Fighting fire with fire: mass antimalarial drug administrations in an era of antimalarial resistance

Abstract

The emergence and spread of antimalarial resistance has been a major liability for malaria control. The spread of chloroquine-resistant Plasmodium falciparum strains had catastrophic consequences for people in malaria-endemic regions, particularly in sub-Saharan Africa. The recent emergence of artemisinin-resistant P. falciparum strains is of highest concern. Current efforts to contain artemisinin resistance have yet to show success. In the absence of more promising plans, it has been suggested to eliminate falciparum malaria from foci of artemisinin resistance using a multipronged approach, including mass drug administrations. The use of mass drug administrations is controversial as it increases drug pressure. Based on current knowledge it is difficult to conceptualize how targeted malaria elimination could contribute to artemisinin resistance, provided a full treatment course is ensured.

Keywords:

• artemisinins
• chloroquine
• drug resistance
• elimination
• malaria
• mass drug administrations
• Plasmodium falciparum
• pyrimethamine
• sulfadoxine

Acknowledgements

This review is indebted to earlier reviews of antimalarial resistance specifically the encyclopedic work by W Peters published in two volumes in 1987 [4] and more recent reviews of the molecular characteristic of antimalarial resistance by T Mita and K Tanabe [48,49]. The review of mass drug administrations is based on the systematic and comprehensive review by G Newby et al. [108]. We are very grateful for the generous permission by G Newby et al. to allow us to use their materials. We thank JL Deen for her contributions as well as the discussions and advice from N White, J Tarning, C Woodrow, A Schapira and many other colleagues.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• The evolution of resistant Plasmodium falciparum strains has been a major limitation for the usefulness of antimalarials. This historical fact is a critical aspect in development and introduction of new antimalarials.

• The period from introduction of an antimalarial drug to emergence of resistant P. falciparum strains can be highly variable. P. falciparum strains that are highly resistant to atovaquone and proguanil emerged within a year of licensing. In contrast, quinine and artemisinins have been in use for hundreds of years before less susceptible strains were documented.

• Chloroquine-resistant P. falciparum strains emerged in South America and Southeast Asia around the same time. Within two decades of the first emergence, chloroquine resistance was detected in sub-Saharan Africa. Current molecular techniques have documented the spread of strains from Southeast Asia to the African continent.

• The spread of chloroquine resistance through the African continent was accompanied by an insidious increase in malaria incidence, morbidity and mortality resulting in a multifold increase in malaria-related morbidity and mortality by the end of the 20th century.

• Similarly, P. falciparum strains resistant to sulfadoxine/pyrimethamine emerged in Southeast Asia and spread within two decades to east Africa.

• There is evidence that P. falciparum strains with reduced susceptibility to artemisinins had emerged in Cambodia by 2008. By 2014, artemisinin resistance to P. falciparum had been documented across mainland Southeast Asia but not yet outside.

• By 2015, there have been several lines of evidence linking artemisinin resistance to polymorphisms in the PF3D7_1343700 kelch propeller domain (‘K13-propeller’).

• Whether all mutations in the K13 propeller confer similar changes in artemisinin resistance, and whether additional compensatory mutations elsewhere in the genome are needed for successful establishment within a parasite population is currently under intense scrutiny.

• In contrast to earlier antimalarials it appears that these P. falciparum strains with reduced susceptibility emerge frequently de novo in multiple locations. If this hypothesis were to be confirmed traditional containment strategies may have limited or no impact and alternative interventions need to be urgently evaluated. So far, containment measures have not shown any impact on the increasing number of sites where P. falciparum strains with reduced susceptibility to artemisinins is detected.

• The global malaria disease burden has been reduced dramatically since the beginning of the century. In many regions, malaria endemic areas are now reduced in size. However, the remaining parasite strains are the most resistant. Over time, these resistant parasite populations are likely to expand and may well lead to a resurgence of malaria.

Notes

¹The International Cooperation Administration a precursor of the Administration for International Development.