The goal of our study was to determine the clinical and economic impact of alternative HBV vaccination strategies for selected U.S. populations. This analysis updates the earlier work of Mulley and colleagues [7] by incorporating more recent data on incidence of HBV infection, cost of acute disease and chronic sequelae, and safety and effectiveness of HBV vaccine, by focusing on a broader range of populations, and by modeling a longer period.

A safe and effective vaccine to prevent HBV infection was introduced in the United States in 1981. Nonetheless, the overall incidence of HBV infection increased 14.5% between 1981 and 1987 [2, 3], especially in selected high-risk groups [8] (77% increase between 1981 and 1988 among injection drug abusers). The clear relationship between HBV infection and primary hepatocellular carcinoma indicates that HBV vaccine is the first effective anti-cancer vaccine [6]. However, the vaccine is not administered to most high-risk people (fewer than 50% of high-risk health care workers have received a complete HBV vaccination series) [3, 9, 10].

Acute HBV infection manifests itself clinically along a spectrum from asymptomatic, subclinical infection through fatal fulminant hepatitis [1, 5, 11]. More than 50% of HBV infections in adolescents and adults in the United States are asymptomatic [2, 9, 12, 13]. Others exhibit a variety of nonspecific viral symptoms; one quarter become ill with jaundice [3]. More than 10 000 people with acute HBV infection are hospitalized annually [3]. About 250 die each year of fulminant infection [3]. Both asymptomatic and nonfulminant symptomatic HBV infection are similarly associated with chronic forms of infection, which, in turn, may lead to cirrhosis and hepatocellular carcinoma [1, 5, 6, 11, 14-16].

The epidemiology of HBV infection varies greatly by geography and sociodemographic factors [1-4, 17]. Populations at greatest risk include those with multiple sex partners, sexually active male homosexuals, injection drug abusers, family members of HBV carriers, newborn children of actively infected mothers, medical personnel who are exposed to blood and blood products, immigrants from HBV endemic areas, and sexual partners of members of high-risk groups [3]. Epidemiologic studies have documented serologic evidence of HBV infection in as many as 50% of members of high-risk groups [2, 3, 18].

This combination of increasing incidence, expanding high-risk populations, and failure to deliver the vaccine to those at highest risk warrants a re-evaluation of current HBV vaccine policy. The Centers for Disease Control (CDC) has recommended universal vaccination of newborns and of high-risk adolescents [19]. The Occupational Safety and Health Administration (OSHA) has issued guidelines requiring HBV vaccination for all at-risk health care workers [20]. Others have proposed more limited vaccination strategies [21].

Methods

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Structure of the Model: Basic Decision Tree

We used decision analysis to model clinical and economic consequences of alternative approaches to prevention and management of HBV infection. We focused on number and costs of cases prevented, deaths prevented, and years of life saved [22]. The decision model examined three different HBV management strategies ["no vaccination," "universal vaccination," and "screen and vaccinate"] in four different U.S. cohorts: 1) newborns; 2) adolescents at age 10; 3) a high-risk adult population with HBV infection incidence of 5% per annum; and, 4) the general adult population (12 to 50 years old). In addition, we examined a mixed population strategy of screening all pregnant women before or during labor for evidence of active HBV infection (HBsAg), administering HBV vaccine and hepatitis B immune globulin (HBIG) to the newborns of mothers who test positive, and then vaccinating all children at age 10 and again 10 years later. Each analysis followed a cohort of 10 000 individuals for three consecutive 10-year periods, because probabilities of infection or sequelae change over time. Cyclical Markov modeling could have been used, but its complexity makes presentation more difficult to understand, and accuracy is not importantly improved. The decision model used in this analysis was developed after a critical review of the literature, with input from five HBV experts to ensure accuracy and validity.

