Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis

Abstract

BackgroundArtemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up.MethodsData from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive.ResultsPC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28–63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2–12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95–4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44–3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007.ConclusionsSeveral factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0874-1) contains supplementary material, which is available to authorized users.

Parasite clearance rates in Upper Myanmar indicate a distinctive artemisinin resistance phenotype: a therapeutic efficacy study

“…The study protocol was designed specifically to assess prolongation of parasite clearance half-lives, the hallmark of artemisinin resistance in P. falciparum [ 29 ]. Parasite clearance half-life is less prone to confounding by baseline parasitaemia than day 3 parasite positivity [ 28 , 30 , 31 ], and remains the gold-standard for determining resistance phenotypes needed for the characterization of artemisinin resistance [ 10 , 32 – 34 ]. The use of clearance half-life to define artemisinin resistance was validated in western Cambodia, where a dichotomous distribution of half-lives is evident and a 5-h cut-off provides satisfactory discrimination [ 30 ].…”

Parasite Clearance and Artemether Pharmacokinetics Parameters Over the Course of Artemether-Lumefantrine Treatment for Malaria in Human Immunodeficiency Virus (HIV)-Infected and HIV-Uninfected Ugandan Children

“…The relationships among HIV status, artemether/DHA exposure, and parasite clearance half-life was further assessed by both mediation and moderation analyses, results that supported a primary role of HIV status in modifying the delay in clearance, rather than variability in artemether/DHA exposure. Other studies have assessed the potential direct impact of artemisinin exposure on parasite clearance, although they have largely focused on artesunate [3, 12, 29–33]. Although these studies have largely found no clear associations of parasitologic responses to PK parameters, an early AL dose-finding study found that higher artemether and DHA AUCs were associated with a decrease in parasite clearance time.…”

Plasmodium bergheiK13 Mutations MediateIn VivoArtemisinin Resistance That is Reversed by Proteasome Inhibition

“…The parasite clearance estimator has been used to generate substantial baseline data that classify ART resistance as parasite clearance half-lives >5.5 hours and ART sensitivity as parasite clearance half-lives <3 hours (12,13). However, interpretation of clearance half-lives can be confounded by differences in initial parasite biomass, the efficacy of the partner drug, and the level of host immunity (12,14).…”

“…The parasite clearance estimator has been used to generate substantial baseline data that classify ART resistance as parasite clearance half-lives >5.5 hours and ART sensitivity as parasite clearance half-lives <3 hours (12,13). However, interpretation of clearance half-lives can be confounded by differences in initial parasite biomass, the efficacy of the partner drug, and the level of host immunity (12,14). Moreover, this in vivo phenotype does not correlate with decreased susceptibility to dihydroartemisinin (DHA) in standard growth inhibition assays where PF parasites (which have an ~48 hour intra-erythrocytic developmental cycle) are exposed to the drug for a total of 72 hours (5,15,16).…”