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

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 <1.0×109/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 (4mg/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

Dose-dependent risk of neutropenia after 7-day courses of artesunate monotherapy in Cambodian patients with acute Plasmodium falciparum malaria.

BACKGROUND: Fears of emerging artemisinin resistance in western Cambodia have prompted a series of clinical trials investigating whether slow responses to antimalarial treatment can be overcome by increasing doses of drug. METHODS: Patients with uncomplicated malaria were allocated 1 of 3 oral artesunate monotherapy regimens (2, 4, or 6 mg/kg/day for 7 days) and were observed for 42 days. A series of safety measures, including complete blood count on days 0, 3, 6, and 14, was implemented because of a lack of safety data for these experimental doses. RESULTS: After 3 doses, geometric mean absolute neutrophil counts were reduced in all groups, and 2 patients required artesunate to be discontinued because of neutropenia (absolute neutrophil count, <1.0 × 10(3) cells/μL). Recipients of the 6 mg/kg/day dosage had significantly lower geometric mean absolute neutrophil counts than did recipients of the 2 and 4 mg/kg/day dosages at 6 and 14 days (P < .001 for each). Overall, 5 (19%) of 26 patients who received the 6 mg/kg/day dosage became neutropenic within 14 days, triggering a cohort-halting rule and ending the trial early. Pharmacokinetic data from neutropenic patients showed wide variance, with plasma clearance occurring significantly slower in neutropenic patients than in nonneutropenic patients. CONCLUSIONS: Artesunate remains a crucial drug for the treatment of malaria, and determining optimal dosing regimens is vital to overcome emerging resistant parasite strains along the Thai-Cambodian border. However, future experimental dosing studies must be designed with care, because the safety of such regimens can no longer be assumed. The artemisinin derivatives remain one of the safest classes of antimalarial drugs, but this study demonstrates that the dosing limit may have been reached

Dose-dependent risk of neutropenia after 7-day courses of artesunate monotherapy in Cambodian patients with acute Plasmodium falciparum malaria.

BACKGROUND: Fears of emerging artemisinin resistance in western Cambodia have prompted a series of clinical trials investigating whether slow responses to antimalarial treatment can be overcome by increasing doses of drug. METHODS: Patients with uncomplicated malaria were allocated 1 of 3 oral artesunate monotherapy regimens (2, 4, or 6 mg/kg/day for 7 days) and were observed for 42 days. A series of safety measures, including complete blood count on days 0, 3, 6, and 14, was implemented because of a lack of safety data for these experimental doses. RESULTS: After 3 doses, geometric mean absolute neutrophil counts were reduced in all groups, and 2 patients required artesunate to be discontinued because of neutropenia (absolute neutrophil count, &lt;1.0 × 10(3) cells/μL). Recipients of the 6 mg/kg/day dosage had significantly lower geometric mean absolute neutrophil counts than did recipients of the 2 and 4 mg/kg/day dosages at 6 and 14 days (P &lt; .001 for each). Overall, 5 (19%) of 26 patients who received the 6 mg/kg/day dosage became neutropenic within 14 days, triggering a cohort-halting rule and ending the trial early. Pharmacokinetic data from neutropenic patients showed wide variance, with plasma clearance occurring significantly slower in neutropenic patients than in nonneutropenic patients. CONCLUSIONS: Artesunate remains a crucial drug for the treatment of malaria, and determining optimal dosing regimens is vital to overcome emerging resistant parasite strains along the Thai-Cambodian border. However, future experimental dosing studies must be designed with care, because the safety of such regimens can no longer be assumed. The artemisinin derivatives remain one of the safest classes of antimalarial drugs, but this study demonstrates that the dosing limit may have been reached

<it>Ex vivo</it> drug sensitivity profiles of <it>Plasmodium falciparum</it> field isolates from Cambodia and Thailand, 2005 to 2010, determined by a histidine-rich protein-2 assay

