Original research Potential impact of 5 years of ivermectin mass drug administration on malaria outcomes in high burden countries Achla Marathe,1,2 Ruoding Shi,2 Ana Mendez-­Lopez,3,4 Zhihao Hu,5 Bryan Lewis,1 Regina Rabinovich,4 Carlos J Chaccour ‍ ‍ ,4,6 Cassidy Rist ‍ ‍ 7 To cite: Marathe A, Shi R, ABSTRACT Mendez-­Lopez A, et al. Key questions Introduction The global progress against malaria has Potential impact of 5 years slowed significantly since 2017. As the current malaria of ivermectin mass drug What is already known? control tools seem insufficient to get the trend back on administration on malaria ►► The global progress in malaria elimination is unlike- track, several clinical trials are investigating ivermectin outcomes in high burden ly to meet the Global Technical Strategy for Malaria countries. BMJ Global Health mass drug administration (iMDA) as a potential additional 2016–2030 targets due to the challenge of residual 2021;6:e006424. doi:10.1136/ vector control tool; however, the health impacts and cost-­ transmission, mosquito resistance to insecticides bmjgh-2021-006424 effectiveness of this new strategy remain unclear. from traditional malaria control tools and more re- Methods We developed an analytical tool based on a cently from challenges introduced by COVID-­19. Handling editor Alberto L full factorial experimental design to assess the potential ►► Ivermectin mass drug administration (iMDA) is a Garcia-­Basteiro impact of iMDA in nine high burden sub-­Saharan African potential additional tool that targets mosquitoes re- countries. The simulated iMDA regimen was assumed ►► Additional supplemental sponsible for residual transmission, and has a differ- to be delivered monthly to the targeted population for material is published online only. ent mode of action in the mosquitoes as compared To view, please visit the journal 3 months each year from 2023 to 2027. A broad set of with current insecticides. online (http://​dx.​doi.​org/​10.​ parameters of ivermectin efficacy, uptake levels and ►► Several clinical trials for iMDA are underway, how- 1136/​bmjgh-​2021-​006424). global intervention scenarios were used to predict averted ever, its potential population-­level health impact and malaria cases and deaths. We then explored the potential cost-­effectiveness have yet to be investigated. averted treatment costs, expected implementation costs RS, AM-­L, CJC and CR and cost-­effectiveness ratios under different scenarios. What are the new findings? contributed equally. Results In the scenario where coverage of malaria ►► The predicted health and economic benefits of iMDA in interventions was maintained at 2018 levels, we found that the nine study countries are most significant when (i) Received 26 May 2021 iMDA in these nine countries has the potential to reverse efficacy of iMDA is high (40% reduction in cases), (ii) Accepted 18 October 2021 the predicted growth of malaria burden by averting 20–50 global progress on malaria is slowed or stagnant and million cases and 36 000–90 000 deaths with an assumed (iii) iMDA is scaled up to the national level rapidly. efficacy of 20%. If iMDA has an efficacy of 40%, we predict ►► Substantial heterogeneity in cost-­effectiveness was between 40–99 million cases and 73 000–179 000 deaths observed across countries mainly due to the differ- will be averted with an estimated net cost per case averted ence in malaria incidence rates. between US$2 and US$7, and net cost per death averted between US$1460 and US$4374. What do the new findings imply? Conclusion This study measures the potential of iMDA to ►► Given the current challenges in malaria control and reverse the increasing number of malaria cases for several elimination globally, adding iMDA to existing vector sub-­Saharan African countries. With additional efficacy control interventions could have significant health information from ongoing clinical trials and country-­level impacts for several sub-­Saharan African countries. modifications, our analytical tool can help determine the ►► When combined with efficacy results from ongoing clin- appropriate uptake strategies of iMDA by calculating potential ical trials with iMDA, investigation of the economic costs marginal gains and costs under different scenarios. and benefits of iMDA as a malaria control tool will better inform country-­level implementation strategy. ►► Given the relationship between malaria incidence © Author(s) (or their and cost-­effectiveness, we anticipate a subnation- employer(s)) 2021. Re-­use al approach that allows countries to target districts permitted under CC BY-­NC. No INTRODUCTION with the highest malaria incidence first, will achieve commercial re-­use. See rights As a longstanding health problem in human the greatest health impact at the lowest net cost. and permissions. Published by history, malaria remains endemic in most WHO BMJ. regions and puts millions of people at risk of For numbered affiliations see infection and death each year.1 2 Despite being for Malaria 2016–2030 (GTS) targets a reduc- end of article. preventable and treatable, malaria dispropor- tion of malaria cases by at least 40% in 2020 Correspondence to tionately threatens vulnerable populations in compared with 2015.1 However, as of 2017, Dr Cassidy Rist; ​crist6@​vt.​edu many countries. The Global Technical Strategy malaria cases have stagnated, and it is anticipated Marathe A, et al. BMJ Global Health 2021;6:e006424. doi:10.1136/bmjgh-2021-006424  1 BMJ Global Health that the 2020 GTS goals for reduction in malaria incidence In response to this gap, a Phase III cluster randomised, and deaths will be missed by 37% and 22%, respectively.3 open label, clinical trial called the Broad One Health This stagnation is due to several unique challenges. First, a Endectocide-­ based Malaria Intervention in Africa lack of sustained domestic and international funding has (BOHEMIA) is testing the efficacy of iMDA on malaria-­ caused the battle against malaria to lose ground in some related epidemiological outcomes when given to humans places, especially in low-­income countries in sub-­Saharan and when given simultaneously to humans and livestock Africa.3 Second, the effectiveness of several widely-­used vector (https://​bohemiaconsortium.