Artemisinin-based combination therapies (ACTs) are the first line treatment for malaria and there is no immediate replacement available. The loss of ACTs will put millions of Africans, mostly children under the age of 5, at risk of drug-resistant malaria infection and death.
One possible solution?
Adding a third drug to current ACT drug combinations. These Triple ACTs or TACTs have been found in clinical trials in Asia to be highly efficacious even in places where ACTs were failing.
“It is so much easier to prevent antimalarial drug resistance than to try and contain it. We are in danger of losing our current antimalarial drugs to resistance,” said Prof Sir Nick White, University of Oxford Professor of Tropical Medicine based at the Mahidol-Oxford Tropical Medicine Research Unit (MORU), in Bangkok.
“Triple artemisinin combination treatments [TACTs] will protect against resistance and help ensure that these drugs remain effective until new drugs arrive in 5-10 years time,” said Prof White.
Before TACTs can be widely deployed in Africa, however, their efficacy, safety and tolerability must be confirmed in African populations, especially children.
To that end, the Development of Triple Artemisinin-based Combination Therapies (DeTACT) trial is studying in eight African and two Asian countries two new TACTs — Artemether+lumefantrine+amodiaquine and Artesunate+piperaquine+mefloquine — to generate evidence that they are safe and effective malaria therapies.
The DeTACT project has also conducted modelling, ethics and market positioning studies to support their use in Africa and thereby prevent or delay the emergence of artemisinin and multi-drug resistant malaria.
“The DeTACT project aims to provide the necessary evidence that TACTs can both delay antimalarial drug resistance to existing drugs, and be an effective treatment for multidrug resistant infections. DeTACT will also deliver a product to market, and engage with national and global policy makers and stakeholders to discuss the potential position of TACTs in the mix of antimalarial drugs,” said University of Oxford Prof Arjen Dondorp, DeTACT project Principal Investigator.
Led by University of Oxford-affiliated researchers based at MORU in Bangkok, and funded by UK Aid administered through the Foreign, Commonwealth and Development Office (FCDO), the DeTACT trial has recruited over ~1800 patients as of April 2023 , with recruitment and follow-up completed in Niger and Nigeria, and no major or unexpected safety signals detected.
Once recruitment and follow-up are completed at the end of 2023, DeTACT investigators will present results in April 2024. Prior to that, they aim to present interim findings at a DeTACT symposium in October 2023 at the American Society of Tropical Medicine and Hygiene (ASTMH) 72nd Annual Meeting in Chicago, USA.
The first modelling study to project the impact of TACTs in preventing or delaying artemisinin resistance, led by Associate Prof Ricardo Aguas, University of Oxford, and Associate Prof Maciej Boni, Pennsylvania State University, has been completed and will soon be published in the prestigious journal, Nature Communications.
“These DeTACT modelling studies and market positioning studies generate data that will be crucial in our efforts to effectively introduce TACTS and to project the impact and cost-effectiveness of TACTs in preventing the spread of artemisinin resistance. Along with the clinical trial, these studies constitute a comprehensive assessment of the expected advantages and potential barriers to the large-scale use of TACTs,” explained Dr Chanaki Amaratunga, DeTACT Project Coordinator.
The DeTACT project has engaged malaria stakeholder engagement officers to communicate directly with National Malaria Control Programmes (NMCPs) to present to them to the DeTACT project and TACTs in general. Presentations on DeTACT and TACTs have been made at the RBM Partnership to End Malaria Case Management Working Group and the Seasonal Malaria Chemoprevention (SMC) Alliance Annual meetings. These efforts have led to significant interest from all parties in participating in future research and exploring the roll-out of TACTs in their countries.
To make TACTs available as quickly as possible where they are most needed it is critical to work with the pharmaceutical industry on the co-formulation. MORU has signed a memorandum of understanding with Fosun Pharma, China, and the Medicines for Malaria Venture (MMV) to develop and pre-qualify fixed-dose combinations of artemether-lumefantrine-amodiaquine, prior to deploying them across Africa.
