Primaquine or other 8‐aminoquinolines for reducing <i>Plasmodium falciparum</i> transmission

Patricia M Graves; Leslie Choi; Hellen Gelband; Paul Garner

doi:10.1002/14651858.CD008152.pub5

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Figure 1

Review logic framework: the potential points in the Plasmodium parasite life cycle that could be impacted by PQ and the outcomes used to measure impact. Abbreviations: AUC: area under the curve. EIR: entomological inoculation rate; PQ: primaquine.

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Figure 2

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

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Figure 3

‘Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included trials.

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Figure 4

Study flow diagram

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Analysis 1.1

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 1 Participants infectious, day 3 or 4, by dose.

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Analysis 1.2

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 2 Participants with gametocytes (PCR), day 3 or 4, by dose.

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Analysis 1.3

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 3 Participants with gametocytes (microscopy), day 3 or 4, by dose.

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Analysis 1.4

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 4 Participants infectious, day 8, by dose.

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Analysis 1.5

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 5 Participants with gametocytes (PCR), day 8, by dose.

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Analysis 1.6

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 6 Participants with gametocytes (microscopy), day 8, by dose.

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Analysis 1.7

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 7 Gametocyte clearance time (PCR), by dose.

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Analysis 1.8

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 8 Area under curve of gametocytes (PCR), days 1 to 15, by dose.

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Analysis 1.9

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 9 Participants with severe haemolysis, by dose.

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Analysis 1.10

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 10 Mean max change in haemoglobin concentration, by dose.

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Analysis 1.11

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 11 Percent change in haemoglobin, day 8, by dose.

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Analysis 1.12

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 12 Max percent change in haemoglobin, by dose.

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Analysis 1.13

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 13 Haemoglobinuria/dark urine.

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Analysis 1.14

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 14 Other adverse effects (CNS symptoms).

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Analysis 1.15

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 15 Other adverse effects (systemic).

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Analysis 1.16

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 16 Other adverse effects (respiratory symptoms).

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Analysis 1.17

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 17 Other adverse effects (gastrointestinal symptoms).

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Analysis 1.18

Comparison 1 Artemisinin treatment regimen: PQ versus no PQ, Outcome 18 Other adverse effects (Miscellaneous).

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Analysis 2.1

Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 1 Participants infectious, day 3 to 4.

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Analysis 2.2

Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 2 Participants with gametocytes (PCR), day 3 to 4.

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Analysis 2.3

Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 3 Participants with gametocytes (microscopy), day 3 to 4.

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Analysis 2.4

Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 4 Participants infectious, day 8.

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Analysis 2.5

Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 5 Participants with gametocytes (PCR), day 8.

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Analysis 2.6

Comparison 2 Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg, Outcome 6 Participants with gametocytes (microscopy), day 8.

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Analysis 3.1

Comparison 3 Non‐artemisinin treatment regimen: PQ versus no PQ, Outcome 1 Participants infectious, day 5, by dose.

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Analysis 3.2

Comparison 3 Non‐artemisinin treatment regimen: PQ versus no PQ, Outcome 2 Participants with gametocytes (microscopy), day 4 to 5, by dose.

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Analysis 3.3

Comparison 3 Non‐artemisinin treatment regimen: PQ versus no PQ, Outcome 3 Participants infectious, day 8, by dose.

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Analysis 3.4

Comparison 3 Non‐artemisinin treatment regimen: PQ versus no PQ, Outcome 4 Participants with gametocytes (microscopy), day 8, by dose.

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Analysis 3.5

Comparison 3 Non‐artemisinin treatment regimen: PQ versus no PQ, Outcome 5 Gametocyte clearance time.

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Analysis 3.6

Comparison 3 Non‐artemisinin treatment regimen: PQ versus no PQ, Outcome 6 Adverse effects.

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Analysis 4.1

Comparison 4 PQ versus other 8AQ, Outcome 1 Participants with gametocytes (microscopy), day 8.

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Summary of findings for the main comparison. Single dose primaquine at 0.2 to 0.25 mg/kg compared to no primaquine, with artemisinin partner, for reducing P. falciparum transmission

Low‐dose primaquine (PQ) given with artemisinin combination treatment Participants or population: adults and children with malaria being treated with artemisinin combination treatment Settings: Mali, Burkina Faso, The Gambia, Tanzania, Senegal Intervention: single dose PQ dose 0.2 to 0.25 mg/kg Comparison: no PQ
Outcomes	Number of participants (trials)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		Certainty of the evidence (GRADE)	Comments
Outcomes	Number of participants (trials)	Relative effect (95% CI)	Risk with no PQ, with artemisinin partner	Risk with single dose PQ at 0.2 to 0.25 mg/kg	Certainty of the evidence (GRADE)	Comments
Participants infectious at day 3‐4	105 (3 RCTs)	RR 0.12 (0.02 to 0.88)	14 per 100	2 per 100 (0 to 13)	⊕⊕⊝⊝ LOW¹ Due to imprecision	Low‐dose PQ may reduce infectiousness
Participants infectious at day 8	243 (4 RCTs)	RR 0.34 (0.07 to 1.58)	4 per 100	1 per 100 (0 to 6)	⊕⊕⊝⊝ LOW¹ Due to imprecision	Low‐dose PQ may reduce infectiousness
Participants with gametocytes at day 3 to 4 by PCR	414 (3 RCTs)	RR 1.02 (0.87 to 1.21)	52 per 100	53 per 100 (45 to 63)	⊕⊕⊕⊝ MODERATE² Due to imprecision	Low‐dose PQ probably has little or no effect on gametocytes detected by PCR at day 3 to 4
Participants with gametocytes at day 8 by PCR	532 (4 RCTs)	RR 0.52 (0.41 to 0.65)	47 per 100	25 per 100 (19 to 31)	⊕⊕⊕⊕ HIGH	Low‐dose PQ reduces gametocytes detected by PCR at day 8
Participants with severe haemolysis	752 (4 RCTs)	RR 0.98 (0.69 to 1.39)	13 per 100	13 per 100 (9 to 18)	⊕⊕⊕⊝ MODERATE² Due to imprecision	Low‐dose PQ probably has little or no effect on severe haemolysis
*The risk in the intervention group (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). Abbreviations: CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Downgraded by 2 for imprecision: the CIs are wide; in addition, there is a large effect combined with a low number of events, which creates further uncertainty around the point estimate. ²Downgraded by 1 for imprecision: the CIs are wide.

