Cost-Effectiveness of a Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia in Older Adults

Clinical Infectious Diseases, May 2007

Background.A vaccine to prevent herpes zoster was recently approved by the United States Food and Drug Administration. We sought to determine the cost-effectiveness of this vaccine for different age groups. Methods.We constructed a cost-effectiveness model, based on the Shingles Prevention Study, to compare varicella zoster vaccination with usual care for healthy adults aged >60 years. Outcomes included cost in 2005 US dollars and quality-adjusted life expectancy. Costs and natural history data were drawn from the published literature; vaccine efficacy was assumed to persist for 10 years. Results.For the base case analysis, compared with usual care, vaccination increased quality-adjusted life expectancy by 0.0007–0.0024 quality-adjusted life years per person, depending on age at vaccination and sex. These increases came almost exclusively as a result of prevention of acute pain associated with herpes zoster and postherpetic neuralgia. Vaccination also increased costs by $94–$135 per person, compared with no vaccination. The incremental cost-effectiveness ranged from $44,000 per quality-adjusted life year saved for a 70-year-old woman to $191,000 per quality-adjusted life year saved for an 80-year-old man. For the sensitivity analysis, the decision was most sensitive to vaccine cost. At a cost of $46 per dose, vaccination cost <$50,000 per quality-adjusted life year saved for all adults >60 years of age. Other variables related to the vaccine (duration, efficacy, and adverse effects), postherpetic neuralgia (incidence, duration, and utility), herpes zoster (incidence and severity), and the discount rate all affected the cost-effectiveness ratio by >20%. Conclusions.The cost-effectiveness of the varicella zoster vaccine varies substantially with patient age and often exceeds $100,000 per quality-adjusted life year saved. Age should be considered in vaccine recommendations.

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Cost-Effectiveness of a Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia in Older Adults

Michael B. Rothberg () 1 2 Anunta Virapongse 1 2 Kenneth J. Smith 0 0 Division of General Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania 1 Tufts University School of Medicine , Boston, Massachusetts 2 Division of General Medicine and Geriatrics, Department of Medicine, Baystate Medical Center , Springfield Background. A vaccine to prevent herpes zoster was recently approved by the United States Food and Drug Administration. We sought to determine the cost-effectiveness of this vaccine for different age groups. Methods. We constructed a cost-effectiveness model, based on the Shingles Prevention Study, to compare varicella zoster vaccination with usual care for healthy adults aged 160 years. Outcomes included cost in 2005 US dollars and quality-adjusted life expectancy. Costs and natural history data were drawn from the published literature; vaccine efficacy was assumed to persist for 10 years. Results. For the base case analysis, compared with usual care, vaccination increased quality-adjusted life expectancy by 0.0007-0.0024 quality-adjusted life years per person, depending on age at vaccination and sex. These increases came almost exclusively as a result of prevention of acute pain associated with herpes zoster and postherpetic neuralgia. Vaccination also increased costs by $94-$135 per person, compared with no vaccination. The incremental cost-effectiveness ranged from $44,000 per quality-adjusted life year saved for a 70-year-old woman to $191,000 per quality-adjusted life year saved for an 80-year-old man. For the sensitivity analysis, the decision was most sensitive to vaccine cost. At a cost of $46 per dose, vaccination cost !$50,000 per quality-adjusted life year saved for all adults 160 years of age. Other variables related to the vaccine (duration, efficacy, and adverse effects), postherpetic neuralgia (incidence, duration, and utility), herpes zoster (incidence and severity), and the discount rate all affected the cost-effectiveness ratio by 120%. Conclusions. The cost-effectiveness of the varicella zoster vaccine varies substantially with patient age and often exceeds $100,000 per quality-adjusted life year saved. Age should be considered in vaccine recommendations. Herpes zoster (shingles) is a dermatomal neurocutaneous disease caused by reactivation of the varicella zoster virus. The lifetime risk of herpes zoster ranges from 10% to 30% [1, 2], and the severity of both the disease and its sequelae