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Meta-Analysis
. 2021 Jan 15;1(1):CD004529.
doi: 10.1002/14651858.CD004529.pub3.

Atovaquone-proguanil for treating uncomplicated Plasmodium falciparum malaria

Andrew Blanshard  1 , Paul Hine  2
Affiliations
Meta-Analysis

Atovaquone-proguanil for treating uncomplicated Plasmodium falciparum malaria

Andrew Blanshard et al. Cochrane Database Syst Rev. .

Abstract

Background: The World Health Organization (WHO) in 2015 stated atovaquone-proguanil can be used in travellers, and is an option in malaria-endemic areas in combination with artesunate, as an alternative treatment where first-line artemisinin-based combination therapy (ACT) is not available or effective. This review is an update of a Cochrane Review undertaken in 2005.

Objectives: To assess the efficacy and safety of atovaquone-proguanil (alone and in combination with artemisinin drugs) versus other antimalarial drugs for treating uncomplicated Plasmodium falciparum malaria in adults and children.

Search methods: The date of the last trial search was 30 January 2020. Search locations for published trials included the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, and LILACS. To include recently published and unpublished trials, we also searched ClinicalTrials.gov, the metaRegister of Controlled Trials and the WHO International Clinical Trials Registry Platform Search Portal.

Selection criteria: Randomized controlled trials (RCTs) reporting efficacy and safety data for atovaquone-proguanil or atovaquone-proguanil with a partner drug compared with at least one other antimalarial drug for treating uncomplicated Plasmodium falciparum infection.

Data collection and analysis: For this update, two review authors re-extracted data and assessed certainty of evidence. We meta-analyzed data to calculate risk ratios (RRs) with 95% confidence intervals (CI) for treatment failures between comparisons, and for safety outcomes between and across comparisons. Outcome measures include unadjusted treatment failures and polymerase chain reaction (PCR)-adjusted treatment failures. PCR adjustment differentiates new infection from recrudescent infection.

Main results: Seventeen RCTs met our inclusion criteria providing 4763 adults and children from Africa, South-America, and South-East Asia. Eight trials reported PCR-adjusted data to distinguish between new and recrudescent infection during the follow-up period. In this abstract, we report only the comparisons against the three WHO-recommended antimalarials which were included within these trials. There were two comparisons with artemether-lumefantrine, one trial from 2008 in Ethiopia with 60 participants had two failures with atovaquone-proguanil compared to none with artemether-lumefantrine (PCR-adjusted treatment failures at day 28). A second trial from 2012 in Colombia with 208 participants had one failure in each arm (PCR-adjusted treatment failures at day 42). There was only one comparison with artesunate-amodiaquine from a 2014 trial conducted in Cameroon. There were six failures with atovaquone-proguanil at day 28 and two with artesunate-amodiaquine (PCR-adjusted treatment failures at day 28: 9.4% with atovaquone-proguanil compared to 2.9% with artesunate-amodiaquine; RR 3.19, 95% CI 0.67 to 15.22; 1 RCT, 132 participants; low-certainty evidence), although there was a similar number of PCR-unadjusted treatment failures (9 (14.1%) with atovaquone-proguanil and 8 (11.8%) with artesunate-amodiaquine; RR 1.20, 95% CI 0.49 to 2.91; 1 RCT, 132 participants; low-certainty evidence). There were two comparisons with artesunate-mefloquine from a 2012 trial in Colombia and a 2002 trial in Thailand where there are high levels of multi-resistant malaria. There were similar numbers of PCR-adjusted treatment failures between groups at day 42 (2.7% with atovaquone-proguanil compared to 2.4% with artesunate-mefloquine; RR 1.15, 95% CI 0.57 to 2.34; 2 RCTs, 1168 participants; high-certainty evidence). There were also similar PCR-unadjusted treatment failures between groups (5.3% with atovaquone-proguanil compared to 6.6% with artesunate-mefloquine; RR 0.8, 95% CI 0.5 to 1.3; 1 RCT, 1063 participants; low-certainty evidence). When atovaquone-proguanil was combined with artesunate, there were fewer treatment failures with and without PCR-adjustment at day 28 (PCR-adjusted treatment failures at day 28: 2.16% with atovaquone-proguanil compared to no failures with artesunate-atovaquone-proguanil; RR 5.14, 95% CI 0.61 to 43.52; 2 RCTs, 375 participants, low-certainty evidence) and day 42 (PCR-adjusted treatment failures at day 42: 3.82% with atovaquone-proguanil compared to 2.05% with artesunate-atovaquone-proguanil (RR 1.84, 95% CI 0.95 to 3.56; 2 RCTs, 1258 participants, moderate-certainty evidence). In the 2002 trial in Thailand, there were fewer treatment failures in the artesunate-atovaquone-proguanil group compared to the atovaquone-proguanil group at day 42 with PCR-adjustment. Whilst there were some small differences in which adverse events were more frequent in the atovaquone-proguanil groups compared to comparator drugs, there were no recurrent associations to suggest that atovaquone-proguanil is strongly associated with any specific adverse event.