Summary of findings for the main comparison. Single dose primaquine at 0.2 to 0.25 mg/kg compared to no primaquine, with artemisinin partner, for reducing P. falciparum transmission

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Summary of findings 2. Single dose primaquine at 0.4 to 0.5 mg/kg compared to no primaquine, with artemisinin partner, for reducing P. falciparum transmission

Moderate‐dose primaquine (PQ) given with artemisinin combination treatment Participants or population: adults and children with malaria being treated with artemisinin combination treatment Settings: Mali, Burkina Faso, The Gambia, Uganda Intervention: single dose PQ 0.4 to 0.5 mg/kg Comparison: no PQ
Outcomes	Number of participants (trials)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		Certainty of the evidence (GRADE)	Comments
Outcomes	Number of participants (trials)	Relative effect (95% CI)	Risk with no PQ, with artemisinin partner,	Risk with single dose PQ at 0.4 to 0.5 mg/kg	Certainty of the evidence (GRADE)	Comments
Participants infectious at day 3‐4	109 (3 RCTs)	RR 0.13 (0.02 to 0.94)	14 per 100	2 per 100 (0 to 13)	⊕⊕⊝⊝ LOW¹ Due to imprecision	Medium dose PQ may reduce infectiousness
Participants infectious at day 8	246 (4 RCTs)	RR 0.33 (0.07 to 1.57)	4 per 100	1 per 100 (0 to 6)	⊕⊕⊝⊝ LOW¹ Due to imprecision	Medium dose PQ may reduce infectiousness
Participants with gametocytes at day 3‐4, by PCR	418 (3 RCTs)	RR 1.09 (0.93 to 1.28)	52 per 100	57 per 100 (48 to 67)	⊕⊕⊕⊝ MODERATE² Due to imprecision	Medium dose PQ probably has little or no effect on gametocytes detected by PCR on day 3 to 4
Participants with gametocytes at day 8, by PCR	758 (5 RCTs)	RR 0.37 (0.29 to 0.48)	43 per 100	16 per 100 (13 to 21)	⊕⊕⊕⊕ HIGH	Medium dose PQ reduces gametocytes detected by PCR on day 8
Participants with severe haemolysis	260 (2 RCTs)	RR 1.54 (0.38 to 6.30)	2 per 100	4 per 100 (1 to 15)	⊕⊕⊝⊝ LOW³ Due to imprecision	Medium dose PQ may increase severe haemolysis
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Downgraded by 2 for imprecision: the CIs are wide; in addition, there is a large effect combined with a low number of events, which creates further uncertainty around the point estimate. ²Downgraded by 1 for imprecision: the CIs are wide. ³Downgraded by 2 for imprecision: the CIs are very wide.

Summary of findings 2. Single dose primaquine at 0.4 to 0.5 mg/kg compared to no primaquine, with artemisinin partner, for reducing P. falciparum transmission

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Summary of findings 3. Single dose primaquine at 0.75 mg/kg compared to no primaquine, with artemisinin partner, for reducing P. falciparum transmission

High‐dose primaquine (PQ) given with artemisinin combination treatment Participants or population: adults and children with malaria being treated with artemisinin combination treatment Settings: Cambodia, Mali, Burkina Faso, The Gambia, Tanzania, Sudan, Uganda Intervention: single dose PQ 0.75 mg/kg Comparison: no PQ
Outcomes	Number of participants (trials)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		Certainty of the evidence (GRADE)	Comments
Outcomes	Number of participants (trials)	Relative effect (95% CI)	Risk with no PQ, with artemisinin partner	Risk with single dose PQ at 0.75mg/kg	Certainty of the evidence (GRADE)	Comments
Participants infectious at day 3‐4	101 (1 RCT)	RR 0.20 (0.02 to 1.68)	10 per 100	2 per 100 (0 to 16)	⊕⊕⊝⊝ LOW^1,2 Due to imprecision	We do not know if high dose PQ may reduce infectiousness
Participants infectious at day 8	181 (2 RCTs)	RR 0.18 (0.02 to 1.41)	5 per 100	1 per 100 (0 to 8)	⊕⊕⊝⊝ LOW¹ Due to imprecision	High dose PQ may reduce infectiousness
Participants with gametocytes at day 3‐4, by PCR	290 (2 RCTs)	RR 0.92 (0.75 to 1.13)	38 per 100	35 per 100 (29 to 43)	⊕⊕⊝⊝ LOW^3,4 Due to indirectness and imprecision	High dose PQ may have little or no effect on gametocytes detected by PCR
Participants with gametocytes at day 8, by PCR	793 (5 RCTs)	RR 0.31 (0.23 to 0.43)	36 per 100	11 per 100 (8 to 16)	⊕⊕⊕⊕ HIGH	High dose PQ reduces gametocytes detected by PCR
Participants with severe haemolysis	106 (1 RCT)	No estimate	Not estimable	Not estimable	No data	We don't know if high dose PQ impacts on haemolysis
*The risk in the intervention group (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). Abbreviations: CI: confidence interval; PCR: polymerase chain reaction; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Downgraded by 2 for imprecision: the CIs are wide; in addition, there is a large effect combined with a low number of events, which creates further uncertainty around the point estimate. In addition, in this one trial baseline. ²Baseline values for this outcome were unbalanced, but the downgrading by 2 for imprecision takes this in to account, as it could be a chance finding. ³Downgraded by 1 for indirectness: all the data for the results come from one trial. ⁴Downgraded by 1 for imprecision: the CIs are wide.

