Artigos

Introduction
Malaria is a preventable and treatable disease, and over the last two decades, it is estimated that 2.1 billion malaria cases and 11.7 million deaths have been averted in the Americas region1. However, approximately 2.5 billion people remain at risk for Plasmodium vivax malaria (P. vivax)2, which accounted for nearly 72% of cases in 20221. In Brazil, around 4 million people are at risk, with approximately 99% of malaria cases concentrated in the Brazilian Amazon, formed by the states of Acre, Amapá, Amazonas, Pará, Rondônia, Roraima, Tocantins, and part of the states of Maranhão, and Mato Grosso3.
Recently, clinical studies have shown favorable efficacy and safety of a single-dose therapeutic regimen based on tafenoquine compared to traditional primaquine-based regimens4,5. Tafenoquine is a single-dose 8-aminoquinoline that has been approved for the radical cure of P. vivax infection in Brazil3. A single-dose of either 300 mg or 600 mg prevented relapses in 89.2% and 91.9% of cases, respectively, during a 6-month follow-up period6. Despite the major advantage of being administered as a single-dose compared with a primaquine regimen lasting 7 or 14 days, both tafenoquine and primaquine can cause drug-induced hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd), an X-linked human inherited blood disorder7,8. Proactive follow-up by healthcare professionals is particularly necessary for tafenoquine, given its average terminal half-life of approximately 15 days and its slow metabolism, which delays elimination in the event of a hemolytic reaction9. Primaquine-induced hemolysis already leads to approximately 6,000 hospitalizations per year among individuals with G6PDd in Brazil10.
Several point-of-care tests for measuring G6PD deficiency (G6PDd) are available, which do not require laboratory infrastructure or specialized personnel, making them advantageous in low-resource settings11,12. Quantitative tests are currently being marketed using biosensors and handheld electronic devices with reagent strips or cartridges that measure both G6PDd and hemoglobin levels simultaneously, through a handheld battery-operated analyzer. After a few minutes, the analyzer provides a numeric measurement of G6PD activity. The STANDARDTM G6PD test (SD Biosensor, South Korea) ('G6PD test') was used to calculate the incremental budget impact of G6PD test from Unified Health System (SUS) perspective (https://www.path.org/programs/diagnostics/gorcop/).
Health technology assessment processes typically rely on two complementary economic analyses. Cost-effectiveness analysis establishes the allocative efficiency of an intervention by comparing health outcomes and costs relative to available alternatives answering whether the technology is worth adopting13. Once cost-effectiveness is demonstrated, the subsequent question for decision-makers concerns the financial feasibility of large-scale implementation, which is addressed by budget impact analysis14,15. Economic evaluations conducted from the SUS perspective have demonstrated the cost-effectiveness of both technologies in the Brazilian Amazon16,17,18. Recently, the Brazilian National Health System (SUS) approved the adoption of a single-dose of tafenoquine for the treatment of relapsing P. vivax malaria following G6PD test19. Budget impact analysis is required in the health technology assessment process within SUS, as outlined by The Ministry of Health's National Committee for Health Technology Incorporation19.
The aim of this study was to estimate the incremental budget impact of introducing the G6PD test to detect G6PDd alongside a novel malaria treatment regimen that includes a single-dose of tafenoquine, compared to the routine recommended by the Brazilian national antimalarial guidelines3.
Methods
Population
The study population comprised confirmed cases of P. vivax malaria in individuals aged 16 years and older of both sexes across the nine states of the Brazilian Amazon, using projections from data reported in the Malaria Epidemiological Surveillance Information System (SIVEP-Malária) from 2009 to 2020. The age threshold of 16 years reflects the minimum eligibility criterion for tafenoquine use, as established by the drug label and Brazil's national antimalarial treatment guidelines3,9.
Budget impact model
The budget impact model was performed from SUS's perspective, following both national and international methodological guidelines for health economic evaluation14,20. A decision-analysis tree was developed using data on clinical effectiveness, safety, and costs for the diagnosis and treatment of P. vivax malaria over a 5-year time horizon (2024–2028). The model was developed considering two scenarios of health care assistance for P. vivax malaria: a) a reference scenario based on currently national antimalarial guidelines, and b) an alternative scenario that included a novel tafenoquine regimen and the G6PDd diagnosis based on the results of the G6PD test. The G6PD test consists of a G6PD analyzer instrument and a G6PD test kit, which contains the G6PD test devices (strips), individual extraction buffer tubes, SD Ezi tube+ sample collectors, and a single lot-specific code chip (https://www.sdbiosensor.com).
