Rotavirus-related diarrhea causes significant burden in countries where mass rotavirus vaccination has not been implemented.1–5 Around 200,000–500,0000 rotavirus-related deaths were estimated worldwide in 2008.6 Two effective and safe rotavirus vaccines have been approved by drug agencies around the world to diminish this burden.7,8 Despite this, competing choices of vaccine effectiveness and prices with either 2-dose monovalent (RV1) or 3-dose pentavalent (RV5) rotavirus vaccine make the selection of either vaccine difficult, especially in low and very low resource settings where vaccine price and its impact on overall health budget make important considerations.
A study by Rheingans et al4 estimated cost-effectiveness of a rotavirus vaccine in low-income and middle-income countries based on country-groups assumptions. Atherly et al,3 Kim et al2 and Atherly et al1 estimated cost-effectiveness in Global Vaccine Alliance-eligible countries, leaving without adequate evidence to introduce vaccination in health decision makers of some lower middle and upper middle income countries. Although those previous analyses have shown that rotavirus vaccination is cost-effective in some low-income and middle-income countries,1–5 no study has attempted to highlight possible differences in cost-effectiveness for these 2 vaccines. Also, new rotavirus vaccines are in development, showing promising preliminary results.9 Besides the need to assess different rotavirus vaccine choices, several studies have improved what is known about diarrheal diseases and rotavirus vaccine efficacy and effectiveness in different settings around the world.6,10–17
Despite the effectiveness, safety, cost-effectiveness and World Health Organization (WHO) recommendations to introduce RV1 or RV5,18,19 most countries have not yet introduced the vaccine, most of these in Africa and Asia. As of August 5, 2014, 68 countries have introduced RV1/RV5 in their Expanded Programs on Immunizations (EPI) schedules.20
The competing choices of vaccination with either RV1 or RV5 and the potential budget impact of vaccines on the EPI with different prices and new evidence make important an updated analysis for health decision makers in each country. The objective of this study was, therefore, to estimate the potential epidemiological and economic impact of different rotavirus vaccines on low-income and middle- income countries and assess potential differences in outcomes (ie, cases, deaths, economical costs and cost- effectiveness) resulted from RV1 and RV5 mass children vaccination.
A decision model was built to estimate the potential epidemiological and economic impact on children burden of disease of RV1 and RV5 in low-income and middle-income countries. This model follows hypothetical 2010 cohorts of children from birth up to 5 years of age for each country (see Fig. 1). Inputs of the burden of disease estimates included live births, diarrhea incidence, probability of diarrhea by setting and probability of rotavirus diarrhea by age (Table 1). To estimate the burden with RV1 and RV5 vaccination, vaccine effectiveness was used to assess potential reduction of cases and deaths. Demographic estimates were drawn from international estimations.21 Incidence of diarrhea in each country was taken from a recent systematic review that estimated all-cause diarrheal incidence for 2010.10 Rotavirus inpatient and outpatient cases were estimated based on estimates of diarrhea incidence and the probability of going from one state to another, depending on estimates of rotavirus cases by setting (probability of all-cause diarrhea by setting and probability of rotavirus diarrhea by age). Mortality because of rotavirus disease was gathered from estimations of Walker et al24 for 2010. To properly estimate vaccination impact on deaths, rates of neonatal mortality (gathered from the World Bank)21 and life tables from WHO22 were used to calculated the probability to die between 6 and 59 months of age.29
A total of 116 countries were selected for analysis (see Appendix, Supplemental Digital Content 1, http://links.lww.com/INF/C130). According to WHO analyses, these countries represent 99.7% of rotavirus-related mortality in the world.22 Results of the 116 countries were stratified by WHO mortality stratum classification and income (based on the World Bank Classification), for a detail overview of this classification, see Appendix, Supplemental Digital Content 1, http://links.lww.com/INF/C130.
This economic decision model was carried out from the perspective of the health care provider, as such, no productivity losses were included in the analysis. The main outcome measure was incremental cost per disability-adjusted life-years (DALYs) averted. Costs were estimated in international U.S. dollars (I$) for 2010. Future cost and benefits were discounted at 3% annual rate. Different scenarios for the 2 available vaccines were constructed to assess the potential differences in cost and outcomes between the 2 interventions.