Authors' conclusions: Atovaquone-proguanil was effective against uncomplicated P falciparum malaria, although in some instances treatment failure rates were between 5% and 10%. The addition of artesunate to atovaquone-proguanil may reduce treatment failure rates. Artesunate-atovaquone-proguanil and the development of parasite resistance may represent an area for further research.

PubMed Disclaimer

Conflict of interest statement

AB has no known conflicts of interest. He is a doctor working full time within the UK National Health Service (NHS).

PH was previously employed full‐time by the Cochrane Infectious Diseases Group (CIDG), is a CIDG Editor, and currently works full‐time within the UK NHS. He received a Registration Scholarship to attend the 23rd Annual British HIV Association Conference 2017 from ViiV healthcare. ViiV had no involvement in the selection of recipients of the scholarship. In 2018, he attended a CPD certified clinical research training programme organized and funded by Gilead Sciences Europe Ltd. To the best of his knowledge, neither financial nor non‐financial conflicts of interests have influenced the current submitted work.

Figures

1
1
PRISMA diagram.
2
2
Risk of bias summary: review authors' judgements about risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Atovaquone‐proguanil (AV+PG) versus artemether‐lumefantrine (AL), Outcome 1: Total failure day 28 PCR‐adjusted
1.2
1.2. Analysis
Comparison 1: Atovaquone‐proguanil (AV+PG) versus artemether‐lumefantrine (AL), Outcome 2: Total failure day 42 PCR‐adjusted
1.3
1.3. Analysis
Comparison 1: Atovaquone‐proguanil (AV+PG) versus artemether‐lumefantrine (AL), Outcome 3: Total failure day 42 PCR‐unadjusted
1.4
1.4. Analysis
Comparison 1: Atovaquone‐proguanil (AV+PG) versus artemether‐lumefantrine (AL), Outcome 4: Adverse events
2.1
2.1. Analysis
Comparison 2: Atovaquone‐proguanil (AV+PG) versus artesunate‐amodiaquine (AS+AQ), Outcome 1: Total failure day 28 PCR‐adjusted
2.2
2.2. Analysis
Comparison 2: Atovaquone‐proguanil (AV+PG) versus artesunate‐amodiaquine (AS+AQ), Outcome 2: Total failure day 28 PCR‐unadjusted
2.3
2.3. Analysis
Comparison 2: Atovaquone‐proguanil (AV+PG) versus artesunate‐amodiaquine (AS+AQ), Outcome 3: Early treatment failure
2.4
2.4. Analysis
Comparison 2: Atovaquone‐proguanil (AV+PG) versus artesunate‐amodiaquine (AS+AQ), Outcome 4: Adverse events
3.1
3.1. Analysis
Comparison 3: Atovaquone‐proguanil (AV+PG) versus artesunate‐mefloquine (AS+MQ), Outcome 1: Total failure day 42 PCR‐adjusted
3.2
3.2. Analysis
Comparison 3: Atovaquone‐proguanil (AV+PG) versus artesunate‐mefloquine (AS+MQ), Outcome 2: Total failure day 42 PCR‐unadjusted
3.3
3.3. Analysis
Comparison 3: Atovaquone‐proguanil (AV+PG) versus artesunate‐mefloquine (AS+MQ), Outcome 3: Adverse events
4.1
4.1. Analysis
Comparison 4: Atovaquone‐proguanil (AV+PG) versus artesunate‐atovaquone‐proguanil (AS+AV+PG), Outcome 1: Total failure day 28 PCR‐adjusted
4.2
4.2. Analysis
Comparison 4: Atovaquone‐proguanil (AV+PG) versus artesunate‐atovaquone‐proguanil (AS+AV+PG), Outcome 2: Total failure day 28 PCR‐unadjusted
4.3
4.3. Analysis
Comparison 4: Atovaquone‐proguanil (AV+PG) versus artesunate‐atovaquone‐proguanil (AS+AV+PG), Outcome 3: Total failure day 42 PCR‐adjusted
4.4
4.4. Analysis
Comparison 4: Atovaquone‐proguanil (AV+PG) versus artesunate‐atovaquone‐proguanil (AS+AV+PG), Outcome 4: Total failure day 42 PCR‐unadjusted
4.5
4.5. Analysis
