Practical info In areas with chloroquine-sensitive P. vivax For chloroquine-sensitive vivax malaria, oral chloroquine at a total dose of 25 mg base/kg bw is effective and well tolerated. Lower total doses are not recommended, as these encourage the emergence of resistance. Chloroquine is given at an initial dose of 10 mg base/kg bw, followed by 10 mg/kg bw on the second day and 5 mg/kg bw on the third day. In the past, the initial 10-mg/kg bw dose was followed by 5 mg/kg bw at 6 h, 24 h and 48 h. As residual chloroquine suppresses the first relapse of tropical P. vivax (which emerges about 3 weeks after onset of the primary illness), relapses begin to occur 5–7 weeks after treatment if radical curative treatment with primaquine is not given. ACTs are highly effective in the treatment of vivax malaria, allowing simplification (unification) of malaria treatment; i.e. all malaria infections can be treated with an ACT. The exception is artesunate + SP, where resistance significantly compromises its efficacy. Although good efficacy of artesunate + SP was reported in one study in Afghanistan, in several other areas (such as South-East Asia) P. vivax has become resistant to SP more rapidly than P. falciparum. The initial response to all ACTs is rapid in vivax malaria, reflecting the high sensitivity to artemisinin derivatives, but, unless primaquine is given, relapses commonly follow. The subsequent recurrence patterns differ, reflecting the elimination kinetics of the partner drugs. Thus, recurrences, presumed to be relapses, occur earlier after artemether + lumefantrine than after dihydroartemisinin + piperaquine or artesunate + mefloquine because lumefantrine is eliminated more rapidly than either mefloquine or piperaquine. A similar temporal pattern of recurrence with each of the drugs is seen in the P. vivax infections that follow up to one third of acute falciparum malaria infections in South-East Asia. In areas with chloroquine-resistant P. vivax ACTs containing piperaquine, mefloquine or lumefantrine are the recommended treatment, although artesunate + amodiaquine may also be effective in some areas. In the systematic review of ACTs for treating P. vivax malaria, dihydroartemisinin + piperaquine provided a longer prophylactic effect than ACTs with shorter half-lives (artemether + lumefantrine, artesunate + amodiaquine), with significantly fewer recurrent parasitaemias during 9 weeks of follow-up (RR, 0.57; 95% CI, 0.40–0.82, three trials, 1066 participants). The half-life of mefloquine is similar to that of piperaquine, but use of dihydroartemisinin + piperaquine in P. vivax mono-infections has not been compared directly in trials with use of artesunate + mefloquine. Uncomplicated P. ovale, P. malariae or P. knowlesi malaria Resistance of P. ovale, P. malariae and P. knowlesi to antimalarial drugs is not well characterized, and infections caused by these three species are generally considered to be sensitive to chloroquine. In only one study, conducted in Indonesia, was resistance to chloroquine reported in P. malariae. The blood stages of P. ovale, P. malariae and P. knowlesi should therefore be treated with the standard regimen of ACT or chloroquine, as for vivax malaria. Mixed Malaria Infections Mixed malaria infections are common in endemic areas. For example, in Thailand, despite low levels of malaria transmission, 8% of patients with acute vivax malaria also have P. falciparum infections, and one third of acute P. falciparum infections are followed by a presumed relapse of vivax malaria (making vivax malaria the most common complication of falciparum malaria). Mixed infections are best detected by nucleic acid-based amplification techniques, such as PCR; they may be underestimated with routine microscopy. Cryptic P. falciparum infections in vivax malaria can be revealed in approximately 75% of cases by RDTs based on the PfHRP2 antigen, but several RDTs cannot detect mixed infection or have low sensitivity for detecting cryptic vivax malaria. ACTs are effective against all malaria species and so are the treatment of choice for mixed infections.

Other considerations The guideline development group recognized that, in the few settings in which P. vivax is the only endemic species and where chloroquine resistance remains low, the increased cost of ACT may not be worth the small additional benefits. Countries where chloroquine is used for treatment of vivax malaria should monitor for chloroquine resistance and change to ACT when the treatment failure rate is > 10% at day 28. Remarks Current methods cannot distinguish recrudescence from relapse or relapse from newly acquired infections, but the aim of treatment is to ensure that the rates of recurrent parasitaemia of any origin are < 10%. Primaquine has significant asexual stage activity against vivax malaria and augments the therapeutic response to chloroquine. When primaquine is given routinely for 14 days, it may mask low-level chloroquine resistance and prevent vivax recurrence within 28 days. Remarks Current methods do not distinguish recrudescence from relapse or relapse from newly acquired infection, but the aim of treatment is to ensure that the rates of recurrent parasitaemia of any origin is < 10% within 28 days. When primaquine is not given for radical cure, slowly eliminated ACT that prevents recurrent parasitaemia before day 28 should be used (dihydroartemisinin + piperaquine or artesunate + mefloquine). Primaquine has significant asexual stage activity against vivax malaria and augments the therapeutic response to chloroquine. When primaquine is given routinely for 14 days, it may mask low-level chloroquine resistance and prevent vivax recurrence within 28 days. When primaquine is given routinely for 14 days, ACTs with shorter half-lives (artemether + lumefantrine, or artesunate + amodiaquine) may be sufficient to keep the rate of recurrent parasitaemia before day 28 below 10%.