Artemisinin‐based combination therapy for treating uncomplicated Plasmodium vivax malaria

Nithya Gogtay; Sridharan Kannan; Urmila M Thatte; Piero L Olliaro; David Sinclair

doi:10.1002/14651858.CD008492.pub3

Cochrane Database of Systematic Reviews

Tratamiento combinado con artemisinina para el tratamiento del paludismo por Plasmodium vivax no complicado

Información

DOI:

https://doi.org/10.1002/14651858.CD008492.pub3 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

25 octubre 2013see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Enfermedades infecciosas

Clasificada:

Pendiente de actualización

Authors currently updating
The update is due to be published in 2019.
Evaluada: 22 March 2019

Copyright:

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Nithya Gogtay

Seth GS Medical College and KEM Hospital, Mumbai, India
Sridharan Kannan

Department of Clinical Pharmacology, Seth GS Medical College & KEM Hospital, Mumbai, India
Urmila M Thatte

Department of Clinical Pharmacology, Seth GS Medical College & KEM Hospital, Mumbai, India
Piero L Olliaro

UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, Geneva, Switzerland
David Sinclair

Correspondencia a: Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK

[email protected]

Contributions of authors

David Sinclair, Felicity Brand, and Piero Olliaro conceived and designed the protocol. For the original review David Sinclair, Felicity Brand, and Nithya Gogtay extracted the data, and David Sinclair analysed the data and wrote the first draft with Nithya Gogtay. For this update. Nithya Gogtay, Kannan Sridharan, and Urmila Thatte screened the search articles, extracted data, and analysed the data. David Sinclair and Piero Olliaro assisted with revising subsequent drafts and preparing the final draft for publication.

Sources of support

Internal sources

Department for International Development (DFID), UK.

External sources

No sources of support supplied

Declarations of interest

None known.

Acknowledgements

We thank Felicity Brand who was an author on the first version of this review. We thank Richard Kirubakaran for his assistance in analysing the data sets from Smithuis 2006 MMR and Smithuis 2010 MMR.

The editorial base for the Cochrane Infectious Disease Group is funded by the Department for International Development (DFID), UK, for the benefit of low‐ and middle‐income countries.

Version history

Published

Title

Stage

Authors

Version

2013 Oct 25

Artemisinin‐based combination therapy for treating uncomplicated Plasmodium vivax malaria

Review

Nithya Gogtay, Sridharan Kannan, Urmila M Thatte, Piero L Olliaro, David Sinclair

https://doi.org/10.1002/14651858.CD008492.pub3

2011 Jul 06

Artemisinin‐based combination therapy for treating uncomplicated Plasmodium vivax malaria

Review

David Sinclair, Nithya Gogtay, Felicity Brand, Piero L Olliaro

https://doi.org/10.1002/14651858.CD008492.pub2

2010 Apr 14

Artemisinin‐based combination therapy for the treatment of uncomplicated Plasmodium vivax malaria and the prevention of relapses

Protocol

Nithya Gogtay, Felicity Brand, Piero Olliaro, David Sinclair

https://doi.org/10.1002/14651858.CD008492

Differences between protocol and review

We made the following adjustments:

The protocol stated: 'For the primary outcome 'Recurrence of P. vivax by day 14 or 28' we will subgroup trials according to those which also gave primaquine and those which did not'. In conducting the review we found that there were too few trials to make this subgroup analysis informative.

The protocol stated: 'For the secondary outcome with prolonged follow‐up 'Recurrence of P. vivax parasitaemia at 1 to 12 months' we will only include trials which also give the WHO recommended dose of primaquine to both treatment arms'. We chose to include the trials where primaquine was not given as this is informative for settings where primaquine is not administered routinely due to either a high local prevalence of G6PD or very high transmission intensity.

When analysing the data for'Recurrent parasitemias after day 28' we excluded the participants who had experienced a recurrence before day 28 from both the numerator and the denominator. This was not explicitly stated in the protocol. The reasoning for this change was to prevent a drug which was superior in the first 28 days (more indicative of treatment of the blood stage) appearing superior at 42 days or longer (more indicative of an effect on relapse or re‐infection) even if there was no difference during the second period.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 ACT versus Chloroquine, Outcome 1 Parasite clearance.