Comparison 4: Atovaquone‐proguanil (AV+PG) versus artesunate‐atovaquone‐proguanil (AS+AV+PG), Outcome 5: Early treatment failure
4.6
4.6. Analysis
Comparison 4: Atovaquone‐proguanil (AV+PG) versus artesunate‐atovaquone‐proguanil (AS+AV+PG), Outcome 6: Adverse events
5.1
5.1. Analysis
Comparison 5: Atovaquone‐proguanil (AV+PG) versus dihydroartemisinin‐piperaquine‐trimethoprim‐primaquine (CV8), Outcome 1: Total failure day 28 PCR‐unadjusted
5.2
5.2. Analysis
Comparison 5: Atovaquone‐proguanil (AV+PG) versus dihydroartemisinin‐piperaquine‐trimethoprim‐primaquine (CV8), Outcome 2: Early treatment failure
5.3
5.3. Analysis
Comparison 5: Atovaquone‐proguanil (AV+PG) versus dihydroartemisinin‐piperaquine‐trimethoprim‐primaquine (CV8), Outcome 3: Adverse events
6.1
6.1. Analysis
Comparison 6: Atovaquone‐proguanil (AV+PG) versus quinine‐tetracycline (QN+TET), Outcome 1: Total failure day 28 PCR‐unadjusted
6.2
6.2. Analysis
Comparison 6: Atovaquone‐proguanil (AV+PG) versus quinine‐tetracycline (QN+TET), Outcome 2: Early treatment failure
6.3
6.3. Analysis
Comparison 6: Atovaquone‐proguanil (AV+PG) versus quinine‐tetracycline (QN+TET), Outcome 3: Adverse events
7.1
7.1. Analysis
Comparison 7: Atovaquone‐proguanil (AV+PG) versus sulfadoxine‐pyrimethamine (SP), Outcome 1: Total failure day 28 PCR‐adjusted
7.2
7.2. Analysis
Comparison 7: Atovaquone‐proguanil (AV+PG) versus sulfadoxine‐pyrimethamine (SP), Outcome 2: Total failure day 28 PCR‐unadjusted
7.3
7.3. Analysis
Comparison 7: Atovaquone‐proguanil (AV+PG) versus sulfadoxine‐pyrimethamine (SP), Outcome 3: Early treatment failure
7.4
7.4. Analysis
Comparison 7: Atovaquone‐proguanil (AV+PG) versus sulfadoxine‐pyrimethamine (SP), Outcome 4: Adverse events
8.1
8.1. Analysis
Comparison 8: Atovaquone‐proguanil (AV+PG) versus quinine (QN), Outcome 1: Total failure day 28 PCR‐adjusted
8.2
8.2. Analysis
Comparison 8: Atovaquone‐proguanil (AV+PG) versus quinine (QN), Outcome 2: Total failure day 42 PCR‐unadjusted
8.3
8.3. Analysis
Comparison 8: Atovaquone‐proguanil (AV+PG) versus quinine (QN), Outcome 3: Early treatment failure
8.4
8.4. Analysis
Comparison 8: Atovaquone‐proguanil (AV+PG) versus quinine (QN), Outcome 4: Adverse events
9.1
9.1. Analysis
Comparison 9: Atovaquone‐proguanil (AV+PG) versus mefloquine (MQ), Outcome 1: Total failure day 28 PCR‐unadjusted
9.2
9.2. Analysis
Comparison 9: Atovaquone‐proguanil (AV+PG) versus mefloquine (MQ), Outcome 2: Early treatment failure
9.3
9.3. Analysis
Comparison 9: Atovaquone‐proguanil (AV+PG) versus mefloquine (MQ), Outcome 3: Adverse events
10.1
10.1. Analysis
Comparison 10: Atovaquone‐proguanil (AV+PG) versus amodiaquine (AQ), Outcome 1: Total failure day 28 PCR‐unadjusted
10.2
10.2. Analysis
Comparison 10: Atovaquone‐proguanil (AV+PG) versus amodiaquine (AQ), Outcome 2: Early treatment failure
10.3
10.3. Analysis
Comparison 10: Atovaquone‐proguanil (AV+PG) versus amodiaquine (AQ), Outcome 3: Adverse events
11.1
11.1. Analysis
Comparison 11: Atovaquone‐proguanil (AV+PG) versus chloroquine (CQ), Outcome 1: Total failure day 28 PCR‐unadjusted
11.2
11.2. Analysis
Comparison 11: Atovaquone‐proguanil (AV+PG) versus chloroquine (CQ), Outcome 2: Early treatment failure
11.3
11.3. Analysis
Comparison 11: Atovaquone‐proguanil (AV+PG) versus chloroquine (CQ), Outcome 3: Adverse events
12.1
12.1. Analysis
Comparison 12: Atovaquone‐proguanil (AV+PG) versus halofantrine (HL), Outcome 1: Total failure day 28 PCR‐unadjusted
12.2
12.2. Analysis
