Cost and cost-effectiveness of indoor residual spraying with pirimiphos-methyl in a high malaria transmission district of Mozambique with high access to standard insecticide-treated nets.

BACKGROUND: As malaria cases increase in some of the highest burden countries, more strategic deployment of new and proven interventions must be evaluated to meet global malaria reduction goals. METHODS: The cost and cost-effectiveness of indoor residual spraying (IRS) with pirimiphos-methyl (Actellic®300 CS) were assessed in a high transmission district (Mopeia) with high access to pyrethroid insecticide-treated nets (ITNs), compared to ITNs alone. The major mosquito vectors in the area were susceptible to primiphos-methyl, but resistant to pyrethoids. A decision analysis approach was followed to conduct deterministic and probabilistic sensitivity analyses in a theoretical cohort of 10,000 children under five years of age (U5) and 10,000 individuals of all ages, separately. Model parameters and distributions were based on prospectively collected cost and epidemiological data from a cluster-randomized control trial and a literature review. The primary analysis used health facility-malaria incidence, while community cohort incidence and cross-sectional prevalence rates were used in sensitivity analyses. Lifetime costs, malaria cases, deaths and disability-adjusted life-years (DALYs) were calculated to determine the incremental costs per DALY averted through IRS. RESULTS: The average IRS cost per person protected was US$8.26 and 51% of the cost was insecticide. IRS averted 46,609 (95% CI 46,570-46,646) uncomplicated and 242 (95% CI 241-243) severe lifetime cases in a theoretical children U5 cohort, yielding an incremental cost-effectiveness ratio (ICER) of US$400 (95% CI 399-402) per DALY averted. In the all-age cohort, the ICER was higher: US$1,860 (95% CI 1,852-1,868) per DALY averted. Deterministic and probabilistic results were consistent. When adding the community protective effect of IRS, the cost per person protected decreased (US$7.06) and IRS was highly cost-effective in children U5 (ICER = US$312) and cost-effective in individuals of all ages (ICER = US$1,431), compared to ITNs alone. CONCLUSION: This study provides robust evidence that IRS with pirimiphos-methyl can be cost-effective in high transmission regions with high pyrethroid ITN coverage where the major vector is susceptible to pirimiphos-methyl but resistant to pyrethroids. The finding that insecticide cost is the main driver of IRS costs highlights the need to reduce the insecticide price without jeopardizing effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02910934 (Registered 22 September 2016). https://clinicaltrials.gov/ct2/show/NCT02910934?term=NCT02910934&draw=2&rank=1.

The economic burden of malaria on households and the health system in a high transmission district of Mozambique.

BACKGROUND: Malaria remains a leading cause of morbidity and mortality in Mozambique. Increased investments in malaria control have reduced the burden, but few studies have estimated the costs of malaria in the country. This paper estimates the economic costs associated with malaria care to households and to the health system in the high burden district of Mopeia in central Mozambique. METHODS: Malaria care-seeking and morbidity costs were routinely collected among 1373 households with at least one child enrolled in an active case detection (ACD) cohort in Mopeia, and through cross-sectional surveys with 824 families in 2017 and 805 families in 2018. Household costs included direct medical expenses, transportation and opportunity costs of the time lost due to illness. Structured questionnaires were used to estimate the health system costs associated with malaria care in all 13 district health facilities. Cost estimations followed an ingredient-based approach with a top-down allocation approach for health system expenses. RESULTS: Among participants in cross-sectional studies, households sought care for nine severe malaria cases requiring hospital admission and for 679 uncomplicated malaria cases. Median household costs associated with uncomplicated malaria among individuals of all ages were US$ 3.46 (IQR US$ 0.07-22.41) and US$ 81.08 (IQR US$ 39.34-88.38) per severe case. Median household costs were lower among children under five (ACD cohort): US$ 1.63 (IQR US$ 0.00-7.79) per uncomplicated case and US$ 64.90 (IQR US$ 49.76-80.96) per severe case. Opportunity costs were the main source of household costs. Median health system costs associated with malaria among patients of all ages were US$ 4.34 (IQR US$ 4.32-4.35) per uncomplicated case and US$ 26.56 (IQR US$ 18.03-44.09) per severe case. Considering household and health system costs, the overall cost of malaria care to society was US$ 7.80 per uncomplicated case and US$ 107.64 per severe case, representing an economic malaria burden of US$ 332,286.24 (IQR US$ 186,355.84-1,091,212.90) per year only in Mopeia. CONCLUSIONS: Despite the provision of free malaria services, households in Mopeia incur significant direct and indirect costs associated with the disease. Furthermore, the high malaria cost on the Mozambican health system underscores the need to strengthen malaria prevention to reduce the high burden and improve productivity in the region.

