Costs and Cost-Effectiveness of Artesunate Against Quinine Treatment Therapy for Severe Malaria in Children Under 14 Years in Zambia.

Methods Cost-effectiveness analysis of severe malaria treatment was conducted from a healthcare provider perspective using a decision tree. Standard costing was performed for the identication, measurement and assessment phases, with data from Zambia annual quantication reports for anti-malaria commodities. The data was collected from Health Management information system, and meta-analysis. Average and incremental cost-effectiveness ratio were estimated. The uncertainties were assessed through probabilistic sensitivity analysis.

analysis the of Artesunate with quinine the ICER was $105 per death averted.

Conclusion
The use of Artesunate over Quinine in the treatment of severe malaria in children under 14years is a highly cost-effective strategy for the healthcare provider in Zambia.

Background
Malaria remains a major public health problem in Zambia, despite signi cant progress made in ghting the disease in the last decade. Malaria prevalence varies across all provinces and districts with 18 million people at risk, including the most vulnerable groups, such as pregnant women and children. The country's last two iterations of the National Malaria Strategic Plan (NMSP) aimed to reduce transmission through multiple strategies, including the distribution of long-lasting insecticide-treated mosquito nets (LLINs), increased indoor residual spaying (IRS), mass drug administration, improved case management using rapid diagnostic tests (RDTs)/Microscopic laboratory tests, and treatment with artemisininbased combination therapy [1] [2]. In the current NMSP (2017-2021), the Government of Zambia through the Ministry of Health and the National Malaria Elimination Program (NMEP) adopted an ambitious agenda to eliminate malaria through deployment of the above outlined interventions, inclusion of new tools and innovations and strengthening of routine surveillance at all levels. The efforts towards nationwide malaria elimination with regard to malaria case management, emphasizes the need to have diagnostic and curative services as close to homes as possible while utilizing community health workers as extensions for the health facility within the community. In the recent past the NMEP has provided an annual sustained supply of more than 15 million treatment courses of the recommended artemisinin combination therapies and over 20 million rapid diagnostic tests. This is in addition to ensuring availability of more than 5.5 million tablets for intermittent presumptive treatment for pregnant women. With an estimated 20.3% parasite prevalence, the NMEP has adopted therapeutic approaches such as mass drug administration (MDA) to accelerate the decline of parasite prevalence. On the other hand, case management coverage has greatly improved through strengthening of general health services and the provision of adequate diagnostics and medicines according to national guidelines. The national objective is to ensure that 100% of all suspected malaria cases in all districts receive parasitological (microscopy or RDT) analysis and all parasitological con rmed malaria cases receive prompt (within 24 hours), effective antimalarial treatment. Moreover, attaining Universal coverage by providing service for all, with early diagnosis and effective treatment is a key strategy in reducing morbidity and mortality. The total malaria commodity needed to meet client needs per year with a full pipeline of 6 months of stock is estimated at around $ 27,374,448 which possess nancial challenges [3].
Despite a better understanding of pathophysiology and management of malaria, childhood mortality remains unacceptably high [4]. Thus, Over the past decade, there has been some progress in de ning best practices for antimalarial treatment. The Artesunate versus Quinine in Severe Malaria in African Children Trial (AQUAMAT), conducted in 9 African countries and involving 5425 children, showed that Artesunate-treated children had a 22.5% (95% con dence interval, 8.1 to 36.9) lower relative risk of death than those receiving the time-honored quinine [5]. Therefore, In 2011 the World Health Organization (WHO) recommended parenteral Artesunate in preference to quinine as rst-line treatment for people with severe malaria. Prior to this recommendation many countries, particularly in Africa, had begun to use artemether, an alternative artemisinin derivative. Nevertheless, Artesunate is recommended for treating adults and children that have severe malaria as studies have shown that it results in fewer deaths compared to treatment with quinine [6].
Notwithstanding, severe and fatal Plasmodium falciparum malaria continues to affect young children in sub-Sahara Africa representing approximately 90% of total global the cases, and one of the main cause of hospital admission and inpatient mortality [7]. Malaria exerts a signi cant economic burden on health care providers and households. Particularly The total annual costs for malaria interventions in Ghana, Tanzania and Kenya were estimated at US$ 37.8 million, US$ 131.9million and US$ 109 million respectively.in addition, out of pocket towards treatment ranged from US$5.98 to US$45.23 for families [8] .Also, the cost of inpatient care for a case of severe malaria has been estimated between US$ 12 and US$ 75 which further exerts a heavy nancial burden on most countries with already limited recourses [9][10] [11] . Most recently, many Governments of the sub-Saharan region adopted plans to aggressively eliminate malaria in the region and sustained efforts towards malaria elimination in most of the countries have been seen to produce desirable results and thus in the right direction to attaining the intended goal. Therefore, In the context of increasing attention towards improved malaria control in settings with budget constraints, competing health problems and weak health systems, it is essential to provide policy makers with relevant economic evidence of the economic bene ts of health care control and prevention strategies.