increase with age [2]. Because it causes acute burning pain, herpes zoster can seriously impair physical, social, and emotional functioning [24]. Acute herpes zoster has been estimated to cost 1$400 per case in physician's fees, antiviral therapy, and lost wages [5]; the total cost of herpes zoster-related hospitalizations in 1 year exceeded $8 million in Connecticut alone [6]. In addition, 10%-70% of patients - with herpes zoster develop postherpetic neuralgia (PHN), which persists for 11 year in up to one-half of patients 155 years of age [4, 7], at a cost exceeding $500 per patient [8]. Antiviral therapy is cost-effective for decreasing the symptoms of herpes zoster [9], and it has been shown to reduce the duration [10], but not the incidence [1], of PHN. Unfortunately, topical analgesics, opioids, tricyclic antidepressants, nerve blocks, neuroactive drugs, and steroids all have limited success in treating the chronic and often debilitating pain associated with the disease [1, 11]. The Shingles Prevention Study (SPS) [12] demonstrated that live attenuated Oka/Merck varicella zoster vaccine protected against herpes zoster and PHN and reduced the symptoms of acute herpes zoster. Although the vaccine is effective, its cost-effectiveness has been debated. Because herpes zoster incidence varies by age and sex, the cost-effectiveness of the vaccine should not be uniform for all patients 160 years of age (the SPSs target population). Moreover, the SPS lasted only 4 years, so the vaccines long-term efficacya potentially important determinant of cost-effectivenesswill not be known for some time. We examined the pharmacoeconomics of the varicella zoster vaccine using a decision analytic model to explore a variety of patient and vaccine scenarios. We constructed a Markov model [13] using standard computer software (Decision Maker software, version 7.07; Pratt Medical Group) to compare the cost-effectiveness of vaccination with the varicella zoster vaccine with no vaccination for healthy immunocompetent adults 160 years of age. The study was conducted from a societal perspective. Costs (expressed in 2005 US dollars) and utilities (expressed in quality-adjusted life years [QALYs]) were both discounted at 3% annually. The entire cohort begins in the unvaccinated state, with individuals undergoing vaccination at the beginning of the first year. For each year, an age- and sex-specific underlying attack rate is applied to calculate the number of cases, major complications, and deaths due to herpes zoster. Vaccinated individuals experience a decrease in cases, complications, burden of illness, PHN, and death proportional to vaccine efficacy, which first wanes and then ceases at the maximal duration. Patients experiencing herpes zoster or its complications incur both costs and utility decrements. In addition to the decision model, we analyzed the costeffectiveness of the vaccine during the SPS, assuming that all costs and benefits accrued within the study period (with the exception of PHN, which could extend for up to 10 years). We calculated the cost of vaccination and then subtracted the savings from avoiding herpes zoster and PHN. We also calculated the difference in quality-adjusted life expectancy by assigning utility values to avoided cases of herpes zoster and PHN on the basis of our model inputs. Data and Assumptions Baseline estimates and ranges for sensitivity analyses are provided in table 1. Zoster incidence and complications. The model incorporates age- and sex-specific incidence from the largest observational cohort study [14]. Rates were similar to those published 10 years earlier [35] and to rates observed in the SPS for subjects 70 years of age, but they were lower than those observed for subjects !70 years of age [12]. Age-specific burden of illness in the first 6 months following infection and the rate of PHN (defined as pain persisting 3 months after the onset of illness) were based on the SPS [12]. Duration of PHN [7, 22] and age-specific rates for complications not reported in the SPS were drawn from observational studies [15, 36] and government databases [6, 20, 21]. Complications included death, hospitalization for disseminated herpes zoster or herpes zoster meningitis, ocular involvement and monocular blindness, and herpes zoster oticus and monaural deafness. Vaccine efficacy and adverse effects. The SPS reported 3 efficacy measures, stratified by age: herpes zoster incidence, burden of illness (BOI), and PHN incidence [12]. BOI and PHN efficacy were reported for the entire population, not just for those who developed herpes zoster; thus, these measures incorporated