Summary of findings 3. Single dose primaquine at 0.75 mg/kg compared to no primaquine, with artemisinin partner, for reducing P. falciparum transmission

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Summary of findings 4. Single dose primaquine at 0.4 to 0.5 mg/kg compared to no primaquine, with non‐artemisinin partner, for reducing P. falciparum transmission

Moderate‐dose primaquine (PQ) given with non‐artemisinin treatment Participants or population: adults and children with malaria being treated with non‐artemisinin treatment Settings: Pakistan Intervention: single dose PQ 0.4 to 0.5 mg/kg Comparison: no PQ
Outcomes	Number of participants (trials)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		Certainty of the evidence (GRADE)	Comments
			Risk with no PQ, with non‐artemisinin partner	Risk with single dose PQ at 0.4 to 0.5 mg/kg
Participants with gametocytes at day 4‐5, by microscopy	221 (2 RCTs)	RR 0.83 (0.62 to 1.13)	48 per 100	40 per 100 (30 to 54)	⊕⊕⊕⊝ MODERATE ¹ Due to indirectness	Medium dose PQ probably reduces gametocytes detected by microscopy
Participants with gametocytes at day 8, by microscopy	216 (2 RCTs)	RR 0.60 (0.49 to 0.75)	81 per 100	49 per 100 (40 to 61)	⊕⊕⊕⊝ MODERATE ¹ Due to indirectness	Medium dose PQ probably reduces gametocytes detected by microscopy
*The risk in the intervention group (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). Abbreviations: CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Downgraded by 1 for indirectness: all the results are from one setting.

Summary of findings 4. Single dose primaquine at 0.4 to 0.5 mg/kg compared to no primaquine, with non‐artemisinin partner, for reducing P. falciparum transmission

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Summary of findings 5. Single dose primaquine at 0.75 mg/kg compared to no primaquine, with non‐artemisinin partner, for reducing P. falciparum transmission

Medium‐dose primaquine (PQ) given with non‐artemisinin treatment Participants or population: adults and children with malaria being treated with non‐artemisinin treatment Settings: China, Colombia, India, Indonesia Intervention: single dose PQ 0.75 mg/kg Comparison: no PQ
Outcomes	Number of participants (trials)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**		Certainty of the evidence (GRADE)	Comments
Outcomes	Number of participants (trials)	Relative effect (95% CI)	Risk with no PQ, with non‐artemisinin partner	Risk with single dose PQ at 0.75 mg/kg	Certainty of the evidence (GRADE)	Comments
Participants infectious at day 5	30 (2 RCTs)	RR 0.09 (0.01 to 0.62)	67 per 100	6 per 100 (1 to 41)	⊕⊝⊝⊝ VERY LOW^1,2 Due to risk of bias and imprecision	We are uncertain whether high dose PQ reduces infectiousness
Participants infectious at day 8	30 (2 RCTs)	RR 0.07 (0.01 to 0.45)	93 per 100	7 per 100 (1 to 42)	⊕⊝⊝⊝ VERY LOW^1,2 Due to risk of bias and imprecision	We are uncertain whether high dose PQ reduces infectiousness
Participants with gametocytes at day 5, by microscopy	52 (2 RCTs)	RR 0.85 (0.48 to 1.50)	50 per 100	43 per 100 (24 to 75)	⊕⊕⊝⊝ LOW^3,4 Due to risk of bias and imprecision	High dose PQ may reduce gametocytes detected by microscopy
Participants with gametocytes at day 8, by microscopy	186 (4 RCTs)	RR 0.39 (0.25 to 0.62)	48 per 100	19 per 100 (12 to 29)	⊕⊕⊕⊝ MODERATE⁵ Due to risk of bias	High dose PQ probably reduces gametocytes detected by microscopy
*The risk in the intervention group (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). Abbreviations: CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; OR: odds ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹Downgraded by 1 for risk of bias: unclear risk of bias in several domains from both studies. ²Downgraded by 2 for imprecision: the CIs are wide; in addition, there is a large effect combined with a low number of events, which creates further uncertainty around the point estimate. ³Downgraded by 1 for risk of bias: Arango 2012 had serious risk for selection bias and Chen 1993a had unclear risk of bias in several domains. ⁴Downgraded by 1 for imprecision: the CIs are wide. ⁵Downgraded by 1 for risk of bias: Arango 2012 had serious risk for selection bias and Chen 1993a had unclear risk of bias in several domains. Kamtekar 2004 had serious risk of bias for several domains.

