Artemisinin-based combination therapy for treating uncomplicated malaria

Abstract

Background: The World Health Organization recommends uncomplicated P. falciparum malaria is treated using Artemisinin-based Combination Therapy (ACT). This review aims to assist the decision making of malaria control programmes by providing an overview of the relative benefits and harms of the available options.

Objectives: To compare the effects of ACTs with other available ACT and non-ACT combinations for treating uncomplicated P. falciparum malaria.

Search strategy: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS, and the metaRegister of Controlled Trials (mRCT) to March 2009.

Selection criteria: Randomized head to head trials of ACTs in uncomplicated P. falciparum malaria.This review is limited to: dihydroartemisinin-piperaquine; artesunate plus mefloquine; artemether-lumefantrine (six doses); artesunate plus amodiaquine; artesunate plus sulfadoxine-pyrimethamine and amodiaquine plus sulfadoxine-pyrimethamine.

Data collection and analysis: Two authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy' and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on P. vivax, gametocytes, haemoglobin, and adverse events.

Main results: Fifty studies met the inclusion criteria. All five ACTs achieved PCR adjusted failure rates of < 10%, in line with WHO recommendations, at most study sites.Dihydroartemisinin-piperaquine performed well compared to the ACTs in current use (PCR adjusted treatment failure versus artesunate plus mefloquine in Asia; RR 0.39, 95% CI 0.19 to 0.79; three trials, 1062 participants; versus artemether-lumefantrine in Africa; RR 0.39, 95% CI 0.24 to 0.64; three trials, 1136 participants).ACTs were superior to amodiaquine plus sulfadoxine-pyrimethamine in East Africa (PCR adjusted treatment failure versus artemether-lumefantrine; RR 0.12, 95% CI 0.06 to 0.24; two trials, 618 participants; versus AS+AQ; RR 0.44, 95% CI 0.22 to 0.89; three trials, 1515 participants).Dihydroartemisinin-piperaquine (RR 0.32, 95% CI 0.24 to 0.43; four trials, 1442 participants) and artesunate plus mefloquine (RR 0.30, 95% CI 0.21 to 0.41; four trials, 1003 participants) were more effective than artemether-lumefantrine at reducing the incidence of P.vivax over 42 days follow up.

Authors' conclusions: Dihydroartemisinin-piperaquine is another effective first-line treatment for P. falciparum malaria.The performance of the non-ACT (amodiaquine plus sulfadoxine-pyrimethamine) falls below WHO recommendations for first-line therapy in parts of Africa.In areas where primaquine is not being used for radical cure of P. vivax, ACTs with long half-lives may provide some benefit.

Conflict of interest statement

None known.

Figures

1

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

2

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

3

How does Dihydroartemisinin‐piperaquine perform? Summary of primary outcome: Effectiveness: Total Failure (P. falciparum) PCR adjusted.

4

Olliaro‐Vaillant plot. Day 28 PCR adjusted treatment failure data for trials of DHA‐P against all comparators are presented in this plot. The horizontal red line represents the WHO standard of 10% treatment failure (PCR corrected). Plots below this line represent trials where DHA‐P performed to this standard. The vertical blue line represents no difference between the two drugs. Plots to the right of this line represent trials where DHA‐P performed better than the comparator drug, and plots to the left represent trials where the comparator drug performed better than DHA‐P.

5

How does Artesunate plus mefloquine perform? Summary of primary outcome: Effectiveness: Total Failure (P. falciparum) PCR adjusted.

6

Olliaro‐Vaillant plot. Day 28 PCR adjusted treatment failure data for trials of AS+MQ against all comparators are presented in this plot. The horizontal red line represents the WHO standard of 10% treatment failure (PCR corrected). Plots below this line represent trials where AS+MQ performed to this standard. The vertical blue line represents no difference between the two drugs. Plots to the right of this line represent trials where AS+MQ performed better than the comparator drug, and plots to the left represent trials where the comparator drug performed better than AS+MQ.

