Cost-Effectiveness of Rotavirus Vaccination in Peru

Transcription

1 Cost-Effectiveness of Rotavirus Vaccination in Peru Andrew D Clark 1, Damian G Walker 1 2, N. Rocio Mosqueira 3, Mary E Penny 3, Claudio F Lanata 3 4, Colin FB Sanderson 1 1 London School of Hygiene and Tropical Medicine 2 Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore 3 Instituto de Investigación Nutricional, Lima, Peru 4 School of Medicine, Peruvian University of Applied Sciences ABSTRACT Background: There are plans to introduce an oral rotavirus vaccine (Rotarix R GlaxoSmithKline, Belgium), one of two recently developed vaccines against rotavirus, in Peru. Methods: We modelled the cost-effectiveness of adding a rotavirus vaccine to the Peruvian immunisation programme under three scenarios for the timing of vaccination: (i) strictly according to schedule at 2 and 4 months (on-time); (ii) distributed around the target ages in the same way as the actual timings in the programme (flexible); and, (iii) flexible but assuming vaccination is not initiated for infants more than 12 weeks old (restricted). We assumed an introductory price of US$ 7.50 per dose, and varied the annual rate of price decay in sensitivity analysis.

2 Results: The discounted US$ per DALY averted for restricted, flexible and on-time schedules was $621, $615, $581 respectively. For each of the three scenarios, we estimated impact on rotavirus deaths of 53%, 66% and 69%. The US$ per DALY averted for alternative what-if scenarios ranged from $229 (assuming a 1 dose schedule, administered on-time) to $1,491 (assuming a 2 dose schedule with half the baseline vaccine efficacy rates, and a restricted timing policy). Conclusions: Based on current WHO guidelines, rotavirus vaccination represents a highly cost-effective intervention in Peru. Withholding the vaccine from children who present for their first dose after 12 weeks of age would reduce the number of deaths averted by approximately 20%. A single dose may be more cost-effective than 2 doses, but more evidence on the protection conferred by a single dose is required. Word count: 250 (abstract), 3,629 (text) Keywords: Peru, Rotavirus, Vaccination, Cost-effectiveness Reprints or correspondence: Andrew Clark Department of Public Health and Policy London School of Hygiene and Tropical Medicine Keppel Street London WC1E 7HT Tel: +44(0) Fax: +44(0) andrew.clark@lshtm.ac.uk Conflict of interest: Claudio Lanata and Mary Penny have both received funding from pharmaceutical companies to conduct clinical trials. Both were investigators on GSK Rotarix trials in Latin America. Funding statement: We acknowledge funding from the United Kingdom Department for International Development (DFID), Project Number R7842.

3 BACKGROUND Rotavirus is the leading identifiable cause of diarrhoea and vomiting in young children throughout the world [1]. Severe gastroenteritis is painful and debilitating for children, creates anxiety and stress for parents, and has costs in terms of treatment, transportation and lost income. In low- and middle-income countries, many children do not receive adequate replacement of fluids and die from the shock caused by severe dehydration. There are plans to introduce an oral rotavirus vaccine (Rotarix R GlaxoSmithKline, Belgium), one of two recently developed vaccines against rotavirus, in Peru. Given the high price of this vaccine ($15 per course when introduced in Brazil and Panama [2]) it is important to consider its likely public health impact and cost-effectiveness. One important feature of a rotavirus vaccine (RV) programme is the extent to which vaccines are administered at the recommended ages. Children often receive vaccines later than the target age, and similar delays for RV can be expected as the vaccine will need to be accommodated within the existing schedule. These delays can lead to prolonged periods without protection, reducing the public health impact of the RV programme. In addition, WHO currently recommends that the RV series should not be initiated in infants more than 12 weeks old as there is insufficient information on safety in older infants [3, 4, 5].

