This brochure complements the Report on antimalarial drug efficacy, resistance and response: 10 years of surveillance (2010–2019). It includes the report's main findings, key definitions and background information for non-experts.
To download the pdf of the brochure, see attachment.
A relatively small number of drugs are currently being used to save the lives of millions of people infected each year by malaria. These drugs need to remain efficacious until new drugs and tools become available.
Monitoring antimalarial drug efficacy and resistance is important for the early detection of resistance which in turn enables timely action to prevent its spread and limit the impact on global health. Measurement of drug efficacy and resistance in malaria is complex. This report provides an overview of the tools currently used to monitor drug efficacy and resistance. The report also provides a summary of activities needed to minimize any public health impact of antimalarial drug resistance as well a review of the data collected from 2010–2019 in the World Health Organization (WHO) global database on antimalarial drug efficacy and resistance.
The last report reviewing the data available on antimalarial drug efficacy and resistance was published in 2010, less than two years after the first report from Cambodia of Plasmodium falciparum parasite with delayed clearance following treatment with artemisinins.1 Artemisinins are the core component of artemisininbased combination therapies (ACTs). This delayed clearance has been termed artemisinin partial resistance. Over the past 10 years much more data have become available on artemisinin partial resistance as well as on the impact of resistance to ACT partner drugs.
Mutations in the P. falciprum Kelch 13 (PfK13) BTB/POZ and propeller domain have been shown to be associated with artemisinin partial resistance. High rate of ACT failure with dihydroartemisinin-piperaquine (DHA-PPQ) has been documented in the Greater Mekong subregion (GMS) and mutations associated with resistance to the ACT partner drug piperaquine were identified. The identification of molecular markers makes surveillance of parasite genotypes an important supplement to monitoring of the parasite response to different treatments.
Responding to the threat of drug resistance
Imperfect coverage and quality of malaria interventions contribute to the emergence and spread of resistance. Correct diagnosis is not always provided, drugs are sometimes misused, some patients may not have access to quality treatments and the coverage of vector control may remain low for some key populations. These failures lead to increased exposure of the malaria parasites to drugs, increasing the risk of drug resistance.
Prolonging the efficaciousness of the currently used drugs will require addressing shortcomings in the quality and coverage of malaria interventions, and adding specific activities that could help to minimize the risk of drug resistance and limit the public health consequences when drug resistance emerges and spreads.
At present, the main challenge of artemisinin and ACT partner drug resistance centres on the need for systems that can quickly inform on the need for changes in treatment policy, and a health system that can implement rapid policy changes so as to provide patients with the specific treatment needed.
WHO global database on antimalarial drug efficacy and resistance
The WHO global database on antimalarial drug efficacy and resistance contains data from therapeutic efficacy studies (TES) conducted on P. falciparum, P. vivax, P. ovale,
P. malariae and P. knowlesi, as well as molecular marker studies of P. falciparum drug resistance. TES are mainly done using first- and second-line treatment as well as treatments considered for introduction into the treatment policy.
The main findings from the analysis of the WHO global database on antimalarial drug efficacy and resistance are:
- Overall, where tested, first- and second-line treatments are efficacious for P. falciparum. Where high treatments failures rates were reported, policy changes have been made or are ongoing.
- In four countries in the GMS – Cambodia, Lao People’s Democratic Republic, Thailand and Viet Nam – high rates of treatment failures have been detected after treatment with some ACTs. However, there are still at least two and sometimes three ACTs available that can effectively treat P. falciparum in these countries.
- Outside the GMS, resistance to sulfadoxine-pyrimethamine has meant that some countries (Sudan, Somalia, north-east India) have had to abandon artesunate+sulfadoxine-pyrimethamine (AS+SP) as a treatment for P. falciparum. These countries have changed to an alternative, highly efficacious ACT.
