Declining Responsiveness of Plasmodium falciparum Infections to Artemisinin-Based Combination Treatments on the Kenyan Coast

Abstract

BackgroundThe emergence of artemisinin-resistant P. falciparum malaria in South-East Asia highlights the need for continued global surveillance of the efficacy of artemisinin-based combination therapies.MethodsOn the Kenyan coast we studied the treatment responses in 474 children 6–59 months old with uncomplicated P. falciparum malaria in a randomized controlled trial of dihydroartemisinin-piperaquine vs. artemether-lumefantrine from 2005 to 2008. (ISRCTN88705995)ResultsThe proportion of patients with residual parasitemia on day 1 rose from 55% in 2005–2006 to 87% in 2007–2008 (odds ratio, 5.4, 95%CI, 2.7–11.1; P<0.001) and from 81% to 95% (OR, 4.1, 95%CI, 1.7–9.9; P = 0.002) in the DHA-PPQ and AM-LM groups, respectively. In parallel, Kaplan-Meier estimated risks of apparent recrudescent infection by day 84 increased from 7% to 14% (P = 0.1) and from 6% to 15% (P = 0.05) with DHA-PPQ and AM-LM, respectively. Coinciding with decreasing transmission in the study area, clinical tolerance to parasitemia (defined as absence of fever) declined between 2005–2006 and 2007–2008 (OR body temperature >37.5°C, 2.8, 1.9–4.1; P<0.001). Neither in vitro sensitivity of parasites to DHA nor levels of antibodies against parasite extract accounted for parasite clearance rates or changes thereof.ConclusionsThe significant, albeit small, decline through time of parasitological response rates to treatment with ACTs may be due to the emergence of parasites with reduced drug sensitivity, to the coincident reduction in population-level clinical immunity, or both. Maintaining the efficacy of artemisinin-based therapy in Africa would benefit from a better understanding of the mechanisms underlying reduced parasite clearance rates.Trial RegistrationControlled-Trials.com ISRCTN88705995

Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria

“…RCTs are initially categorized as high quality but can be downgraded after assessment of five criteria: risk of bias, consistency, directness, imprecision, and publication bias. Similarly, observational studies are initially categorized as low quality and can be downgraded by the same criteria, but in exceptional circumstances may be upgraded by three further criteria; large effect size, all plausible confounders would act to reduce the effect size, and evidence of a dose-response effect (Guyatt 2008). …”

Host immunity to Plasmodium falciparum and the assessment of emerging artemisinin resistance in a multinational cohort

“…The operational implications of an effect of host immunity on parasite clearance measures are that in populations with high levels of immunity and faster parasite clearance, early signs of low-grade drug resistance could go undetected, and conversely, that in populations with lower immunity and slower parasite clearance, a false impression of reduced drug efficacy could arise (16)(17)(18). The available immunological evidence for this comes from previous single-study-site investigations, predominantly in hightransmission settings in Africa, which have reported conflicting associations between immunity and treatment failure to historical first-line treatments (e.g., chloroquine, sulfadoxine-pyrimethamine) and ACTs (19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Of the four single-site studies looking at artemisinin derivatives, all examined ACT, where associations may be confounded by the partner drug, and all were performed in areas before the emergence of artemisinin resistance or in areas where resistance is yet to arise (24)(25)(26)(27).…”

“…The available immunological evidence for this comes from previous single-study-site investigations, predominantly in hightransmission settings in Africa, which have reported conflicting associations between immunity and treatment failure to historical first-line treatments (e.g., chloroquine, sulfadoxine-pyrimethamine) and ACTs (19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Of the four single-site studies looking at artemisinin derivatives, all examined ACT, where associations may be confounded by the partner drug, and all were performed in areas before the emergence of artemisinin resistance or in areas where resistance is yet to arise (24)(25)(26)(27). Only one of these studies investigated an outcome measure included in the current WHO definition of artemisinin resistance (PCt 1/2 ) and found an unquantified inverse correlation (25).…”

The Polymorphic Linker Domain of pfmdr1 Is Associated with Resistance-Conferring Mutations in Plasmodium falciparum Populations from East and West Africa

“…he malaria parasite Plasmodium falciparum is becoming less sensitive to the artemisinin class of drugs in Asia (1,2), and variable responses in East Africa have been reported (3). Artemisinin is a component of all current combination therapies, and while their clinical efficacy remains high, understanding of parasite genetic factors that contribute to variation in artemisinin sensitivity is essential.…”