4 METHODS Model framework A static cohort model was used to produce the cost-effectiveness estimates. Figure 1 shows the structure of the model. For each successive birth cohort in the period , projections of life years lived between 1 and 59 months [6] are multiplied by the incidence of disease in children to give the total number of rotavirus gastroenteritis cases expected to occur by the time the children are five years old. Cases are then distributed into subgroups classified by age and severity. In Peru the child mortality rate in rural areas is around twice the urban rate, so urban and rural areas were modelled separately [7]. Numbers of incident cases are reduced by vaccine efficacy and estimates of vaccination coverage at 12 weeks and 6, 9, 12, 24, 36 and 48 months of age. The number of cases determines the number of outpatient visits, inpatient admissions and deaths. The model evaluates the incremental costs and effects of introducing the vaccine compared to not introducing it. Cost savings due to reductions in outpatient visits and inpatient admissions are subtracted from the costs of the vaccination programme. The primary outcome measure was the cost per DALY (disability-adjusted life year) averted, based on numbers of rotavirus cases (severe and non-severe) and deaths. Costs are in 2006 US$ with ratios presented in both discounted (3% costs and effects) and undiscounted form. Age weights were used in the base case, and removed in scenario analysis. Cost-effectiveness ratios were based on the cumulative future costs and effects attributed to children born in the period This time-series

5 allows investigation of trends in births, urbanisation, rotavirus mortality, and can be a useful way to investigate vaccine coverage and price projections. The model was developed in Excel [8]. Cases The incidence of rotavirus gastroenteritis was assumed to be 0.13 episodes per child aged less than five per year. This was based on a review of the rotavirus burden in Peru which drew from a limited number of community studies of diarrhoea incidence, and the proportion of diarrhoea episodes attributed to rotavirus in stool samples [9]. We assumed that 26% of rotavirus gastroenteritis episodes would ultimately progress to severe symptoms, defined as a Vesikari severity score of 11 or more [10]. This was based on reported severity of gastroenteritis episodes in the placebo group of a vaccination trial conducted in urban areas of Brazil, Venezuela and Mexico [11]. This is lower than the proportion of rotavirus gastroenteritis episodes classified as severe in the same trial, but a community surveillance study of 2,500 children aged less than 2 years in Lima suggests that rates of dehydrating diarrhoea may be much lower than this in urban areas of Peru. Severity may be higher in rural areas where there is more limited access to rehydration treatment, so we assumed severe cases accounted for 17% of urban episodes and 43% of rural episodes; a ratio of 0.4 was used based on the urban-rural ratio of under-five mortality. The mean duration of illness was assumed to be six days for all cases of rotavirus gastroenteritis, irrespective of severity [12]. A disability weight of was used for

6 non-severe cases of rotavirus gastroenteritis based on WHO expert panel estimates [13]. A weight of was used for severe cases of rotavirus gastroenteritis based on the reported disutility of hospitalisation for gastrointestinal disorders [14]. Deaths According to a recent community-based survey in Peru there were 50 diarrhoea deaths per 100,000 children aged <5 years, with rates ranging from 203 in regions of the Amazon to 12 in the urban coastal areas of Lima [15]. This is approximately 6% of the total number of under-five deaths reported for the same period. In 2002, the Pan American Health Organization PAHO estimated that diarrhoea contributed 3.5% of the total number of registered child deaths [16]. Both estimates are markedly less than those from earlier studies [17, 18]. Studies from the national Children s Hospital in Lima in 1987, 1991 and 1997, identified rotavirus in the stools of 28%, 32% and 52% of children aged <5yrs admitted with severe gastroenteritis, and this has led researchers to conclude that rotavirus is responsible for a similar percentage of overall diarrhoeal deaths in children [19, 20, 21]. For the base case, we used the mid estimate of 32% which is in line with the mean of 13 hospital studies reported in an earlier review [9]. Applying this figure to the annual 50 diarrhoea deaths per 100,000 (<5yrs) gives a rate of 16 rotavirus deaths per 100,000 children aged <5yrs. This is 2% of the under-five mortality rate in the same period, or 1 in every 1265 newborns dying of rotavirus before their fifth birthday. This lies between the rate estimated (1 in 642) using

