Abstract
BackgroundIn a recent trial of artemisinin-naphthoquine (artemisinin-NQ) and artemether-lumefantrine (AM-LM) therapy in young children from Papua New Guinea (PNG), there were no treatment failures in artemisinin-NQ-treated children with Plasmodium falciparum or Plasmodium vivax compared with 2.2% and 30.0%, respectively, in AM-LM-treated children during 42 days of follow-up. To determine whether, consistent with the long elimination half-life of NQ, this difference in efficacy would be more durable, clinical episodes of malaria were assessed in a subset of trial patients followed for six months post-treatment.MethodsFor children completing trial procedures and who were assessable at six months, all within-trial and subsequent clinical malaria episodes were ascertained, the latter by clinic attendances and/or review of hand-held health records. Presentations with non-malarial illness were also recorded. Differences between allocated treatments for pre-specified endpoints were determined using Kaplan-Meier survival analysis.ResultsOf 247 children who were followed to Day 42, 176 (71.3%) were included in the present sub-study, 87 allocated to AM-LM and 89 to artemisinin-NQ. Twenty children in the AM-LM group (32.8%) had a first episode of clinical malaria within six months compared with 10 (16.4%) in the artemisinin-NQ group (P = 0.033, log rank test). The median (interquartile range) time to first episode of clinical malaria was 64 (50–146) vs 116 (77–130) days, respectively (P = 0.20). There were no between-group differences in the incidence of first presentation with non-malarial illness (P = 0.31).ConclusionsThe greater effectiveness of artemisinin-NQ over conventional AM-LM extends to at least six months post-treatment for clinical malaria but not non-malarial illness.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12610000913077.
Highlights
In a recent trial of artemisinin-naphthoquine and artemether-lumefantrine (AM-LM) therapy in young children from Papua New Guinea (PNG), there were no treatment failures in artemisinin-NQ-treated children with Plasmodium falciparum or Plasmodium vivax compared with 2.2% and 30.0%, respectively, in AM-LM-treated children during 42 days of follow-up
Artemisinin-based combination therapy (ACT) has emerged as first-line treatment for uncomplicated malaria in most malaria-endemic countries because of the high cure rate, relative safety, transmission-blocking potential, and ability to delay the development of parasite drug resistance [1]
The World Health Organization (WHO) currently recommends Day 42 as the maximum follow-up time-point for trials involving longer half-life ACT partner drugs [2,3], but there is theoretical evidence that at least 56 days of follow-up should be considered for trials of falciparum malaria involving ACT partner drugs with elimination half-lives that are longer than one week [4]
Summary
In a recent trial of artemisinin-naphthoquine (artemisinin-NQ) and artemether-lumefantrine (AM-LM) therapy in young children from Papua New Guinea (PNG), there were no treatment failures in artemisinin-NQ-treated children with Plasmodium falciparum or Plasmodium vivax compared with 2.2% and 30.0%, respectively, in AM-LM-treated children during 42 days of follow-up. Consistent with the long elimination half-life of NQ, this difference in efficacy would be more durable, clinical episodes of malaria were assessed in a subset of trial patients followed for six months post-treatment. Its place in management of malaria has been cemented through randomized clinical trials, but there is uncertainty regarding the optimal duration of follow-up for determining efficacy. A longer duration of follow-up increases the complexity and cost of clinical trials, while attrition rates of patients, and trained research staff [6], are likely to increase
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