Burden of Disease
Rotavirus-Related Hospitalizations and Clinic Visits
Diarrheal disease incidence was taken from estimates by Fischer Walker et al.10. This article contains country-specific estimates of diarrhea incidence in 2010.10 Fischer Walker et al10 assumed that the shape of the distribution across age-groups would be the same across countries and estimated incidence in countries without studies based on this assumption. In addition, these estimates were based mostly on studies with data before 2000, the pre-vaccination period.10
Probabilities of children requiring inpatient admission (hospitalization) or outpatient care (clinic visit) are based on previous assumptions for all countries.5 A percentage of 1.5% in <1 year and 0.2% from 1 to 4 years of age were assumed for rate of inpatient admission in all selected countries. Outpatient admissions were assumed as 10.3% in <1 year and 7.9% between 1 and 4 years of age of all-cause diarrhea cases.
Rotavirus-related diarrhea cases by setting were assumed as 39% of all inpatient admissions and 18.8% of outpatient care, according to estimations and assumptions from previous studies.5 Mortality because of rotavirus disease was gathered from estimations of Walker et al,24 for country groups stratified by WHO geographical classification of countries for 2010.28
Costs of Rotavirus Burden of Disease
Currently, no estimation of economic costs of diarrhea has been made in all selected countries. To standardize health care costs in all countries, estimates from WHO CHOosing Interventions that are Cost-Effective (WHO-CHOICE) for each country for 2008 in U.S. dollars were converted to international dollars. Inflation for each country was collected from World Bank databases and was used to estimate costs in 2010 international dollars (I$ 2010). To reflect the severity of rotavirus disease,30 estimates from WHO-CHOICE for inpatient and outpatient care were country-specific tertiary hospital estimations. The mean inpatient stay was assumed as 4 days in all countries.31 No productivity loss or transportation costs were estimated or used in the decision model.
Epidemiological and Economic Impact of Monovalent and Pentavalent Vaccines
The effectiveness of RV1 and RV5 vaccines for preventing deaths was assumed based on a Cochrane systematic review of clinical trials for each vaccine. To estimate the RV1 and RV5 vaccines impact on deaths and inpatient cases of rotavirus-related diarrhea, estimated vaccine effectiveness was deemed as the impact on severe rotavirus diarrhea for each vaccine.28 Vaccine effectiveness was deemed greater in low-mortality countries (WHO mortality stratum B and C) versus high mortality countries (stratum D and E), Table 1 shows relative risks of each stratum.
Base-case vaccination costs were taken from Pan American Health Organization (PAHO)/WHO Revolving Fund. The PAHO Revolving Fund set prices for all Latin American and Caribbean countries.32 This pricing scheme was chosen because through special arrangements, PAHO Revolving Fund has access to vaccines at privileged lowest commercial prices. RV1 assumed price was US$6.88 per dose (US$13.76 per schedule). For RV5 vaccine, price was US$5.25 per dose (US$15.75 per schedule).32 Vaccine coverage target was assumed as the coverage of the third dose diphtheria–pertussis–tetanus vaccine in each country.21 Scenario analyses were made with different vaccine prices. Administration costs were assumed as reported by Rheingans et al.4
Cost-effectiveness was estimated through incremental cost-effectiveness ratios. The main, but not only, outcome in this study was incremental costs per DALYs averted, which was calculated without age-weighting (K = 0) according to Global Burden of Disease study recommendations.33,34 Life expectancy data to calculate DALYs were collected from World Bank databases.21 Willingness-to-pay was assumed as 3 times the per capita gross domestic product, in international dollars, according to WHO recommendations.35
Other outcomes included incremental costs per deaths averted, per inpatient case averted and rotavirus-related diarrhea case averted. Incremental cost-effectiveness ratios were calculated for each intervention (either with RV1 or RV5) and compared with the status quo assuming no vaccination in 2010.
All results were grouped and reported by country-group according to WHO mortality regions and World Bank income groups.22 The Appendix, Supplemental Digital Content 1, http://links.lww.com/INF/C130, describes and reports country- specific results.
To assess uncertainty of key drivers of rotavirus burden of disease and rotavirus vaccine cost-effectiveness, one-way sensitivity analyses were carried out. In addition, following current recommendations, a probabilistic sensitivity analysis was made for each of the 3 scenarios, varying inputs by selected country.
Several scenarios were constructed with differing vaccine prices per scheme (a scheme includes 2 vaccine doses for RV1 and 3 doses for RV5). Vaccine schemes of US$5 and US$15 were built to assess cost-effectiveness. A $5/course vaccine price is the current price of the monovalent vaccine provided to Global Vaccine Alliance.