Abstract Background In vitro drug susceptibility assay of Plasmodium falciparum field isolates processed “immediate ex vivo” (IEV), without culture adaption, and tested using histidine-rich protein-2 (HRP-2) detection as an assay, is an expedient way to track drug resistance. Methods From 2005 to 2010, a HRP-2 in vitro assay assessed 451 P. falciparum field isolates obtained from subjects with malaria in western and northern Cambodia, and eastern Thailand, processed IEV, for 50% inhibitory concentrations (IC50) against seven anti-malarial drugs, including artesunate (AS), dihydroartemisinin (DHA), and piperaquine. Results In western Cambodia, from 2006 to 2010, geometric mean (GM) IC50 values for chloroquine, mefloquine, quinine, AS, DHA, and lumefantrine increased. In northern Cambodia, from 2009–2010, GM IC50 values for most drugs approximated the highest western Cambodia GM IC50 values in 2009 or 2010. Conclusions Western Cambodia is associated with sustained reductions in anti-malarial drug susceptibility, including the artemisinins, with possible emergence, or spread, to northern Cambodia. This potential public health crisis supports continued in vitro drug IC50 monitoring of P. falciparum isolates at key locations in the region.</p

Efficacy of Two versus Three-Day Regimens of Dihydroartemisinin-Piperaquine for Uncomplicated Malaria in Military Personnel in Northern Cambodia: An Open-Label Randomized Trial

<div><p>Introduction</p><p>Emerging antimalarial drug resistance in mobile populations remains a significant public health concern. We compared two regimens of dihydroartemisinin-piperaquine in military and civilians on the Thai-Cambodian border to evaluate national treatment policy.</p><p>Methods</p><p>Efficacy and safety of two and three-day regimens of dihydroartemisinin-piperaquine were compared as a nested open-label evaluation within a malaria cohort study in 222 otherwise healthy volunteers (18% malaria-infected at baseline). The first 80 volunteers with slide-confirmed <i>Plasmodium falciparum</i> or <i>vivax</i> malaria were randomized 1:1 to receive either regimen (total dose 360mg dihydroartemisinin and 2880mg piperaquine) and followed weekly for up to 6 months. The primary endpoint was malaria recurrence by day 42. Volunteers with <i>vivax</i> infection received primaquine at study discharge with six months follow-up.</p><p>Results</p><p>Eighty patients (60 <i>vivax</i>, 15 <i>falciparum</i>, and 5 mixed) were randomized to dihydroartemisinin-piperaquine. Intention-to-treat all-species efficacy at Day 42 was 85% for the two-day regimen (95% CI 69–94) and 90% for the three-day regimen (95% CI 75–97). PCR-adjusted <i>falciparum</i> efficacy was 75% in both groups with nearly half (45%) still parasitemic at Day 3. Plasma piperaquine levels were comparable to prior published reports, but on the day of recrudescence were below measurable <i>in vitro</i> piperaquine IC₅₀ levels in all <i>falciparum</i> treatment failures.</p><p>Conclusions</p><p>In the brief period since introduction of dihydroartemisinin-piperaquine, there is early evidence suggesting declining efficacy relative to previous reports. Parasite IC₅₀ levels in excess of plasma piperaquine levels seen only in treatment failures raises concern for clinically significant piperaquine resistance in Cambodia. These findings warrant improved monitoring of clinical outcomes and follow-up, given few available alternative drugs.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT01280162" target="_blank">NCT01280162</a></p></div

QTcB and QTcF interval changes according to treatment arm.

<p>Mean changes from baseline in QTcB and QTcF following daily treatment with DHA-piperaquine (360/2880 mg cumulative dose) divided over 2 versus 3 days.</p

Mean trough QTcF intervals for patients treated daily with DHA-piperaquine (360/2880 mg cumulative) divided over 2 or 3 days (n = 40 in each group).

<p>Error bars indicate +1 standard deviation.</p

Baseline characteristics of enrolled patients according to treatment arm.

<p>All data are number (%) unless otherwise indicated. There were no statistical or clinically significant differences between groups. *Non-PCR adjusted. **Only 1 sample in this subgroup so actual parasitemia reported.</p