Comparison 12: Atovaquone‐proguanil (AV+PG) versus halofantrine (HL), Outcome 2: Early treatment failure
12.3
12.3. Analysis
Comparison 12: Atovaquone‐proguanil (AV+PG) versus halofantrine (HL), Outcome 3: Adverse events
13.1
13.1. Analysis
Comparison 13: Artesunate‐atovaquone‐proguanil (AS+AV+PG) versus quinine (QN), Outcome 1: Total failure day 28 PCR‐adjusted
13.2
13.2. Analysis
Comparison 13: Artesunate‐atovaquone‐proguanil (AS+AV+PG) versus quinine (QN), Outcome 2: Total failure day 42 PCR‐adjusted
13.3
13.3. Analysis
Comparison 13: Artesunate‐atovaquone‐proguanil (AS+AV+PG) versus quinine (QN), Outcome 3: Total failure day 28 PCR‐unadjusted
13.4
13.4. Analysis
Comparison 13: Artesunate‐atovaquone‐proguanil (AS+AV+PG) versus quinine (QN), Outcome 4: Total failure day 42 PCR‐unadjusted
13.5
13.5. Analysis
Comparison 13: Artesunate‐atovaquone‐proguanil (AS+AV+PG) versus quinine (QN), Outcome 5: Early treatment failure
13.6
13.6. Analysis
Comparison 13: Artesunate‐atovaquone‐proguanil (AS+AV+PG) versus quinine (QN), Outcome 6: Adverse events
14.1
14.1. Analysis
Comparison 14: Chloroquine‐atovaquone‐proguanil (CQ+AV+PG) versus chloroquine (CQ), Outcome 1: Total failure day 28 PCR‐unadjusted
14.2
14.2. Analysis
Comparison 14: Chloroquine‐atovaquone‐proguanil (CQ+AV+PG) versus chloroquine (CQ), Outcome 2: Early treatment failure
14.3
14.3. Analysis
Comparison 14: Chloroquine‐atovaquone‐proguanil (CQ+AV+PG) versus chloroquine (CQ), Outcome 3: Adverse events
15.1
15.1. Analysis
Comparison 15: Chloroquine‐atovaquone‐proguanil (CQ+AV+PG) versus chloroquine‐artesunate (CQ+AS), Outcome 1: Total failure day 28 PCR‐adjusted
15.2
15.2. Analysis
Comparison 15: Chloroquine‐atovaquone‐proguanil (CQ+AV+PG) versus chloroquine‐artesunate (CQ+AS), Outcome 2: Total failure day 28 PCR‐unadjusted
15.3
15.3. Analysis
Comparison 15: Chloroquine‐atovaquone‐proguanil (CQ+AV+PG) versus chloroquine‐artesunate (CQ+AS), Outcome 3: Early treatment failure
15.4
15.4. Analysis
Comparison 15: Chloroquine‐atovaquone‐proguanil (CQ+AV+PG) versus chloroquine‐artesunate (CQ+AS), Outcome 4: Adverse events
16.1
16.1. Analysis
Comparison 16: Chloroquine‐atovaquone‐proguanil (CQ+AV+PG) versus chloroquine‐azithromycin (CQ+AZ), Outcome 1: Total failure day 28 PCR‐adjusted
16.2
16.2. Analysis
Comparison 16: Chloroquine‐atovaquone‐proguanil (CQ+AV+PG) versus chloroquine‐azithromycin (CQ+AZ), Outcome 2: Total failure day 28 PCR‐unadjusted
16.3
16.3. Analysis
Comparison 16: Chloroquine‐atovaquone‐proguanil (CQ+AV+PG) versus chloroquine‐azithromycin (CQ+AZ), Outcome 3: Early treatment failure
16.4
16.4. Analysis
Comparison 16: Chloroquine‐atovaquone‐proguanil (CQ+AV+PG) versus chloroquine‐azithromycin (CQ+AZ), Outcome 4: Adverse events
17.1
17.1. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 1: Serious adverse events
17.2
17.2. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 2: Adverse events leading to withdrawal
17.3
17.3. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 3: Anaemias
17.4
17.4. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 4: Appetite disorders
17.5
17.5. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 5: Asthenic conditions
17.6
17.6. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 6: Auditory nerve disorders
17.7
17.7. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 7: Hypotensive disorders
17.8
17.8. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 8: Breathing abnormalities
17.9
