Atovaquone‐proguanil for treating uncomplicated malaria

Alex Osei‐Akoto; Lois C Orton; Shirley Owusu‐Ofori

doi:10.1002/14651858.CD004529.pub2

Atovacuona‐proguanil para el tratamiento del paludismo no complicado

Contraer todo Desplegar todo

Referencias

Referencias de los estudios incluidos en esta revisión

Ir a:

estudios excluidos
otras referencias

Anabwani G, Canfield CJ, Hutchinson DB. Combination atovquone and proguanil hydrochloride vs. halofantrine for treatment of acute Plasmodium falciparum malaria in children. Pediatric Infectious Disease Journal 1999;18(5):456‐61.

Borrmann S, Faucher J‐F, Bagaphou T, Missinou MA, Binder RK, Pabisch S, et al. Atovaquone and proguanil versus amodiaquine for the treatment of Plasmodium falciparum malaria in African infants and young children. Clinical Infectious Diseases 2003;37(11):1441‐7.

Bouchaud O, Monlun E, Muanza K, Fontanet A, Scott T, Goetschel A, et al. Atovaquone plus proguanil versus halofantrine for the treatment of imported acute uncomplicated Plasmodium falciparum malaria in non‐immune adults: a randomized comparative trial. American Journal of Tropical Medicine and Hygiene 2000;63(5‐6):274‐9.

de Alencar FE, Cerutti C, Durlacher RR, Boulos M, Alves FP, Milhous W, et al. Atovaquone and proguanil for the treatment of malaria in Brazil. Journal of Infectious Diseases 1997;175(6):1544‐7.

Giao PT, de Vries PJ, Hung le Q, Binh TQ, Nam NV, Kager PA. CV8, a new combination of dihydroartemisinin, piperaquine, trimethoprim and primaquine, compared with atovaquone‐proguanil against falciparum malaria in Vietnam. Tropical Medicine and International Health 2004;9(2):209‐16.

Llanos‐Cuentas A, Campos P, Clendenes M, Canfield CJ, Hutchinson DB. Atovaquone and proguanil hydrochloride compared with chloroquine or pyrimethamine/sulfadoxine for treatment of acute Plasmodium falciparum malaria in Peru. Brazilian Journal of Infectious Diseases 2001;5(2):67‐72.

Google Scholar

Looareesuwan S, Wilairatana P, Chalermarut K, Rattanapong Y, Canfield CJ, Hutchinson DB. Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand. American Journal of Tropical Medicine and Hygiene 1999;60(4):526‐32.

Mulenga M, Sukwa TY, Canfield CJ, Hutchinson DB. Atovaquone and proguanil versus pyrimethamine/sulfadoxine for the treatment of acute falciparum malaria in Zambia. Clinical Therapeutics 1999;21(5):841‐52.

Radloff PD, Philipps J, Nkeyi M, Hutchinson D, Kremsner PG. Atovaquone and proguanil for Plasmodium falciparum malaria. Lancet 1996;347(9014):1511‐4.

van Vugt M, Leonardi E, Phaipun L, Slight T, Thway KL, McGready R, et al. Treatment of uncomplicated multidrug‐resistant falciparum malaria with artesunate‐atovaquone‐proguanil. Clinical Infectious Diseases 2002;35(12):1498‐504.

Referencias de los estudios excluidos de esta revisión

Ir a:

estudios incluidos
otras referencias

Bustos DG, Canfield CJ, Canete‐Miguel E, Hutchinson DB. Atovaquone‐proguanil compared with chloroquine‐sulfadoxine‐pyrimethamine for treatment of acute Plasmodium falciparum malaria in the Philippines. The Journal of Infectious Diseases 1999;179(6):1587‐90.

Referencias adicionales

Ir a:

estudios incluidos
estudios excluidos

Beerahee M. Clinical pharmacology of atovaquone and proguanil hydrochloride (http://www.malarone.com/hcp/clinical.html). Journal of Travel Medicine1999; Vol. 6 Suppl 1.

Google Scholar

Blanchard TJ, Mabey DC, Hunt‐Cooke A, Edwards G, Hutchinson DB, Benjamin S, et al. Multiresistant falciparum malaria cured using atovaquone and proguanil. Transactions of the Royal Society of Tropical Medicine and Hygiene 1994;88(6):693.

Bloland PB, Kazembe PN, Watkins WM, Doumbo OK, Nwanyanwu OC, Ruebush TK. Malarone‐donation programme in Africa. Lancet 1997;350(9091):1624‐5.

Brockman A, Paul RE, Anderson TJ, Hackford I, Phaiphun L, Looareesuwan S, et al. Application of genetic markers to the identification of recrudescent Plasmodium falciparum infections on the northwestern border of Thailand. American Journal of Tropical Medicine and Hygiene 1999;60(1):14‐21.

Canfield CJ, Pudney M, Gutteridge WE. Interactions of atovaquone with other antimalarial drugs agaist Plasmodium falciparum in vitro. Experimental Parasitology 1995;80(3):373‐81.

