Slowing the spread of treatment failure to artemisinin-based combination therapies in Uganda

Abstract

Background The multiple emergences and continuing spread of partially artemisinin-resistant Plasmodium falciparum in Africa, where about 95% of malaria occurs, is a health challenge that requires urgent attention. The World Health Organization has developed a resistance response strategy that centers on enhancing surveillance, reducing drug pressure, and evaluating novel tools to slow resistance evolution which includes the deployment of multiple first-line therapies (MFT). Developing a specific resistance response is critical for Uganda, where four pfkelch13 mutations are at local allele frequencies >0.20.Methods Using a previously validated Uganda-calibrated individual-based mathematical model of P. falciparum transmission and evolution, we evaluated 53 public-sector deployment strategies for artemisinin-based combination therapies (ACTs) aimed at reducing treatment failure and slowing the spread of pfkelch13 alleles from 2025 to 2031. We assume that artemether-lumefantrine (AL) will continue to be used in the private sector.Results A change of first-line therapy from AL to artesunate-amodiaquine (ASAQ) is projected to reduce treatment failures by 34.7% to 38.3% (90% range of simulation outcomes) over six years, while a change to dihydroartemisinin-piperaquine (DHA-PPQ) is projected to reduce treatment failures over the same period by 10.0% to 12.9%. This pessimistic projection for DHA-PPQ deployment rests on a model assumption – supported by clinical data from SE Asia – that piperaquine resistance evolution will lead to high rates of treatment failure. Optimal MFT deployments and cycling approaches are projected to reduce treatment failure counts by ∼36% when compared to status quo AL use, an outcome similar to country-wide ASAQ deployment. MFT and cycling approaches are predicted to work best when ASAQ is recommended for a majority of malaria cases and DHA-PPQ for a smaller proportion of cases. Deployment of the triple ACT artemether-lumefantrine-amodiaquine has the potential to reduce treatment failures by ∼42% if enacted immediately.Conclusions Increased adoption of and coverage with ASAQ is projected to play a large role in reducing malaria treatment failure counts in Uganda over the next six years. With continued AL use in the private sector, ASAQ and DHA-PPQ deployment in the public sector creates a public-private MFT mix of antimalarial use. DHA-PPQ deployment should be accompanied by real-time molecular surveillance for piperaquine-resistant genotypes.Competing Interest StatementPJR consulted for GSK in 2023 and Merck in 2024 on new antimalarial drug discovery.Funding StatementTDN, RJZ, KTT, CCF, MFB, DMG were funded by National Institutes of Health grant NIAID R01AI153355 and Bill and Melinda Gates Foundation grant INV-005517. TDN, KTT, CCF, MFB were funded by National Institutes of Health grant NIAID R01AI153355 and Bill and Melinda Gates Foundation grant INV-056612. VA was funded by Bill and Melinda Gates Foundation grant INV-037316. GBR, BBA, MRK, JO are funded by US President's Malaria Initiative prime contract 72061722C00003 and sub-contract 14070-IDRC-01. The study was additionally funded by the National Institutes of Health (R01AI075045, R01AI173557, U19AI089674, RO1AI117001, R01AI139179, and D43TW010526), the Medicines for Malaria Venture (RD/15/0001), and the Gates Foundation (INV-035751). Computations for this research were performed on the Pennsylvania State University's Institute for Computational and Data Sciences Roar supercomputer and on Temple University's College of Science and Technology Owl's Nest Cluster.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study cites many published sources on 'malaria treatment failure' which are estimated from therapeutic efficacy studies (TESs) that are approved by IRBs and published in the medical literature. In addition to citing this published literature, paragraph 1 of the discussion mentions a 15.4% treatment failure rate and a 17.1% treatment failure rate that are estimates from TESs (conducted in 2022-2023) that are not yet published. These two results were presented in Nov 2023 at a World Health Organization MPAG meeting that was open to the public, and is currently available here https://www.who.int/publications/m/item/malaria-policy-advisory-group-to-the-who-day-2-of-the-october-2023-meeting. The current study is a mathematical modeling scenario evaluation of future treatment policies. No new data were generated for this study, no ethical approval was needed to generate these scenario comparisons.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll simulation code and outputs are available at https://github.com/bonilab/Uganda-phase-1 https://github.com/bonilab/Uganda-phase-1