​ org/). As a preparatory control tools has been weakened by mosquitoes’ resistance to analysis for the BOHEMIA trial, this study investigates insecticides and mosquitoes’ behaviours, leading to residual potential implementation costs and impact of iMDA in transmission.1 4 5 Finally, the recent outbreak of COVID-­19 humans with different assumptions of iMDA efficacy and has had an overwhelming impact on the health systems of uptake levels. The analysis is performed for select coun- countries that suffer from malaria and may significantly tries included in the WHO’s high-­ burden-­high-­impact restrict their ability to implement usual prevention and treat- (HBHI) strategy,3 which was released in 2018 and iden- ment interventions.6 These challenges call for combining tifies 11 countries in which approximately 70% of the existing malaria control strategies with innovative methods world’s malaria burden is concentrated. and implementable programmes in countries that bear the The global progress towards malaria elimination highest burden of disease.7 Current and future innovations mainly depends on how these countries can adopt inno- in novel vector control tools face considerable challenges, as vative solutions that are cost-­effective and fit their finan- they must address the intrinsic limitations of current vector cial capacity, which is the main focus of this study. Based control tools, as well as demonstrate cost-­effectiveness given on previous literature, available data and a few assump- the current funding deficits. tions, the present work provides an analytical tool to esti- Mass drug administration with systemic insecticides is mate the marginal benefits and costs added by iMDA, a potential vector control tool that partly addresses the including averted cases and averted deaths from malaria limitations of indoor residual spraying and insecticide-­ under different counterfactual intervention scenarios. treated nets.8 Specifically, this study focuses on iver- While insufficient field data for a new vector control mectin mass drug administration (iMDA), which is intervention impede a formal cost-­effectiveness analysis, currently applied in several African countries as part of this analytical tool can serve as an intermediary way to neglected tropical disease (NTD) control and elimina- guide policymakers and help evaluate potential outcomes tion activities. iMDA has been considered by the WHO of different uptake strategies. as a potential additional tool for targeting both indoor and outdoor biting mosquitoes responsible for residual malaria transmission, given its safety and feasibility of METHODS implementation.9–12 After taking ivermectin, the blood of Patient and public involvement treated humans has a measurable impact on the survival This study did not involve patient or public involvement. of Anopheles mosquitoes feeding on them that may last up to 28 days. This effect is dependent on the ivermectin Study design dose used and the susceptibility of the particular species This study used an experimental full factorial design involved.13 14 Blood meals containing ivermectin not to simulate the potential impact of an iMDA interven- only increase vector mortality, but also reduce sporo- tion on malaria-­related health and economic outcomes gony, and delay refeeding frequency.15 Beyond looking for the period 2023–2027, which is the 5-­year period at entomological outcomes, a small-­scale iMDA trial to following the expected finalisation of the BOHEMIA trial assess impact on malaria incidence has been performed in 2022. This time period was chosen given an assump- under field conditions in Burkina Faso, with positive tion that BOHEMIA and other trials being conducted in results.16 West Africa and Asia have positive results (ie, the iMDA Although several studies are investigating the safety is effective and does reduce malaria incidence), and and mosquitocidal efficacy of iMDA as a malaria vector provide adequate data to support a WHO policy recom- control tool, little is known about the population-­level mendation for iMDA as a new class of complementary health impacts and cost-­effectiveness of this strategy due malaria vector control tool. Three key assumptions, some to the lack of large-­scale field data. To prioritise a potential derived from previous literature, were used in the simula- new intervention, policymakers need cost-­effectiveness tion work: (1) the mosquitocidal impact of iMDA is posi- analyses to assess the trade-­off between needed resources tive and significant13; (2) several standard malaria control and the potential improvement in health outcomes. interventions are likely to occur during the study period Numerous studies have estimated cost-­effectiveness for and will follow one of the global scenarios developed by existing malaria control interventions,17–19 but assessing GTS based on the work by Griffin, et al20 and (3) it is the economic viability and potential impacts of an inno- assumed that, during the 2023–2027 period, funds could vative control tool with minimal data can be challenging, be available to cover the delivery costs as well as the costs making policymakers reluctant to add the new tool to required to implement and sustain iMDA campaigns. For existing programmes. the estimated health benefits, we simulated the impact 2 Marathe A, et al. BMJ Global Health 2021;6:e006424. doi:10.1136/bmjgh-2021-006424 BMJ Global Health of iMDA on annual cumulative number of averted cases near forest fringes.21 Given the size of India’s population and deaths from 2023 to 2027; during which the iMDA and low national-­level incidence, simulating iMDA imple- regimen was assumed to be a single dose of 400 µg/kg mentation at the national level as designed by this model- using 6 mg tablets (population average 3.3 tablets per ling study would include a scenario that would not be a person per round) delivered monthly to the targeted prudent use of resources. population