Dollery C, editor. Poguanil hydrochloride. Therapeutic Drugs. 2nd Edition. Vol. 2, New York: Churchill Livingstone, 1991:247‐51.

Google Scholar

Foege WH. Malarone‐donation programme. The Lancet 1997;350:1628‐9.

Fry M, Pudney M. Site of action of the antimalarial hydroxynaphttoquinone, 2‐[trans‐4‐(4'‐chlophenyl) cyclohexyl]‐3‐hydroxy‐1, 4 naphthoquinone (566C80). Biochemical Pharmarmacology 1992;43(7):1545‐53.

Higgins J, Green S, editors. Highly sensitive search strategies for identifying reports of randomized controlled trials in MEDLINE. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 [updated May 2005]; Appendix 5b. http://www.cochrane.org/resources/handbook/index.htm (accessed 10 August 2005).

Hogh B, Clarke PD, Camus D, Nothdurft HD, Overbosch D, Gunther M, et al. Malarone International Study Team. Atovaquone‐proguanil versus chloroquine‐proguanil for malaria prophylaxis in non‐immune travellers: a randomised, double‐blind study. Lancet 2000;356(9245):1888‐94.

Jüni P, Altman DG, Egger M. Systematic reviews in health care: Assessing the quality of controlled clinical trials. BMJ 2001;323(7303):42‐6.

Kamya MR, Bakyaita NN, Talisuna AO, Were WM, Staedke SG. Increasing antimalarial drug resistance in Uganda and revision of the national drug policy. Tropical Medicine and International Health 2002;7(12):1031‐41.

Looareesuwan S, Viravan C, Webster HK, Kyle DE, Hutchinson DB, Canfield CJ. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. American Journal of Tropical Medicine and Hygiene 1996;54(1):62‐6.

Looareesuwan S, Chulay JD, Canfield CJ, Hutchinson DB. Malarone (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Malarone Clinical Trials Study Group. American Journal of Tropical Medicine and Hygiene 1999;60(4):533‐41.

Ohrt C, Mirabelli‐Primdahl L, Karnasuta C, Chantakulkij S, Kain KC. Distinguishing Plasmodium falciparum treatment failures from reinfections by restriction fragment length polymorphism and polymerase chain reaction genotyping. American Journal of Tropical Medicine and Hygiene 1997;57(4):430‐7.

Overbosch D, Schilthuis H, Bienzle U, Behrens RH, Kain KC, Clarke PD, et al. Atovaquone‐proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double‐blind study. Clinical Infectious Diseases 2001;33(7):1015‐21.

Oyediran AB, Ddumba EM, Ochola SA, Lucas AO, Koporc K, Dowdle WR. A public‐private partnership for malaria control: lessons from the Malarone Donation Programme. Bulletin of the World Health Organization 2002;80(10):817‐21.

Initiative on Public‐Private Partnerships for Health. Malarone Donation Program (Historical). www.ippph.org/data/abstract.cfm?id=28 (accessed 16 July 2002).

Global Partnership to Roll Back Malaria. The use of antimalarial drugs: report of an WHO informal consultation, 13‐17 November 2000. Geneva: World Health Organization, 2001:17.

Global Partnership to Roll Back Malaria. The use of antimalarial drugs: report of an WHO informal consultation, 13‐17 November 2000. Geneva: World Health Organization, 2001:32.

Global Partnership to Roll Back Malaria. World malaria report: 2005. Geneva: World Health Organization, 2005.

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008.

Ringwald P, Basco LK. Malarone‐donation programme in Africa. Lancet 1998;351(9103):673‐4.

Sabchareon A, Attanath P, Phanuaksook P, Chanthavanich P, Poonpanich Y, Mookmanee D, et al. Efficacy and pharmacokinetics of atovaquone and proguanil in children with multidrug‐resistant Plasmodium falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 1998;92(2):201‐6.

Shretta R, Brugha R, Robb A, Snow RW. Sustainability, affordability, and equity of corporate drug donations: the case of Malarone. Lancet 2000;355(9216):1718‐20.

Shretta R, Walt G, Brugha R, Snow RW. A political analysis of corporate drug donations: the example of Malarone in Kenya. Health Policy and Planning 2001;16(2):161‐70.

Stepniewska K, Taylor WR, Mayxay M, Price R, Smithuis F, Guthmann JP, et al. In vivo assessment of drug efficacy against Plasmodium falciparum malaria: duration of follow‐up. Antimicrobial Agents and Chemotherapy 2004;48(11):4271‐80.

Sukwa TY, Mulenga M, Chisdaka N, Roskell NS, Scott TR. A randomised, double‐blind, placebo‐controlled field trial to determine the efficacy and safety of Malarone (atovaquone/proguanil) for prophylaxis of malaria in Zambia. American Journal of Tropical Medicine and Hygiene 1999;60(4):521‐5.

