A hybrid effectiveness-implementation study protocol to assess the effectiveness and chemoprevention efficacy of implementing seasonal malaria chemoprevention in five districts in Karamoja region, Uganda

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Abstract

Background

The World Health Organization (WHO) recommends seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine (SPAQ) for children aged 3 to 59 months, living in areas where malaria transmission is highly seasonal. However, due to widespread prevalence of resistance markers, SMC has not been implemented at scale in East and Southern Africa. An initial study in Uganda showed that SMC with SPAQ was feasible, acceptable, and protective against malaria in eligible children in Karamoja region. Nonetheless, exploration of alternative regimens is warranted since parasite resistance threats persist.

Objective

The study aims to test the effectiveness of SMC with Dihydroartemisinin-piperaquine (DP) or SPAQ (DP-SMC & SPAQ-SMC), chemoprevention efficacy as well as the safety and tolerability of DP compared to that of SPAQ among 3-59 months old children in Karamoja region, an area of Uganda where malaria transmission is highly seasonal.

Methods

A Type II hybrid effectiveness-implementation study design consisting of four components: 1) a cluster randomized controlled trial (cRCT) using passive surveillance to establish confirmed malaria cases in children using both SPAQ and DP; 2a) a prospective cohort study to determine the chemoprevention efficacy of SPAQ and DP (if SPAQ or DP clears sub-patent infection and provides 28 days of protection from new infection) and whether drug concentrations and/or resistance influence the ability to clear and prevent infection; 2b) a sub study examining pharmacokinetics of DP in children between 3 to <6 months; 3) a resistance markers study in children 3–59 months in the research districts plus the standard intervention districts to measure changes in resistance marker prevalence over time and finally; 4) a process evaluation.

Discussion

This study evaluates the effects of SPAQ-SMC versus DP-SMC on clinical malaria in vulnerable children in the context of high parasite SP resistance, whilst informing on the best implementation strategies.

Conclusion

This study will inform malaria policy in high-burden countries, specifically on utility of SMC outside the sahel, and contribute to progress in malaria control.

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Most cited references 16

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Mechanisms of resistance of malaria parasites to antifolates.

Aric Gregson, Christopher Plowe (2005)

Antifolate antimalarial drugs interfere with folate metabolism, a pathway essential to malaria parasite survival. This class of drugs includes effective causal prophylactic and therapeutic agents, some of which act synergistically when used in combination. Unfortunately, the antifolates have proven susceptible to resistance in the malaria parasite. Resistance is caused by point mutations in dihydrofolate reductase and dihydropteroate synthase, the two key enzymes in the folate biosynthetic pathway that are targeted by the antifolates. Resistance to these drugs arises relatively rapidly in response to drug pressure and is now common worldwide. Nevertheless, antifolate drugs remain first-line agents in several sub-Saharan African countries where chloroquine resistance is widespread, at least partially because they remain the only affordable, effective alternative. New antifolate combinations that are more effective against resistant parasites are being developed and in one case, recently introduced into use. Combining these antifolates with drugs that act on different targets in the parasite should greatly enhance their effectiveness as well as deter the development of resistance. Molecular epidemiological techniques for monitoring parasite drug resistance may contribute to development of strategies for prolonging the useful therapeutic life of this important class of drugs.

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Mapping 'partially resistant', 'fully resistant', and 'super resistant' malaria.

Cally Roper, Inbarani Naidoo (2013)

Sulfadoxine-pyrimethamine (SP) is used throughout Africa for intermittent preventive treatment (IPT) of malaria, but resistance threatens its efficacy. We found marked regional differences in the genotypes responsible for SP resistance when mapping recent surveys of dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutations. In West Africa, a 'partially resistant' combination of dhfr N51I, N59R, and S108N with dhps A437G predominates, whereas in East Africa the 'fully resistant' combination of dhfr N51I, N59R, and S108N with dhps A437G+K540E is found. There are three East African foci where 'fully resistant' populations have additionally acquired dhps 581G and/or dhfr 164L to become 'super resistant'. SP-IPT in infants and pregnant women is reported to have failed in super resistant areas prompting review of SP-IPT use in affected areas. Copyright © 2013 Elsevier Ltd. All rights reserved.

