Artemisinin-derivative combination therapies (ACT) are highly efficacious against multidrug-resistant Plasmodium falciparum malaria. Few efficacy data, however, are available for vivax malaria. With high rates of chloroquine (CQ) resistance in both vivax and falciparum malaria in Papua Province, Indonesia, new combination therapies are required for both species. We recently found artesunate plus sulfadoxine-pyrimethamine (ART-SP) to be highly effective (96%) in the treatment of falciparum malaria in Papua Province. Following a preliminary study of CQ plus sulfadoxine-pyrimethamine (CQ-SP) for the treatment of Plasmodium vivax infection, we used modified World Health Organization criteria to evaluate the efficacy of ART-SP for the treatment of vivax malaria in Papua. Nineteen of 22 patients treated with ART-SP could be evaluated on day 28, with no early treatment failures. Adequate clinical and parasitological responses were found by day 14 in all 20 (100%) of the patients able to be evaluated and by day 28 in 17 patients (89.5%). Fever and parasite clearance times were short, with hematological improvement observed in 70.6% of the patients. Double (at positions 58 and 117) and quadruple (at positions 57, 58, 61, and 117) mutations in the P. vivax dihydrofolate reductase (PvDHFR) were common in Papuan P. vivax isolates (46 and 18%, respectively). Treatment failure with SP-containing regimens was significantly higher with isolates with this PvDHFR quadruple mutation, which included a novel T3M mutation at residue 61 linked to an S3T (but not an S3N) mutation at residue 117. ART-SP ACT resulted in a high cure rate for both major Plasmodium species in Papua, though progression of DHFR mutations in both species due to the continued use of SP monotherapy for clinically diagnosed malaria threatens the future utility of this combination.High rates of chloroquine (CQ) resistance and CQ treatment failure have been found in both vivax and falciparum malaria in Papua Province (formerly Irian Jaya), Indonesia (2,3,5,21,28,38), and new combination therapies are required for each species. Artemisinin-derivative combination therapies (ACT) are being used increasingly for the treatment of multidrug-resistant Plasmodium falciparum malaria (29) because of their excellent efficacy (23,31,39,41), their ability to slow or reverse the emergence of resistance (24, 30), and their ability to reduce malaria transmission (24, 30). Despite the coexistence of falciparum and vivax malaria in many parts of the world where malaria treatment is usually based on clinical diagnosis, there have been few studies assessing the efficacy of artemisinin derivatives in treating vivax malaria and none in the area of CQ-resistant P. vivax. Studies of artesunate (ART) monotherapy for P. vivax infection have demonstrated rapid clearance of fever and parasites (1,6,33,43). However, with its very short half-life, no ART remains by the time of the first relapse of P. vivax infection, approximately 3 weeks after treatment begins, resulting in a high frequency of...

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In areas such as eastern Indonesia where both Plasmodium falciparum and Plasmodium vivax occur, rapid antigen detection tests for malaria need to be able to detect both species. We evaluated the new combined P. falciparum-P. vivaximmunochromatographic test (ICT Malaria P.f/P.v.) in Radamata Primary Health Centre, Sumba, Indonesia, from February to May 1998 with 560 symptomatic adults and children with a presumptive clinical diagnosis of malaria. Blinded microscopy was used as the “gold standard,” with all discordant and 20% of concordant results cross-checked blindly. Only 50% of those with a presumptive clinical diagnosis of malaria were parasitemic. The ICT Malaria P.f/P.v immunochromatographic test was sensitive (95.5%) and specific (89.8%) for the diagnosis of falciparum malaria, with a positive predictive value (PPV) and a negative predictive value (NPV) of 88.1 and 96.2%, respectively. HRP2 and panmalarial antigen line intensities were associated with parasitemia density for both species. Although the specificity and NPV for the diagnosis of vivax malaria were 94.8 and 98.2%, respectively, the overall sensitivity (75%) and PPV (50%) for the diagnosis of vivax malaria were less than the desirable levels. The sensitivity for the diagnosis of P. vivax malaria was 96% with parasitemias of >500/μl but only 29% with parasitemias of <500/μl. Nevertheless, compared with the test with HRP2 alone, use of the combined antigen detection test would reduce the rate of undertreatment from 14.7 to 3.6% for microscopy-positive patients, and this would be at the expense of only a modest increase in the rate of overtreatment of microscopy-negative patients from 7.1 to 15.4%. Cost remains a major obstacle to widespread use in areas of endemicity.

