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The value of varicella vaccination in healthy children: cost–benefit analysis of the situation in France
PERGAMON
Vaccine 17 (1999) 142±151
The value of varicella vaccination in healthy children: cost± bene®t analysis of the situation in France Laurent Coudeville *, Franc° ois Paree, TheÂreÁse Lebrun, Jean-claude Sailly Centre de Recherches Economiques, Sociologiques et de Gestion (CRESGE-LABORES, URA-CNRS 362), 1 rue Norbert SEGARD, BP 109, 59016 Lille Cedex, France Received 14 October 1997; received in revised form 6 April 1998; accepted 28 April 1998
Abstract The purpose of the cost±bene®t analysis described in this article is to determine the economic value of vaccination of healthy children against varicella in France. It is based on the results of two speci®c investigations Ð an epidemiological model and a prospective observational study (1832 cases studied) of the socio-economic consequences of varicella. This cost±bene®t analysis was conducted from the viewpoint of the society and that of the patient, for vaccination coverage rates ranging from 10 to 90%. This analysis demonstrates the value of varicella vaccination when associated with measles±mumps±rubella (MMR) vaccination: if varicella and MMR vaccines are co-administered, the vaccination of 80% of the children against varicella leads to a reduction in medical costs associated with varicella including that of vaccination, ranging from 10 to 77% according to the values adopted for vaccination costs, varicella treatment costs, discount rate and vaccine ecacy. The results of this study also underline the bene®ts of a vaccination policy that aims to achieve a high rate of coverage, thereby reaping the highest bene®t from vaccination, and also avoiding potential negative consequences. # 1998 Elsevier Science Ltd. All rights reserved. Keywords: Varicella; Vaccination; Cost±bene®t analysis; Child; Prevention
1. Introduction The varicella vaccine, developed in Japan at the start of the 1970s [1], is a live attenuated vaccine speci®c for VZV (varicella-zoster-virus, the virus responsible for varicella and zona); this vaccine was for a long time reserved exclusively for subjects particularly at risk for serious forms of the disease (mainly immunode®cient children) [2]. Following Japan and South Korea, the United States and Germany have recently authorized the use of this vaccine in healthy subjects. In many other countries, such as France, the debate over targeted vaccination versus mass vaccination remains open. In order to allow proper discussion, it is necessary to assess the medico-economic value of a vaccination programme, thus implying measurement of the medical impact, as well as the socio-economic consequences of vaccination. * Corresponding author. Tel.: +33-320-134060; fax: +33-320134070. 0264-410X/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 4 - 4 1 0 X ( 9 8 ) 0 0 1 6 1 - 3
As regards the medical aspects, the following three points should be considered: . ®rst, reduction in the incidence of varicella in vaccinated subjects, but also in non-vaccinated subjects, for whom there is a decreased risk of exposure; . second, a decrease in the number of complications associated with varicella. A complication is reported in 2% of the cases seen in 1996 by the general practitioners involved in the French epidemiologic surveillance network sentinel [3]. This rate is similar to the one observed by Chow et al. [4] (2.0%) with US data. Yawn et al. [5], also in the US case, recently reported a higher rate for varicella complications (3.7%). If most of these complications are mild, varicella complications may be severe (encephalitis and Reye's Syndrome: between 1 and 2/100 000 cases of varicella [6]), and even fatal (2/100 000 cases of varicella in non-immunode®cient subjects [6]). . ®nally, the possible reoccurrence of cases of varicella in adults, who are reputed to be at greater risk.
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Various socio-economic aspects must also be considered. . ®rst, the cost of the vaccination programme. The coadministration of the varicella vaccine with the MMR vaccine may however decrease this cost. . second, reduction in the economic costs related to the illness (cost of treatment for all cases of varicella, management of complications, working days lost...). The purpose of the present article is to provide a cost±bene®t analysis regarding the potential advantages of varicella vaccination in healthy children built on a thorough examination of these dierent elements.
2. Materials and methods This cost±bene®t analysis, involving successive examination of the viewpoint of the society and that of the patient, is based on comparison of costs of a preventive strategy (vaccination programme for the children aged less than 6 years and medical treatment of residual cases of varicella) and of a curative strategy (no vaccination and medical treatment of individual patients presenting with varicella). Since only those consequences evaluative in ®nancial terms were considered in the analysis, this is a cost±bene®t analysis in the strict sense of the word [7]. We considered in this analysis the usefulness of a varicella vaccine diused in the same conditions that vaccines against measles, mumps and rubella, namely a recommended vaccine for the children aged between 9 months and 6 years. We then focused our analysis on the co-administration of the varicella vaccine with the MMR vaccine to children aged between 9 months and 6 years. The vaccine coverage analysed in the base case, 80% of 6 year-old children, is close to the one observed for measles, mumps, rubella in France (respectively 81, 77 and 80% in 1993 [8]). Other scenarios, with vaccine coverage ranging from 10 to 90%, are also studied. Within the same scenario, the vaccine coverage is identical for all cohorts involved in vaccination. In order to ensure proper analysis, information was required in three areas: . the epidemiological outcome of vaccination (changes in the number and age-related distribution of cases of varicella and complications thereof) evaluated by means of modelling; . the socio-economic consequences of varicella as determined by a speci®c survey;
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. ®nally, the costs associated with vaccination as determined by comparison of several sources of information.
2.1. Collection of data required for the cost±bene®t analysis 2.1.1. Modelling of the epidemiological consequences of vaccination against varicella Modelling of the epidemiological consequences of vaccination against varicella are based on a model developed by Halloran et al. [9]. This model, which takes account of heterogeneity in the risk of transmission and contraction of infection according to the individual's age group, allows simulation for an entire population of the changes in number of cases of varicella and age-related distribution as a result of vaccination. This type of deterministic model, based on the principle of mass action and de®ned by a system of non-linear dierential equations, is known as the RAS model (realistic-age-structured model) [10]. Simulations were performed for a population with characteristics similar to those of the French population. The simulated population was thus divided into 75 cohorts of 700 000 individuals at birth. The size of the cohort falls regularly as a function of mortality rates, up to the age limit for individual subjects. Old people having practically no role in the spread of the virus, the age limit is set at 75 years. The data used in the model are shown in Table 1. It has to be noted that the data used for age-speci®c rate of complications, based on the results of epidemiologic surveillance achieved by Sentinel network from 1991 to 1994 [11], are the same whatever varicella occurs in vaccinated or non-vaccinated persons. Considering that varicella in vaccinated persons is almost exclusively mild [12], this assumption is conservative. In the same way, following previously published studies on the usefulness of varicella vaccination in the USA [13, 14] or Germany [15], the eects of varicella vaccination on zoster were not taken into account in this analysis. As it has been shown that varicella vaccination results in a reduced risk of zoster for children with leukemia [16] and in reductions of both the incidence and the severity of zoster for healthy individuals [17], this assumption is also conservative. We simulated the implementation of a vaccination programme for children aged under 6 years. Distribution of children according to age of vaccination was calculated using data for the MMR vaccine [8]. This distribution remains stable in the dierent simulations, whatever the coverage rate.
