Early parasitological response following artemisinin-containing regimens: a critical review of the literature

Abstract

BackgroundParasitaemia on Day 3 has been proposed as a useful alert of potential artemisinin resistance, however, the normal variation of parasite clearance observed in artemisinin-based combination therapy clinical trials is poorly documented.MethodsThe trends in early parasitological response following treatment with an artemisinin anti-malarial regimen were reviewed. A PubMed literature search identified all studies using an artemisinin regimen for uncomplicated falciparum malaria published between January 2000 and December 2011. Data from clinical studies were extracted for analysis using a standardized questionnaire.ResultsIn total 65,078 patients were enrolled into 213 clinical trials with 413 treatment arms containing either an artemisinin derivative alone (n=26) or in combination with a partner drug (n=387). The proportion of patients remaining parasitaemic at 24, 48 and 72 hours was documented in 115 (28%), 167 (40%) and 153 (37%) treatment arms, respectively. Excluding resistance studies in Cambodia, the median proportion of patients still parasitaemic was 53.8% [range 3–95, IQR=30.5-69.2] on Day 1, 6% [range 0–65.9, IQR=2-11.5] on Day 2 and 0 [range 0–12.6, IQR=0-2] on Day 3. Comparing studies from 2000 to 2005 and 2006 to 2011, the median proportion of patients reported to remain parasitaemic at 72 hours decreased in Africa (1.2% vs 0%, p=0.007), but increased in Asia (0.4% vs 3.9%, p=0.076). In 95% of studies the proportion of patients with peripheral parasitaemia was less than 6% at 72 hours.ConclusionsThese results highlight the normal distribution of early parasitological responses following ACT, and the influence that heterogeneity in study design, host and parasite factors have in confounding a surveillance system based on Day 3 parasite positivity. Greater understanding of factors influencing parasite clearance is crucial, but will require analysis of pooled data from individual patient records.

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

“…Several of these factors, as well as studies of age and parasite clearance, suggest that antimalarial immunity plays an important role in early parasitological responses [10, 11]. Our findings further support this notion, because HIV-infected children displayed longer parasite clearance half-lives, even when controlling for baseline parasite density [22].…”

Therapeutic efficacy of artemether-lumefantrine for treatment of uncomplicated <i>plasmodium falciparum</i> malaria in Enugu, Nigeria

“…However, this approach may be difficult to implement in settings of routine in vivo drug efficacy studies among outpatients. An alternative approach is to measure the detectable proportion of patients with parasitaemia after one, two or three days of the initiation of therapy [16,17]. Hence in this study, detectable proportion of patients with parasitaemia three days after the initiation of therapy was employed.…”

K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015

“…In SEA, K13 propeller polymorphism is considered a reliable molecular marker of ART-resistant P. falciparum parasites, which show increased survival rates in RSAs and delayed clearance (i.e., "D3 positivity") in ACT-treated patients (13). Although D3 positivity is considered a useful tool to detect the emergence of ART resistance in a population (14), especially in resource-limited countries where standardized parasite clearance studies (15) are not feasible, the results can be confounded by host immunity and initial parasite density (14); therefore, follow-up studies to obtain parasite clearance half-life data are needed to confirm D3-positivity rates.…”