Efficacy of dihydroartemisinin/piperaquine and artesunate monotherapy for the treatment of uncomplicated Plasmodium falciparum malaria in Central Vietnam

Abstract

Background Artemisinin-based combination therapies (ACTs) have significantly contributed to reduce Plasmodium falciparum malaria burden in Vietnam, but their efficacy is challenged by treatment failure of dihydroartemisinin/piperaquine ACT in Southern provinces. Objectives To assess the efficacy of dihydroartemisinin/piperaquine for uncomplicated P. falciparum malaria in Gia Lai, Central Vietnam, and determine parasite resistance to artemisinin (ClinicalTrials.gov identifier NCT02604966). Methods Sixty patients received either dihydroartemisinin/piperaquine (4 mg/kg/day, 3 days; n = 33) or artesunate monotherapy (4 mg/kg/day, 3 days; n = 27) followed by dihydroartemisinin/piperaquine (AS + DHA/PPQ). Clinical phenotypes were determined during a 42 day follow-up and analysed together with ex vivo susceptibility to antimalarials and molecular markers of drug resistance. Results Day 3 positivity rate was significantly higher in the AS + DHA/PPQ arm compared with dihydroartemisinin/piperaquine (70.4% versus 39.4%, P = 0.016). Parasite clearance time was 95.2 h (AS + DHA/PPQ) versus 71.9 h (dihydroartemisinin/piperaquine, P = 0.063) and parasite clearance half-life was 7.4 h (AS + DHA/PPQ) versus 7.0 h (dihydroartemisinin/piperaquine, P = 0.140). Adequate clinical and parasitological response at Day 42 was 100% in both arms. By RT–qPCR, 36% (19/53) patients remained positive until Day 7. No recurrences were detected. kelch13 artemisinin resistance mutations were found in 87% (39/45) of isolates and 50% (20/40) were KEL1/C580Y. The piperaquine resistance marker plasmepsin-2 was duplicated in 10.4% (5/48). Isolates from Day 3-positive patients (n = 18) had higher ex vivo survival rates to artemisinin compounds (P < 0.048) and prevalence of kelch13 mutations (P = 0.005) than Day 3-negative patients (n = 5). The WHO definition of artemisinin resistance was fulfilled in 60% (24/40) of cases. Conclusions Although dihydroartemisinin/piperaquine remained effective to treat P. falciparum, the high Day 3 positivity rate and prevalence of KEL1 strains calls for continuous monitoring of dihydroartemisinin/piperaquine efficacy in Central Vietnam.

High proportion of genome-wide homology and increased basal pvcrt levels in Plasmodium vivax late recurrences: a chloroquine therapeutic efficacy study

“…Malaria control by the provincial malaria station relies on early diagnosis by light microscopy (LM) or rapid diagnostic tests, annual distribution of long-lasting insecticidal treated nets, promotion of community-based prevention behavior and monitoring of drug resistance through regular TES. The presence of P. falciparum artemisinin resistance was confirmed in the province in 2017 (25).…”

“…The same method was adapted as a P. vivax monoplex qPCR and used for P. vivax quantification in follow-up samples. RNA was extracted from RNAprotect samples collected at Day 0 and from all follow-up samples positive in the pv18S rRNA qPCR, using RNeasy Plus 96-kit (Qiagen) (25). Final RNA elution was conducted in 100 µl of RNAse-free water, and the presence of quality RNA was confirmed in a random selection of 80 samples by one-step reverse transcription qPCR (RTqPCR) targeting pv18S rRNA transcripts, using LightCycler Multiplex RNA Virus Master mix in a LightCycler480 thermocycler (Roche).…”

“…In all samples with a ring-stage proportion ≥65%, 150 µl iRBC were separated for ex vivo drug sensitivity SMA and remaining iRBC pellet was cryopreserved in liquid nitrogen or stored at −20°C. SMA was performed by adapting WHO microtest, as previously described (25,29). A stock solution of 640µM CQ in water (Sigma-Aldrich, C6628) was pre-dosed in seven 2-fold serial dilutions in water (800-12.5nM), and 25 µl/well were distributed in a 96-well plate, air-dried overnight inside a laminar-flow cabinet and stored at 4°C (30).…”

“…A molecular barcode consisting of 38 SNPs across the P. vivax genome was used to genotype samples in the context of MalariaGEN SpotMalaria Project (Welcome Sanger Institute, Hinxton, UK), using MALDI-TOF mass spectrometry of PCR amplicons in a MassARRAY® System (Agena BioScience) (25)(35). Nucleotide sequence results were provided in the form of a Genetic Report Card (see Data S1).…”

No evidence of amplified Plasmodium falciparum plasmepsin II gene copy number in an area with artemisinin-resistant malaria along the China–Myanmar border

“…Recently, the emergence of DHA-PPQ resistance was observed in Cambodia with high treatment failure rate and recrudescent infections. Resistance then rapidly spread to other countries in Southeast Asia [ 16 – 22 ], and subsequent investigations confirmed the presence of high treatment failure and PPQ resistance in Cambodia and Vietnam [ 16 , 21 , 23 ]. The evidence prompted a treatment policy change in Cambodia and Vietnam from DHA-PPQ to other artemisinin-based combinations in areas where DHA-PPQ was failing.…”