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

Kamala Ley-Thriemer, Nguyen Hong, Anna Rosanas-Urgell, Bui Phuc, Do Ha, Evi Pockele, Pieter Guetens, Nguyen Van, Tran Duong, Alfred Amambua-Ngwa, Umberto D'Alessandro, Annette Erhart

    Research output: Contribution to journalArticleResearchpeer-review

    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.) Copyright � 2014, American Society for Microbiology. All Rights Reserved.
    Original languageEnglish
    Pages (from-to)7049-7055
    Number of pages7
    JournalAntimicrobial Agents and Chemotherapy
    Volume58
    Issue number12
    DOIs
    Publication statusPublished - 2014

    Fingerprint

    dihydroartemisinin
    Falciparum Malaria
    Vietnam
    Parasites
    Polymerase Chain Reaction
    Therapeutics
    Plasmodium falciparum
    Alleles
    Myanmar
    piperaquine
    Chloroquine
    Microbiology

    Cite this

    Ley-Thriemer, Kamala ; Hong, Nguyen ; Rosanas-Urgell, Anna ; Phuc, Bui ; Ha, Do ; Pockele, Evi ; Guetens, Pieter ; Van, Nguyen ; Duong, Tran ; Amambua-Ngwa, Alfred ; D'Alessandro, Umberto ; Erhart, Annette. / Delayed Parasite Clearance after Treatment with Dihydroartemisinin-Piperaquine in Plasmodium falciparum Malaria Patients in Central Vietnam. In: Antimicrobial Agents and Chemotherapy. 2014 ; Vol. 58, No. 12. pp. 7049-7055.
    @article{e99750846ffd4c1ca22da62e98163d58,
    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.) Copyright � 2014, American Society for Microbiology. All Rights Reserved.",
    keywords = "chloroquine, dihydroartemisinin, dihydroartemisinin plus piperaquine, piperaquine, actin binding protein, antimalarial agent, artemisinin derivative, protozoal protein, quinoline derivative, absence of side effects, adolescent, antimalarial drug susceptibility, Article, child, clinical trial, drug efficacy, drug half life, female, gametocyte, genotype, human, in vitro study, in vivo study, major clinical study, malaria falciparum, male, nonhuman, parasite clearance, polymerase chain reaction, preschool child, prevalence, recurrent infection, single nucleotide polymorphism, trophozoite, Viet Nam, adult, drug combination, drug effects, drug resistance, drug sensitivity, erythrocyte, genetics, genotyping technique, growth, development and aging, IC50, infant, Malaria, Falciparum, metabolism, middle aged, molecular typing, mutation, parasitology, Plasmodium falciparum, time, Adolescent, Adult, Antimalarials, Artemisinins, Child, Child, Preschool, Drug Resistance, Drug Therapy, Combination, Erythrocytes, Female, Genotyping Techniques, Humans, Infant, Inhibitory Concentration 50, Male, Microfilament Proteins, Middle Aged, Molecular Typing, Mutation, Parasitic Sensitivity Tests, Protozoan Proteins, Quinolines, Time Factors, Vietnam",
    author = "Kamala Ley-Thriemer and Nguyen Hong and Anna Rosanas-Urgell and Bui Phuc and Do Ha and Evi Pockele and Pieter Guetens and Nguyen Van and Tran Duong and Alfred Amambua-Ngwa and Umberto D'Alessandro and Annette Erhart",
    year = "2014",
    doi = "10.1128/AAC.02746-14",
    language = "English",
    volume = "58",
    pages = "7049--7055",
    journal = "Antimicrobial Agents and Chemotherapy",
    issn = "0066-4804",
    publisher = "American Society for Microbiology",
    number = "12",

    }

    Ley-Thriemer, K, Hong, N, Rosanas-Urgell, A, Phuc, B, Ha, D, Pockele, E, Guetens, P, Van, N, Duong, T, Amambua-Ngwa, A, D'Alessandro, U & Erhart, A 2014, 'Delayed Parasite Clearance after Treatment with Dihydroartemisinin-Piperaquine in Plasmodium falciparum Malaria Patients in Central Vietnam', Antimicrobial Agents and Chemotherapy, vol. 58, no. 12, pp. 7049-7055. https://doi.org/10.1128/AAC.02746-14

