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Atovaquone-proguanil for treating uncomplicated malaria

  1. Alex Osei-Akoto1,*,
  2. Lois C Orton2,
  3. Shirley Owusu-Ofori3

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 21 JAN 2009

Assessed as up-to-date: 26 JUN 2005

DOI: 10.1002/14651858.CD004529.pub2

Database Title

Additional Information

How to Cite

Osei-Akoto A, Orton LC, Owusu-Ofori S. Atovaquone-proguanil for treating uncomplicated malaria. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD004529. DOI: 10.1002/14651858.CD004529.pub2.

Author Information

  1. 1

    Komfo Anokye Teaching Hospital, Department of Child Health, Kumasi, Ghana

  2. 2

    University of Manchester, School of Nursing, Midwifery and Social Work, Manchester, UK

  3. 3

    Komfo Anokye Teaching Hospital, Department of Medicine, Kumasi, Ghana

*Alex Osei-Akoto, Department of Child Health, Komfo Anokye Teaching Hospital, Kumasi, Ghana. oseiyakoto@hotmail.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 21 JAN 2009

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Characteristics of included studies [ordered by study ID]
Anabwani 1999
MethodsRandomized controlled trial

Length of follow up: 28 d

Generation of allocation sequence: random assignment of study number

Allocation concealment: unclear

Blinding: none

Inclusion of all randomized participants in the analysis: 164 analysed/168 randomized (97.6%)
ParticipantsNumber: 168 enrolled; 164 analysed; 4 discontinued intervention and were excluded

Age range: 3 to 12 years

Gender: male and female

Inclusion criteria: age 3 to 12 years; uncomplicated malaria; fever; parasitaemia between 1000 to 200,000 parasites/µL; ability to tolerate oral therapy; weight > 10 kg; written informed consent given by parent or guardian

Exclusion criteria: severe or cerebral malaria; prolonged QTc interval (above 0.44 s); mixed infections with other Plasmodium species;
concomitant disease
Interventions1. Atovaquone-proguanil (60 mg/kg atovaquone and 24 mg/kg proguanil over 3 d)
2. Halofantrine (24 mg/kg over 12 h)
Outcomes1. 28-d cure rate
2. Parasite clearance time
3. Fever clearance time
4. Adverse events
NotesLocation: Kenya

Drug resistance: not stated




Borrmann 2003
MethodsRandomized controlled trial

Length of follow up: 28 d

Generation of allocation sequence: blocks of 10 and sequentially assigned to groups

Allocation concealment: sealed envelopes

Blinding: none

Inclusion of all randomized participants in the final analysis: 170 analysed/200 randomized (85%)
ParticipantsNumber: 200 enrolled; 170 analysed, 92 for the atovaquone-proguanil group and 78 for amodiaquine group

Gender: male and female

Age range: 3 to 43 months

Inclusion criteria: documented uncomplicated falciparum malaria with parasitaemia between 1000 and 200,000 parasites/µL; weight between 5 kg and 11 kg; written or verbal informed consent by parent or guardian

Exclusion criteria: administration of antimalarials or medications with antimalarials or haemolytic effects with previous 7 d; underlying severe diseases or concomitant infections causing fever; hypersensitivity to atovaquone, proguanil, or amodiaquine; predefined abnormal laboratory values at screening; symptoms and signs of severe malaria
Interventions1. Atovaquone-proguanil (fixed dose combination containing 62.5 mg atovaquone and 25 mg proguanil for 3 d)
2. Amodiaquine (10 mg/kg of a 1% suspension of amodiaquine chlorohydrate once daily for 3 d)
Outcomes1. 28-d cure rate
2. Parasite clearance time
3. Fever clearance time
4. Adverse events
NotesLocation: Gabon

Drug resistance: not stated




Bouchaud 2000
MethodsRandomized controlled trial

Length of follow up: 35 d

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: none

Inclusion of all randomized participants in the final analysis: 41 analysed/48 randomized (85%)
ParticipantsNumber enrolled: 48