The cut-off values for thresholds for G6PDd adopted in the budget impact model, including both the prevalence of deficiency and the diagnostic test accuracy, followed the recommendations of the test manufacturer. G6PDd was defined for both men and women with 30% or less enzyme activity. Women with intermediate G6PD activity had thresholds greater than 30% and equal to or less than 70%. These were summarized into three levels: up to 70% (normal), 30% to 70% (intermediate), and less than 30% (deficient). In both deficiency and intermediate activity cases, the use of tafenoquine is not recommended4,5,9. Based on the availability and results of G6PD activity (normal, intermediate, or deficient), the therapeutic regimen was defined as either tafenoquine or primaquine, depending on the scenario under analysis. Additionally, the probability of mean recurrence in a year and the risk of hemolysis (in false-negative cases) were considered throughout the time horizon.
Estimate of diagnosed cases of P. vivax malaria
Quarterly notified cases data were used for each of the nine states of the Brazilian Amazon to predict the population or the number of confirmed P. vivax malaria cases over a 5-year period. Initially, for each state, the databases were divided into two sets: training and validation data. The training data, which covered from the 1st quarter of 2009 to the 4th quarter of 2018, were used to develop the prediction model. The validation data spanned the period from the 1st quarter of 2019 to the end of 2020.
Four alternative models were considered for performance comparison: the exponential smoothing state space (ETS) model, the double-seasonal Holt-Winters (DSHW) model, the autoregressive integrated moving average (ARIMA) model, and the TBATS model (exponential smoothing state space model with Box-Cox transformation, ARMA errors, trend, and seasonal components). The quality of fit and validity of the proposed models were assessed based on the mean absolute percentage error (MAPE) using the validation data (from the 1st quarter of 2019 to the 4th quarter of 2020) and through the analysis of the autocorrelation function (ACF) and partial autocorrelation function (PACF) of the model residuals. Predictions of confirmed P. vivax malaria cases per quarter in the study population were made based on the best-performing model, with annual predictions derived from the sum of the quarterly predictions. The method for estimating the number of G6PD quantitative test kits needed over the time horizon was the same as that used for determining the number of confirmed diagnosed cases of P. vivax malaria.
Diffusion rate and the estimation of the number of analyzers
The model assumed that all analyzers would be acquired and distributed in the first year of incorporation into SUS. Three scenarios were developed to estimate the number of analyzers based on reported cases for each state of the Brazilian Amazon in 2019. Firstly, we considered the reported cases of P. vivax malaria in individuals aged 16 and older, as informed by public health units. Next, we obtained the number of laboratories with at least one case of P. vivax malaria reported per year, identifying a total of 2,164 laboratories with notifications. In the third scenario, an additional analyzer was considered for every five additional cases in the average weekly cases per unit. A total of 1,595 public health units reported 89,482 P. vivax malaria cases in 2019.
Cost of the G6PD test
Costs were based on the market value provided by the manufacturer and included the following items: analyzer, test kit, quality control reagents, local taxes, training, lab materials, batteries, and costs to handle the local logistics. Additionally, based on studies conducted in the Brazilian Amazon [personal communication, the Tafenoquine Roll-out Study (TRuST - https://www.vivaxmalaria.org/projects-0/partnership-for-vivax-elimination-pavefeasibility-
studies-and-operational-research/the)], the analyzer cost was not annualized because the equipment operated for two years with no significant failures. Training costs were derived from the cost-effectiveness study by Brito-Sousa et al16. An incremental margin of 10% to 25% was added for the test kit. This margin accounts for potential losses during test execution and includes a quantity of analyzers for replacement in case of breakage or malfunction. All cost components were converted into a per-test/per-patient unit cost as described in Table 1.
Cost of P. vivax malaria treatment
The treatment of P. vivax malaria was modeled in the reference scenario based on the Brazilian antimalarial treatment guidelines and comprised a combination of chloroquine administered over 3 days and primaquine administered over 7 or 14 days. In cases of G6PDd, the patient would receive only a low-dose of primaquine3. The alternative scenario included chloroquine plus a single-dose of tafenoquine after performing the G6PD test. Individuals with confirmed G6PDd would receive only low-dose primaquine, while those with intermediate G6PD activity receive normal-dose primaquine treatment3. The costs of the medicines were obtained through the Brazilian Malaria Control Programme.