7 recently published WHO rotavirus mortality rates for Peru [22] and the estimate by Rheingans for eight Latin American countries combined (1 in 1554) [23]. Total numbers of projected rotavirus deaths in children aged under 5 in each year were divided into age groups based on recently published global estimates by WHO [24]: 3.2% aged <3m, 11.6% 3-5m, 18.9% 6-8m, 22% 9-11m, 22.1% 12-23m and 22.2% 24m+. We assumed the same age distribution for both cases and deaths. Visits and admissions 15.4% of children surveyed in the DHS (Demographic and Health Survey) national household survey (ENDES 2000) were reported to have had an episode of diarrhoea at some time in the last two weeks. From these data we estimated 397 outpatient visits per 1,000 cases, irrespective of severity (422 urban, 375 rural); excluding visits to the private sector and social insurance (ESSALUD) scheme reduced the rate to 291 (240 urban, 339 rural). For hospitals it was assumed, based on the mean proportion of diarrhoea cases requiring hospitalisation in Government facilities in Lima, that 22% of the health care contacts in the survey were inpatient admissions [9]. We estimated 151 (214 urban, 92 rural) inpatient admissions for every 1000 severe (Vesikari 11+) episodes of gastroenteritis. Based on DHS estimates, 79% of these hospitalisations were estimated to occur in Government hospitals, with the remainder in Private and ESSALUD hospitals. The same outpatient visit rates were used for non-severe and severe cases of rotavirus gastroenteritis, with visits distributed across ten outpatient settings according

8 to the reported distribution in the DHS (see Table 1). It was assumed that only severe cases could become inpatients, with admissions distributed across five inpatient settings according to the reported distribution in the DHS. Expert consensus panels of public health professionals and medical practitioners were asked to estimate the % of secondary or tertiary care contacts for diarrhoea that were seen in tertiary hospitals. The median value was 0.9% (1.2% for urban children, 0% for rural children). Treatment costs Data on the costs borne by the Government in providing care for diarrhoea patients were collected during the period January-December Costs borne by patients, their families and informal carers in accessing these services were collected between January and December Costs arising from activity in the private sector and by the ESSALUD social insurance scheme were excluded, together with any costs borne by households in accessing these services. Facilities from three of the 24 Peruvian departments were selected to reflect the three geographical types of region: Lima (the coast), Ayacucho (the mountains) and San Martin (the jungle). Standard costing methods were used in 19 facilities (Table 2). Government facilities were grouped into clinics and primary, secondary and tertiary hospitals. All costs were inflated to 2006 Peruvian soles using the World Bank GDP deflators [25] and then converted to 2006 US$ using a period average exchange rate of US$ 1.00 = 3.36 [26]. Weighted averages of cost and length of stay were

9 generated to reflect the proportions of the population living in coastal (52%), mountain (36%) and jungle (12%) regions based on DHS survey estimates. Estimated costs are presented in Table 1. Step-down cost allocation methods were used to estimate hotel costs per bed-day. Costs of drugs, procedures and length of stay associated with diarrhoea were collected through a retrospective review of inpatient records (n=30). Records reporting either some or severe dehydration were categorised as severe rotavirus gastroenteritis. Diarrhoea without dehydration was categorised as non-severe rotavirus gastroenteritis. The records system in Peru does not classify visits to outpatient departments and health centres by disease, and so the average costs of an outpatient visit (less drugs) was estimated and supplemented by additional data from physician interviews (n=49) about drugs dispensed for diarrhoea. Data on the household costs of outpatient visits (out-of-pocket expenditure and indirect costs borne by families and caregivers when accessing government outpatient services) were collected in structured interviews (n=33). Inpatient household costs were estimated by multiplying the outpatient household cost by 2.5 based on the ratio reported by Rheingans for Venezuela [23]. Vaccination coverage and timing scenarios We evaluated three different scenarios for the timing of administration: (i) strictly according to schedule at 2 and 4 months (on-time); (ii) distributed around the scheduled date in the same way as actual timings in the programme (flexible); and, (iii) flexible but assuming vaccination is not initiated for infants aged 12 weeks or more (restricted). The age-specific coverage rates used for the flexible scenario were