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Effectiveness of seasonal malaria chemoprevention at scale in west and central Africa: an observational study

(2020)

Summary Background Seasonal malaria chemoprevention (SMC) aims to prevent malaria in children during the high malaria transmission season. The Achieving Catalytic Expansion of SMC in the Sahel (ACCESS-SMC) project sought to remove barriers to the scale-up of SMC in seven countries in 2015 and 2016. We evaluated the project, including coverage, effectiveness of the intervention, safety, feasibility, drug resistance, and cost-effectiveness. Methods For this observational study, we collected data on the delivery, effectiveness, safety, influence on drug resistance, costs of delivery, impact on malaria incidence and mortality, and cost-effectiveness of SMC, during its administration for 4 months each year (2015 and 2016) to children younger than 5 years, in Burkina Faso, Chad, The Gambia, Guinea, Mali, Niger, and Nigeria. SMC was administered monthly by community health workers who visited door-to-door. Drug administration was monitored via tally sheets and via household cluster-sample coverage surveys. Pharmacovigilance was based on targeted spontaneous reporting and monitoring systems were strengthened. Molecular markers of resistance to sulfadoxine–pyrimethamine and amodiaquine in the general population before and 2 years after SMC introduction was assessed from community surveys. Effectiveness of monthly SMC treatments was measured in case-control studies that compared receipt of SMC between patients with confirmed malaria and neighbourhood-matched community controls eligible to receive SMC. Impact on incidence and mortality was assessed from confirmed outpatient cases, hospital admissions, and deaths associated with malaria, as reported in national health management information systems in Burkina Faso and The Gambia, and from data from selected outpatient facilities (all countries). Provider costs of SMC were estimated from financial costs, costs of health-care staff time, and volunteer opportunity costs, and cost-effectiveness ratios were calculated as the total cost of SMC in each country divided by the predicted number of cases averted. Findings 12 467 933 monthly SMC treatments were administered in 2015 to a target population of 3 650 455 children, and 25 117 480 were administered in 2016 to a target population of 7 551 491. In 2015, among eligible children, mean coverage per month was 76·4% (95% CI 74·0–78·8), and 54·5% children (95% CI 50·4–58·7) received all four treatments. Similar coverage was achieved in 2016 (74·8% [72·2–77·3] treated per month and 53·0% [48·5–57·4] treated four times). In 779 individual case safety reports over 2015–16, 36 serious adverse drug reactions were reported (one child with rash, two with fever, 31 with gastrointestinal disorders, one with extrapyramidal syndrome, and one with Quincke's oedema). No cases of severe skin reactions (Stevens-Johnson or Lyell syndrome) were reported. SMC treatment was associated with a protective effectiveness of 88·2% (95% CI 78·7–93·4) over 28 days in case-control studies (2185 cases of confirmed malaria and 4370 controls). In Burkina Faso and The Gambia, implementation of SMC was associated with reductions in the number of malaria deaths in hospital during the high transmission period, of 42·4% (95% CI 5·9 to 64·7) in Burkina Faso and 56·6% (28·9 to 73·5) in The Gambia. Over 2015–16, the estimated reduction in confirmed malaria cases at outpatient clinics during the high transmission period in the seven countries ranged from 25·5% (95% CI 6·1 to 40·9) in Nigeria to 55·2% (42·0 to 65·3) in The Gambia. Molecular markers of resistance occurred at low frequencies. In individuals aged 10–30 years without SMC, the combined mutations associated with resistance to amodiaquine (pfcrt CVIET haplotype and pfmdr1 mutations [86Tyr and 184Tyr]) had a prevalence of 0·7% (95% CI 0·4–1·2) in 2016 and 0·4% (0·1–0·8) in 2018 (prevalence ratio 0·5 [95% CI 0·2–1·2]), and the quintuple mutation associated with resistance to sulfadoxine–pyrimethamine (triple mutation in pfdhfr and pfdhps mutations [437Gly and 540Glu]) had a prevalence of 0·2% (0·1–0·5) in 2016 and 1·0% (0·6–1·6) in 2018 (prevalence ratio 4·8 [1·7–13·7]). The weighted average economic cost of administering four monthly SMC treatments was US$3·63 per child. Interpretation SMC at scale was effective in preventing morbidity and mortality from malaria. Serious adverse reactions were rarely reported. Coverage varied, with some areas consistently achieving high levels via door-to-door campaigns. Markers of resistance to sulfadoxine–pyrimethamine and amodiaquine remained uncommon, but with some selection for resistance to sulfadoxine–pyrimethamine, and the situation needs to be carefully monitored. These findings should support efforts to ensure high levels of SMC coverage in west and central Africa. Funding Unitaid.

