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Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial.

Bethell D, Se Y, Lon C, Tyner S, Saunders D, Sriwichai S, Darapiseth S, Teja-Isavadharm P, Khemawoot P, Schaecher K, Ruttvisutinunt W, Lin J, Kuntawungin W, Gosi P, Timmermans A, Smith B, Socheat D, Fukuda MM - PLoS ONE (2011)

Bottom Line: Cure rates were high in all treatment groups at 42 days despite almost half the patients remaining parasitemic on Day 3.There was no impact of increasing AS dose on median parasite clearance times, median parasite clearance rates or on the proportion of patients remaining parasitemic on Day 3.However at the lowest dose used (2 mg/kg/d) patients with parasitemia >10,000/µL had longer median (IQR) parasite clearance times than those with parasitemia <10,000/µL (63 (48-75) vs. 84 (66-96) hours, p<0.0001). 19% of patients in the high-dose arm developed neutropenia (absolute neutrophil count <1.0×10(9)/L) by Day 14 and resulted in the arm being halted early.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. delia.bethell@afrims.org

ABSTRACT

Background: The emergence of artemisinin resistance has raised concerns that the most potent antimalarial drug may be under threat. The currently recommended daily dose of artesunate (AS) is 4 mg/kg, and is administered for 3 days together with a partner antimalarial drug. This study investigated the impact of different AS doses on clinical and parasitological responses in malaria patients from an area of known artemisinin resistance in western Cambodia.

Methods: Adult patients with uncomplicated P. falciparum malaria were randomized into one of three 7-day AS monotherapy regimens: 2, 4 or 6 mg/kg/day (total dose 14, 28 and 42 mg/kg). Clinical, parasitological, pharmacokinetic and in vitro drug sensitivity data was collected over a 7-day inpatient period and during weekly follow-up to 42 days.

Results: 143 patients were enrolled (n = 75, 40 and 28 to receive AS 2, 4 and 6 mg/kg/day respectively). Cure rates were high in all treatment groups at 42 days despite almost half the patients remaining parasitemic on Day 3. There was no impact of increasing AS dose on median parasite clearance times, median parasite clearance rates or on the proportion of patients remaining parasitemic on Day 3. However at the lowest dose used (2 mg/kg/d) patients with parasitemia >10,000/µL had longer median (IQR) parasite clearance times than those with parasitemia <10,000/µL (63 (48-75) vs. 84 (66-96) hours, p<0.0001). 19% of patients in the high-dose arm developed neutropenia (absolute neutrophil count <1.0×10(9)/L) by Day 14 and resulted in the arm being halted early.

Conclusion: There is no pharmacodynamic benefit of increasing the daily dose of AS (4 mg/kg) currently recommended for short-course combination treatment of uncomplicated malaria, even in regions with emerging artemisinin resistance, as long as the partner drug retains high efficacy.

Trial registration: ClinicalTrials.gov NCT00722150.

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Related in: MedlinePlus

Modified intention-to-treat analysis: proportion of patients remaining parasitemic by treatment arm.
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pone-0019283-g004: Modified intention-to-treat analysis: proportion of patients remaining parasitemic by treatment arm.

Mentions: ITT analysis showed no differences between groups in median PCT100, PCT90, or PCT50, or in parasite reduction ratios at 24, 48 or 72 hours (Table 3, Figure 4). However, within AS2 patients with parasitemia >10,000/µL had significantly longer median (IQR) PCT100 than those with baseline parasitemia <10,000/µL (63 (48–75) vs. 84 (66–96) hours, p<0.0001); there was a similar but smaller effect seen in AS4 (p = 0.049), but not in AS6 (p = 0.65). This dose-effect was not seen for PCT90 or PCT50. Comparison of the slope of the log10 transformed parasite clearance curves showed no significant difference between treatment groups, and multiple regression analysis using slope as the dependent variable showed no significant association with parasitemia, history of previous malaria, IC50 DHA or treatment allocation. However comparison of the parasite clearance slopes between patients with a subsequent per protocol failure and those cured at 42 days showed a small but significant difference (0.037 (0.032–0.039 vs 0.041 (0.034–0.054, p = 0.032). Seventy-two hours after AS treatment commenced almost 50% of patients still had asexual parasites on a peripheral blood smear (49%, 46% and 48% in AS2, 4 and 6 respectively).


Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: a randomized clinical trial.