Establishment of the Ivermectin Research for Malaria Elimination Network: updating the research agenda.

The potential use of ivermectin as an additional vector control tool is receiving increased attention from the malaria elimination community, driven by the increased importance of outdoor/residual malaria transmission and the threat of insecticide resistance where vector tools have been scaled-up. This report summarizes the emerging evidence presented at a side meeting on "Ivermectin for malaria elimination: current status and future directions" at the annual meeting of the American Society of Tropical Medicine and Hygiene in New Orleans on November 4, 2014. One outcome was the creation of the "Ivermectin Research for Malaria Elimination Network" whose main goal is to establish a common research agenda to generate the evidence base on whether ivermectin-based strategies should be added to the emerging arsenal to interrupt malaria transmission.

Ivermectin to reduce malaria transmission: a research agenda for a promising new tool for elimination.

BACKGROUND: The heterogeneity of malaria transmission makes widespread elimination a difficult goal to achieve. Most of the current vector control measures insufficiently target outdoor transmission. Also, insecticide resistance threatens to diminish the efficacy of the most prevalent measures, indoor residual spray and insecticide treated nets. Innovative approaches are needed. The use of endectocides, such as ivermectin, could be an important new addition to the toolbox of anti-malarial measures. Ivermectin effectively targets outdoor transmission, has a novel mechanism of action that could circumvent resistance and might be distributed over the channels already in place for the control of onchocerciasis and lymphatic filariasis. METHODS: The previous works involving ivermectin and Anopheles vectors are reviewed and summarized. A review of ivermectin's safety profile is also provided. Finally three definitive clinical trials are described in detail and proposed as the evidence needed for implementation. Several smaller and specific supportive studies are also proposed. CONCLUSIONS: The use of ivermectin solves many challenges identified for future vector control strategies. It is an effective and safe endectocide that was approved for human use more than 25 years ago. Recent studies suggest it might become an effective and complementary strategy in malaria elimination and eradication efforts; however, intensive research will be needed to make this a reality.

Ivermectin as a novel malaria control tool: Getting ahead of the resistance curse.

Reduction in malaria clinical cases is strongly dependent on the ability to prevent Anopheles infectious bites. Vector control strategies using long-lasting insecticidal nets and indoor residual spraying with insecticides have contributed to significantly reduce the incidence of malaria in many endemic countries, especially in the Sub-Saharan region. However, global progress in reducing malaria cases has plateaued since 2015 mostly due to the increased insecticide resistance and behavioral changes in Anopheles vectors. Additional control strategies are thus required to further reduce the burden of malaria and contain the spread of resistant and invasive Anopheles vectors. The use of endectocides such as ivermectin as an additional malaria control tool is now receiving increased attention, driven by its different mode of action compared to insecticides used so far and its excellent safety record for humans. In this opinion article, we discuss the advantages and disadvantages of using ivermectin for malaria control with a focus on the risk of selecting ivermectin resistance in malaria vectors. We also highlight the importance of understanding how ivermectin resistance could develop in mosquitoes and what its underlying mechanisms and associated molecular markers are, and propose a research agenda to manage this phenomenon.

Alternative approaches for creating a wealth index: the case of Mozambique.

INTRODUCTION: The wealth index is widely used as a proxy for a household's socioeconomic position (SEP) and living standard. This work constructs a wealth index for the Mopeia district in Mozambique using data collected in year 2021 under the BOHEMIA (Broad One Health Endectocide-based Malaria Intervention in Africa) project. METHODS: We evaluate the performance of three alternative approaches against the Demographic and Health Survey (DHS) method based wealth index: feature selection principal components analysis (PCA), sparse PCA and robust PCA. The internal coherence between four wealth indices is investigated through statistical testing. Validation and an evaluation of the stability of the wealth index are performed with additional household income data from the BOHEMIA Health Economics Survey and the 2018 Malaria Indicator Survey data in Mozambique. RESULTS: The Spearman's rank correlation between wealth index ventiles from four methods is over 0.98, indicating a high consistency in results across methods. Wealth rankings and households' income show a strong concordance with the area under the curve value of ~0.7 in the receiver operating characteristic analysis. The agreement between the alternative wealth indices and the DHS wealth index demonstrates the stability in rankings from the alternative methods. CONCLUSIONS: This study creates a wealth index for Mopeia, Mozambique, and shows that DHS method based wealth index is an appropriate proxy for the SEP in low-income regions. However, this research recommends feature selection PCA over the DHS method since it uses fewer asset indicators and constructs a high-quality wealth index.