An estimated 292,561 rotavirus deaths in 2010 would have occurred under the no-vaccination scenario in the 116 selected countries. Under this scenario, 49.55 DALYs per 1000 children younger than 5 years of age are expected, and a total of 3.34 million inpatient and 23.09 million outpatient cases would present in 2010. Direct medical treatment costs would account for I$987.83 million in 2010. A summary of burden of disease results with no rotavirus vaccination by country-group is shown in Table 2.
Estimates of RV1/RV5 Impact on Burden of Disease
Vaccination with RV1 would have prevented approximately 132,000 deaths in 2010, or 45.4% of all annual deaths because of rotavirus (Table 2). All these reductions would account for a decline in medical direct costs of 57.8% for all selected countries. Vaccination costs with RV1 would be approximately I$1.91 billion in 2010. A detail overview of averted costs of monovalent vaccine is available in Table 2.
Averted deaths with RV5 would be approximately 120,000 in 2010, representing a 41.4% of all rotavirus deaths in children younger than 5 years of age. For inpatient cases, averted hospitalizations would be around 1.7 million cases in 2010, or 51.4% of annual cases. Medical disease costs with RV5 would reduce by 55.2% annually, and it would represent I$545.4 million in 2010.
The lowest cost per DALY averted would be in low income economies with greater children mortality. The highest cost per DALY averted, and hence, the lesser cost-effectiveness was seen in upper middle income economies.
RV1 cost-effectiveness in all countries was I$372 cost per DALY averted, and RV5 was I$453 cost per DALY averted. Breakeven price of RV1 for the 2010 cohort was $2.02 per dose, and RV5 was $1.40 per dose.
RV1 and RV5 vaccination was cost-effective according to WHO criteria (less than per capita gross domestic product) for 96.5% of all selected countries. RV1 and RV5 were not cost-effective for Albania, Maldives, Mauritius and Moldova. Cost-effectiveness results per mortality stratum are shown in Table 3, and by country in the Appendix, Supplemental Digital Content 1, http://links.lww.com/INF/C130.
Univariate uncertainty analysis is shown in Figure 2 and Table 4. In low-income economies, univariate analysis shows that cost- effectiveness varies little, and in upper middle income countries, cost-effectiveness varies more for each univariate change in inputs. This means a greater uncertainty in model results as economies are richer. In addition, small variations in parameters produce a greater change in cost-effectiveness in these richer countries.
Probabilistic cost-effectiveness plane is shown in Figure 3.
Price Scenario Analysis
At $5/course, RV1 and RV5 were cost-effectiveness in all 116 countries. At $15/course, RV1 and RV5 were not cost-effective only for the countries of Albania, Maldives, Mauritius and Moldova.
Several studies have assessed the cost-effectiveness of rotavirus vaccination in world countries.1–5 This is the first study that assesses competing choices of rotavirus vaccines and is a significant update to previous reports because new evidence on diarrheal burden of disease has recently emerged. The most important finding of our study shows that rotavirus vaccination is justified in most world countries. Depending on the vaccine, almost half of all rotavirus deaths would be prevented.
This study, besides confirming previous findings,1–5 highlights how different choices of vaccines may affect hospitalizations, clinic visits, deaths and cost-effectiveness. The increased costs and scheduling of RV5 diminish its cost-effectiveness. A recent Cochrane review found that RV1 was more efficacious to prevent severe rotavirus diarrhea than RV5, and RV5 is more efficacious to prevent hospitalizations.28 These 2 conflicting findings, mainly, RV1 is more efficacious to prevent severe disease and RV5 is more efficacious to prevent hospitalizations (hospitalization are severe cases of the disease), are difficult to explain but may be explicated by the fact that some studies assessing efficacy of RV5 measured severe diarrhea with the Clark scale and others with the Vesikari scale.36 Besides that, it is unclear for some studies in the RV1 assessment which scale they used to assess severe diarrhea.28 Despite this lack of clarity in effectiveness, cost-effectiveness was similar for both vaccines, with a slight advantage of RV1. In fact, a recent study showed that strain diversity has no important role in vaccine effectiveness, strengthening the argument that both RV1 and RV5 have similar effectiveness profiles.37 This leads decision makers in each country with difficult choices, and the deciding factor might be vaccine price.
Despite both vaccine prices have steadily decline since introduction, further drops in prices are unknown. Vaccine breakeven prices should encourage decision makers to assess introduction rotavirus vaccination in the EPI schedule of most world countries.
