Artesunate plus mefloquine versus mefloquine for treating uncomplicated malaria

Hasifa Bukirwa; Lois C Orton

doi:10.1002/14651858.CD004531.pub2

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Analysis 1.1

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 1 Treatment failure.

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Analysis 1.2

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 2 Parasitaemia.

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Analysis 1.3

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 3 Fever.

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Analysis 1.4

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 4 Mean fever clearance time (h).

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Analysis 1.5

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 5 Mean parasite clearance time (h).

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Analysis 1.6

Comparison 1 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 6 Adverse events.

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Analysis 2.1

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 1 Treatment failure.

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Analysis 2.2

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 2 Parasitaemia.

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Analysis 2.3

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 3 Fever.

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Analysis 2.4

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 4 Mean fever clearance time (h).

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Analysis 2.5

Comparison 2 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg), Outcome 5 Mean parasite clearance time (h).

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Analysis 3.1

Comparison 3 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 1 Parasitaemia.

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Analysis 3.2

Comparison 3 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 2 Fever.

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Analysis 3.3

Comparison 3 Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 3 Adverse event.

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Analysis 4.1

Comparison 4 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 1 Treatment failure.

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Analysis 4.2

Comparison 4 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 2 Parasitaemia.

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Analysis 4.3

Comparison 4 Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg), Outcome 3 Fever.

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Table 1. Detailed search strategies

Search set	CIDG SR^a	CENTRAL	MEDLINE^b	EMBASE^b	LILACS^b	BIOSIS
1	artesunate	artesunate	ARTESUNATE	ARTESUNATE	artesunate	artesunate
2	mefloquine	mefloquine	artesunate	artesunate	mefloquine	mefloquine
3	Lariam	Lariam	arsumax	arsumax	malaria	Lariam
4	—	2 or 3	1 or 2 or 3	1 or 2 or 3	1 and 2 and 3	—
5	—	1 and 4	MEFLOQUINE	mefloquine	—	—
6	—	—	mefloquine	MEFLOQUINE	—	—
7	—	—	Lariam	mephaquim	—	—
8	—	—	5 or 6 or 7	Lariam	—	—
9	—	—	4 and 8	5 or 6 or 7 or 8	—	—
10	—	—	exp MALARIA	4 and 9	—	—
11	—	—	malaria	malaria	—	—
12	—	—	exp PLASMODIUM	MALARIA	—	—
13	—	—	plasmodium	PLASMODIUM‐FALCIPARUM	—	—
14	—	—	10 or 11 or 12 or 13	11 or 12 or 13	—	—
15	—	—	9 and 14	10 and 14	—	—
^aCochrane Infectious Diseases Group Specialized Register. ^bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration Higgins 2005; upper case: MeSH or EMTREE heading; lower case: free text term.

Table 1. Detailed search strategies

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Table 2. Methods for future updates

Method	Details
Recrudesced and new infections	In areas of intense malaria transmission, blood smears positive for malaria parasites after day 14 may be a result of new infections or a recrudescence of the original infection. Polymerase chain reaction (PCR) is a method that can be used to differentiate between new and old infections. We will use the results of PCR analyses, if they become available, to differentiate between recrudesced and new infections
Continuous data reported with geometric means	We will extract the standard deviations on the log scale, and extract minimum and maximum values for medians. We will combine the findings on a log scale and report on the original scale; we will report medians and ranges in tables
Exploring potential sources of heterogeneity using subgroup analyses	1. Intervention: simultaneous versus sequential regimens; mefloquine dose; and artesunate dose 2. Trial setting: level of background mefloquine resistance; high malaria transmission (an area of hyperendemicity or holoendemicity) versus low transmission (an area of hypoendemicity or mesoendemicity) 3. Pre‐treatment malaria parasite density: < 250,000/µL or 5% of total red blood cells and at least 250,000/µL or 5% of total red blood cells 4. Age: ≤ 5 years and > 5 years
Sensitivity analyses	We will conduct sensitivity analyses for each of the components of methodological quality
Funnel plots	We will examine funnel plots for asymmetry, keeping in mind that the asymmetry could be caused by publication bias, differences in methodological quality, or heterogeneity

Table 2. Methods for future updates

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Table 3. Total dose and regimens: artesunate and mefloquine

Trial	Artesunate		Mefloquine
Trial	Total dose (mg/kg)	Regimen	Total dose (mg/kg)	Regimen
Karbwang 1994	3.33^a	1 dose	21^b	2 doses over 1 day
Looareesuwan 1992a	10	11 doses over 5 days	21^b	2 doses over 1 day
Marquino 2003	12	3 doses over 3 days	15	1 dose
Nosten 1994a	4	1 dose	25	1 dose
Nosten 1994b	10	4 doses over 3 days	25	1 dose
Price 1995	12	3 doses over 3 days	25	1 dose
Smithius 2004	4	1 dose	15	1 dose
Thimasarn 1997	10^a	2 doses over 2 days	21^b	2 doses over 3 days
^aAssuming 60 kg person (actual dose 200 mg). ^bAssuming 60 kg person (actual dose 1250 mg).

