University of Khartoum

Evaluation of Artemisinin Efficacy and Investigation of Genetic Polymorphisms Associated with Resistance among Recurrent Plasmodium Falciparum Malaria Patients.

Evaluation of Artemisinin Efficacy and Investigation of Genetic Polymorphisms Associated with Resistance among Recurrent Plasmodium Falciparum Malaria Patients.

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Title: Evaluation of Artemisinin Efficacy and Investigation of Genetic Polymorphisms Associated with Resistance among Recurrent Plasmodium Falciparum Malaria Patients.
Author: Elobied, Maha Elobied Elhussien
Abstract: Background According to the national protocol ArtesunateSulfadoxine/Pyrimethamine (ASP) is the first line treatment of non-complicated Plasmodium falciparum malaria in Sudan since 2004. Several studies in Africa reported reduced efficacy of first line artemisinin based combination therapies (ACTs). Suspected artemisinin resistance is defined as a high prevalence of the delayed parasite clearance phenotype or high prevalence of Kelch13 gene (K13) mutants while confirmed artemisinin resistance is defined as a combination of delayed parasite clearance and K13 resistance associated mutations. The objectives of the current study were to assess parasite clearance rate following ASP treatment in patients with history of recurrent P. falciparum malaria and to determine possible genetic polymorphisms in ASP resistance candidate genes (P. falciparumdihydrofolatereductase (Pfdhfr) candidate gene for SP resistance and K13 candidate gene for Artemisinin resistance). Methods Ethical clearance was obtained from the Ministry of Health Khartoum State. A pharmacovigilance study was carried out in Khartoum and Damazin during 2013-2015. A total of 210 uncomplicated malaria suspected patients with history of recurrent malaria were screened for malaria using microscopy and confirmed by PCR as P. falciparum mono-infection. Patients who met the inclusion criteria were followed up for 28days in scheduled visits (day 0, 3, 7, 14, 21 and 28) to monitor the parasite clearance rate. Randomly selected 25 patients (23 phenotyped with delayed parasite clearance and 2 with adequate parasitological responses) were genotyped for K13 and Pfdhfr using PCR/RFLP and DNA sequencing. Data was analyzed using SPSS v. 20 and Bioinformatics softwares. Results Out of 210 screened patients 171 patients were enrolled in the study of which 81 were successfully followed up and parasite clearance rate was measured. Forty patients (49.4%) had adequate parasitological response while 41 patients (50.6%) had delayed parasite clearance. According to PCR results 17.9% of microscopic results were false positive results and 26.4% false negative results. Genotyping of Pfdhfr showed 22 samples out of 25 (88%) harbored Asn 108 mutant allele. There was a significant association between the mutant Pfdhfr allele and delayed parasite clearance phenotype (P = 0.002350). K13 genotyping results showed that one sample out of 23 with delayed parasite clearance (4.3%) harbored a universal SNP (T508N) of artemisinin resistance. One sample (4.3%) and three samples (13%) harbored two novel non-synonymous mutations Q633H and E424L respectively that have damaging effects on Kelch protein structure and biological function. Conclusion Reduced P. falciparum susceptibility to artesunate characterized by delayed parasite clearance has been detected in central and south east Sudan among study population. Five cases of confirmed artemisinin resistance were reported. Artemisinin resistance appears to be multigenic which involves more than one gene locus and/or multiple mutations.
Description: 119 page
URI: http://khartoumspace.uofk.edu/123456789/25497


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