The basic decision tree Figure 1 incorporated the sensitivity and specificity of screening tests for previous or current HBV infection, estimates of compliance with vaccine administration, the probability of protection if vaccine is administered, the probability of exposure to HBV, and the probability of acute infection after exposure to HBV. All strategies assume that some individuals will be protected from HBV by virtue of previous infection. The terminal branches that end with "no hepatitis B infection" identify persons who remain uninfected with HBV at the end of the period. They enter the model again at the same starting point as everyone else (no previous HBV infection) for up to two additional consecutive 10-year periods. The terminal branches of the basic tree that end with "hepatitis B infection" lead to a subtree Figure 2 that reflects the distribution of types of acute disease and the probability of long-term sequelae of HBV infection.

View larger version (21K): [in this window] [in a new window]   Figure 1. Structure of basic adult decision tree for first 10-year period. Terminal branches ending in "\#9679;" represent persons who lived through the period without contracting hepatitis B (HB). These persons re-enter the model for two subsequent 10-year time periods. Terminal branches ending in " " reflect persons who contract active hepatitis B infection and are subject to various acute presentations and long-term sequelae of infection. Persons with a true-positive (TP) test result are eligible only for the chronic sequelae following subclinical infection. Persons with a false-positive (FP) test result enter the "no intervention" arm of the tree (that is, they are incorrectly reassured that they are protected from future hepatitis B infection). Persons with a true negative (TN) test result enter the "vaccinate all" arm of the tree. Persons with a false-negative (FN) test result are rare (approximately 1/1000) and are not included in the model. All strategies shown (screen, vaccinate all, no intervention) account for the fact that previously infected members of the cohort are protected from recurrent hepatitis B infection.

View larger version (25K): [in this window] [in a new window]   Figure 2. Structure of the decision tree for persons who contract hepatitis B virus. CAH = chronic active hepatitis; CPH = chronic persistent hepatitis.

Data Sources

We obtained the data used in the model from three sources. First, we critically reviewed the medical literature and found probability estimates of incidence and prevalence, clinical course and patient management of HBV infection and its sequelae in the community; safety and efficacy of HBV vaccine; and compliance with the administration of HBV vaccines. Second, using a modified Delphi technique, an expert panel reviewed these estimates, reconciled conflicting data, and provided consensus estimates for probabilities, events, patient management in the community, and outcomes for which reliable data were unavailable in the medical literature. Third, we obtained data on costs from actual private insurer payments, adjusted for expected patient out-of-pocket expenditures.

Screening Strategies

We used two screening strategies. First, the antibody to hepatitis B surface antigen (anti-HBsAg) was used in the adult populations to screen for previous infection to identify those individuals who were protected from recurrent infection and who, therefore, did not require vaccination. Second, HBV surface antigen (HBsAg) was used to screen mothers for active infection to identify newborns at high risk for HBV infection who would benefit from HBV vaccine and HBIG [22, 23].

Compliance and Vaccine Effectiveness

Table 1 shows the input values for screening tests, vaccine compliance, and vaccine effectiveness used for the base case analysis. We assumed 100% compliance with maternal screening for HBV before or at the time of delivery. For other groups, we assumed compliance with screening to be 20% greater than the probability that they would comply with at least the first dose of vaccine. The literature and expert panel suggested a 50% compliance rate with the full series of three vaccinations (0, 1, and 6 months) among adults and adolescents, with lower compliance rates among high-risk populations and higher compliance rates among newborns because of accessibility in the hospital for the first dose of vaccine. People who did not comply with any of the initial series of vaccinations were assumed not to comply with any subsequent vaccine booster doses.

