Drug-resistant malaria is not new. In the 1970s and 1980s, Plasmodium falciparum — the deadliest human malaria parasite species — developed widespread resistance to older antimalarial medicines, such as chloroquine and sulfadoxine-pyrimethamine.
Artemisinin-based combination therapies (ACTs)
What they are and how they work
Artemisinin-based combination therapies (ACTs), introduced in the 1990s, are the most effective drugs we have ever had to treat malaria. Extracted from the sweet wormwood plant, Artemisia annua, artemisinin and its derivatives (artesunate and dihydro-artemisinin) rapidly reduce the burden of parasites in the blood. However, they are also eliminated from the body very quickly.
Using artemisinin in combination with another effective, longer-acting drug that has a different mechanism of action — a partner drug — helps to ensure that any remaining parasites are cleared over a treatment course of three days. Using this combined treatment (ACT) ensures that all parasites are completely removed in a shorter time than using artemisinin alone. This also helps to reduce the risk of resistance to artemisinin developing.
Emergence of ACT resistance
In southeast Asia, some malaria parasites have developed resistance to artemisinin-based drugs. Artemisinin resistance was first reported along the Thailand-Cambodia border in 2008 and has continued to spread in the region. It has also been shown to arise independently in different locations, including some countries in Africa and South America.
Resistance to artemisinin treatment leads to a significant delay in the time it takes to clear malaria parasites from infected patients. Delayed clearance means more parasites survive and are exposed to the partner drug over a longer period, allowing them more time to develop resistance to that drug too.
Since there are no equally effective alternatives to ACTs for treating malaria, the development of resistance to artemisinin — and, consequently, the partner drugs — could be a setback to global elimination and control efforts.
Partial resistance
Resistance identified to artemisinin is known as 'partial resistance'. Unlike full resistance, which has emerged to chloroquine and sulfadoxine-pyrimethamine, rendering these drugs ineffective in some areas, partial resistance results in delayed clearance of parasites. When artemisinin is used in combination with an effective partner drug, infection will still be cleared at 28 days following treatment.
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Artemisinin resistance: Understanding the challenge
All organisms that cause infections, and which come into contact with drugs to control them, will develop resistance over time. Many factors are thought to have contributed to the emergence and spread of artemisinin resistance, with the overuse and misuse of drugs being a major cause.
Other contributing factors include: failure to complete full treatment courses; the use of substandard and counterfeit antimalarial drugs; the widespread over-prescription of antimalarials without a diagnostic test (particularly in the private sector); and the challenge of controlling the spread of malaria within migrant populations.
Selection pressure placed on the malaria parasite through the use of oral or injectable artemisinins as monotherapy — instead of WHO-recommended ACTs — also contributes to resistance. While treatment with artemisinin monotherapy can eliminate susceptible parasites from a patient’s blood, it may leave them with parasites that are resistant to the effects of the drug. These resistant parasites can survive and reproduce before being transmitted by mosquitoes to other people.
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Artemisinin resistance: The solution
The WHO Global Action Plan for Artemisinin Resistance Containment (GPARC), published in 2011, outlines comprehensive recommendations for the containment of drug resistance. Addressing the development of resistance requires different approaches depending on the context.
Diagnostic tools and therapeutic efficacy tests
The introduction of malaria diagnostic tools and the World Health Organization’s ‘test before treat’ policy has helped reduce the overuse of antimalarial drugs.
Carrying out therapeutic efficacy tests to identify resistance to antimalarial drugs means the most effective treatment combinations can be selected and changed as necessary. In the case of ACTs, this means changing the partner drug or the drug combination in relation to identified patterns of resistance.
Accelerating towards elimination
Concerted efforts to accelerate countries towards malaria elimination, backed by political will, have seen malaria incidence and prevalence decline over the last 15−20 years — with China achieving elimination status in 2021.
Important factors in this progress have included increased surveillance with dedicated malaria information systems, a regional database supported by WHO, high coverage and use of insecticide-treated nets, and rotation of ACTs according to regular therapeutic efficacy testing. Countries have also supported elimination efforts by promoting the use of ACTs and making monotherapies illegal, as well as making malaria a notifiable disease.
Social and behaviour change communication is key in engaging communities with elimination efforts. Alongside this, a focus on community-based delivery — including cross-border testing and treatment — via village malaria workers and mobile malaria workers has improved access to early diagnosis and treatment, especially among remote and marginalised communities, and mobile populations.
Resistance monitoring and research
In Africa, where artesunate resistance is spreading — and may be more widespread than previously realised — national malaria programmes must decide how best to address falling drug efficacy. Continuous monitoring of drug resistance in malaria-endemic countries, along with research into its contributing factors, will enable health authorities and practitioners to more effectively prevent drug resistance from spreading.
