Date Published: March 22, 2018
Publisher: The American Society of Tropical Medicine and Hygiene
Author(s): Elizabeth Hemming-Schroeder, Emuejevuoke Umukoro, Eugenia Lo, Becky Fung, Pedro Tomás-Domingo, Guofa Zhou, Daibin Zhong, Amruta Dixit, Harrysone Atieli, Andrew Githeko, Anne Vardo-Zalik, Guiyun Yan.
Antimalarial drug resistance has threatened global malaria control since chloroquine (CQ)-resistant Plasmodium falciparum emerged in Asia in the 1950s. Understanding the impacts of changing antimalarial drug policy on resistance is critical for resistance management. Plasmodium falciparum isolates were collected from 2003 to 2015 in western Kenya and analyzed for genetic markers associated with resistance to CQ (Pfcrt), sulfadoxine–pyrimethamine (SP) (Pfdhfr/Pfdhps), and artemether–lumefantrine (AL) (PfKelch13/Pfmdr1) antimalarials. In addition, household antimalarial drug use surveys were administered. Pfcrt 76T prevalence decreased from 76% to 6% from 2003 to 2015. Pfdhfr/Pfdhps quintuple mutants decreased from 70% in 2003 to 14% in 2008, but increased to near fixation by 2015. SP “super resistant” alleles Pfdhps 581G and 613S/T were not detected in the 2015 samples that were assessed. The Pfmdr1 N86-184F-D1246 haplotype associated with decreased lumefantrine susceptibility increased significantly from 4% in 2005 to 51% in 2015. No PfKelch13 mutations that have been previously associated with artemisinin resistance were detected in the study populations. The increase in Pfdhfr/Pfdhps quintuple mutants that associates with SP resistance may have resulted from the increased usage of SP for intermittent preventative therapy in pregnancy (IPTp) and for malaria treatment in the community. Prevalent Pfdhfr/Pfdhps mutations call for careful monitoring of SP resistance and effectiveness of the current IPTp program in Kenya. In addition, the commonly occurring Pfmdr1 N86-184F-D1246 haplotype associated with increased lumefantrine tolerance calls for surveillance of AL efficacy in Kenya, as well as consideration for a rotating artemisinin-combination therapy regimen.
Antimalarial drug resistance has significantly hindered malaria control efforts and played a key role in shaping global drug policies since the first reports of chloroquine (CQ) resistance arose from Southeast Asia in 1957.1 Since then, because of widespread drug resistance, global recommendations for the first-line treatment of malaria have changed from CQ to sulfadoxine–pyrimethamine (SP), and again, most recently, from SP to artemisinin-combination therapy (ACT).1 As both CQ and SP drug resistance arose in Southeast Asia before spreading to Africa,2 the emergence of ACT resistance in several Southeast Asian countries and recent report on the emergence of indigenous artemisinin-resistant Plasmodium falciparum in Africa3 triggers major concern on the efficacy of malaria control programs in Africa where most of the global malaria burden falls.4
Significant changes in frequencies of drug resistance molecular markers were observed with changes in antimalarial drug policy and reported use over the 13-year study period in western Kenya. A decreasing trend in Pfcrt 76T mutation, associated with CQ resistance,2 was observed from 2003 to 2015 at both study sites (Figure 1A). However, differences were observed between the sites in 2008 when the Pfcrt 76T mutation was observed at a significantly higher frequency in Kakamega at 91.9% than in Kombewa at 61.0%. By 2015, Pfcrt 76T mutation frequencies declined to 2.7% and 11.8% in Kombewa and Kakamega, respectively.
This study examined the impact of past and present antimalarial drug policy and usage on drug resistance genetic markers of P. falciparum, the most common and deadly malarial parasite in sub-Saharan Africa.4 We found that mutations associated with resistance have declined for CQ, but have increased for SP following an initial decline. In addition, the prevalence of polymorphisms associated with lumefantrine tolerance has increased since pre-AL distribution levels. No known mutations associated with artemisinin resistance in Asia were detected.