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Table 1. Data used for modelling of the epidemiological consequences of a vaccination programme against varicella Mean value (range) Proportion of the population contracting the virus in the absence of vaccination Distribution of cases of varicella by age group [11] (years) 0±4 5±9 10±19 > 20
52.2% 33.4% 8.0% 6.4%
Complication rates in the dierent age groups [11] (years) 0±4 5±9 10±19 > 20
29/1000 16/1000 16/1000 60/1000
Mortality rates in the population [20] Annual mortality rates for subjects aged 0±50 years Annual mortality rates for subjects over 50 years Age limit in the population (years)
1.4/1000 15/1000 75
Protection of newborn infants by maternal antibodies Proportion of infants with protection conferred by maternal antibodiesa Mean duration of protection through maternal antibodies [9]
96% 180 days
Duration of varicella [9] Duration of the latent infection period Duration of the infectious period
14 days 5 days
Parameters of vaccine ecacy [9] Proportion of vaccinated subjects who remains partly susceptible to develop varicella Relative propensity to contract the virus of vaccinated subjects partly susceptible to develop varicellab Relative propensity of vaccinated subjects to transmit the virus when they have been infectedb Proportion of fully protected vaccinated subjects immunized after re-exposure to the virus Proportion of vaccinated subjects remaining susceptible immunized after re-exposure to the virus Proportion of fully protected vaccinated subjects becoming partly susceptible to develop varicellac Distribution of children by age of vaccinationd Under 1 year 1±2 years 2±6 years
99%
10% (5±17%) 12% (5±16%) 40% (10±83%) 50% (0±100%) 44% (0±95%) 15% (6±35%) 5.8% 67.0% 27.2%
a
Mean proportion according to the results of the model in the absence of a vaccination programme. As compared to the non-vaccinated subjects propensity. c Loss of immunity calculated on the basis of lifespan of individuals. d Estimated from the distribution noted for the MMR vaccine [8]. b
2.1.2. Survey of the socio-economic consequences of varicella In order to obtain information on the direct and indirect costs associated with varicella, we carried out a prospective observational survey by mail among general practitioners and paediatricians in France. 1393 physicians (1208 general practitioners, 185 paediatricians) agreed to participate to this survey. Their characteristics, regarding age, sex and professional status distribution were similar to the general population of general practitioners and paediatricians in France ( p < 0.05). These physicians were required to include, from the date they agreed to participate in this survey, the ®rst three non-immunodepressed patients consulting for the ®rst time due to varicella. Information
regarding medical care, work stoppage and child-minding arrangements due to varicella, was obtained from both doctors and patients. The questionnaire for adult patients (18 years or more) was dierentiated from the questionnaire for child patients (under 18 years). 2.1.3. Estimation of the cost of varicella vaccination Our analysis is focused on the co-administration of varicella vaccine with the MMR vaccine. Physicians being paid in France on the same basis whatever the number of vaccines they administer jointly during the same consultation, there are no additional costs induced by varicella vaccine administration. As noted by Beutels et al. [15], the relevant cost for a vaccination is the incremental cost of adding this vacci-
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nation to an existing immunization program. We can then use, in the base case, a null cost for the administration of the varicella vaccine. In a sensitivity analysis, we also considered a case in which half of the varicella vaccinations were achieved separately from MMR vaccination. In this case, the cost of the administration of the vaccine had been determined by using the national tari for the consultation of a general practitioner in France (FF110). The price of varicella vaccine (FF 100 in the base case, ranging from FF50 to 150 in sensitivity analyses) was determined using as a reference the price of this vaccine in countries in which it is widely used (United States, Japan, South Korea). Following Lieu et al. [13] and Huse et al. [14], we postulated that from 0.31 and 2% of vaccinations (1% in the base case), result in a consultation due to side eects. We therefore ®xed the cost of varicella vaccination, borne at 35% by the patients, at FF101.2 in the base case, varying from FF50.4 to 207.4 in sensitivity analysis. 2.2. Calculation of cost±bene®t ratio 2.2.1. Viewpoint of society In this viewpoint, comparison is made between all direct and indirect costs of varicella for a ®xed duration of 30 years. Regarding methodological problems raise by their addition [7], the indirect costs were separated in the analysis of direct costs and were not evaluated in monetary terms. Comparison of direct costs made by means of the actualized net bene®t (ANB) calculation, which is as follows: ANB
tX 0 30
tX 0 30 C 0t Ct Vt ÿ tÿt0 tÿt0 1 r tt0 1 r
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2.2.2. Patient viewpoint The actualized cost of varicella (ACV) either for vaccinated and non-vaccinated subjects may be calculated as follows: ACV
L X Ca Va a0
1 ra
The ACV is the mean total spending, actualized at a rate r, by individual patients, (Ca) and of vaccination (Va) during their lifetime (a represents the age of the individual patients, and L represents the age limit of the population). Comparison of ACVs for vaccinated and non-vaccinated subjects can be used to determine the group for whom a vaccination programme is ®nancially advantageous. It has to be noted that the costs considered as supported by patients are those which are not supported by the national Social Security system. Additional private reimbursement schemes have not been taken into account. The results of the cost±bene®t analysis are expressed in 1995 French Francs. They underwent sensitivity analysis based on values for the most favourable and least favourable parameters for vaccination. The indicators used were adapted to the size of the French population. The actualization rate used in the central hypothesis was ®xed at 5%, and was 0% for the most favourable hypothesis for vaccination and 10% for the least favourable hypothesis for vaccination.
3. Results 3.1. Epidemiological consequences of the establishment of a varicella vaccination programme
The ANB is the dierence, updated for rate r, between annual cost of treatment for varicella (C 0 t) without a vaccination program, and annual cost of treatment of varicella (Ct) where there is a varicella vaccination programme (Vt) at t0. Comparison of the indirect costs for each of these strategies is based on the number of days of absence from work avoided due to the vaccination programme (AA) calculated as follows: ! tX tX 0 30 0 30 0 At ÿ At =30 AA
Figure 1 shows changes over time in the incidence of varicella following a vaccination programme. It shows that over the ®rst years, the vaccination programme is accompanied by wider changes in the incidence of varicella, but this situation subsequently stabilizes. Consequently, isolated consideration of the ®rst years following a vaccination programme would lead to bias in the analysis of the consequences of vaccination. Table 2 and Fig. 2 show that, although vaccination appears bene®cial in all cases for the population, the situation diers depending on whether one considers the group of vaccinated subjects or that of non-vaccinated subjects:
This indicator is based on the dierence between the annual number of days of work stoppage (A 0 t) where there is no vaccination programme and the annual number of days of work days lost due to varicella (At) where there is a vaccination programme at t0.
. Vaccinated subjects bene®t both from the protection acquired through vaccination and from the indirect eects of vaccination (reduction of the risk to contract the disease due to the decrease of the number of infectious subjects in the population). When 80% of the children born after the diusion of the vac-
tt0
tt0
tt0
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L. Coudeville et al. / Vaccine 17 (1999) 142±151
Fig. 1. Changes in the annual number of cases of varicella following the introduction of a varicella vaccine. Vaccine coverage rate: 80%.
Table 2. Number of vaccinated and non-vaccinated subjects contracting varicella or a complication of varicella in cohorts having and having not bene®ted from vaccinationa. Vaccine coverage rate: 80% Age classes (years)
No vaccination programme Non-vaccinated subjects Cases of varicella in the subpopulation Complications of varicella in the subpopulation Vaccination programme Ð mean vaccine ecacy Vaccinated subjectsb Cases of varicella in the subpopulation Complications of varicella in the subpopulation Non-vaccinated subjectsc Cases of varicella in the subpopulation Complications of varicella in the subpopulation Vaccination programme Ð high vaccine ecacy Vaccinated subjectsb Cases of varicella in the subpopulation Complications of varicella in the subpopulation Non-vaccinated subjectsc Cases of varicella in the subpopulation Complications of varicella in the subpopulation Vaccination programme Ð low vaccine ecacy Vaccinated subjectsb Cases of varicella in the subpopulation Complications of varicella in the subpopulation Non-vaccinated subjectsc Cases of varicella in the subpopulation Complications of varicella in the subpopulation a
0±4
5±9
10±14
15±19
51 990 1518
32 798 541
5624 82
2104 41
6260 378
98 776 2560
43 1
101 2
60 1
47 1
755 46
1006 50
16 594 485
7590 125
3563 52
2518 49
25 875 1563
56 140 2273
133 8
179 9
8 0.2
19 0.3
11 0.2
8 0.2
20±75
15 449 451
7116 117
3341 49
2368 46
24 202 1462
52 476 2125
134 4
300 5
176 3
139 3
2314 140
3063 154
20 594 601
9320 154
4337 63
3025 58
31 224 1886
68 499 2763
Number of individuals concerned/100 000 individuals in the subpopulation considered (vaccinated or non-vaccinated subjects). Individuals having not contracted varicella before their vaccination. c Individuals not vaccinated or having contracted varicella before their vaccination. b
Total
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ease, the risk of complications tends to increase for non-vaccinated subjects when mean values are adopted for vaccine ecacy (rising from 2.6% in the absence of vaccination to 3.5% in the least favourable scenario). This increased risk of complications in non-vaccinated subjects is due to an increase in cases of varicella among adults, for whom the risk of complications is higher than for children. If vaccine coverage rate achieved for varicella is similar to the one observed for measles, mumps and rubella in France (80%), vaccination leads to a decrease of the risk of complications for non-vaccinated subjects when high values (2.3%) or mean values (2.1%) are adopted for vaccine ecacy but not when low values are adopted (2.8%). Fig. 2. Percentage of complications of varicella in vaccinated subjects, non-vaccinated subjects and the entire cohort relative to the vaccine coverage rate. Mean vaccine ecacy.