for 3 months in each year. Scenario settings Study area This section describes the scenario settings for which the The potential impact of iMDA was modelled for nine impact was evaluated. These scenarios assume varying countries out of the following 11 HBHI countries: levels of drug efficacy, uptake levels, proportions of Burkina Faso, Democratic Republic of the Congo, severe cases and underlying global malaria intervention Ghana, Mali, Mozambique, Niger, Nigeria, Uganda, strategies (table 1). United Republic of Tanzania, India and Cameroon. There are considerable variations in malaria incidence Efficacy and severity rates and deaths among these nine countries in sub-­ The assumed efficacy of iMDA captures the potential Saharan Africa (online supplemental file S0). The two reduction in malaria incidence in the at-­ risk popula- countries excluded from this analysis, Cameroon and tion. The starting at-­risk population for our simulation India, are excluded for the following reasons: Ivermectin was taken from Annex 3—F in the 2019 World Malaria can cause severe encephalopathy in patients with high Report,2 and includes people living in both low, moderate Loa loa burden. Cameroon has a high prevalence Loa and high transmission areas. Preliminary mathematical loa with clinical eye worm infections in at least half of modelling work conducted for the BOHEMIA trial sites its territory. In India, although the majority of the coun- predicted that iMDA, delivered as one dose of 400 µg/ try’s population is considered to be at risk, malaria trans- kg a month for three consecutive months to 80% of the mission intensities are generally very low, with moderate eligible population, was expected to reduce clinical inci- transmission areas concentrated in only 7 out of 36 states dence in the covered population by 40%–46% for 1 year. Table 1 A brief description of the various factors used in iMDA* impact assessment 20% efficacy (very conservative estimate based on 40% efficacy Efficacy scenarios minimally required criteria of the PPC†) (estimated based on BOHEMIA preliminary modelling) Severity 1% 3% Uptake levels Conservative Rapid National‡ 5% coverage of population at risk in 2023, with 5% coverage of population Start at 5% in 2023 and double each increase of 3% coverage per year. at risk in 2023, with year for first 3 years and then by 20% per increase of 10% coverage year, with goal of reaching total national per year. coverage in 7 years. GTS§ scenarios Accelerate 1 (incidence: −21%, mortality: −40%) 2016–2030 Increased coverage to 80% with a switch from quinine to injectable artesunate for management of severe disease and seasonal malaria chemoprevention. Accelerate 2 (incidence: −59%, mortality: −74%) Increased coverage to 90% with a switch from quinine to injectable artesunate for management of severe disease, seasonal malaria chemoprevention and rectal artesunate for pre-­referral treatment at the community level. Innovate (incidence: −74%, mortality: −81%) Near-­term innovation, including longer-­lasting insecticidal nets and expansion of seasonal malaria chemoprevention. Sustain (incidence: +28%, mortality: +11%) Malaria interventions remain at the coverage levels of 2011–2013. Coverage comprises vector control and access to treatment. No change (incidence: 0%, mortality: 0%) Interventions remain constant over time at the 2018 levels. This scenario is used as a benchmark and is not a GTS strategy. Note: This table shows the scenario setting for the full factorial experimental design, including four factors. The efficacy of iMDA is defined as the assumed reduction in malaria incidence among the at-­risk population. Severity refers to the percentage of severe cases among all malaria cases. Uptake levels capture the timeline and coverage of iMDA over 64% of population at risk of malaria. The projected GTS global scenarios of malaria transmission 2016–2030 were developed by Griffin, et al20 and indicated expected reduction percentages of incidence and mortality in 2030 as compared with 2015 levels. *iMDA: ivermectin mass drug administration. †PPC: WHO Preferred Product Characteristics. ‡Specifically, the ‘National’ uptake coverage rate is 5% in 2023, 10% in 2024, 20% in 2025, 40% in 2026, 60% in 2027, 80% in 2028 and 100% in 2029, but this study only simulates for the 2023–2027 period. §GTS: Global Technical Strategy for Malaria. BOHEMIA, Broad One Health Endectocide-­based Malaria Intervention in Africa. Marathe A, et al. BMJ Global Health 2021;6:e006424. doi:10.1136/bmjgh-2021-006424 3 BMJ Global Health The preliminary modelling work was conducted by Dr additional scenario not described by Griffin et al that we Hannah C Slater (Malaria Modelling Research Group at have labelled ‘no change’. In their original work, the last Imperial College London) under a consulting contract scenario is ‘reverse’, which means the coverage of inter- with the BOHEMIA team. The modelling details are ventions declines to levels reported in 2006–2008. This not publicly available as required by the terms of the study replaces the ‘reverse’ scenario with ‘no change’ as contract, but similar modelling approaches are described a baseline category, which assumes interventions remain in Slater et al.12. The eligible population excluded chil- constant over time at the 2018 level. All scenarios are dren under 15 kg, pregnant women and the severely ill, briefly described in table 1. which collectively account for approximately 20% of the population at risk, so the target population to cover was Calculations and data sources 64% of population at risk (80% of the eligible 80%). To estimate the potential health benefits of this inter- The current analysis assumed two levels of intervention vention, yearly malaria incidence rates and cumulative efficacy: the minimum efficacy was a 20% reduction in averted cases and deaths were modelled for the nine incidence of all clinical malaria episodes as a minimally countries from 2023 to 2027 in the following manner: (1) required criterion in the WHO Preferred Product Char- We estimated the target population over time. This was