Summary of findings 5. Single dose primaquine at 0.75 mg/kg compared to no primaquine, with non‐artemisinin partner, for reducing P. falciparum transmission

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Table 1. Trial locations, partner drugs, gametocyte status at onset, G6PD status, and PQ dose and treatment schedule

Comparator	Trial	Arm	Place	G6PD status	Parasite species	Partner or alternative drug	Proportion with gametocytes at onset (control group)	Proportion with gametocytes at onset (experimental group)	*Day(s) PQ given**	Target PQ dose per day
Artemisinin‐based partner
AS or ACT	Arango 2012	b	Colombia	Not reported	Pf only	AS+MQ days 1 to 3	34.8% Mic (N = 23)	26.3% Mic (N = 19)	day 2	0.75 mg/kg
	Dicko 2016	a	Mali	Only non‐deficient included¹	Pf only	DHAP days 1 to 3	100% Mic (N = 15) Table 1	100% Mic (N = 16)	day 1	0.0625 mg/kg**
		b						100% Mic (N = 16)	day 1	0.125 mg/kg**
		c						100% Mic (N = 15)	day 1	0.25 mg/kg
		d						100% Mic (N = 17)	day 1	0.5 mg/kg
	El‐Sayed 2007		Sudan (east)	Not reported	Pf only	AS+SP days 1 to 3	11.5% PCR (N = 52) Table 2	11.5% PCR (N = 52)	day 4	0.75 mg/kg
	Eziefula 2013	a	Uganda	Only non‐deficient included² (PCR testing of those included after FST)	Pf only	AL days 1 to 3	23.1% Mic (N = 117) 79.8% PCR (N = 114) Table 1	24.3% MIc (N = 115) 86.7% PCR (N = 113)	day 3	0.1 mg/kg**
		b						20.4% Mic (N = 113) 78.7% PCR (N = 108)	day 3	0.4 mg/kg
		c						22.4% Mic (N = 116) 82.0% PCR (N = 111)	day 3	0.75 mg/kg
	Gonçalves 2016a	a	Burkina Faso	Only non‐deficient included³	Pf only	AL days 1 to 3	17.7% Mic (N = 62) Table 2	32% Mic (N = 75) 92.9% PCR (N = 70)	day 3	0.25 mg/kg
	Gonçalves 2016a	b	Burkina Faso	Only non‐deficient included³	Pf only	AL days 1 to 3	17.7% Mic (N = 62) Table 2	20.5% Mic (N = 73) 85.5% PCR (N = 62)	day 3	0.4 mg/kg
	Gonçalves 2016b	a	Burkina Faso	Only non‐deficient included³	Pf only	AL days 1 to 3	69.4% Mic (N = 49) Table 2	55.3% Mic (N = 47) 93.7% PCR (N = 48)	day 3	0.25 mg/kg
	Gonçalves 2016b	b	Burkina Faso	Only non‐deficient included³	Pf only	AL days 1 to 3	69.4% Mic (N = 49) Table 2	83.3% Mic (N = 46) 100.0% PCR (N = 46)	day 3	0.4 mg/kg
	Lin 2017		Cambodia	Screened and severely deficient excluded⁴	Pf or Pf+Pv	DHAP days 1 to 3	10% Mic 44% PCR (N = 51) Table 1	8% Mic 49% PCR (N = 50) Table 1	day 3	0.75 mg/kg
	Mwaiswelo 2016		Tanzania	Screened and all included⁵	Pf only	AL days 1 to 3	1 patient had gametocytes at recruitment but treatment group not given	0.5% Mic (N = 220) both groups	day 1	0.25 mg/kg
	Okebe 2016	a	The Gambia	Only non‐deficient included²	Pf only	DHAP days 1 to 3	47.7% PCR (N = 153) Table 1	53.4% PCR (N = 148)	day 3	0.2 mg/kg
		b						54.6% PCR (N = 152)	day 3	0.4 mg/kg
		c						53.4% PCR (N = 146)	day 3	0.75 mg/kg
	Pukrittayakamee 2004	c	Thailand	Only non‐deficient included¹⁰	Pf only	AS days 1 to 7	26.1% Mic (N = 23) Table 3	26.0% Mic (N = 50)	days 1 to 7	0.5 mg/kg
	Shekalaghe 2007		Tanzania (North east)	Screened and all included⁶	Pf only	AS+SP days 1 to 3	26.4% Mic (N = 63) 88.2% PCR (N = 51) Table 1	18.9% Mic (N = 53) 90.6% PCR (N = 53)	day 3	0.75 mg/kg
	Smithuis 2010	a	Myanmar (3 states)	Not screened	Pf or mixed	AS+AQ days 1 to 3	32.1% Mic (N = 84)	36.6% Mic (N = 71)	day 1	0.75 mg/kg
		b				AL days 1 to 3	34.5% Mic (N = 84)	32.1% Mic (N = 78)	day 1	0.75 mg/kg
		c				AS+MQ fixed dose days 1 to 3	31.3% Mic (N = 83)	27.9%% Mic (N = 86)	day 1	0.75 mg/kg
		d				AS days 1 to 3 + MQ day 1 loose	30.5% Mic (N = 82)	26.6% Mic (N = 79)	day 1	0.75 mg/kg
		e				DHAP days 1 to 3	43.6% Mic (N = 78)	32.5% Mic (N = 83)	day 1	0.75 mg/kg
	Sutanto 2013		Indonesia (south Sumatra)	Only non‐deficient included⁷	Pf only	DHAP days 1 to 3	17.4% Mic (N = 178) Figure 1	24.0% Mic (on day 3) (N = 171)	day 4	0.75 mg/kg
	Tine 2017	a	Senegal	Screened and all included⁵	Pf only	AL days 1 to 3	6.7% Mic (N = 135) Table 5	7.9% Mic (N = 139) Table 5	day 1	0.25 mg/kg
		b				DHAP days 1 to 3
		c				AS+AQ days 1 to 3