Cost of hospitalization due to P. vivax malaria
The mean hospitalization costs of P. vivax malaria and for one episode of hemolysis due to antimalarial treatment, as well as the number of treated cases of malaria P. vivax, were estimated through the SUS Hospital Information System records in 2022 (www.datasus.gov.br). The probability of hospitalization was calculated based on a study carried out in the Brazilian Amazon21 which reported that 94 out of 672 hospitalizations were due to hemolysis, while the remaining 578 were hospitalizations without hemolysis. The probability of hospitalization due to hemolysis (9.84%) was applied only to individuals with G6PDd. Given that an individual had a diagnosis of P. vivax malaria and G6PDd, the final probability of hospitalization due to hemolysis was estimated using the following equation:
pa = a / (b × fd)
pa = 94 / (28,095 × 0.034)
pa ? 9.84%
Where: pa is the probability of hospitalization due to hemolysis; a is the number of patients hospitalized due to hemolysis21; b is the number of treated cases of P. vivax (from SUS Hospital Information System); fd is a fraction of individuals with G6PDd22.
The probability of hospitalization of patients without hemolysis was estimated from those with P. vivax malaria diagnosis and no G6PDd:
pb = c / (b × (1 ? fd))
pb = 578 / (28,095 × (1 ? 0.034))
pb ? 578 / (28,095 × 0.966)
pb ? 2.13%
Where: pb is the probability of hospitalization of patients without hemolysis. c: number of P. vivax malaria patients hospitalized without hemolysis diagnosis. b: number of P. vivax malaria patients treated. fd: fraction of individuals with G6PDd.
Cost of primaquine and chloroquine recurrence
The average annual primaquine recurrence rate of P. vivax malaria was estimated at 1.134, with a range from 0.9206 to 1.38306. The model adopted a conservative assumption of equivalence between primaquine and tafenoquine recurrence rates, based on the absence of robust evidence supporting superiority of either regimen. This is consistent with currently available real-world data23. For patients diagnosed with P. vivax malaria who experienced treatment failure with chloroquine or primaquine between day 5 and day 60 after the start of treatment, the recommended therapeutic regimen included artesunate and mefloquine, both used in combination with selected active antimalarial drugs. The cost of antimalarial medicines was sourced from the Brazilian Control Malaria Programme, while costs related to healthcare assistance for primaquine and tafenoquine recurrences were obtained from the SUS Procedures, Medicines, and OPM Management System (SIGTAP: http://sigtap.datasus.gov.br/).
Incremental budget impact
The incremental budget impact of tafenoquine and the G6PD test was calculated by comparing the cost difference between the alternative scenario (tafenoquine and G6PD activity diagnosis) and the reference scenario. The incremental budget was categorized into the main cost components, which included tafenoquine and primaquine regimens, recurrence costs, hospitalizations, and the components of the G6PD test.
All costs were adjusted to 2023 Brazilian reais (R$) and then converted to 2023 US dollars using the annual average rate (US$1 = R$5; www.ipeadata.gov.br). The budget impact model was developed using a Microsoft Excel® spreadsheet. Data storage, processing, and analysis were performed using R 4.0.3. All parameters are presented in Table 1.
Uncertainty
Both deterministic univariate and bivariate sensitivity analyses were performed to identify the parameters that could have the most significant impact on the results of the budget impact model over a 5-year time horizon. The results of the univariate sensitivity analysis are presented as a tornado diagram (Figure 1), which displays the main parameters with the greatest influence on the incremental budget impact. All model parameters were included in the analysis and parameters not displayed in the figure were included but did not exert material influence on the results.
Validation
Face validity, recommended as a good practice in budget impact analysis14, was conducted through two consensus meetings in 2022 with experts from the Ministry of Health who have experience in national malaria health policy and health economic evaluation from SUS perspective. An interview guide was developed to gather information regarding the feasibility of incorporating tafenoquine and the G6PD test in the Brazilian Amazon addressing practical aspects, resource availability, and model parameters. Additionally, internal validity was performed by the researchers through a thorough review of all formulas, calculations, and parameters used in the model structure.
Results
In the reference scenario, 546,360 patients without G6PDd would receive normal-dose primaquine while 1,834 patients with G6PDd would receive low-dose primaquine. In the alternative scenario, approximately 102,000 patients per year would be eligible to receive tafenoquine, totaling 507,733 patients over the study period. A total of 10,443 patients with intermediate G6PD activity and 30,038 patients with G6PDd would receive low-dose primaquine. Based on population estimates, 548,194 G6PD tests were predicted to be performed, with an annual average of 109,639 tests, ranging from 106,570 to 114,206 tests (Table 2).