“The DeTACT trial will generate data not only on the efficacy and safety of TACTs but also on the pharmacokinetics of each of the drug components, including in malnourished children – a particularly vulnerable sub-population. In addition, there will be cutting-edge analyses, combining clinical trial data with that from whole genome and transcriptome studies, to improve our understanding of artemisinin and antimalarial drug resistance,” said Dr Mehul Dhorda, DeTACT-Africa Coordinator.
DeTACT builds on the historic SEAQUAMAT and AQUAMAT trials, two large, randomised, multi-centre collaborative studies earlier this century led my MORU and funded by the Wellcome Trust that clearly demonstrated the superiority of parenteral artesunate over quinine in safely and effectively treating severe malaria. For more details, Artesunate versus quinine: the controlled trials watershed, Conrad Keating, The Lancet 22 April 2023.
TRAC and TRACII
DeTACT is the third of three FCDO-supported multi-country, multi-site trials (TRAC and TRACII) that have characterised artemisinin resistance and tested triple therapies for multi-drug resistant malaria in Southeast Asia. The work related to pharmacokinetics of antimalarials in malnourished children is supported by a grant from the Wellcome Trust.
DeTACT publications to date
Ethical considerations in deploying triple artemisinin-based combination therapies for malaria: An analysis of stakeholders' perspectives in Burkina Faso and Nigeria. Tindana P, Guissou R, Bolarinwa OA, Tou F, de Haan F, Dhorda M, Dondorp AM, Amaratunga C, Mokuolu OA, Ouedraogo JB, Cheah PY. PLoS One. 2022 Sep 9;17(9):e0273249. doi: 10.1371/journal.pone.0273249. PMID: 36083995; PMCID: PMC9462557.
Ethical, Regulatory and Market related aspects of Deploying Triple Artemisinin-Based Combination Therapies for Malaria treatment in Africa: A study protocol. [version 1; peer review: 3 approved]. Tindana P, de Haan F, Mokuolu OA et al. Wellcome Open Res 2021, 6:75 (https://doi.org/10.12688/wellcomeopenres.16065.1)
Deploying triple artemisinin-based combination therapy (TACT) for malaria treatment in Africa: ethical and practical considerations.Tindana P, de Haan F, Amaratunga C, Dhorda M, van der Pluijm RW, Dondorp AM, Cheah PY. Malar J. 2021 Feb 27;20(1):119. doi: 10.1186/s12936-021-03649-7. PMID: 33639946; PMCID: PMC7910789.
Expert perspectives on the introduction of Triple Artemisinin-based Combination Therapies (TACTs) in Southeast Asia: a Delphi study. de Haan F, Boon WPC, Amaratunga C, Dondorp AM. BMC Public Health. 2022 Apr 30;22(1):864. doi: 10.1186/s12889-022-13212-x. PMID: 35490212; PMCID: PMC9055751.
To what extent are the antimalarial markets in African countries ready for a transition to triple artemisinin-based combination therapies? de Haan F, Bolarinwa OA, Guissou R, Tou F, Tindana P, Boon WPC, Moors EHM, Cheah PY, Dhorda M, Dondorp AM, Ouedraogo JB, Mokuolu OA, Amaratunga C. PLoS One. 2021 Aug 31;16(8):e0256567. doi: 10.1371/journal.pone.0256567. PMID: 34464398; PMCID: PMC8407563.
Market Formation in a Global Health Transition. de Haan F, Moors EHM, Dondorp AM, Boon WPC. Environ Innov Soc Transit. 2021 Sep;40:40-59. doi: 10.1016/j.eist.2021.05.003. PMID: 35106274; PMCID: PMC7612298.
Triple Artemisinin-Based Combination Therapies for Malaria - A New Paradigm? van der Pluijm RW, Amaratunga C, Dhorda M, Dondorp AM. Trends Parasitol. 2021 Jan;37(1):15-24. doi: 10.1016/j.pt.2020.09.011. Epub 2020 Oct 12. PMID: 33060063.