A CUA was undertaken to estimate costs and health outcomes of routine Hib vaccination (DTP-HepB-Hib: diphtheria, tetanus, pertussis, hepatitis B, and Hib infections) with three-dose primary series at 2, 4, and 6 months with or without booster dose (3 + 0 and 3 + 1 schedules) compared to “no vaccination” (DTP-HepB) among children in Thailand. Since some cases of Hib meningitis have long-term sequelae, i.e., hearing loss, epilepsy, the lifetime time horizon was used. Discount rate of 3% was used for costs and health outcomes. Results were presented incremental cost-effectiveness ratio (ICER) in terms of monetary value (THB) per quality-adjusted life year (QALY) gained. Societal perspective was used recommended by Thailand’s HTA Guideline (18).

Decision tree combined with Markov model was constructed based on the natural history of diseases from Hib infection (Figure 1). Decision tree captures Hib infections occurred during the first 5-year of life, while Markov captures long-term outcomes throughout their life. The decision tree model captures the incidence of Hib meningitis, Hib pneumonia, Hib non-pneumonia non-meningitis (NPNM, including sepsis/bacteremia, cellulitis, and epiglottitis) during the first 5-year of life since Hib infections occur in this period of time. Hib meningitis leads to three clinical consequences including full recovery, recovery with sequelae, and death. Sequalae included hearing loss, epilepsy, and developmental deficit. The Markov model captures long-term consequences after 5-year period in decision tree model. Patients who survived from acute Hib infection were moved to Markov states which were classified into four heath statuses including (1) healthy (full recovery), (2) survived with hearing loss, (3) survived with epilepsy, and (4) survived with developmental deficit. Patients could die with different mortality rate depending on their health status after acute Hib infection. The herd effect and the vaccine adverse effects were not considered in this model. Cycle length of 1 year was used. We assumed that Hib infection could occur only once for each individual.

Model input parameters were obtained from retrospective electronic hospital database of NHSO and published evidence (Tables 1–3). Five types of stakeholders, including health economist, health care providers (pediatrician and pediatric infectious disease specialist), patients’ representative, third-party payers, and representatives from pharmaceutical industry have participated in two stakeholder consultation meetings in order to define study population, intervention, model structure, outcome, and comparator, assumptions used, validating data inputs, providing comments on interim findings.

The disease incidences were derived from prospective studies of Hib meningitis incidence in Thailand and a previously published economic evaluation study (14, 20, 25). While incidence of other Hib infections was not available, the incidence of Hib pneumonia was assumed as 7 times (range of 4–10 times) of Hib meningitis incidence based on WHO estimation (21). The incidence of Hib NPNM infection consisting mainly of bacteremia was estimated to be 5.4 times less than that of Hib meningitis based on global estimates (1).

Case-fatality ratios (CFRs) associated with Hib infections were derived using electronic hospital database of NHSO covering 80% of insured Thai population during January 2008 and December 2013. CFR was calculated based on patients less than 5 years of age with primary diagnosis code of Hib meningitis [International Classification of Disease (ICD)-10: G00.0], Hib pneumonia (ICD-10: J14), or sepsis due to Hib (ICD-10: A41.3)]. The CFR of Hib meningitis, pneumonia, and sepsis that assumed to represent Hib NPNM were 2.9% (1.8–4.0%), 1.9% (1.2–2.6%), and 5.0% (2.2–7.8%), respectively. In addition, CFR from international estimates were alternatively used in a scenario analysis (1, 22). The probabilities of developing hearing loss, epilepsy, and development deficit after Hib meningitis were based on estimates in previous CBA and meta-analysis studies (14, 23). The relative risks of dying among those with sequalae were based on previous CUA study (24). These relative risks were multiplied with Thai age-specific mortality to derive the likelihood of dying from all health states in the Markov model (26) (Table 1).

Vaccine effectiveness against vaccine-type Hib meningitis and invasive Hib disease (pneumonia and NPNM) was based on a systematic review and meta-analysis (Table 1) (15, 27, 28). It was assumed that the vaccination effect lasted over a 5-year period (15). Vaccination coverage rate was based on 2013 cluster survey study of DTP-HepB vaccine among Thai children conducted by Department of Disease Control of Thai MOPH (personal communication with expert in EPI committee) (Table 2).

