Efficacy of artemether-lumefantrine for treating uncomplicated Plasmodium falciparum cases and molecular surveillance of drug resistance genes in Western Myanmar

Abstract

Background Currently, artemisinin-based combination therapy (ACT) is the first-line anti-malarial treatment in malaria-endemic areas. However, resistance in Plasmodium falciparum to artemisinin-based combinations emerging in the Greater Mekong Sub-region is a major problem hindering malaria elimination. To continuously monitor the potential spread of ACT-resistant parasites, this study assessed the efficacy of artemether-lumefantrine (AL) for falciparum malaria in western Myanmar. Methods Ninety-five patients with malaria symptoms from Paletwa Township, Chin State, Myanmar were screened for P. falciparum infections in 2015. After excluding six patients with a parasite density below 100 or over 150,000/µL, 41 P. falciparum patients were treated with AL and followed for 28 days. Molecular markers associated with resistance to 4-amino-quinoline drugs ( pfcrt and pfmdr1 ), antifolate drugs ( pfdhps and pfdhfr ) and artemisinin ( pfk13 ) were genotyped to determine the prevalence of mutations associated with anti-malarial drug resistance. Results For the 41 P. falciparum patients (27 children and 14 adults), the 28-day AL therapeutic efficacy was 100%, but five cases (12.2%) were parasite positive on day 3 by microscopy. For the pfk13 gene, the frequency of NN insert after the position 136 was 100% in the day-3 parasite-positive group as compared to 50.0% in the day-3 parasite-negative group, albeit the difference was not statistically significant ( P = 0.113). The pfk13 K189T mutation (10.0%) was found in Myanmar for the first time. The pfcrt K76T and A220S mutations were all fixed in the parasite population. In pfmdr1 , the Y184F mutation was present in 23.3% of the parasite population, and found in both day-3 parasite-positive and -negative parasites. The G968A mutation of pfmdr1 gene was first reported in Myanmar. Prevalence of all the mutations in pfdhfr and pfdhps genes assessed was over 70%, with the exception of the pfdhps A581G mutation, which was 3.3%. Conclusions AL remained highly efficacious in western Myanmar. Pfk13 mutations associated with artemisinin resistance were not found. The high prevalence of mutations in pfcrt , pfdhfr and pfdhps suggests high-degree resistance to chloroquine and antifolate drugs. The pfmdr1 N86/184F/D1246 haplotype associated with selection by AL in Africa reached...

Molecular Profiles of Multiple Antimalarial Drug Resistance Markers in Plasmodium falciparum and Plasmodium vivax in the Mandalay Region, Myanmar

“…Concurrent mutations were also identified in pfdhps . Frequencies of the mutations were similar to or slightly higher than those of P. falciparum collected from northern (Banmauk, Sagaing State and Laiza, Kachin State) and western (Paletwa, Chin State) Myanmar [ 25 , 34 ]. However, more diverse haplotypes of pfdhps were identified in P. falciparum isolates collected from Mandalay region.…”

“…In the case of pfdhfr , these mutations were commonly identified as concurrent mutations rather single mutations in the gene. Frequencies of quadruple mutation (AIRNL), triple mutation (AIRNI or ANRNL), and double mutation (ANRNI) were comparable to or slightly different from those of P. falciparum collected from northern (Banmauk, Sagaing State and Laiza, Kachin State) and western (Paletwa, Chin State) Myanmar [ 25 , 34 ]. Concurrent mutations were also identified in pfdhps .…”

Making data map-worthy—enhancing routine malaria data to support surveillance and mapping of Plasmodium falciparum anti-malarial resistance in a pre-elimination sub-Saharan African setting: a molecular and spatiotemporal epidemiology study

“…However, no other African studies have demonstrated an increased therapeutic failure rate when these alleles are present [ 74 – 76 ]. In Asia, clinical failure rates have been linked to the increase in mdr1 copy number as compared to the mdr 86ASN alleles [ 77 ]. The increase in mdr1 copy number has rarely been reported in Africa [ 52 , 78 ], and this study did not observe any such increase.…”

Multidisciplinary Investigations of Sustained Malaria Transmission in the Greater Mekong Subregion

“…163 In Northeast Myanmar, where the G6PD Mahidol variant is prevalent, we conducted an observational study in a cohort of 152 vivax patients to follow the risk of acute hemolysis 122 Laos, 192 Vietnam, 193 Thailand, 194,195 and Myanmar. 124,127,142 This figure appears in color at www.ajtmh.org.…”

“…Map of the GMS showing the prevalence and distribution of major PfK13 mutations as pie graphs above the malaria incidence heatmap of the region in 2020. The PfK13 mutation status was updated using malaria parasites collected primarily in 2016 from Cambodia,122 Laos,192 Vietnam,193 Thailand,194,195 and Myanmar 124,127,142. This figure appears in color at www.ajtmh.org.…”