Artemisinin-based combination therapy for ... - The Cochrane Library

of findings tables’. For these tables we asked the following questions:
1) Is dihydroartemsinin-piperaquine a suitable
alternative to the currently recommended ACTs?
There is high quality evidence that DHA-P is at least as effective
(at reducing PCR corrected treatment failure) as AS+MQ in Asia,
and AL6 in Africa, and moderate quality evidence that DHA-P is
at least as effective as AS+AQ (Appendix 6).
2) Does amodiaquine plus sulfadoxine-pyrimethamine
remain a valid alternative to ACTs?
The performance of AQ+SP is highly variable and so it is difficult
to make general statements on relative effects. There is moderate
quality evidence that AQ+SP is inferior to DHA-P and AL6 in
East Africa and very low quality evidence that it is also inferior to
AS+AQ (Appendix 6).
3) Does artesunate plus sulfadoxine-pyrimethamine remain a valid
alternative to other ACTs?
There is no good quality evidence comparing AS+SP to DHA-P,
AS+MQ or AL6. In trials comparing AS+SP to AS+AQ both drugs
performed well and no clear difference was shown (Appendix 6).
4) Is artesunate plus mefloquine a valid alternative to the currently
used ACTs in Africa?
AS+MQ generally performed well in trials in Asia against DHA-
P and AL6 (Appendix 6). The direct evidence from Africa versus
AS+AQ and AQ+SP is of low quality (Summary of findings table 7;
Summary of findings table 8). The high performance of AS+MQ
is likely to be maintained in Africa where resistance to mefloquine
is low.
For the comparison artemether-lumefantrine versus artesunate
plus amodiaquine see Appendix 6.
Potential biases in the review process
Data extraction was unblinded. All included trials are published;
we were unable to obtain further unpublished data from pharmaceutical
companies.
A U T H O R S ’ C O N C L U S I O N S
Implications for practice
All five ACTs performed adequately, to be used as first-line therapies,
in most sites where they were studied, however there are
examples of failure rates above 10% with all combinations, emphasizing
the need for continued monitoring and evaluation.
Artemisinin-based combination therapy for treating uncomplicated malaria (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
There is now a growing weight of evidence available to justify
the use of dihydroartemisinin-piperaquine as a first-line treatment
option for P. falciparum malaria.
There is evidence that the non-artemisinin combination AQ+SP
is failing in parts of East Africa where DHA-P, AL6, and AS+AQ
have been shown to be superior. There is also evidence that ACTs
have a superior effect on gametocytes that may be of public health
benefit particularly in low transmission settings.
The ACTs appear to be effective in treating the blood stage of
P. vivax. There may also be some benefit in using drugs with
long half-lives to delay spontaneous relapses. This prophylactic
effect needs to be balanced with the theoretical risk of promoting
the development of drug resistance. Additionally, in areas where
primaquine is being used to provide a radical cure this effect may
not be be of clinical significance.
Evidence of the safety of artemisinins is accumulating. Serious
adverse events with these drugs appear to be rare. However, these
trials are not powered to detect rare but clinically important events
and so it is imperative that active monitoring continues.
Implications for research
There are several new ACT combinations in development which
are likely to become commercially available in the next few years.
Policy makers therefore have a greater range of potential products.
In these circumstances, improved information on comparative efficacy,
adverse events, and tolerability is invaluable for informed
decision making.
Many trials are using relatively standardized primary outcomes. A
move towards standardized approaches to measuring and reporting
secondary outcomes, and adverse events, would greatly improve
comparability between trials and meta-analysis.
In the absence of mefloquine resistance, AS+MQ is likely to be
highly effective in African countries but concerns regarding poor
tolerability in young infants have restricted its use in this setting.
There is in fact little evidence on the use of any of the ACTs in
this age group, and head to head randomized trials are necessary
to clarify or refute the specific concerns regarding AS+MQ and to
provide more general guidance on the choice and use of ACTs in
infants.
Further research is needed to clarify the role of specific ACTs in
the treatment of P. vivax. It remains unclear as to whether a long
acting ACT offers individual or public health benefits compared
to standard treatments for radical cure.
The most vulnerable populations (pregnant women and very
young infants) were excluded from all trials, and represent a critical
gap in current knowledge.
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