FAQs - Antimalarial resistance

Resistance occurs when the malaria parasites develop the ability to survive and multiply despite exposure to the recommended dose of a previously effective antimalarial drug, making the treatment less effective or ineffective. For currently recommended antimalarials (artemisinin-based combination treatments or ACTs), drug resistance is not a “switch” that results immediately in that treatment failing. Still, drug resistance develops gradually over a while. Although they take longer to work, the drugs still have some effect, particularly if used in combination with another effective antimalarial partner drug. This level of artemisinin resistance is often termed 'partial resistance’, including by the World Health Organization.

Kelch13 mutations are changes in the kelch13 gene of the malaria parasite. Some of these mutations can make the parasite less sensitive to artemisinin-based malaria drugs, so the treatment might take longer to work or be less effective. However, not every kelch13 mutation has this effect. Scientists assess each mutation to see whether it is associated with slow parasite clearance and, therefore, a good marker of artemisinin (partial) resistance. A single drop of blood containing malaria parasites, collected on filter paper from a representative sample of malaria-infected people, can be used for larger-scale artemisinin resistance surveillance. This information will indicate sites where further investigation (e.g. therapeutic efficacy studies) or response is most needed.

Histidine-Rich Protein 2 (HRP2) and Histidine-Rich Protein 3 (HRP3) are proteins produced by Plasmodium falciparum parasites during the stage of a malaria infection that makes people sick. The HPR2 protein is used in most malaria rapid diagnostic tests (RDTs), which confirm a malaria infection by detecting HRP2 and/or HRP3 proteins in a patient’s blood. Recently, some regions in Africa, Asia, and South America have reported P. falciparum malaria parasites with mutations that “delete” the genes that make HRP2 and HRP3 proteins. This can lead to false-negative HRP-based RDT results. It is important to note that parasites with deletions in only the hrp2 or hrp3 gene are generally still detected by the HRP2-based RDTs. However, when parasites have deletions in both the hrp2 and hrp3 genes, the HRP2-based RDT will not detect malaria infection, potentially leading to failure or delay in malaria diagnosis. In such areas, alternative diagnostics, such as LDH-based RDTs or microscopy, should be used.

Currently, available ACTs contain short-lasting but fast-acting artemisinin and a longerlasting, slower-acting partner drug (e.g. lumefantrine, amodiaquine, pyronaridine, mefloquine, or piperaquine). Artemisinins rapidly reduce the number of malaria parasites in the blood, so within a day or two of starting ACTs, malaria parasites are not detectable by microscopy in most patients. However, in areas with (partial) artemisinin resistance, parasites are cleared more slowly, and malaria parasites remain present on the second or third day after starting ACT treatment, a phenomenon known as “delayed parasite clearance.” Parasites with delayed clearance have specific mutations in the malaria parasite’s kelch13 gene. These (partially) artemisinin-resistant parasites can also be more infectious, increasing the spread of this resistance and potentially increasing malaria transmission. Single low-dose primaquine was thus recommended for malaria transmission-blocking in areas of artemisinin resistance, although its effectiveness in areas of moderate to high malaria transmission needs further evaluation. When artemisininresistant parasites are still susceptible to partner drugs, these infections can still be effectively treated with ACTs, at least initially. However, when only the partner drug is still effective, these parasites evolve further and learn to resist the effects of that partner drug. An ACT treatment fails when parasites develop resistance to a given partner drug as well as the artemisinin, as seen repeatedly in Southeast Asia and is starting to be seen in Africa.

Resistance to antimalarial drugs is not a new challenge. It has been encountered and addressed in past efforts to control malaria. Southeast Asia, in particular, has provided crucial insights, as it was the first to face the emergence and spread of resistance to chloroquine, SP, mefloquine and artemisinins. Artemisinin (partial) resistance was repeatedly followed by ACT treatment failure in Southeast Asia. The Southeast Asian experience showed the importance of reducing antimalarial drug pressure: involving the rational use of antimalarials – only in combination; adherence to treatment guidelines; and strengthening malaria control and elimination measures, including single low-dose primaquine to reduce the malaria burden and the use of antimalarials. Historically, Sub-Saharan Africa carried the highest burden of chloroquine resistance, where chloroquine resistance was associated with a 2- to 6-fold increase in malariarelated deaths. This showed the importance of early detection of antimalarial resistance, for which resistance surveillance must be strong in every endemic country. Equally important is the need for a proactive, coordinated, effective regional response to resistance. These lessons must shape our strategies in the ongoing battle against antimalarial resistance.

While the WHO recommends several different ACTs, when we change from one failing ACT to another ACT, we are only addressing one part of the problem. Artemisinin resistance remains a problem, but if the new partner drug is more effective, the new ACT efficacy will be higher, at least for a while. Unfortunately, malaria parasites continue to evolve, and as parasite clearance by the artemisinin remains slow, the new ACT will also fail sooner or later. This is the logic behind current advocacy to diversify ACTs used across sub-Saharan Africa, instead of the current situation where most malaria infections are treated with the ACT, artemetherlumefantrine. Multiple first-line therapy is a model that diversifies ACT use within a given country but can be complex to implement effectively. This also explains future antimalarial options being developed, such as the triple ACT, artemether-lumefantrine-amodiaquine (ALAQ), and combining lumefantrine with the novel antimalarial ganaplacide, which works more rapidly than the artemisinins and is expected to work in artemisinin (partially) resistant areas. Unfortunately, AL-AQ and ganaplacide-lumenfantrine are only expected to become licensed and available from 2027, so concerted effort is needed to keep our currently available antimalarials as effective as possible for as long as possible.

The WHO recommends a policy change when the recommended ACT fails in more than 10% of patients (i.e. cure rates below 90%). This threshold has been crossed in several countries in subSaharan Africa, but questions still need to be answered about what to do with such results for various reasons, which delay action. The issues on which clarification is often sought, and needs debate include: • Other reasons could explain the >10% treatment failure, so therapeutic efficacy studies must be as detailed as possible to exclude these other reasons. The science behind these studies continues to improve. • Whether >10% treatment failure at one or two sites is enough to change national treatment guidelines if sub-national treatment guidelines are not feasible. • Whether >10% treatment failure, even on average across study sites in a country, detected once is sufficient to inform a national change in malaria treatment policy. Significant costs are associated with responding to antimalarial resistance, from strengthened vector control and health promotion to procurement of new antimalarials, with the training and supportive supervision needed for its effective implementation. However, delaying responding to antimalarial resistance can be more costly and result in an avoidable increase in malaria cases and, eventually, deaths; thus, WHO recommends that countries pre-plan for a rapid change in treatment policy.