Therapy of uncomplicated falciparum malaria: a randomized trial comparing artesunate plus sulfadoxine-pyrimethamine versus sulfadoxine-pyrimethamine alone in Irian Jaya, Indonesia.

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 Six from the combination group were withdrawn from analysis, as were six of the sulfadoxine-pyrimethamine group.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 = 0.12). Treatment failure rates on day 28 were 4.4% and 15.2%, respectively (P = 0.16). Relative risk of treatment failure at 28 days was 0.3 (95% confidence interval [CI] = 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 sulfadoxine-pyrimethamine group than in the sulfadoxine-pyrimethamine group (P = 0.08 and P < 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 = 0.000001, relative risk [RR] = 0.4, 95% CI = 0.3-0.6). Gametocyte carriage was lower following artesunate plus sulfadoxine-pyrimethamine than following sulfadoxine-pyrimethamine (RR = 0.5, 95% CI = 0.2-1.0 on day 7 and RR = 0.5, 95% CI = 0.2-1.1 on day 14). Mild diarrhea, rash, and itching resolved without treatment. Combined artesunate plus sulfadoxine-pyrimethamine resulted in more rapid fever and parasiteclearance, was well tolerated, reduced risk of treatment failure, and lowered gametocyte carriage.

Detection of histidine rich protein 2 and panmalarial ICT Malaria Pf/Pv test antigens after chloroquine treatment of uncomplicated falciparum malaria does not reliably predict treatment outcome in eastern Indonesia.

In regions with drug-resistant malaria, the ability to rapidly detect or predict treatment failure (TF) soon after a course of standard therapy for Plasmodium falciparum malaria would facilitate the prompt institution of second-line therapy. We thus evaluated longitudinally the ability of the ICT Malaria Pf/Pv immunochromatographic test to predict treatment outcome. Sixty-six Sumbanese Indonesians with uncomplicated falciparum malaria were treated with chloroquine and followed for 28 days by use of 1997 World Health Organization criteria for assessment of therapeutic efficacy of antimalarial drugs. The ICT Pf/Pv testing could be compared with microscopy in approximately half of the patients on each day of follow-up. Although strongly positive histidine rich protein 2 (HRP2) line intensities (equal to or greater than the control band) in convalescence were highly predictive of TF, any degree of positivity for the HRP2 and panmalarial antigens in convalescence was only moderately predictive of TE Positive predictive values of the HRP2 and panmalarial antigens for TF were 76.9% and 87.0%, respectively, on Day 3, 82.4% and 87.5% on Day 7, and 78.9% and 78.9% on Day 14. Negative HRP2 and panmalarial antigen results in convalescence were even less predictive of an adequate clinical response, and false-negative HRP2 and panmalarial antigen test results were found in one-sixth (6 of 37) of recrudescent infections diagnosed by microscopy among patients with late treatment failure. To reliably predict treatment outcome with rapid antigen tests, further development appears necessary to improve sensitivity for viable asexual parasites while avoiding detection of both gametocytes and persistent antigen in convalescence.

Field evaluation of the ICT malaria P.f/P.v immunochromatographic test for detection of Plasmodium falciparum and Plasmodium vivax in patients with a presumptive clinical diagnosis of malaria in eastern Indonesia.

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. vivax immunochromatographic 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/microl but only 29% with parasitemias of <500/microl. 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.

Persistent ICT malaria P.f/P.v panmalarial and HRP2 antigen reactivity after treatment of Plasmodium falciparum malaria is associated with gametocytemia and results in false-positive diagnoses of Plasmodium vivax in convalescence.

A problem with rapid Plasmodium falciparum-specific antigen histidine-rich protein 2 (HRP2) detection tests for malaria is the persistence of antigen in blood after the disappearance of asexual-stage parasitemia and clinical symptoms, resulting in false-positive (FP) test results following treatment. The ICT P.f/P.v immunochromatographic test detects both HRP2 and a panmalarial antigen (PMA) found in both P. falciparum and Plasmodium vivax. To examine posttreatment antigen persistence with this test and whether persistent sexual-stage forms (gametocytes) are a cause of FP tests after treatment, we compared serial antigen test results with microscopy results from patients symptomatic with P. falciparum malaria in Indonesia for 28 days following treatment with chloroquine (CQ; n = 66), sulfadoxine-pyrimethamine (SP; n = 36), and artesunate plus sulfadoxine-pyrimethamine (ART + SP; n = 15). Persistent FP antigenemia following SP treatment occurred in 29% (HRP2) and 42% (PMA) of the patients on day 7 and in 10% (HRP2) and 23% (PMA) on day 14. The high rates of persistent HRP2 and PMA antigenemia following CQ and SP treatment were strongly associated with the presence of gametocytemia, with the proportion with gametocytes on day 7 posttreatment being significantly greater in those with FP results than in those with true-negative PMA and HRP2 results. Gametocyte frequency on day 14 post-SP treatment was also greater in those with FP PMA results. Following SP treatment, PMA persisted longer than HRP2, giving an FP diagnosis of P. vivax in up to 16% of patients on day 14, with all FP P. vivax diagnoses having gametocytemia. In contrast, PMA was rapidly cleared following ART + SP treatment in association with rapid clearance of gametocytemia. Gametocytes appear to be an important cause of persistent posttreatment panmalarial antigenemia in areas of endemicity and may also contribute in part to persistent HRP2 antigenemia following treatment.