cine receive vaccination, from 0.2 to 3.0% of the vaccinated children contract varicella according to the values adopted for vaccine ecacy. The residual risk of complication is then very low among vaccinated subjects (always less than 0.1%) even if, as done here, one considers that the risk of complications is the same for vaccinated persons than for non-vaccinated persons. Vaccination is thus pro®table in all cases for this population. . The results of a vaccination programme is less clearcut for non-vaccinated subjects. For coverage rates of 70% or less and, while there is a decrease in the proportion of this population contracting the dis-
3.2. Survey on the socio-economic consequences of varicella 1832 cases of varicella (1678 children cases and 154 adult cases) have been included in our survey from February 1994 to March 1995. The mean age was 4.1 years (S.D. 3.2) for children (under 18 years) and 30.5 years (10.8) for adults. The results obtained concerning medical care, hospitalizations, lost work days, and child-care arrangements are synthesized in Table 3. Whatever the element considered, medical care is signi®catively higher for adults. Adults consult physicians more often (1.5 consultation versus 1.2), are prescribed more expensive medications (FF176 versus FF84) and are
Table 3. Medical care, lost work days and child-care arrangements in the event of varicella Varicella in children
Varicella in adults
Signi®cance of the dierencec
Medical care M.D. consultations (mean value) Pharmaceutical prescriptions (mean cost in FF) Purchase of O.T.C medications (mean cost in FF) Additional examinations (proportion of casesa)
1.2 consult. 87.4 2.6 0.8%
1.5 consult. 175.8 5.5 6.4%
*** *** * ***
Hospitalizations Hospitalizations (proportion of casesa) Mean duration of hospitalization noted (in days)
36/104 3.5
195/104 5.6
** NS
Lost work days Incidence of work stoppage (proportion of casesa) Mean duration of work stoppage noted (in days)
17.3%b 3.4
51.9% 10.9
*** ***
Child-care arrangements Changes in child-minding arrangements (proportion of casesa) Mean cost per change in child-minding arrangements noted (in FF)
20.1% 47
Ð Ð
Ð Ð
a
Proportion of cases in wich the event was noted at least once. Work stoppage of the parents of the children infected. c Tests used: Mann±Whitney test for comparisons of means, w 2 test for comparisons of proportions. NS: Not signi®cant; *Signi®cance threshold = 5%; **signi®cance threshold = 1%; *** signi®cance threshold = 1-. b
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Security System. The mean cost associated to work stoppage borne by an adult having varicella was FF279 (158±399). Finally, the parents of a child having varicella supported on average, FF62 (43±81) owing to work stoppage and child-care arrangements. Mean values and con®dence interval bounds presented above are used respectively to determine cost±bene®t results in the base case and in sensitivity analysis. 3.3. Cost±bene®t analysis 3.3.1. Viewpoint of society Whatever the vaccine coverage rate (cf. Fig. 3), the actualized net bene®t (ANB) is positive when mean values are used for the parameters of the analysis (base case). A varicella vaccination programme induces a slight increase of varicella-related direct medical costs (11%) only if one considers the least favourable values for the parameters and a vaccine coverage rate of 40% or less. When the coverage rate is stable at 80% (cf. Table 4), the actualized net bene®t rises for the base case to FF1826 million. In this case, ANB is sensitive to the value adopted for the discount rate (inducing an ANB variation ranging from ÿ50 to +100% of the value obtained for the base case, cf. Table 4), the cost of vaccination (224%), the cost of varicella (226%) and, to a smaller extent, the ecacy of the vaccine (ÿ1 to +3%). Nevertheless, when the vaccine is administered to 80% of the children born after the diusion
Fig. 3. Actualized net bene®t associated with a vaccination programme against varicella. Viewpoint of society.
more often concerned by additional examinations (6.4% versus 0.8%). Nine cases of hospitalizations (6 children and 3 adults) have been observed through this survey. These hospitalizations are notably related to high fever, cutaneous or ORL complications for children and pulmonary complications for adults. Overall, the mean medical cost for a varicella case, including expenses related to complications, was FF274 (con®dence interval: 240±308) for children, and FF637 (328±945) for adults. About 65% of these medical costs were ®nanced throughout the French Social
Table 4. Sensitivity analysis: actualized net bene®t (ANB) and number of days of absence from work avoided (AA) due to a vaccination programme. Vaccine coverage rate: 80% Direct medical costsa
Absence from workb
Vaccination
No vaccination
ANB
Vaccination
No vaccination
AA
Base case Most favourable values for vaccination Least favourable values for vaccination
3190 7335 1608
1364 1654 1440
1826 5681 168
698 823 580
94 106 95
605 717 485
Cost of vaccination Low cost High cost
3190 3190
926 2278
2264 912
698 698
94 94
605 605
Cost of varicella High cost Low cost
3758 2622
1461 1267
2298 1355
823 580
111 77
711 504
Discount rate High rate Low rate
6226 1956
2392 939
3834 1017
698 698
94 94
605 605
Vaccine ecacy High ecacy Low ecacy
3190 3190
1354 1410
1836 1780
698 698
89 117
609 582
a b
Discounted millions of French Francs over the ®rst 30 years of a vaccination programme. Average annual number of thousands days over the ®rst 30 years of a vaccination programme.
L. Coudeville et al. / Vaccine 17 (1999) 142±151
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Fig. 4. Actualized cost of varicella (ACV) for vaccinated and non-vaccinated subjects according to the vaccine coverage rate.
of the vaccine, vaccination always leads to a reduction of the medical costs associated with varicella ranging from 10 to 77% and rising to 57% for the base case. The number of days of absence from work avoided each year through vaccination reaches 33 871 for a coverage rate of 10% and 643 831 for a coverage rate of 90% when mean values are adopted for the parameters of the analysis. When the most and least favourable values are used for each of the parameters, the mean number of days of absence from work varies by 220%. 3.3.2. Viewpoint of the patient Paradoxically, those who are not vaccinated bene®t most in ®nancial terms from broadening of vaccine coverage, particularly where the latter exceeds 70% (cf. Fig. 4). In the mean hypothesis, the actualized cost associated with varicella for a non-vaccinated person falls from FF123 where the vaccine is not generally given to FF16 when the rate of coverage reaches 90%. For a subject vaccinated, this cost falls from FF33, for a coverage rate of 10%, to FF31 for a coverage rate of 90%. The sensitivity of results to the value of the parameters re¯ects the fact that the way in which individuals assess the advantage of vaccination is highly dependent on their characteristics.
