Abstract
Introduction
Malaria is a major health problem in the tropics, with 300 to 500 million new clinical cases annually, most of them cases of uncomplicated malaria. An estimated 1.1 to 2.7 million deaths occur annually as a result of severe falciparum malaria. Uncomplicated malaria can progress to severe malaria, become chronic, or resolve, depending on host immunity and prompt access to appropriate treatment.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: Are artemisinin combination treatments more effective than non-artemisinin combination treatments in people living in endemic areas (excluding South-East Asia)? Which artemisinin combination treatment is most effective in people living in endemic areas? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 25 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: amodiaquine plus sulfadoxine-pyrimethamine; artemether-lumefantrine; artesunate plus mefloquine; artesunate plus amodiaquine; and artesunate plus sulfadoxine-pyrimethamine.
Key Points
Uncomplicated malaria is where the person has symptomatic infection with malaria parasites, but no signs of vital organ disturbance.
Uncomplicated malaria can progress to severe malaria, become chronic, or resolve, depending on host immunity and prompt access to appropriate treatment.
Severe malaria is more likely to develop in people with no prior immunity, and accounts for over one million deaths worldwide each year.
The choice between treatment regimens depends partly on background drug-resistance patterns in the relevant country or region.
In most RCTs, artemether-lumefantrine was more effective than amodiaquine plus sulfadoxine-pyrimethamine. However, it was not more effective in all RCTs.
Artesunate plus amodiaquine is more effective at curing a current infection than amodiaquine plus sulfadoxine-pyrimethamine, but, in terms of people being parasite free at day 28, there is little to choose between them, since the risk of new infections appears greater with artesunate plus amodiaquine.
Amodiaquine plus sulfadoxine-pyrimethamine achieved higher cure rates than artesunate plus sulfadoxine-pyrimethamine. Gametocyte clearance was better with artesunate plus sulfadoxine-pyrimethamine.
Evidence suggests that a six-dose regimen of artemether-lumefantrine is more effective than a four-dose regimen.
Both artemether-lumefantrine (6 doses) and artesunate plus amodiaquine were effective, but artemether-lumefantrine (6 doses) was superior in some trials.
Artesunate plus mefloquine performs better than artemether-lumefantrine in terms of cure in some areas where this has been studied.
The choice between artesunate plus amodiaquine and artesunate plus sulfadoxine-pyrimethamine depends on background drug-resistance patterns in the relevant country or region.
We found insufficient evidence on the effects of artemer-lumefantrine (6 doses) versus artesunate plus sulfadoxine-pyrimethamine, artesunate plus mefloquine versus artesunate plus amodiaquine, or artesunate plus mefloquine versus artesunate plus sulfadoxine-pyrimethamine.
About this condition
Definition
Malaria is a parasite transmitted by Anopheles mosquitoes. There are four types of human malaria: falciparum, vivax, ovale, and malariae. The falciparum type is the most important cause of illness and death, and Plasmodium falciparum, the responsible organism, is known to develop resistance to antimalarial drugs. This review covers treatments for falciparum malaria only, in a population of adults and children living in endemic malarial areas exposed (seasonally or all year round) to malaria. It does not cover treatment of malaria in non-immune travellers, pregnant women, and people infected with HIV. Repeated episodes of falciparum malaria result in temporary and incomplete immunity. Therefore, adults living in areas where malaria is common are often found to be "semi-immune" — presenting with asymptomatic or chronic forms of malaria, with clinical episodes attenuated by their immunity. "Severe malaria" is defined as a form of symptomatic malaria with signs of vital organ disturbance (WHO 2000). Any person with symptomatic malaria who does not develop any such signs is defined as having "uncomplicated malaria". This review assesses the effectiveness of antimalarial drugs only in people with uncomplicated malaria.
Incidence/ Prevalence
Malaria is a major health problem in the tropics, with 300 to 500 million new clinical cases annually, most of them cases of uncomplicated malaria. An estimated 1.1 to 2.7 million deaths occur annually as a result of severe falciparum malaria.