World Health Organization. The world health report: 1999: Making a difference. Geneva: World Health Organization, 1999:1.

World Health Organization. Severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 2000;94(1):1‐10.

PubMed

World Health Organization. Training manual for management of malaria at district level, facilitator's guide. Harare: World Health Organization (Regional Office for Africa), 2001:4‐6.

World Health Organization. Malaria Control Unit. The Africa malaria report 2003. Geneva: World Health Organization, 2003:19.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ir a:

estudios excluidos

Anabwani 1999

Methods	Randomized 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%)
Participants	Number: 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
Interventions	1. Atovaquone‐proguanil (60 mg/kg atovaquone and 24 mg/kg proguanil over 3 d) 2. Halofantrine (24 mg/kg over 12 h)
Outcomes	1. 28‐d cure rate 2. Parasite clearance time 3. Fever clearance time 4. Adverse events
Notes	Location: Kenya Drug resistance: not stated

Borrmann 2003

Methods	Randomized 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%)
Participants	Number: 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
Interventions	1. 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)
Outcomes	1. 28‐d cure rate 2. Parasite clearance time 3. Fever clearance time 4. Adverse events
Notes	Location: Gabon Drug resistance: not stated

Bouchaud 2000

Methods	Randomized 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%)
Participants	Number 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
Interventions	1. 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)
Outcomes	1. 28‐d cure rate 2. Parasite clearance time 3. Fever clearance
Notes	Location: France Drug resistance: difficult to say as malaria was imported

De Alencar 1997

Methods	Randomized 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%)
Participants	Number 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
Interventions	1. 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)
Outcomes	1. 28‐d cure rate 2. Parasite clearance time 3. Fever clearance time 4. Adverse events
Notes	Location: Brazil Drug resistance: high for chloroquine, sulfadoxine‐pyrimethamine, and quinine to some extent

Giao 2004

Methods	Randomized 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%)
Participants	Number 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
Interventions	1. 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
Outcomes	1. Radical cure at d 28 2. Recrudescence (early and late) 3. Parasite clearance time 4. Fever clearance time 5. Adverse events
Notes	Location: Binh Thuan, south Viet Nam Drug resistance: unclear

Llanos‐Cuentas 2001

Methods	Randomized 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%)
Participants	Number 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
Interventions	1. 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)
Outcomes	1. 28‐d cure rate 2. Parasite clearance time 3. Fever clearance time 4. Adverse events
Notes	Location: Peru Drug resistance: high for chloroquine

Looareesuwan 1999a

Methods	Randomized 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%)
Participants	Number 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
Interventions	1. Atovaquone plus proguanil (1000 mg atovaquone and 400 mg proguanil daily over 3 d) 2. Mefloquine (1250 mg over 6 h)
Outcomes	1. 28‐d cure rate 2. Parasite clearance time 3. Fever clearance
Notes	Location: Thailand Drug resistance: high for chloroquine and sulfadoxine‐pyrimethamine

Mulenga 1999

Methods	Randomized 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%)
Participants	Number 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
Interventions	1. 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)
Outcomes	1. 28‐d cure rate 2. Parasite clearance time 3. Fever clearance time
Notes	Location: Zambia Drug resistance: high for chloroquine

Radloff 1996

Methods	Randomized 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%)
Participants	Number 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
Interventions	1. 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)
Outcomes	1. 28‐d cure rate 2. Parasite clearance time 3. Fever clearance time
Notes	Location: Gabon Drug resistance: high for chloroquine

Van Vugt 2002

Methods	Randomized 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%)
Participants	Number 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
Interventions	1. 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
Outcomes	1. Incidence of microscopically and genetically confirmed recrudescent infections 2. Parasite clearance time 3. Fever clearance time 4. Adverse events 5. Degree of anaemia
Notes	Location: Thailand Drug resistance: multiple‐drug resistance except artemisinin derivatives

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study

Reason for exclusion

Bustos 1999

Trial 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

Data and analyses

Open in table viewer

Comparison 1. Atovaquone‐proguanil (AP) versus chloroquine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 28 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.1 Comparison 1 Atovaquone‐proguanil (AP) versus chloroquine, Outcome 1 Treatment failure on or by day 28.
2 Parasite clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.2 Comparison 1 Atovaquone‐proguanil (AP) versus chloroquine, Outcome 2 Parasite clearance time (mean; h).
3 Fever clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.3 Comparison 1 Atovaquone‐proguanil (AP) versus chloroquine, Outcome 3 Fever clearance time (mean; h).
4 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.4 Comparison 1 Atovaquone‐proguanil (AP) versus chloroquine, Outcome 4 Adverse events.
4.1 Abdominal pain	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Chills/rigors	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Dizziness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 Headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.5 Insomnia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.6 Nausea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.7 Palpitations	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.8 Pruritus	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.9 Severe	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.10 Vomiting	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.11 Weakness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Open in table viewer