Table 3. Total dose and regimens: artesunate and mefloquine

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Table 4. Risk of bias assessment

Trial	Generation of allocation sequence^c	Allocation concealment^d	Blinding^e	Inclusion of all randomized participants in final analysis^b
Karbwang 1994	Unclear	Unclear	Unclear	Adequate
Looareesuwan 1992a	Unclear	Unclear	Unclear	Inadequate
Marquino 2003	Adequate	Unclear	Unclear	Inadequate
Nosten 1994a	Unclear	Unclear	Unclear	Inadequate
Nosten 1994b	Unclear	Unclear	Unclear	Inadequate
Smithius 2004	Unclear	Unclear	Unclear	Inadequate
Thimasarn 1997	Unclear	Unclear	Unclear	Adequate
Price 1998	Unclear	Unclear	Unclear	Inadequate
^aSee the 'Assessment of risk of bias in included studies' for the assessment methods, and the Characteristics of included studies' for the methods used in each trial. ^bFor primary outcomes. ^cUnclear: reported as random but method not revealed. ^dUnclear: not mentioned. ^eUnclear: unlikely to be blinded.

Table 4. Risk of bias assessment

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Comparison 1. Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg)

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

1.1 Day 28	4	824	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.06, 0.47]
1.2 Day 42	1	298	Risk Ratio (M‐H, Random, 95% CI)	0.23 [0.14, 0.39]
1.3 Day 63	2	501	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.09, 0.77]
2 Parasitaemia Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Day 3	2	716	Risk Ratio (M‐H, Fixed, 95% CI)	0.04 [0.02, 0.11]
2.2 Day 7	2	700	Risk Ratio (M‐H, Fixed, 95% CI)	0.02 [0.00, 0.11]
2.3 Day 14	1	339	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.03, 0.28]
3 Fever Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Day 2	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Mean fever clearance time (h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5 Mean parasite clearance time (h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

6 Adverse events Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 Serious adverse events	1	368	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 8.04]
6.2 Adverse events requiring discontinuation of treatment	2	444	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.04, 3.23]
6.3 Abdominal pain	2	196	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.31, 1.20]
6.4 Cardiovascular abnormalities	1	120	Risk Ratio (M‐H, Random, 95% CI)	1.95 [0.08, 46.79]
6.5 Central nervous system abnormalities	1	120	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.53, 1.36]
6.6 Diarrhoea	2	196	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.48, 2.77]
6.7 Dizziness	1	76	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.10, 1.24]
6.8 Headache	2	196	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.38, 0.69]
6.9 Itching and rash	1	76	Risk Ratio (M‐H, Random, 95% CI)	2.85 [0.12, 67.83]
6.10 Nausea	2	196	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.33, 1.16]
6.11 Palpitations/anxiety	1	368	Risk Ratio (M‐H, Random, 95% CI)	2.97 [0.12, 72.38]
6.12 Psychosis	1	654	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.01, 7.91]
6.13 Vomiting	4	1218	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.39, 1.62]
6.14 Other adverse events	1	120	Risk Ratio (M‐H, Random, 95% CI)	8.43 [0.49, 146.28]

Comparison 1. Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (25 mg)

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Comparison 2. Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg)

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

1.1 Day 28	2	259	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.50, 1.38]
1.2 Day 42	1	20	Risk Ratio (M‐H, Fixed, 95% CI)	2.67 [0.36, 19.71]
2 Parasitaemia Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.1 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Day 7	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 Day 14	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Fever Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Day 2	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Mean fever clearance time (h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5 Mean parasite clearance time (h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Comparison 2. Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (25 mg)

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Comparison 3. Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Parasitaemia Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Fever Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.1 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Adverse event Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.1 Insomnia	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 3. Artesunate (AS) (≥ 10 mg) plus mefloquine (MQ) versus MQ (15 mg)

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Comparison 4. Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg)

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

1.1 Day 14	1	149	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.35, 4.53]
1.2 Day 28	1	142	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.16, 1.21]
1.3 Day 42	1	147	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.48, 1.65]
2 Parasitaemia Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Day 3	1	156	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.14, 1.29]
3 Fever Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Day 3	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 4. Artesunate (AS) (4 mg) plus mefloquine (MQ) versus MQ (15 mg)

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