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close this bookGuidelines for the Treatment of Malaria (WHO; 2006; 266 pages) View the PDF document
View the documentGlossary
View the documentAbbreviations
open this folder and view contents1. Introduction
View the document2. The clinical disease
open this folder and view contents3. Treatment objectives
open this folder and view contents4. Diagnosis of malaria
open this folder and view contents5. Resistance to antimalarial medicines9
open this folder and view contents6. Antimalarial treatment policy
close this folder7. Treatment of uncomplicated P. Falciparum malaria10
View the document7.1 Assessment
View the document7.2 Antimalarial combination therapy
View the document7.3 The choice of artemisinin-based combination therapy options
View the document7.4 Practical aspects of treatment with recommended ACTs
View the document7.5 Incorrect approaches to treatment
View the document7.6 Additional aspects of clinical management
View the document7.7 Operational issues in treatment management
View the document7.8 Management of treatment failures
View the document7.9 Treatment in specific populations and situations
View the document7.10 Coexisting morbidities
open this folder and view contents8. Treatment of severe falciparum malaria14
open this folder and view contents9. Treatment of malaria caused by P. vivax, P. ovale or P. malariae19
View the document10. Mixed malaria infections
open this folder and view contents11. Complex emergencies and epidemics
open this folder and view contentsAnnexes
 

7.3 The choice of artemisinin-based combination therapy options

Although there are some minor differences in oral absorption and bioavailability between the different artemisinin derivatives, there is no evidence that these differences are clinically significant in current formulations. It is the properties of the partner medicine that determine the effectiveness and choice of combination. ACTs with amodiaquine, atovaquone-proguanil, chloroquine, clindamycin, doxycycline, lumefantrine, mefloquine, piperaquine, pyronaridine, proguanil-dapsone, sulfadoxine-pyrimethamine and tetracycline have all been evaluated in trials carried out across the malaria-affected regions of the world. Some of these are studies for product development.

Though there are still gaps in our knowledge, there is reasonable evidence on safety and efficacy on which to base recommendations.

EVIDENCE: trials comparing ACTsa

Interventions: oral AL, AS+AQ, AS+MQ, AS+SP

Summary of RCTs: AL 6-dose regimen compared with 4-dose regimen; 6 doses resulted in higher cure rate in 1 trial in Thailand (RR: 0.19; 95% CI: 0.06-0.62).

AS+MQ compared with AL 6-dose regimen; systematic review including 2 small RCTs from Thailand. Higher proportion of patients with parasitaemia at day 28 with AL but difference not statistically significant. One additional RCT in Lao People's Democratic Republic also reported higher proportions of patients with parasitaemia at day 42 with AL but also not statistically significant.

AS+AQ compared with AL 6-dose regimen; 1 trial in Tanzania found a significantly higher proportion of parasitological failures on day 28 with AS+AQ.

No trials of AL compared with AS+SP.

Expert comment: the efficacy of ACTs with AQ or SP as partner medicines is insufficient where cure rates with these medicines as monotherapies is less than 80%. The efficacy of AL and AS+MQ generally exceeds 90% except at the Thai-Cambodian border, where AL failure rate was 15%.

Basis of decision: expert opinion.


Recommendations

1. Use the following ACTs: AL (6-dose regimen), AS+AQ, AS+MQ, AS+SP.

2. In areas with AQ and SP resistance exceeding 20% (PCR-corrected at day 28 of follow-up), use AS+MQ or AL.

 

a See also Annex 7.4


The following ACTs are currently recommended (alphabetical order):

• artemether-lumefantrine,
• artesunate + amodiaquine,
• artesunate + mefloquine,
• artesunate + sulfadoxine-pyrimethamine.


Note: amodiaquine + sulfadoxine-pyrimethamine may be considered as an interim option where ACTs cannot be made available, provided that efficacy of both is high.

7.3.1 Rationale for the exclusion of certain antimalarials

Several available drugs that were considered by the Technical Guidelines Development Group are currently not recommended.

• Chlorproguanil-dapsone has not yet been evaluated as an ACT partner drug, so there is insufficient evidence of both efficacy and safety to recommend it as a combination partner.

• Atovaquone-proguanil has been shown to be safe and effective as a combination partner in one large study, but is not included in these recommendations for deployment in endemic areas because of its very high cost.

• Halofantrine has not yet been evaluated as an ACT partner medicine and is not included in these recommendations because of safety concerns.

• Dihydroartemisinin (artenimol)-piperaquine has been shown to be safe and effective in large trials in Asia, but is not included in these recommendations as it is not yet available as a formulation manufactured under good manufacturing practices, and has not yet been evaluated sufficiently in Africa and South America.


Several other new antimalarial compounds are in development but do not yet have a sufficient clinical evidence to support recommendation here.

7.3.2 Deployment considerations affecting choice

Although for many countries, artemether-lumefantrine and artesunate + mefloquine may give the highest cure rates, there may be problems of affordability and availability of these products. Also, there is currently insufficient safety and tolerability data on artesunate + mefloquine at the recommended dose of 25mg/kg in African children to support its recommendation there. Trials with mefloquine monotherapy (25mg/kg) have raised concerns of tolerability in African children. Countries may therefore opt instead to use artesunate + amodiaquine and artesunate + sulfadoxine-pyrimethamine, which may have lower cure rates because of resistance. Although still effective in some areas, sulfadoxine-pyrimethamine and amodiaquine are widely available as monotherapies, providing continued selection pressure, and it is likely that resistance will continue to worsen despite deployment of the corresponding ACTs. This may be a particular problem in settings where sulfadoxine-pyrimethamine is being used for intermittent preventive treatment in pregnancy; artesunate + sulfadoxine-pyrimethamine should probably not be used in such settings.

Summary of recommendations on treatment for uncomplicated falciparum malaria

RECOMMENDATIONS

LEVEL OF EVIDENCE

The treatment of choice for uncomplicated falciparum malaria is a combination of two or more antimalarials with different mechanisms of action.

S, T, O

ACTs are the recommended treatments for uncomplicated falciparum malaria.

S

The following ACTs are currently recommended:

- artemether-lumefantrine, artesunate + amodiaquine, artesunate + mefloquine, artesunate + sulfadoxine-pyrimethamine.

S, T, O

The choice of ACT in a country or region will be based on the level of resistance of the partner medicine in the combination:

- in areas of multidrug resistance (South-East Asia), artesunate + mefloquine or artemether-lumefantrine

- in Africa, artemether-lumefantrine, artesunate + amodiaquine; artesunate + sulfadoxine-pyrimethamine.

E S

The artemisinin derivative components of the combination must be given for at least 3 days for an optimum effect.

S

Artemether-lumefantrine should be used with a 6-dose regimen.

T, E

Amodiaquine + sulfadoxine-pyrimethamine may be considered as an interim option in situations where ACTs cannot be made available.

E

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