	Vásquez 2009		Colombia (Antioquia)	Not reported	Pf only	AS+MQ days 1 to 3 (MQ only on day 2 for children < 6)	16% Mic (N = 25) Figure 1 estimated	24.0% Mic (N = 25)	day 3	45 mg (˜0.75 mg/kg)
	Wang 2006		Gabon	Not reported	Pf	AS i.m. days 1 to 5	Not reported (N = 106)	Not reported (N = 108)	days 1 to 5	22.5 mg (˜0.38 mg/kg)
Non‐artemisinin partner
CQ or (CQ+SP)	Kamtekar 2004	a	India (Mumbai)	Not screened	Pf only	CQ days 1 to 3 or CQ days 1 to 3 + SP day 1	100% Mic (N = 44)	100% Mic (within 3 days) (N = 45)	day 4	45 mg (˜0.75 mg/kg)
	Khoo 1981		Malaysia (Sabah)	Only deficient included⁸	Pf, Pv or mixed	CQ days 1 to 3	Not reported	Not reported	days 1 to 3	25 mg (˜0.42 mg/kg)
	Kolaczinski 2012	a	Pakistan (3 Afghan refugee camps)	Not reported	Pf only	CQ days 1 to 3	17.6% Mic (N = 239) Table 2 (combined CQ, CQ+AS, SP, SP+AS groups)	19.7% Mic (N = 76)	day 3	0.5 mg/kg
	Lederman 2006	a	Indonesia (Central Java)	Only non‐deficient included⁹	Pf only	CQ days 1 to 3 + SP day 1	8.2% Mic (N = 61) Figure 3 est (combined CQ, CQ+SP groups)	25% Mic (N = 28) Figure 3 est	day 1	45 mg (˜0.75 mg/kg)
	Lederman 2006	b	Indonesia (Central Java)	Only non‐deficient included⁹	Pf only	CQ days 1 to 3 + SP day 1		14.3% (N = 28) Figure 3 est	day 3	45 mg (˜0.75 mg/kg)
SP	Kolaczinski 2012	b	Pakistan (2 Afghan refugee camps)	Not reported	Pf only	SP day 1	See above under Kolaczinski 2012 a	27.1% Mic (N = 85)	day 1	0.5 mg/kg
AQ+SP	Arango 2012	a	Colombia	Not reported	Pf only	AQ days 1 to 3 + SP day 1	15% Mic (N = 20) Table 3	30% Mic (N = 20)	day 2	0.75 mg/kg
MQ or (MQ+SP)	Chen 1993a		China	Not reported	Pf only	MQ day 1	100% Mic (N = 6)	100% Mic (N = 6)	day 1	45 mg (˜0.75 mg/kg)
	Chen 1994		China (Hainan province)	Not reported	Pf only	MQ day 1	100% Mic (N = 9) MQ group only	100% Mic (N = 9)	day 1	45 mg (˜0.75 mg/kg)
	Singhasivanon 1994		Thailand (Bangkok)	Not reported	Pf only	MQ+SP fixed day 1	Not reported (N = 11)	Not reported (N = 7)	day 1	0.75 mg/kg
QN	Kamtekar 2004	b	India (Mumbai)	Not screened	Pf only	QN i.v. days 1 to 2 and orally days 1 to 7	88.6% Mic (N = 44)	100% Mic (within 3 days) (N = 45)	day 8	45 mg (˜0.75 mg/kg)
	Pukrittayakamee 2004	a	Thailand	Only non‐deficient included¹⁰	Pf only	QN days 1 to 7	23.3% Mic (N = 60) QN, QN+TC groups	18.6% Mic (N = 59)	days 1 to 7	0.25 mg base/kg
	Pukrittayakamee 2004	b	Thailand	Only non‐deficient included¹⁰	Pf only	QN days 1 to 7	23.3% Mic (N = 60) QN, QN+TC groups	22.4% Mic (N = 67)	days 1 to 7	0.5 mg base/kg
Comparison of different 8AQ
PQ versus Bulaquine	Gogtay 2004		India (Mumbai)	Only non‐deficient included¹⁰	Pf	QN + doxycycline days 1 to 7 + BQ day 4	No control group without 8‐AQ	100% Mic (N = 22)	day 4	45 mg (˜0.75 mg/kg)
PQ versus Bulaquine	Gogtay 2006		India	Only non‐deficient included¹⁰	Pf	QN + doxycycline days 1 to 7 + BQ day 4	No control group without 8‐AQ	100% Mic (N = 93)	day 4	45 mg (˜0.75 mg/kg)
first day of any treatment = day 1 arm excluded as dose < 0.2 mg/kg ¹G6PD colorimetric method, R&D diagnostics, Papagos, Greece. ²G6PD by fluorescence spot test. ³G6PD by Binax Now Alere rapid test. ⁴G6PD by fluorescent spot test (R&D diagnostics, Greece) and quantitative enzyme activity testing (Trinity Biotech, Ireland). ⁵G6PD (phenotypic) by CareStart ™ Access Bio test; (genotypic) by PCR and RFLP digestion for the two most common Afrcian G6PD polymorphisms. ⁶G6PD by detection of single nucleotide polymorphisms (G202A, A376G) by PCR and ELISA. ⁷G6PD by qualitative test. ⁸G6PD by Brewer's methaemoglobin reduction test. ⁹G6PD by semi‐quantitative G6PD assay. ¹⁰G6PD method not reported. Abbreviations: G6PD = glucose‐6‐phosphate dehydrogenase; FST = fluorescent spot test; PQ = primaquine; CQ = chloroquine; SP = sulfadoxine‐pyrimethamine; MQ = mefloquine; QN = quinine; AS = artesunate; ACT = artemisinin‐based combination therapy; 8AQ: 8‐aminoquinoline; AQ = amodiaquine; AL = artemether‐lumefantrine; DHAP = dihydroxyartemisinin‐piperaquine; BQ = bulaquine; i.v. = intravenous injection; i.m. = intramuscular injection; Mic = microscopy; Pf = P. falciparum; Pv = P. vivax*.