Aetiology/ Risk factors
The malaria parasite is transmitted by infected Anopheles mosquitoes. Risk factors for developing the disease include exposure to infected mosquitoes (living in an endemic area; housing that allows mosquitoes to enter and absence of mosquito nets; and living in an area where Anopheles mosquitoes can thrive). Risk factors in relation to severity of the illness relate to host immunity, determined mainly by exposure to the parasite, and therefore varying with level of transmission in the area, and the age of the host. Malaria is uncommon in the first 6 months of life (fetal haemoglobin is protective); it is, however, common in children over 6 months of age. In areas of intense transmission, infection is attenuated by host immunity in older age groups; however, morbidity and mortality can also be high in adults in areas of less-intense transmission.
Prognosis
Uncomplicated malaria may progress to severe malaria, become chronic, or resolve with effective treatment or the development of improved immunity. The outcome is therefore dependent on host immunity and prompt access to effective treatment. In the absence of effective treatment, people with no or low immunity are at increased risk of developing severe malaria (see review on malaria: severe, life-threatening) resulting in high morbidity and mortality.
Aims of intervention
To alleviate symptoms; to prevent progression to severe disease; to cure the infection, with minimal adverse effects.
Outcomes
Treatment effectiveness (variously measured) including: clinical failure rate (defined as the proportion of people with symptoms of malaria plus parasitaemia at or before day 28); clinical failure rate at time frames other than day 28 (where no 28-day evidence is available); total failure rate (defined as clinical failure rate plus the proportion of people with asymptomatic parasitaemia at day 28); parasitological failure rate (defined as proportion of people with parasitaemia at day 28); parasitological failure rate at time frames other than day 28 (where no 28-day evidence is available); early treatment failure (evidence of clinical or parasitological symptoms during the first 3 days of follow-up); adequate clinical and parasitological response (ACPR) rate; parasitological conversion rate; parasitological success rate; fever clearance time; rate of progression to severe disease; and need for rescue treatment (quinine treatment given in the case of treatment failure). Day 14 failure does not sufficiently predict treatment failure in trials of drugs with a terminal elimination half life of more than a few days. Some of the differences in rates of treatment failure at day 14 may result from differences in elimination kinetics between the drugs. For comparisons of most drugs, follow-up to day 28 is adequate, although shorter follow-up data are reported if 28-day outcomes are not available. With mefloquine, however, 42-day follow-up is preferable because of its longer half life. Where 42-day or longer follow-up data are not available, 28-day outcomes are reported. Transmission potential including gametocytaemia rate; gametocyte clearance time. Adverse effects requiring admission to hospital or discontinuation of treatment.
Methods
The contributors searched the Cochrane Infectious Diseases Group’s trials register, Cochrane Central Register of Controlled Trials (Central) published in The Cochrane Library, 2007, Issue 3, Medline 1966 to November 2007, Embase 1980 to November 2007, and Lilacs; using the term arte* in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2006). The contributors conducted their search and identified the questions in collaboration with the WHO Malaria Technical Guidelines Development Group for evidence-based guidelines for uncomplicated malaria treatment that draw explicitly on this review. An independent Clinical Evidence search and appraisal was also completed in December 2007. We searched: Medline and Embase to December 2007, Cochrane Central Register of Controlled Trials Issue 4 2007, The Cochrane Database of Systematic reviews, Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment Database and the TRIP database. Results of the Clinical Evidence search and appraisal were compared with the contributor search, and any additional studies found were assessed by the contributors. Results were then assessed and sorted into groups for the various drug combinations examined. Study design criteria for evaluation in this review were: published systematic reviews and RCTs in any language, including open studies, and containing more than 20 individuals of whom more than 80% were followed up. We have excluded certain questions irrelevant to current policies because of drug resistance — namely those examining the following: monotherapy (globally) with chloroquine, sulfadoxine-pyrimethamine, amodiaquine; combination therapy with chloroquine (globally); and non-artemisinin combinations (and artemisinin in combination with amodiaquine or sulfadoxine-pyrimethamine) in South-East Asia. In addition, because quinine has traditionally been reserved for treatment failures or severe malaria because of its toxicity, it is not reviewed here. We have summarised results from RCTs in each option under the overall outcome headings of treatment effectiveness, transmission potential, and adverse effects (see outcomes section). To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to statistics such as relative risks (RRs) and odds ratios (ORs).