10 based on a survival analysis using age of vaccination data from the 2000 Peruvian DHS survey [7]. In Peru, Rotarix would be given alongside the first and third doses of DTP (diphtheria-tetanus pertussis vaccine) at 2 and 4 months of age. Coverage for the first dose of DTP in Peru was estimated to be 97% in 1999/2000 [27], but has fluctuated since then. We assumed that DTP1 coverage would remain constant at 97% once fully integrated into the Expanded Program of Immunization - EPI programme. For logistic, financial and political reasons, it may be necessary to gradually phase RV into the existing EPI programme. Based on the precedent set by the recent introduction of Hib (Haemophilus influenzae type b) vaccine, we assumed national RV dose 1 coverage rates of 21%, 41%, 64%, 69% and 96.7% in the first five years and 97% thereafter. These national estimates were based on DHS reported coverage of DTP1 by department among 12 month old children [7], and reflects 8 departments in the first year, 13 in the second year, 20 in the third, 23 in the fourth, and all 25 departments by the fifth year. We assumed that the difference between coverage for the first and second doses of rotavirus vaccine would reduce by 5% annually. This is more conservative than the annual improvement in drop-out reported for DTP between two recent DHS surveys. Reported differences between rural and urban coverage for doses 1 and 2 were based on the DHS estimates for DTP1 and DTP3 [7]. We assumed RV dose 2 coverage of 93% in the year 2009 (96% urban, 85% rural) increasing to 95% (97% urban, 90% rural) in the year 2024.

11 Vaccine efficacy An efficacy trial in 2,155 infants in Brazil, Mexico and Venezuela in 2001/02 reported 86% efficacy against severe rotavirus gastroenteritis (Vesikari 11+) and 70% efficacy against rotavirus gastroenteritis of any severity [11]. A subsequent large trial in 20,169 infants from 11 Latin American countries in 2003/04 reported 84.8% efficacy against severe rotavirus gastroenteritis (Vesikari 11+), and 84.7% against episodes considered severe using clinical case definitions [28]. Another more recent trial in Latin America has also demonstrated vaccine efficacy of 80.5% against severe rotavirus disease after a mean follow-up duration of 20 months [29]. We assumed efficacy of 85% against severe disease with 2 doses. Using reported efficacy against rotavirus gastroenteritis of any severity of 70% we estimated an efficacy in non-severe disease of 65%. Evidence from the Rotarix trial in three Latin American countries reported similar take following 1 and 2 doses, and other rotavirus vaccines have reported high vaccine protection following the first dose [1, 30, 31] suggesting that the first dose of Rotarix is also likely to be protective. The efficacy of a single dose has recently been reported as 89.8% (95% CI ) against any episode of rotavirus gastroenteritis [32]. However, since this was based on a very short follow-up period (approximately 2 months), we assumed 75% protection against severe disease with 1 dose, and 57% efficacy against non-severe. Costs of vaccination

12 The introductory vaccine price of US$ 7.50 per dose was based on 2008 PAHO revolving fund prices [33]. Incremental vaccination costs, based on coverage level, included the cost of the vaccine itself and the cost of administering it, namely the cost of additional staff, training, cold chain maintenance, storage space, and social mobilisation. Because the rotavirus vaccine will be administered alongside the existing schedule these incremental administrative costs are assumed to be low; we assumed an incremental administration cost of US$0.50 per dose including wastage [34]. Given the safety profile of the vaccine in the large trial in 11 Latin American countries, no costs for adverse events were included. In the base case we assumed a 5% annual decline in the vaccine price per dose, from $7.50 to $3.30 over the period However, since the future price of the vaccine is highly uncertain we also evaluated a scenario with no decline in price over time. RESULTS We estimate that a flexible RV programme could prevent 2,227 rotavirus deaths, 2.5 million cases of rotavirus gastroenteritis, 1 million outpatient visits, and 116,000 inpatient admissions over the period with disease benefits discounted to 2009 at 3% (Table 3). (During the year 2015, there would be an undiscounted 212 averted deaths, 223,218 averted cases, 90,573 averted outpatient visits and 10,266 averted hospitalisations.) The total cost of vaccination over this period is estimated to be US$ 68 million, or US$ 84 million if undiscounted. The projected annual cost varies over time based on assumptions made about phased introduction of coverage

