Dihydroartemisinin plus piperaquine, an artemisinin combination therapy (ACT) for treating multidrug-resistant Plasmodium falciparum malaria, should no longer be used in southeast Asia as a result of new resistance mutations linked with even higher treatment failure rates, according to results of 2 studies published in the Lancet Infectious Diseases.1,2  

Interim study results from a multicountry, open-label, randomized trial (TRACII; ClinicalTrials.gov identifier: NCT02453308) evaluating the efficacy, safety, and tolerability of a triple ACT (dihydroartemisinin plus piperaquine and mefloquine) compared with dihydroartemisinin plus piperaquine at 7 sites in Cambodia, Vietnam, and Thailand in 140 patients (84% men; median age, 27 years) showed a 50% treatment failure rate at day 42 with dihydroartemisinin plus piperaquine .1

Polymerase chain reaction-corrected efficacies at day 42 were 12.7% in northeastern Thailand, 38.2% in western Cambodia, 73.4% in Ratanakiri (northeastern Cambodia), and 47.1% in Binh Phuoc (southwestern Vietnam).

Researchers believe the principle reason for the substantial decline in efficacy of dihydroartemisinin plus piperaquine may be the result of a co-lineage of multidrug-resistant P falciparum malaria, KEL1/PLA1, with several genetic KEL1/PLA1 subgroups that now carry mutations in the chloroquine resistance transporter (crt) gene.

Most parasites with the kelch13 C580Y mutation (referred to as KEL1, a marker artemisinin resistance) and amplification of the plasmepsin 2/3 genes (referred to as PLA1, marker of piperaquine resistance) were derived from a single parasite co-lineage that was found only in western Cambodia before 2009. Looking at the evolution and spread of KEL1/PLA1 from 2007 to 2018 from Cambodia, Laos, northeastern Thailand, and Vietnam revealed that KEL1/PLA1 spread rapidly from Cambodia across all the surveyed countries, with prevalence increasing to higher than 50% in all regions apart from Laos.2

Genomic data using 1673 P falciparum samples, in which 1615 were reliably identified with KEL1/PLA1 status, showed that KEL1/PLA1 parasites maintained a high level of genetic relatedness, reflecting their common origin. In particular, the new crt mutations, increasing the parasites’ ability to resist piperaquine, drove the increased rates of treatment failure with dihydroartemisinin plus piperaquine.

In addition to the plasmepsin 2/3 amplification status, 4 mutations in the crt gene (Thr93Ser, His97Tyr, Phe145Ile, and Ile218Phe) were independently associated with treatment failure.1 These 4 crt mutations were rare in the early period but became more prevalent by 2016 to 2017: Thr93Ser rose to 19.8%; His97Tyr rose to 11.2%; Phe145Ile rose to 5.5%; and Ile218Phe rose to 11.1%.2

Related Articles

Cambodia used dihydroartemisinin plus piperaquine between 2008 and 2016 but has since adopted artesunate-mefloquine as first-line treatment. Vietnam has used dihydroartemisinin plus piperaquine as first-line treatment since 2004 and Thailand since 2015, and both countries are reviewing current policy and procedure.

In the absence of new drug classes to replace current first-line therapies, the use of existing drugs in the form of triple artemisinin combination therapies, could be a viable alternative. Results of the TRACII study, investigating efficacy of 2 different triple artemisinin combination therapies, are expected to be published later this year.

Given that these “2 studies illustrate the accelerated pace at which resistance of P falciparum to [dihydroartemisinin plus piperaquine] has evolved and spread across southeast Asia, decimating the efficacy of this drug combination…findings also demonstrate the advantages of implementing a regional strategy rather than country-specific programs to address population movements and to integrate regional clinical and genetic surveillance systems into a coordinated campaign, with the goal of achieving malaria elimination in southeast Asia,” concluded Ménard and Fidock in an editorial commentary.3

References

  1. van der Pluijm RW, Imwong M, Chau NH, et al. Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study [published online July 22, 2019]. Lancet Infect Dis. doi:10.1016/S1473-3099(19)30391-3
  2. Hamilton WL, Amato R, van der Pluijm RW, et al. Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study [published online July 22, 2019]. Lancet Infect Dis. doi:10.1016/S1473-3099(19)30392-53.
  3. Ménard D, Fidock DA. Accelerated evolution and spread of multidrug-resistant Plasmodium falciparum takes down the latest first-line antimalarial drug in southeast Asia [published online July 22, 2019]. Lancet Infect Dis. doi:10.1016/S1473-3099(19)30394-9