Both direct medical and direct non-medical costs were estimated. It was assumed that lost or impaired ability to work or engage in leisure activities due to morbidity would be captured in the disutility of QALY. Indirect costs were thus not included to evade double counting (18). The cost of the vaccination program included vaccine acquisition cost and wastage cost based on wastage rate of single-dosed DTP-HepB-Hib and multiple-dosed DTP-HepB vaccines from Thailand’s survey study (29). Direct medical costs for hospitalized episode of Hib infection were obtained from three cost estimation approaches in order to provide a broader possible range of cost estimates. The first approach was to derive cost estimates based on DRG using the abovementioned NHSO database (2008–2013). The adjusted relative weights (adjRW) of Hib-specific infections were multiplied with base-rate reimbursement of THB 8,200 ($250) for 1 adjRW. These costs were used in base-case analysis. The second approach was based on cost estimates obtained from a study determining cost estimates for Hib-specific infection, conducted in Thailand in year 2002 in 42 patients (30). We adjusted the estimates using medical care consumer price index (CPI) for the whole aggregated value from 2002 to 2014. The third approach was similar to the second approach where both were based on cost estimates from a study in Thailand (30). However, in the third approach, we adjusted labor cost item with the ratio of the aggregated amount for wage and salary of health care professionals of 2002 and 2014 by Thai Ministry of Health, while other cost items were adjusted using CPI (Table 1) (31). The rationale for the separated adjustment for labor cost was the observed substantial increase of health care professionals’ compensation rates in the last decade. The cost estimates from the second and third approach were used in scenario analyses. Direct non-medical costs, including transportation, meals, accommodation, facilities, caregivers’ productivity loss for hospital visits, or providing informal care, were derived from a previous study (24).

The budget impact analysis was analyzed to estimate the whole budget required and the real incremental budget for implementing of national DTP-HepB-Hib vaccination program compared to DTP-HepB in EPI among 782,129 Thai children (the number of cohort of children in year 2013). All cost values are presented in 2014 and could be converted to US dollars ($) using exchange rates THB 32.8 = $1 for international comparison (32) (Table 3).

Utility reduction was not applied for healthy individuals in our model. For infected individuals, we applied their utility weights deriving from published studies that conducted among Thai patients in the same health states of Hib infection (Table 3) (24, 33). The utility weights were based on Health Utility Index mark 3, which they were used to analyze the cost-utility of pneumococcal vaccine under the Thai context (24).

Primary outcomes were the difference of Hib infections with/without sequelae and death over 5 years, incremental costs, life year gained, QALYs gained, and ICER. For base-case analysis, we calculated the expected lifetime costs and outcomes for each program. The results are presented as ICER of DTP-HepB-Hib versus DTP-HepB as a part of EPI. An official willingness-to-pay (WTP) of the Thai Health Economic Working Group threshold (THB 160,000; $4,878 per QALY gained) for drug listing in NLEM year 2012 was used as cost-effectivenessthreshold (16, 17).

One-way sensitivity analysis was performed to evaluate the uncertainties surrounding each input within plausible ranges of 95% CI including disease incidence, VE, costs, utilities, and discounting rate at 0 and 6% per annum and were presented using tornado diagram (Figure 2). Scenario analyses were performed when a four-dose of DPT-HB-Hib regimen (at 2, 4 and 6 months of age plus a booster dose at age between 12 and 18 months) or 3 + 1 schedule was considered, assuming the similar effectiveness between 3 + 0 and 3 + 1 dose regimens (15, 34). Scenario analyses were also performed using another two different cost estimating approaches as described previously CFR of Hib-specific infections based on published article was used in another scenario analysis. We also provide threshold analysis for vaccine acquisition cost.

Multivariate probabilistic sensitivity analysis (PSA) was conducted to simultaneously examine the effects of all parameter uncertainty using a Monte Carlo simulation performed by Microsoft Excel 2003 (Microsoft Corp., Redmond, WA) (35). The various probability distributions were defined: (a) probability and utility ranging between zero and one would follow beta-distributions, (b) costs and length of stay normally positively skewed and positive would follow gamma-distributions, and (c) VE and relative risk of dying parameters would follow a log-normal distribution. 1,000 Monte Carlo simulations were run and results were presented as cost-effectiveness acceptability curve (Figure 3) (36). The expected net monetary benefit was calculated for WTP of NLEM 2012 threshold in Thailand in order to show the probability that DPT-HB-Hib vaccination program is cost-effective.