7

How does Artemether‐lumefantrine perform? Summary of primary outcome: Effectiveness: Total Failure (P. falciparum) Day PCR adjusted.

8

Olliaro‐Vaillant plot. Day 28 PCR adjusted treatment failure data for trials of AL6 against all comparators are presented in this plot. The horizontal red line represents the WHO standard of 10% treatment failure (PCR corrected). Plots below this line represent trials where AL6 performed to this standard. The vertical blue line represents no difference between the two drugs. Plots to the right of this line represent trials where AL6 performed better than the comparator drug, and plots to the left represent trials where the comparator drug performed better than AL6.

9

How does Artesunate plus amodiaquine perform? Summary of primary outcome: Effectiveness: Total Failure (P. falciparum) PCR adjusted.

10

Olliaro‐Vaillant plot. Day 28 PCR adjusted treatment failure data for trials of AS+AQ against all comparators are presented in this plot. The horizontal red line represents the WHO standard of 10% treatment failure (PCR corrected). Plots below this line represent trials where AS+AQ performed to this standard. The vertical blue line represents no difference between the two drugs. Plots to the right of this line represent trials where AS+AQ performed better than the comparator drug, and plots to the left represent trials where the comparator drug performed better than AS+AQ.

1.1. Analysis

Comparison 1 Dihydroartemisinin‐piperaquine vs Artesunate plus mefloquine, Outcome 1 Total Failure (P. falciparum) Day 63 PCR unadjusted.

1.2. Analysis

Comparison 1 Dihydroartemisinin‐piperaquine vs Artesunate plus mefloquine, Outcome 2 Total Failure (P. falciparum) Day 63 PCR adjusted.

1.3. Analysis

Comparison 1 Dihydroartemisinin‐piperaquine vs Artesunate plus mefloquine, Outcome 3 Total Failure (P. falciparum) Day 42 PCR unadjusted.

1.4. Analysis

Comparison 1 Dihydroartemisinin‐piperaquine vs Artesunate plus mefloquine, Outcome 4 Total Failure (P. falciparum) Day 42 PCR adjusted.

1.5. Analysis

Comparison 1 Dihydroartemisinin‐piperaquine vs Artesunate plus mefloquine, Outcome 5 Total Failure (P. falciparum) Day 28 PCR unadjusted.

1.6. Analysis

Comparison 1 Dihydroartemisinin‐piperaquine vs Artesunate plus mefloquine, Outcome 6 Total Failure (P. falciparum) Day 28 PCR adjusted.

1.7. Analysis

Comparison 1 Dihydroartemisinin‐piperaquine vs Artesunate plus mefloquine, Outcome 7 P. vivax parasitaemia.

1.8. Analysis

Comparison 1 Dihydroartemisinin‐piperaquine vs Artesunate plus mefloquine, Outcome 8 Gametocyte development (in those negative at baseline).

1.9. Analysis

Comparison 1 Dihydroartemisinin‐piperaquine vs Artesunate plus mefloquine, Outcome 9 Gametocytaemia carriage.

1.10. Analysis

Comparison 1 Dihydroartemisinin‐piperaquine vs Artesunate plus mefloquine, Outcome 10 Serious adverse events (including deaths).

1.11. Analysis

Comparison 1 Dihydroartemisinin‐piperaquine vs Artesunate plus mefloquine, Outcome 11 Early vomiting.

1.12. Analysis

Comparison 1 Dihydroartemisinin‐piperaquine vs Artesunate plus mefloquine, Outcome 12 Sensitivity analysis: Total Failure Day 63 PCR unadjusted.

1.13. Analysis

Comparison 1 Dihydroartemisinin‐piperaquine vs Artesunate plus mefloquine, Outcome 13 Sensitivity analysis: Total Failure Day 63 PCR adjusted.

