Artesunate Dose Escalation for the Treatment of Uncomplicated Malaria in a Region of Reported Artemisinin Resistance: A Randomized Clinical Trial

Abstract

BackgroundThe 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.MethodsAdult 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.Results143 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.ConclusionThere 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.Trial RegistrationClinicalTrials.gov NCT00722150.

Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia

“…In our study, DHA IC 50 had low heritability, was significantly associated with no SNPs, and did not overlap with candidate SNPs associated with clinical parasite clearance phenotypes. These findings confirm that DHA IC 50 does not capture the delayed clearance phenotype that is the hallmark of artemisinin resistance in Cambodia (6)(7)(8) and emphasize the need to develop in vitro assays of artemisinin susceptibility that can be used for functional validation of candidate resistance genes.…”

“…Extremely fast-acting, artemisinins kill both young ring forms and mature blood-stage parasites (3). The World Health Organization (WHO) recommended in 2001 that artemisinins be used strictly in combination therapies in hopes of delaying the emergence of resistance (2), but ACT treatment failure rates were rising on the Thailand/Cambodia border by 2006 (4,5) and progressively prolonged parasite clearance after treatment with artemisinin derivatives soon followed (6)(7)(8). This evidence that artemisinin resistance has emerged in western Cambodia, historically an epicenter of drug-resistant malaria, is an ominous development that threatens the recent major global investment in ACTs (3).…”

No Evidence of Delayed Parasite Clearance after Oral Artesunate Treatment of Uncomplicated Falciparum Malaria in Mali

“…Our incidental finding that the parasite clearance time of participants who received 6 mg/kg on Day 0 was significantly shorter than that of participants receiving the standard 4 mg/kg dose contrast with a recent study from Cambodia that found no change in clearance time or rate with higher artemisinin doses. 21 This observation, although based on small numbers, provides potentially important empirical evidence for the ability of higher artemisinin doses to hasten the parasite clearance of African isolates in the current stage of artemisinin usage on the continent.…”

Genetic markers of artemisinin resistance in Plasmodium spp. parasites

“…artesunate is activated for the rest of intra-erythrocytic development, and thus, K13 variant parasites are fully susceptible to prolonged exposure to artemisinin, as clearly seen in vitro [2,4,5] and in vivo [3,22,23].…”

“…• P. falciparum harbouring variant K13 alleles, and/or demonstrating slow clearance at day 3, are clearly susceptible to extended-duration artemisinin-based treatment, as an ACPR of more than 90% has been achieved in the GMS with 6 days of artesunate monotherapy [23,24] or 3 days of artesunate monotherapy followed by 3 days of ACT [3]. Thus, regimens such as two sequential ACTs with different partner drugs have been postulated as a rational response to signs of falling 3-day ACT efficacy, and a protocol has been developed to evaluate such regimes before ACT failure becomes a serious problem [25].…”