Glossary
- Adequate clinical and parasitological response (ACPR)
According to the WHO definition, absence of parasitaemia at day 28 irrespective of axillary temperature and without previously meeting any of the WHO criteria for early or late treatment failure, or late parasitological failure.
- Clinical failure
Symptoms of malaria with parasitaemia on or before day 28.
- Gametocytaemia
Microscopic evidence of gametocytes in the blood.
- Gametocyte clearance time
Time to clearance of gametocytes from the blood after treatment.
- PCR-adjusted treatment failure rate
Parasitaemia on or by day 28 may be due to recrudescence of the original infection or caused by a new infection. PCR-adjusted values exclude parasitaemia caused by a new infection.
- Parasitological conversion
Clearance of parasitaemia within a specified time after treatment.
- Parasitological failure
Parasitaemia detected within a specified time after treatment.
- Parasitological success
Absence of parasitaemia within a specified time after treatment.
- Total failure
People presenting with clinical failure or with parasitaemia on day 28.
- Treatment failure
This term is used loosely in the literature, but it generally means total failure or failure (clinical or parasitological) within the period of follow-up. The WHO modified definitions of treatment failure in 2003 to include late parasitological failures.
Malaria: prevention in travellers
Malaria: severe, life-threatening
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Dr David Taylor-Robinson, Liverpool School of Tropical Medicine, Liverpool, UK.
Dr Katharine Jones, Liverpool School of Tropical Medicine, Liverpool, UK.
Professor Paul Garner, Liverpool School of Tropical Medicine, Liverpool, UK.
David Sinclair, Liverpool School of Tropical Medicine, Liverpool, UK.
References
- 1.World Health Organization. WHO expert committee on malaria (twentieth report). World Health Organ Tech Rep Ser 2000;892:1–74. Available online at http://mosquito.who.int/docs/ecr20_toc.htm (last accessed 3 June 2009). [PubMed] [Google Scholar]
- 2.Stepniewska K, Taylor WR, Mayxay M, et al. In vivo assessment of drug efficacy against Plasmodium falciparum malaria: duration of follow-up. Antimicrob Agents Chemother 2004;48:4271–4280. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Omari AAA, Gamble C, Garner P. Artemether-lumefantrine (six-dose regimen) for treating uncomplicated falciparum malaria (Cochrane review). In: The Cochrane Library, Issue 4, 2007. Chichester, UK: John Wiley & Sons. Search date 2005; primary sources Medline, Embase, Lilacs, Cochrane Central Register of Controlled Trials, and Cochrane Infectious Diseases Group Specialised Register. [Google Scholar]
- 4.Obonyo CO, Juma EA, Ogutu BR, et al. Amodiaquine combined with sulfadoxine/pyrimethamine versus artemisinin-based combinations for the treatment of uncomplicated falciparum malaria in Africa: a meta-analysis. Trans R Soc Trop Med Hyg 2007;101:117–126. [DOI] [PubMed] [Google Scholar]
- 5.Zongo I, Dorsey G, Rouamba N, et al. Artemether-lumefantrine versus amodiaquine plus sulfadoxine-pyrimethamine for uncomplicated falciparum malaria in Burkina Faso: a randomised non-inferiority trial.Lancet 2007;369:491–498. [DOI] [PubMed] [Google Scholar]
- 6.Zongo I, Dorsey G, Rouamba N, et al. Randomized comparison of amodiaquine plus sulfadoxine-pyrimethamine, artemether-lumefantrine, and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Burkina Faso. Clin Infect Dis 2007;45:1453–1461. [DOI] [PubMed] [Google Scholar]
- 7.Faye B, Ndiaye JL, Ndiaye D, et al. Efficacy and tolerability of four antimalarial combinations in the treatment of uncomplicated Plasmodium falciparum malaria in Senegal. Malar J 2007;6:80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Fanello CI, Karema C, van DorenW, et al. A randomised trial to assess the safety and efficacy of artemether-lumefantrine (Coartem) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwanda. Trans R Soc Trop Med Hyg 2007;101:344–350. [DOI] [PubMed] [Google Scholar]