2.1. Analysis

Comparison 2 Dihydroartemisinin‐piperaquine vs Artemether‐lumefantrine, Outcome 1 Total Failure (P. falciparum) Day 42 PCR unadjusted.

2.2. Analysis

Comparison 2 Dihydroartemisinin‐piperaquine vs Artemether‐lumefantrine, Outcome 2 Total Failure (P. falciparum) Day 42 PCR adjusted.

2.3. Analysis

Comparison 2 Dihydroartemisinin‐piperaquine vs Artemether‐lumefantrine, Outcome 3 Total Failure (P. falciparum) Day 28 PCR unadjusted.

2.4. Analysis

Comparison 2 Dihydroartemisinin‐piperaquine vs Artemether‐lumefantrine, Outcome 4 Total Failure (P. falciparum) Day 28 PCR adjusted.

2.5. Analysis

Comparison 2 Dihydroartemisinin‐piperaquine vs Artemether‐lumefantrine, Outcome 5 P. vivax parasitaemia.

2.6. Analysis

Comparison 2 Dihydroartemisinin‐piperaquine vs Artemether‐lumefantrine, Outcome 6 Gametocyte development (in those negative at baseline).

2.7. Analysis

Comparison 2 Dihydroartemisinin‐piperaquine vs Artemether‐lumefantrine, Outcome 7 Anaemia.

2.8. Analysis

Comparison 2 Dihydroartemisinin‐piperaquine vs Artemether‐lumefantrine, Outcome 8 Serious adverse events (including deaths).

2.9. Analysis

Comparison 2 Dihydroartemisinin‐piperaquine vs Artemether‐lumefantrine, Outcome 9 Early vomiting.

3.1. Analysis

Comparison 3 Dihydroartemisinin‐piperaquine vs Artesunate plus amodiaquine, Outcome 1 Total Failure (P. falciparum) Day 28 PCR unadjusted.

3.2. Analysis

Comparison 3 Dihydroartemisinin‐piperaquine vs Artesunate plus amodiaquine, Outcome 2 Total Failure (P. falciparum) Day 28 PCR adjusted.

3.3. Analysis

Comparison 3 Dihydroartemisinin‐piperaquine vs Artesunate plus amodiaquine, Outcome 3 Total Failure (P. falciparum) Day 42 PCR unadjusted.

3.4. Analysis

Comparison 3 Dihydroartemisinin‐piperaquine vs Artesunate plus amodiaquine, Outcome 4 Total Failure (P. falciparum) Day 42 PCR adjusted.

3.5. Analysis

Comparison 3 Dihydroartemisinin‐piperaquine vs Artesunate plus amodiaquine, Outcome 5 P. vivax parasitaemia.

3.6. Analysis

Comparison 3 Dihydroartemisinin‐piperaquine vs Artesunate plus amodiaquine, Outcome 6 Serious adverse events (including deaths).

3.7. Analysis

Comparison 3 Dihydroartemisinin‐piperaquine vs Artesunate plus amodiaquine, Outcome 7 Early vomiting.

4.1. Analysis

Comparison 4 Dihydroartemisinin‐piperaquine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 1 Total Failure (P. falciparum) Day 42 PCR unadjusted.

4.2. Analysis

Comparison 4 Dihydroartemisinin‐piperaquine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 2 Total Failure (P. falciparum) Day 42 PCR adjusted.

4.3. Analysis

Comparison 4 Dihydroartemisinin‐piperaquine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 3 Total Failure (P. falciparum) Day 28 PCR unadjusted.

4.4. Analysis

Comparison 4 Dihydroartemisinin‐piperaquine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 4 Total Failure (P. falciparum) Day 28 PCR adjusted.

4.5. Analysis

Comparison 4 Dihydroartemisinin‐piperaquine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 5 P. vivax parasitaemia by day 42.

5.1. Analysis

Comparison 5 Dihydroartemisinin‐piperaquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 1 Total Failure (P. falciparum) Day 28 PCR unadjusted.

