Antimalarial drug efficacy and drug resistance
Monitoring the efficacy of antimalarial medicines is a key component of malaria control. The steady appearance of Plasmodium falciparum resistance to many antimalarial medicines over the past several decades has since led malaria endemic countries to adopt artemisinin-based combination therapies (ACTs). Protecting the efficacy of ACTs as the current first-line treatment for P. falciparum malaria is among the top global public health priorities.
Antimalarial drug efficacy
Antimalarial drug efficacy is assessed through therapeutic efficacy studies (TES). TES are conducted in a controlled environment in which drug administration is supervised, the results of microscopic examinations of blood films are validated, and the origin and quality of the drugs are verified.
TES are prospective evaluations of patients’ clinical and parasitological responses to directly observed treatment for uncomplicated malaria. Studies at regular intervals at the same sites allow for the early detection of resistance. Findings also provide evidence for guiding national malaria treatment policy.
Therapeutic outcomes are assessed on the final day of the study (day 28, or day 42 for drugs with longer elimination half-lives). For infections appearing during follow-up, genotyping must be conducted to distinguish new infections from recrudescence.
While TES can help to predict the likelihood of antimalarial drug resistance, additional tools are needed to confirm its presence, such as in vitro tests, molecular analysis and measurements of drug concentrations. WHO has developed a standard protocol for monitoring therapeutic efficacy as well as tools for analysing TES results. The use of these standardized procedures facilitates the comparison of results within and across regions over time.
Antimalarial drug resistance
To date, parasite resistance to antimalarial medicines has been documented in 3 of the 5 malaria species known to affect humans: P. falciparum, P. vivax and P. malariae. Parasite resistance results in a delayed or incomplete clearance of parasites from the patient’s blood when the person is being treated with an antimalarial.
The problem of antimalarial drug resistance is compounded by cross resistance, in which resistance to one drug confers resistance to other drugs that belong to the same chemical family or which have similar modes of action.
Artemisinin-based combination therapies and drug resistance
WHO recommends ACTs for the treatment of uncomplicated malaria caused by P. falciparum. ACTs have been an integral part of the remarkable recent success in global malaria control, and there is broad consensus that protecting the efficacy of these combination medicines is an urgent priority.
Resistance and treatment failures to antimalarial medicines can be defined as follow:
- Antimalarial resistance is defined as the ability of a parasite strain to survive and/or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within tolerance of the subject;
- Artemisinin resistance is defined as delayed parasite clearance following treatment with an artesunate monotherapy or with an ACT – this represents partial resistance/tolerance;
- Multidrug resistance (MDR) requires resistance to more than 2 operational antimalarial compounds of different chemical classes;
- Treatment failure is the inability to clear parasites from a patient’s blood or to prevent their recrudescence after the administration of an antimalarial. Many factors can contribute to treatment failure, including incorrect dosage, poor patient compliance, poor drug quality, and drug interactions and resistance. Most of these factors are addressed by therapeutic efficacy studies.
In reporting the findings of therapeutic efficacy tests, ACT resistance is imprecise. ACT treatment failure (defined as treatment failure following treatment with an ACT, regardless of the presence artemisinin resistance) is a more appropriate term that notes the specific ACT and the nature of the resistance if confirmed (i.e. artemisinin partial resistance/tolerance or partner drug resistance, or both).
Networks on monitoring antimalarial drug efficacy
Taking the experience of the East African Network for Monitoring Antimalarial Treatment (EANMAT) as its guide, WHO supported the creation of several subregional networks for monitoring antimalarial resistance. Through these networks, WHO is able to:
- provide updates on the global situation of antimalarial drug resistance;
- advise on protocol implementation, microscopy, data analysis and validation, and support;
- reporting and publication, which in turn improves data quality.
The information on therapeutic efficacy generated by the networks and the experience acquired in the process are shared among countries in order to provide the best possible advice to ministries of health. The creation of networks allows for effective management of problems in border areas, where population movement is intense.
Reports of recent network meetings provide essential insights on monitoring of drug efficacy and resistance in the subregions.
Bhutan-Bangladesh-India-Nepal-Sri Lanka network (BBINS), Greater Mekong Subregion (GMS) Network and Pacific Malaria Drug Resistance Monitoring network
Second bi-regional meeting of Asia-Pacific malaria drug resistance monitoring networks (2016)
South-East Asia and Western Pacific bi-regional meeting of malaria drug resistance monitoring networks (2015)
Greater Mekong subregion (GMS) network
- Meeting of the Greater Mekong Subregion (GMS) therapeutic efficacy study (TES) network (2014)
Reviewing and planning therapeutic efficacy studies (TES) to monitor antimalarial drug resistance in the Greater Mekong Subregion (2012)
Pacific Malaria Drug Resistance Monitoring network
Third meeting of the Pacific malaria drug resistance monitoring network (2014)
Second Pacific malaria drug resistance monitoring network (2013)
Pacific malaria drug resistance monitoring network (2011)
Pakistan-Iran-Afghanistan network (PIAMNET) and Horn of Africa Network for Monitoring Antimalarial Treatment (HANMAT)
Summary report on the eighth intercountry meeting of national malaria programme managers from HANMAT and PIAM-Net countries (2017)
Summary report on the seventh intercountry meeting of national malaria programme managers from HANMAT and PIAM-net countries (2016)
Report on the intercountry meeting of national malaria programme managers from HANMAT and PIAM-net countries (2014)
Report on the sixth intercountry meeting of national malaria control programme managers from HANMAT and PIAM-Net countries (2013)
Summary report on the intercountry meeting of national malaria programme managers from countries of HANMAT and PIAM-Net (2012)