Longitudinal surveillance of drug resistance in Plasmodium falciparum isolates from the China-Myanmar border reveals persistent circulation of multidrug resistant parasites

Abstract

Multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion of Southeast Asia is a major threat to malaria elimination and requires close surveillance. In this study, we collected 107 longitudinal clinical samples of P. falciparum in 2007–2012 from the malaria hypoendemic region of the China-Myanmar border and measured their in vitro susceptibilities to 10 antimalarial drugs. Overall, parasites had significantly different IC50 values to all the drugs tested as compared to the reference 3D7 strain. Parasites were also genotyped in seven genes that were associated with drug resistance including pfcrt, pfmdr1, pfmrp1, pfdhfr, pfdhps, pfnhe1, and PfK13 genes. Despite withdrawal of chloroquine and antifolates from treating P. falciparum, parasites remained highly resistant to these drugs and mutations in pfcrt, pfdhfr, and pfdhps genes were highly prevalent and almost reached fixation in the study parasite population. Except for pyronaridine, quinine and lumefantrine, all other tested drugs exhibited significant temporal variations at least between some years, but only chloroquine and piperaquine had a clear temporal trend of continuous increase of IC50s. For the pfmrp1 gene, several mutations were associated with altered sensitivity to a number of drugs tested including chloroquine, piperaquine, lumefantrine and dihydroartemisinin. The association of PfK13 mutations with resistance to multiple drugs suggests potential evolution of PfK13 mutations amid multidrug resistance genetic background. Furthermore, network analysis of drug resistance genes indicated that certain haplotypes associated multidrug resistance persisted in these years, albeit there were year-to-year fluctuations of the predominant haplotypes.

<p>Trends in Molecular Markers Associated with Resistance to Sulfadoxine-Pyrimethamine (SP) Among <em>Plasmodium falciparum</em> Isolates on Bioko Island, Equatorial Guinea: 2011–2017</p>

“…Consistent with our previous finding (2013-2014), this study revealed an intense level of Pfdhfr triple mutants (IRNI) and a single-mutant Pfdhps haplotype (SGKAA) among Bioko parasites. 20 Global data [27][28][29][30][31][32][33][34][35][36] were also applied in the comparison analysis, and the patterns for African countries in this study were in line with previous research. 43 High similarity of the distribution of Pfdhfr and Pfdhps haplotypes was found between Bioko Island and its neighbouring countries.…”

“…25 Pfdhfr and Pfdhps sequences from 20 other countries (18 for Pfdhps and 18 for Pfdhfr) were downloaded from NCBI or our previous study 26 to analyse global genetic diversity. [27][28][29][30][31][32][33][34][35][36]…”

Changing epidemiology and challenges of malaria in China towards elimination

“…For instance, the importation and autochthonous transmission of P. vivax have been presented in the regions along the China–Myanmar border, considering the similar climate and natural environment and vectors [48, 49]. Moreover, the importation of parasites may also introduce the drug-resistance malaria into China, and a longitudinal surveillance of drug resistance in P. falciparum along the China–Myanmar border revealed the persistent circulation of multidrug resistant parasites [50]. Surveillance systems need to be well planned and managed to ensure timely case detection and prompt response to prevent and interrupt onward transmission in China [49].…”

Genetic features of P. falciparum parasites collected in 2012-2016 and anti-malaria resistance along China-Myanmar border

“…Following the spreading pattern of resistance to chloroquine and sulfadoxine/pyrimethamine which firstly emerged in the South East Asia region in 1970s and then expanded to Africa [29,33,41], ACTs resistance appeared in Cambodia and then spread to nearly the whole GMS [16,[25][26][27][28][42][43].…”