Methods
This study was designed to compare the costs involved in Artesunate and Quinine treatment regimen for severe malaria in Children under 14 years . Products compared were injectable formulations, Quinin 300mg ampoule and Artesunate 60mg ampoule and also the costs relating to severe malaria treatment. To determine the e cacy parameter, literature searches were conducted to identify published clinical trials for each of these products in the treatment of severe malaria.
Search strategies included the generic drug names combined with hazard ratios. Selected articles were restricted to human studies published in English.
The cost-effectiveness model was constructed as a Markov model using stochastic parameters, created in Microsoft excel, with cycles having 1 year time period. Beta distributions were used for treatment probabilities and utilities in view of the fact that it restricts values between 0.0 and 1.0. while Gamma distributions were used for cost variables because of data skewness [12]. considering cost effectiveness is primarily utilized for formulary and reimbursement decision making, the perspective of the analysis was that of a health payer, a managed-care organization as a healthcare provider. It's worth mentioning that individual variables for costs, utilities, and probabilities were stochastic and based on their respective distributions [3] [13] [14] [15]. Data collection was from 1 st January to 31 st October,2020 and analysis was conducted in November of the same year.

Model overview
We modelled the disease progression for severe malaria. Five main states of health were distinguished: (1) healthy or disease-free; (2) transition state of uncomplicated malaria; (3) severe malaria; (4) transition state of hospitalization; and (5) death from severe malaria Figure 1. Other model input data, included mortality rates, hazard ratio and possible transitions probabilities between health states. Thus, these were deterministic within the Markov cycles taking a form that healthy children can either remain healthy, die or acquire uncomplicated malaria which progresses to severe malaria. Children in severe malaria state get hospitalized and receive Artesunate or quinine. Children in severe malaria state either recover fully or die. Children who recover after treatment enter the state healthy Utilities Due to scarcity of quality of life estimations in children affected by severe malaria, we took an approach to apply the methodology described McCarthy et al to estimate the age-speci c quality-of-life utility weights for the different health states. Also, using a self-administered visual analogue scale (VAS) based on the scale employed as part of the EQ-5D instrument as well as Published articles were used to identify utilities for severe malaria [16].

Costs
The Zambia annual quanti cation report for anti-malaria commodities 2017-2018 was used to determine monthly costs of each treatment. This document was selected because it integrates both product cost and any applicable freight cost from all suppliers of the commodities, is readily available, and avoids the ambiguity of various product discounts and additional costs without freight charges from average landing cost. Other costs were obtained from hospital local procurement documents and local wholesalers and published literature. Drug administration cost per dose of Artesunate and quinine included costs of a pair of examination gloves,2 needles,5mg syringe and ,2 needles ,5mg syringe,1000ml normal saline, IV infusion set respectively. Also, diagnostic costs were included in the model. Treatment costs for severe malaria were divided into pharmacological treatment, laboratory and nursing care. all cost conversions from Zambian kwacha to united states dollar was based on the exchange rate of October month end of the same year.

Cost-effectiveness analysis
The cost-effectiveness model was constructed as a Markov model using stochastic parameters. The Markov model, created in Microsoft excel, with cycles having of 1 year time period. Beta distributions were used for treatment probabilities and utilities in view of the fact that it restricts values between 0.0 and 1.0. while Gamma distributions were used for cost variables because of data skewness [12]. considering cost effectiveness is primarily utilized for formulary and reimbursement decision making, the perspective of the analysis was that of a health payer, a managed-care organization as a healthcare provider. In addition, populations were created and followed until death to estimate costs and QALYs time horizon of 14 years. Also, the model was employed to calculate the ICER for the case of a single cohort of 1,000 children aged between1-14 years who are healthy and are prone to the high prevalence of malaria. As costeffectiveness analysis is generally applied for a single cohort, these complementary results permit comparison with published data.

Probabilistic sensitivity analysis
In any economic evaluation such as this there are a number of key variables that are subject to uncertainty. A probabilistic sensitivity analysis was in excel using Monte Carlo simulation to assess the effect of uncertainty surrounding the costs Page 5/13 and effectiveness estimates. Each variable was allocated a distribution tting the range of all possible values with each simulation randomly generating and select the value for each variable from the speci ed distribution. Consequently, examining the effect of joint uncertainty in the variables of the model through cost-effectiveness plane and acceptability curve. The cost-effectiveness plane shows the incremental cost on the vertical axis and effectiveness on the horizontal axis for 1,000 simulation runs. Also, results showed the mean value and 95 % con dence intervals (CI) for total costs and QALYs. Sensitivity analysis allows exploration of the impact of change in one or more of these variables on the result robustness [18].

