Artemisinin-resistant malaria

Abstract

SUMMARYThe artemisinin antimalarials are the cornerstone of current malaria treatment. The development of artemisinin resistance in Plasmodium falciparum poses a major threat to malaria control and elimination. Recognized first in the Greater Mekong subregion of Southeast Asia nearly 20 years ago, artemisinin resistance has now been documented in Guyana, South America, in Papua New Guinea, and most recently, it has emerged de novo in East Africa (Rwanda, Uganda, South Sudan, Tanzania, Ethiopia, Eritrea, and eastern DRC) where it has now become firmly established. Artemisinin resistance is associated with mutations in the propeller region of the PfKelch gene, which play a causal role, although the parasites' genetic background also makes an important contribution to the phenotype. Clinically, artemisinin resistance manifests as reduced parasiticidal activity and slower parasite clearance and thus an increased risk of treatment failure following artemisinin-based combination therapy (ACT). This results from the loss of artemisinin activity against the younger circulating ring stage parasites. This loss of activity is likely to diminish the life-saving advantage of artesunate in the treatment of severe falciparum malaria. Gametocytocidal and thus transmission blocking activities are also reduced. At current levels of resistance, artemisinin-resistant parasites still remain susceptible at the trophozoite stage of asexual development, and so, artemisinin still contributes to the therapeutic response. As ACTs are the most widely used antimalarial drugs in the world, it is essential from a malaria control perspective that ACT cure rates remain high. Better methods of identifying uncomplicated hyperparasitemia, the main cause of ACT treatment failure, are required so that longer courses of treatment can be given to these high-risk patients. Reducing the use of artemisinin monotherapies will reduce the continued selection pressure which could lead potentially to higher levels of artemisinin resistance. Triple artemisinin combination therapies should be deployed as soon as possible to protect the ACT partner drugs and thereby delay the emergence of higher levels of resistance. As new affordable antimalarial drugs are still several years away, the control of artemisinin resistance must depend on the better use of available tools.

Keywords: Plasmodium falciparum; antimalarial agents; artemisinin; drug resistance evolution; malaria.

Fig 1

Immunofluorescent labeling of ring erythrocyte surface antigen stained red cells in acute malaria. In artemisinin-sensitive infections, the ring form parasites are killed by artemisinin drugs and the once-infected erythrocytes (red arrow) are returned to the circulation (19, 20), where they have shortened survival (21). In artemisinin-resistant infections, ring stage susceptibility is lost and this process, called pitting, is markedly reduced.

Fig 2

Parasite clearance following artesunate treatment of adult patients with acute falciparum malaria in western Cambodia compared with western Thailand from June 2007 to May 2008 [adapted from reference (5) with permission of the publisher (copyright Massachusetts Medical Society)]. The data are log10 normalized median parasite densities and interquartile ranges over time. The slow-clearing parasites were later shown to be PfKelch 13 C580Y genotypes.

Fig 3

Measuring parasite clearance rates. A comparison of parasitological responses in acute falciparum malaria between artemisinin-sensitive (in green) and artemisinin-resistant parasitemias (in red) at two initial parasite densities (high: circa 2% parasitemia on the thin blood film; low: circa 30 parasites per 200 white cells on a thick blood film) following the start of treatment with an artemisinin derivative. The parasite clearance time and the “day 3 positivity” are strongly dependent both on the initial parasite density and the accuracy of detection at low densities, whereas parasite clearance rates (or the derivative half-life) are not. [Adapted from reference (33) (published under a Creative Commons license).] Note that, at lower parasite densities, even the slowly clearing artemisinin-resistant parasites are “parasite negative” by microscopy on day 3.

Fig 4

The relationship between parasite clearance half-life following artesunate treatment and mutations in the P. falciparum Kelch gene. These data are from the TRAC study, which enrolled 1,241 adults and children with acute falciparum malaria in Asia and Africa between May 2011 and April 2013 [adapted from reference (34) with permission of the publisher (copyright Massachusetts Medical Society)]. Common genotypes found either in this or in other studies are in boldface; WT, wild type.

Fig 5

Geometric mean (95%CI) parasite clearance half-lives in northern Uganda (40) and in the GMS (34) following artesunate treatment of acute falciparum malaria. A comparison of responses in PfKelch wild-type and A675V mutant infections. The A675V mutation arose independently in the two locations.

Fig 6

A comparison of parasitological responses in PfKelch wild-type and C580Y mutant infections. Geometric mean (95% CI) parasite clearance half-lives on the western border of Thailand and in the eastern GMS (34) following artesunate treatment of acute falciparum malaria. The C580Y mutation arose independently in the two locations.

Fig 7

Countries with endogenous P. falciparum malaria that have reported artemisinin resistance (as of June 2024).

Fig 8

Transnational spread of artemisinin-resistant P. falciparum lineages in the GMS in the previous decade (42, 119). The yellow areas and associated names are the provinces from where the genotyped parasites were obtained.

Fig 9

P. falciparum parasite clearance half-lives measured in Rwanda during phase 2 studies of cipargamin (132). The artemisinin-treated patients received artemether-lumefantrine. These results are compared with those of the first phase 2 study conducted earlier in Thailand (192) and the wild-type PC_1/2 values from the GMS in the multi-country TRAC study (34). Cipargamin (green circles) treatment resulted in very rapid parasite clearance in both artemisinin-sensitive and artemisinin-resistant infections. The R563H mutation arose independently in the two locations.

Fig 10

Both diagrams depict parasitological responses following ACTs in artemisinin-sensitive (AS) and artemisinin-resistant (AR) acute falciparum malaria (118). The initial decline in parasite densities resulting from the artemisinin component is much greater in AS infections. After the rapid elimination of the artemisinin component, there are a million times more parasites for the partner drugs to eliminate in AR infections in this extreme example. TACTs, shown on the right, have two slowly eliminated partner drugs. These two slowly eliminated drugs provide mutual protection against the selection of resistance and ensure efficacy. TACTs provide a readily deployable approach to protecting the ACT partner drugs from resistance and extending the life of current therapies. The most advanced of these TACTs, artemether-lumefantrine-amodiaquine, is well tolerated, is already co-formulated in a fixed dose combination, and is only marginally more expensive than artemether-lumefantrine. It is less expensive than the pyronaridine and piperaquine containing ACTs.