Table 1. Trial locations, partner drugs, gametocyte status at onset, G6PD status, and PQ dose and treatment schedule

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Table 2. Infectivity to mosquitoes baseline

Dose	Study	With PQ			Without PQ			Absolute difference (reduction or increase) in % of mosquitoes infected in PQ group	Average number of mosquitoes dissected per participant (both arms combined)
Dose	Study	Total number of participants	Number of infectious people	Average % of mosquitoes infected	Total number of participants	Number of infectious people	Average % of mosquitoes infected
0.25 mg/kg	Dicko 2016	15	14	35.5	14	10	6.7	+28.8	143.1
0.25 mg/kg	Gonçalves 2016b	27	8	4.5	32	15	14.8	−10.3	44.0
0.4 to 0.5 mg/kg	Dicko 2016	14	12	11.0	14	10	6.7	+4.3	136.6
0.4 to 0.5 mg/kg	Gonçalves 2016b	20	7	8.9	32	15	14.8	−5.8	44.3
0.75 mg/kg	Lin 2017	50	1	1.4	51	6	5.3	−3.9	50
Abbreviations: PQ: primaquine.

Table 2. Infectivity to mosquitoes baseline

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Table 3. Infectivity to mosquitoes day 3‐4

Dose	Study	With PQ			Without PQ			Absolute difference (reduction or increase) in % of mosquitoes infected in PQ group	Average number of mosquitoes dissected per participant (both arms combined)
Dose	Study	Total number of participants	Number of infectious people	Average % of mosquitoes infected	Total number of participants	Number of infectious people	Average % of mosquitoes infected
0.25 mg/kg	Dicko 2016	15	1	0.6	13	7	8.1	−7.5	71.6
	Gonçalves 2016a	27	0	0.0	32	0	0.0	0.0	26.9
	Gonçalves 2016b	23	0	0.0	19	0	0.0	0.0	45.6
0.4 to 0.5 mg/kg	Dicko 2016	14	1	0.3	13	7	8.1	−7.8	70.2
	Gonçalves 2016a	20	0	0.0	32	0	0.0	0.0	33.4
	Gonçalves 2016b	28	0	0.0	19	0	0.0	0.0	45.6
0.75 mg/kg	Lin 2017	50	1	1.4	51	5	6.6	‐5.2	50
Abbreviations: PQ: primaquine.

Table 3. Infectivity to mosquitoes day 3‐4

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Table 4. Infectivity to mosquitoes day 8

Dose	Study	With PQ			Without PQ			Absolute difference (reduction or increase) in % of mosquitoes infected in PQ group	Average number of mosquitoes dissected per participant (both arms combined)
Dose	Study	Total number of participants	Number of infectious people	Average % of mosquitoes infected	Total number of participants	Number of infectious people	Average % of mosquitoes infected
0.2 to 0.25 mg/kg	Dicko 2016	15	0	0.0	13	3	3.7	−3.7	72.8
	Gonçalves 2016a	27	0	0.0	32	0	0.0	0.0	26.6
	Gonçalves 2016b	49	0	0.0	49	1	0.2	−0.2	43.7
	Okebe 2016¹	44	1	29.2	46	1	1.3	+27.9	80
0.4 to 0.5 mg/kg	Dicko 2016	14	1	0.1	13	3	3.7	−3.6	71
	Gonçalves 2016a	20	0	0.0	32	0	0.0	0.0	31.4
	Gonçalves 2016b	46	0	0.0	49	1	0.2	−0.2	43.4
	Okebe 2016	42	0	0.0	46	1	1.3	−1.3	80
0.75 mg/kg	Lin 2017	48	0	0.0	48	4	6.9	−6.9	50
0.75 mg/kg	Okebe 2016¹	39	0	0.0	46	1	1.3	−1.3	80
¹Okebe 2016 reported the median number of mosquitoes per person. Abbreviations: PQ: primaquine.