- 9.Dorsey G, Staedke S, Clark TD, et al. Combination therapy for uncomplicated falciparum malaria in Ugandan children: a randomized trial. JAMA 2007;297:2210–2219. [DOI] [PubMed] [Google Scholar]
- 10.Mutabingwa TK, Anthony D, Heller A, et al. Amodiaquine alone, amodiaquine+sulfadoxine-pyrimethamine, amodiaquine+artesunate, and artemether-lumefantrine for outpatient treatment of malaria in Tanzanian children: a four-arm randomised effectiveness trial. Lancet 2005;365:1474–1480. [DOI] [PubMed] [Google Scholar]
- 11.Menard D, Andrianina NN, Ramiandrasoa Z, et al. Randomized clinical trial of artemisinin versus non-artemisinin combination therapy for uncomplicated falciparum malaria in Madagascar. Malar J 2007;6:65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Karema C, Fanello CI, Van Overmeir C, et al. Safety and efficacy of dihydroartemisinin/piperaquine (Artekin) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan children. Trans R Soc Trop Med Hyg 2006;100:1105–1111. [DOI] [PubMed] [Google Scholar]
- 13.Staedke SG, Mpimbaza A, Kamya MR, et al. Combination treatments for uncomplicated falciparum malaria in Kampala, Uganda: randomised clinical trial. Lancet 2004;364:1950–1957. [DOI] [PubMed] [Google Scholar]
- 14.Abacassamo F, Enosse S, Aponte JJ, et al. Efficacy of chloroquine, amodiaquine, sulphadoxine-pyrimethamine and combination therapy with artesunate in Mozambican children with non-complicated malaria. Trop Med Int Health 2004;9:200–208. [DOI] [PubMed] [Google Scholar]
- 15.Yeka A, Banek K, Bakyaita N, et al. Artemisinin versus nonartemisinin combination therapy for uncomplicated malaria: randomized clinical trials from four sites in Uganda. PLoS Med 2005;2:e190. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Bukirwa H, Critchley J. Sulfadoxine-pyrimethamine plus artesunate versus sulfadoxine-pyrimethamine plus amodiaquine for treating uncomplicated malaria (Cochrane review). In: The Cochrane Library, Issue 4, 2007. Chichester, UK: John Wiley & Sons. Search date 2005; primary sources Medline, Embase, Lilacs, Cochrane Central Register of Controlled Trials, and Cochrane Infectious Diseases Group Specialised Register. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Blair S, Carmona-Fonseca J, Pineros JG, et al. Therapeutic efficacy test in malaria falciparum in Antioquia, Colombia. Malar J 2006;5:14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Bousema JT, Schneider P, Gouagna LC, et al. Moderate effect of artemisinin-based combination therapy on transmission of Plasmodium falciparum. J Infect Dis 2006;193:1151–1159. [DOI] [PubMed] [Google Scholar]
- 19.Mockenhaupt FP, Ehrhardt S, Dzisi SY, et al. A randomized, placebo-controlled, double-blind trial on sulfadoxine-pyrimethamine alone or combined with artesunate or amodiaquine in uncomplicated malaria. Trop Med Int Health 2005;10:512–520. [DOI] [PubMed] [Google Scholar]
- 20.Dorsey G, Njama D, Kamya MR, et al. Sulfadoxine/pyrimethamine alone or with amodiaquine or artesunate for treatment of uncomplicated malaria: a longitudinal randomised trial. Lancet 2002;360:2031–2038. [DOI] [PubMed] [Google Scholar]
- 21.Rwagacondo CE, Niyitegeka F, Sarushi J, et al. Efficacy of amodiaquine alone and combined with sulfadoxine-pyrimethamine and of sulfadoxine pyrimethamine combined with artesunate. Am J Trop Med Hyg 2003;68:743–747. [PubMed] [Google Scholar]
