Artemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria

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 themetaRegister 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. 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 effect may be clinically important in high transmission settings whether primaquine is also given or not.