17.9. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 9: Cardiac signs and symptoms
17.10
17.10. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 10: Coughing and associated symptoms
17.11
17.11. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 11: Diarrhoea
17.12
17.12. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 12: Disturbances in initiating and maintaining sleep
17.13
17.13. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 13: Dizziness
17.14
17.14. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 14: Febrile disorders
17.15
17.15. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 15: Feelings and sensations
17.16
17.16. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 16: Gastrointestinal and abdominal pains
17.17
17.17. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 17: Haemorrhages
17.18
17.18. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 18: Headaches
17.19
17.19. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 19: Hearing problems
17.20
17.20. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 20: Hepatobiliary signs and symptoms
17.21
17.21. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 21: Hypoglycaemic conditions
17.22
17.22. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 22: Inner ear signs and symptoms
17.23
17.23. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 23: Liver function tests abnormal
17.24
17.24. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 24: Lower respiratory tract and lung infections
17.25
17.25. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 25: Muscle pains
17.26
17.26. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 26: Nausea and vomiting
17.27
17.27. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 27: Oral dryness and saliva altered
17.28
17.28. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 28: Oral soft tissue signs and symptoms
17.29
17.29. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 29: Pruritis
17.30
17.30. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 30: Rashes, eruptions, and exanthems
17.31
17.31. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 31: Rubeola viral infections
17.32
17.32. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 32: Seizures and seizure disorders
17.33
17.33. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 33: Spleen disorders
17.34
17.34. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 34: Sepsis, bacteraemia, viraemia, fungaemia
17.35
17.35. Analysis
Comparison 17: Adverse events: atovaquone‐proguanil (AV+PG) versus all other antimalarials, Outcome 35: Upper respiratory tract infections
18.1
18.1. Analysis
Comparison 18: Supplementary: atovaquone‐proguanil (AV+PG) versus WHO‐recommended artemisinin‐based combination therapy (ACT), Outcome 1: Total failure day 28 PCR‐adjusted
18.2
18.2. Analysis
Comparison 18: Supplementary: atovaquone‐proguanil (AV+PG) versus WHO‐recommended artemisinin‐based combination therapy (ACT), Outcome 2: Total failure day 28 PCR‐unadjusted
18.3
18.3. Analysis
Comparison 18: Supplementary: atovaquone‐proguanil (AV+PG) versus WHO‐recommended artemisinin‐based combination therapy (ACT), Outcome 3: Total failure day 42 PCR‐adjusted
18.4
18.4. Analysis
Comparison 18: Supplementary: atovaquone‐proguanil (AV+PG) versus WHO‐recommended artemisinin‐based combination therapy (ACT), Outcome 4: Total failure day 42 PCR‐unadjusted
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Update of