Correction: A systematic review and an individual patient data meta-analysis of ivermectin use in children weighing less than fifteen kilograms: Is it time to reconsider the current contraindication?

[This corrects the article DOI: 10.1371/journal.pntd.0009144.].

Inferring the epidemiological benefit of indoor vector control interventions against malaria from mosquito data.

The cause of malaria transmission has been known for over a century but it is still unclear whether entomological measures are sufficiently reliable to inform policy decisions in human health. Decision-making on the effectiveness of new insecticide-treated nets (ITNs) and the indoor residual spraying of insecticide (IRS) have been based on epidemiological data, typically collected in cluster-randomised control trials. The number of these trials that can be conducted is limited. Here we use a systematic review to highlight that efficacy estimates of the same intervention may vary substantially between trials. Analyses indicate that mosquito data collected in experimental hut trials can be used to parameterize mechanistic models for Plasmodium falciparum malaria and reliably predict the epidemiological efficacy of quick-acting, neuro-acting ITNs and IRS. Results suggest that for certain types of ITNs and IRS using this framework instead of clinical endpoints could support policy and expedite the widespread use of novel technologies.

Potential impact of 5 years of ivermectin mass drug administration on malaria outcomes in high burden countries.

INTRODUCTION: The global progress against malaria has slowed significantly since 2017. As the current malaria control tools seem insufficient to get the trend back on track, several clinical trials are investigating ivermectin mass drug administration (iMDA) as a potential additional vector control tool; however, the health impacts and cost-effectiveness of this new strategy remain unclear. METHODS: We developed an analytical tool based on a full factorial experimental design to assess the potential impact of iMDA in nine high burden sub-Saharan African countries. The simulated iMDA regimen was assumed to be delivered monthly to the targeted population for 3 months each year from 2023 to 2027. A broad set of parameters of ivermectin efficacy, uptake levels and global intervention scenarios were used to predict averted malaria cases and deaths. We then explored the potential averted treatment costs, expected implementation costs and cost-effectiveness ratios under different scenarios. RESULTS: In the scenario where coverage of malaria interventions was maintained at 2018 levels, we found that iMDA in these nine countries has the potential to reverse the predicted growth of malaria burden by averting 20-50 million cases and 36 000-90 000 deaths with an assumed efficacy of 20%. If iMDA has an efficacy of 40%, we predict between 40-99 million cases and 73 000-179 000 deaths will be averted with an estimated net cost per case averted between US$2 and US$7, and net cost per death averted between US$1460 and US$4374. CONCLUSION: This study measures the potential of iMDA to reverse the increasing number of malaria cases for several sub-Saharan African countries. With additional efficacy information from ongoing clinical trials and country-level modifications, our analytical tool can help determine the appropriate uptake strategies of iMDA by calculating potential marginal gains and costs under different scenarios.

A systematic review and an individual patient data meta-analysis of ivermectin use in children weighing less than fifteen kilograms: Is it time to reconsider the current contraindication?

BACKGROUND: Oral ivermectin is a safe broad spectrum anthelminthic used for treating several neglected tropical diseases (NTDs). Currently, ivermectin use is contraindicated in children weighing less than 15 kg, restricting access to this drug for the treatment of NTDs. Here we provide an updated systematic review of the literature and we conducted an individual-level patient data (IPD) meta-analysis describing the safety of ivermectin in children weighing less than 15 kg. METHODOLOGY/PRINCIPAL FINDINGS: A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for IPD guidelines by searching MEDLINE via PubMed, Web of Science, Ovid Embase, LILACS, Cochrane Database of Systematic Reviews, TOXLINE for all clinical trials, case series, case reports, and database entries for reports on the use of ivermectin in children weighing less than 15 kg that were published between 1 January 1980 to 25 October 2019. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017056515. A total of 3,730 publications were identified, 97 were selected for potential inclusion, but only 17 sources describing 15 studies met the minimum criteria which consisted of known weights of children less than 15 kg linked to possible adverse events, and provided comprehensive IPD. A total of 1,088 children weighing less than 15 kg were administered oral ivermectin for one of the following indications: scabies, mass drug administration for scabies control, crusted scabies, cutaneous larva migrans, myiasis, pthiriasis, strongyloidiasis, trichuriasis, and parasitic disease of unknown origin. Overall a total of 1.4% (15/1,088) of children experienced 18 adverse events all of which were mild and self-limiting. No serious adverse events were reported. CONCLUSIONS/SIGNIFICANCE: Existing limited data suggest that oral ivermectin in children weighing less than 15 kilograms is safe. Data from well-designed clinical trials are needed to provide further assurance.