Comparison 2. Atovaquone‐proguanil (AP) versus amodiaquine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 28 Show forest plot	2	342	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.13, 0.36]
Open in figure viewer Analysis 2.1 Comparison 2 Atovaquone‐proguanil (AP) versus amodiaquine, Outcome 1 Treatment failure on or by day 28.
2 Treatment failure on or by day 14 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.2 Comparison 2 Atovaquone‐proguanil (AP) versus amodiaquine, Outcome 2 Treatment failure on or by day 14.
3 Parasite clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.3 Comparison 2 Atovaquone‐proguanil (AP) versus amodiaquine, Outcome 3 Parasite clearance time (mean; h).
4 Fever clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.4 Comparison 2 Atovaquone‐proguanil (AP) versus amodiaquine, Outcome 4 Fever clearance time (mean; h).
5 Adverse events Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 2.5 Comparison 2 Atovaquone‐proguanil (AP) versus amodiaquine, Outcome 5 Adverse events.
5.1 Abdominal pain	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	2.8 [1.07, 7.31]
5.2 Diarrhoea	2	326	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.57, 1.61]
5.3 Dizziness	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.08, 0.93]
5.4 Insomnia	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.12, 0.75]
5.5 Nausea	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	2.63 [1.26, 5.48]
5.6 Pruritus	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.04, 0.35]
5.7 Respiratory infections	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.62, 14.51]
5.8 Vomiting	2	326	Risk Ratio (M‐H, Fixed, 95% CI)	1.39 [0.80, 2.41]
5.9 Weakness	2	326	Risk Ratio (M‐H, Fixed, 95% CI)	0.12 [0.02, 0.64]
5.10 Any event	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.82, 1.51]

Open in table viewer

Comparison 3. Atovaquone‐proguanil (AP) versus sulfadoxine‐pyrimethamine (SP)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 28 Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 3.1 Comparison 3 Atovaquone‐proguanil (AP) versus sulfadoxine‐pyrimethamine (SP), Outcome 1 Treatment failure on or by day 28.
2 Parasite clearance time (mean; h) Show forest plot	2	174	Mean Difference (IV, Fixed, 95% CI)	11.23 [5.43, 17.03]
Open in figure viewer Analysis 3.2 Comparison 3 Atovaquone‐proguanil (AP) versus sulfadoxine‐pyrimethamine (SP), Outcome 2 Parasite clearance time (mean; h).
3 Fever clearance time (mean; h) Show forest plot	2	156	Mean Difference (IV, Fixed, 95% CI)	‐13.73 [‐21.31, ‐6.16]
Open in figure viewer Analysis 3.3 Comparison 3 Atovaquone‐proguanil (AP) versus sulfadoxine‐pyrimethamine (SP), Outcome 3 Fever clearance time (mean; h).
4 Progression to severe disease Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 3.4 Comparison 3 Atovaquone‐proguanil (AP) versus sulfadoxine‐pyrimethamine (SP), Outcome 4 Progression to severe disease.
5 Adverse events Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
Open in figure viewer Analysis 3.5 Comparison 3 Atovaquone‐proguanil (AP) versus sulfadoxine‐pyrimethamine (SP), Outcome 5 Adverse events.
5.1 Abdominal pain	2	189	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.58, 1.24]
5.2 Chills/rigors	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.06, 32.05]
5.3 Diarrhoea	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	43.0 [2.65, 697.91]
5.4 Dizziness	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.06, 32.05]
5.5 Headache	2	189	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.81, 1.67]
5.6 Insomnia	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.09, 1.21]
5.7 Nausea	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	2.25 [0.31, 16.59]
5.8 Orthostatic hypotension	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	0.03 [0.00, 0.57]
5.9 Pruritus	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.16 [0.01, 3.56]
5.10 Raised liver enzymes	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.25, 1.79]
5.11 Severe	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.06, 32.05]
5.12 Vomiting	2	189	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.50, 1.90]
5.13 Weakness	2	189	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.82, 2.62]

Open in table viewer

Comparison 4. Atovaquone‐proguanil (AP) versus quinine plus tetracycline (Q plus T)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 28 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 4.1 Comparison 4 Atovaquone‐proguanil (AP) versus quinine plus tetracycline (Q plus T), Outcome 1 Treatment failure on or by day 28.
2 Parasite clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 4.2 Comparison 4 Atovaquone‐proguanil (AP) versus quinine plus tetracycline (Q plus T), Outcome 2 Parasite clearance time (mean; h).
3 Fever clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 4.3 Comparison 4 Atovaquone‐proguanil (AP) versus quinine plus tetracycline (Q plus T), Outcome 3 Fever clearance time (mean; h).
4 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 4.4 Comparison 4 Atovaquone‐proguanil (AP) versus quinine plus tetracycline (Q plus T), Outcome 4 Adverse events.
4.1 Abdominal pain	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Anorexia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Diarrhoea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 Dizziness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.5 Headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.6 Nausea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.7 Pruritus	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.8 Tinnitus	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.9 Vomiting	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.10 Weakness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Open in table viewer