5.2. Analysis

Comparison 5 Dihydroartemisinin‐piperaquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 2 Total Failure (P. falciparum) Day 28 PCR adjusted.

5.3. Analysis

Comparison 5 Dihydroartemisinin‐piperaquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 3 Total Failure (P. falciparum) Day 42 PCR unadjusted.

5.4. Analysis

Comparison 5 Dihydroartemisinin‐piperaquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 4 Total Failure (P. falciparum) Day 42 PCR adjusted.

5.5. Analysis

Comparison 5 Dihydroartemisinin‐piperaquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 5 Gametocyte development.

5.6. Analysis

Comparison 5 Dihydroartemisinin‐piperaquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 6 Anaemia.

5.7. Analysis

Comparison 5 Dihydroartemisinin‐piperaquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 7 Early vomiting.

6.1. Analysis

Comparison 6 Artesunate plus mefloquine vs Artemether‐lumefantrine, Outcome 1 Total Failure (P. falciparum) Day 42 PCR unadjusted.

6.2. Analysis

Comparison 6 Artesunate plus mefloquine vs Artemether‐lumefantrine, Outcome 2 Total Failure (P. falciparum) Day 42 PCR adjusted.

6.3. Analysis

Comparison 6 Artesunate plus mefloquine vs Artemether‐lumefantrine, Outcome 3 Total Failure (P. falciparum) Day 28 PCR unadjusted.

6.4. Analysis

Comparison 6 Artesunate plus mefloquine vs Artemether‐lumefantrine, Outcome 4 Total Failure (P. falciparum) Day 28 PCR adjusted.

6.5. Analysis

Comparison 6 Artesunate plus mefloquine vs Artemether‐lumefantrine, Outcome 5 P. vivax parasitaemia.

6.6. Analysis

Comparison 6 Artesunate plus mefloquine vs Artemether‐lumefantrine, Outcome 6 Gametocyte development (in those negative at baseline).

6.7. Analysis

Comparison 6 Artesunate plus mefloquine vs Artemether‐lumefantrine, Outcome 7 Gametocyte carriage.

6.8. Analysis

Comparison 6 Artesunate plus mefloquine vs Artemether‐lumefantrine, Outcome 8 Serious adverse events (including deaths).

6.9. Analysis

Comparison 6 Artesunate plus mefloquine vs Artemether‐lumefantrine, Outcome 9 Early vomiting.

7.1. Analysis

Comparison 7 Artesunate plus mefloquine vs Artesunate plus amodiaquine, Outcome 1 Total Failure (P. falciparum) Day 28 PCR unadjusted.

7.2. Analysis

Comparison 7 Artesunate plus mefloquine vs Artesunate plus amodiaquine, Outcome 2 Total Failure (P. falciparum) Day 28 PCR adjusted.

7.3. Analysis

Comparison 7 Artesunate plus mefloquine vs Artesunate plus amodiaquine, Outcome 3 Gametocyte carriage.

8.1. Analysis

Comparison 8 Artesunate plus mefloquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 1 Total Failure (P. falciparum) Day 28 PCR unadjusted.

8.2. Analysis

Comparison 8 Artesunate plus mefloquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 2 Total Failure (P. falciparum) Day 28 PCR adjusted.

8.3. Analysis

Comparison 8 Artesunate plus mefloquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 3 Gametocyte carriage.

9.1. Analysis

Comparison 9 Artemether‐lumefantrine vs Artesunate plus amodiaquine, Outcome 1 Total Failure (P. falciparum) Day 28 PCR unadjusted.

9.2. Analysis

Comparison 9 Artemether‐lumefantrine vs Artesunate plus amodiaquine, Outcome 2 Total Failure (P. falciparum) Day 28 PCR adjusted.