A total of 1,704 analyzers would need to be acquired, with additional equipment distributed to accommodate an average weekly increase of five cases per healthcare unit. The minimum and maximum scenarios considered acquiring 1,595 and 2,164 analyzers, respectively, based on the notified P. vivax malaria cases in the healthcare units or laboratories responsible for diagnosing malaria within the SUS healthcare network (Table 1).
In the reference scenario, the breakdown of costs showed that hospitalizations were the main cost driver (USD 870,296), followed by the primaquine regimen (USD 450,075) and treatment of P. vivax malaria recurrences (USD 436,139). In the alternative scenario, the cost of the G6PD test accounted for the largest portion of expenses, totaling USD 5.82 million, followed by the tafenoquine regimen (USD 1.004 million). The model predicted that the adoption of both technologies would reduce hospitalization costs by approximately 22% compared to the reference scenario — an absolute reduction of approximately R$778,000 over the 5-year period. A similar reduction in total costs was observed for the treatment of recurrences, estimated at 3% (Table 3).
The tafenoquine regimen and the G6PD quantitative test could generate an average annual incremental budget impact of approximately USD 1.25 million, reaching a total increment of USD 6.26 million at the end of 5 years (Table 4). The tornado diagram (Figure 1) presents the results of the univariate deterministic sensitivity analysis. The parameter with the greatest effect on the incremental budget impact was the price of the reagent strip. Additionally, losses during diagnosis and the purchase costs of the analyzer also significantly influenced the results. The probability of hospitalization due to hemolysis was included in the analysis but did not emerge among the main parameters with the greatest impact on the model output.
Face validity with the experts addressed various aspects, including the model parameters and assumptions, with a broader discussion on the recurrence rates of P. vivax malaria and the definition of the estimated number of analyzers to be distributed by state in the Brazilian Amazon. These issues were resolved by consensus, allowing the model to be thoroughly validated during the face validity process. Additionally, expert suggestions were incorporated into the revised model.
Discussion
The main finding of this budget impact analysis was an incremental cost of USD 6.26 million over five years (2024–2028) for the SUS to incorporate tafenoquine and G6PD testing for P. vivax malaria management across the Brazilian Amazon, assuming 100% coverage of all nine states. The largest cost component in the alternative scenario was the G6PD reagent strip, which accounted for 73% of the total budget impact and was identified in the sensitivity analysis as the primary driver of model uncertainty, a critical finding for procurement planning. Both technologies are predicted to generate a 22% reduction in hospitalization costs and a 3% reduction in recurrence treatment costs over the time horizon. The incremental budget impact can be considered an affordable cost given the urgency and challenges faced by P. vivax malaria-endemic regions in Brazil in recent years24,25.
This study complements the existing body of economic evidence on these technologies from the SUS perspective. Brito-Sousa et al.16 demonstrated the cost-effectiveness of real-life quantitative G6PD screening for P. vivax patients in the Brazilian Amazon. Price et al.17 modelled the cost-effectiveness of tafenoquine following G6PD screening against primaquine using a transmission model. Additionally, a multi-country pooled analysis, including Brazil, demonstrated that the G6PD quantitative test performed well and reduced the risk of induced hemolysis18. Together, these analyses constitute a comprehensive economic evidence package to support the SUS and guide resource allocation in the Brazilian Amazon.
The budget impact model estimated the potential costs and savings associated with the introduction of the tafenoquine regimen and G6PD test, providing valuable insights for SUS decision-makers regarding budget planning. Brazil is one of the P. vivax-endemic countries in the Americas with national antimalarial guidelines that explicitly recommend G6PD testing3. Recently, both technologies were approved by the Ministry of Health for adoption within SUS, following the World Health Organization's recommendation to test for G6PD deficiency prior to administering radical cure treatments for P. vivax malaria1. As highlighted by Nekkab et al.26, in endemic regions, the use of tafenoquine could increase the radical cure rate from 42% to 62%, potentially reducing P. vivax transmission by 38%, which could prevent over 214,000 cases. Despite these promising results, further clinical studies on efficacy and safety are needed, especially considering evidence suggesting that the currently recommended dose of tafenoquine may be insufficient for curing adults27.
Hospitalization costs represent a significant expenditure for SUS in treating malaria. Our results indicated a reduction in hospitalization costs of approximately 22%, reflecting a cost-saving outcome within the alternative scenario. Although the reference hospitalization cost did not emerge among the main drivers of uncertainty in the tornado diagram, the clinical importance of preventing hemolytic episodes, particularly in G6PDd patients, who face a 9.84% probability of hospitalization, should not be underestimated.