acteristics (PPC), and the maximum efficacy was 40%, 64% of each country’s 2018 population at risk adjusted the most likely estimate based on preliminary modelling. for population growth using country population growth According to World Malaria Report 2019,2 between 1% rates from the World Bank’s World Development Indi- and 3% of uncomplicated cases were expected to move to cators 2018 database.22 (2) Starting from the baseline the severe stage, so two proportions of severe cases were without iMDA, we predicted the yearly rate of change used in the simulation as a sensitivity analysis. of the malaria incidence based on 2015 incidence rate and the expected targets by 2030 under each Griffin Uptake scenarios scenario,20 assuming the total change was equally distrib- The uptake coverage rate was measured as the percent of uted across the 15 years. (3) Then, the baseline malaria the target population (ie, 64% of at-­risk population) that cases (‍ Mbase‍) for country ‍c‍ at year ‍t‍ without iMDA were would receive ivermectin in a given year, with the assump- predicted using 2018 actual cases (‍M2018,c ), ‍ population tion that the drug would be delivered evenly regardless growth rates (‍prc‍) in country c, and the yearly rate of of differences in incidence rates across regions within a change (‍roc‍) derived in step (2) as follows, country. Three hypothetical uptake scenarios were used: base [( ) ]t−2018 ‘Conservative’, ‘Rapid’ and ‘National’. In the ‘Conserva- ‍Mt,c = M2018,c 1 + prc × roc (1) ‍ The baseline scenario served as a counterfactual against tive’ scenario, the uptake strategy was specified as targeting which the impact of the iMDA intervention was assessed. a random sample of districts per country encompassing Building on the baseline, hypothetical cases under inter- at least 5% of the target population in the starting year vention were modelled for every country as follows of 2023. Then, the proportion of uptake would increase    [( ) ] M2018, c 1 + prc × roc t−2018 , if 2018 < t < 2023  every year by 3%, by which in 2027, uptake would equal MiMDA = t,c 17% of the target population in each selected country.    [( ) ] ( ) M2018, c 1 + prc × roc t−2018 × 1 − E × Ut , if 2023 ≤ t ≤ 2027 The ‘Rapid’ uptake level assumed a starting coverage rate ‍ (2) of 5% in 2023, then increasing by an increment of 10% ‍ each year until 2027, reaching a total of 45% of the target ‍ t ‍is the uptake coverage rate at year ‍t‍described where U population. The most ambitious scenario was ‘National’, in which the iMDA coverage rate would start at 5% of the in table 1, and ‍ E‍is an assumed efficacy level (20% or target population in 2023 and double each year for the first 3 years and then by 20% per year afterwards, with a goal to reach the entire target population nationwide 40%) of ivermectin. The baseline yearly malaria deaths, base in 7 years, or 60% of the target population at the end of ‍Dt,c ‍, were predicted in a similar way as steps (2) and 2027. (3) by replacing incidence rate and cases with mortality rate and deaths, respectively. The numbers of averted GTS intervention scenarios cases (‍Maverted t,c = Mbase iMDA t,c − Mt,c ‍) and averted deaths averted base iMDA The GTS intervention scenarios were built on an (‍Dt,c = Dt,c − Dt,c )‍ were defined as the reduction individual-­based simulation model conducted by Griffin of simulated cases and deaths after applying ivermectin et al20 so we refer to the intervention scenarios as Griffin compared with the baseline. The data on population at scenarios in the following discussion. Griffin et al risk and malaria cases and deaths were collected from the described the potential changes in malaria transmission WHO’s World Malaria Report 2019.2 around the world for 2016–2030 in five scenarios based To assess the economic impact from the health provid- on different uptake levels of current preventive or treat- er’s perspective, we simulated the averted treatment costs ment measures as well as the availability of innovative associated with the number of averted cases between options. The scenarios applied in this study were ‘Accel- 2023 and 2027 attributable to the ivermectin interven- erate 1’, ‘Accelerate 2’, ‘Innovate’, ‘Sustain’ and one tion. Regardless of public or private provider, the averted 4 Marathe A, et al. BMJ Global Health 2021;6:e006424. doi:10.1136/bmjgh-2021-006424 BMJ Global Health cost reflects the total averted healthcare expenditure on treating malaria including out-­of-­pocket spending. The treatment cost measures were specified as the median provider economic cost of treating an episode of malaria from the systematic review by Conteh, et al,23 which reported the treatment cost of an uncomplicated episode as US$9.31 and that of a severe episode as US$89.93 in 2018. From 2023 to 2027, the averted treatment cost (‍Caverted ‍) due to iMDA for country ‍c‍ at year ‍t‍ given a proportion of severe episodes (‍s‍) was ( ) averted C ‍ t,c = 30.26 × Maverted t,c × s + 5.84 × Maverted t,c × 1 − s .(3)‍ The total cost of scaling up the intervention to the eligible population (ie, 64% of the country’s at-­risk popu- lation ‍ P ‍) was estimated from the project implementer’s perspective, including the cost of the drug and the cost of distribution in response to different uptake levels of iMDA. Based on BOHEMIA final dosage form and the Figure 1 Simulated malaria incidence in all nine countries estimated delivery costs for NTD programmes in African for different Griffin scenarios and uptake levels. countries,24 we assumed a conservative purchasing cost of US$0.15 per 6 mg tablet and a distribution cost of US$0.46 per person per round. There are three rounds RESULTS in each year, delivering a mean of 3.3 tablets per person Aggregated results across all countries in each round. For ‍2023 ≤ t ≤ 2027,‍ the implementation Health impact cost was modelled as Figure 1 illustrates the estimated impact of iMDA on C iMDA ( )t−2023 [ ] × Ut × 3 × 0.46 + 0.15 × 3.3 .