    Delayed Parasite Clearance after Treatment with Dihydroartemisinin-Piperaquine in Plasmodium falciparum Malaria Patients in Central Vietnam. / Ley-Thriemer, Kamala; Hong, Nguyen; Rosanas-Urgell, Anna; Phuc, Bui; Ha, Do; Pockele, Evi; Guetens, Pieter; Van, Nguyen; Duong, Tran; Amambua-Ngwa, Alfred; D'Alessandro, Umberto; Erhart, Annette.

    In: Antimicrobial Agents and Chemotherapy, Vol. 58, No. 12, 2014, p. 7049-7055.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Delayed Parasite Clearance after Treatment with Dihydroartemisinin-Piperaquine in Plasmodium falciparum Malaria Patients in Central Vietnam

    AU - Ley-Thriemer, Kamala

    AU - Hong, Nguyen

    AU - Rosanas-Urgell, Anna

    AU - Phuc, Bui

    AU - Ha, Do

    AU - Pockele, Evi

    AU - Guetens, Pieter

    AU - Van, Nguyen

    AU - Duong, Tran

    AU - Amambua-Ngwa, Alfred

    AU - D'Alessandro, Umberto

    AU - Erhart, Annette

    PY - 2014

    Y1 - 2014

    N2 - 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.) Copyright � 2014, American Society for Microbiology. All Rights Reserved.

    AB - 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.) Copyright � 2014, American Society for Microbiology. All Rights Reserved.

    KW - chloroquine

    KW - dihydroartemisinin

    KW - dihydroartemisinin plus piperaquine

    KW - piperaquine

    KW - actin binding protein

    KW - antimalarial agent

    KW - artemisinin derivative

    KW - protozoal protein

    KW - quinoline derivative

    KW - absence of side effects

    KW - adolescent

    KW - antimalarial drug susceptibility

    KW - Article

    KW - child

    KW - clinical trial

    KW - drug efficacy

    KW - drug half life

    KW - female

    KW - gametocyte

    KW - genotype

    KW - human

    KW - in vitro study

    KW - in vivo study

    KW - major clinical study

    KW - malaria falciparum

    KW - male

    KW - nonhuman

    KW - parasite clearance

    KW - polymerase chain reaction

    KW - preschool child

    KW - prevalence

    KW - recurrent infection

    KW - single nucleotide polymorphism

    KW - trophozoite

    KW - Viet Nam

    KW - adult

    KW - drug combination

    KW - drug effects

    KW - drug resistance

    KW - drug sensitivity

    KW - erythrocyte

    KW - genetics

    KW - genotyping technique

    KW - growth, development and aging

    KW - IC50

    KW - infant

    KW - Malaria, Falciparum

    KW - metabolism

    KW - middle aged

    KW - molecular typing

    KW - mutation

    KW - parasitology

    KW - Plasmodium falciparum

    KW - time

    KW - Adolescent

    KW - Adult

    KW - Antimalarials

    KW - Artemisinins

    KW - Child

    KW - Child, Preschool

    KW - Drug Resistance

    KW - Drug Therapy, Combination

    KW - Erythrocytes

    KW - Female

    KW - Genotyping Techniques

    KW - Humans

    KW - Infant

    KW - Inhibitory Concentration 50

    KW - Male

    KW - Microfilament Proteins

    KW - Middle Aged

    KW - Molecular Typing

    KW - Mutation

    KW - Parasitic Sensitivity Tests

    KW - Protozoan Proteins

    KW - Quinolines

    KW - Time Factors

    KW - Vietnam

    UR - http://www.scopus.com/inward/record.url?scp=84912144570&partnerID=8YFLogxK

    U2 - 10.1128/AAC.02746-14

    DO - 10.1128/AAC.02746-14

    M3 - Article

    VL - 58

    SP - 7049

    EP - 7055

    JO - Antimicrobial Agents and Chemotherapy

    JF - Antimicrobial Agents and Chemotherapy

    SN - 0066-4804

    IS - 12

    ER -