the decreasing herpes zoster incidencein effect, double counting. To see if there was efficacy beyond the decrease in herpes zoster incidence, we calculated the efficacy per case of herpes zoster by dividing the cases of PHN and the burden of illness scores by the number of cases of herpes zoster illness. Efficacy in decreasing herpes zoster incidence varied with age, from 65% among subjects aged 5964 years to 8% in subjects aged 85 years. Vaccination also appeared to prevent PHN during the first year following vaccination, but it had no statistically significant additional efficacy in subsequent years (table 2). Moreover, this apparent efficacy was due to placebo recipients experiencing PHN at a significantly higher rate during the year following vaccination, relative to subsequent years, rather than to any reduction in PHN among vaccinees. We therefore assumed no reduction in PHN beyond that afforded by reducing the incidence of herpes zoster illness. In contrast, the vaccine demonstrated efficacy in reducing the severity per case in patients aged 70 years (BOI score, 225 vs. 160 in the placebo and vaccination groups), but not in patients aged !70 years (BOI score, 134 vs. 128 in the placebo and vaccination groups). In their US Food and Drug Administration briefing, the manufacturer of the vaccine provided data for each of the 3 efficacy measures, stratified by years after vaccination [23]. Efficacy waned in the first year after vaccination and then appeared to level off, but there were only 4 data points (1 for each year of the trial). We fit a declining logarithmic function for efficacy against zoster incidence (y p 0.1018 ln(x) + 0.5903; R 2 p .56) and then calculated age-specific efficacy for each year using age-specific ORs derived from US Food and Drug Administration data. In sensitivity analysis, we tested other functions, ranging from no decrease after year 4 to complete lack of efficacy following the study period. We assumed no decrease in efficacy for decreasing severity of illness per case. The most common adverse effect was arm soreness, but 0.7% of vaccinees experienced a serious reaction not experienced by participants who received placebo (95% CI, 0.1%1.3%). In the absence of any other details, we assumed that serious reactions would be equivalent to spending 3 days in the hospital. Utilities. SPS participants used the worst-pain component of the herpes zoster brief pain inventory to record their pain daily for up to 182 days, generating an area under the pain Value at baseline Sensitivity range Variable Herpes zoster illness Annual incidence per 1000 persons Women Men Complications Any ophthalmic complications Monocular blindness, given ophthalmic complications Herpes oticus Monaural deafness, given herpes oticus PHN, given herpes zoster, by age 6069 Years 70 Years Proportion of PHN lasting 12 months, by age 6069 Years 70 Years Hospitalization, given herpes zoster Death due to herpes zoster, death per 100,000 persons Duration of hospitalization, mean days Duration of PHN, yearsc Vaccination Efficacy against herpes zoster illness Likelihood ratio for vaccine efficacy, by age 6064 Years 6569 Years 7074 Years 7579 Years 8084 Years 85 Years Efficacy in decreasing burden of illness, by age 6069 Years 70 Years Adverse effect Local reaction Serious adverse effect Utilitiese Monocular blindness Monaural deafness PHN after 6 months Short term morbidities, QALYs Acute herpes zoster, by age 6069 Years 70 years Hospitalization Local reaction Serious reaction Costs, US dollars Vaccinef Vaccine administration Acute herpes zoster Indirect costs, by age or condition 6064 Years 1.01.5b 1.01.5b 0.0120.032 0.0110.067 00.005 0.0130.12 0.030.09 0.130.29 0.240.64 0.350.75 0.51.5b 0.751.3b 0.340.36 0.0010.013 0.880.96 0.9580.982 0.630.70 [7, 12, 19] [7, 12, 19] Assumption Value at baseline Sensitivity range NOTE. Data are probabilities, unless otherwise indicated. PHN, postherpetic neuralgia; QALY, quality-adjusted life year. a Baseline value varies with age. b For parameters that vary by patient age or year since vaccination, we conducted sensitivity analysis by multiplying the value for each patient by a constant factor. Probabilities were converted into odds, then multiplied by the factor and converted back into probabilities. c If 112 months. d 0.59030.1018 ln(vaccine year). Efficacy also varies by age. Each year, this result is converted to odds, multiplied by the age-specific likelihood ratio, and then converted back to efficacy. e Utilities range from 1.0, signifying perfect health, to 0, signifying death. Utilities in the model are adjusted for age by multiplying