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Analysis 1.2

Comparison 1 ACT versus Chloroquine, Outcome 2 Fever clearance.

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Analysis 1.3

Comparison 1 ACT versus Chloroquine, Outcome 3 Recurrence of parasitaemia.

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Analysis 1.4

Comparison 1 ACT versus Chloroquine, Outcome 4 Gametocytemia.

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Analysis 1.5

Comparison 1 ACT versus Chloroquine, Outcome 5 Serious adverse events.

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Analysis 2.1

Comparison 2 ACT versus Chloroquine plus Sulfadoxine‐pyrimethamine, Outcome 1 Parasite clearance.

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Analysis 2.2

Comparison 2 ACT versus Chloroquine plus Sulfadoxine‐pyrimethamine, Outcome 2 Fever clearance.

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Analysis 2.3

Comparison 2 ACT versus Chloroquine plus Sulfadoxine‐pyrimethamine, Outcome 3 Recurrence of parasitaemia.

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Analysis 2.4

Comparison 2 ACT versus Chloroquine plus Sulfadoxine‐pyrimethamine, Outcome 4 Serious adverse events.

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Analysis 3.1

Comparison 3 ACT versus Quinine, Outcome 1 Parasite clearance.

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Analysis 3.2

Comparison 3 ACT versus Quinine, Outcome 2 Recurrence of parasitaemia.

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Analysis 4.1

Comparison 4 ACT versus ACT, Outcome 1 Remaining parasitemic after 24 hours.

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Analysis 4.2

Comparison 4 ACT versus ACT, Outcome 2 Remaining parasitemic after 48 hours.

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Analysis 4.3

Comparison 4 ACT versus ACT, Outcome 3 Remaining febrile after 24 hours.

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Analysis 4.4

Comparison 4 ACT versus ACT, Outcome 4 Remaining febrile after 48 hours.

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Analysis 4.5

Comparison 4 ACT versus ACT, Outcome 5 Recurrent parasitaemia before day 28.

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Analysis 4.6

Comparison 4 ACT versus ACT, Outcome 6 Recurrent parasitaemia after day 28.

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Analysis 4.7

Comparison 4 ACT versus ACT, Outcome 7 Recurrent parasitaemia during full follow‐up period (0 to 42 or 63 days).

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Analysis 5.1

Comparison 5 DHA‐P versus alternative ACTs, Outcome 1 Recurrent parasitaemia ‐ settings described as low transmission.

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Analysis 5.2

Comparison 5 DHA‐P versus alternative ACTs, Outcome 2 Recurrent parasitaemia ‐ settings described as high transmission.

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Summary of findings for the main comparison. Summary of findings: ACT versus CQ