4. Discussion The presentation of the results of the cost±bene®t analysis clearly show the potential advantages of the vaccination of healthy children aged under 6 years, both in terms of morbidity and of the socio-economic consequences associated with varicella:
. In each scenario studied, a vaccination programme leads to an overall reduction in the incidence and complications associated with varicella in relation to the current situation. The reduction in the number of varicella-related complications reaches 98% for a coverage rate of 90%. This result is based on all the complications, including mild ones, seen by the general practitioners involved in the French epidemiologic network Sentinel [11]. According to Lieu et al. [13], the percentage of reduction associated with a high rate of vaccination seems however to be similar when only major sequelae of varicella are considered (reduction of 94% of major sequelae of varicella for a coverage rate of 97%). It also have to be noted that, considering the same rate of complications for varicella occurring among vaccinated and non-vaccinated subjects, we have adopted a conservative assumption [12]. The impact of this assumption remains nevertheless limited (according to the value adopted for vaccine ecacy when the coverage rate is stable at 80%, complications among vaccinated subjects represents from 1 to 15% of all the complications). . The survey of the socio-economic consequences of this illness also con®rms that the hospitalizations for varicella, while infrequent, are not extremely rare. The annual incidence of hospitalizations seen is approximately 2500 for children and 1000 for adults in France. Care should naturally be taken in interpreting the results of a study not intended to provide indicators of an epidemiological nature. Nevertheless, the rates of hospitalizations noted in our study [36/ 104 (con®dence interval:14±77) in the age group 0± 18 years and 195/104 (41±558) for adults aged r18 years] are in accordance with the one reported
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by Choo et al. [4] for the US case (from 20/104 to 65/104 for age groups between 0 and 20 years, 125/ 104 for the age group of r20 years and a global rate of 43/104). Wharton et al. [18], always for the US case, reported lower ®gures (a global rate of 27/104) but precise, as observed in our study and by Choo et al. [4], than the risk for adults is six times the one observed in the age group 5±9 years. . When the vaccine coverage rate is higher than 40%, vaccination against varicella leads to a reduction in direct medical costs associated with varicella for all values examined for the various parameters of the analysis. When 80% of children are vaccinated, The savings that can be achieved by the French Social Security Oces each year are about FF115 million. In fact, the situations in which a vaccination programme induces an increase of medical costs associated to varicella are rather unlikely (least favourable values at the same time for vaccination costs, varicella treatment costs and vaccine ecacy and a coverage rate of 40% or less) and, if they occur, this increase is limited (11%). The ®nancial bene®ts of varicella vaccination are then clear in the French case even if one considers, as we have done in a sensitivity analysis, that half of the varicella vaccinations are achieved separately from MMR vaccination. . When indirect costs are taken into account, the advantage of vaccination is con®rmed. Widespread use of a varicella vaccine would result in a substantial reduction in work days lost due to illness: when there is a stable coverage rate of 80%, the annual number of lost work days avoided due to vaccination is equivalent to the annual number of work days in a company with a sta of more than 2700 persons. It must also be noted that, if in our study we have chosen not to evaluate absence from work in monetary terms, Lieu et al. [13] and Huse et al. [14] estimate that indirect costs represent 85% of the total costs associated to varicella in United States. Widespread use of a varicella vaccine may have negative consequences that should not be overlooked:
year-olds who have a negative history of varicella infection (catch-up programme) has not been taken into account. Such a catch-up programme, by limiting the number of persons contracting varicella during adulthood, is able to prevent an increased risk of complications for non-vaccinated observed in some scenarios analysed in our study. Lieu et al. [13] and Beutels et al. [15], underline the positive impact of a catch-up programme. Lieu et al. [13] is precise, however, in stating that its bene®ts are minimal when the coverage rate among 6-year-olds is high. Achieving a high coverage rate among 6-year-old children clearly remains the main objective of a varicella vaccination programme and the best way to avoid its potential negative consequences. . Analysis from the patient's viewpoint underlines the fact that the attitude of individuals may in fact impede achievement of high coverage rates. It is thus seen that an increase in the overall coverage rate decreases the relative value of vaccination for individual subjects, since their own risk of contracting the disease decreases without their having to be vaccinated. Similarly, the results of sensitivity analyses show that because of the dierence in status, individuals do not stand to gain exactly the same advantages from vaccination. The dierence between private and public interest of vaccination, which has been studied on a theoretical basis by Geoard and Philipson [19], has to be connected to the diculty in France in achieving a rate of vaccine coverage of more than 80% against measles, mumps and rubella [8]. The relevance of a comparison, based on an actualized cost, to interpretation of the attitude of individual subjects towards vaccination, is naturally open to question. Moreover, we have not taken into account that some of the patients bene®t from an additional private reimbursement scheme. However, considering patient viewpoint has, essentially, an illustrative interest. The mechanisms demonstrated by this means may be readily transposed to a decision by the individual depending on his perception of the risks of serious forms of the illness and his perception of the inconvenience of vaccination.
. In order to prevent an increase of complications in the group of non-vaccinated subjects, a coverage rate of at least 70% must be achieved. This increase in risk of complications in the non-vaccinated population remains however slight (2.6 versus 3.5% in the least favourable scenario) and is accompanied, in all scenarios studied, by a reduction in the absolute number of complications associated with the illness. Moreover, our study is focused on a vaccination programme for children aged under 6 years and the impact of a vaccination among 12-
These issues should not lead one to reject the idea of vaccination, the bene®ts of which are, on the whole, positive. It should also be noted that the long-term possibility of eradicating the illness, such as the possible positive impact of varicella vaccination on zoster, have not been taken into account in the assessment presented in this article. However, the results of this analysis con®rm the advantages, in the context of a vaccination programme, of a policy aimed at achievement of high coverage rates, both in order to avoid any negative consequences of vaccination, and to de-
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rive maximum bene®t from the vaccination programme. Such a policy could in fact be an extension of that recommended by the WHO and carried out in France by the Public Health Authorities in the case of vaccination against rubella, mumps and measles. 5. Conclusion This cost±bene®t analysis demonstrates the value of varicella vaccination when associated with MMR vaccination. This association actually presents two advantages: by reducing the cost of vaccine administration it makes sure, on one hand, that varicella vaccination leads to a decrease in the total medical costs associated with varicella and it allows, on the other hand, varicella vaccination to bene®t from high coverage rates achieved by vaccination against MMR. Regarding potential negative consequences of a low coverage rate, this second advantage is a major one. Acknowledgements This research project, which was selected by the Scienti®c Committee for Tenders of the Department of `Economic Evaluation of preventive, Diagnostic and Therapeutic Strategies' of the French Ministry of Research and Space, was supported by Pasteur MeÂrieux MSD. References [1] Takahashi M, Otsuka T, Ikuno Y, Asano Y, Yazaki T, Isomura M. Live vaccine used to prevent the spread of varicella in children in hospital. Lancet 1974;II:1288±90. [2] Weller TH. Varicella-Herpes Zoster Virus in Viral Infections of Humans. Epidemiology and Control, 3rd edn, Ch. 25. Plenum Medical Book Company, New York, 1991. [3] Flahaut A, Dreau H, Farran N et al. EpideÂmiologie des maladies transmissibles en meÂdecine libeÂrale: bilan du reÂseau sentinelles en 1996. BEH, 1997, 33.
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[4] Choo PW, Donahue JG, Manson JE. The epidemiology of varicella and its complications. Journal of Infectious Diseases 1995;172:706±12. [5] Yawn B, Yawn R, Lydick E. Community impact of childhood varicella infections. Journal of Pediatrics 1997;130:759±65. [6] Preblud SR. Varicella: complications and costs. Pediatrics 1986;78(Suppl):728±35. [7] Lily Moto, Sante et multidisciplinariteÂ: choix et deÂcisions. Editions HermeÁs, 1995. [8] Guignon N. Evaluation de la couverture vaccinale rougeoleoreillons-rubeÂole aÁ 6 ans pour les enfants neÂs en 1987 (EnqueÃte en milieu scolaire.). BEH, 1996, 4. [9] Halloran ME, Cochi SL, Lieu TA, Wharton M, Fehrs L. Theoretical epidemiologic and morbidity eects of routine varicella immunization of preschool children in the United States. American Journal of Epidemiology 1994;140:81±103. [10] Bolker BM, Grenfell BT. Chaos and biological complexity in measles dynamics. Proceedings of the Royal Society London B 1993;251:75±81. [11] Reseau National de Telesurveillance des Maladies Transmissibles, Base de donneÂes des reÂsultats de la surveillance eÂpideÂmiologique de la varicelle par les meÂdecins sentinelles en France entre 1990 et 1994. RNTMT, 1995. [12] Watson BM, Piercy SA, Plotkin SA, Starr SE. Modi®ed chickenpox in children immunized with Oka/Merck varicella vaccine. Pediatrics 1993;91:17±22. [13] Lieu TA, Cochi SL, Black SB et al. Cost-eectiveness of a routine varicella vaccination programme for US children. JAMA 1994;271:375±81. [14] Huse DM, Meissner HC, Lacey MJ, Oster G. Childhood vaccination against chickenpox: an analysis of bene®ts and costs. Journal of Pediatrics 1994;124:869±74. [15] Beutels P, Clara R, Tormans G, Van Doorslaer E. Costs and bene®ts of routine varicella vaccination in german children. Journal of Infectious Diseases 1996;174(Suppl 3):S335±2341. [16] Hardy I, Gershon AA, Steinberg SP et al. The incidence of zoster after immunization with live attenuated varicella vaccine: a study in children with leukemia. New England Journal of Medicine 1991;325:1545±50. [17] Gershon AA, Steinberg SP et al. Live attenuated varicella vaccine: protection in healthy adults compared with leukemic children. Journal of Infectious Diseases 1990;161:661±6. [18] Wharton M, Fehrs LJ, Cochi SL, Stroup, NE. Health impact of varicella in the 1980s. Paper presented at the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy. Atlanta, 24 October 1994. [19] Geoard PY, Philipson T. Disease eradication: private versus public vaccination. American Economic Review 1997;87:222±30. [20] INSEE, La situation deÂmographique en 1992. INSEE ReÂsultats 1995, SeÂrie DeÂmographie et SocieÂteÂs. No 42±43.
