Authors: Ellen Colvin, Future Science Group
Collaborative genomic surveillance research from scientists at the Wellcome Sanger Institute (Cambridge, UK), the University of Oxford (UK) and Mahidol University (Bangkok, Thailand), has identified rapidly spreading antimalarial resistance in Asia to two first-line antimalarials.
Published in The Lancet Infectious Diseases, the study reveals how local Plasmodium falciparum parasite populations are being replaced by the descendants of one multi-drug resistant strain in Laos, Vietnam and northeastern Thailand. In addition, new genetic changes were identified, which the team suggest could be further antimalarial resistance in Asia.
First author, Roberto Amato (Wellcome Sanger Institute) commented: “We discovered that the multi-drug resistant KEL1/PLA1 malaria strain had spread aggressively, replacing local malaria parasites, and had become the dominant strain in Vietnam, Laos and northeastern Thailand. Our large-scale genomic approach demonstrates how surveillance can provide crucial information to malaria control programs, supporting them in evaluating available treatment options.”
With the inclusion of 1673 parasite DNA isolates, this comprehensive sequence analysis is the most recent whole genome study for P. falciparum in Southeast Asia.
Genetic variants of KEL1 and PLA1, which when mutated have been found to cause resistance to dihydroartemisinin and piperaquine (DHA-PPQ), the first-line combination therapy for malaria in Asia, were the focal loci for this analysis of parasitic DNA taken from the blood of malaria patients between 2008 and 2018.
Importantly, the study found that the level of resistance had worsened after 2013, with KEL1/PLA1 resistance mutants widening across nations and in some local regions, forming a large majority of over 80% of the regionally analyzed Plasmodium.
Previously, a study had identified that the KEL1/PLA1 antimalarial-resistant strain had spread across Cambodia under the radar between 2007 and 2013. This study has demonstrated the spread of this resistance to neighboring southeast Asian countries.
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“The speed at which these resistant malaria parasites have spread in southeast Asia is very worrying. Other drugs may be effective at the moment, but the situation is extremely fragile, and this study highlights that urgent action is needed to eliminate the parasites from the Greater Mekong Subregion, to prevent them spreading and evolving further,” commented Olivo Miotto (Wellcome Sanger Institute).
Furthermore, the researchers identified genetic adaptations in the resistant strain, such as the added mutations in chloroquine resistance transporter gene (crt), which may be advantageous for rapid spread and enhance resistance. A different study, also published in The Lancet Infectious Diseases, was able to associate these crt mutations with complete treatment failure of DHA-PPQ, giving evidence towards the worsening severity of the evolving resistance under drug pressure.
The findings are supported by interim evidence from a randomized, multi-country trial evaluating the efficacy, safety, and tolerability of triple artemisinin combination therapy, compared with the current double artemisinin combination therapy in areas with multidrug-resistance malaria strains. These findings suggest that failure rate for DHA-PPQ is as high as 27% in northeastern Cambodia, 67% in western Cambodia and 87% in northeastern Thailand.
Increasing resistance will impede global initiatives working to eliminate malaria and fast response to the rising, spreading resistance is vital. This research emphasizes how important continued genomic surveillance is for updating strategies in efforts to control malaria and monitoring antimalarial resistance in Asia.
Dominic Kwiatkowski (Wellcome Sanger Instituteand University of Oxford concluded: “Our study provides a clear picture of how malaria that is resistant to the first-line treatment is spreading, and demonstrates the importance of using genetics to detect patterns of resistance in each area. Active genomic surveillance is now vital to inform national malaria control programs, to help reduce the risk of a major global outbreak.”
Sources: Hamilton WL, Amato R, van der Pluijm, RW et al. Evolution and expansion of multidrug resistant malaria in Southeast Asia: a genomic epidemiology study. Lancet Infect. Dis. doi:10.1016/S1473-3099(19)30392-5 (2019); Van der Pluijm R, Imwong M, Chau NH et al. Determinants of dihydroartemisinin-piperaquine treatment failure in falciparum malaria in Cambodia, Thailand and Vietnam: a prospective clinical, pharmacological and genetic study. Lancet Infect. Dis. doi:10.1016/S1473-3099(19)30391-3 (2019); www.eurekalert.org/pub_releases/2019-07/tl-pss071919.php