Results
The total costs of direct and non-direct medical costs of the two arms Artesunate and Quinine as well as the variables used in the model are as shown in Table 1.  The incremental cost-effectiveness ratios were estimated as the total healthcare cost per death averted. Compared with the strategy of using Artesunate/ quinine has an ICER of $105 per death averted. According to gure 3, base-case acceptability curve for Artesunate therapy versus Quinine therapy generated from 1000 samples of mean incremental costs versus mean incremental effectiveness generated for 1000 patients treated with either Artesunate therapy or Quinine. The acceptability curve shows how likely it will be that Artesunate therapy is costeffective for any particular willingness to-pay.

Discussion
The introduction of injectable Artesunate by governments requires effective communications on its effectiveness and bene ts in the context of each country, for a clear de nition of the projected national funding requirements and availability of nancial sources. The cost of severe malaria treatment is high and households bear a greater portion of this cost due to a high level of indirect costs. To some households this may be catastrophic. There is need to buffer this with some sort of nancial risk protection mechanisms and the health care system needs to be strengthened to function more effectively and decrease overall out of pocket payments to aid in alleviating economic burden of malaria.
Severe Malaria in Children has been shown to account for over 45% of the total monthly curative healthcare costs incurred by households compared to the mean per capita monthly income. On the other hand, the cost of treating severe malaria depleted 7.67% of the monthly average household income [36]. In addition, the cost attributed to loss of income in taking care of a sick child is the highest contributor $10.5 of total cost followed by direct medical costs $7.75 as shown in Table 2. In our study, the cost of Artesunate was $65.6 which was costly than the quinine arm, this result compares favorably to the mean costs from studies by Lubell et al. who recorded $66.5 for the Artesunate arm and 61.4 for the quinine arm respectively [29]. According to the 2015 living condition monitoring survey by the central statistics of Zambia, the mean per capita monthly household income as de ned by the total household income divided by the number of persons in the household was $40. thus, treatment of malaria with possess a nancial burden on families as it costs more than the estimated monthly total expenditure, hence the need for government to sustain the provision of free malaria treatment [30].On the other hand, our model-based analyses suggest that the health bene ts associated with the use of Artesunate in children with severe malaria is cost-effective when compared with the use of quinine at commonly accepted willingness-to-pay thresholds derived from the gross domestic product per capita [17].As shown in gure 3 treatment with Artesunate over quinine indicating increased costs and increased effectiveness as well as some cases showing dominance. Moreover, use of Artesunate could signi cantly have cost savings through avoided drug administration costs and nursing care to alleviate risk of cardiotoxicity, as intravenous quinine administration needs rate-controlled infusion over four hours, three times a day, accompanied by cardiac monitoring if possible. A study examining malaria deaths showed that one in four patients had received incorrect dosing. [31]. in addition, due to high mortality rate among children, the bene ts of expanded use of Artesunate could be a right step in the right direction to reduce the malaria burden [32]. Other researchers also suggest that administrative cost and nursing care time are more on the quinine arm and would even favor Artesunate to be more cost effective [35]. Not only Artesunate is cost effective but injectable Artesunate is simpler to administer, and given once a day while the comparative drug requires multiple dosing and close monitoring for cardiotoxicity. To add on, Artesunate also reduces episodes of hypoglycemia during treatment by 45% hence a cost saving therapy [32]. Consequently, the use of Artesunate in the management of severe malaria in children is seen to have more monetary bene ts.
Furthermore, the robustness of our results over a range of varying assumptions was tested in the sensitivity analysis, even with conservative estimates around the parameters used in the model for sensitivity analysis, the ndings remain cost-effective across a range of estimates in the model on assumptions at the threshold of willingness to pay. This threshold has been used frequently in similar studies and the World Health Organization recognizing 3 times the gross domestic product per capita as an upper threshold [33]. This study also revealed the cost-effectiveness acceptability curve having the probability of Artesunate being cost-effective being approximately 12% without any additional investment. In addition, with a willingness-to-pay of $150 and $300, Artesunate therapy produces a probability around 70%, and above 95% respectively. Figure 3.

Limitation
Our assessment had considerable limitations that are expected in the construction of any decision model. Firstly, societal perspective of economic evaluation has a more comprehensive framework for analysis but we took a healthcare perspective because Malaria treatment is free of charge from all government hospitals. Also, our assumptions were that of a patient having only one episode of severe malaria during the one year cycle.
Owing to the fact that cost effectiveness models can be sensitive to time horizon of the analysis, and in most cases covering a life expectancy time horizon. In the case the incremental cost comparisons may be somewhat accurate, but the cumulated incremental bene ts may be signi cantly underestimated.

Conclusion
Injectable Artesunate is the WHO-recommended treatment for severe malaria in children and adults. Thus, Countries that have not yet made a clear recommendation of injectable Artesunate as a rst-line treatment, should also work with WHO to align its guidance to global WHO recommendations. https://www.severemalaria.org/resources/injectable-artesunateassessment-report The Artesunate therapy is highly cost effective and anticipated to signi cantly reduce the current mortality caused by severe malaria in Zambia. Unfortunately, to date, not all malaria-endemic countries have adopted and implemented the WHO recommendations. There is an urgent need to speed up the adoption and implementation of this new policy.