Vaccine 17 (1999) 142±151
The value of varicella vaccination in healthy children: cost± bene®t analysis of the situation in France Laurent Coudeville *, Franc° ois Paree, TheÂreÁse Lebrun, Jean-claude Sailly Centre de Recherches Economiques, Sociologiques et de Gestion (CRESGE-LABORES, URA-CNRS 362), 1 rue Norbert SEGARD, BP 109, 59016 Lille Cedex, France Received 14 October 1997; received in revised form 6 April 1998; accepted 28 April 1998
Abstract The purpose of the cost±bene®t analysis described in this article is to determine the economic value of vaccination of healthy children against varicella in France. It is based on the results of two speci®c investigations Ð an epidemiological model and a prospective observational study (1832 cases studied) of the socio-economic consequences of varicella. This cost±bene®t analysis was conducted from the viewpoint of the society and that of the patient, for vaccination coverage rates ranging from 10 to 90%. This analysis demonstrates the value of varicella vaccination when associated with measles±mumps±rubella (MMR) vaccination: if varicella and MMR vaccines are co-administered, the vaccination of 80% of the children against varicella leads to a reduction in medical costs associated with varicella including that of vaccination, ranging from 10 to 77% according to the values adopted for vaccination costs, varicella treatment costs, discount rate and vaccine ecacy. The results of this study also underline the bene®ts of a vaccination policy that aims to achieve a high rate of coverage, thereby reaping the highest bene®t from vaccination, and also avoiding potential negative consequences. # 1998 Elsevier Science Ltd. All rights reserved. Keywords: Varicella; Vaccination; Cost±bene®t analysis; Child; Prevention
1. Introduction The varicella vaccine, developed in Japan at the start of the 1970s [1], is a live attenuated vaccine speci®c for VZV (varicella-zoster-virus, the virus responsible for varicella and zona); this vaccine was for a long time reserved exclusively for subjects particularly at risk for serious forms of the disease (mainly immunode®cient children) [2]. Following Japan and South Korea, the United States and Germany have recently authorized the use of this vaccine in healthy subjects. In many other countries, such as France, the debate over targeted vaccination versus mass vaccination remains open. In order to allow proper discussion, it is necessary to assess the medico-economic value of a vaccination programme, thus implying measurement of the medical impact, as well as the socio-economic consequences of vaccination. * Corresponding author. Tel.: +33-320-134060; fax: +33-320134070. 0264-410X/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 4 - 4 1 0 X ( 9 8 ) 0 0 1 6 1 - 3
As regards the medical aspects, the following three points should be considered: . ®rst, reduction in the incidence of varicella in vaccinated subjects, but also in non-vaccinated subjects, for whom there is a decreased risk of exposure; . second, a decrease in the number of complications associated with varicella. A complication is reported in 2% of the cases seen in 1996 by the general practitioners involved in the French epidemiologic surveillance network sentinel [3]. This rate is similar to the one observed by Chow et al. [4] (2.0%) with US data. Yawn et al. [5], also in the US case, recently reported a higher rate for varicella complications (3.7%). If most of these complications are mild, varicella complications may be severe (encephalitis and Reye's Syndrome: between 1 and 2/100 000 cases of varicella [6]), and even fatal (2/100 000 cases of varicella in non-immunode®cient subjects [6]). . ®nally, the possible reoccurrence of cases of varicella in adults, who are reputed to be at greater risk.
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Various socio-economic aspects must also be considered. . ®rst, the cost of the vaccination programme. The coadministration of the varicella vaccine with the MMR vaccine may however decrease this cost. . second, reduction in the economic costs related to the illness (cost of treatment for all cases of varicella, management of complications, working days lost...). The purpose of the present article is to provide a cost±bene®t analysis regarding the potential advantages of varicella vaccination in healthy children built on a thorough examination of these dierent elements.
2. Materials and methods This cost±bene®t analysis, involving successive examination of the viewpoint of the society and that of the patient, is based on comparison of costs of a preventive strategy (vaccination programme for the children aged less than 6 years and medical treatment of residual cases of varicella) and of a curative strategy (no vaccination and medical treatment of individual patients presenting with varicella). Since only those consequences evaluative in ®nancial terms were considered in the analysis, this is a cost±bene®t analysis in the strict sense of the word [7]. We considered in this analysis the usefulness of a varicella vaccine diused in the same conditions that vaccines against measles, mumps and rubella, namely a recommended vaccine for the children aged between 9 months and 6 years. We then focused our analysis on the co-administration of the varicella vaccine with the MMR vaccine to children aged between 9 months and 6 years. The vaccine coverage analysed in the base case, 80% of 6 year-old children, is close to the one observed for measles, mumps, rubella in France (respectively 81, 77 and 80% in 1993 [8]). Other scenarios, with vaccine coverage ranging from 10 to 90%, are also studied. Within the same scenario, the vaccine coverage is identical for all cohorts involved in vaccination. In order to ensure proper analysis, information was required in three areas: . the epidemiological outcome of vaccination (changes in the number and age-related distribution of cases of varicella and complications thereof) evaluated by means of modelling; . the socio-economic consequences of varicella as determined by a speci®c survey;
143
. ®nally, the costs associated with vaccination as determined by comparison of several sources of information.
2.1. Collection of data required for the cost±bene®t analysis 2.1.1. Modelling of the epidemiological consequences of vaccination against varicella Modelling of the epidemiological consequences of vaccination against varicella are based on a model developed by Halloran et al. [9]. This model, which takes account of heterogeneity in the risk of transmission and contraction of infection according to the individual's age group, allows simulation for an entire population of the changes in number of cases of varicella and age-related distribution as a result of vaccination. This type of deterministic model, based on the principle of mass action and de®ned by a system of non-linear dierential equations, is known as the RAS model (realistic-age-structured model) [10]. Simulations were performed for a population with characteristics similar to those of the French population. The simulated population was thus divided into 75 cohorts of 700 000 individuals at birth. The size of the cohort falls regularly as a function of mortality rates, up to the age limit for individual subjects. Old people having practically no role in the spread of the virus, the age limit is set at 75 years. The data used in the model are shown in Table 1. It has to be noted that the data used for age-speci®c rate of complications, based on the results of epidemiologic surveillance achieved by Sentinel network from 1991 to 1994 [11], are the same whatever varicella occurs in vaccinated or non-vaccinated persons. Considering that varicella in vaccinated persons is almost exclusively mild [12], this assumption is conservative. In the same way, following previously published studies on the usefulness of varicella vaccination in the USA [13, 14] or Germany [15], the eects of varicella vaccination on zoster were not taken into account in this analysis. As it has been shown that varicella vaccination results in a reduced risk of zoster for children with leukemia [16] and in reductions of both the incidence and the severity of zoster for healthy individuals [17], this assumption is also conservative. We simulated the implementation of a vaccination programme for children aged under 6 years. Distribution of children according to age of vaccination was calculated using data for the MMR vaccine [8]. This distribution remains stable in the dierent simulations, whatever the coverage rate.
