TY - JOUR
T1 - High proportion of genome-wide homology and increased pre-treatment pvcrt levels in Plasmodium vivax late recurrences: a chloroquine therapeutic efficacy study
AU - Rovira-Vallbona, Eduard
AU - Van Hong, Nguyen
AU - Kattenberg, Johanna H
AU - Huan, Ro Mah
AU - Binh, Nguyen Thi Huong
AU - Ngọc, Nguyen Thi Hong
AU - Guetens, Pieter
AU - Hieu, Nguyen Luong
AU - Hien, Nguyen Thị Thu
AU - Sang, Vu Thi
AU - Long, Nguyen Duc
AU - Sauve, Erin
AU - Duong, Tran Thanh
AU - Xuan Xa, Nguyen
AU - Erhart, Annette
AU - Rosanas-Urgell, Anna
N1 - NPP; OGOA; Copyright © 2021 American Society for Microbiology.
PY - 2021
Y1 - 2021
N2 - Chloroquine (CQ) is the first-line treatment for Plasmodium vivax malaria in most countries where malaria is endemic. Monitoring P. vivax CQ resistance (CQR) is critical but remains challenged by the difficulty to distinguish real treatment failure from reinfection or liver relapse. The therapeutic efficacy of CQ against uncomplicated P. vivax malaria was evaluated in Gia Lai Province, Vietnam. Sixty-seven patients were enrolled and followed for 42 days using microscopy and quantitative PCR. Adequate clinical and parasitological response (ACPR) was 100% (66/66) on day 28 but 75.4% (49/65) on day 42. Eighteen recurrences (27.7%) were detected, with a median time to recurrence of 42 days (interquartile range [IQR], 35 to 42) and blood CQ concentration of <100 ng/ml. Primary infections leading to recurrence occurred in younger individuals (median age for ACPR = 25 years [IQR, 20 to 28]; recurrences = 18 [16 to 21];
P = 0.002) had a longer parasite clearance time (PCT for ACPR
= 47.5 h [IQR, 36.2 to 59.8 h]; recurrences = 54.2 [48.4 to 62.0];
P = 0.035) and higher
pvcrt gene expression (median relative expression ratio for ACPR
= 0.09 [IQR, 0.05 to 0.22]; recurrences = 0.20 [0.15 to 0.56];
P = 0.002), but showed no differences in
ex vivo CQ sensitivity. Parasite genotyping by microsatellites, single nucleotide polymorphism (SNP) barcoding, and whole-genome sequencing (WGS) identified a majority of homologous recurrences, with 80% (8/10) showing >98% identity by descent to paired day 0 samples. This study shows that CQ remained largely efficacious to treat P. vivax in Gia Lai; i.e., recurrences occurred late (>day 28) and in the presence of low blood CQ concentrations. However, the combination of both WGS and gene expression analysis (
pvcrt) data with clinical data (PCT) allowed us to identify potential emergence of low-grade CQR, which should be closely monitored. (This study has been registered at ClinicalTrials.gov under identifier NCT02610686.).
AB - Chloroquine (CQ) is the first-line treatment for Plasmodium vivax malaria in most countries where malaria is endemic. Monitoring P. vivax CQ resistance (CQR) is critical but remains challenged by the difficulty to distinguish real treatment failure from reinfection or liver relapse. The therapeutic efficacy of CQ against uncomplicated P. vivax malaria was evaluated in Gia Lai Province, Vietnam. Sixty-seven patients were enrolled and followed for 42 days using microscopy and quantitative PCR. Adequate clinical and parasitological response (ACPR) was 100% (66/66) on day 28 but 75.4% (49/65) on day 42. Eighteen recurrences (27.7%) were detected, with a median time to recurrence of 42 days (interquartile range [IQR], 35 to 42) and blood CQ concentration of <100 ng/ml. Primary infections leading to recurrence occurred in younger individuals (median age for ACPR = 25 years [IQR, 20 to 28]; recurrences = 18 [16 to 21];
P = 0.002) had a longer parasite clearance time (PCT for ACPR
= 47.5 h [IQR, 36.2 to 59.8 h]; recurrences = 54.2 [48.4 to 62.0];
P = 0.035) and higher
pvcrt gene expression (median relative expression ratio for ACPR
= 0.09 [IQR, 0.05 to 0.22]; recurrences = 0.20 [0.15 to 0.56];
P = 0.002), but showed no differences in
ex vivo CQ sensitivity. Parasite genotyping by microsatellites, single nucleotide polymorphism (SNP) barcoding, and whole-genome sequencing (WGS) identified a majority of homologous recurrences, with 80% (8/10) showing >98% identity by descent to paired day 0 samples. This study shows that CQ remained largely efficacious to treat P. vivax in Gia Lai; i.e., recurrences occurred late (>day 28) and in the presence of low blood CQ concentrations. However, the combination of both WGS and gene expression analysis (
pvcrt) data with clinical data (PCT) allowed us to identify potential emergence of low-grade CQR, which should be closely monitored. (This study has been registered at ClinicalTrials.gov under identifier NCT02610686.).
U2 - 10.1128/AAC.00095-21
DO - 10.1128/AAC.00095-21
M3 - A1: Web of Science-article
C2 - 34031050
VL - 65
SP - e0009521
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 8
ER -