Haemophilus influenzae type b vaccination program among 782,129 Thai children could avert 3,960 Hib-infected cases, which includes 240 Hib meningitis, 3,624 Hib pneumonia, and 96 Hib NPNM over 5 years (Table 4). It could prevent 27 hearing losses, 12 epilepsies, and 20 developmental deficits which are long-term Hib meningitis-related sequelae. The vaccination would avert 89 Hib-related deaths (13 due to Hib meningitis, 71 due to Hib pneumonia, and 5 due to Hib NPNM). Table 4 also presents incremental cost per capita of implementing both three-dose universal Hib vaccination program as THB 141.19 ($4.3). The incremental vaccination program cost of a three-dose vaccination schedule would require is THB 291.64 ($8.9) based on a unit cost of THB 148.5 ($4.5) per dose and wastage cost of 5% for DTP-HepB-Hib single-dose dosage form (39% for 10-dose vial), compared to THB 42.05 ($1.3) per dose of DTP-HepB multiple-dose preparation.

Our model estimates that vaccinating children with Hib vaccine would save nearly THB 118.24 ($3.6) in direct medical care costs and THB 32.20 ($1) in direct non-medical care costs per vaccinated child. Therefore, a universal Hib infant vaccination with three-dose regimen is expected to lead to an ICER value of THB 1,099.13 ($33.5) per QALY gained under societal perspective.

In Figure 2, the one-way sensitivity analyses showed that the uncertainty around incidence of Hib pneumonia for those below 5 years of age led to the largest variation of ICER from THB 479 ($14.6) to THB 2,511 ($76.6) per QALY gained. All the remaining parameters seemed to have moderate to minimal impact on cost-effectiveness results. Results of the PSA based on 1,000 Monte Carlo simulations are presented in cost-effectiveness acceptability curve (Figure 3). Despite variation in base-case parameter inputs, around 1.40% of the simulated ICERs were in the lower-right hand quadrant, indicating that Hib vaccination program is always less costly and more effective than no vaccination (dominant). Another 98.6% of ratios which lie in the upper-right hand quadrant indicate that the vaccination program is more effective but also costlier than no vaccination. However, all simulated outcomes were well below the cost-effectiveness threshold line. As shown in Figure 3, the three-dose universal Hib vaccination program from societal perspective will have 100% probability of being cost-effective if the WTP threshold is set at THB 160,000 ($4,878) per QALY gained.

Based on current evidence of VE and coverage, 3 + 1 vaccination schedule provide costlier than 3 + 0 with the ICER was THB 1,835.53 ($56.5) per QALY gained. Two scenarios mentioned in the methodology section of higher cost estimates from previous costing study were also analyzed in order to provide an implication of varying Hib-infected direct medical care cost. For cost estimates using CPI for all cost items of previous costing study, the ICER was reduced to THB 56 ($1.7) per QALY gained, while it was cost-saving (less incremental cost with higher QALY gained) under separated labor cost adjustment using wage and salary with CPI adjustment for other cost items of previous costing study. In addition, when we used CFR from published article, which had higher CFR among Hib meningitis cases and lower CFR among Hib NPNM (Table 1), the ICER was slightly reduced to THB 1,098.23 ($33.5) per QALY gained. When analysis considered the effect of Hib vaccine only on Hib meningitis, ICER was increased to THB 31,753.21 ($968.1) per QALY gained.

At current pricing, universal Hib infant vaccination is unlikely to be cost-saving compared to no vaccination under societal perspective. The price of DTP-HepB-Hib vaccine should be THB ≤101 ($3.1) per dose for being cost-saving intervention. For cost estimates using CPI for all cost items of previous costing study, the maximum price per dose are THB 149 ($4.5) for cost-saving. In addition, prices should be THB 232 ($7.1) under separated labor cost adjustment using wage and salary with CPI adjustment for other cost items.

Based on a birth cohort of 782,129 children under base-case analysis, Thai government should invest about THB 228 ($7.0) million to implement 3 + 0 Hib vaccination program. However, total numbers of cases prevented can provide a cost reduction about THB 118 ($3.6) million. Therefore, an extra budget needed is about THB 110 ($3.4) million.