High efficacy of artemether-lumefantrine and declining efficacy of artesunate + sulfadoxine-pyrimethamine against Plasmodium falciparum in Sudan (2010-2015): evidence from in vivo and molecular marker studies

Abstract

Background: The present paper reports on studies that evaluated artesunate + sulfadoxine-pyrimethamine (AS + SP) which is the first-line drug and artemether-lumefantrine (AL) which is a second-line drug against uncomplicated falciparum malaria in Sudan. This evaluation was performed in twenty studies covering six sentinel sites during five successive annual malaria transmission seasons from 2010 to 2015.

Methods: The standard World Health Organization protocol was used for a follow-up period of 28 days. The frequency distribution of molecular markers for antifolate resistance in dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes was studied in pre-treatment samples in four sites in 2011.

Results: In the nine studies of AL conducted at five sites (n = 595), high PCR-corrected cure rates were found, ranging from 96.8 to 100 %. Among the eleven studies of AS + SP (n = 1013), a decline in the PCR-corrected cure rates was observed in Gedaref in Eastern Sudan: 91.0 % in the 2011-12 season and 86.5 % in the 2014-15 season. In the remaining sites, the AS + SP cure rates ranged between 95.6 and 100 %. The rate of clearance of microscopic gametocytaemia after treatment was not significantly different with AL or AS + SP on days 7, 14, 21 and 28 of follow-up. A total of 371 pre-treatment samples were analysed for molecular markers of SP resistance. The temporal changes and geographical differences in the frequency distribution of SP-resistance genotypes showed evidence of regional differentiation and selection of resistant strains.

Conclusion: The findings of this study call for a need to review the Sudan malaria treatment policy. Epidemiological factors could play a major role in the emergence of drug-resistant malaria in eastern Sudan.

Australian new zealand clinical trials registry: Trial registration numbers 2011-2012: ACTRN12611001253998, 2013-2015: ACTRN12613000945729.

Keywords: Artemether-lumefantrine antimalarial drugs; Artesunate; Drug resistance; Molecular markers; Sudan; Sulfadoxine-pyrimethamine; dhfr; dhps.

Fig. 1

Map of Sudan showing six sentinel sites for therapeutic efficacy tests in Sudan 2010–2015. “X” indicates the location of three villages where isolates were collected in previous SP molecular marker studies in 2003. Pie charts indicate the proportion with quintuple/sextuple mutations. Black segments indicate the percentage of samples with quintuple or sextuple mutations in each site

Fig. 2

Time to disappearance of microscopic gametocytaemia in gametocyte-positive individuals at enrolment and following treatment. AL artemether-lumefantrine (n 23), AS + SP sulfadoxine-pyrimethamine (n 24)