Abstract
BackgroundThis is an investigation of anti-malarial molecular markers coupled with a therapeutic efficacy test of chloroquine (CQ) against falciparum malaria in an area of unstable malaria in Lahj Governorate, Yemen. The study was aimed at assessment of therapeutic response to CQ and elucidation of baseline information on molecular markers for Plasmodium falciparum resistance against CQ and sulphadoxine/pyrimethamine (SP).MethodsBetween 2002 and 2003 the field test was conducted according to the standard WHO protocol to evaluate the therapeutic efficacy of CQ in 124 patients with falciparum malaria in an endemic area in Lahj Governorate in Yemen. Blood samples collected during this study were analysed for P. falciparum chloroquine resistance transporter gene (pfcrt)-76 polymorphisms, mutation pfcrt-S163R and the antifolate resistance-associated mutations dihydrofolate reductase (dhfr)-C59R and dihydropteroate synthase (dhps)-K540E. Direct DNA sequencing of the pfcrt gene from three representative field samples was carried out after DNA amplification of the 13 exons of the pfcrt gene.ResultsTreatment failure was detected in 61% of the 122 cases that completed the 14-day follow-up. The prevalence of mutant pfcrt T76 was 98% in 112 amplified pre-treatment samples. The presence of pfcrt T76 was poorly predictive of in vivo CQ resistance (PPV = 61.8%, 95% CI = 52.7-70.9). The prevalence of dhfr Arg-59 mutation in 99 amplified samples was 5%, while the dhps Glu-540 was not detected in any of 119 amplified samples. Sequencing the pfcrt gene confirmed that Yemeni CQ resistant P. falciparum carry the old world (Asian and African) CQ resistant haplotype CVIETSESI at positions 72,73,74,75,76,220,271, 326 and 371.ConclusionThis is the first study to report baseline information on the characteristics and implications of anti-malarial drug resistance markers in Yemen. It is also the first report of the haplotype associated with CQR P. falciparum parasites from Yemen. Mutant pfcrtT76 is highly prevalent but it is a poor predictor of treatment failure in the study population. The prevalence of mutation dhfrArg59 is suggestive of emerging resistance to SP, which is currently a component of the recommended combination treatment of falciparum malaria in Yemen. More studies on these markers are recommended for surveillance of resistance in the study area.
Highlights
This is an investigation of anti-malarial molecular markers coupled with a therapeutic efficacy test of chloroquine (CQ) against falciparum malaria in an area of unstable malaria in Lahj Governorate, Yemen
In-vivo treatment outcomes Of 644 febrile patients coming to the hospital, 225 (34.9%) were positive for P. falciparum mono infection, of which 124 (55.1%) were qualified for enrollment because they met all the inclusion criteria mentioned in the methods section
Of the122 cases that completed the follow-up, 48 (39.3%) had adequate clinical and parasitological response (ACPR), the remaining 74 (60.7%) were treatment failures. They were classified as Early Treatment Failures (ELF) 28 (23%), Late Clinical Failures (LCF) 16 (13.1%), and Late Parasitological Failures (LPF) 30 (24.6%)
Summary
This is an investigation of anti-malarial molecular markers coupled with a therapeutic efficacy test of chloroquine (CQ) against falciparum malaria in an area of unstable malaria in Lahj Governorate, Yemen. In some areas, where CQ resistance was highly prevalent, studies have highlighted that withdrawal of CQ drug pressure may lead to a reversion to CQ-susceptible phenotypes as indicated by molecular marker studies [10]. Such a phenomenon might be missed if molecular prevalence surveys have not been conducted. A recent global meta-analysis concluded that both pfcrt and pfmdr polymorphisms are associated with chloroquine resistance, with the odds ratio (OR) of the pfcrt K76T mutation for therapeutic failure after chloroquine exceeding 7.0 at 28 days and 2.0 at day 14 [13]
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