Age range: 15 to 65 years

Gender: male and female

Inclusion criteria: > 16 years old; had malaria from a short stay in an endemic country; non-immune individual; parasitaemia between 1000 and 100,000 parasites/µL

Exclusion criteria: severe malaria; prolonged QTc interval (above 0.44 s); presence of mixed infections with other Plasmodium species; presence of concomitant disease; inability to take oral treatment; history of syncope; pregnancy; breastfeeding mother; weighed < 40 kg; resided in an endemic area for the previous year
Interventions1. Atovaquone-proguanil (4 x 250 mg atovaquone and 4 x 100 mg proguanil as single daily dose for 3 d)
2. Halofantrine (total of 1500 mg in 3 doses of 500 mg 6 h apart)
Outcomes1. 28-d cure rate
2. Parasite clearance time
3. Fever clearance
NotesLocation: France

Drug resistance: difficult to say as malaria was imported




De Alencar 1997
MethodsRandomized controlled trial

Length of follow up: 28 d

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: none

Inclusion of all randomized participants in the final analysis: 154 analysed/175 randomized (88%)
ParticipantsNumber enrolled: 175

Age range: 18 to 65 years

Gender: male

Inclusion criteria: adult men; age 18 to 68 years; smear positive falciparum malaria; general good health; parasitaemia between 1000 and 100,000 parasites/µL

Exclusion criteria: grossly abnormal laboratory results; refusal to be hospitalized for 28 d; inability to tolerate study medication; missing study medication
Interventions1. Atovaquone plus proguanil (atovaquone 1 g and proguanil 400 mg daily for 3 d)
2. Quinine plus tetracycline (600 mg quinine 3 times a day and 250 mg tetracycline 4 times a day for 7 d)
Outcomes1. 28-d cure rate
2. Parasite clearance time
3. Fever clearance time
4. Adverse events
NotesLocation: Brazil

Drug resistance: high for chloroquine, sulfadoxine-pyrimethamine, and quinine to some extent




Giao 2004
MethodsRandomized controlled trial

Length of follow up: all followed up for 28 d; 92 participants followed up for 56 d

Generation of allocation sequence: codes were allocated in randomized blocks of 10

Allocation concealment: sealed envelope

Blinding: none

Inclusion of all randomized participants in the final analysis: 161 analysed/165 randomized (98%)
ParticipantsNumber enrolled: 165; 161 analysed; 4 excluded for P. vivax infection

Age range: 17 to 64 years for atovaquone-proguanil group; 16 to 73 years for dihydroartemisinin-piperaquine-trimethoprim-primaquine group

Gender: male and female; though slight difference in ratio

Inclusion criteria: uncomplicated falciparum malaria with parasitaemia > 1000 parasites/µL; age > 16 years

Exclusion criteria: pregnancy; lactation; complicated malaria; inability to take oral medication; known allergy to study drugs; verbal confirmation of taking artemisinin within 24 h, mefloquine/tetracycline/doxycycline in 7 days and quinine in previous 12 h
Interventions1. Atovaquone-proguanil (4 x 250 mg atovaquone and 4 x 100 mg proguanil) as single dose daily for 3 d
2. Dihydroartemisinin-piperaquine-trimethoprim-primaquine (2 x 32 mg dihydroartemisinin + 320 mg piperaquine phosphate + 90 mg trimethoprim + 5 mg primaquine phosphate at time 0, 8 h, 24 h, and 48 h
Outcomes1. Radical cure at d 28
2. Recrudescence (early and late)
3. Parasite clearance time
4. Fever clearance time
5. Adverse events
NotesLocation: Binh Thuan, south Viet Nam

Drug resistance: unclear




Llanos-Cuentas 2001
MethodsRandomized controlled trial

Length of follow up: 28 d

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: none

Inclusion of all randomized participants in the final analysis: 39 analysed/43 randomized (91%)
ParticipantsNumber enrolled: 43