Efficacy for full and partial vaccination series were estimated from randomized and historical clinical trials Table 1 [7, 17, 23-34]. Antibody titers decrease over time after vaccination [26, 35-38]. Although epidemiologic studies do not indicate that such decreases in titers result in reduced protection against HBV infection, such studies have been limited to 7 or fewer years after vaccination [38]. The CDC currently does not recommend administration of vaccine boosters but is following populations of immunized patients to determine if such boosters will be required. The base case model we report here assumed that vaccine efficacy persisted for 10 years, after which a single booster dose was required to provide continuing protection against HBV infection for an additional 10 years, a conservative assumption that biases the model against the cost-effectiveness of all vaccination strategies. Among those who responded to the vaccine by developing protective antibodies, we made counterbalancing assumptions: no decrease in protection from HBV vaccine before 10 years but no protection after 10 years unless a booster is administered. We assumed that HBV vaccine did not incur any side effects that required medical care [26, 27] and that persons infected with HBV despite vaccination followed the same clinical course as those never vaccinated. Newborns of mothers who tested positive for active hepatitis B infection (HBsAg+) were assumed to be treated with HBIG plus HBV vaccine. These infants also underwent serologic testing at 1 year of age and those with low antibody titers (10% of neonates receiving a full primary series of HBV immunizations) received a booster dose of vaccine. The probabilities of compliance with, and response to, all boosters, was assumed to be the same as the probabilities of compliance with, and response to, initial vaccination series.

Epidemiologic Parameters

Table 1 also shows the input values for disease epidemiology used in the base case analysis. Age-adjusted probabilities of contracting HBV during a 10-year period were extrapolated from existing data [2-4]. We assumed that HBV infection conferred lifelong protection against recurrent infection and that persons with true-positive screening results were therefore protected from subsequent acute infection. All HBV infection in newborns was assumed to result from maternal exposure during birth (vertical transmission). Disease presentation and outcomes in newborns differ from those of adolescents and adults (see Table 1). Few newborns develop clinically apparent acute infection. Approximately 8% of acutely infected adults and adolescents with nonfulminant disease develop chronic HBV infection [HBsAg+ antigenemia lasting for 6 months or more]; 4% become asymptomatic carriers; 2% develop chronic persistent hepatitis; and 2% develop chronic active hepatitis [4, 5, 11, 13, 14, 39, 40]. Among adults, fulminant infection occurs in fewer than 1% of those infected with HBV and usually is fatal [39]. Among neonates, fulminant infection and death are rare [25]. Chronic sequelae of HBV occur rarely in survivors of fulminant infection [13, 25]. We ignored death from non-HBV causes in all populations.

Asymptomatic carriers and those with chronic persistent hepatitis have negligible reductions in life expectancy due to HBV infection. People with chronic active hepatitis have reduced 5-year survival rates (86%) and are at marked increased risk for severe long-term sequelae, such as cirrhosis and hepatocellular carcinoma (5-year survival rate, 55%) [15]. Infected newborns more frequently progress to the latter outcomes than adults, especially if the mother is also infected with the HBe antigen [23].

Patient Management Profiles

We developed patient management profiles reflecting community practice for acute and chronic states of HBV infection and their sequelae, based on a review of the literature and the judgment of the expert panel. Each expert was asked how physicians would manage each presentation of HBV infection, for example, frequency and content of physician visits, hospitalizations, diagnostic tests, and other therapeutic options. Patients with asymptomatic acute infection were assumed not to incur any costs of acute disease, but the subset of these patients who developed symptomatic chronic active hepatitis were assumed to incur attributable costs. We assumed that one third of asymptomatic HBV carriers, one third of patients with chronic persistent HBV infection, and 90% of patients with chronic active hepatitis were identified by physicians, monitored beyond their acute illness, and received continuing medical care. Based on advice on the expert panel, we incorporated interferon into the management of chronic active HBV and liver transplantation for persons with fulminant hepatitis, cirrhosis, or hepatocellular carcinoma.

Costs

Data for 1989 on actual mean payments by diagnosis for inpatient hospital care, outpatient care, diagnostic tests and procedures, and therapies were obtained from Independence Blue Cross of Greater Philadelphia and used for model costs. Mean payments to physicians were obtained from Pennsylvania Blue Shield. Costs of medications, HBV vaccine, and HBIG were obtained from the pharmacies at the Hospital of the University of Pennsylvania and The Children's Hospital of Philadelphia and from a survey of five randomly selected local pharmacies. Vaccine cost ($225 for adults, $160 for newborns) included an administration fee, but it was assumed that vaccine administration did not result in a separate charge for an office visit.