References

References to studies included in this review

Anabwani 1999 {published data only}
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    1. 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. - PubMed
McGready 2005 {published data only}
    1. McGready R, Ashley EA, Moo E, Cho T, Barends M, Hutagalung R, et al. A randomized comparison of artesunate-atovaquone-proguanil versus quinine in treatment for uncomplicated falciparum malaria during pregnancy. Journal of Infectious Diseases 2005;192(5):846-53. - PubMed
Mulenga 1999 {published data only}
    1. 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. - PubMed
Mulenga 2006 {published data only}
    1. Mulenga M, Malunga F, Bennett S, Thuma PE, Shulman C, Fielding K, et al. A randomised, double-blind, placebo-controlled trial of atovaquone-proguanil vs. sulphadoxine-pyrimethamine in the treatment of malarial anaemia in Zambian children. Tropical Medicine & International Health 2006;11(11):1643-52. - PubMed
Radloff 1996 {published data only}
    1. Radloff PD, Philipps J, Nkeyi M, Hutchinson D, Kremsner PG. Atovaquone and proguanil for Plasmodium falciparum malaria. Lancet 1996;347(9014):1511-4. - PubMed
Tahar 2014 {published data only}
    1. Tahar R, Almelli T, Debue C, Foumane Ngane V, Djaman Allico J, Whegang Youdom S, et al. Randomized trial of artesunate-amodiaquine, atovaquone-proguanil, and artesunate-atovaquone-proguanil for the treatment of uncomplicated falciparum malaria in children. Journal of Infectious Diseases 2014;210(12):1962-71. - PubMed
Van Vugt 2002 {published data only}
    1. Gupta RK, Van Vugt M, Paiphun L, Slight T, Looareesuwan S, White NJ, et al. Short report: no evidence of cardiotoxicity of atovaquone-proguanil alone or in combination with artesunate. American Journal of Tropical Medicine and Hygiene 2005;73(2):267-8. - PubMed
    1. 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. - PubMed
Wojnarski 2019 {published data only}
    1. Lon C, Ittiverakul M, Somethy S, Chann S, Kuntawunginn W, Kong N, et al. Therapeutic efficacy of atovaquone-proguanil and artesunate atovaquone-proguanil for the treatment of uncomplicated Plasmodium falciparum malaria in areas of multidrug resistance in Cambodia. American Journal of Tropical Medicine and Hygiene 2015;93(4 Suppl):459.
    1. NCT02297477. The ASAP study – therapeutic efficacy of atovaquone-proguanil vs. artesunate-atovaquone-proguanil in Cambodia (ASAP). clinicaltrials.gov/ct2/show/record/NCT02297477 (first received 21 November 2014).
    1. Wojnarski M, Lon C, Gosi P, Vanachayangkul P, Harrison D, Berjohn C, et al. Update on the asexual and sexual stage-efficacy of atovaquone-proguanil and single low dose primaquine with or without artesunate in Cambodia. American Journal of Tropical Medicine and Hygiene 2016;95 (5 Suppl 1):466-7.
    1. Wojnarski M, Lon C, Vanachayangkul P, Gosi P, Sok S, Rachmat A, et al. Atovaquone-proguanil in combination with artesunate to treat multidrug-resistant P. falciparum malaria in Cambodia: an open-label randomized trial. Open Forum Infect Diseases 2019;6(9):ofz314. - PMC - PubMed

References to studies excluded from this review

Bustos 1999 {published data only}
    1. 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. Journal of Infectious Diseases 1999;179(6):1587-90. - PubMed
Gupta 2005 {published data only}
    1. Gupta RK, Van Vugt M, Paiphun L, Slight T, Looareesuwan S, White NJ, et al. Short report: no evidence of cardiotoxicity of atovaquone-proguanil alone or in combination with artesunate. American Journal of Tropical Medicine and Hygiene 2005;73(2):267-8. - PubMed
Hitani 2006 {published data only}
    1. Hitani A, Nakamura T, Ohtomo H, Nawa Y, Kimura M. Efficacy and safety of atovaquone-proguanil compared with mefloquine in the treatment of nonimmune patients with uncomplicated P. falciparum malaria in Japan. Journal of Infection and Chemotherapy 2006;12(5):277-82. - PubMed
Krudsood 2007 {published data only}
    1. Krudsood S, Patel SN, Tangpukdee N, Thanachartwet W, Leowattana W, Pornpininworakij K, et al. Efficacy of atovaquone-proguanil for treatment of acute multidrug-resistant Plasmodium falciparum malaria in Thailand. American Journal of Tropical Medicine and Hygiene 2007;76(4):655-8. - PubMed
Looareesuwan 1996 {published data only}
    1. 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. - PubMed

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References to other published versions of this review

Osei‐Akoto 2005
    1. Osei-Akoto A, Orton L, Owusu-Ofori SP. Atovaquone-proguanil for treating uncomplicated malaria. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No: CD004529. [DOI: 10.1002/14651858.CD004529.pub2] - DOI - PMC - PubMed

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