The introduction of new vaccines into existing EPI schedules is complex. Many factors come into consideration, including vaccination impact on current burden of disease, vaccine prices and logistics of implementations.12,38,39 Cost-effectiveness studies are cited as “essential” by health decision makers for introducing new vaccines;38 however, many of the existing national immunizations advisory committees do not have the expertise on their board to fully interpret them.38 The sustainability of new vaccines implementation in many low-income and middle-income countries is also severely limited by funding availability. In Nicaragua, for example, a 5-year public–private partnership reduced the pneumococcal 13-valent vaccine price per dose by 97%.40 Nicaragua decided for introduction for this vaccine (instead of the 7-valent or 10-valent pneumococcal vaccine) despite the uncertainty after those 5-years.
The rotavirus vaccines have shown decrease effectiveness a year post-introduction in developing countries.41–44 This study did not include this possible decrease (or “waning” effectiveness) because more evidence in developing countries is needed to cement this finding. Despite this, decision makers of each country would need to evaluate periodically studies on RV1 and RV5 vaccine to assess the need for a booster dose at 1 year, as it has been suggested by Patel et al.6 This booster dose would significantly increase vaccination costs. A significant drop in vaccine price per dose would have to occur to offset prices of a new dose and vaccination in target children.
Another important conclusion can be drawn from our study, sensitivity analysis shows that uncertainty in the cost-effectiveness construct varies depending on the income of the country, which means the greater the income of the setting the greater the uncertainty is likely to change cost-effectiveness results (see Fig. 1). This is an important result that highlights inequality in world countries and should encourage decision makers, funding agencies and potential donors to focus on low-income economies in which the value for the money would be better justified, despite data/evidence limitations. Also, these more “robust” cost-effectiveness results in low-income settings may help to counterbalance the uncertainty of the vaccine effectiveness and different assumptions found in our study and previous assessments.45
This study has several limitations. The most important limitation is related to uncertainty around the model and some important parameters. This model was chosen because availability of case fatality rate data on rotavirus diarrhea is extremely limited in poor resource settings around the world, and available data may underestimate this burden if not population based. This is because, in poor-settings, all deaths may not occur at a health institution and a count of setting-based deaths would not properly include all mortality. This rational would put this type of decision model design above other designs when there is scarcity of good-quality data of case fatality rate, especially for international economic analyses.
The frequency of inpatient admissions, clinic visits and rotavirus frequency in each setting of every country is unknown. This limitation may impair conclusions of the cost-effectiveness of the intervention. Despite this, estimations on diarrhea incidence and rotavirus mortality are in good quality and reflect current knowledge of rotavirus diarrheal disease in the world.10,22 The lesser uncertainty in lower income economies strongly suggests the lack of precision in certain parameters, which may not be as important. Also, although the use of WHO-CHOICE may not reflect the precise costs of direct medical attention because of rotavirus disease, a study in Mexico by Constenla et al46 compared WHO-CHOICE costs with the study of hospital-based estimations, finding marginal differences in rotavirus disease direct costs (US$28.1 for WHO-CHOICE versus US$27.2 for hospital-based surveillance). Despite this, WHO-CHOICE may overestimate cost of disease, because it includes costs for all pathologies in children and adults. This would also overestimate cost-effectiveness because averted costs would be greater. Another limitation that would overestimate impact is the no inclusion of timing of vaccination and the potential reduction of vaccine effectiveness this could had.47 This study also only included a rough estimate of marginal administration costs in the EPI schedule for rotavirus vaccines, a frequent assumption in the health economics literature.48
Another assumption is related to the expected vaccine coverage of rotavirus vaccination. Our study assumed diphtheria–pertussis–tetanus vaccine coverage, which would underestimate expected vaccine coverage because acceptance and delivery of an oral vaccine (which is the case for rotavirus), would be greater to an injected vaccine. Another limitation is related to the lack of inclusion of indirect effects of vaccines in the dynamics of rotavirus infection. This limitation would underestimate cost-effectiveness in this study.
Rotavirus vaccine introduction with RV1 or RV5 is cost-effective in all selected countries at current lowest commercial prices (used by PAHO revolving fund). Both vaccines show a significant reduction of burden of disease, especially in countries with low or lower middle income and high children mortality.
Several important data gaps remain in the literature regarding RV1 and RV5 vaccine effectiveness, mainly, the lower effectiveness in low-income/high-mortality settings, the waning effect on older children and overall comparisons of vaccine effectiveness between the 2 vaccines.
Finally, despite similar vaccine prices, for the decision to introduce either vaccine into the EPI schedule, decision makers of each country must take into consideration expected effectiveness, vaccination uptake and vaccine impact on the EPI budget before introduction.
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