(4) malaria incidence for the nine HBHI countries as a ‍ t,c = 64% × P2023, c 1 + prc ‍ whole. Cumulative averted cases from 2023 to 2027 are In sum, the full-­factorial design consisted of 9 coun- tries, 3 uptake levels, 2 ivermectin efficacy levels, 5 reported in figure 2A. With a ‘Conservative’ uptake level scenarios and 2 severity levels of malaria cases. A total (ie, starting at 5% and increasing by 3% each year), the impact of iMDA on national malaria incidence is relatively of 540 (=‍ 9 × 3 × 2 × 5 × 2‍) experiments were simulated small, especially when the scenarios are ‘Accelerate 2’ or using statistical data processing applications in R. We ‘Innovate’. The largest impact is observed in the ‘Sustain’ adjusted all costs to 2020 US$ using the annual inflation scenario with an efficacy of 40%, but it cannot reverse rate of Consumer Price Index from the US Bureau of the predicted growth of malaria burden, increasing from Labor Statistics. 285.1 to 307.6 cases per 1000 population at risk by 2027. Compared with the baseline, the cumulative averted Outcome variables cases in this scenario are 46 million (figure 2A). Six outcome metrics were constructed: (i) malaria inci- The ‘Rapid’ uptake of iMDA with an efficacy of 40% dence per 1000 population at risk, (ii) averted cases, is expected to reverse the growth of malaria incidence. (iii) averted deaths, (iv) implementation cost of scaling Even under the worst ‘Sustain’ scenario, the intervention up, (v) cumulative averted treatment cost and (vi) generates a downward trend in malaria incidence after average cost-­effectiveness ratios (CERs). Malaria inci- initiation in 2023. Malaria incidence under the ‘Sustain’ dence rates were predicted for the 2023–2027 period scenario falls below the ‘No change’ baseline scenario under different intervention scenarios. The net cost after 2025, and a similar overlapping is observed between of iMDA was modelled as the scaling-­up cost minus ‘No change’ and ‘Accelerate 1’ scenarios. Even though averted treatment cost attributable to iMDA. In each the projected malaria incidence is not lower than 2018 country, the average CERs for cost per averted case levels when the efficacy is 20% under ‘Sustain’ scenario, (‍CERcase c ) death ‍ and cost per averted death (‍CERc )‍ were cumulative averted cases are notable, ranging from 23 calculated by dividing the cumulative net cost over million in the ‘Innovative’ scenario to 52 million in the cumulative averted cases and deaths from 2023 to 2027, ‘Sustain’ scenario (figure 2A). respectively: ( ) The impact of iMDA is most considerable if the interven- ∑2027 t=2023 Ct,c iMDA −Caverted tion can be quickly expanded nationwide in 7 years. The CERcase c = ∑2027 (5) t,c ‍ t=2023 ( M‍ averted t,c ) lower panel of figure 1 shows that even for ‘Sustain’ and ∑2027 t=2023 Ct,c iMDA −Caverted ‘No change’ scenarios (ie, the least favourable for malaria CERcdeath = ∑2027 (6) t,c ‍ averted t=2023 Dt,c ‍ control), iMDA leads to a downward-­sloping curve from Along with other impact estimates, these two ratios are 2024. Take the ‘Sustain’ scenario as an example. With of particular interest because they identify the scenarios an efficacy of 20%, iMDA can bring the growing malaria that yield the greatest reduction of malaria burden for burden back to the 2018 level within 10 years and avert the least resources and help to guide uptake decisions. 57 million cases from 2023 to 2027 (figure 2A). With 40% Marathe A, et al. BMJ Global Health 2021;6:e006424. doi:10.1136/bmjgh-2021-006424 5 BMJ Global Health Figure 2 Simulated impacts of ivermectin mass drug administration in all nine countries for different Griffin scenario and uptake levels. (A) Cumulative averted cases and deaths and (B) cumulative averted financial costs. efficacy, iMDA is estimated to avert 113 million cases and 20%, a ‘Conservative’ iMDA uptake can avert a total of 38 reduce malaria incidence to 249.5 per 1000 population 000 deaths in 5 years and the numbers of averted deaths at risk by the end of 2027, which is lower than the base- are 88 000 and 95 000 under ‘Rapid’ and ‘National’ line incidence in the ‘No change’ scenario. However, the uptake scenarios, respectively. Under the ‘No change’ impact tends to be smaller under the ‘Innovate’ scenario global progress with an efficacy of 20%, the number of compared with other scenarios, which includes longer-­ averted deaths range from 36 000 to 90 000. Consistent lasting insecticidal nets and expanded seasonal malaria with the results of averted cases, the numbers are smaller chemoprevention for children aged 3 months up to 10 when the global progress is ‘Innovate’ compared with the years.20 Under the ‘Innovate’ scenario, the estimated ‘Sustain’ and ‘No change’ cases. cumulative averted cases are between 24 million (effi- cacy=20%) to 48 million (efficacy=40%). Economic impact and CER In addition to cumulative averted cases, figure 2A Figure 2B shows the cumulative averted financial costs presents cumulative averted deaths due to three uptake due to iMDA under three uptake levels. Since the treat- levels of ivermectin, compared with the baseline. When ment cost of a severe episode is about 10 times higher the global malaria scenario is ‘Sustain’ with an efficacy of than that of an uncomplicated episode, the averted costs 6 Marathe A, et al. BMJ Global Health 2021;6:e006424. doi:10.1136/bmjgh-2021-006424 BMJ Global Health Table 2 An overall summary of gross/net cost and cost-­effectiveness of iMDA* for all nine countries Scale-­up cost† Net cost‡ CER§ for averted CER§ for averted Uptake Efficacy Griffin scenario (million US$) (million US$) cases (US$) deaths (US$) Conservative 40% Sustain 667.8 112.1 2 1460   No change 667.8 177.4 4 2435   Accelerate 1 667.8 232.3 6 4123   20% Sustain 667.8 389.7 17 10 141   No change 667.8 422.3 21 11 585   Accelerate 1 667.8 449.8 25 15 954 Rapid 40% Sustain 1528.8 258.4 2 1475   No change 1528.8 412.0 4 2484   Accelerate 1 1528.8 540.9 7 4253   20% Sustain 1528.8 892.1 17 10 164   No change 1528.8 969.1 21 11 659   Accelerate 1 1528.8 1033.7 25 16 217 National 40% Sustain 1662.3 282.2 2 1487   No change 1662.3 453.7 5 5057   Accelerate 1 1662.3 597.2 7 4374   20% Sustain 1662.3 970.5 17 10 199   No change 1662.3 1056.5 