Fight against drug-resistant malaria in critical new phase: 'We are in danger of losing our current antimalarial drugs to resistance.'

On World Malaria Day 2023, the global fight against malaria has hit a critical point in Africa. Recent studies have confirmed that malaria parasites resistant to artemisinin have emerged in Rwanda, Uganda and the Horn of Africa.

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 losing of our current antimalarial drugs to resistance,' said Professor 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 Professor 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 Professor 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 Professor Ricardo Aguas, University of Oxford, and Associate Professor 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.

Further reading

Ethical considerations in deploying triple artemisinin-based combination therapies for malaria: An analysis of stakeholders' perspectives in Burkina Faso and Nigeria.

Ethical, Regulatory and Market related aspects of Deploying Triple Artemisinin-Based Combination Therapies for Malaria treatment in Africa: A study protocol.

Deploying triple artemisinin-based combination therapy (TACT) for malaria treatment in Africa: ethical and practical considerations.

Expert perspectives on the introduction of Triple Artemisinin-based Combination Therapies (TACTs) in Southeast Asia: a Delphi study.

To what extent are the antimalarial markets in African countries ready for a transition to triple artemisinin-based combination therapies? 

Market Formation in a Global Health Transition.

Triple Artemisinin-Based Combination Therapies for Malaria - A New Paradigm?