Drugs for preventing malaria in travellers

Frederique A Jacquerioz; Ashley M Croft

doi:10.1002/14651858.CD006491.pub2

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Figure 1

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Figure 2

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Figure 3

Forest plot of comparison: 2 Atovaquone‐proguanil vs mefloquine, outcome: 2.1 Any adverse outcome.

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Figure 4

Forest plot of comparison: 2 Atovaquone‐proguanil vs mefloquine, outcome: 2.3 Any gastrointestinal adverse outcome.

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Figure 5

Forest plot of comparison: 2 Atovaquone‐proguanil vs mefloquine, outcome: 2.4 Any neuropsychiatric adverse outcome.

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Figure 6

Forest plot of comparison: 2 Atovaquone‐proguanil vs mefloquine, outcome: 2.7 Total Mood Disturbance (TMD) scores.

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Figure 7

Forest plot of comparison: 3 Doxycycline vs mefloquine, outcome: 3.5 Any neuropsychiatric adverse outcome.

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Figure 8

Forest plot of comparison: 4 Any standard drugs vs chloroquine‐proguanil, outcome: 4.2 Any adverse outcome.

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Figure 9

Forest plot of comparison: 4 Any standard drugs vs chloroquine‐proguanil, outcome: 4.4 Any gastrointestinal adverse outcome.

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Analysis 1.1

Comparison 1 Atovaquone‐proguanil vs doxycycline, Outcome 1 Any adverse outcome.

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Analysis 1.2

Comparison 1 Atovaquone‐proguanil vs doxycycline, Outcome 2 Dermatological adverse outcome.

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Analysis 1.3

Comparison 1 Atovaquone‐proguanil vs doxycycline, Outcome 3 Gastrointestinal adverse outcome.

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Analysis 1.4

Comparison 1 Atovaquone‐proguanil vs doxycycline, Outcome 4 Neuropsychiatric adverse outcome.

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Analysis 1.5

Comparison 1 Atovaquone‐proguanil vs doxycycline, Outcome 5 Discontinuation of study drug for any reason.

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Analysis 2.1

Comparison 2 Atovaquone‐proguanil vs mefloquine, Outcome 1 Any adverse outcome.

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Analysis 2.2

Comparison 2 Atovaquone‐proguanil vs mefloquine, Outcome 2 Dermatological adverse outcome.

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Analysis 2.3

Comparison 2 Atovaquone‐proguanil vs mefloquine, Outcome 3 Gastrointestinal adverse outcome.

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Analysis 2.4

Comparison 2 Atovaquone‐proguanil vs mefloquine, Outcome 4 Neuropsychiatric adverse outcome.

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Analysis 2.5

Comparison 2 Atovaquone‐proguanil vs mefloquine, Outcome 5 Serious adverse event.

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Analysis 2.6

Comparison 2 Atovaquone‐proguanil vs mefloquine, Outcome 6 Discontinuation of study drug for any reason.

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Analysis 2.7

Comparison 2 Atovaquone‐proguanil vs mefloquine, Outcome 7 Total Mood Disturbance (TMD) scores.

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Analysis 3.1

Comparison 3 Doxycycline vs mefloquine, Outcome 1 Clinical cases of malaria.

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Analysis 3.2

Comparison 3 Doxycycline vs mefloquine, Outcome 2 Any adverse outcome.

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Analysis 3.3

Comparison 3 Doxycycline vs mefloquine, Outcome 3 Dermatological adverse outcome.

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Analysis 3.4

Comparison 3 Doxycycline vs mefloquine, Outcome 4 Gastrointestinal adverse outcome.

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Analysis 3.5

Comparison 3 Doxycycline vs mefloquine, Outcome 5 Neuropsychiatric adverse outcome.

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Analysis 3.6

Comparison 3 Doxycycline vs mefloquine, Outcome 6 Discontinuation of study drug for any reason.

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Analysis 4.1

Comparison 4 Any standard drugs vs chloroquine‐proguanil, Outcome 1 Clinical cases of malaria.

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Analysis 4.2

Comparison 4 Any standard drugs vs chloroquine‐proguanil, Outcome 2 Any adverse outcome.

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Analysis 4.3

Comparison 4 Any standard drugs vs chloroquine‐proguanil, Outcome 3 Dermatological adverse outcome.

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Analysis 4.4

Comparison 4 Any standard drugs vs chloroquine‐proguanil, Outcome 4 Gastrointestinal adverse outcome.

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Analysis 4.5

Comparison 4 Any standard drugs vs chloroquine‐proguanil, Outcome 5 Neuropsychiatric adverse outcome.

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Analysis 4.6

Comparison 4 Any standard drugs vs chloroquine‐proguanil, Outcome 6 Serious adverse event.