*Artemisinin‐based combination therapy compared with chloroquine for uncomplicated P. vivax* malaria**
Patient or population: Adults and children with uncomplicated P. vivax malaria Settings: Endemic areas where chloroquine is still an effective treatment for the first 28 days Intervention: Artemisinin‐based combination therapy Comparison: Chloroquine
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Chloroquine	ACT
Remaining parasitaemic at 24 hours	52 per 100	22 per 100 (19 to 26)	RR 0.42 (0.36 to 0.50)	1652 (4 studies¹)	high^2,3,4,5
Remaining febrile after 24 hours	29 per 100	16 per 100 (12 to 20)	RR 0.55 (0.43 to 0.7)	990 (2 studies⁶)	moderate^2,4,5,7
Effective treatment of the blood stage parasite As assessed by: Recurrent parasitaemia before day 28	3 per 100	2 per 100 (1 to 6)	RR 0.58 (0.18 to 1.90)	1622 (5 studies⁸)	high^2,3,4,9
Post‐treatment prophylaxis As assessed by: Recurrent parasitaemia between day 28 and day 42/56/63	With primaquine		RR 0.27 (0.08 to 0.94)	376 (1 study¹⁰)	low^11,12
	6 per 100	2 per 100 (0 to 6)
	Without primaquine		RR 0.57 (0.40 to 0.82)	1066 (3 studies¹³)	moderate^3,5,14
	40 per 100	23 per 100 (16 to 33)
Serious adverse events	0 per 100	0 per 100 (0 to 2)	RR 1 (0.14 to 7.04)	1775 (5 studies⁸)	high^2,3,4,9
The basis for the assumed risk* (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; ACT: artemisinin‐based combination therapy.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Awab 2010 AFG (Afghanistan), Kolaczinski 2007 AFG (Afghanistan), Poravuth 2010 ASIA (multi‐site), and Phyo 2011 THA (Thailand). ² No serious study limitations: Awab 2010 AFG , Poravuth 2010 ASIA and Phyo 2011 THA adequately concealed allocation, Kolaczinski 2007 AFG did not, and Krudsood 2007 THA did not adequately describe allocation concealment. ³ No serious inconsistency: The findings of all the trials are consistent. ⁴ No serious indirectness: The findings of these three studies can reasonably be applied to other settings with similar transmission and resistance patterns. ⁵ No serious imprecision: The finding is of a clinically and statistically significant benefit with ACTs. ⁶Awab 2010 AFG (Afghanistan) and Poravuth 2010 ASIA (multi‐site). ⁷ Downgraded by 1 for serious inconsistency: The two additional trials (Kolaczinski 2007 AFG; Krudsood 2007 THA) report that fever clearance was not significantly different between the groups. ⁸Awab 2010 AFG (Afghanistan), Kolaczinski 2007 AFG (Afghanistan), Krudsood 2007 THA (Thailand), Poravuth 2010 ASIA (multi‐site), and Phyo 2011 THA (Thailand). ⁹ No serious imprecision: The finding is of no clinically important difference between ACTs and CQ. Although the 95% CI around the relative effect is very wide, recurrent parasitaemia before day 28 and serious adverse events were very rare and consequently the 95% CI around the absolute effect is very narrow. ¹⁰Poravuth 2010 ASIA. ¹¹ Downgraded by 1 for serious indirectness: Poravuth 2010 ASIA delayed primaquine until day 28 and so the course will not have completed until day 42 the last day of the trial. The effect seen may not be present if primaquine is given in the usual way (on completion of 3 days of ACT). The period of follow‐up is also not long enough to fully assess this effect, the inevitable relapse may simply be delayed, rather than a reduction in clinical episodes. ¹² Downgraded by 1 for serious imprecision: Although statistically significant the 95% CI is wide and includes the possibility of no appreciable benefit. ¹³Awab 2010 AFG continued until day 56, Kolaczinski 2007 AFG to day 42 and Phyo 2011 THA to day 63 (Primaquine was administered to the participants after day 63). ¹⁴ Downgraded by 1 for serious indirectness: Both studies are from Afghanistan Awab 2010 AFG and Kolaczinski 2007 AFG where primaquine is not recommended due to a high prevalence of G6PD. The period of follow‐up is also not long enough to fully assess this effect, the inevitable relapse may simply be delayed, rather than a reduction in clinical episodes.

Summary of findings for the main comparison. Summary of findings: ACT versus CQ

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Summary of findings 2. Summary of findings: DHA‐P versus alternative ACTs in high transmission settings with known CQ resistance