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Table 1. Data used for modelling of the epidemiological consequences of a vaccination programme against varicella Mean value (range) Proportion of the population contracting the virus in the absence of vaccination Distribution of cases of varicella by age group [11] (years) 0±4 5±9 10±19 > 20
52.2% 33.4% 8.0% 6.4%
Complication rates in the dierent age groups [11] (years) 0±4 5±9 10±19 > 20
29/1000 16/1000 16/1000 60/1000
Mortality rates in the population [20] Annual mortality rates for subjects aged 0±50 years Annual mortality rates for subjects over 50 years Age limit in the population (years)
1.4/1000 15/1000 75
Protection of newborn infants by maternal antibodies Proportion of infants with protection conferred by maternal antibodiesa Mean duration of protection through maternal antibodies [9]
96% 180 days
Duration of varicella [9] Duration of the latent infection period Duration of the infectious period
14 days 5 days
Parameters of vaccine ecacy [9] Proportion of vaccinated subjects who remains partly susceptible to develop varicella Relative propensity to contract the virus of vaccinated subjects partly susceptible to develop varicellab Relative propensity of vaccinated subjects to transmit the virus when they have been infectedb Proportion of fully protected vaccinated subjects immunized after re-exposure to the virus Proportion of vaccinated subjects remaining susceptible immunized after re-exposure to the virus Proportion of fully protected vaccinated subjects becoming partly susceptible to develop varicellac Distribution of children by age of vaccinationd Under 1 year 1±2 years 2±6 years
99%
10% (5±17%) 12% (5±16%) 40% (10±83%) 50% (0±100%) 44% (0±95%) 15% (6±35%) 5.8% 67.0% 27.2%
a
Mean proportion according to the results of the model in the absence of a vaccination programme. As compared to the non-vaccinated subjects propensity. c Loss of immunity calculated on the basis of lifespan of individuals. d Estimated from the distribution noted for the MMR vaccine [8]. b
2.1.2. Survey of the socio-economic consequences of varicella In order to obtain information on the direct and indirect costs associated with varicella, we carried out a prospective observational survey by mail among general practitioners and paediatricians in France. 1393 physicians (1208 general practitioners, 185 paediatricians) agreed to participate to this survey. Their characteristics, regarding age, sex and professional status distribution were similar to the general population of general practitioners and paediatricians in France ( p < 0.05). These physicians were required to include, from the date they agreed to participate in this survey, the ®rst three non-immunodepressed patients consulting for the ®rst time due to varicella. Information
regarding medical care, work stoppage and child-minding arrangements due to varicella, was obtained from both doctors and patients. The questionnaire for adult patients (18 years or more) was dierentiated from the questionnaire for child patients (under 18 years). 2.1.3. Estimation of the cost of varicella vaccination Our analysis is focused on the co-administration of varicella vaccine with the MMR vaccine. Physicians being paid in France on the same basis whatever the number of vaccines they administer jointly during the same consultation, there are no additional costs induced by varicella vaccine administration. As noted by Beutels et al. [15], the relevant cost for a vaccination is the incremental cost of adding this vacci-
L. Coudeville et al. / Vaccine 17 (1999) 142±151
nation to an existing immunization program. We can then use, in the base case, a null cost for the administration of the varicella vaccine. In a sensitivity analysis, we also considered a case in which half of the varicella vaccinations were achieved separately from MMR vaccination. In this case, the cost of the administration of the vaccine had been determined by using the national tari for the consultation of a general practitioner in France (FF110). The price of varicella vaccine (FF 100 in the base case, ranging from FF50 to 150 in sensitivity analyses) was determined using as a reference the price of this vaccine in countries in which it is widely used (United States, Japan, South Korea). Following Lieu et al. [13] and Huse et al. [14], we postulated that from 0.31 and 2% of vaccinations (1% in the base case), result in a consultation due to side eects. We therefore ®xed the cost of varicella vaccination, borne at 35% by the patients, at FF101.2 in the base case, varying from FF50.4 to 207.4 in sensitivity analysis. 2.2. Calculation of cost±bene®t ratio 2.2.1. Viewpoint of society In this viewpoint, comparison is made between all direct and indirect costs of varicella for a ®xed duration of 30 years. Regarding methodological problems raise by their addition [7], the indirect costs were separated in the analysis of direct costs and were not evaluated in monetary terms. Comparison of direct costs made by means of the actualized net bene®t (ANB) calculation, which is as follows: ANB
tX 0 30
tX 0 30 C 0t Ct Vt ÿ tÿt0 tÿt0 1 r tt0 1 r
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2.2.2. Patient viewpoint The actualized cost of varicella (ACV) either for vaccinated and non-vaccinated subjects may be calculated as follows: ACV
L X Ca Va a0
1 ra
The ACV is the mean total spending, actualized at a rate r, by individual patients, (Ca) and of vaccination (Va) during their lifetime (a represents the age of the individual patients, and L represents the age limit of the population). Comparison of ACVs for vaccinated and non-vaccinated subjects can be used to determine the group for whom a vaccination programme is ®nancially advantageous. It has to be noted that the costs considered as supported by patients are those which are not supported by the national Social Security system. Additional private reimbursement schemes have not been taken into account. The results of the cost±bene®t analysis are expressed in 1995 French Francs. They underwent sensitivity analysis based on values for the most favourable and least favourable parameters for vaccination. The indicators used were adapted to the size of the French population. The actualization rate used in the central hypothesis was ®xed at 5%, and was 0% for the most favourable hypothesis for vaccination and 10% for the least favourable hypothesis for vaccination.
3. Results 3.1. Epidemiological consequences of the establishment of a varicella vaccination programme
The ANB is the dierence, updated for rate r, between annual cost of treatment for varicella (C 0 t) without a vaccination program, and annual cost of treatment of varicella (Ct) where there is a varicella vaccination programme (Vt) at t0. Comparison of the indirect costs for each of these strategies is based on the number of days of absence from work avoided due to the vaccination programme (AA) calculated as follows: ! tX tX 0 30 0 30 0 At ÿ At =30 AA
Figure 1 shows changes over time in the incidence of varicella following a vaccination programme. It shows that over the ®rst years, the vaccination programme is accompanied by wider changes in the incidence of varicella, but this situation subsequently stabilizes. Consequently, isolated consideration of the ®rst years following a vaccination programme would lead to bias in the analysis of the consequences of vaccination. Table 2 and Fig. 2 show that, although vaccination appears bene®cial in all cases for the population, the situation diers depending on whether one considers the group of vaccinated subjects or that of non-vaccinated subjects:
This indicator is based on the dierence between the annual number of days of work stoppage (A 0 t) where there is no vaccination programme and the annual number of days of work days lost due to varicella (At) where there is a vaccination programme at t0.
. Vaccinated subjects bene®t both from the protection acquired through vaccination and from the indirect eects of vaccination (reduction of the risk to contract the disease due to the decrease of the number of infectious subjects in the population). When 80% of the children born after the diusion of the vac-
tt0
tt0
tt0
146
L. Coudeville et al. / Vaccine 17 (1999) 142±151
Fig. 1. Changes in the annual number of cases of varicella following the introduction of a varicella vaccine. Vaccine coverage rate: 80%.
Table 2. Number of vaccinated and non-vaccinated subjects contracting varicella or a complication of varicella in cohorts having and having not bene®ted from vaccinationa. Vaccine coverage rate: 80% Age classes (years)
No vaccination programme Non-vaccinated subjects Cases of varicella in the subpopulation Complications of varicella in the subpopulation Vaccination programme Ð mean vaccine ecacy Vaccinated subjectsb Cases of varicella in the subpopulation Complications of varicella in the subpopulation Non-vaccinated subjectsc Cases of varicella in the subpopulation Complications of varicella in the subpopulation Vaccination programme Ð high vaccine ecacy Vaccinated subjectsb Cases of varicella in the subpopulation Complications of varicella in the subpopulation Non-vaccinated subjectsc Cases of varicella in the subpopulation Complications of varicella in the subpopulation Vaccination programme Ð low vaccine ecacy Vaccinated subjectsb Cases of varicella in the subpopulation Complications of varicella in the subpopulation Non-vaccinated subjectsc Cases of varicella in the subpopulation Complications of varicella in the subpopulation a
0±4
5±9
10±14
15±19
51 990 1518
32 798 541
5624 82
2104 41
6260 378
98 776 2560
43 1
101 2
60 1
47 1
755 46
1006 50
16 594 485
7590 125
3563 52
2518 49
25 875 1563
56 140 2273
133 8
179 9
8 0.2
19 0.3
11 0.2
8 0.2
20±75
15 449 451
7116 117
3341 49
2368 46
24 202 1462
52 476 2125
134 4
300 5
176 3
139 3
2314 140
3063 154
20 594 601
9320 154
4337 63
3025 58
31 224 1886
68 499 2763
Number of individuals concerned/100 000 individuals in the subpopulation considered (vaccinated or non-vaccinated subjects). Individuals having not contracted varicella before their vaccination. c Individuals not vaccinated or having contracted varicella before their vaccination. b
Total
L. Coudeville et al. / Vaccine 17 (1999) 142±151
147
ease, the risk of complications tends to increase for non-vaccinated subjects when mean values are adopted for vaccine ecacy (rising from 2.6% in the absence of vaccination to 3.5% in the least favourable scenario). This increased risk of complications in non-vaccinated subjects is due to an increase in cases of varicella among adults, for whom the risk of complications is higher than for children. If vaccine coverage rate achieved for varicella is similar to the one observed for measles, mumps and rubella in France (80%), vaccination leads to a decrease of the risk of complications for non-vaccinated subjects when high values (2.3%) or mean values (2.1%) are adopted for vaccine ecacy but not when low values are adopted (2.8%). Fig. 2. Percentage of complications of varicella in vaccinated subjects, non-vaccinated subjects and the entire cohort relative to the vaccine coverage rate. Mean vaccine ecacy.