Comparison 5. Atovaquone‐proguanil (AP) versus halofantrine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 28 Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 5.1 Comparison 5 Atovaquone‐proguanil (AP) versus halofantrine, Outcome 1 Treatment failure on or by day 28.
2 Parasite clearance time (mean; h) Show forest plot	2	205	Mean Difference (IV, Fixed, 95% CI)	14.76 [10.41, 19.10]
Open in figure viewer Analysis 5.2 Comparison 5 Atovaquone‐proguanil (AP) versus halofantrine, Outcome 2 Parasite clearance time (mean; h).
3 Fever clearance time (mean; h) Show forest plot	2	205	Mean Difference (IV, Fixed, 95% CI)	‐1.70 [‐9.41, 6.02]
Open in figure viewer Analysis 5.3 Comparison 5 Atovaquone‐proguanil (AP) versus halofantrine, Outcome 3 Fever clearance time (mean; h).
4 Adverse events Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 5.4 Comparison 5 Atovaquone‐proguanil (AP) versus halofantrine, Outcome 4 Adverse events.
4.1 Abdominal pain	2	216	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.14, 4.68]
4.2 Chills/Rigors	1	168	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.11, 3.89]
4.3 Cough	1	168	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.34, 1.52]
4.4 Diarrhoea	2	216	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.23, 1.39]
4.5 Headache	2	216	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.17, 6.84]
4.6 Insomnia	2	216	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.15, 2.60]
4.7 Moderate or severe	1	168	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.15, 0.91]
4.8 Myalgia	1	168	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.72]
4.9 Nausea	1	48	Risk Ratio (M‐H, Random, 95% CI)	2.76 [0.62, 12.33]
4.10 Palpitations	1	168	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.05, 5.41]
4.11 Pruritus	2	216	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.51, 2.87]
4.12 Vomiting	2	216	Risk Ratio (M‐H, Random, 95% CI)	3.47 [0.66, 18.43]
4.13 Weakness	1	168	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.03, 2.19]

Open in table viewer

Comparison 6. Atovaquone‐proguanil (AP) versus mefloquine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 28 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 6.1 Comparison 6 Atovaquone‐proguanil (AP) versus mefloquine, Outcome 1 Treatment failure on or by day 28.
2 Parasite clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 6.2 Comparison 6 Atovaquone‐proguanil (AP) versus mefloquine, Outcome 2 Parasite clearance time (mean; h).
3 Fever clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 6.3 Comparison 6 Atovaquone‐proguanil (AP) versus mefloquine, Outcome 3 Fever clearance time (mean; h).
4 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 6.4 Comparison 6 Atovaquone‐proguanil (AP) versus mefloquine, Outcome 4 Adverse events.
4.1 Abdominal pain	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Anaemia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Diarrhoea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 Dizziness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.5 Headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.6 Insomnia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.7 Nausea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.8 Raised liver enzymes	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.9 Sore throat	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.10 Vomiting	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.11 Any event	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Open in table viewer

Comparison 7. Atovaquone‐proguanil (AP) versus artesunate plus mefloquine (AS plus MQ)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 14 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 7.1 Comparison 7 Atovaquone‐proguanil (AP) versus artesunate plus mefloquine (AS plus MQ), Outcome 1 Treatment failure on or by day 14.
2 Treatment failure on or by day 28 adjusted by PCR Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 7.2 Comparison 7 Atovaquone‐proguanil (AP) versus artesunate plus mefloquine (AS plus MQ), Outcome 2 Treatment failure on or by day 28 adjusted by PCR.
3 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 7.3 Comparison 7 Atovaquone‐proguanil (AP) versus artesunate plus mefloquine (AS plus MQ), Outcome 3 Adverse events.
3.1 Anorexia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Dizziness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Nausea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.4 Palpitations	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.5 Skin rash	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.6 Sleeping disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.7 Tremor	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.8 Vomiting	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Open in table viewer

Comparison 8. Atovaquone‐proguanil (AP) versus dihydroartemisinin, piperaquine, trimethoprim, and primaquine (CV8)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 28 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 8.1 Comparison 8 Atovaquone‐proguanil (AP) versus dihydroartemisinin, piperaquine, trimethoprim, and primaquine (CV8), Outcome 1 Treatment failure on or by day 28.
2 Parasite clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 8.2 Comparison 8 Atovaquone‐proguanil (AP) versus dihydroartemisinin, piperaquine, trimethoprim, and primaquine (CV8), Outcome 2 Parasite clearance time (mean; h).
3 Fever clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 8.3 Comparison 8 Atovaquone‐proguanil (AP) versus dihydroartemisinin, piperaquine, trimethoprim, and primaquine (CV8), Outcome 3 Fever clearance time (mean; h).
4 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 8.4 Comparison 8 Atovaquone‐proguanil (AP) versus dihydroartemisinin, piperaquine, trimethoprim, and primaquine (CV8), Outcome 4 Adverse events.
4.1 Diarrhoea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Dry mouth	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 Itch	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.5 Vomiting	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Analysis 1.1

