What is P. vivax malaria and how do ACTs work?
P. 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 P. 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
We examined the research published up to 28 March 2013.
Compared to chloroquine
People who are treated with an 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.
ACTs appear at least equivalent to chloroquine at effectively treating the blood stage of P. vivax infection. Even in areas where chloroquine remains effective, this finding may allow for simplified protocols for treating all forms of malaria with ACTs. In areas where chloroquine no longer cures the infection, ACTs offer an effective alternative.
Dihydroartemisinin-piperaquine is the most studied ACT. It may provide a longer period of post-treatment prophylaxis than artemether-lumefantrine or artesunate plus amodiaquine. This effect may be clinically important in high transmission settings whether primaquine is also given or not.
Plasmodium vivax is an important cause of malaria in many parts of Asia and South America, and parasite 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 increasing chloroquine resistance.
To compare artemisinin-based combination therapies (ACTs) with alternative antimalarial regimens for treating acute uncomplicated P. vivax malaria.
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) up to 28 March 2013 using “vivax” and “arte* OR dihydroarte*” as search terms.
Randomized controlled trials comparing ACTs versus standard therapy, or comparing alternative ACTs, in adults and children with uncomplicated P. vivax malaria.
Two authors independently assessed trials for eligibility and risk of bias, and extracted data. We used recurrent parasitaemia prior to day 28 as a proxy for effective treatment of the blood stage parasite, and compared drug treatments using risk ratios (RR) and 95% confidence intervals (CIs). We used trials following patients for longer than 28 days to assess the duration of the post-treatment prophylactic effect of ACTs. We assessed the quality of the evidence using the GRADE approach.
We included 14 trials, that enrolled 2592 participants, and were all conducted in Asia and Oceania between 2002 and 2011.
ACTs versus chloroquine
ACTs clear parasites from the peripheral blood quicker than chloroquine monotherapy (parasitaemia after 24 hours of treatment: RR 0.42, 95% CI 0.36 to 0.50, four trials, 1652 participants, high quality evidence).
In settings where chloroquine remains effective, ACTs are as effective as chloroquine at preventing recurrent parasitaemias before day 28 (RR 0.58, 95% CI 0.18 to 1.90, five trials, 1622 participants, high quality evidence). In four of these trials, recurrent parasitaemias before day 28 were very low following treatment with both chloroquine and ACTs. The fifth trial, from Thailand in 2011, found increased recurrent parasitaemias following treatment with chloroquine (9%), while they remained low following ACT (2%) (RR 0.25, 95% CI 0.09 to 0.66, one trial, 437 participants).
ACT combinations with long half-lives probably also provide a longer prophylactic effect after treatment, with significantly fewer recurrent parasitaemias between day 28 and day 42 or day 63 (RR 0.57, 95% CI 0.40 to 0.82, three trials, 1066 participants, moderate quality evidence). One trial, from Cambodia, Thailand, India and Indonesia, gave additional primaquine to both treatment groups to reduce the risk of spontaneous relapses. Recurrent parasitaemias after day 28 were lower than seen in the trials that did not give primaquine, but the ACT still appeared to have an advantage (RR 0.27, 95% CI 0.08 to 0.94, one trial, 376 participants, low quality evidence).
ACTs versus alternative ACTs
In high transmission settings, dihydroartemisinin-piperaquine is probably superior to artemether-lumefantrine, artesunate plus sulphadoxine-pyrimethamine and artesunate plus amodiaquine at preventing recurrent parasitaemias before day 28 (RR 0.20, 95% CI 0.08 to 0.49, three trials, 334 participants, moderate quality evidence).
Dihydroartemisinin-piperaquine may also have an improved post-treatment prophylactic effect lasting for up to six weeks, and this effect may be present even when primaquine is also given to achieve radical cure (RR 0.21, 95% CI 0.10 to 0.46, two trials, 179 participants, low quality evidence).
The data available from low transmission settings is too limited to reliably assess the relative effectiveness of ACTs.