Chloroquine (CQ) treatment of CQ-resistant Plasmodium falciparum is associated with a significantly higher prevalence of post-treatment gametocytaemia which has been linked to the preferential transmission of CQ-resistant parasites. It is not known whether treatment failure (TF) with sulfadoxine-pyrimethamine (SP) is associated with the same higher prevalence of gametocytaemia as that seen with CQ TF. Using 1997 WHO in-vivo drug efficacy protocols for malaria, we therefore compared (in a study in 1999) the frequency of gametocytaemia in those with TF to the frequency seen in those with an adequate clinical and parasitological response (ACPR) following treatment with one of 3 regimens in Papua, Indonesia: SP monotherapy (n = 87; TF 20.7%), CQ monotherapy (n = 48; TF 83.3%), and the combination of CQ plus SP (n = 34; TF 38.2%). Following SP, day 7 prevalence was significantly higher in those with TF (67%) than with ACPR (38%, P = 0.03). Following combination treatment with CQ + SP, the day 14 gametocyte prevalence was significantly higher in those with TF (100% vs 38%, P = 0.016). The higher prevalence of SP TF-associated gametocytaemia may contribute to increased transmission of antifolate-resistant strains, and further cautions against the use of SP as monotherapy. Adding SP to CQ, after significant resistance has emerged to both drugs, may not prevent enhanced transmission of dual-resistant strains and progression of anti-folate resistance.

Abstract. Combining artesunate with existing antimalarial drugs may improve cure rates, delay emergence of resistance, and reduce transmission. We performed a randomized comparative trial to quantify the effect of adding artesunate to sulfadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria in Indonesia. Using a modified 1997 World Health Organization protocol for assessment of therapeutic efficacy of antimalarial drugs, 105 patients (stratified by age/ethnic group) were randomized: 53 received artesunate orally, 4 mg/kg of body weight, a single daily dose for three days, plus sulfadoxine-pyrimethamine orally (1.25 mg of pyrimethamine/kg of body weight), a single dose on day 0, and 52 patients received sulfadoxine-pyrimethamine alone. Six from the combination group were withdrawn from analysis, as were six of the sulfadoxine-pyrimethamine group. Treatment failure rates on day 14 were 0% in the artesunate plus sulfadoxine-pyrimethamine group and 8.7% in the sulfadoxine-pyrimethamine group (P ϭ 0.12). Treatment failure rates on day 28 were 4.4% and 15.2%, respectively (P ϭ 0.16). Relative risk of treatment failure at 28 days was 0.3 (95% confidence interval [CI] ϭ 0.1-1.3). Mean fever clearance time (1.3 versus 1.7 days) and mean parasite clearance time (1.4 versus 2.0 days) were both faster in the artesunate plus sulfadoxinepyrimethamine group than in the sulfadoxine-pyrimethamine group (P ϭ 0.08 and P Ͻ 0.0001, respectively). Only 20 (39.2%) of 51 patients treated with artesunate plus sulfadoxine-pyrimethamine were still parasitemic on day 1 compared with 45 (86.5%) of 52 patients treated with sulfadoxine-pyrimethamine alone (P ϭ 0.000001, relative risk [RR] ϭ 0.4, 95% CI ϭ 0.3-0.6). Gametocyte carriage was lower following artesunate plus sulfadoxine-pyrimethamine than following sulfadoxine-pyrimethamine (RR ϭ 0.5, 95% CI ϭ 0.2-1.0 on day 7 and RR ϭ 0.5, 95% CI ϭ 0.2-1