Comparison 1 Atovaquone‐proguanil (AP) versus chloroquine, Outcome 1 Treatment failure on or by day 28.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.2

Comparison 1 Atovaquone‐proguanil (AP) versus chloroquine, Outcome 2 Parasite clearance time (mean; h).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.3

Comparison 1 Atovaquone‐proguanil (AP) versus chloroquine, Outcome 3 Fever clearance time (mean; h).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 1.4

Comparison 1 Atovaquone‐proguanil (AP) versus chloroquine, Outcome 4 Adverse events.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.1

Comparison 2 Atovaquone‐proguanil (AP) versus amodiaquine, Outcome 1 Treatment failure on or by day 28.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.2

Comparison 2 Atovaquone‐proguanil (AP) versus amodiaquine, Outcome 2 Treatment failure on or by day 14.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.3

Comparison 2 Atovaquone‐proguanil (AP) versus amodiaquine, Outcome 3 Parasite clearance time (mean; h).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.4

Comparison 2 Atovaquone‐proguanil (AP) versus amodiaquine, Outcome 4 Fever clearance time (mean; h).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 2.5

Comparison 2 Atovaquone‐proguanil (AP) versus amodiaquine, Outcome 5 Adverse events.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.1

Comparison 3 Atovaquone‐proguanil (AP) versus sulfadoxine‐pyrimethamine (SP), Outcome 1 Treatment failure on or by day 28.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.2

Comparison 3 Atovaquone‐proguanil (AP) versus sulfadoxine‐pyrimethamine (SP), Outcome 2 Parasite clearance time (mean; h).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.3

Comparison 3 Atovaquone‐proguanil (AP) versus sulfadoxine‐pyrimethamine (SP), Outcome 3 Fever clearance time (mean; h).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.4

Comparison 3 Atovaquone‐proguanil (AP) versus sulfadoxine‐pyrimethamine (SP), Outcome 4 Progression to severe disease.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 3.5

Comparison 3 Atovaquone‐proguanil (AP) versus sulfadoxine‐pyrimethamine (SP), Outcome 5 Adverse events.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 4.1

Comparison 4 Atovaquone‐proguanil (AP) versus quinine plus tetracycline (Q plus T), Outcome 1 Treatment failure on or by day 28.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 4.2

Comparison 4 Atovaquone‐proguanil (AP) versus quinine plus tetracycline (Q plus T), Outcome 2 Parasite clearance time (mean; h).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 4.3

Comparison 4 Atovaquone‐proguanil (AP) versus quinine plus tetracycline (Q plus T), Outcome 3 Fever clearance time (mean; h).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 4.4

Comparison 4 Atovaquone‐proguanil (AP) versus quinine plus tetracycline (Q plus T), Outcome 4 Adverse events.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.1

Comparison 5 Atovaquone‐proguanil (AP) versus halofantrine, Outcome 1 Treatment failure on or by day 28.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.2

Comparison 5 Atovaquone‐proguanil (AP) versus halofantrine, Outcome 2 Parasite clearance time (mean; h).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.3

Comparison 5 Atovaquone‐proguanil (AP) versus halofantrine, Outcome 3 Fever clearance time (mean; h).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 5.4

Comparison 5 Atovaquone‐proguanil (AP) versus halofantrine, Outcome 4 Adverse events.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 6.1

Comparison 6 Atovaquone‐proguanil (AP) versus mefloquine, Outcome 1 Treatment failure on or by day 28.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 6.2

Comparison 6 Atovaquone‐proguanil (AP) versus mefloquine, Outcome 2 Parasite clearance time (mean; h).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 6.3

Comparison 6 Atovaquone‐proguanil (AP) versus mefloquine, Outcome 3 Fever clearance time (mean; h).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 6.4

Comparison 6 Atovaquone‐proguanil (AP) versus mefloquine, Outcome 4 Adverse events.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 7.1

Comparison 7 Atovaquone‐proguanil (AP) versus artesunate plus mefloquine (AS plus MQ), Outcome 1 Treatment failure on or by day 14.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 7.2

Comparison 7 Atovaquone‐proguanil (AP) versus artesunate plus mefloquine (AS plus MQ), Outcome 2 Treatment failure on or by day 28 adjusted by PCR.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 7.3

Comparison 7 Atovaquone‐proguanil (AP) versus artesunate plus mefloquine (AS plus MQ), Outcome 3 Adverse events.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 8.1

Comparison 8 Atovaquone‐proguanil (AP) versus dihydroartemisinin, piperaquine, trimethoprim, and primaquine (CV8), Outcome 1 Treatment failure on or by day 28.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 8.2

Comparison 8 Atovaquone‐proguanil (AP) versus dihydroartemisinin, piperaquine, trimethoprim, and primaquine (CV8), Outcome 2 Parasite clearance time (mean; h).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 8.3

Comparison 8 Atovaquone‐proguanil (AP) versus dihydroartemisinin, piperaquine, trimethoprim, and primaquine (CV8), Outcome 3 Fever clearance time (mean; h).