13 and vaccine price decay (Figure 2). These vaccination costs are set against total treatment cost savings of US$ 19 million (US$ 25 million undiscounted) with average discounted annual savings over the period of approximately $US 1 million per year; 77% of the cost savings were to the Government health providers, with the remaining 23% to the families who access those services. Table 4 presents one-way sensitivity analyses of incremental costs per DALY averted to adjustments in base case parameters of +/-10%. The parameters with the greatest influence on results were rotavirus mortality, vaccine efficacy against severe disease, and vaccination price. The discounted US$ per DALY averted for restricted, flexible and on-time schedules was $621, $615, $581 respectively. Equivalent undiscounted ratios were $244, $242, $228. For each of the three scenarios, effectiveness in reducing deaths was 53%, 66% and 69% respectively. In the rural areas mortality was higher and the programme more cost-effective than in the urban areas. However since the coverage in children 12 weeks old was lower in rural areas, a restricted policy tilted the balance of expenditure on the programme towards the less cost-effective urban areas, and made the restricted scenario slightly less cost-effective overall than the flexible scenario. The effect of select changes in assumptions on the results are shown in Table 5. This included the assumption that case fatality ratios (CFRs) remain constant over time rather than declining in line with overall trends in under-five mortality, shorter periods of evaluation, and a pessimistic pricing scenario which assumed no decline in price over time. A single dose strategy was also evaluated. The discounted $US per DALY averted in these additional scenarios ranged from $229 (assuming a 1 dose

14 schedule which is administered on-time) to $1,491 (assuming half the baseline vaccine efficacy rates, and a restricted timing policy). The percentage change in deaths prevented from the base case for each scenario evaluated for the full period ranged from -56% for a 1 dose schedule using half the base case vaccine efficacy, to +90% under the assumption that rotavirus accounts for 3.8% of under-five mortality (or 52% of diarrhoeal mortality) as recently estimated by WHO [22]. DISCUSSION The Commission for Macroeconomics and Health considers any intervention with a ratio lower than Gross National Income (GNI) per capita to be 'highly cost-effective', a view endorsed by the WHO [35]. Based on reported 2006 GNI per capita of US$ 2,920 [36], a rotavirus vaccination programme would thus be considered highly costeffective in Peru. The most cost-effective scenario would be to administer only 1 dose of the vaccine, but this would avert approximately 10% fewer deaths than a 2 dose strategy, and requires further investigation as it is highly dependent on our optimistic and untested assumption about the efficacy of 1 dose of Rotarix. Our results are within the range of RV cost-effectiveness results estimated for eight Latin American and Caribbean countries [34]. At a cost of US$ 24 per course (for a two-dose vaccine), the authors estimated that the incremental cost per DALY averted would range from $269 in Honduras to $10,656 in Chile. Our results are also of a similar order of magnitude to those estimated by Constenla et al. (2007) for a pneumococcal vaccine in Latin America and the Caribbean; the authors estimated the

15 cost per DALY averted could range from $129 (assuming $5 per dose) to $5,106 (assuming $53 per dose) [37]. During the year 2006, approximately 5% (US$ 36 million) of the Ministry of Health s budget was spent on immunizations [38]. Our estimates of annual cost fluctuate over time due to changes in coverage, births, child mortality and price, but the average annual cost of the period is in the region of US$ 5 million per year (US$ 4 million if discounted). This would represent a 10-15% increase in immunization spending based on the 2006 budget. We estimate that these costs would be offset by approximately US$1.4 million (US$ 1.1 million discounted) in cost savings per year; 23% of these savings would be to the families who access Government services. We estimate that the number of rotavirus deaths averted by the RV programme would decline from 66% to 53% if safety recommendations are strictly adhered to. The safety recommendations are designed to avoid any increased risk of adverse events among infants vaccinated at older ages. Prior to its withdrawal, RotaShield (Wyeth- Ayerst) increased the risk of a rare bowel disorder, intussusception, when administered to older infants. However, no such association has yet been found with new rotavirus vaccines, so we did not include increased risks and costs of adverse events in our flexible vaccination scenario. It is difficult to know whether or not this is a valid assumption given that children in clinical safety trials receive the vaccine within the recommended age window. However, it has been argued that, even if the risk of such complications were material, the benefit of averting death from rotavirus may outweigh the risk in settings with high rotavirus mortality rates [39].

