The effect of dosing regimens on the antimalarial efficacy of dihydroartemisinin-piperaquine: a pooled analysis of individual patient data.

BACKGROUND: Dihydroartemisinin-piperaquine (DP) is increasingly recommended for antimalarial treatment in many endemic countries; however, concerns have been raised over its potential under dosing in young children. We investigated the influence of different dosing schedules on DP's clinical efficacy. METHODS AND FINDINGS: A systematic search of the literature was conducted to identify all studies published between 1960 and February 2013, in which patients were enrolled and treated with DP. Principal investigators were approached and invited to share individual patient data with the WorldWide Antimalarial Resistance Network (WWARN). Data were pooled using a standardised methodology. Univariable and multivariable risk factors for parasite recrudescence were identified using a Cox's regression model with shared frailty across the study sites. Twenty-four published and two unpublished studies (n = 7,072 patients) were included in the analysis. After correcting for reinfection by parasite genotyping, Kaplan-Meier survival estimates were 97.7% (95% CI 97.3%-98.1%) at day 42 and 97.2% (95% CI 96.7%-97.7%) at day 63. Overall 28.6% (979/3,429) of children aged 1 to 5 years received a total dose of piperaquine below 48 mg/kg (the lower limit recommended by WHO); this risk was 2.3-2.9-fold greater compared to that in the other age groups and was associated with reduced efficacy at day 63 (94.4% [95% CI 92.6%-96.2%], p<0.001). After adjusting for confounding factors, the mg/kg dose of piperaquine was found to be a significant predictor for recrudescence, the risk increasing by 13% (95% CI 5.0%-21%) for every 5 mg/kg decrease in dose; p = 0.002. In a multivariable model increasing the target minimum total dose of piperaquine in children aged 1 to 5 years old from 48 mg/kg to 59 mg/kg would halve the risk of treatment failure and cure at least 95% of patients; such an increment was not associated with gastrointestinal toxicity in the ten studies in which this could be assessed. CONCLUSIONS: DP demonstrates excellent efficacy in a wide range of transmission settings; however, treatment failure is associated with a lower dose of piperaquine, particularly in young children, suggesting potential for further dose optimisation

Patient flowchart.

<p>Patient flowchart.</p

Studies included in the meta-analysis.

<p>Full details of the references and study design are available in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001564#pmed.1001564.s001" target="_blank">Text S1</a>.</p

Total piperaquine and dihydroartemisinin dose by age and weight categories.

<p><a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001564#pmed.1001564-WHO1" target="_blank">[5]</a>. No patient was exposed to a DHA dose >30 mg/kg.^a The WHO therapeutic guidelines recommend a target dose for PIP of 54 mg/kg over 3 days with a range from 48 to 78 mg/kg; and a target dose for DHA of 12 mg/kg over 3 days with a range from 6 to 30 mg/kg </p

PCR-corrected adequate clinical and parasitological response of dihydroartemisinin-piperaquine by major categories.

<p>–Meier estimates were generated using all the individual data rather than combining estimates from individual trials.^a Kaplan</p><p>^b One study from Peru with no failures after day 25.</p

Univariate and multivariate risk factors for PCR confirmed recrudescent failures at day 42.

<p><i>n</i>) for each variable/levels of factor with number of recrudescence [<i>n</i>] by day 42.^a Number of patients (</p><p><i>p</i> = 0.32 for global test for proportional hazards assumption. Variance of random effect  = 1.17. Non-significant likelihood ratio test for weight (<i>p</i> = 0.27) and hemoglobin (<i>p</i> = 0.26) and thus dropped from the multivariable analysis. Baseline gametocytemia (<i>p</i> = 0.02) improved the model but 22.3% (1,576/7,070) of patient had missing observation for this variable and hence not kept for multivariable analysis. Inclusion (or exclusion) of gametocytemia didn't alter the significance of the other variable and its effect on model coefficient for age and dose was small.^b</p>c<p>Overall PAR for model: 65.1%.</p>d<p>HR (95% CI) = 1.48 [0.99–2.19] <i>p</i> = 0.054 and AHR (95% CI) = 1.39 [0.94–2.06], <i>p</i> = 0.10 for mg/kg PIP dose <48 mg/kg in univariable and multivariable analysis, respectively.</p

Available patient data within each age category for (A) dihydroartemisinin and (B) piperaquine.

<p>The patients receiving a total mg/kg dose below the WHO therapeutic range (6 mg/kg and 48 mg/kg, respectively) are shown in dark columns and as a percentage of all patients on top of the bar.</p

Baseline characteristics of patients included in the analysis.

<p>^a Data from one study conducted in Peru.</p><p>+ 320 mg PIP or 20 mg DHA + 160 mg PIP in paediatric formulation (full details are given in <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001564#pmed.1001564.s001" target="_blank">Text S1</a>).^b DHA-PIP tablets strength was 40 mg DHA </p

Kaplan–Meier curve for PCR-confirmed recrudescence for children from 1 up to 5 years of age exposed to a dose below or above 59 mg/kg.

<p>Log rank test stratified by study sites <i>p</i><0.001. The HR for exposure to a PIP dose below 59 mg/kg was 2.36 (95% CI 1.42–3.91), <i>p</i><0.001 and the AHR 2.03 (95% CI 1.20–3.43), <i>p</i> = 0.008; after controlling for parasitemia and body weight.</p