*Dihydroartemisinin‐piperaquine compared with alternative artemisinin‐based combination treatments for uncomplicated P. vivax* malaria**
Patient or population: Adults and children with uncomplicated P. vivax malaria Settings: Settings with high transmission of P. vivax (chloroquine resistance is also reported as high) Intervention: Dihydroartemisinin‐piperaquine Comparison: Alternative ACTs
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Alternative ACT	DHA‐P
Effective treatment of the blood stage parasite As assessed by: Recurrent parasitaemia before day 28	35 per 100	7 per 100 (3 to 17)	RR 0.20 (0.08 to 0.49)	334 (3 studies^1,2)	moderate^3,4,5,6
Post‐treatment prophylaxis As assessed by: Recurrent parasitaemia between day 28 and 42	With primaquine		RR 0.21 (0.1 to 0.46)	179 (2 studies²)	low^6,7,8,9
	34 per 100	7 per 100 (3 to 16)
	Without primaquine		RR 0.40 (0.14 to 1.10)	66 (1 study¹)	very low^10,11,12
	33 per 100	13 per 100 (5 to 37)
The basis for the assumed risk* (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; DHA‐P: dihydroartemisinin‐piperaquine; ACT: Artemisinin‐based combination therapy.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Karunajeewa 2008 PNG (Papua New Guinea). ²Hasugian 2007 IDN and Ratcliff 2007 IDN (Indonesia). ³ No serious risk of bias: Allocation was adequately concealed in these studies to be considered at low risk of bias. ⁴ Downgraded by 1 for serious inconsistency: There was some clinical heterogeneity between trials. DHA‐P did not perform as well in Papua New Guinea as it has elsewhere, however it was still superior to AL6 and AS+SP. ⁵ No serious indirectness: Studies include adults and children and were conducted in areas where transmission is high and chloroquine resistance is well documented. ⁶ No serious imprecision: Both limits of the 95% CI suggest an appreciable clinical benefit with DHA‐P. ⁷ Downgraded by 1 for serious risk of bias: Losses to follow‐up were high (> 20% at this time‐point). ⁸ No serious inconsistency: Statistical heterogeneity was low. ⁹ Downgraded by 1 for serious indirectness: Ratcliff 2007 IDN delayed the administration of Primaquine until day 28 and so the course will not have been completed until the last day of the trial. Hasugian 2007 IDN offered unsupervised primaquine to all participants on completion of their ACT, this reflects normal practice but it is not clear how many participants completed their course. The period of follow‐up is also not long enough to fully assess this effect, the inevitable relapse may simply be delayed, rather than a reduction in clinical episodes. ¹⁰ Downgraded by 1 for serious risk of bias: Losses to follow‐up were high (>20% at this time‐point). ¹¹ Downgraded by 1 for serious indirectness: Only one study has assessed this outcome. Recurrent parasitaemia was higher with all three ACTs than seen elsewhere. This trial is therefore not easily extrapolated to other sites. ¹² Downgraded by 1 for serious imprecision: The 95% CI of the effect estimate is wide and includes an important clinical benefit and no difference between the treatments.

Summary of findings 2. Summary of findings: DHA‐P versus alternative ACTs in high transmission settings with known CQ resistance

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Table 1. Detailed search strategy

Search set	Search terms used for all databases¹
1	vivax
2	Arte*
3	Dihydroarte*
4	2 or 3
5	1 and 4
6	(search terms for RCTs)
7	5 and 6
8	Limit 7 to Human
¹ Cochrane Infectious Disease Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE; EMBASE; and LILACS.

Table 1. Detailed search strategy

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Table 2. Median parasite clearance times

Study ID	Comparison	Median parasite clearance time (range)		P value
Study ID	Comparison	ACT	CQ	P value
Krudsood 2007 THA	AL6 versus CQ	41.6 hrs	55.8 hrs	< 0.01
Poravuth 2010 ASIA	AS‐Py versus CQ	23.0 hrs (7.0 to 55.9)	32.0 hrs (7.5 to 63.9)	< 0.0001

Table 2. Median parasite clearance times

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Table 3. Fever clearance times

Study ID	Comparison	Median fever clearance time (range)		P value
Study ID	Comparison	ACT	CQ	P value
Krudsood 2007 THA	AL6 versus CQ	21.8 hrs	25.3 hrs	0.12
Poravuth 2010 ASIA	AS‐Py versus CQ	15.9 hrs	23.8 hrs	0.0017