Table 4. Infectivity to mosquitoes day 8

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Comparison 1. Artemisinin treatment regimen: PQ versus no PQ

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants infectious, day 3 or 4, by dose Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 0.2 to 0.25 mg/kg	3	105	Risk Ratio (M‐H, Fixed, 95% CI)	0.12 [0.02, 0.88]
1.2 0.4 to 0.5 mg/kg	3	109	Risk Ratio (M‐H, Fixed, 95% CI)	0.13 [0.02, 0.94]
1.3 0.75 mg/kg	1	101	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.02, 1.68]
2 Participants with gametocytes (PCR), day 3 or 4, by dose Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 0.2 to 0.25 mg/kg	3	414	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.87, 1.21]
2.2 0.4 to 0.5 mg/kg	3	418	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.93, 1.28]
2.3 0.75 mg/kg	2	394	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.75, 1.13]
3 Participants with gametocytes (microscopy), day 3 or 4, by dose Show forest plot	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 0.2 to 0.25 mg/kg	3	490	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.21, 2.50]
3.2 0.4 to 0.5 mg/kg	2	225	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.33, 2.25]
3.3 0.75 mg/kg	3	248	Risk Ratio (M‐H, Random, 95% CI)	0.42 [0.20, 0.85]
4 Participants infectious, day 8, by dose Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 0.2 to 0.25 mg/kg	4	243	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.07, 1.58]
4.2 0.4 to 0.5 mg/kg	4	246	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.07, 1.57]
4.3 0.75 mg/kg	2	181	Risk Ratio (M‐H, Fixed, 95% CI)	0.18 [0.02, 1.41]
5 Participants with gametocytes (PCR), day 8, by dose Show forest plot	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 0.2 to 0.25 mg/kg PQ	4	532	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.41, 0.65]
5.2 0.4 to 0.5 mg/kg PQ	5	758	Risk Ratio (M‐H, Fixed, 95% CI)	0.37 [0.29, 0.48]
5.3 0.75 mg/kg PQ	5	793	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.23, 0.43]
6 Participants with gametocytes (microscopy), day 8, by dose Show forest plot	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 0.2 to 0.25 mg/kg	3	491	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.16, 0.78]
6.2 0.4 to 0.5 mg/kg	2	225	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.08, 0.75]
6.3 0.75 mg/kg	6	1443	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.19, 0.37]
7 Gametocyte clearance time (PCR), by dose Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

7.1 0.2 to 0.25 mg/kg	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.2 0.4 to 0.5 mg/kg	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Area under curve of gametocytes (PCR), days 1 to 15, by dose Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

8.1 0.2 to 0.25 mg/kg	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.2 0.4 to 0.5 mg/kg	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Participants with severe haemolysis, by dose Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

9.1 0.2 to 0.25 mg/kg	4	752	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.69, 1.39]
9.2 0.4 to 0.5 mg/kg	2	260	Risk Ratio (M‐H, Fixed, 95% CI)	1.54 [0.38, 6.30]
9.3 0.75 mg/kg	1	102	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Mean max change in haemoglobin concentration, by dose Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

10.1 0.2 to 0.25 mg/kg	2	435	Mean Difference (IV, Random, 95% CI)	0.13 [‐0.07, 0.33]
10.2 0.4 to 0.5 mg/kg	2	475	Mean Difference (IV, Random, 95% CI)	0.18 [‐0.08, 0.44]
10.3 0.75 mg/kg	3	538	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.04, 0.14]
11 Percent change in haemoglobin, day 8, by dose Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

11.1 0.2 to 0.25 mg/kg	2	492	Mean Difference (IV, Random, 95% CI)	0.25 [‐0.99, 1.50]
11.2 0.4 to 0.5 mg/kg	1	230	Mean Difference (IV, Random, 95% CI)	0.43 [‐3.40, 4.26]
11.3 0.75 mg/kg	2	334	Mean Difference (IV, Random, 95% CI)	1.46 [‐1.70, 4.63]
12 Max percent change in haemoglobin, by dose Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

12.1 0.2 to 0.25 mg/kg	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.2 0.4 to 0.5 mg/kg	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.3 0.75 mg/kg	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Haemoglobinuria/dark urine Show forest plot	3	527	Odds Ratio (M‐H, Fixed, 95% CI)	3.40 [2.15, 5.38]

14 Other adverse effects (CNS symptoms) Show forest plot	6		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

14.1 Headache	5	1706	Odds Ratio (M‐H, Fixed, 95% CI)	0.95 [0.66, 1.36]
14.2 Paresthesia	1	331	Odds Ratio (M‐H, Fixed, 95% CI)	0.95 [0.13, 6.80]
14.3 Dizziness	4	1335	Odds Ratio (M‐H, Fixed, 95% CI)	0.95 [0.74, 1.23]
14.4 Meningitis	1	441	Odds Ratio (M‐H, Fixed, 95% CI)	0.08 [0.00, 2.13]
14.5 Blurred vision	1	217	Odds Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 8.12]
14.6 Insomnia	1	808	Odds Ratio (M‐H, Fixed, 95% CI)	0.97 [0.64, 1.47]
15 Other adverse effects (systemic) Show forest plot	6	4142	Odds Ratio (M‐H, Fixed, 95% CI)	0.96 [0.74, 1.24]

15.1 Fatigue	2	236	Odds Ratio (M‐H, Fixed, 95% CI)	1.00 [0.46, 2.19]
15.2 Pruritis	1	347	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.3 Fever	4	1056	Odds Ratio (M‐H, Fixed, 95% CI)	1.01 [0.65, 1.55]
15.4 Muscle ache/pain	2	398	Odds Ratio (M‐H, Fixed, 95% CI)	0.66 [0.12, 3.55]
15.5 Skin rash	3	921	Odds Ratio (M‐H, Fixed, 95% CI)	1.51 [0.46, 5.01]
15.6 Pallor	2	704	Odds Ratio (M‐H, Fixed, 95% CI)	0.95 [0.59, 1.54]
15.7 Weakness/asthenia	2	480	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.43, 1.49]
16 Other adverse effects (respiratory symptoms) Show forest plot	5		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