- 22.Omari AA, Gamble C, Garner P. Artemether-lumefantrine (four-dose regimen) for treating uncomplicated falciparum malaria (Cochrane review). In: The Cochrane Library, Issue 4, 2007. Chichester, UK: John Wiley & Sons. Search date 2005; primary sources Medline, Embase, Lilacs, Cochrane Central Register of Controlled Trials, and Cochrane Infectious Diseases Group Specialised Register. [Google Scholar]
- 23.Vugt MV, Wilairatana P, Gemperli B, et al. Efficacy of six doses of artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria. Am J Trop Med Hyg 1999;60:936–942. [DOI] [PubMed] [Google Scholar]
- 24.Koram KA, Abuaku B, Duah N, et al. Comparative efficacy of antimalarial drugs including ACTs in the treatment of uncomplicated malaria among children under 5 years in Ghana. Acta Tropica 2005;95:194–203. [DOI] [PubMed] [Google Scholar]
- 25.Martensson A, Stromberg J, Sisowath C, et al. Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania. Clin Infect Dis 2005;41:1079–1086. [DOI] [PubMed] [Google Scholar]
- 26.Guthmann JP, Cohuet S, Rigutto C, et al. High efficacy of two artemisinin-based combinations (artesunate + amodiaquine and artemether + lumefantrine) in Caala, Central Angola. Am J Trop Med Hyg 2006;75:143–145. [PubMed] [Google Scholar]
- 27.Bukirwa H, Yeka A, Kamya MR, et al. Artemisinin combination therapies for treatment of uncomplicated malaria in Uganda. PLoS Clin Trials 2006;1:e7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.van den Broek I, Kitz C, Al Attas S, et al. Efficacy of three artemisinin combination therapies for the treatment of uncomplicated Plasmodium falciparum malaria in the Republic of Congo. Malari J 2006;5:113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Mukhtar EA, Gadalla NB, El-Zaki SE, et al. A comparative study on the efficacy of artesunate plus sulphadoxine/pyrimethamine versus artemether-lumefantrine in eastern Sudan. Malar J 2007;6:92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Hutagalung R, Paiphun L, Ashley EA, et al. A randomized trial of artemether-lumefantrine versus mefloquine-artesunate for the treatment of uncomplicated multi-drug resistant Plasmodium falciparum on the western border of Thailand Malar J 2005;4:46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.van den Broek IV, Maung UA, Peters A, et al. Efficacy of chloroquine + sulfadoxine--pyrimethamine, mefloquine + artesunate and artemether + lumefantrine combination therapies to treat Plasmodium falciparum malaria in the Chittagong Hill Tracts, Bangladesh. Trans R Soc Trop Med Hyg 2005;99:727–735. [DOI] [PubMed] [Google Scholar]
- 32.Hamour S, Melaku Y, Keus K, et al. Malaria in the Nuba Mountains of Sudan: baseline genotypic resistance and efficacy of the artesunate plus sulfadoxine-pyrimethamine and artesunate plus amodiaquine combinations. Trans R Soc Trop Med Hyg 2005;99:548–554. [DOI] [PubMed] [Google Scholar]
- 33.van den Broek I, Amsalu R, Balasegaram M, et al. Efficacy of two artemisinin combination therapies for uncomplicated falciparum malaria in children under 5 years, Malakal, Upper Nile, Sudan. Malar J 2005;4:14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Swarthout TD, van denBroek IV, Kayembe G, et al. Artesunate + amodiaquine and artesunate + sulphadoxine-pyrimethamine for treatment of uncomplicated malaria in Democratic Republic of Congo: a clinical trial with determination of sulphadoxine and pyrimethamine-resistant haplotypes. Trop Med Int Health 2006;11:1503–1511. [DOI] [PubMed] [Google Scholar]
- 35.Bonnet M, Roper C, Felix M, et al. Efficacy of antimalarial treatment in Guinea: In vivo study of two artemisinin combination therapies in Dabola and molecular markers of resistance to sulphadoxine-pyrimethamine in N'Zérékoré. Malar J 2007;6:54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.World Health Organization. Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated malaria. 2003. http://mosquito.who.int/resistance.html (last accessed 3 June 2009). [Google Scholar]