Artemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria.

Abstract

Background
Plasmodium vivax is an important cause of malaria in many parts of Asia and South America, and resistance to the standard treatment (chloroquine) is now high in some parts of Oceania. This review aims to assess the current treatment options in the light of rising chloroquine resistance.

Objectives
To compare Artemisinin-based combination therapies (ACTs) with alternative antimalarial regimens for treating acute uncomplicated P.vivax malaria.

Search strategy
We searched the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS and the metaRegister of Controlled Trials (mRCT) using \"vivax\" and \"arte* OR dihydroarte*\" as search terms.

Selection criteria
Randomized controlled trials comparing ACTs versus standard therapy, or comparing alternative ACTs, in adults and children with uncomplicated P. vivax malaria.

Data collection and analysis
Two authors independently assessed trials for eligibility and risk of bias, and extracted data. Recurrent parasitaemia prior to day 28 was taken as a proxy for effective treatment of the blood stage parasite, and drugs compared using risk ratios (RR) and 95% confidence intervals (CI). Trials following patients for longer than 28 days were used to assess the duration of the post-treatment prophylactic effect of ACTs. The quality of evidence has been assessed using the GRADE methodology.

Main results
ACTs vs chloroquine In settings where chloroquine remains effective, ACTs are equivalent at preventing recurrent parasitemias before day 28 (four trials, 1185 participants; RR 1, 95% CI 0.30 to 3.39, high quality evidence). ACT combinations with long half-lives are probably superior to chloroquine over six to eight weeks follow-up, with significantly fewer recurrent episodes 0 after day 28 (two trials, 668 participants, RR 0.47, 95% CI 0.29 to 0.76, moderate quality evidence). It is not clear if this effect is still present if primaquine is given. Dihydroartemisinin-piperaquine versus alternative ACTs Dihydroartemisinin-piperaquine is the most studied ACT for the treatment of P. vivax. In high transmission settings it is probably superior to artemether-lumefantrine, artesunate plus sulphadoxine-pyrimethamine and artesunate plus amodiaquine at preventing recurrent parasitemias before day 28 (three trials, 334 participants, RR 0.20, 95% CI 0.08 to 0.49, moderate quality evidence). This advantage with dihydroartemisinin-piperaquine may last for at least six weeks even when primaquine is also given to achieve radical cure; with fewer recurrent parasitemias occurring between day 28 and day 42 (two trials, 179 participants, RR 0.21, 95% CI 0.10 to 0.46, low quality evidence). The data available from low transmission settings is too limited to make conclusions about the relative effectiveness of ACTs.

Authors' conclusions
ACTs appear at least equivalent to chloroquine at effectively treating the blood stage P. vivax infection. Even where chloroquine remains effective this finding may allow for simplified protocols treating all forms of malaria with ACTs. Dihydroartemisinin-piperaquine may provide a longer period of post-treatment prophylaxis than artemether-lumefantrine or artesunate plus amodiaquine, which is likely to be a function of the long elimination half-life of piperaquine. This effectmay be clinically important in high transmission settings whether primaquine is also given or not.

Plain Language Summary

What is P. vivax malaria and how do ACTs work?
Plasmodium vivax is one of five species of the malaria parasite known to cause clinical illness. It is a common cause of malaria in Asia, South America and Oceania. Unlike P. falciparum (the commonest cause of malaria in Africa), P.vivax has a liver stage which is not treated by most common antimalarial drugs. This liver stage can become active and cause a relapse of clinical illness weeks or even years after the initial illness. The standard treatment for vivax malaria has been chloroquine to treat the clinical illness, and a 14 day course of primaquine to clear the liver stage. In some parts of Oceania the P. vivax parasite in now highly resistant to chloroquine, which makes this treatment ineffective. Artemisinin-based combination therapies (ACTs) are now the recommended treatment for falciparum malaria worldwide. As the effectiveness of chloroquine for P. vivax declines, alternative therapies are needed. If ACTs are also effective against P. vivax they could become the standard treatment for all forms of malaria. Current ACT combinations do not contain drugs effective against the liver stage of P. vivax so primaquine would still be necessary to achieve complete cure.

What the research says about the effect of using ACTs
Compared to chloroquine - People who are treated with ACT are probably less likely to have another episode of P. vivax malaria during the next six to eight weeks than those treated with chloroquine (only dihydroartemisinin-piperaquine, artesunate plus sulphadoxine-pyrimethamine, and artesunate-pyronaridine have been compared with chloroquine). It is not clear whether this advantage is still present when primaquine is given to achieve a complete cure.Compared to alternative ACTs - People who are treated with dihydroartemisinin-piperaquine are probably less likely to have another episode of P. vivax malaria during the next six weeks than those treated with alternative ACTs (only artemether-lumefantrine, artesunate plus sulphadoxine-pyrimethamine and artesunate plus amodiaquine have been compared). This advantage may be present even when additional primaquine is given to achieve a complete cure.

Citation

Cochrane Database of Systematic Reviews 2011, Issue 7. Art. No.: CD008492. [DOI: 10.1002/14651858.CD008492.pub2.]

Artemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria.

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