21 11 742   Accelerate 1 1662.3 1128.4 26 16 486 All numbers are inflation-­adjusted to 2020 US$ and reflect summations from 2023 to 2027 in the nine countries where the ivermectin intervention is applied; severity is set at 3%. *iMDA: ivermectin mass drug administration. †Scale-­up cost is the cost of implementing iMDA and includes costs of drug and drug delivery. ‡Net cost of iMDA is the scale-­up cost of iMDA minus the cumulative treatment cost averted due to iMDA. §CER: cost-­effectiveness ratio. not only depend on the efficacy of ivermectin but also because of potential delaying or interrupting treatments on the proportion of severe cases. Under the ‘Conserv- and intervention programmes. Therefore, the selected ative’ uptake level, the cumulative averted treatment scenarios of ‘Sustain’, ‘No change’ and ‘Accelerate 1’ costs can range from US$108 million at 2020 (in ‘Innova- are more likely to reflect the possible current paths than tive’ scenario, efficacy 20% and severity 1%) to US$556 the scenarios of ‘Accelerate 2’ and ‘Innovate’. As results million (in ‘Sustain’ scenario, efficacy 40% and severity do not change significantly with severity proportions, we 3%) across all nine countries. The figure shows that the use 3% severity for the main set of results. Similar results simulated averted costs are most sensitive to the assump- based on 1% severity can be found in online supple- tion of efficacy but quite robust to different severity mental tables A-­C in S1 file. proportions. The gross intervention costs reflect the scale-­up costs Following a similar pattern, the cumulative averted of purchasing and delivering ivermectin to the target costs under ‘Rapid’ uptake range from US$241 million population. Uptake level is the only factor that affects to US$1.27 billion, which are more than twice of the the gross intervention cost from 2023 to 2027, which is averted costs in the ‘Conservative’ uptake scenario. US$667.8 million under ‘Conservative’ uptake, US$1.53 Under ‘National’, the averted costs are slightly higher billion under ‘Rapid’ uptake and US$1.66 billion under compared with the costs under the ‘Rapid’ uptake, that ‘National’ uptake. The net intervention costs measure is, from US$255 million up to US$1.38 billion. the costs of the intervention after accounting for the Table 2 shows the overall gross and net costs of imple- saving in treatment costs due to averted cases. Table 2 menting the iMDA in these nine countries for the period shows that the net costs of implementing iMDA can be from 2023 to 2027, as well as CERs calculated based on as low as US$112.1 million in the ‘Sustain’ scenario with averted cases and deaths. Although there are a total of 60 40% efficacy and ‘Conservative’ uptake, and as high as scenarios in the full-­factorial design (online supplemental US$1.13 billion in ‘Accelerate 1’ with 20% efficacy and file S1), only 18 selected scenarios are presented in this ‘National’ uptake. The cost per case averted indicates that table. According to a geospatial modelling estimated by the most cost-­effective scenario for iMDA occurs when WHO,6 the current COVID-­19 pandemic is a top evolving this vector control tool is highly efficacious (ie, 40%) and risk to increase malaria cases and deaths for the year 2020 when the scenario for global progress on malaria is the Marathe A, et al. BMJ Global Health 2021;6:e006424. doi:10.1136/bmjgh-2021-006424 7 BMJ Global Health least favourable (ie, ‘Sustain’ scenario). In this case, the Cost-effectiveness for averted deaths lowest net cost is $2 per case averted and $1460 to $1487 Table 3 panel B shows the country-­ specific net costs per death averted, depending on the uptake strategy. per death averted due to iMDA. A comparison between However, if ivermectin is less efficacious (ie, 20%), the countries suggests that iMDA in Burkina Faso, Mali and net cost per case averted can range between $17 and $26, Niger are expected to have lower CERs than in other and the net cost per death averted is between $10 141 countries. For instance, if global malaria interventions and $16 486. reverse back to the coverage levels of 2011–2013 (ie, ‘Sustain’ scenario) due to the COVID-­19 pandemic, the Country-specific results averted cost per death by an iMDA with 40% efficacy in We conducted the above analyses for each country sepa- these three countries will exceed its implementation cost. rately. The online Supplementary Material shows each Take Burkina Faso as an example, the implementation country’s simulated malaria incidence (online supple- cost of a rapid uptake in ‘Sustain’ scenario is US$60.3 mental figure A in S11 – S19 files), cumulative averted million, and the averted treatment cost is US$70.3 cases (online supplemental figure B in S11 – S19 files), million with 18 852 averted deaths (online supplemental cumulative averted deaths (online supplemental figure file S6 table B). However, if the scenario is ‘Innovative’, C in S11 – S19 files) and cumulative averted financial a rapid uptake of iMDA in Burkina Faso can only avert costs (online supplemental figure D in S11 – S19 files). 7576 deaths and US$30.8 million treatment costs, in A summary of net costs per case and per death averted which‍CERdeath c = 3, 895.