The cost of each clinical outcome was determined by aggregating the various elements of Blue Cross, Blue Shield, and pharmacy payments into a gross amount (see Table 1). All costs of the acute HBV episode were attributed to the year in which illness was contracted. Patients with chronic HBV infection and sequelae incurred costs for 30 years, regardless of the year in which acute disease was contracted. For example, even if a patient became infected at the end of the third 10-year cycle of the model, appropriately discounted costs were attributed for 30 additional years of follow-up.

The model took the perspective of the payer of medical care and was confined to direct medical costs. Direct nonmedical costs such as travel costs incurred in the course of receiving medical care, indirect costs (for example, reduced productivity and intangible costs such as pain and suffering) were excluded from the analyses. All costs of the vaccine and its administration were assumed to be paid by third-party payers (no out-of-pocket costs were incurred for the individual being vaccinated). Thus, our analysis presents conservative cost-effectiveness estimates of alternative HBV strategies in the populations studied. All costs were discounted at 5% per annum. However, there is on-going controversy about discounting nonmonetary benefits. Therefore, we chose to present outcomes both discounted (at 5% per year) and not discounted in the base case.

Incremental Outcome Effectiveness and Cost-Effectiveness

Health outcomes per 10 000 population and costs per person related to HBV infection were calculated. Each population studied was followed for 30 years. Incremental cost-effectiveness was calculated to compare each alternative management strategy to the "no vaccination" option and was expressed as the difference in dollar cost incurred per additional adverse outcome prevented. Incremental cost-effectiveness was not calculated when one alternative was dominant to another (superior to another for both cost and outcome).

Sensitivity Analysis

Modeling always involves uncertainties. For example, HBV vaccine has been available for only 10 years, and the length of immunity conferred is still uncertain. We therefore performed sensitivity analyses to test robustness of results to changes of input variables. The extreme range of plausible values representing the degree of uncertainty surrounding key variables was identified, as determined from the literature and estimated by the expert panel. The impact of such changes on health outcomes, costs, and cost-effectiveness was calculated. A worst-case scenario using the lowest rates of vaccine efficacy and of acute and chronic outcomes of HBV infection and a best-case scenario using the highest rates of efficacy and of acute and chronic outcomes of HBV infection were examined for each study population. For example, in the general adult population, the worst-case scenario included the lowest estimate of vaccine protection (0.85 for three vaccine doses; 0.50 for a weighted average of one or two doses) and the lowest estimates of sequelae as a result of HBV infections (chronic carrier, 0.03; chronic persistent hepatitis, 0.01; chronic active hepatitis, 0.01). The best-case scenario included the highest estimate of vaccine protection (0.95 for three vaccine doses; 0.80 for a weighted average of one or two doses) and the highest estimates of sequelae as a result of HBV infections (chronic carrier, 0.05; chronic persistent hepatitis, 0.025; chronic active hepatitis, 0.025).

Our study adhered to recently published principles to minimize bias in economic analyses funded by pharmaceutical companies [41]. Specifically, we made conservative assumptions when data were uncertain or unavailable, performed best- and worst-case sensitivity analyses, selected members of the expert panel, independently developed the model, and analyzed and interpreted the results.

Results

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Base Case Analysis: Clinical Outcomes and Costs

Health outcomes per 10 000 population, cost per case of HBV prevented, and cost-per-year of life saved are shown in Table 2 for each strategy in each of the populations studied. With high-risk populations (those with HBV incidence greater than 5%), vaccination with or without screening is a dominant strategy—simultaneously lowering cost with greater benefit relative to the "no vaccination" strategy.

The "screen and vaccinate" strategy is both more effective and more expensive than the "vaccinate all" strategy in newborns because of increased effectiveness and cost of HBIG in babies born to mothers with active HBV infection. In the general adult population the opposite is true—the "vaccinate all" strategy is more effective but more expensive than the "screen and vaccinate" strategy. Because the prevalence of previous HBV infection is relatively low in the general population, screening this population produces a relatively large number of false-positive tests. This results in lower rates of vaccination, lower costs, and lower levels of protection. In contrast, false-positive screening results in mothers of neonates lead to unnecessary treatment of newborns and higher costs.