cine receive vaccination, from 0.2 to 3.0% of the vaccinated children contract varicella according to the values adopted for vaccine ecacy. The residual risk of complication is then very low among vaccinated subjects (always less than 0.1%) even if, as done here, one considers that the risk of complications is the same for vaccinated persons than for non-vaccinated persons. Vaccination is thus pro®table in all cases for this population. . The results of a vaccination programme is less clearcut for non-vaccinated subjects. For coverage rates of 70% or less and, while there is a decrease in the proportion of this population contracting the dis-
3.2. Survey on the socio-economic consequences of varicella 1832 cases of varicella (1678 children cases and 154 adult cases) have been included in our survey from February 1994 to March 1995. The mean age was 4.1 years (S.D. 3.2) for children (under 18 years) and 30.5 years (10.8) for adults. The results obtained concerning medical care, hospitalizations, lost work days, and child-care arrangements are synthesized in Table 3. Whatever the element considered, medical care is signi®catively higher for adults. Adults consult physicians more often (1.5 consultation versus 1.2), are prescribed more expensive medications (FF176 versus FF84) and are
Table 3. Medical care, lost work days and child-care arrangements in the event of varicella Varicella in children
Varicella in adults
Signi®cance of the dierencec
Medical care M.D. consultations (mean value) Pharmaceutical prescriptions (mean cost in FF) Purchase of O.T.C medications (mean cost in FF) Additional examinations (proportion of casesa)
1.2 consult. 87.4 2.6 0.8%
1.5 consult. 175.8 5.5 6.4%
*** *** * ***
Hospitalizations Hospitalizations (proportion of casesa) Mean duration of hospitalization noted (in days)
36/104 3.5
195/104 5.6
** NS
Lost work days Incidence of work stoppage (proportion of casesa) Mean duration of work stoppage noted (in days)
17.3%b 3.4
51.9% 10.9
*** ***
Child-care arrangements Changes in child-minding arrangements (proportion of casesa) Mean cost per change in child-minding arrangements noted (in FF)
20.1% 47
Ð Ð
Ð Ð
a
Proportion of cases in wich the event was noted at least once. Work stoppage of the parents of the children infected. c Tests used: Mann±Whitney test for comparisons of means, w 2 test for comparisons of proportions. NS: Not signi®cant; *Signi®cance threshold = 5%; **signi®cance threshold = 1%; *** signi®cance threshold = 1-. b
148
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Security System. The mean cost associated to work stoppage borne by an adult having varicella was FF279 (158±399). Finally, the parents of a child having varicella supported on average, FF62 (43±81) owing to work stoppage and child-care arrangements. Mean values and con®dence interval bounds presented above are used respectively to determine cost±bene®t results in the base case and in sensitivity analysis. 3.3. Cost±bene®t analysis 3.3.1. Viewpoint of society Whatever the vaccine coverage rate (cf. Fig. 3), the actualized net bene®t (ANB) is positive when mean values are used for the parameters of the analysis (base case). A varicella vaccination programme induces a slight increase of varicella-related direct medical costs (11%) only if one considers the least favourable values for the parameters and a vaccine coverage rate of 40% or less. When the coverage rate is stable at 80% (cf. Table 4), the actualized net bene®t rises for the base case to FF1826 million. In this case, ANB is sensitive to the value adopted for the discount rate (inducing an ANB variation ranging from ÿ50 to +100% of the value obtained for the base case, cf. Table 4), the cost of vaccination (224%), the cost of varicella (226%) and, to a smaller extent, the ecacy of the vaccine (ÿ1 to +3%). Nevertheless, when the vaccine is administered to 80% of the children born after the diusion
Fig. 3. Actualized net bene®t associated with a vaccination programme against varicella. Viewpoint of society.
more often concerned by additional examinations (6.4% versus 0.8%). Nine cases of hospitalizations (6 children and 3 adults) have been observed through this survey. These hospitalizations are notably related to high fever, cutaneous or ORL complications for children and pulmonary complications for adults. Overall, the mean medical cost for a varicella case, including expenses related to complications, was FF274 (con®dence interval: 240±308) for children, and FF637 (328±945) for adults. About 65% of these medical costs were ®nanced throughout the French Social
Table 4. Sensitivity analysis: actualized net bene®t (ANB) and number of days of absence from work avoided (AA) due to a vaccination programme. Vaccine coverage rate: 80% Direct medical costsa
Absence from workb
Vaccination
No vaccination
ANB
Vaccination
No vaccination
AA
Base case Most favourable values for vaccination Least favourable values for vaccination
3190 7335 1608
1364 1654 1440
1826 5681 168
698 823 580
94 106 95
605 717 485
Cost of vaccination Low cost High cost
3190 3190
926 2278
2264 912
698 698
94 94
605 605
Cost of varicella High cost Low cost
3758 2622
1461 1267
2298 1355
823 580
111 77
711 504
Discount rate High rate Low rate
6226 1956
2392 939
3834 1017
698 698
94 94
605 605
Vaccine ecacy High ecacy Low ecacy
3190 3190
1354 1410
1836 1780
698 698
89 117
609 582
a b
Discounted millions of French Francs over the ®rst 30 years of a vaccination programme. Average annual number of thousands days over the ®rst 30 years of a vaccination programme.
L. Coudeville et al. / Vaccine 17 (1999) 142±151
149
Fig. 4. Actualized cost of varicella (ACV) for vaccinated and non-vaccinated subjects according to the vaccine coverage rate.
of the vaccine, vaccination always leads to a reduction of the medical costs associated with varicella ranging from 10 to 77% and rising to 57% for the base case. The number of days of absence from work avoided each year through vaccination reaches 33 871 for a coverage rate of 10% and 643 831 for a coverage rate of 90% when mean values are adopted for the parameters of the analysis. When the most and least favourable values are used for each of the parameters, the mean number of days of absence from work varies by 220%. 3.3.2. Viewpoint of the patient Paradoxically, those who are not vaccinated bene®t most in ®nancial terms from broadening of vaccine coverage, particularly where the latter exceeds 70% (cf. Fig. 4). In the mean hypothesis, the actualized cost associated with varicella for a non-vaccinated person falls from FF123 where the vaccine is not generally given to FF16 when the rate of coverage reaches 90%. For a subject vaccinated, this cost falls from FF33, for a coverage rate of 10%, to FF31 for a coverage rate of 90%. The sensitivity of results to the value of the parameters re¯ects the fact that the way in which individuals assess the advantage of vaccination is highly dependent on their characteristics.
