Advances and roadblocks in the treatment of malaria

Abstract

The deployment of artesunate for severe malaria and the artemisinin combination therapies (ACTs) for uncomplicated malaria has been a major advance in antimalarial therapeutics. These drugs have reduced treated mortality, accelerated recovery and reduced treatment failure rates and transmission from the treated infection. Artemisinin derivatives remain highly effective against falciparum malaria in most malaria endemic areas, but significant resistance has emerged in the Greater Mekong subregion of Southeast Asia. Resistance to artemisinins was followed by resistance to the ACT partner drugs, and fit multidrug resistant parasite lineages have now spread widely across the region. ACTs remain highly effective against P. vivax and the other malaria species. Recent studies have shown that radical curative regimens of primaquine (to prevent relapse) can be shortened to 7 days, and that the newly introduced single dose tafenoquine is an alternative, although the currently recommended dose is insufficient in Southeast Asia and Oceania. Targeted malaria elimination using focal mass treatments with dihydroartemisinin-piperaquine have proved safe and effective malaria elimination accelerators, but progress overall towards malaria elimination is slow. Indeed since 2015 overall malaria case numbers globally have risen. As new drugs will not become widely available in the near future, active measures to preserve the current antimalarials should be given the highest priority.

Keywords: antimalarial drugs; artemisinin; malaria; resistance.

FIGURE 1

Mortality by treatment arms in randomized comparative controlled trials in strictly defined severe falciparum malaria (which together enrolled 2874 adults and 7424 children). The size of the circle is approximately proportional to the size of the trial and the error bars are 95% confidence intervals. The adults were enrolled mainly in Southeast Asia and the children mainly in Africa, , ,

FIGURE 2

In artemisinin‐sensitive malaria infections (AS) the 3‐day artemisinin regimen in ACTs (A), results in rapid parasite killing and consequent decline in parasitaemia. The logarithmic scale vertical axis shows the total number of malaria parasites in the body of an adult with approximately 2% parasitaemia. The ACT partner drug has only approximately 1000 parasites to remove in this example (green triangle). In contrast, in an artemisinin‐resistant infection (AR) there is substantially less parasite killing initially and so the ACT partner drug now has approximately 100 million parasites to remove (alone) with a substantially greater risk of treatment failure (recrudescence) and thus selective pressure to the emergence of partner drug resistance. In B, with TACTs there are now two slowly eliminated drugs providing a potentially greater antimalarial effect in resistant infections and ensuring mutual protection against the emergence of resistance. The detection limit (black dotted line) is the limit for microscopy to identify a malaria infection

FIGURE 3

The parasite clearance half‐lives (PC₅₀) associated with Pfkelch mutations in patients with acute falciparum malaria studied in the TRAC1 study. WT, wild type (note parasite clearance half‐life estimates can still exceed 5 hours in Pfkelch wild‐type infections). Mutations in the “propeller “region are usually associated with slow parasite clearance, the phenotypic hallmark of artemisinin resistance, although there is substantial interindividual variation and some mutations (A578S, pink arrow) are clearly not associated with artemisinin resistance. In the GMS parasite lineages associated with the F446I mutation have spread widely in Myanmar, and a lineage associated with C580Y was common along the Thailand‐Myanmar border before targeted elimination activities. In the Eastern GMS lineages associated with R539T and C580Y both spread, but in recent years a C580Y lineage (termed PfPailin) has dominated, (Figure 4). Modified from Ashley et al. with permission

FIGURE 4

The spread of artemisinin‐resistant P. falciparum parasite lineages across the GMS. A single long pfKelch C580Y haplotype (from −50 to +31.5 kb either side of the Pfkelch gene), which emerged in Western Cambodia in or before 2008 (PfPailin), has spread across the Eastern GMS. In Myanmar C580Y parasites of a different lineage have spread widely but not dominated and a single pfKelch F446I haplotype, which probably originated in the north of Myanmar, has spread widely across the country. Modified from Imwong et al. with permission

FIGURE 5

Radical cure of vivax malaria with tafenoquine. Individual patient meta‐analysis of freedom from recurrence of P. vivax malaria (relapse prevention) in the two tafenoquine pivotal phase 3 studies in adults. These compared tafenoquine single dose (300 mg) with a low‐dose primaquine regimen (15 mg base day for 14 days)., The dashed vertical line represents the prespecified noninferiority margin of an odds ratio for recurrence of 1.45 (tafenoquine vs primaquine). In Southeast Asia, which has high relapse rates, tafenoquine was significantly inferior (orange highlighting) to the low‐dose primaquine regimen (which is considered inferior to a high‐dose primaquine regimen of 30 mg base/day). Modified from Llanos‐Cuentas et al. with permission