Abstract:
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BACKGROUND: Achieving adequate antimalarial drug exposure is
essential for curing malaria. Day 7 blood or plasma lumefantrine
concentrations provide a simple measure of drug exposure that
correlates well with artemether-lumefantrine efficacy. However,
the 'therapeutic' day 7 lumefantrine concentration threshold
needs to be defined better, particularly for important patient
and parasite sub-populations. METHODS: The WorldWide
Antimalarial Resistance Network (WWARN) conducted a large pooled
analysis of individual pharmacokinetic-pharmacodynamic data from
patients treated with artemether-lumefantrine for uncomplicated
Plasmodium falciparum malaria, to define therapeutic day 7
lumefantrine concentrations and identify patient factors that
substantially alter these concentrations. A systematic review of
PubMed, Embase, Google Scholar, ClinicalTrials.gov and
conference proceedings identified all relevant studies. Risk of
bias in individual studies was evaluated based on study design,
methodology and missing data. RESULTS: Of 31 studies identified
through a systematic review, 26 studies were shared with WWARN
and 21 studies with 2,787 patients were included. Recrudescence
was associated with low day 7 lumefantrine concentrations (HR
1.59 (95% CI 1.36 to 1.85) per halving of day 7 concentrations)
and high baseline parasitemia (HR 1.87 (95% CI 1.22 to 2.87) per
10-fold increase). Adjusted for mg/kg dose, day 7 concentrations
were lowest in very young children (<3 years), among whom
underweight-for-age children had 23% (95% CI -1 to 41%) lower
concentrations than adequately nourished children of the same
age and 53% (95% CI 37 to 65%) lower concentrations than adults.
Day 7 lumefantrine concentrations were 44% (95% CI 38 to 49%)
lower following unsupervised treatment. The highest risk of
recrudescence was observed in areas of emerging artemisinin
resistance and very low transmission intensity. For all other
populations studied, day 7 concentrations >/=200 ng/ml were
associated with >98% cure rates (if parasitemia
<135,000/muL). CONCLUSIONS: Current artemether-lumefantrine
dosing recommendations achieve day 7 lumefantrine concentrations
>/=200 ng/ml and high cure rates in most uncomplicated
malaria patients. Three groups are at increased risk of
treatment failure: very young children (particularly those
underweight-for-age); patients with high parasitemias; and
patients in very low transmission intensity areas with emerging
parasite resistance. In these groups, adherence and treatment
response should be monitored closely. Higher, more frequent, or
prolonged dosage regimens should now be evaluated in very young
children, particularly if malnourished, and in patients with
hyperparasitemia. |