Table 2 also shows the incremental cost-effectiveness of the two vaccination strategies relative to "no vaccination" for each population studied. For example, among newborns in the base case using undiscounted benefits, the two vaccination strategies reduce the number of cases of HBV infection by approximately 33% and deaths from HBV infection by 45% to 48%; the cost-per-year-of-life saved ranges from $3066 to $3332 (undiscounted nonmonetary benefits) to $38 632 to $42 067 (discounted nonmonetary benefits), depending on the vaccination strategy selected (Figure 3).

View larger version (37K): [in this window] [in a new window]   Figure 3. Cost-per-year-of-life saved for each age category of "vaccinate all" hepatitis B virus vaccination strategy.

Because severe adverse events such as cirrhosis, hepatocellular carcinoma, and death occur far into the future, discounting years of life saved leads to 7- to 12-fold increases in incremental cost-per-year-of-life saved compared with undiscounted benefits Table 2 and Figure 3. Unlike the effects of discounting on other strategies, discounting benefits in the high-risk group leads to increases of cases and deaths prevented per 10 000 population because these are incremental numbers; the difference between doing nothing (no vaccination) and doing something (vaccination) is larger when outcomes are discounted. More cases occur earlier when the high-risk group is not vaccinated; therefore, discounting affects this group relatively less than others.

Of those examined, the mixed strategy is optimal—screen all pregnant women, administer vaccine and HBIG to babies of mothers who test positive for active disease (HBsAg+), vaccinate all children at age 10, and deliver a booster dose 10 years later. This strategy prevents more infections, chronic sequelae, and deaths from HBV than that of either universal vaccination of newborns or adolescents alone and does so at lower cost. In the base case, the combined strategy reduces both cases of and deaths from HBV by 20% relative to the newborn strategy alone, and by 17% and 49%, respectively, relative to the adolescent strategy. The incremental cost-per-year-of-life saved with the combined strategy (relative to the "no vaccination" strategy) is only $375 in the base case when nonmonetary benefits are not discounted and $3695 if discounted life-years are used (see Table 2).

Sensitivity Analysis

We varied vaccine cost to determine the break-even point (the cost of the vaccine at which vaccination saves money relative to "no vaccination"). For universal vaccination to be cost saving, the cost per vaccine dose (including the cost of administration) must be $7 for the general adult population, $13 for the adolescent population, and $34 for newborns.

The analyses were relatively insensitive to the ranges of inputs examined except for vaccine cost. The differences in cost-per-year-of-life saved between the best- and worst-case scenarios varied only approximately twofold, and relative preferences of the strategies examined did not change.

Discussion

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A decade ago, when HBV vaccine was first entering the U.S. market, Mulley and colleagues examined its cost-effectiveness [7]. During the subsequent 10 years, the incidence of HBV infection has increased, although most people at high risk remain unvaccinated. The expanded model presented here provides new and important information: It is based on 30 years of follow-up (three 10-year intervals compared to a single 20-year follow-up period); provides for revaccination every 10 years (rather than every 5 years); considers patient compliance with vaccination and revaccination schedules; incorporates updated data on the efficacy of recombinant vaccine, the natural history of HBV infection, and the cost of medical management of acute HBV infection and its chronic sequelae; and models subpopulations not previously examined. As a result, we found HBV vaccine to be more cost-effective than previously reported by Mulley and colleagues [7].

Table 3 compares cost-effectiveness (without discounting nonmonetary benefits) of accepted medical interventions. Compared to most other common interventions studied using similar methods, HBV vaccination is cost-effective for newborn and adolescent populations. For example, HBV vaccination for all study populations are of comparable cost-effectiveness (using undiscounted outcomes for all interventions) compared to that of pharmacological therapy of hypercholesterolemia, generally accepted as an appropriate clinical intervention. Additionally, our results support OSHA recommendations to vaccinate health workers at risk for HBV infection. When the risk for HBV infection approaches 0.05 per year, cost savings are realized for universal vaccination of this population. The CDC recommendation for universal vaccination of newborns [19] is also supported by our results, as well as by those of Arevalo and Washington [42]. However, universal vaccination of newborns is not as cost-effective as the mixed newborn-adolescent vaccination strategy. Our results underscore the benefit and efficiency of administering HBV vaccine early in life, and also support further intervention beyond the perinatal period.

