title: Delayed parasite clearance after treatment with dihydroartemisinin-piperaquine in Plasmodium falciparum malaria patients in central Vietnam.
abstract: Reduced 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 (IC50s) 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.).
authors.affiliation: Institute of Tropical Medicine, Antwerp, Belgium k.leythriemer@gmail.com.
authors.forename: Kamala
authors.initials: K
authors.lastname: Thriemer
authors.affiliation: Institute of Tropical Medicine, Antwerp, Belgium National Institute of Malariology, Parasitology and Entomology, Hanoi, Vietnam.
authors.forename: Nguyen Van
authors.initials: NV
authors.lastname: Hong
authors.affiliation: Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Anna
authors.initials: A
authors.lastname: Rosanas-Urgell
authors.affiliation: National Institute of Malariology, Parasitology and Entomology, Hanoi, Vietnam.
authors.forename: Bui Quang
authors.initials: BQ
authors.lastname: Phuc
authors.affiliation: National Institute of Malariology, Parasitology and Entomology, Hanoi, Vietnam.
authors.forename: Do Manh
authors.initials: do M
authors.lastname: Ha
authors.affiliation: Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Evi
authors.initials: E
authors.lastname: Pockele
authors.affiliation: Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Guetens
authors.affiliation: Center for Malaria and Goitre Control of Quang Nam Province, Phan Thiet, Vietnam.
authors.forename: Nguyen Van
authors.initials: NV
authors.lastname: Van
authors.affiliation: National Institute of Malariology, Parasitology and Entomology, Hanoi, Vietnam.
authors.forename: Tran Thanh
authors.initials: TT
authors.lastname: Duong
authors.affiliation: MRC Unit, Fajara, The Gambia.
authors.forename: Alfred
authors.initials: A
authors.lastname: Amambua-Ngwa
authors.affiliation: Institute of Tropical Medicine, Antwerp, Belgium MRC Unit, Fajara, The Gambia.
authors.forename: Umberto
authors.initials: U
authors.lastname: D'Alessandro
authors.affiliation: Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Annette
authors.initials: A
authors.lastname: Erhart
mesh_terms: D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D005260:Female; D060005:Genotyping Techniques; D006801:Humans; D007223:Infant; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D058889:Molecular Typing; D009154:Mutation; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D015800:Protozoan Proteins / Q000235:genetics; D011804:Quinolines / Q000627:therapeutic use*; D013997:Time Factors; D014744:Vietnam; D010879:Piperazines
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D008840:Microfilament Proteins; D015800:Protozoan Proteins; D011804:Quinolines; C039060:artenimol; C034759:piperaquine; D010879:Piperazines