Targeting cattle for malaria elimination: marked reduction of Anopheles arabiensis survival for over six months using a slow-release ivermectin implant formulation.

BACKGROUND: Mosquitoes that feed on animals can survive and mediate residual transmission of malaria even after most humans have been protected with insecticidal bednets or indoor residual sprays. Ivermectin is a widely-used drug for treating parasites of humans and animals that is also insecticidal, killing mosquitoes that feed on treated subjects. Mass administration of ivermectin to livestock could be particularly useful for tackling residual malaria transmission by zoophagic vectors that evade human-centred approaches. Ivermectin comes from a different chemical class to active ingredients currently used to treat bednets or spray houses, so it also has potential for mitigating against emergence of insecticide resistance. However, the duration of insecticidal activity obtained with ivermectin is critical to its effectiveness and affordability. RESULTS: A slow-release formulation for ivermectin was implanted into cattle, causing 40 weeks of increased mortality among Anopheles arabiensis that fed on them. For this zoophagic vector of residual malaria transmission across much of Africa, the proportion surviving three days after feeding (typical mean duration of a gonotrophic cycle in field populations) was approximately halved for 25 weeks. CONCLUSIONS: This implantable ivermectin formulation delivers stable and sustained insecticidal activity for approximately 6 months. Residual malaria transmission by zoophagic vectors could be suppressed by targeting livestock with this long-lasting formulation, which would be impractical or unacceptable for mass treatment of human populations.

Combination of indoor residual spraying with long-lasting insecticide-treated nets for malaria control in Zambezia, Mozambique: a cluster randomised trial and cost-effectiveness study protocol.

BACKGROUND: Most of the reduction in malaria prevalence seen in Africa since 2000 has been attributed to vector control interventions. Yet increases in the distribution and intensity of insecticide resistance and higher costs of newer insecticides pose a challenge to sustaining these gains. Thus, endemic countries face challenging decisions regarding the choice of vector control interventions. METHODS: A cluster randomised trial is being carried out in Mopeia District in the Zambezia Province of Mozambique, where malaria prevalence in children under 5 is high (68% in 2015), despite continuous and campaign distribution of long-lasting insecticide-treated nets (LLINs). Study arm 1 will continue to use the standard, LLIN-based National Malaria Control Programme vector control strategy (LLINs only), while study arm 2 will receive indoor residual spraying (IRS) once a year for 2 years with a microencapsulated formulation of pirimiphos-methyl (Actellic 300 CS), in addition to the standard LLIN strategy (LLINs+IRS). Prior to the 2016 IRS implementation (the first of two IRS campaigns in this study), 146 clusters were defined and stratified per number of households. Clusters were then randomised 1:1 into the two study arms. The public health impact and cost-effectiveness of IRS intervention will be evaluated over 2 years using multiple methods: (1) monthly active malaria case detection in a cohort of 1548 total children aged 6-59 months; (2) enhanced passive surveillance at health facilities and with community health workers; (3) annual cross-sectional surveys; and (4) entomological surveillance. Prospective microcosting of the intervention and provider and societal costs will be conducted. Insecticide resistance status pattern and changes in local Anopheline populations will be included as important supportive outcomes. DISCUSSION: By evaluating the public health impact and cost-effectiveness of IRS with a non-pyrethroid insecticide in a high-transmission setting with high LLIN ownership, it is expected that this study will provide programmatic and policy-relevant data to guide national and global vector control strategies. TRIAL REGISTRATION NUMBER: NCT02910934.