Table 3. Fever clearance times

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Comparison 1. ACT versus Chloroquine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Parasite clearance Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Remaining parasitaemic after 24 hours	4	1652	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.36, 0.50]
1.2 Remaining parasitaemic after 48 hours	4	1648	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.05, 0.74]
1.3 Remaining parasitaemic after 72 hours	4	1648	Risk Ratio (M‐H, Random, 95% CI)	0.08 [0.01, 0.43]
2 Fever clearance Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Remaining febrile after 24 hours	2	990	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.43, 0.70]
2.2 Remaining febrile after 48 hours	3	1390	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.31, 0.91]
2.3 Remaining febrile after 72 hours	2	985	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.27, 1.36]
3 Recurrence of parasitaemia Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 Before day 14	1	427	Risk Ratio (M‐H, Random, 95% CI)	2.88 [0.12, 70.22]
3.2 Before day 28	5	1622	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.18, 1.90]
3.3 After day 28 (primaquine not given)	3	1066	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.40, 0.82]
3.4 After day 28 (primaquine given)	1	376	Risk Ratio (M‐H, Random, 95% CI)	0.27 [0.08, 0.94]
3.5 During full follow‐up period (42 or 56 days)	4	1460	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.44, 0.78]
4 Gametocytemia Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4.1 On Day 0	2		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 On Day 1	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 On Day 2	2		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 On Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Serious adverse events Show forest plot	5	1775	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.14, 7.04]

Comparison 1. ACT versus Chloroquine

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Comparison 2. ACT versus Chloroquine plus Sulfadoxine‐pyrimethamine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Parasite clearance Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Remaining parasitaemic after 24 hours	1	195	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.15, 0.34]
1.2 Remaining parasitaemic after 48 hours	1	195	Risk Ratio (M‐H, Random, 95% CI)	0.09 [0.03, 0.27]
1.3 Remaining parasitaemic after 72 hours	1	195	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.03, 0.81]
2 Fever clearance Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Remaining febrile after 24 hours	1	195	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.75, 1.48]
2.2 Remaining febrile after 48 hours	1	195	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.31, 1.23]
2.3 Remaining febrile after 72 hours	1	195	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.29, 2.02]
3 Recurrence of parasitaemia Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Before day 14	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Before day 28	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 After day 28	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.4 During full follow‐up period (42 days)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Serious adverse events Show forest plot	1	209	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 2. ACT versus Chloroquine plus Sulfadoxine‐pyrimethamine

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Comparison 3. ACT versus Quinine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Parasite clearance Show forest plot	1	72	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.19, 21.09]

1.1 Remaining parasitaemia after 72 hours	1	72	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.19, 21.09]
2 Recurrence of parasitaemia Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.1 Before day 14	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Before day 28	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 After day 28	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.4 During full follow‐up period (42 days)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 3. ACT versus Quinine

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Comparison 4. ACT versus ACT