the utility in the table by the mean utility for a patient of that age (e.g., a 70-year-old patient has a baseline utility of 0.836. With monocular blindness, the utility would be 0.92 0.836 p 0.769). f Cost per dose, assuming the purchase of a 10-pack of vaccine. curve (BOI score range, 01820). We transformed BOI scores into utilities on the basis of results of another study [27] that compared the area under the curve of the worst-pain component of the herpes zoster brief pain inventory and the EuroQOL-5D, a validated measure of patient utilities [37]. In that study, herpes zoster brief pain inventory scores over 35 days were linearly correlated with utilities (utility p 0.1001 BOI score + 95.767, R 2 p .95). We multiplied average BOI scores from the vaccine trial by this formula and then multiplied by 365/35 to calculate the number of QALYs lost. The utility for mild, moderate, and severe PHN was based on a survey of PHN involving 385 elderly patients [26]. The proportion of patients experiencing mild, moderate, and severe symptoms came from the only population-based study reporting severity at 1 year [7]. All utilities were adjusted for age [38]. Costs. At least 7 economic analyses have measured costs associated with herpes zoster or PHN [5, 8, 3134, 39]. We chose our direct cost estimate for acute herpes zoster illness from the largest of these [5] but tested the results of all trials in sensitivity analysis. Age-specific indirect costs, primarily patient and caregiver lost wages, came from a prospective population-based study [31]. The costs of PHN [8, 39] and ocular complications of herpes ophthalmicus [5] were based on antiviral trials. The cost of treating herpes oticus included an initial consult, audiometry, treatment with prednisone, and a follow-up visit. Hospitalization costs came from the Healthcare Utilization Project Web site [21], using national cost-to-charge ratios. Vaccine costs assumed the purchase price for a 10-pack of vaccine [29], plus 5 min of a nurses time for vaccination [30]. We did not assign a cost to adverse effects of the vaccine. Costs were updated to 2005 US dollars [40]. Base Case Analysis On the basis of the results of the SPS, without modeling vaccine efficacy beyond the study period or discounting, the cost to vaccinate the entire study population against herpes zoster was $2.9 million, which prevented 327 cases of herpes zoster and 53 cases of PHN and extended quality-adjusted life expectancy Vaccine group Placebo group Cases of herpes zoster Cases of herpes zoster Years following vaccination Adjusted totalb Rate of PHN per case of herpes zoster Herpes zoster Postherpetic neuralgia 6069 years old (n p 10,370) 1,543,367 70 years old (n p 8884) QALYs Cases gained prevented by 22.4 years (71% of which came from preventing PHN that pitalizations and mortality accounted for !5% of the vaccine lasted 16 months) (table 3). Savings attributable to preventing benefit, even in the oldest age group. herpes zoster and PHN offset 12% of the cost of vaccination. The cost per QALY gained by vaccination ranged from $201,000 for patients aged 6069 years to $75,000 for patients aged In the decision model, we assumed that vaccine efficacy persisted beyond the study period and we considered healthy men and women of 3 different ages (table 4). At all ages, vaccination resulted in the greatest quality-adjusted life expectancy. Overall benefits (range, 0.00070.0024 QALYs per person) came almost exclusively from improvements in quality of life. Depending on patient age, 50%65% of the difference in quality-adjusted life expectancy was attributable to preventing PHN, whereas 35%50% came from preventing acute herpes zoster. The vaccine was less effective in reducing PHN in our analysis than in Vaccination increased total health expenditures in all groups by $94$135 per person, compared with no vaccination. Incremental costs increased with age, because productivity gains associated with preventing acute herpes zoster partially offset the cost of the vaccine for younger patients. The incremental cost to extend life by 1 QALY ranged from $44,000 for a 70year-old woman to $191,000 for an 80-year-old man. Disease incidence increased with age, but vaccine efficacy fell, producing a U-shaped curve for cost-effectiveness (figure 1). As a result, vaccination was most cost-effective for patients aged 70 years and, at every age, vaccination was more cost-effective for women than it was for men. Sensitivity Analysis the SPS, because we did not model a reduction in PHN beyond We varied all the parameters through the ranges presented in the reduction in herpes zoster incidence. Reductions in hos Female 70 Years 80 Years Male Female Total cost, US$ Vaccine Incremental costs, QALE, years No vaccine Vaccine Incremental QALE, Cost-effectiveness ratio,c US$ per QALY saved NOTE. QALE, quality-adjusted life expectancy; QALY, quality-adjusted life years. cination by 20% included variables related to the vaccine (duration, cost, efficacy, and side effects), PHN (incidence, duration, and utility), herpes zoster (incidence and severity), and the discount rate. Vaccine variables. The model was most sensitive to vaccine cost (figure 2). At a cost of $46 per dose, vaccination had an incremental cost-effectiveness ratio !