‍ are presented here to compare the cost-­effectiveness of On the other hand, Tanzania, Uganda and Ghana iMDA among countries. Full results for each country are and have relatively high CERs among study coun- reported in online supplemental S2–S9. tries. Take Tanzania as an example, the net cost in the ‘Sustain’ scenario is higher than that in other countries, ranging from US$7505 to US$19 211 per death averted, Cost-effectiveness for averted cases depending on the level of efficacy. However, in this case, The net cost per case averted under different scenarios the intervention still averts 7438 to 14 842 additional are shown in table 3 panel A. The CERs are robust to deaths (online supplemental file S10 table B), which is different severity assumptions and change little between not insignificant. uptake levels (see table 2 for instance). Therefore, table 3 only reports the CERs calculated based on the assumption of ‘Rapid’ uptake and 3% of cases becoming DISCUSSION severe. The main findings highlight a few observations about the Depending on the Griffin scenario, the net cost per potential impact and economic viability of iMDA. First, it case averted ranges from US$−2 to US$141. The negative is important to know the current level of progress being net cost means that total averted treatment costs exceed made against malaria globally. Due to the disruption the scale-­up costs of purchasing and delivering ivermectin of COVID-­19, the ‘Sustain’ and ‘No change’ scenarios to the target population in a country. In general, iMDA’s are more likely to be reflective of the future malaria value added increases as the global malaria progress slows landscape,6 25 so we focus on these two scenarios in the down from ‘Innovate’ to ‘Sustain’. In other words, iMDA following discussion. Simulated malaria incidence shows is more cost-­effective when other malaria interventions that while only ‘Rapid’ or ‘National’ uptake of iMDA can remain at coverage levels of 2011–2013, as compared with tame the increasing overall malaria burden, a ‘Conserv- a situation where there are innovative gains in coverage ative’ uptake would still help slow down the increasing and treatment. Based on net cost per case averted, we can trends by averting malaria cases and deaths. Second, rank the nine countries from lowest to highest CER as averted treatment costs are most sensitive to iMDA effi- follows: Burkina Faso, Mali, Niger, Democratic Republic cacy. Nonetheless, even if a higher efficacy level (40%) of the Congo, Mozambique, Nigeria, Uganda, Ghana yields lower net costs, a lower efficacy level (20%) still and Tanzania. The ranking is the same under different contributes to reducing the global malaria burden. Large-­ uptake levels, and under the two levels of efficacy (20% scale, randomised controlled trials of iMDA in at-­ risk and 40%). Burkina Faso has the lowest CER, with a net populations are currently underway with BOHEMIA benefit of US$2 under ‘Sustain’ scenario and a break-­ (https://​bohemiaconsortium.​org/) and other relevant even in ‘No change’ scenario, assuming an efficacy of trials.26–29 Results of these trials will better estimate effi- 40%. When an efficacy of 20% is assumed, the CERs cacy of iMDA, and can be used to further refine expec- increase by US$11 to US$23, reaching the highest value tations of the cost-­effectiveness of iMDA strategies.16 30 31 under the ‘Innovate’ scenario where the net cost is US$35 Even with the lowest efficacy of iMDA estimated at 20%, per case averted. Comparatively, iMDA in Tanzania has the simulated results suggest that a rapid uptake of iMDA the highest CER, where net costs per case averted range can avert a total of 46–52 million malaria cases in these from US$21 to US$65 with an assumed efficacy of 40%, countries, leading to a treatment cost savings of around or US$55 to US$141 (more than double) when an effi- US$500 million and over 80 000 deaths averted. Given cacy of 20% is assumed. the 218 million estimated total malaria cases in 2015,25 8 Marathe A, et al. BMJ Global Health 2021;6:e006424. doi:10.1136/bmjgh-2021-006424 Table 3 Net cost of iMDA* per case averted and per death averted by country under two ivermectin efficacy levels Net cost (US$) (A) Per case averted (B) Per death averted Griffin scenario Sustain No change Accelerate1 Accelerate2 Innovate Sustain No change Accelerate1 Accelerate2 Innovate Efficacy 40%  Burkina Faso −2 0 1 7 12 −531 −84 411 2403 3895  Mali −1 0 2 7 12 −916 75 1239 5782 9139  Niger 0 1 3 9 15 −227 545 1571 5339 8041  COD† 1 3 5 11 18 581 1623 3221 8710 12 503  Mozambique 2 3 5 13 19 1019 2120 3909 9900 13 979  Nigeria 2 4 6 14 20 1378 2452 4290 10 309 14 353  Uganda 2 4 6 14 21 2299 3996 6930 16 504 22 920  Ghana 6 9 12 21 30 4195 5437 8192 16 347 21 463 Marathe A, et al. BMJ Global Health 2021;6:e006424. doi:10.1136/bmjgh-2021-006424  Tanzania 21 26 31 49 65 7505 8468 11 639 19 936 24 636 Efficacy 20%  Burkina Faso 9 12 15 25 35 2653 3277 4795 9149 11 815  Mali 9 12 16 27 37 6297 1330 11 171 21 067 27 087  Niger 11 14 18 30 41 5658 6760 9678 17 823 22 703  COD† 14 17 21 35 47 9022 10 536 14 846 26 602 33 513  Mozambique 15 19 23 37 50 10 178 11 792 16 520 29 306 36 765  Nigeria 16 20 25 39 53 10 532 12 119 16 893 29 699 37 117  Uganda 17 21 25 40 54 16 797 19 446 26 901 47 256 59 036  Ghana 25 30 36 55 73 16 239 18 154 24 770 41 844 51 394  Tanzania 55 64 74 109 141 19 211 20 829 27 758 44 746 53 768 All net costs are inflation-­adjusted to 2020 US$ and simulated based on severity=3% and ‘Rapid’ uptake level. *iMDA: ivermectin mass drug administration. †COD: Democratic Republic of the Congo. BMJ Global Health 9 BMJ Global Health this scenario would lead to a total of 21%–23% reduction Limitations in world malaria cases over the 5-­year period from 2023 Common to previous cost-­effectiveness literature using to 2027, contributing to the GTS goal considerably. On simulation methods, this study has several limitations. the other hand, iMDA will widen the gap between the First, the costs for treatment were estimated based on invested funding and the financing targets for malaria previous literature that provides an average cost across control and elimination under the GTS goal.32 This multiple studies instead of being collected from an study finds that scaling up iMDA in the nine selected existing country-­ specific iMDA programme, and the HBHI countries can cost a total of US$0.67 billion under benefits were restricted to treatment cost savings without ‘Conservative’ uptake, US$1.53 billion under ‘Rapid’ other social benefits, such as increased productivity from uptake and US$1.66 billion under ‘National’ uptake from the cases averted, value of life years saved and the poten- 2023 to 2027. From 2016 to 2018, there was an estimated tial reduction in incidence of other NTDs. Nonetheless, US$3.5 billion reported by the 11 HBHI countries to the cost of delivery was based on evidence from iMDAs fight against malaria.2 Assuming funding levels for HBHI for