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Analysis 4.7

Comparison 4 Any standard drugs vs chloroquine‐proguanil, Outcome 7 Discontinuation of study drug for any reason.

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Summary of findings for the main comparison. Atovaquone‐proguanil compared to Mefloquine for Non immune child and adult travellers

Atovaquone‐proguanil compared to Mefloquine for Non immune child and adult travellers
Patient or population: Non immune child and adult travellers Settings: International travel Intervention: Atovaquone‐proguanil Comparison: Mefloquine
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Mefloquine	Atovaquone‐proguanil
Any adverse effect	422 per 1000	304 per 1000 (253 to 359)	RR 0.72 (0.6 to 0.85)	976 (1 study)	⊕⊕⊝⊝ low^1,2
Gastrointestinal adverse effect	288 per 1000	156 per 1000 (121 to 202)	RR 0.54 (0.42 to 0.7)	976 (1 study)	⊕⊕⊝⊝ low^1,3
Neuropsychiatric adverse event	771 per 1000	663 per 1000 (578 to 763)	RR 0.86 (0.75 to 0.99)	317 (1 study)	⊕⊕⊕⊝ moderate⁴
Neuropsychiatric adverse effect	288 per 1000	141 per 1000 (109 to 181)	RR 0.49 (0.38 to 0.63)	976 (1 study)	⊕⊕⊝⊝ low^1,3
Total Mood Disturbance (TMD) scores Scale from: ‐20 to 108.		The mean Total Mood Disturbance (TMD) scores in the intervention groups was 7.2 lower (10.79 to 3.61 lower)		119 (1 study)	⊕⊕⊝⊝ low^4,5
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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). CI: Confidence interval; RR: Risk ratio;
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.
¹ Serious indirectness. The trial enrolled both adults and children (>= 3 years), but it was unclear how many participants were children as data were not reported separately. ² Serious imprecision.The 95% CI of the pooled estimate includes appreciable benefit (<0.75) and non‐appreciable benefit (>= 0.75 and <=1.00) with atovaquone‐proguanil ³ Serious limitation in design (selective reporting bias). It is unclear if both adverse events and adverse effects for dermatological, gastrointestinal, and neuropsychiatric were measured, but only the adverse effects reported. ⁴ Serious indirectness. The trial enrolled only adults. ⁵ Serious limitation in design. High risk of bias due to incomplete outcome data (>10%). Some reasons for attrition and exclusion were likely to be related to true outcome (adverse events).

Summary of findings for the main comparison. Atovaquone‐proguanil compared to Mefloquine for Non immune child and adult travellers

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Summary of findings 2. Doxycycline compared to Mefloquine for Non Immune Child and Adult Travellers

Doxycycline compared to Mefloquine for Non Immune Child and Adult Travellers
Patient or population: Non Immune Child and Adult Travellers Settings: International travel Intervention: Doxycycline Comparison: Mefloquine
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Mefloquine	Doxycycline
Neuropsychiatric adverse event	688 per 1000	578 per 1000 (502 to 660)	RR 0.84 (0.73 to 0.96)	441 (2 studies)	⊕⊕⊝⊝ low^1,2
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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). CI: Confidence interval; RR: Risk ratio;
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.
¹ Serious indirectness. Both trials enrolled only adults. ² Serious imprecision. The 95% CI of the pooled estimate includes appreciable benefit (<0.75) and non‐appreciable benefit (>=0.75 and <=1.00) with doxycycline.

Summary of findings 2. Doxycycline compared to Mefloquine for Non Immune Child and Adult Travellers

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Summary of findings 3. Any standard drugs compared to Chloroquine‐proguanil for Non Immune Child and Adult Travellers

Any standard drugs compared to Chloroquine‐proguanil for Non Immune Child and Adult Travellers
Patient or population: Non Immune Child and Adult Travellers Settings: International travel Intervention: Any standard drugs Comparison: Chloroquine‐proguanil
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Chloroquine‐proguanil	Any standard drugs
Any adverse effect	338 per 1000	284 per 1000 (247 to 324)	RR 0.84 (0.73 to 0.96)	1530 (3 studies)	⊕⊝⊝⊝ very low^1,2,3
Gastrointestinal adverse effect	253 per 1000	180 per 1000 (152 to 215)	RR 0.71 (0.6 to 0.85)	1530 (3 studies)	⊕⊝⊝⊝ very low^2,3,4
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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). CI: Confidence interval; RR: Risk ratio;
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.
¹ Serious limitation in design. One trial is open label. In one trial, incomplete outcome data is largely >10% and it is unclear if mild and moderate side effects were measured but not reported in the results. ² Serious indirectness. One trial included children only, one trial adult soldiers, and one trial adults and children (>= 14 years). ³ Serious imprecision. The 95% CI of the pooled estimate includes appreciable benefit (<0.75) and non‐appreciable benefit (>=0.75 and <=1.00) with any standard drugs (atovaquone‐proguanil, doxycycline, mefloquine). ⁴ Serious limitation in design. One trial is open label. In one trial, incomplete outcome data is largely >10% and it is unclear if mild and moderate side effects were measured but not reported in the results. For the third trial, it is unclear if both adverse events and adverse effects for dermatological, gastrointestinal, and neuropsychiatric were measured, but only adverse effects reported.