9.3. Analysis

Comparison 9 Artemether‐lumefantrine vs Artesunate plus amodiaquine, Outcome 3 Gametocyte development.

9.4. Analysis

Comparison 9 Artemether‐lumefantrine vs Artesunate plus amodiaquine, Outcome 4 Gametocyte carriage.

9.5. Analysis

Comparison 9 Artemether‐lumefantrine vs Artesunate plus amodiaquine, Outcome 5 Anaemia.

9.6. Analysis

Comparison 9 Artemether‐lumefantrine vs Artesunate plus amodiaquine, Outcome 6 Proportion anaemic (Haemoglobin

9.7. Analysis

Comparison 9 Artemether‐lumefantrine vs Artesunate plus amodiaquine, Outcome 7 Serious adverse events (including deaths).

9.8. Analysis

Comparison 9 Artemether‐lumefantrine vs Artesunate plus amodiaquine, Outcome 8 Early vomiting.

9.9. Analysis

Comparison 9 Artemether‐lumefantrine vs Artesunate plus amodiaquine, Outcome 9 Sensitivity analysis: Total Failure Day 28 PCR unadjusted.

9.10. Analysis

Comparison 9 Artemether‐lumefantrine vs Artesunate plus amodiaquine, Outcome 10 Sensitivity analysis: Total Failure Day 28 PCR adjusted.

10.1. Analysis

Comparison 10 Artemether‐lumefantrine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 1 Total Failure (P. falciparum) Day 42 PCR unadjusted.

10.2. Analysis

Comparison 10 Artemether‐lumefantrine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 2 Total Failure (P. falciparum) Day 42 PCR adjusted.

10.3. Analysis

Comparison 10 Artemether‐lumefantrine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 3 Total Failure (P. falciparum) Day 28 PCR unadjusted.

10.4. Analysis

Comparison 10 Artemether‐lumefantrine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 4 Total Failure (P. falciparum) Day 28 PCR adjusted.

10.5. Analysis

Comparison 10 Artemether‐lumefantrine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 5 P. vivax parasitaemia.

10.6. Analysis

Comparison 10 Artemether‐lumefantrine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 6 Sensitivity analysis Total Failure Day 28 PCR unadjusted.

10.7. Analysis

Comparison 10 Artemether‐lumefantrine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 7 Sensitivity analysis: Total Failure Day 28 PCR adjusted.

11.1. Analysis

Comparison 11 Artemether‐lumefantrine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 1 Total Failure (P. falciparum) Day 28 PCR unadjusted.

11.2. Analysis

Comparison 11 Artemether‐lumefantrine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 2 Total Failure (P. falciparum) Day 28 PCR adjusted.

11.3. Analysis

Comparison 11 Artemether‐lumefantrine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 3 Total Failure (P. falciparum) Day 42 PCR unadjusted.

11.4. Analysis

Comparison 11 Artemether‐lumefantrine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 4 Total Failure (P. falciparum) Day 42 PCR adjusted.

11.5. Analysis

Comparison 11 Artemether‐lumefantrine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 5 Gametocyte carriage.

11.6. Analysis

Comparison 11 Artemether‐lumefantrine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 6 Gametocyte development (in those negative at baseline).

11.7. Analysis

Comparison 11 Artemether‐lumefantrine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 7 Anaemia.

11.8. Analysis

Comparison 11 Artemether‐lumefantrine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 8 Serious adverse events (including deaths).

11.9. Analysis

Comparison 11 Artemether‐lumefantrine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 9 Early vomiting.

12.1. Analysis

Comparison 12 Artesunate plus amodiaquine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 1 Total Failure (P. falciparum) Day 28 PCR unadjusted.

12.2. Analysis

Comparison 12 Artesunate plus amodiaquine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 2 Total Failure (P. falciparum) Day 28 PCR adjusted.

12.3. Analysis

Comparison 12 Artesunate plus amodiaquine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 3 Gametocyte carriage.