Age range: 15 to 65 years

Gender: male and female

Inclusion criteria: age 12 to 65 years; presence of acute uncomplicated falciparum malaria; lifelong residents of the study area; parasitaemia between 1000 and 200,000 parasites/µL

Exclusion criteria: severe malaria; presence of mixed infections with other Plasmodium species; presence of concomitant disease; inability to take oral treatment; pregnancy; breastfeeding mother
Interventions1. Atovaquone plus proguanil (1000 mg atovaquone, 400 mg proguanil over 3 d)
2. Chloroquine (1500 mg over 3 d)
3. Sulfadoxine-pyrimethamine (1500 mg sulfadoxine and 75 mg pyrimethamine)
Outcomes1. 28-d cure rate
2. Parasite clearance time
3. Fever clearance time
4. Adverse events
NotesLocation: Peru

Drug resistance: high for chloroquine




Looareesuwan 1999a
MethodsRandomized controlled trial

Length of follow up: 28 d

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: none

Inclusion of all randomized participants in the final analysis: 158 analysed/182 randomized (87%)
ParticipantsNumber enrolled: 182

Age range: 15 to 63 years

Gender: male and female

Inclusion criteria: age 16 to 65 years; presence of acute uncomplicated falciparum malaria; parasitaemia between 1000 and 200,000/µL; weight 40 kg and above

Exclusion criteria: presence of mixed infections with other Plasmodium species; presence of concomitant disease (intercurrent febrile infections); inability to take oral treatment (persistent vomiting); pregnancy; breastfeeding mother
Interventions1. Atovaquone plus proguanil (1000 mg atovaquone and 400 mg proguanil daily over 3 d)
2. Mefloquine (1250 mg over 6 h)
Outcomes1. 28-d cure rate
2. Parasite clearance time
3. Fever clearance
NotesLocation: Thailand

Drug resistance: high for chloroquine and sulfadoxine-pyrimethamine




Mulenga 1999
MethodsRandomized controlled trial

Length of follow up: 28 d

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: none

Inclusion of all randomized participants in the final analysis: 160 analysed/163 randomized (98%)
ParticipantsNumber randomized: 163

Age range: 14 to 54 years

Gender: male and female (mainly male)

Inclusion criteria: age 12 to 65 years; presence of acute uncomplicated falciparum malaria; parasitaemia between 1000 and 200,000/µL; weight 40 kg and above; no underlying disease

Exclusion criteria: presence of mixed infections with other Plasmodium species; presence of concomitant disease (intercurrent febrile infections); inability to take oral treatment (persistent vomiting); pregnancy
breastfeeding mother
Interventions1. Atovaquone plus proguanil (1000 mg atovaquone and 400 mg proguanil daily over 3 d)
2. Sulfadoxine-pyrimethamine (1500 mg sulfadoxine and 75 mg pyrimethamine as single dose)
Outcomes1. 28-d cure rate
2. Parasite clearance time
3. Fever clearance time
NotesLocation: Zambia

Drug resistance: high for chloroquine




Radloff 1996
MethodsRandomized controlled trial

Length of follow up: 28 d

Generation of allocation sequence: participants given a sequential study number, which was randomly assigned to treatment option

Allocation concealment: unclear

Blinding: none

Inclusion of all randomized participants in the final analysis: 126 analysed/142 randomized (89%)
ParticipantsNumber enrolled: 142

Age range: 15 to 65 years

Gender: male and female (mainly male)

Inclusion criteria: age 15 to 65 years; presence of acute uncomplicated falciparum malaria; parasitaemia between 200 and 100,000 parasites/µL; weight 40 kg and above; urine test negative for chloroquine or sulphonamides