16.1 Cough	2	488	Odds Ratio (M‐H, Fixed, 95% CI)	1.39 [0.77, 2.54]
16.2 Runny nose	1	47	Odds Ratio (M‐H, Fixed, 95% CI)	0.49 [0.07, 3.61]
16.3 URTI/respiratory infection	2	488	Odds Ratio (M‐H, Fixed, 95% CI)	2.57 [0.68, 9.72]
16.4 Bronchitis	1	351	Odds Ratio (M‐H, Fixed, 95% CI)	2.34 [0.50, 10.87]
16.5 Rhinitis/rhinobronchitis	2	398	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.10, 5.83]
16.6 Shortness of breath	1	47	Odds Ratio (M‐H, Fixed, 95% CI)	0.16 [0.01, 4.45]
16.7 Otitis	1	351	Odds Ratio (M‐H, Fixed, 95% CI)	2.36 [0.11, 50.02]
16.8 Epistaxis	1	351	Odds Ratio (M‐H, Fixed, 95% CI)	1.41 [0.06, 35.04]
16.9 Pneumonia	1	441	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.05, 2.24]
16.10 Cold sores	1	217	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [0.29, 6.10]
16.11 Cyanosis	1	263	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
17 Other adverse effects (gastrointestinal symptoms) Show forest plot	7		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

17.1 Nausea	5	1624	Odds Ratio (M‐H, Fixed, 95% CI)	1.20 [0.88, 1.64]
17.2 Vomiting	7	2459	Odds Ratio (M‐H, Fixed, 95% CI)	1.00 [0.65, 1.56]
17.3 Abdominal pain	7	2453	Odds Ratio (M‐H, Fixed, 95% CI)	1.14 [0.86, 1.51]
17.4 Diarrhoea/dysentery/stooling	7	2462	Odds Ratio (M‐H, Fixed, 95% CI)	0.74 [0.50, 1.10]
17.5 Anorexia/loss of appetite	3	1296	Odds Ratio (M‐H, Fixed, 95% CI)	0.66 [0.45, 0.95]
18 Other adverse effects (Miscellaneous) Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

18.1 Back pain	1	47	Risk Ratio (M‐H, Fixed, 95% CI)	0.28 [0.04, 2.05]
18.2 Burning with urination	1	47	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.06, 29.31]
18.3 Pain with urination	1	47	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.06, 29.31]
18.4 Whitlow	1	47	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.06, 29.31]
18.5 Leg osteoarthritis	1	47	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.01, 4.14]
18.6 Uncomplicated malaria	1	351	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.12, 4.04]
18.7 Dental pain	1	351	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 3.67]
18.8 High transaminase	1	351	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 3.67]
18.9 Palpebral inflammation	1	351	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 3.67]
18.10 Wound/trauma	2	792	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.12, 0.97]
18.11 Foot trauma	1	351	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [0.06, 33.01]
18.12 Foot inflammation	1	351	Risk Ratio (M‐H, Fixed, 95% CI)	1.4 [0.06, 33.83]
18.13 Skin infection	1	441	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.30, 2.29]
18.14 Palpitations	1	808	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.80, 1.37]
18.15 Unspecified	2	655	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.46, 1.96]

Comparison 1. Artemisinin treatment regimen: PQ versus no PQ

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Comparison 2. Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants infectious, day 3 to 4 Show forest plot	3	116	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.06, 13.54]

2 Participants with gametocytes (PCR), day 3 to 4 Show forest plot	3	424	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.80, 1.09]

3 Participants with gametocytes (microscopy), day 3 to 4 Show forest plot	2	231	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.68, 2.20]

4 Participants infectious, day 8 Show forest plot	4	237	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.14, 6.48]

5 Participants with gametocytes (PCR), day 8 Show forest plot	4	559	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.97, 1.82]

6 Participants with gametocytes (microscopy), day 8 Show forest plot	2	235	Risk Ratio (M‐H, Fixed, 95% CI)	1.80 [0.51, 6.38]

Comparison 2. Artemisinin treatment regimen: PQ 0.25 versus 0.50 mg/kg

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Comparison 3. Non‐artemisinin treatment regimen: PQ versus no PQ

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants infectious, day 5, by dose Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 0.75 mg/kg	2	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.01, 0.62]
2 Participants with gametocytes (microscopy), day 4 to 5, by dose Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 0.4 to 0.5 mg/kg	1	221	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.62, 1.13]
2.2 0.75 mg/kg	2	52	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.48, 1.50]
3 Participants infectious, day 8, by dose Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 0.75 mg/kg PQ	2	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.07 [0.01, 0.45]
4 Participants with gametocytes (microscopy), day 8, by dose Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 0.4 to 0.5 mg/kg PQ	1	216	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.49, 0.75]
4.2 0.75 mg/kg PQ	4	186	Risk Ratio (M‐H, Fixed, 95% CI)	0.39 [0.25, 0.62]
5 Gametocyte clearance time Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

6 Adverse effects Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6.1 Nausea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 Vomiting	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.3 Dizziness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.4 Any adverse effect	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 3. Non‐artemisinin treatment regimen: PQ versus no PQ

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Comparison 4. PQ versus other 8AQ

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participants with gametocytes (microscopy), day 8 Show forest plot	2	112	Risk Ratio (M‐H, Fixed, 95% CI)	0.41 [0.26, 0.66]

Comparison 4. PQ versus other 8AQ

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