Ir a la figura de la revisiónAbrir en una pestaña nueva

Analysis 8.4

Comparison 8 Atovaquone‐proguanil (AP) versus dihydroartemisinin, piperaquine, trimethoprim, and primaquine (CV8), Outcome 4 Adverse events.

Ir a la figura de la revisiónAbrir en una pestaña nueva

Table 1. Risk of bias assessment

Trial	Allocation sequence generation	Allocation concealment	Blinding	Inclusion^a
Anabwani 1999	Unclear	Unclear	None	Adequate
Borrmann 2003	Adequate	Adequate	None	Inadequate
Bouchaud 2000	Unclear	Unclear	None	Inadequate
De Alencar 1997	Unclear	Unclear	None	Inadequate
Giao 2004	Adequate	Adequate	None	Adequate
Llanos‐Cuentas 2001	Unclear	Unclear	None	Adequate
Looareesuwan 1999a	Unclear	Unclear	None	Inadequate
Mulenga 1999	Unclear	Unclear	None	Adequate
Radloff 1996	Adequate	Unclear	None	Inadequate
Van Vugt 2002	Adequate	Adequate	None	Adequate
^aSee the 'Characteristics of included studies' for details. ^bInclusion of all randomized participants in the final analysis.

Table 1. Risk of bias assessment

Ir a la tabla de la revisión

Comparison 1. Atovaquone‐proguanil (AP) versus chloroquine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 28 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Parasite clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3 Fever clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

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

4.1 Abdominal pain	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Chills/rigors	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Dizziness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 Headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.5 Insomnia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.6 Nausea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.7 Palpitations	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.8 Pruritus	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.9 Severe	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.10 Vomiting	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.11 Weakness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. Atovaquone‐proguanil (AP) versus chloroquine

Ir a la tabla de la revisión

Comparison 2. Atovaquone‐proguanil (AP) versus amodiaquine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 28 Show forest plot	2	342	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.13, 0.36]

2 Treatment failure on or by day 14 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Parasite clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4 Fever clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5 Adverse events Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Abdominal pain	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	2.8 [1.07, 7.31]
5.2 Diarrhoea	2	326	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.57, 1.61]
5.3 Dizziness	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.27 [0.08, 0.93]
5.4 Insomnia	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.12, 0.75]
5.5 Nausea	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	2.63 [1.26, 5.48]
5.6 Pruritus	1	126	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.04, 0.35]
5.7 Respiratory infections	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.62, 14.51]
5.8 Vomiting	2	326	Risk Ratio (M‐H, Fixed, 95% CI)	1.39 [0.80, 2.41]
5.9 Weakness	2	326	Risk Ratio (M‐H, Fixed, 95% CI)	0.12 [0.02, 0.64]
5.10 Any event	1	200	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.82, 1.51]

Comparison 2. Atovaquone‐proguanil (AP) versus amodiaquine

Ir a la tabla de la revisión

Comparison 3. Atovaquone‐proguanil (AP) versus sulfadoxine‐pyrimethamine (SP)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 28 Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Parasite clearance time (mean; h) Show forest plot	2	174	Mean Difference (IV, Fixed, 95% CI)	11.23 [5.43, 17.03]

3 Fever clearance time (mean; h) Show forest plot	2	156	Mean Difference (IV, Fixed, 95% CI)	‐13.73 [‐21.31, ‐6.16]

4 Progression to severe disease Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5 Adverse events Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Abdominal pain	2	189	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.58, 1.24]
5.2 Chills/rigors	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.06, 32.05]
5.3 Diarrhoea	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	43.0 [2.65, 697.91]
5.4 Dizziness	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.06, 32.05]
5.5 Headache	2	189	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.81, 1.67]
5.6 Insomnia	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.09, 1.21]
5.7 Nausea	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	2.25 [0.31, 16.59]
5.8 Orthostatic hypotension	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	0.03 [0.00, 0.57]
5.9 Pruritus	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.16 [0.01, 3.56]
5.10 Raised liver enzymes	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.25, 1.79]
5.11 Severe	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.06, 32.05]
5.12 Vomiting	2	189	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.50, 1.90]
5.13 Weakness	2	189	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.82, 2.62]

Comparison 3. Atovaquone‐proguanil (AP) versus sulfadoxine‐pyrimethamine (SP)

Ir a la tabla de la revisión

Comparison 4. Atovaquone‐proguanil (AP) versus quinine plus tetracycline (Q plus T)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 28 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Parasite clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3 Fever clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

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

4.1 Abdominal pain	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Anorexia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Diarrhoea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 Dizziness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.5 Headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.6 Nausea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.7 Pruritus	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.8 Tinnitus	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.9 Vomiting	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.10 Weakness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 4. Atovaquone‐proguanil (AP) versus quinine plus tetracycline (Q plus T)