Exclusion criteria: severe malaria; presence of mixed infections with other Plasmodium species; presence of concomitant disease (intercurrent febrile infections); 2-week history of antimalarial administration; pregnancy; breastfeeding mother
Interventions1. Atovaquone plus proguanil (1000 mg atovaquone and 400 mg proguanil daily over 3 d)
2. Amodiaquine (1500 mg over 3 d: 600 mg on admission, 600 mg 24 h later, and 300 mg after a further 24 h)
Outcomes1. 28-d cure rate
2. Parasite clearance time
3. Fever clearance time
NotesLocation: Gabon

Drug resistance: high for chloroquine




Van Vugt 2002
MethodsRandomized controlled trial

Length of follow up: 42 d

Generation of allocation sequence: block randomization

Allocation concealment: sealed envelopes

Blinding: none

Inclusion of all randomized participants in the final analysis: 1063 analysed/1063 randomized (100%)
ParticipantsNumber enrolled:1063

Age range: 2 to 70 years

Gender: male and female

Inclusion criteria: age 2 to 70 years; slide confirmed acute uncomplicated falciparum malaria; weight > 10 kg; written informed consent by patient or guardian; not pregnant; not received mefloquine in the previous 63 d; not obtunded; not vomiting; no other clinical or laboratory signs of severe illness

Exclusion criteria: severe malaria; presence of mixed infections with other Plasmodium species; presence of concomitant disease (intercurrent febrile infections); 2-week history of antimalarial administration; pregnancy; breastfeeding mother
Interventions1. Atovaquone plus proguanil (atovaquone 15 mg/kg/d, proguanil 8 mg/kg/d for 3 d)
2. Artesunate plus mefloquine (artesunate 4 mg/kg/d for 3 d; mefloquine 15 mg/kg on day 1 and 10 mg/kg on day 2)

Participants with axillary temperature > 38 °C given antipyretics and cooled by tepid sponging before drug administration
Outcomes1. Incidence of microscopically and genetically confirmed recrudescent infections
2. Parasite clearance time
3. Fever clearance time
4. Adverse events
5. Degree of anaemia
NotesLocation: Thailand

Drug resistance: multiple-drug resistance except artemisinin derivatives


 
Characteristics of excluded studies [ordered by study ID]
StudyReason for exclusion
Bustos 1999Trial protocol initially randomized participants to receive chloroquine or atovaquone-proguanil. However, after 40 participants had been recruited, the cure rate for chloroquine was found to be < 35%, thus subsequent participants in the chloroquine arm were given sulfadoxine-pyrimethamine in addition. This ultimately resulted in a 3-arm study. Participants in the atovaquone-proguanil arm at the time of the protocol amendment should have been separated from those who were recruited after the amendment in order to make the comparisons


 
Comparison 1. Atovaquone-proguanil (AP) versus chloroquine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Treatment failure on or by day 281Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 2 Parasite clearance time (mean; h)1Mean Difference (IV, Fixed, 95% CI)Totals not selected
 3 Fever clearance time (mean; h)1Mean Difference (IV, Fixed, 95% CI)Totals not selected
 4 Adverse events1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
    4.1 Abdominal pain
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.2 Chills/rigors
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.3 Dizziness
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.4 Headache
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.5 Insomnia
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.6 Nausea
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.7 Palpitations
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.8 Pruritus
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.9 Severe
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.10 Vomiting
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.11 Weakness
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 
Comparison 2. Atovaquone-proguanil (AP) versus amodiaquine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Treatment failure on or by day 282342Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.13, 0.36]
 2 Treatment failure on or by day 141Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 3 Parasite clearance time (mean; h)1Mean Difference (IV, Fixed, 95% CI)Totals not selected
 4 Fever clearance time (mean; h)1Mean Difference (IV, Fixed, 95% CI)Totals not selected
 5 Adverse events2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
    5.1 Abdominal pain
1126Risk Ratio (M-H, Fixed, 95% CI)2.8 [1.07, 7.31]
    5.2 Diarrhoea
2326Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.57, 1.61]
    5.3 Dizziness
1126Risk Ratio (M-H, Fixed, 95% CI)0.27 [0.08, 0.93]
    5.4 Insomnia
1126Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.12, 0.75]
    5.5 Nausea
1126Risk Ratio (M-H, Fixed, 95% CI)2.63 [1.26, 5.48]
    5.6 Pruritus
1126Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.04, 0.35]
    5.7 Respiratory infections
1200Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.62, 14.51]
    5.8 Vomiting
2326Risk Ratio (M-H, Fixed, 95% CI)1.39 [0.80, 2.41]
    5.9 Weakness
2326Risk Ratio (M-H, Fixed, 95% CI)0.12 [0.02, 0.64]
    5.10 Any event
1200Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.82, 1.51]
 