16 We used conservative estimates of rotavirus mortality (2% of U5MR rather than 3.8% as estimated by WHO). Also we used a static model with no allowance for indirect benefits due to reduced shedding in the community [40]. Health care utilisation rates were based on DHS surveys which are prone to underestimation since some children may not receive care for illnesses reported until after the survey. However, these rates for diarrhoea should provide at least a conservative proxy for care-seeking associated with rotavirus gastroenteritis. Our estimates of the inpatient cost per bed day (US$ for 2006) were in line with estimates from WHO-CHOICE (US$ in 2000) after adjusting for inflation. Estimates for outpatient visit costs ($2-5) were also comparable. One of the eight United Nations Millennium Development Goals (MDG 4) is to reduce by two-thirds the under-five mortality rate between 1990 and Between 1990 and 2006, the rate of under-five mortality in Peru declined from 78 to 25 per 1000 live births, representing a 68% reduction [41]. There remains however, a stark difference in under-five mortality rates between rural and urban areas, and the official status of the target is possible to achieve if some changes are made. We estimate that rotavirus vaccination could reduce under-5 mortality by at least 1% once fully established into the EPI programme. CONCLUSIONS Based on current WHO guidelines and conservative assumptions, rotavirus vaccination in Peru is highly cost-effective. However, a policy to withhold the vaccine from children who arrive after 12 weeks of age would reduce its impact on

17 rotavirus deaths from 66% to 53% If considered affordable and cost-effective, RV could provide a valuable stimulus for improving adherence to the EPI schedule and help to protect infants as early in life as possible.

18 Figure 1. Schematic of model framework

19 Table 1 Distribution and cost of outpatient visits and inpatient admissions Private Nonmedic al Private Drug store Private Clinic Private Hosp. Es Salud Clinic Es Salud Hosp. Govt. Clinic Govt. 1ary Hosp. Govt. 2ary Hosp. Govt. 3ary Hosp. Visits / admissions OPD: any severity U 1.6% 14.8% 9.1% 5.1% 4.5% 7.9% 23.2% 17.9% 15.8% 0.2% R 2.0% 2.8% 2.6% 0.4% 0.4% 1.4% 69.5% 16.5% 4.5% 0.0% IPD: severe U % % % 33.7% 0.4% R % - 6.0% % 19.7% 0.0% OPD $: non-severe Household $ - (*) (*) (*) (*) (*) (*) 2.78 a b 9.44 Provider $ Cost per visit Drugs/tests b 3.06 OPD $: severe Household $ - (*) (*) (*) (*) (*) (*) 2.78 a b 9.44 Provider $ Cost per visit Drugs/tests b IPD $: severe Household $ (*) - (*) c c c Provider $ Cost / bed day Length of stay Drugs/tests Costs are in 2006 US$, Exchange rate = 1$ = 3.66 Peruvian soles OPD = Outpatient department visit, IPD = Inpatient department admission U = urban child, R = rural child (*) Reflects settings beyond the scope of the cost survey a assume 50% of the household $ in a Govt. 1ary Hosp. where data are unavailable for Govt. Clinic b assume average of Govt. 1ary $ + Govt. 3ary $ where data are unavailable for Govt. 2ary Hosp. c use outpatient household $ multiplied by 2.5 based on ratio reported by Rheingans for Venezuela ($13.76/$5.65)

20 Table 2 Type and number of facilities in treatment cost surveys Type of providers Level Beds Lima Ayacucho San Martin Total (coast) (mountain) (jungle) Health post Govt: clinic Health centre / rural hospital Provincial / department hospital National specialist children s hospital Govt: primary hospital Govt: secondary hospital Govt: tertiary hospital <