$50,000 per QALY for all adults aged 6080 years. Duration of immunity was important for younger patients, who were unlikely to develop herpes zoster immediately but who had a long life expectancy. If efficacy lasted only 6 years, the cost to vaccinate a 60-year-old patient was 1$200,000 per QALY saved (figure 3), but it improved out to 25 years. For patients aged 70 years, cost-effectiveness curves were flat beyond 10 years. Variation in vaccine efficacy within the 95% CI had modest effects (10%) on the costeffectiveness. If, however, the vaccine was able to prevent an additional 33% of cases of herpes zoster in patients 169 years of age, the cost-effectiveness ratio for 80-year-olds would be reduced by one-half. Disease variables. Because preventing PHN comprises the majority of the vaccines benefit, the model was sensitive to increases in the incidence, duration, or severity of PHN. Vaccination cost !$50,000 per QALY for 70-year-old men if the utility of PHN was !0.72 and it cost !$50,000 per QALY for 60-year-old women if the utility was !0.64 and the probability exceeded 8.5% (figure 4). For 80-year-old patients, no combination of utility and probability produced a cost-effectiveness ratio below that threshold. Other sequelae were too rare to have a substantial impact. DISCUSSION This cost-effectiveness analysis demonstrates that, although the varicella zoster vaccine improved quality-adjusted life expectancy for all adults 60 years of age, the benefits of vaccination were not evenly distributed. Although the vaccine is most effective for younger patients, most cases of herpes zoster and PHN occur among older patients. Consequently, vaccination is most cost-effective for patients aged 70 years. At any age, it is more cost-effective to vaccinate women than men, because women experience a disproportionate amount of herpes zoster and PHN. Although the cost-effectiveness for 70-year-old women is attractive, compared with other commonly accepted interventions, the cost-effectiveness in other groups often exceeds $100,000 per QALY, an amount that would be considered expensive. At $150 per dose, the vaccine does not appear to be cost-saving under any assumptions. Two formal analyses have explored the cost-effectiveness of varicella zoster vaccine. Because both were conducted before vaccine pricing, neither estimates the actual cost-effectiveness of the vaccine. The first analysis, performed by Edmunds et al. [33] before the SPS, concluded that the vaccine would be costeffective for patients aged 65 years at a cost of $148 if the vaccine was 60% effective and lasted at least 10 years. The second, conducted by Hornberger and Robertus [41] before vaccine licensure, concluded that, at a price of $50, the vaccine would have a cost-effectiveness of !$50,000 per QALY gained and, at a price of $200, would cost 1$100,000 per QALY gained. Both of these conclusions are compatible with our findings. Our results diverge regarding the effects of age. Edmunds et al. [33] accurately modeled increasing incidence and morbidity of herpes zoster with age but assumed equal vaccine efficacy at all ages. Consequently, they found vaccination to be most cost-effective at age 80 years. In contrast, Hornberger and Robertus [41] correctly modeled the differential efficacy by age, but they assumed risk of PHN to be the same at all ages and thus found vaccination to be most cost-effective for patients aged 60 years. Incorporating age-related changes in both parameters, we observed a U-shaped curve for cost-effectiveness. Both private insurers and Medicare have grappled with paying for varicella zoster vaccine [42]. There are 61 million Americans aged 60 years. At the bulk price of $145.45 per vaccination, vaccinating all eligible Americans would cost $9 Figure 3. Cost-effectiveness of vaccination against herpes zoster in women as a function of duration of vaccine efficacy. Curves for men (not shown) are similar, but they shift upwards. QALY, quality-adjusted life