NTDs in African countries and, thus, we expect the countries remains the same, implementing this interven- costs of our intervention to be fairly similar, although this tion under the three uptake levels will potentially increase may be overly optimistic. Second, our estimated scale-­up yearly funding needs by 11.5%, 26.2% and 28.5%, respec- costs were the lower-­bounds of the actual costs because tively. Moreover, the costs of rapid scale-­up of iMDA can some cost items, such as personnel training costs, capital be relatively large for some countries and challenges the costs and management/monitoring costs, were not economic viability of adopting this new tool nationwide. included in the simulation. However, due to economies Given this, there may be options for countries to consider of scale,19 the unit cost of drug delivery tends to decrease that may help lower costs while targeting the highest as the intervention coverage increases, which may partly at-­risk populations at a subnational level or sharing cost offset the underestimation of scale-­up costs. Third, some with some NTD programmes. For example, several NTD parameters in the model were assumed to be fixed, such programmes deliver ivermectin to people once a year as the fraction of a country’s eligible population and iver- in all HBHI countries, as ivermectin is effective against mectin efficacy. As a result, the model could not account a number of other parasites, namely onchocerciasis and for feedback and potential changes in immunity when lymphatic filariasis. If their implementation period can endemicity is changed by the intervention. We acknowl- partly overlap with iMDA for malaria, one possible way to edge that accurate prediction is very challenging since reduce the scale-­up cost and improve cost-­effectiveness many factors may change the parameters over time. By is to share one round of ivermectin delivery. Moreover, conducting a full-­factorial design, we used a wide range the collaboration with NTD programmes may reduce of scenario settings to partly accommodate the uncer- implementation budgets by benefiting from existing tainty. Future studies may build on this approach by NTD programme infrastructure and human resources, changing factors, for instance, including the correlation as well as the population’s social acceptance of iMDA between per cent of severe cases and mortality rate, trans- given longstanding NTD interventions. However, coordi- mission setting and insecticide resistance. Fourth, with a nation may not be easy, given differences in target popu- focus on country-­level health impacts, this model does lations and timing of programmes. A significant amount not consider subnational iMDA strategies. Future studies of discussion would need to occur at the country-­level to may consider scaling up the intervention targeting to the ensure benefits would be achieved for both the NTD and areas within a country where it would be most effective to malaria programmes. improve the overall cost-­effectiveness of iMDA. The heterogeneity in country-­specific results implies that there is no one-­size-­fits-­all malaria control strategy and countries should select the most effective malaria CONCLUSIONS control strategy for the least cost. The difference in simu- The analytical tool developed by this study will help lated CERs is mainly due to different initial malaria inci- frame investments in ivermectin trials, cost-­effectiveness dence rates between countries. Holding other factors studies, as well as investments in innovations related to the same, iMDA is expected to avert more malaria cases implementation in HBHI countries. The modelling in a country with a higher incidence than in a country framework can be expanded to account for country-­ with a lower incidence. This approach could be taken at specific factors, such as level of malaria transmission, a subnational level, where rather than scaling-­up equally opportunities for cost-­sharing with NTD programmes, across the at-­risk population as a whole (as was modelled distribution of the at-­risk population over space and time, in this study), countries target scale-­up in districts with infrastructure and personnel available for programme the highest malaria incidence first, to have the greatest implementation and financial resources. When refined health impacts for the lowest net cost. Although imple- with actual data and country inputs on delivery strategy menting iMDA in countries or districts at the subnational and targeting, this can be an increasingly robust tool to level with lower incidence is more costly, it has a potential support national decision-­making. This study finds that to accelerate malaria elimination, which needs to be eval- iMDA is more cost-­effective to implement in some coun- uated by future studies. tries (eg, Burkina Faso, Mali and Niger) than in others, 10 Marathe A, et al. BMJ Global Health 2021;6:e006424. doi:10.1136/bmjgh-2021-006424 BMJ Global Health such as Tanzania and Uganda; although when it comes properly cited, appropriate credit is given, any changes made indicated, and the to making policy decisions, country-­specific evaluation of use is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. the cost-­effectiveness of iMDA relative to or in conjunc- ORCID iDs tion with other in-­country options is more relevant than Carlos J Chaccour http://​orcid.​org/​0000-​0001-​9812-​050X simply comparing values across countries. Cassidy Rist http://​orcid.​org/​0000-​0002-​7558-​8094 Most significantly, the results are sensitive to the effi- cacy of ivermectin and the underlying global interven- REFERENCES tion scenario that best reflects the current situation 1 World Health Organization. Global technical strategy for malaria relative to progress on malaria intervention delivery 2016-­2030. Geneva: WHO, 2015. 2 World Health Organization. World malaria report 2019. Geneva: and future innovations. The recent COVID-­19 outbreak WHO, 2019. is likely resulting in substantial increase in morbidity 3 World Health Organization. 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