Summary of findings 3. Any standard drugs compared to Chloroquine‐proguanil for Non Immune Child and Adult Travellers

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Comparison 1. Atovaquone‐proguanil vs doxycycline

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

1.1 Any adverse event	1	317	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.88, 1.08]
2 Dermatological adverse outcome Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Dermatological adverse event	1	317	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.58, 1.33]
3 Gastrointestinal adverse outcome Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Gastrointestinal adverse event	1	317	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.82, 1.25]
4 Neuropsychiatric adverse outcome Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Neuropsychiatric adverse event	1	317	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.83, 1.13]
5 Discontinuation of study drug for any reason Show forest plot	1	317	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.20, 2.73]

Comparison 1. Atovaquone‐proguanil vs doxycycline

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Comparison 2. Atovaquone‐proguanil vs mefloquine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any adverse outcome Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Any adverse event	2	1293	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.86, 1.14]
1.2 Any adverse effect	1	976	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.60, 0.85]
2 Dermatological adverse outcome Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Dermatological adverse event	1	317	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.58, 1.33]
2.2 Dermatological adverse effect	1	976	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.37, 1.66]
3 Gastrointestinal adverse outcome Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Gastrointestinal adverse event	1	317	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.76, 1.12]
3.2 Gastrointestinal adverse effect	1	976	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.42, 0.70]
4 Neuropsychiatric adverse outcome Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Neuropsychiatric adverse event	1	317	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.75, 0.99]
4.2 Neuropsychiatric adverse effect	1	976	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.38, 0.63]
5 Serious adverse event Show forest plot	2	1293	Risk Ratio (M‐H, Fixed, 95% CI)	0.39 [0.12, 1.24]

6 Discontinuation of study drug for any reason Show forest plot	2	1293	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.59, 1.06]

7 Total Mood Disturbance (TMD) scores Show forest plot	1	119	Mean Difference (IV, Fixed, 95% CI)	‐7.20 [‐10.79, ‐3.61]

Comparison 2. Atovaquone‐proguanil vs mefloquine

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Comparison 3. Doxycycline vs mefloquine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clinical cases of malaria Show forest plot	2	388	Risk Ratio (M‐H, Fixed, 95% CI)	3.04 [0.13, 73.42]

2 Any adverse outcome Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Any adverse event	2	441	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.90, 1.04]
3 Dermatological adverse outcome Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Dermatological adverse event	2	441	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.72, 1.28]
4 Gastrointestinal adverse outcome Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Gastrointestinal adverse event	2	441	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.68, 1.00]
4.2 Gastrointestinal adverse effect	1	253	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.79, 1.32]
5 Neuropsychiatric adverse outcome Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Neuropsychiatric adverse event	2	441	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.73, 0.96]
5.2 Neuropsychiatric adverse effect	1	253	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.25, 1.80]
6 Discontinuation of study drug for any reason Show forest plot	2	441	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.31, 1.46]

Comparison 3. Doxycycline vs mefloquine

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Comparison 4. Any standard drugs vs chloroquine‐proguanil

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Clinical cases of malaria Show forest plot	3	1853	Risk Ratio (M‐H, Fixed, 95% CI)	0.14 [0.01, 2.79]

2 Any adverse outcome Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Any adverse event	3	1866	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.90, 1.03]
2.2 Any adverse effect	3	1530	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.73, 0.96]
3 Dermatological adverse outcome Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Dermatological adverse event	1	623	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.63, 1.18]
3.2 Dermatological adverse effect	2	1309	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.67, 2.13]
4 Gastrointestinal adverse outcome Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Gastrointestinal adverse event	2	844	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.77, 1.03]
4.2 Gastrointestinal adverse effect	3	1530	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.60, 0.85]
5 Neuropsychiatric adverse outcome Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Neuropsychiatric adverse event	2	844	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.89, 1.13]
5.2 Neuropsychiatric adverse effect	3	1530	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.81, 1.27]
6 Serious adverse event Show forest plot	3	1866	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.32, 3.08]

7 Discontinuation of study drug for any reason Show forest plot	4	2490	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.75, 1.47]

Comparison 4. Any standard drugs vs chloroquine‐proguanil

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