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

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

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

PCR adjusted risk of recrudescent and new infections at day 42 for individual studies.

<p>The full citations for these studies 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>. The figure excludes data from 6 studies in which active follow-up was stopped at Day 28 [12,17,18,26,29,36]. The results for Ashley-2004 [19] and Ashley-2005 [20] are presented pooled since the datasets did not distinguish between the studies.</p

Percentiles of predicted risk [5th-median-95th] of recrudescent failure at day 42 in children aged from 1 up to 5 years computed from multivariate model.

<p>Risk was calculated for each individual using their own values. The error bars show the 5th and 95th percentiles of predicted risk of recrudescence failure.</p