21 Table 3 Summary costs and benefits of a flexible rotavirus vaccination programme Discounted aggregate future costs and effects attributed to all evaluated cohorts ( ) a Undiscounted costs and effects occurring annually (during the year 2015) No vaccine Vaccine (Difference) No vaccine Vaccine (Difference) Cases 4,566,556 2,056,539 (2,510,017 ) 372, ,856 (223,218) Rota diarrhoea (non-severe) 3,379,251 1,650,562 (1,728,689 ) 275, ,536 (153,799) Rota diarrhoea (severe) 1,187, ,977 (781,327) 96,739 27,321 (69,419) Deaths 3,467 1,240 (2,227) (212) DALYs 122,971 43,928 (79,043) % averted DALYs due to mortality % Outpatient visits 1,854, ,450 (1,019,222) 151,021 60,449 (90,573) Hospitalisations 174,298 58,046 (116,252) 14,129 3,863 (10,266) Vaccination costs $0 $67,756,170 ($67,756,170) $0 $6,641,931 ($6,641,931) Treatment costs b $30,675,649 $11,501,530 ($19,174,118) $2,492,824 $794,587 ($1,698,237) % of savings to Government c % % Net cost - - ($48,582,051) - - ($4,943,694) a costs and effects discounted at 3% b excludes treatment costs at Private providers and ESSALUD social insurance providers c excludes treatment cost savings to families who access Government providers (e.g. travel, food, loss of income etc.)

22 Figure 2 Annual undiscounted annual cost and treatment cost savings of a flexible rotavirus vaccination programme $8,000,000 Vaccination costs Cost savings to Government Cost savings to Government + families $7,000,000 $6,000,000 Costs in 2006 US$ $5,000,000 $4,000,000 $3,000,000 $2,000,000 $1,000,000 $

23 Table 4. Sensitivity of discounted US$ per DALY averted to +/-10% change in parameters Parameter Range % change in US$ per DALY Averted (flexible timing scenario) $US per DALY averted (all cohorts ) $615 Rotavirus disease burden parameters % of U5MR due to rotavirus gastroenteritis 2.0% +/- 10% 8.8% Incidence of rotavirus gastroenteritis per child per year /- 10% 4.3% % of rotavirus diarrhoea cases which progress to severe 26% +/- 10% 0.6% Average duration any rotavirus gastroenteritis (days) /- 10% 0.4% Disability weight for non-severe gastroenteritis /- 10% 0.1% Disability weight for severe gastroenteritis /- 10% 0.2% Outpatient visits per 1000 cases <5yrs Urban children, any rotavirus gastroenteritis 422 +/- 10% 0.9% Rural children, any rotavirus gastroenteritis 375 +/- 10% 0.6% Inpatient admissions per 1000 cases <5yrs Urban children, severe rotavirus gastroenteritis 214 +/- 10% 1.7% Rural children, severe rotavirus gastroenteritis 92 +/- 10% 0.8% Outpatient costs per case Provider $: non-severe, Gov clinic $4.14 +/- 10% 0.1% Provider $: non-severe, Gov 1ary hospital $4.95 +/- 10% 0.0% Provider $: non-severe, Gov 2ary hospital $3.83 +/- 10% 0.0% Provider $: non-severe, Gov 3ary hospital $6.34 +/- 10% 0.1% Provider $: severe, Gov clinic $9.42 +/- 10% 0.2% Provider $: severe, Gov 1ary hospital $8.01 +/- 10% 0.0% Provider $: severe, Gov 2ary hospital $ /- 10% 0.0% Provider $: severe, Gov 3ary hospital $ /- 10% 0.1% Household $: Gov clinic $2.78 +/- 10% 0.1% Household $: Gov 1ary hospital $5.56 +/- 10% 0.1% Household $: Gov 2ary hospital $7.50 +/- 10% 0.1% Household $: Gov 3ary hospital $9.44 +/- 10% 0.1% Inpatient costs per case Provider $: severe, Gov 1ary hospital $ /- 10% 0.8% Provider $: severe, Gov 2ary hospital $ /- 10% 1.2% Provider $: severe, Gov 3ary hospital $ /- 10% 0.1% Household $: Gov 1ary hospital $ /- 10% 0.1% Household $: Gov 2ary hospital $ /- 10% 0.0% Household $: Gov 3ary hospital $ /- 10% 0.1% Vaccine coverage RV dose 1 coverage % +/- 10% 0.5% % annual reduction in drop out rate from dose 1 to 2 5.0% +/- 10% 0.1% Vaccine costs Introductory price of Rotarix per dose $7.50 +/- 10% 12.7% % annual reduction in price component 5.0% +/- 10% 4.6% Administration cost per dose $0.50 +/- 10% 1.2% Rotavirus vaccine efficacy 2 doses versus severe 85% +/- 10% 11.8% 2 doses versus non-severe 65% +/- 10% 0.9% Relative efficacy of 1 dose compared to 2 88% +/- 10% 1.4%