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Author and article information

Contributors

Richard Kajubi: Role: InvestigationRole: SupervisionRole: Writing – Review & Editing

ORCID: https://orcid.org/0000-0002-9179-9182

Jennifer Ainsworth: Role: Data CurationRole: SupervisionRole: Writing – Original Draft Preparation

Kevin Baker: Role: ConceptualizationRole: Funding AcquisitionRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing – Review & Editing

ORCID: https://orcid.org/0000-0002-2040-3662

Sol Richardson: Role: ConceptualizationRole: Data CurationRole: MethodologyRole: ValidationRole: Writing – Review & Editing

Craig Bonnington: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: Writing – Review & Editing

Christian Rassi: Role: ConceptualizationRole: Funding AcquisitionRole: Project AdministrationRole: ResourcesRole: SupervisionRole: Writing – Original Draft PreparationRole: Writing – Review & Editing

Jane Achan: Role: InvestigationRole: MethodologyRole: Writing – Review & Editing

ORCID: https://orcid.org/0000-0001-8111-025X

Godfrey Magumba: Role: Funding AcquisitionRole: Project AdministrationRole: ResourcesRole: SupervisionRole: Writing – Review & Editing

Denis Rubahika: Role: SupervisionRole: Writing – Review & Editing

Jane Nabakooza: Role: MethodologyRole: SupervisionRole: Writing – Review & Editing

James Tibenderana: Role: ConceptualizationRole: Funding AcquisitionRole: InvestigationRole: MethodologyRole: Project AdministrationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing – Review & Editing

Anthony Nuwa: Role: ConceptualizationRole: Funding AcquisitionRole: InvestigationRole: MethodologyRole: Project AdministrationRole: SupervisionRole: Writing – Original Draft PreparationRole: Writing – Review & Editing

Jimmy Opigo: Role: ResourcesRole: SupervisionRole: Writing – Review & Editing

Journal

Journal ID (nlm-ta): Gates Open Res

Journal ID (iso-abbrev): Gates Open Res

Title: Gates Open Research

Publisher: F1000 Research Limited (London, UK )

ISSN (Electronic): 2572-4754

Publication date (Electronic): 18 December 2023

Publication date Collection: 2023

Volume: 7

Electronic Location Identifier: 14

Affiliations

[1 ]Technical, Malaria Consortium, Kampala, Uganda

[2 ]Technical, Malaria Consortium, London, UK

[3 ]Department of Global Public Health, Karolinska Institute, Stockholm, Sweden

[4 ]National Malaria Control Division, Ministry of Health of Uganda, Kampala, Uganda

[1 ]Department of Mathematics Faculty of Science and Engineering, Nusa Cendana University, Kupang, East Nusa Tenggara, Indonesia

Malaria Consortium, Uganda

[1 ]Universidade Nova de Lisboa, Lisbon, Lisbon, Portugal

Malaria Consortium, Uganda

[1 ]Medicines for Malaria Venture, Geneva, Geneva, Switzerland

Malaria Consortium, Uganda

Author notes

[a ] k.baker@ 123456malariaconsortium.org

No competing interests were disclosed.

Competing interests: No competing interests were disclosed.

Competing interests: I have no competing interests to declare

Competing interests: No competing interests were disclosed.

Competing interests: I have competing interests to declare

Competing interests: No competing interests were disclosed.

Author information

Richard Kajubi https://orcid.org/0000-0002-9179-9182

Kevin Baker https://orcid.org/0000-0002-2040-3662

Jane Achan https://orcid.org/0000-0001-8111-025X

Article

DOI: 10.12688/gatesopenres.14287.2

PMC ID: 10774186

PubMed ID: 38196920

SO-VID: ab6be99b-2ea5-4667-8716-3afafe2cce9f

License:

This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date accepted : 9 January 2024

Funding

Funded by: GiveWell

This work was supported by the Bill and Melinda Gates Foundation [INV-039889].

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

A hybrid effectiveness-implementation study protocol to assess the effectiveness and chemoprevention efficacy of implementing seasonal malaria chemoprevention in five districts in Karamoja region, Uganda

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Abstract

Background

Objective

Methods

Discussion

Conclusion

Related collections

Malaria vaccine development

Most cited references 16

Mechanisms of resistance of malaria parasites to antifolates.

Mapping 'partially resistant', 'fully resistant', and 'super resistant' malaria.

Effectiveness of seasonal malaria chemoprevention at scale in west and central Africa: an observational study

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