The combined strategy of screening mothers, vaccinating and administering HBIG to babies whose mothers test positive for active infection, and then vaccinating (with three doses) all children at age 10 followed by a booster shot administered 10 years later was the optimal vaccination strategy we examined. With modest decreases in the cost of HBV vaccine and its administration, this strategy actually would lead to savings in cost. This mixed strategy achieves its success because almost all cases of HBV infection that occur in the first decade of life result from vertical transmission from mother to child at birth [43, 44]. Thus, those at highest risk are rather easily identified. Universal vaccination of all adolescents at age 10 provides protection to the larger population before the age at which HBV infection increases substantially.

Decision analysis permits evaluations to be performed over a broad range of input probabilities and variable values. However, all clinical models are limited by using imperfect data and by simplifying assumptions. The probabilities and costs used here are the best estimates available. Moreover, the costs and benefits of the various strategies examined did not change relative to one another over a wide range of assumptions in the sensitivity analyses.

No evidence yet exists for life-long immunity following a complete initial vaccination series, given the limited time for which the vaccine has been clinically available. Vaccine titers gradually decrease after vaccination [35-38]. The long-term immunity of populations from a single series of HBV vaccine has been studied for only 7 years [38], and epidemiologic studies of the duration of vaccine protection have been examined in very few populations. Thus, although HBV vaccine boosters currently are not recommended [3, 19], we assumed that a complete initial vaccination series would result in HBV immunity lasting only 10 years. If immunity from an initial HBV vaccine series persists significantly longer than 10 years and a booster dose is not required, all vaccination strategies will be more cost effective than reported here.

This analysis considered only the direct medical costs of vaccination or management of HBV infection. Including other costs, such as nonmedical direct costs and indirect costs such as premature death and work loss, will increase the benefits of all vaccination strategies relative to the "no vaccination" strategy. (Margolis and colleagues have estimated indirect costs to be 10 times greater than direct medical costs) [45]. We also ignored programmatic costs necessary to ensure a high level of compliance with full vaccination.

Overall costs or savings are sensitive to the costs of HBV vaccine and administration. Reductions in the costs of vaccine and its administration (as might occur through price reductions and large-scale, institutionally based or public administration programs) offers the potential to improve vaccine cost-effectiveness substantially. In addition, the opportunities to improve vaccine compliance may be greater among adolescents than among adults, because of better vaccination performance by pediatricians than by internists and because of the potential of schools to implement vaccination programs and enforce vaccine policy. As expected, discounting benefits reduces cost-effectiveness of all vaccine strategies, as it would with all prevention programs aimed at young populations.

The controversy about discounting nonmonetary benefits (and at what rate) is not likely to be resolved soon. However, economic analysis requires a standardized approach so that alternative strategies can be fairly compared. When nonmonetary benefits such as lives saved or life-years saved are discounted, prevention will fare worse than acute care.

In conclusion, HBV vaccine is a cost-effective intervention that demands increased attention and emphasis. We recommend a two-pronged strategy. First, all pregnant women should be screened before delivery, and newborns of mothers who test positive (HBsAg+) should be given HBIG and vaccination. Second, all adolescents should show proof of complete HBV vaccination at entry to middle or junior high school, just as children entering elementary school must have proof of vaccination against polio, measles, and other contagious childhood diseases. The existing vaccination policy must be re-evaluated if the stated goals for the year 2000 (vaccination of 90% of those at high risk for HBV) are to be realized. The means to achieve substantial improvements in the public health in a cost-effective fashion are now available and should be pursued aggressively.