Oral, Slow-Release Ivermectin: Biting Back at Malaria Vectors.

Bellinger and colleagues offer an elegant twist for a promising new tool against malaria. This formulation is designed to release ivermectin, a mosquito-killing drug for 10 days after a single oral dose. This could reduce the vector population and serve as a complementary tool for malaria elimination.

Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae.

Mass administration of endectocides, drugs that kill blood-feeding arthropods, has been proposed as a complementary strategy to reduce malaria transmission. Ivermectin is one of the leading candidates given its excellent safety profile. Here we provide proof that the effect of ivermectin can be boosted at two different levels by drugs inhibiting the cytochrome or ABC transporter in the mammal host and the target mosquitoes. Using a mini-pig model, we show that drug-mediated cytochrome P450/ABC transporter inhibition results in a 3-fold increase in the time ivermectin remains above mosquito-killing concentrations. In contrast, P450/ABC transporter induction with rifampicin markedly impaired ivermectin absorption. The same ketoconazole-mediated cytochrome/ABC transporter inhibition also occurs outside the mammal host and enhances the mortality of Anopheles gambiae. This was proven by using the samples from the mini-pig experiments to conduct an ex-vivo synergistic bioassay by membrane-feeding Anopheles mosquitoes. Inhibiting the same cytochrome/xenobiotic pump complex in two different organisms to simultaneously boost the pharmacokinetic and pharmacodynamic activity of a drug is a novel concept that could be applied to other systems. Although the lack of a dose-response effect in the synergistic bioassay warrants further exploration, our study may have broad implications for the control of parasitic and vector-borne diseases.

Going beyond personal protection against mosquito bites to eliminate malaria transmission: population suppression of malaria vectors that exploit both human and animal blood.

Protecting individuals and households against mosquito bites with long-lasting insecticidal nets (LLINs) or indoor residual spraying (IRS) can suppress entire populations of unusually efficient malaria vector species that predominantly feed indoors on humans. Mosquitoes which usually feed on animals are less reliant on human blood, so they are far less vulnerable to population suppression effects of such human-targeted insecticidal measures. Fortunately, the dozens of mosquito species which primarily feed on animals are also relatively inefficient vectors of malaria, so personal protection against mosquito bites may be sufficient to eliminate transmission. However, a handful of mosquito species are particularly problematic vectors of residual malaria transmission, because they feed readily on both humans and animals. These unusual vectors feed often enough on humans to be potent malaria vectors, but also often enough on animals to evade population control with LLINs, IRS or any other insecticidal personal protection measure targeted only to humans. Anopheles arabiensis and A. coluzzii in Africa, A. darlingi in South America and A. farauti in Oceania, as well as A. culicifacies species E, A. fluviatilis species S, A. lesteri and A. minimus in Asia, all feed readily on either humans or animals and collectively mediate residual malaria transmission across most of the tropics. Eliminating malaria transmission by vectors exhibiting such dual host preferences will require aggressive mosquito population abatement, rather than just personal protection of humans. Population suppression of even these particularly troublesome vectors is achievable with a variety of existing vector control technologies that remain underdeveloped or underexploited.

Developing an expanded vector control toolbox for malaria elimination.

Vector control using long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) accounts for most of the malaria burden reductions achieved recently in low and middle-income countries (LMICs). LLINs and IRS are highly effective, but are insufficient to eliminate malaria transmission in many settings because of operational constraints, growing resistance to available insecticides and mosquitoes that behaviourally avoid contact with these interventions. However, a number of substantive opportunities now exist for rapidly developing and implementing more diverse, effective and sustainable malaria vector control strategies for LMICs. For example, mosquito control in high-income countries is predominantly achieved with a combination of mosquito-proofed housing and environmental management, supplemented with large-scale insecticide applications to larval habitats and outdoor spaces that kill off vector populations en masse, but all these interventions remain underused in LMICs. Programmatic development and evaluation of decentralised, locally managed systems for delivering these proactive mosquito population abatement practices in LMICs could therefore enable broader scale-up. Furthermore, a diverse range of emerging or repurposed technologies are becoming available for targeting mosquitoes when they enter houses, feed outdoors, attack livestock, feed on sugar or aggregate into mating swarms. Global policy must now be realigned to mobilise the political and financial support necessary to exploit these opportunities over the decade ahead, so that national malaria control and elimination programmes can access a much broader, more effective set of vector control interventions.