24 Table 5 Deaths averted and cost of averting a DALY in the base case and under selected variants Undiscounted Discounted at 3% Restricted Flexible On-time Restricted Flexible On-time $ per DALY Deaths averted $ per DALY Deaths averted $ per DALY Deaths averted $ per DALY Deaths averted $ per DALY Deaths averted $ per DALY Deaths averted Base case scenario ( ) $244 2,349 $242 2,922 $228 3,047 $621 1,793 $615 2,227 $581 2, Base + only 1 dose of RV $90 2,087 $91 2,617 $86 2,702 $241 1,593 $243 1,996 $229 2, Base + Rota = 3.8% of U5MR $130 4,463 $128 5,552 $121 5,790 $333 3,406 $329 4,232 $311 4, Base + constant CFR $207 2,777 $205 3,455 $193 3,602 $534 2,094 $529 2,602 $500 2, Base + no phased introduction $256 2,752 $253 3,425 $239 3,572 $651 2,167 $643 2,694 $608 2, Base + no DALY age weights $266 2,349 $264 2,922 $249 3,047 $652 1,793 $647 2,227 $610 2, Base + only $276 1,449 $272 1,803 $258 1,881 $687 1,194 $679 1,484 $643 1, Base + only 1 dose + 50% of VE $289 1,043 $288 1,309 $276 1,351 $ $ $699 1, Base + only $ $ $ $ $ $ Base + no cost savings $352 2,349 $347 2,922 $333 3,047 $870 1,793 $857 2,227 $822 2, Base + constant price $405 2,349 $400 2,922 $380 3,047 $987 1,793 $976 2,227 $927 2, Base + 50% of Base VE $596 1,175 $589 1,461 $561 1,524 $1, $1,472 1,114 $1,403 1, Schedule consists of 1 dose of rotavirus vaccine rather than 2 2. Rotavirus accounts for 3.8% of under-5 mortality rather than 6% 3. Case fatality ratio remains constant rather than falling in line with projected under-5 mortality rates 4. Rotavirus vaccine is phased in over 5 years rather than introduced in all regions simultaneously 5. Age weights were removed from DALY calculations 6. Effects and costs aggregated over the period rather than dose rather than 2. Efficacy against severe disease = 37% rather than 75%; non-severe = 29% rather than 57% 8. Effects and costs aggregated over the period rather than Savings in treatment costs due to episodes of disease prevented by the vaccination programme excluded 10. The price of a dose of vaccine remains constant at $7.50 per dose over the period, rather than falling dose vaccine efficacy against severe disease = 37% rather than 75%; non-severe = 29% rather than 57%. 2 dose vaccine efficacy against severe disease = 43% rather than 85%; non-severe = 33% rather than 65%.

25 Acknowledgements We acknowledge the Immunization Strategy and Epidemiology and Statistics Office of the Ministry of Health, the staff of the regional health authorities of Ayacucho, San Martin and South Lima, and the staff of the Instituto Nacional de Salud del Niño (INSN). We also acknowledge the public health professionals and medical practitioners who gave their time to provide local estimates. We also acknowledge the personnel who collected illness data physician and nurse in each region; IIN personnel who interviewed mothers of patients and children in the immunization services. We acknowledge Maria Torres for providing support with data collection, and the mothers of the patients who participated in the interviews in health facilities. We also acknowledge the ProVac initiative within the Pan American Health Organisation (PAHO) for use of a combined Rota+Pneumococcal vaccine cost-effectiveness model.

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