‘Cornerstone’ of Modern Malaria Therapy in Growing Jeopardy

Strains of Plasmodium falciparum carrying mutations that help the malaria-causing parasite to survive treatment with artemisinin compounds have been confirmed in a new region within Africa, adding to mounting concern about drug resistance.

Researchers led by Betty Balikagala, MD, PhD, of Juntendo University in Tokyo, found that 19.8% of P. falciparum isolates from northern Uganda tested in 2019 were carrying artemisinin-resistance mutations in the kelch13 gene, up from just 3.9% in 2015, the group reported in the New England Journal of Medicine.

It’s the first confirmation of artemisinin-resistant P. falciparum in this part of Africa, the researchers said. Their conclusion was based on an analysis of parasite clearance half-life in patients treated with intravenous artesunate, in which longer periods are associated with greater resistance. Ex vivo susceptibility was assessed with a ring-stage survival assay.

Just as worryingly, it appears that these resistant parasites were not imported from other endemic areas but arose spontaneously. Single-nucleotide polymorphism analysis showed unique patterns in these Ugandan bugs relative to resistant strains from Southeast Asia, where such mutations were first identified.

It’s not the end of the world for artemisinin, at least in the short term. The degree of resistance seen with the particular mutations from northern Uganda was less than in the Southeast Asian strains.

Wild-type parasite strains showed clearance half-lives averaging 1.78 hours, whereas those with the A675V or C469Y kelch13 mutations had mean half-lives of 3.95 and 3.30 hours, respectively. But half-lives seen in resistant Southeast Asian strains have recently been much longer, with medians approaching 7 hours, Balikagala and colleagues indicated.

Also, current best-practice therapy is a combination of an artemisinin derivative, artemether, with a different agent called lumefantrine; this double-action drug still seems effective against clinical illness with the new resistant strains, said Nicholas White, FRS, of Mahidol University in Bangkok, in an accompanying editorial.

Nevertheless, the “emergence of artemisinin resistance in Africa is serious” because it “puts greater pressure” on the lumefantrine component, he wrote. “High-grade lumefantrine resistance has not yet emerged, but if it did, it would be a major threat to current control and elimination efforts.”

Such back-and-forth between resistance to current drugs and development of new drugs has been a recurring cycle in the fight against malaria, a scourge of tropical regions since time began. Balikagala and colleagues noted that, as of 2019, nearly 230 million malaria cases and some 409,000 deaths were recorded worldwide. Quinine was once the mainstay of therapy and prevention — hence the popularity of tonic water among Britons stationed in the tropics in the 19th century — but resistance developed. Chloroquine, a quinine derivative, was then effective for a while but it, too, began to lose efficacy within a few decades. The same happened with its derivative, hydroxychloroquine.

Artemisinin is an herbal compound contained in Chinese folk medicines and isolated in the 1970s, when it was discovered to have extraordinary efficacy against P. falciparum malaria, to the point that its synthetic derivatives are now the “cornerstone” of malaria treatment, as White put it.

To the extent that resistance to it is spreading geographically — it was previously identified in neighboring Rwanda — it’s a major setback for efforts to bring the disease under control in Africa where, Balikagala and colleagues observed, 90% of global cases and deaths occur.

The current findings, they concluded, “suggest a potential risk of cross-border spread across Africa and highlight the need to perform large-scale surveys.” In particular, the two mutations they assessed in the study, A675V and C469Y, could serve as easily tracked markers for resistance in conducting such surveys, the group said.