year. billion. There is no doubt that the vaccine is effective, but would this enormous investment represent good value? The answer is yes and no. The vaccine is much more cost-effective for some recipients than for others. Vaccinating a 70-year-old woman costs the same as vaccinating a 60-year-old man, but it offers 3 times the health benefit. Using a threshold of $50,000 per QALY, only 70-year-old women would be eligible for vaccination. At a more liberal threshold of $100,000 per QALY, men aged 6575 years and women aged 6075 years would be eligible to receive the vaccine. By comparison, influenza virus and pneumococcus vaccination are generally cost-saving in the elderly population [43, 44], and varicella vaccine, which costs $66, appears to be cost-saving in children [45]. Less cost-effective vaccines, such as meningococcal [46] and pneumococcal [47] conjugate vaccines, have been accepted into the childhood vaccination schedule, but not all states universally cover their costs. Notably, a reduction in the cost of the varicella zoster vaccine would have a dramatic effect on the value it represents. At a price of $46, it could be universally recommended as being cost-effective and sometimes cost-saving. Our analysis has several limitations. First, although many of our inputs were based on large studies that provided stable estimates, a few key values are based on limited information or vary widely among studies. A single study of 127 patients provided both the percentage of patients who have symptoms of PHN for 11 year and the proportion of long-standing symptoms that are mild, moderate, and severe [7]. We explored the effects of varying these inputs, but larger, long-term studies of both the probability and severity of PHN at 1 year are necessary to reliably determine the cost-effectiveness of the vaccine. Second, it is not known how long vaccine efficacy will last, and it will be at least 5 years before we know whether our 10-year assumption was correct. Measures of cell-mediated immunity show the vaccines protection to have a half-life of 56 months [48], leaving little efficacy after 1015 years. Third, the incidence of herpes zoster observed for subjects aged 6069 years in the SPS was higher than that observed by Insinga et al. [14], although both are contemporaneous, multicenter studies. The discrepancy could represent underdiagnosis in the observational cohort or a recent increase in cases among younger age groups attributable to lack of boosting that followed widespread childhood vaccination against primary varicella infection [49]. Although increased herpes zoster incidence improves the costeffectiveness of vaccination, even given a 40% increase among 60-year-old individuals, vaccination would still cost $84,000 per QALY. Finally, our estimates for the cost of PHN are based on data that is 110 years old, albeit updated to 2005 US dollars. Newer, more expensive drugs and treatments may have increased the cost and decreased the morbidity associated with PHN. Additional studies would be welcome. Having successfully conquered many of the major infectious diseases afflicting Western countries, vaccine manufacturers have turned to rarer or less harmful diseases. As the potential number of childhood and adult vaccines mushrooms, both policy makers and payers struggle with decisions about which ones to recommend or cover. The Institute of Medicine (Washington, DC) has recommended that the Advisory Committee on Immunization Practices incorporate societal benefits and costs into its vaccine coverage decisions [50], and cost-effectiveness analysis offers one tool with which to do this [51]. Trying to pay for all available interventions, regardless of cost, strains budgets and causes inequity, because the rising cost of care forces some patients out of the health care system entirely. Considering both costs and benefits, the varicella zoster vaccine does not seem to represent a good value for all patients 160 years of age, although it may be reasonable for patients 70 years old, depending on the cost-effectiveness criterion used. Lowering the cost to that of the varicella vaccine would make it competitive with other generally accepted interventions. Acknowledgments Financial support. (to M.B.R.). Potential conflicts of interest. Doris Duke Clinical Scientist Development Award All authors: no conflicts.


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Michael B. Rothberg, Anunta Virapongse, Kenneth J. Smith. Cost-Effectiveness of a Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia in Older Adults, Clinical Infectious Diseases, 2007, 1280-1288, DOI: 10.1086/514342