12.4. Analysis

Comparison 12 Artesunate plus amodiaquine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 4 Proportion of participants with anaemia.

12.5. Analysis

Comparison 12 Artesunate plus amodiaquine vs Artesunate plus sulfadoxine‐pyrimethamine, Outcome 5 Serious adverse events (including deaths).

13.1. Analysis

Comparison 13 Artesunate plus amodiaquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 1 Total Failure (P. falciparum) Day 28 PCR unadjusted.

13.2. Analysis

Comparison 13 Artesunate plus amodiaquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 2 Total Failure (P. falciparum) Day 28 PCR adjusted.

13.3. Analysis

Comparison 13 Artesunate plus amodiaquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 3 Gametocyte development.

13.4. Analysis

Comparison 13 Artesunate plus amodiaquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 4 Gametocyte carriage.

13.5. Analysis

Comparison 13 Artesunate plus amodiaquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 5 Anaemia.

13.6. Analysis

Comparison 13 Artesunate plus amodiaquine vs Amodiaquine plus sulfadoxine‐pyrimethamine, Outcome 6 Serious adverse events (including deaths).

14.1. Analysis

Comparison 14 Dihydroartemisinin‐piperaquine dose analysis: 3 dose vs 4 dose regimen, Outcome 1 Total Failure PCR unadjusted.

14.2. Analysis

Comparison 14 Dihydroartemisinin‐piperaquine dose analysis: 3 dose vs 4 dose regimen, Outcome 2 Total Failure PCR adjusted.

15.1. Analysis

Comparison 15 Dihydroartemisinin‐piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 1 Total Failure Day 63 PCR unadjusted.

15.2. Analysis

Comparison 15 Dihydroartemisinin‐piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 2 Total Failure Day 63 PCR adjusted.

15.3. Analysis

Comparison 15 Dihydroartemisinin‐piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 3 Total Failure Day 42 PCR unadjusted.

15.4. Analysis

Comparison 15 Dihydroartemisinin‐piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 4 Total Failure Day 42 PCR adjusted.

15.5. Analysis

Comparison 15 Dihydroartemisinin‐piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 5 Total Failure Day 28 PCR unadjusted.

15.6. Analysis

Comparison 15 Dihydroartemisinin‐piperaquine dose analysis (versus Artesunate plus mefloquine), Outcome 6 Total Failure Day 28 PCR adjusted.

16.1. Analysis

Comparison 16 Artesunate Mefloquine dose analysis: FDC versus split dose regimen, Outcome 1 Total Failure Day 63 PCR unadjusted.

16.2. Analysis

Comparison 16 Artesunate Mefloquine dose analysis: FDC versus split dose regimen, Outcome 2 Total Failure Day 63 PCR adjusted.

17.1. Analysis

Comparison 17 Artesunate plus mefloquine dose analysis (versus Dihydroartemisinin‐piperaquine), Outcome 1 Total Failure Day 63 PCR adjusted.

17.2. Analysis

Comparison 17 Artesunate plus mefloquine dose analysis (versus Dihydroartemisinin‐piperaquine), Outcome 2 Total Failure Day 28 PCR adjusted.

18.1. Analysis

Comparison 18 How does Dihydroartemisinin‐piperaquine perform?, Outcome 1 Effectiveness: Total Failure (P. falciparum) PCR adjusted.

19.1. Analysis

Comparison 19 How does Artesunate plus mefloquine perform?, Outcome 1 Effectiveness: Total Failure (P. falciparum) PCR adjusted.

20.1. Analysis

Comparison 20 How does Artemether‐lumefantrine perform?, Outcome 1 Effectiveness: Total Failure (P. falciparum) Day PCR adjusted.

21.1. Analysis

Comparison 21 How does Artesunate plus amodiaquine perform?, Outcome 1 Effectiveness: Total Failure (P. falciparum) PCR adjusted.