4. Discussion The presentation of the results of the cost±bene®t analysis clearly show the potential advantages of the vaccination of healthy children aged under 6 years, both in terms of morbidity and of the socio-economic consequences associated with varicella:
. In each scenario studied, a vaccination programme leads to an overall reduction in the incidence and complications associated with varicella in relation to the current situation. The reduction in the number of varicella-related complications reaches 98% for a coverage rate of 90%. This result is based on all the complications, including mild ones, seen by the general practitioners involved in the French epidemiologic network Sentinel [11]. According to Lieu et al. [13], the percentage of reduction associated with a high rate of vaccination seems however to be similar when only major sequelae of varicella are considered (reduction of 94% of major sequelae of varicella for a coverage rate of 97%). It also have to be noted that, considering the same rate of complications for varicella occurring among vaccinated and non-vaccinated subjects, we have adopted a conservative assumption [12]. The impact of this assumption remains nevertheless limited (according to the value adopted for vaccine ecacy when the coverage rate is stable at 80%, complications among vaccinated subjects represents from 1 to 15% of all the complications). . The survey of the socio-economic consequences of this illness also con®rms that the hospitalizations for varicella, while infrequent, are not extremely rare. The annual incidence of hospitalizations seen is approximately 2500 for children and 1000 for adults in France. Care should naturally be taken in interpreting the results of a study not intended to provide indicators of an epidemiological nature. Nevertheless, the rates of hospitalizations noted in our study [36/ 104 (con®dence interval:14±77) in the age group 0± 18 years and 195/104 (41±558) for adults aged r18 years] are in accordance with the one reported
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by Choo et al. [4] for the US case (from 20/104 to 65/104 for age groups between 0 and 20 years, 125/ 104 for the age group of r20 years and a global rate of 43/104). Wharton et al. [18], always for the US case, reported lower ®gures (a global rate of 27/104) but precise, as observed in our study and by Choo et al. [4], than the risk for adults is six times the one observed in the age group 5±9 years. . When the vaccine coverage rate is higher than 40%, vaccination against varicella leads to a reduction in direct medical costs associated with varicella for all values examined for the various parameters of the analysis. When 80% of children are vaccinated, The savings that can be achieved by the French Social Security Oces each year are about FF115 million. In fact, the situations in which a vaccination programme induces an increase of medical costs associated to varicella are rather unlikely (least favourable values at the same time for vaccination costs, varicella treatment costs and vaccine ecacy and a coverage rate of 40% or less) and, if they occur, this increase is limited (11%). The ®nancial bene®ts of varicella vaccination are then clear in the French case even if one considers, as we have done in a sensitivity analysis, that half of the varicella vaccinations are achieved separately from MMR vaccination. . When indirect costs are taken into account, the advantage of vaccination is con®rmed. Widespread use of a varicella vaccine would result in a substantial reduction in work days lost due to illness: when there is a stable coverage rate of 80%, the annual number of lost work days avoided due to vaccination is equivalent to the annual number of work days in a company with a sta of more than 2700 persons. It must also be noted that, if in our study we have chosen not to evaluate absence from work in monetary terms, Lieu et al. [13] and Huse et al. [14] estimate that indirect costs represent 85% of the total costs associated to varicella in United States. Widespread use of a varicella vaccine may have negative consequences that should not be overlooked:
year-olds who have a negative history of varicella infection (catch-up programme) has not been taken into account. Such a catch-up programme, by limiting the number of persons contracting varicella during adulthood, is able to prevent an increased risk of complications for non-vaccinated observed in some scenarios analysed in our study. Lieu et al. [13] and Beutels et al. [15], underline the positive impact of a catch-up programme. Lieu et al. [13] is precise, however, in stating that its bene®ts are minimal when the coverage rate among 6-year-olds is high. Achieving a high coverage rate among 6-year-old children clearly remains the main objective of a varicella vaccination programme and the best way to avoid its potential negative consequences. . Analysis from the patient's viewpoint underlines the fact that the attitude of individuals may in fact impede achievement of high coverage rates. It is thus seen that an increase in the overall coverage rate decreases the relative value of vaccination for individual subjects, since their own risk of contracting the disease decreases without their having to be vaccinated. Similarly, the results of sensitivity analyses show that because of the dierence in status, individuals do not stand to gain exactly the same advantages from vaccination. The dierence between private and public interest of vaccination, which has been studied on a theoretical basis by Geoard and Philipson [19], has to be connected to the diculty in France in achieving a rate of vaccine coverage of more than 80% against measles, mumps and rubella [8]. The relevance of a comparison, based on an actualized cost, to interpretation of the attitude of individual subjects towards vaccination, is naturally open to question. Moreover, we have not taken into account that some of the patients bene®t from an additional private reimbursement scheme. However, considering patient viewpoint has, essentially, an illustrative interest. The mechanisms demonstrated by this means may be readily transposed to a decision by the individual depending on his perception of the risks of serious forms of the illness and his perception of the inconvenience of vaccination.
. In order to prevent an increase of complications in the group of non-vaccinated subjects, a coverage rate of at least 70% must be achieved. This increase in risk of complications in the non-vaccinated population remains however slight (2.6 versus 3.5% in the least favourable scenario) and is accompanied, in all scenarios studied, by a reduction in the absolute number of complications associated with the illness. Moreover, our study is focused on a vaccination programme for children aged under 6 years and the impact of a vaccination among 12-
These issues should not lead one to reject the idea of vaccination, the bene®ts of which are, on the whole, positive. It should also be noted that the long-term possibility of eradicating the illness, such as the possible positive impact of varicella vaccination on zoster, have not been taken into account in the assessment presented in this article. However, the results of this analysis con®rm the advantages, in the context of a vaccination programme, of a policy aimed at achievement of high coverage rates, both in order to avoid any negative consequences of vaccination, and to de-
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rive maximum bene®t from the vaccination programme. Such a policy could in fact be an extension of that recommended by the WHO and carried out in France by the Public Health Authorities in the case of vaccination against rubella, mumps and measles. 5. Conclusion This cost±bene®t analysis demonstrates the value of varicella vaccination when associated with MMR vaccination. This association actually presents two advantages: by reducing the cost of vaccine administration it makes sure, on one hand, that varicella vaccination leads to a decrease in the total medical costs associated with varicella and it allows, on the other hand, varicella vaccination to bene®t from high coverage rates achieved by vaccination against MMR. Regarding potential negative consequences of a low coverage rate, this second advantage is a major one. Acknowledgements This research project, which was selected by the Scienti®c Committee for Tenders of the Department of `Economic Evaluation of preventive, Diagnostic and Therapeutic Strategies' of the French Ministry of Research and Space, was supported by Pasteur MeÂrieux MSD. References [1] Takahashi M, Otsuka T, Ikuno Y, Asano Y, Yazaki T, Isomura M. Live vaccine used to prevent the spread of varicella in children in hospital. Lancet 1974;II:1288±90. [2] Weller TH. Varicella-Herpes Zoster Virus in Viral Infections of Humans. Epidemiology and Control, 3rd edn, Ch. 25. Plenum Medical Book Company, New York, 1991. [3] Flahaut A, Dreau H, Farran N et al. EpideÂmiologie des maladies transmissibles en meÂdecine libeÂrale: bilan du reÂseau sentinelles en 1996. BEH, 1997, 33.
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[4] Choo PW, Donahue JG, Manson JE. The epidemiology of varicella and its complications. Journal of Infectious Diseases 1995;172:706±12. [5] Yawn B, Yawn R, Lydick E. Community impact of childhood varicella infections. Journal of Pediatrics 1997;130:759±65. [6] Preblud SR. Varicella: complications and costs. Pediatrics 1986;78(Suppl):728±35. [7] Lily Moto, Sante et multidisciplinariteÂ: choix et deÂcisions. Editions HermeÁs, 1995. [8] Guignon N. Evaluation de la couverture vaccinale rougeoleoreillons-rubeÂole aÁ 6 ans pour les enfants neÂs en 1987 (EnqueÃte en milieu scolaire.). BEH, 1996, 4. [9] Halloran ME, Cochi SL, Lieu TA, Wharton M, Fehrs L. Theoretical epidemiologic and morbidity eects of routine varicella immunization of preschool children in the United States. American Journal of Epidemiology 1994;140:81±103. [10] Bolker BM, Grenfell BT. Chaos and biological complexity in measles dynamics. Proceedings of the Royal Society London B 1993;251:75±81. [11] Reseau National de Telesurveillance des Maladies Transmissibles, Base de donneÂes des reÂsultats de la surveillance eÂpideÂmiologique de la varicelle par les meÂdecins sentinelles en France entre 1990 et 1994. RNTMT, 1995. [12] Watson BM, Piercy SA, Plotkin SA, Starr SE. Modi®ed chickenpox in children immunized with Oka/Merck varicella vaccine. Pediatrics 1993;91:17±22. [13] Lieu TA, Cochi SL, Black SB et al. Cost-eectiveness of a routine varicella vaccination programme for US children. JAMA 1994;271:375±81. [14] Huse DM, Meissner HC, Lacey MJ, Oster G. Childhood vaccination against chickenpox: an analysis of bene®ts and costs. Journal of Pediatrics 1994;124:869±74. [15] Beutels P, Clara R, Tormans G, Van Doorslaer E. Costs and bene®ts of routine varicella vaccination in german children. Journal of Infectious Diseases 1996;174(Suppl 3):S335±2341. [16] Hardy I, Gershon AA, Steinberg SP et al. The incidence of zoster after immunization with live attenuated varicella vaccine: a study in children with leukemia. New England Journal of Medicine 1991;325:1545±50. [17] Gershon AA, Steinberg SP et al. Live attenuated varicella vaccine: protection in healthy adults compared with leukemic children. Journal of Infectious Diseases 1990;161:661±6. [18] Wharton M, Fehrs LJ, Cochi SL, Stroup, NE. Health impact of varicella in the 1980s. Paper presented at the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy. Atlanta, 24 October 1994. [19] Geoard PY, Philipson T. Disease eradication: private versus public vaccination. American Economic Review 1997;87:222±30. [20] INSEE, La situation deÂmographique en 1992. INSEE ReÂsultats 1995, SeÂrie DeÂmographie et SocieÂteÂs. No 42±43.