Delayed Parasite Clearance after Treatment with Dihydroartemisinin-Piperaquine in Plasmodium falciparum Malaria Patients in Central Vietnam

Abstract

dReduced susceptibility of Plasmodium falciparum toward artemisinin derivatives has been reported from the Thai-Cambodian and Thai-Myanmar borders. Following increasing reports from central Vietnam of delayed parasite clearance after treatment with dihydroartemisinin-piperaquine (DHA-PPQ), the current first-line treatment, we carried out a study on the efficacy of this treatment. Between September 2012 and February 2013, we conducted a 42-day in vivo and in vitro efficacy study in Quang Nam Province. Treatment was directly observed, and blood samples were collected twice daily until parasite clearance. In addition, genotyping, quantitative PCR (qPCR), and in vitro sensitivity testing of isolates was performed. The primary endpoints were parasite clearance rate and time. The secondary endpoints included PCR-corrected and uncorrected cure rates, qPCR clearance profiles, in vitro sensitivity results (for chloroquine, dihydroartemisinin, and piperaquine), and genotyping for mutations in the Kelch 13 propeller domain. Out of 672 screened patients, 95 were recruited and 89 available for primary endpoint analyses. The median parasite clearance time (PCT) was 61.7 h (interquartile range [IQR], 47.6 to 83.2 h), and the median parasite clearance rate had a slope half-life of 6.2 h (IQR, 4.4 to 7.5 h). The PCR-corrected efficacy rates were estimated at 100% at day 28 and 97.7% (95% confidence interval, 91.2% to 99.4%) at day 42. At day 3, the P. falciparum prevalence by qPCR was 2.5 times higher than that by microscopy. The 50% inhibitory concentrations (IC 50 s) of isolates with delayed clearance times (>72 h) were significantly higher than those with normal clearance times for all three drugs. Delayed parasite clearance (PCT, >72 h) was significantly higher among day 0 samples carrying the 543 mutant allele (47.8%) than those carrying the wild-type allele (1.8%; P ‫؍‬ 0.048). In central Vietnam, the efficacy of DHA-PPQ is still satisfactory, but the parasite clearance time and rate are indicative of emerging artemisinin resistance. (This study has been registered at ClinicalTrials.gov under registration no. NCT01775592.)

Artemisinin resistance, some facts and opinions

“…More recently, a mutation on the K13-Propeller locus has been observed to be associated to DPC in Cambodia [9]; subsequently, additional mutations on the same gene have been observed in other regions in South Asia [10][11][12][13][14][15][16]. This promising marker is currently used in association with DPC to identify ART resistance but both still require a substantial clinical validation.…”

Role of K13 Mutations in Artemisinin-Based Combination Therapy

“…Unsurprisingly, ASMQ efficacy in 5 Cambodian provinces where DP was failing in 2014-2016 was 100% at day 42 (n = 305), even though 94.2% (278/295) of parasites carried the K13 C580Y mutation (Amaratunga et al, unpublished data; Rithea et al, unpublished data). High ACT efficacy despite high K13 mutation prevalence has also been reported in neighboring countries [4][5][6][7].…”

“…To this end, the World Health Organization has supported the development of a malaria elimination strategy for this region, and is currently integrating it into the national malaria control programs of all GMS countries [9]. Charlotte Rasmussen, 1 Frédéric Ariey, 2 Rick M. Fairhurst, 3 Pascal Ringwald, 1 and Didier Ménard 4,5,6 …”

Methods for monitoring artemisinin-based combination therapies efficacy

“…This in vivo phenotype was not coupled with any in vitro resistance phenotype as per the standard in vitro susceptibility testing (Ashley et al, 2014;Dondorp et al, 2012;Takala-Harrison et al, 2014;Thriemer et al, 2014;Tun et al, 2016).…”

“…The 42-day in vivo and in vitro efficacy study of was conducted in Quang Nam Province in Central Vietnam to evaluate delayed parasite clearance after treatment with DHA-PQP in P. falciparum Malaria patients (Thriemer et al, 2014). The median PCT was 61.7 h and the median parasite clearance rate had a slope half-life of 6.2 h. The IC 50 of isolates with delayed PCT (>72 h) was significantly higher than those with normal PCT for DHA and PQP.…”