 2154 discounted QALYs (Table 3). Routine vaccination at age 1 year would cost $49.3 million more than no vaccination, resulting in cost-effectiveness ratios of $284 per infection averted, $199000 per life year gained, and $28000 per QALY saved. Compared with coverage levels in 2003,10 routine nationwide vaccination at age 1 year would result in 112411 fewer infections and cost an additional $55.8 million, with incremental cost-effectiveness ratios of $496 per infection averted, $338000 per life year gained, and $45000 per QALY saved. From the perspective of the health care system (ie, excluding productivity losses), nationwide routine vaccination costs $40000 per QALY saved compared with no vaccination and $57000 per QALY saved when compared with coverage levels in 2003.


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  		TABLE 3 Impact of Childhood Immunization at 1 Year of Age Compared With No Vaccination in 2 US Regions and Compared Nationally With No Vaccination

 
Cost-effectiveness varied by region. Compared with no vaccination, routine vaccination at age 1 year was cost saving in regions 1 and 2 and cost $933000 per life year saved and $133000 per QALY saved in region 3. Compared with immunization at 2003 vaccine coverage levels, routine vaccination was cost saving in regions 1 and 2 and cost $927000 per life year saved and $132000 per QALY saved in region 3. From the perspective of the health care system (ie, excluding productivity losses), routine vaccination costs $8000 per QALY saved in regions 1 and 2 and $143000 per QALY saved in region 3 when compared with no vaccination and $9000 per QALY saved in regions 1 and 2 and $143000 per QALY saved in region 3 when compared with 2003 vaccine coverage levels.

Sensitivity Analyses
The cost-effectiveness of vaccination was fairly sensitive to the combined cost of a vaccine dose and administration, the baseline incidence value, the discount rate, and the use of a more conservative QALY decrement associated with illness (Fig 2) If the total vaccination cost per dose, including acquisition and administration costs, decreased to $17 (roughly the public sector cost of vaccination at age 1 year), the incremental cost per QALY of routine vaccination at age 1 would fall to approximately $7000 compared with no vaccination and approximately $18000 compared with vaccination at 2003 vaccine coverage levels. Decreasing the baseline incidence in each region by 25% resulted in a cost-effectiveness ratio of $73000 per QALY. Likewise, increasing the discount rate decreased the cost-effectiveness of vaccination. Reducing the QALY decrements associated with symptomatic hepatitis A illness by half increased the cost-effectiveness of nationwide vaccination to $71000 per QALY compared with no vaccination.


Figure 2
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  		FIGURE 2 Univariate sensitivity analysis of the nationwide cost/QALY for vaccination at age 1 versus no vaccination (axis = baseline cost-effectiveness ratio = $28000)

 
Our results were moderately sensitive to the rate of decline in vaccine-induced antibody to HAV. Assuming a vaccine that was half as effective as what has been observed in clinical trials thus far would yield a cost-effectiveness ratio of $62000 per QALY. Relative to these other variables, the model was fairly insensitive to the inclusion of public health costs, the annual rate of decline in HAV incidence, and the inclusion of adult vaccination costs.

In 10000 simulations of the probabilistic sensitivity analysis for immunization at age 1 year compared with no vaccination, the cost per QALY ratio fell below $50000 in 82% of the simulations, between $50000 and $75000 in 15% of the simulations, between $75000 and $100000 in <3% of the simulations, and above $100000 in <1% of the simulations. Vaccination was essentially cost-neutral or cost-saving in 8% of the simulations (Fig 3).


Figure 3
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  		FIGURE 3 Probabilistic sensitivity analysis: distribution of cost per QALY ratios from 10000 replications of routine nationwide vaccination at age 1, vs no vaccination, accounting for multivariate parameter uncertainty.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Hepatitis A causes relatively few deaths but often results in prolonged, temporarily disabling illness and is, thus, responsible for substantial morbidity. In the model presented here, without immunization, the 2005 US birth cohort could expect ~200000 HAV infections and $133.5 million of related economic losses. In this scenario, the cost-effectiveness ratio of introducing routine childhood hepatitis A immunization ($28000 per QALY saved) is comparable to that of other public health interventions, such as expanded HIV screening among high-risk patients ($36000 per QALY)32 and the general population ($42000 per QALY, excluding secondary benefits)33 and diabetes screening among patients with hypertension ($34000).34 This favorable cost-effectiveness ratio is similar to findings from a previous analysis of the economics of nationwide hepatitis A vaccination of children.35 However, that analysis depended on the inclusion of benefits from averted secondary infections whereas this one does not.