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Remaining parasitemic after 24 hours Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 DHA‐P versus AS+MQ	3	120	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.28, 4.92]
1.2 DHA‐P versus AL6	1	83	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.31, 1.94]
1.3 AS+MQ versus AL6	1	24	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.60, 1.72]
1.4 DHA‐P versus AS+SP	1	95	Risk Ratio (M‐H, Random, 95% CI)	1.35 [0.49, 3.72]
2 Remaining parasitemic after 48 hours Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 DHA‐P versus AS+MQ	3	120	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 DHA‐P versus AL6	1	83	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.04, 4.70]
2.3 AS+MQ versus AL6	1	24	Risk Ratio (M‐H, Random, 95% CI)	5.13 [0.29, 89.57]
2.4 DHA‐P versus AS+SP	1	95	Risk Ratio (M‐H, Random, 95% CI)	3.47 [0.14, 83.00]
3 Remaining febrile after 24 hours Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 DHA‐P versus AL6	1	83	Risk Ratio (M‐H, Random, 95% CI)	1.39 [0.83, 2.33]
3.2 DHA‐P versus AS+SP	1	95	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.64, 1.40]
4 Remaining febrile after 48 hours Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 DHA‐P versus AL6	1	83	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.22, 1.83]
4.2 DHA‐P versus AS+SP	1	95	Risk Ratio (M‐H, Random, 95% CI)	1.45 [0.41, 5.06]
5 Recurrent parasitaemia before day 28 Show forest plot	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 DHA‐P versus AS+MQ	4	186	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.02, 1.45]
5.2 DHA‐P versus AL6	3	237	Risk Ratio (M‐H, Random, 95% CI)	0.15 [0.04, 0.58]
5.3 DHA‐P versus AS+AQ	2	108	Risk Ratio (M‐H, Random, 95% CI)	0.04 [0.00, 0.73]
5.4 DHA‐P versus AS+SP	1	77	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.15, 0.72]
5.5 AS+MQ versus AL6	2	56	Risk Ratio (M‐H, Random, 95% CI)	0.06 [0.01, 0.40]
5.6 AS+MQ versus AS+AQ	1	34	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.7 AL6 versus AS+AQ	1	28	Risk Ratio (M‐H, Random, 95% CI)	16.06 [1.03, 249.60]
5.8 AL6 versus AS+SP	1	72	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.67, 1.68]
6 Recurrent parasitaemia after day 28 Show forest plot	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 DHA‐P versus AS+MQ	4	169	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.58, 1.09]
6.2 DHA‐P versus AL6	3	168	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.11, 1.38]
6.3 DHA‐P versus AS+AQ	2	95	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.12, 2.40]
6.4 DHA‐P versus AS+SP	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.14, 1.38]
6.5 AS+MQ versus AL6	2	45	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.61, 1.37]
6.6 AS+MQ versus AS+AQ	1	36	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.72, 1.55]
6.7 AL6 versus AS+AQ	1	18	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.68, 1.80]
6.8 AL6 versus AS+SP	1	38	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.29, 1.84]
7 Recurrent parasitaemia during full follow‐up period (0 to 42 or 63 days) Show forest plot	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7.1 DHA‐P versus AS+MQ	4	186	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.02, 1.45]
7.2 DHA‐P versus AL6	3	237	Risk Ratio (M‐H, Random, 95% CI)	0.15 [0.04, 0.58]
7.3 DHA‐P versus AS+AQ	2	108	Risk Ratio (M‐H, Random, 95% CI)	0.04 [0.00, 0.73]
7.4 DHA‐P versus AS+SP	1	77	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.15, 0.72]
7.5 AS+MQ versus AL6	2	56	Risk Ratio (M‐H, Random, 95% CI)	0.06 [0.01, 0.40]
7.6 AS+MQ versus AS+AQ	1	34	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7.7 AL6 versus AS+AQ	1	28	Risk Ratio (M‐H, Random, 95% CI)	16.06 [1.03, 249.60]
7.8 AL6 versus AS+SP	1	72	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.67, 1.68]

Comparison 4. ACT versus ACT

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Comparison 5. DHA‐P versus alternative ACTs

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Recurrent parasitaemia ‐ settings described as low transmission Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Before day 28	4	239	Risk Ratio (M‐H, Random, 95% CI)	0.12 [0.02, 0.63]
1.2 After day 28 ‐ without primaquine	4	187	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.59, 1.09]
1.3 During full follow‐up period (42 to 63 days) ‐ without primaquine	4	201	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.56, 1.02]
2 Recurrent parasitaemia ‐ settings described as high transmission Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 Before day 28	3	334	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.08, 0.49]
2.2 After day 28 ‐ with primaquine	2	179	Risk Ratio (M‐H, Random, 95% CI)	0.21 [0.10, 0.46]
2.3 After day 28 ‐ without primaquine	1	66	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.14, 1.10]
2.4 During full follow‐up period (42 days) ‐ with primaquine	2	210	Risk Ratio (M‐H, Random, 95% CI)	0.16 [0.08, 0.32]
2.5 During full follow‐up period (42 days) ‐ without primaquine	1	108	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.24, 0.72]

Comparison 5. DHA‐P versus alternative ACTs

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Tratamiento combinado con artemisinina para el tratamiento del paludismo por Plasmodium vivax no complicado

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