The National Malaria Elimination Plan launched by the Brazilian Government aims to reduce the number of local malaria cases to fewer than 68,000 by 2025 and achieve zero deaths by 2030, with the ultimate goal of eliminating the disease in Brazil by 203528. Although data from the Global Burden of Disease (GBD) indicate a declining trend in malaria burden from 1990 to 2017, the loss of years due to disability remains high, particularly in Acre, Roraima, and Rondônia28. Therefore, ensuring access to diagnostic and treatment technologies that require minimal infrastructure could be an important strategy for reducing the morbidity and mortality of P. vivax malaria in Brazil.
Our results demonstrated that, over a 5-year period, the states of Amazonas (173,259 tests) and Rondônia (102,208 tests) would require the highest number of tests annually, followed by Pará (89,611 tests) and Roraima (88,574 tests), accounting for approximately 83% of the total quantity. However, the adoption of both technologies should also consider other factors within municipalities in the Brazilian Amazon, such as feasibility of adoption, costs associated with training, laboratory and clinical infrastructure needs, and dependency on foreign suppliers for reagents and test kits. Furthermore, incorporating these technologies into SUS depends on several variables related to access to health care for P. vivax malaria. As SUS is a universal health system oriented towards Primary Health Care, efficiently managing the logistics of medicines and equipment, as well as ensuring adherence to new technologies by patients and health professionals, should be a priority in the municipalities of the Brazilian Amazon29.
A recent modeling study predicted that tafenoquine has the potential to enhance effective radical cure through improved adherence26. Additionally, the portability of the quantitative G6PD test and its rapid execution by healthcare professionals facilitate the logistics of offering both the test and the tafenoquine regimen in resource-limited settings. The G6PD test has shown good performance across various temperature and humidity conditions30. These features could lead to more timely diagnoses of G6PD deficiency and enable the selection of the most appropriate treatment option. However, the infrastructure of the settings where the G6PD test will be implemented should be continuously evaluated to ensure the effectiveness of both technologies.
This study has several limitations. Firstly, the time series used for projections extended only to 2020, which may have led to overestimation of the number of cases over the 5-year horizon, given the declining trend in P. vivax malaria incidence observed from 2022–2023 onwards. Evaluating the real-world impact of the incorporation of both technologies, using more recent incidence data and controlling for confounding variables, constitutes an important future research agenda. Secondly, the model assumed equivalence in recurrence rates between primaquine and tafenoquine. This conservative assumption was adopted given the absence of robust evidence supporting superiority of either regimen and available real-world data suggest that tafenoquine is not superior to primaquine in preventing recurrences23. Thirdly, the analyzers and test kits are imported from other countries, and the sensitivity analysis did not account for fluctuations in the exchange rate, which could introduce uncertainty regarding currency appreciation against the Brazilian Real over the time horizon. The costs of the G6PD test and the tafenoquine regimen constituted 73% and 13% of the budget impact analysis, respectively. Brazil has experienced a steady increase in the health sector trade balance deficit over recent decades, and the adoption of new imported technologies contributes to this growing economic dependency31. Additionally, for some states in the Brazilian Amazon, the estimated series of P. vivax malaria cases from 2009 to 2020 have not shown a clear trend of growth or reduction but rather a cyclical pattern. In these cases, the model predictions follow the observed cyclical trend of the data series.
Despite being a crucial stage in budget impact analysis studies, face validity is not yet routinely performed in economic evaluations. However, previous studies have highlighted the benefits of conducting face validity32,33. In this study, face validity was a key advantage for ensuring transparency throughout the budget impact development process and for providing an economic evaluation framework to optimize the use of health resources, thereby supporting healthcare decision-making for SUS.
Conclusion
This budget impact analysis can assist healthcare managers in evaluating the feasibility of incorporating the G6PD test and tafenoquine in the Brazilian Amazon. The total 5-year incremental cost of USD 6.26 million represents an affordable investment given the malaria burden in the region, with both technologies predicted to reduce hospitalization costs by 22% and recurrence treatment costs by 3%. The main cost driver — and the primary parameter of uncertainty — is the price of the G6PD reagent strip, which should be a priority target for price negotiation and supply chain development. However, health decision-makers do not rely solely on economic analyses. Factors such as ease of implementation, adherence, accessibility of supplies, and the potential for scaling up are also crucial considerations. A prospective evaluation of the actual budget impact following incorporation, using post-2022 incidence data, is recommended as a future research priority.
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