Compared with no vaccination, the cost-effectiveness of nationwide routine hepatitis A vaccination at age 1 year is similar to that of other recently recommended vaccine policies.36,37 Even compared with the preexisting regional policy, which focused vaccination efforts on areas with the highest disease burden, the cost-effectiveness of nationwide routine vaccination is more favorable than that of nationwide routine adolescent vaccination for meningitis ($138000 per QALY),38 also recently recommend by the ACIP. Nationwide hepatitis A vaccination would be less cost-effective than vaccination against varicella39 or hepatitis B,40 which are both cost-saving. Cost-effectiveness varied substantially by region, and the cost-effectiveness of vaccinating only in region 3 was less favorable ($132000 per QALY) but comparable to routine adolescent vaccination for meningitis.37

Both the cost-effectiveness ratio comparing nationwide vaccination to no vaccination and the incremental cost-effectiveness ratio of expanding immunization recommendations from the 1999 regional strategy support a policy of expanded vaccination. Although some economists might consider the incremental analysis the best reflection of the costs and benefits of the new policy, many policy-makers doubt its relevance in public health practice. From its inception, the regional strategy was considered to be an interim step and not a permanent recommendation. Concerns about its sustainability complicates the definition of a status quo against which to compare the new policy. For this analysis, we assumed that without a change in policy, immunization would continue at 2003 levels. At these levels, half of children in region 1, 75% of children in region 2, and 99% of children in region 3 would remain unprotected from hepatitis A. If immunization rates were to fall, hepatitis A incidence would likely increase. HAV infection has not been eradicated and, except for the presence of immunization, the epidemiological conditions that allow the spread of HAV in the United States have not changed.

This study has several limitations. First, the modeled hepatitis A incidence represents an averaged value observed over a 5-year period, whereas the actual incidence of hepatitis A is cyclical and varies greatly within each region.14 This variation is important, because the actual incidence will influence the degree of economic benefit derived from vaccination in any given year and locality. Second, in practice, it may take several years after issuance of any new vaccination recommendation for coverage to reach that of other childhood vaccines. We did not consider this phase-in period for nationwide hepatitis A vaccination in our analysis. During this period, the costs and the benefits will be lower than those used in this analysis, because fewer doses of vaccine will be administered. The effect of these differences on the interim cost-effectiveness of the policy is unknown. Third, except for the productivity costs associated with caretakers of infected children, our model excludes any costs incurred outside of the birth cohort, nor does it include the benefits of vaccination associated with herd immunity. Previous research suggests substantial economic benefits from a reduction in secondary infections among household and social contacts of immunized children.35 The cost-effectiveness of immunization against hepatitis A becomes substantially more cost-effective over the first 10 years of implementation when these out-of-cohort effects are included in our model.40

Finally, some authors have argued that the standard method of assessing QALY decrements may overvalue the benefit of preventing short-term health states.26 However, even halving the decrement, as was done in the sensitivity analysis, results in a nationwide cost-effectiveness ratio that is comparable to that of other recently recommended vaccinations.

From an epidemiological perspective, the interim regional ACIP recommendations were highly successful, reducing hepatitis A rates to all-time lows.10 However, even at current low rates, there remains a substantial burden of disease from hepatitis A, with the majority in states not covered by the regional recommendations. These and other factors, including the ability now to readily incorporate the vaccine into the routine early childhood vaccination schedule, prompted the ACIP to bring recommendations for using this vaccine into line with those for vaccines for other common infections. The results of the analysis presented here, indicating that the economics of an expanded vaccination policy are reasonable, formed an essential component of the ACIP conclusion that the time was right for finalizing national universal hepatitis A vaccination of children in the United States.


   FOOTNOTES
 
Accepted Aug 15, 2006.

Address correspondence to David B. Rein, PhD, RTI International, 2951 Flowers Rd, Suite 119, Atlanta, GA 30306. E-mail: drein{at}rti.org

The author has indicated he has no financial relationships relevant to this article to disclose.

{dagger} Deceased. Back


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics



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