- The efficacy of ACTs in Africa is being monitored in most malaria-endemic countries. Artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) are the first-line treatment policies used in most African countries, with some countries adding DHA-PPQ. Between 2010 and 2019, the overall average efficacy rates of AL, AS-AQ and DHA-PPQ were 98.0%, 98.4%, and 99.4% respectively. Efficacy is consistently high with a >10% failure rate only being identified in studies of AL and only in four of the 300 AL studies conducted over the past 10 years. Treatment failures following treatment with AL have been reported in travellers coming back from Africa to Europe, but resistance to lumefantrine has not been confirmed in Africa.
- While P. vivax resistance to chloroquine has been reported from all WHO regions, chloroquine remains efficacious in most part of the world. P. vivax resistance to artemisinin has not be identified.
- Data on PfK13 mutations are available from all regions. Of the samples collected 2010-2019, 83.4% were found to be PfK13 wild type. However, sampling is undertaken more frequently where resistance is suspected, so the prevalence in the samples may differ from the overall prevalence in parasites. The validated marker for artemisinin partial resistance C580Y is the mutation most frequently identified; it was found in 9.8% of samples. The highest prevalence of PfK13 mutations is in countries in the GMS where the majority of the samples is found to carry PfK13 mutations.
- Outside GMS, findings of PfK13 mutations in two countries give cause for concern:
- In Guyana, C580Y mutations were found in surveys in 2010 and 2017.
- In Rwanda, R561H was found in 11.9% of all the samples collected in 2018 (n=219). R561H is a validated marker of artemisinin partial resistance. There is evidence suggesting that the R561H mutation may be affecting the clearance rate, although to date, the ACTs tested remain efficacious.
- High prevalence of markers of P. falciparum resistance to piperaquine has been identified in the four GMS countries Cambodia, Lao People’s Democratic Republic, Thailand and Viet Nam where high failure rates after treatment with DHA-PPQ have been detected. In several African countries, studies and surveys have detected significant proportions of the samples carrying the marker of piperaquine resistance.
- After a change in treatment policy in Cambodia from DHA-PPQ to artesunatemefloquine (AS-MQ), fewer parasites appear to carry both C580Y and the marker of piperaquine resistance.
Countries and partners need to continue to work to improve coverage and quality of malaria interventions. This will both ensure better patient care and decrease the risk and impact of drug resistance. Up-to-date, quality data are needed on the efficacy of the recommended treatments, to ensure that patients receive efficacious treatment.
Conducting these studies can be challenging, but the investment of time and resources is small when compared with the funding spent on treatments and the millions of patients depending on the continued efficacy of these treatments. Molecular markers are an asset for confirming resistance, in the analysis of trends and as an early warning signal. The identification of additional markers of resistance will further strengthen the efforts of resistance monitoring.
While chloroquine resistance will continue to pose a challenge for P. vivax, the primary challenge of P. vivax chemotherapeutics is that of successful radical cure.
More countries are likely to have to change to the more expensive ACT treatments if chloroquine resistance continues to spread. The use of 8-aminoquinolines is limited by its efficacy, safety, patient adherence and drug interactions.
Currently, there are ACTs available capable of treating all P. falciparum strains. In some countries of the GMS, most of the P. falciparum parasites now carry mutations associated with artemisinin partial resistance. Where resistance to the ACT partner drug has also been identified, high failure rates to treatments have been identified.
However, even in the GMS there are highly efficacious ACTs available to treat patients.
There is evidence that R561H, a validated marker of artemisinin partial resistance, has emerged and is being selected for in Rwanda. The ACTs tested in Rwanda remain efficacious, meaning that any immediate impact for patients is unlikely. However it is of concern that parasites have emerged with partial resistance to the central component in the drugs used to treat millions across Africa. In the GMS, artemisinin partial resistance is likely to have been involved in the spread of resistance to partner drugs.
It is worth noting that China was able to eliminate malaria despite the presence of malaria parasites partially resistant to artemisinins, and that great progress is being made towards elimination in the GMS where resistance poses the greatest challenge.
To download the pdf of the report, see attachment.