Comparison 3. Atovaquone-proguanil (AP) versus sulfadoxine-pyrimethamine (SP)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Treatment failure on or by day 282Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 2 Parasite clearance time (mean; h)2174Mean Difference (IV, Fixed, 95% CI)11.23 [5.43, 17.03]
 3 Fever clearance time (mean; h)2156Mean Difference (IV, Fixed, 95% CI)-13.73 [-21.31, -6.16]
 4 Progression to severe disease1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 5 Adverse events2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
    5.1 Abdominal pain
2189Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.58, 1.24]
    5.2 Chills/rigors
129Risk Ratio (M-H, Fixed, 95% CI)1.43 [0.06, 32.05]
    5.3 Diarrhoea
1160Risk Ratio (M-H, Fixed, 95% CI)43.0 [2.65, 697.91]
    5.4 Dizziness
129Risk Ratio (M-H, Fixed, 95% CI)1.43 [0.06, 32.05]
    5.5 Headache
2189Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.81, 1.67]
    5.6 Insomnia
129Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.09, 1.21]
    5.7 Nausea
129Risk Ratio (M-H, Fixed, 95% CI)2.25 [0.31, 16.59]
    5.8 Orthostatic hypotension
1160Risk Ratio (M-H, Fixed, 95% CI)0.03 [0.00, 0.57]
    5.9 Pruritus
129Risk Ratio (M-H, Fixed, 95% CI)0.16 [0.01, 3.56]
    5.10 Raised liver enzymes
1160Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.25, 1.79]
    5.11 Severe
129Risk Ratio (M-H, Fixed, 95% CI)1.43 [0.06, 32.05]
    5.12 Vomiting
2189Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.50, 1.90]
    5.13 Weakness
2189Risk Ratio (M-H, Fixed, 95% CI)1.47 [0.82, 2.62]
 
Comparison 4. Atovaquone-proguanil (AP) versus quinine plus tetracycline (Q plus T)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Treatment failure on or by day 281Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 2 Parasite clearance time (mean; h)1Mean Difference (IV, Fixed, 95% CI)Totals not selected
 3 Fever clearance time (mean; h)1Mean Difference (IV, Fixed, 95% CI)Totals not selected
 4 Adverse events1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
    4.1 Abdominal pain
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.2 Anorexia
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.3 Diarrhoea
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.4 Dizziness
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.5 Headache
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.6 Nausea
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.7 Pruritus
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.8 Tinnitus
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.9 Vomiting
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.10 Weakness
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 
Comparison 5. Atovaquone-proguanil (AP) versus halofantrine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Treatment failure on or by day 282Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 2 Parasite clearance time (mean; h)2205Mean Difference (IV, Fixed, 95% CI)14.76 [10.41, 19.10]
 3 Fever clearance time (mean; h)2205Mean Difference (IV, Fixed, 95% CI)-1.70 [-9.41, 6.02]
 4 Adverse events2Risk Ratio (M-H, Random, 95% CI)Subtotals only
    4.1 Abdominal pain
2216Risk Ratio (M-H, Random, 95% CI)0.81 [0.14, 4.68]
    4.2 Chills/Rigors
1168Risk Ratio (M-H, Random, 95% CI)0.67 [0.11, 3.89]
    4.3 Cough
1168Risk Ratio (M-H, Random, 95% CI)0.71 [0.34, 1.52]
    4.4 Diarrhoea
2216Risk Ratio (M-H, Random, 95% CI)0.57 [0.23, 1.39]
    4.5 Headache
2216Risk Ratio (M-H, Random, 95% CI)1.09 [0.17, 6.84]
    4.6 Insomnia
2216Risk Ratio (M-H, Random, 95% CI)0.62 [0.15, 2.60]
    4.7 Moderate or severe
1168Risk Ratio (M-H, Random, 95% CI)0.38 [0.15, 0.91]
    4.8 Myalgia
1168Risk Ratio (M-H, Random, 95% CI)0.14 [0.01, 2.72]
    4.9 Nausea
148Risk Ratio (M-H, Random, 95% CI)2.76 [0.62, 12.33]
    4.10 Palpitations
1168Risk Ratio (M-H, Random, 95% CI)0.5 [0.05, 5.41]
    4.11 Pruritus
2216Risk Ratio (M-H, Random, 95% CI)1.20 [0.51, 2.87]
    4.12 Vomiting
2216Risk Ratio (M-H, Random, 95% CI)3.47 [0.66, 18.43]
    4.13 Weakness
1168Risk Ratio (M-H, Random, 95% CI)0.25 [0.03, 2.19]
 