Ir a la tabla de la revisión

Comparison 5. Atovaquone‐proguanil (AP) versus halofantrine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 28 Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Parasite clearance time (mean; h) Show forest plot	2	205	Mean Difference (IV, Fixed, 95% CI)	14.76 [10.41, 19.10]

3 Fever clearance time (mean; h) Show forest plot	2	205	Mean Difference (IV, Fixed, 95% CI)	‐1.70 [‐9.41, 6.02]

4 Adverse events Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Abdominal pain	2	216	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.14, 4.68]
4.2 Chills/Rigors	1	168	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.11, 3.89]
4.3 Cough	1	168	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.34, 1.52]
4.4 Diarrhoea	2	216	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.23, 1.39]
4.5 Headache	2	216	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.17, 6.84]
4.6 Insomnia	2	216	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.15, 2.60]
4.7 Moderate or severe	1	168	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.15, 0.91]
4.8 Myalgia	1	168	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.72]
4.9 Nausea	1	48	Risk Ratio (M‐H, Random, 95% CI)	2.76 [0.62, 12.33]
4.10 Palpitations	1	168	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.05, 5.41]
4.11 Pruritus	2	216	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.51, 2.87]
4.12 Vomiting	2	216	Risk Ratio (M‐H, Random, 95% CI)	3.47 [0.66, 18.43]
4.13 Weakness	1	168	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.03, 2.19]

Comparison 5. Atovaquone‐proguanil (AP) versus halofantrine

Ir a la tabla de la revisión

Comparison 6. Atovaquone‐proguanil (AP) versus mefloquine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 28 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Parasite clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3 Fever clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

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

4.1 Abdominal pain	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Anaemia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Diarrhoea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 Dizziness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.5 Headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.6 Insomnia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.7 Nausea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.8 Raised liver enzymes	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.9 Sore throat	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.10 Vomiting	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.11 Any event	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 6. Atovaquone‐proguanil (AP) versus mefloquine

Ir a la tabla de la revisión

Comparison 7. Atovaquone‐proguanil (AP) versus artesunate plus mefloquine (AS plus MQ)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 14 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Treatment failure on or by day 28 adjusted by PCR Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

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

3.1 Anorexia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Dizziness	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Nausea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.4 Palpitations	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.5 Skin rash	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.6 Sleeping disorders	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.7 Tremor	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.8 Vomiting	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 7. Atovaquone‐proguanil (AP) versus artesunate plus mefloquine (AS plus MQ)

Ir a la tabla de la revisión

Comparison 8. Atovaquone‐proguanil (AP) versus dihydroartemisinin, piperaquine, trimethoprim, and primaquine (CV8)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment failure on or by day 28 Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2 Parasite clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3 Fever clearance time (mean; h) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

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

4.1 Diarrhoea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Dry mouth	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 Itch	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.5 Vomiting	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 8. Atovaquone‐proguanil (AP) versus dihydroartemisinin, piperaquine, trimethoprim, and primaquine (CV8)

Ir a la tabla de la revisión

	Idioma de la Revisión Cochrane Escoja su idioma de preferencia para las revisiones Cochrane y otros contenidos. Las secciones sin una traducción aparecerán en inglés.

	Idioma de la web Escoja su idioma de preferencia para la web de la Biblioteca Cochrane.

Idioma de la Revisión Cochrane

Idioma de la web

Referencias

Referencias de los estudios incluidos en esta revisión

Anabwani 1999 {published data only}

Borrmann 2003 {published data only}

Bouchaud 2000 {published data only}

De Alencar 1997 {published data only}

Giao 2004 {published data only}

Llanos‐Cuentas 2001 {published data only}

Looareesuwan 1999a {published data only}

Mulenga 1999 {published data only}

Radloff 1996 {published data only}

Van Vugt 2002 {published data only}

Referencias de los estudios excluidos de esta revisión

Bustos 1999 {published data only}

Referencias adicionales

Beerahee 1999

Blanchard 1994

Bloland 1997

Brockman 1999

Canfield 1995

Dollery 1991

Foege 1997

Fry 1992

Higgins 2005

Hogh 2000

Jüni 2001

Kamya 2002

Looareesuwan 1996

Looareesuwan 1999b

Ohrt 1997

Overbosch 2001

Oyediran 2002

Partnerships 2002

RBM 2001a

RBM 2001b

RBM 2005

Review Manager 5 [Computer program]

Ringwald 1998

Sabchareon 1998

Shretta 2000

Shretta 2001

Stepniewska 2004

Sukwa 1999

WHO 1999

WHO 2000

WHO 2001

WHO 2003

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

Copiar o descargar referencia

Idioma de la Revisión Cochrane

Idioma de la web

Instituciones a las que se accedió previamente

Usuarios institucionales

Instituciones a las que se accedió previamente

Otras opciones de acceso