Bethell D, Se Y, Lon C, Tyner S, Saunders D, Sriwichai S, Darapiseth S, Teja-Isavadharm P, Khemawoot P, Schaecher K, Ruttvisutinunt W, Lin J, Kuntawungin W, Gosi P, Timmermans A, Smith B, Socheat D, Fukuda MM - PLoS ONE (2011)

Modified intention-to-treat analysis: proportion of patients remaining parasitemic by treatment arm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3094355&req=5

pone-0019283-g004: Modified intention-to-treat analysis: proportion of patients remaining parasitemic by treatment arm.
Mentions: ITT analysis showed no differences between groups in median PCT100, PCT90, or PCT50, or in parasite reduction ratios at 24, 48 or 72 hours (Table 3, Figure 4). However, within AS2 patients with parasitemia >10,000/µL had significantly longer median (IQR) PCT100 than those with baseline parasitemia <10,000/µL (63 (48–75) vs. 84 (66–96) hours, p<0.0001); there was a similar but smaller effect seen in AS4 (p = 0.049), but not in AS6 (p = 0.65). This dose-effect was not seen for PCT90 or PCT50. Comparison of the slope of the log10 transformed parasite clearance curves showed no significant difference between treatment groups, and multiple regression analysis using slope as the dependent variable showed no significant association with parasitemia, history of previous malaria, IC50 DHA or treatment allocation. However comparison of the parasite clearance slopes between patients with a subsequent per protocol failure and those cured at 42 days showed a small but significant difference (0.037 (0.032–0.039 vs 0.041 (0.034–0.054, p = 0.032). Seventy-two hours after AS treatment commenced almost 50% of patients still had asexual parasites on a peripheral blood smear (49%, 46% and 48% in AS2, 4 and 6 respectively).

Bottom Line: Cure rates were high in all treatment groups at 42 days despite almost half the patients remaining parasitemic on Day 3.There was no impact of increasing AS dose on median parasite clearance times, median parasite clearance rates or on the proportion of patients remaining parasitemic on Day 3.However at the lowest dose used (2 mg/kg/d) patients with parasitemia >10,000/µL had longer median (IQR) parasite clearance times than those with parasitemia <10,000/µL (63 (48-75) vs. 84 (66-96) hours, p<0.0001). 19% of patients in the high-dose arm developed neutropenia (absolute neutrophil count <1.0×10(9)/L) by Day 14 and resulted in the arm being halted early.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Medicine, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand. delia.bethell@afrims.org

ABSTRACT

Background: The emergence of artemisinin resistance has raised concerns that the most potent antimalarial drug may be under threat. The currently recommended daily dose of artesunate (AS) is 4 mg/kg, and is administered for 3 days together with a partner antimalarial drug. This study investigated the impact of different AS doses on clinical and parasitological responses in malaria patients from an area of known artemisinin resistance in western Cambodia.

Methods: Adult patients with uncomplicated P. falciparum malaria were randomized into one of three 7-day AS monotherapy regimens: 2, 4 or 6 mg/kg/day (total dose 14, 28 and 42 mg/kg). Clinical, parasitological, pharmacokinetic and in vitro drug sensitivity data was collected over a 7-day inpatient period and during weekly follow-up to 42 days.

Results: 143 patients were enrolled (n = 75, 40 and 28 to receive AS 2, 4 and 6 mg/kg/day respectively). Cure rates were high in all treatment groups at 42 days despite almost half the patients remaining parasitemic on Day 3. There was no impact of increasing AS dose on median parasite clearance times, median parasite clearance rates or on the proportion of patients remaining parasitemic on Day 3. However at the lowest dose used (2 mg/kg/d) patients with parasitemia >10,000/µL had longer median (IQR) parasite clearance times than those with parasitemia <10,000/µL (63 (48-75) vs. 84 (66-96) hours, p<0.0001). 19% of patients in the high-dose arm developed neutropenia (absolute neutrophil count <1.0×10(9)/L) by Day 14 and resulted in the arm being halted early.

Conclusion: There is no pharmacodynamic benefit of increasing the daily dose of AS (4 mg/kg) currently recommended for short-course combination treatment of uncomplicated malaria, even in regions with emerging artemisinin resistance, as long as the partner drug retains high efficacy.

Trial registration: ClinicalTrials.gov NCT00722150.

Show MeSH
Related in: MedlinePlus