Comparison 6. Atovaquone-proguanil (AP) versus mefloquine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Treatment failure on or by day 281Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 2 Parasite clearance time (mean; h)1Mean Difference (IV, Fixed, 95% CI)Totals not selected
 3 Fever clearance time (mean; h)1Mean Difference (IV, Fixed, 95% CI)Totals not selected
 4 Adverse events1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
    4.1 Abdominal pain
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.2 Anaemia
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.3 Diarrhoea
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.4 Dizziness
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.5 Headache
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.6 Insomnia
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.7 Nausea
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.8 Raised liver enzymes
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.9 Sore throat
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.10 Vomiting
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.11 Any event
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 
Comparison 7. Atovaquone-proguanil (AP) versus artesunate plus mefloquine (AS plus MQ)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Treatment failure on or by day 141Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 2 Treatment failure on or by day 28 adjusted by PCR1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 3 Adverse events1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
    3.1 Anorexia
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    3.2 Dizziness
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    3.3 Nausea
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    3.4 Palpitations
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    3.5 Skin rash
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    3.6 Sleeping disorders
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    3.7 Tremor
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    3.8 Vomiting
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 
Comparison 8. Atovaquone-proguanil (AP) versus dihydroartemisinin, piperaquine, trimethoprim, and primaquine (CV8)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
 1 Treatment failure on or by day 281Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
 2 Parasite clearance time (mean; h)1Mean Difference (IV, Fixed, 95% CI)Totals not selected
 3 Fever clearance time (mean; h)1Mean Difference (IV, Fixed, 95% CI)Totals not selected
 4 Adverse events1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
    4.1 Diarrhoea
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.2 Dry mouth
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.3 Headache
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.4 Itch
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
    4.5 Vomiting
1Risk Ratio (M-H, Fixed, 95% CI)Not estimable
 
Table 1. Risk of bias assessment
TrialAllocation sequence generationAllocation concealmentBlindingInclusiona
Anabwani 1999UnclearUnclearNoneAdequate
Borrmann 2003AdequateAdequateNoneInadequate
Bouchaud 2000UnclearUnclearNoneInadequate
De Alencar 1997UnclearUnclearNoneInadequate
Giao 2004AdequateAdequateNoneAdequate
Llanos-Cuentas 2001UnclearUnclearNoneAdequate
Looareesuwan 1999aUnclearUnclearNoneInadequate
Mulenga 1999UnclearUnclearNoneAdequate
Radloff 1996AdequateUnclearNoneInadequate
Van Vugt 2002AdequateAdequateNoneAdequate
 aSee the 'Characteristics of included studies' for details.
bInclusion of all randomized participants in the final analysis.
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