Efficacy of Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine for Treatment of Uncomplicated Malaria in Children in Zaire and Uíge Provinces, Angola

Pluciński, Mateusz M.; Talundzic, Eldin; Morton, Lindsay; Dimbu, Pedro Rafael; Macaia, Aleixo Panzo; Fortes, Filomeno; Goldman, Ira F.; Lucchi, Naomi W.; Stennies, Gail; MacArthur, John; Udhayakumar, Venkatachalam

doi:10.1128/aac.04181-14

Cited by 87 publications

(83 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some studies in Africa have observed a low frequency of other mutations, some of which are found in the propeller domain, in parasites from Africa (38)(39)(40). To date, many of the therapeutic efficacy studies conducted in Africa have indicated that artemisinin-based combination therapies are still efficacious (21,41,42). Therefore, the role of the novel African K13 mutations in artemisinin resistance, if any, is still to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity

Lucchi

Komino

Okoth

et al. 2015

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Malaria control is hindered by the evolution and spread of resistance to antimalarials, necessitating multiple changes to drug policies over time. A comprehensive antimalarial drug resistance surveillance program is vital for detecting the potential emergence of resistance to antimalarials, including current artemisinin-based combination therapies. An antimalarial drug resistance surveillance study involving 203 Plasmodium falciparum malaria-positive children was conducted in western Kenya between 2010 and 2013. Specimens from enrolled children were analyzed in vitro for sensitivity to chloroquine (CQ), amodiaquine (AQ), mefloquine (MQ), lumefantrine, and artemisinin derivatives (artesunate and dihydroartemisinin) and for drug resistance allele polymorphisms in P. falciparum crt (Pfcrt), Pfmdr-1, and the K13 propeller domain (K13). We observed a significant increase in the proportion of samples with the Pfcrt wild-type (CVMNK) genotype, from 61.2% in 2010 to 93.0% in 2013 (P < 0.0001), and higher proportions of parasites with elevated sensitivity to CQ in vitro. The majority of isolates harbored the wild-type N allele in Pfmdr-1 codon 86 (93.5%), with only 7 (3.50%) samples with the N86Y mutant allele (the mutant nucleotide is underlined). Likewise, most isolates harbored the wild-type Pfmdr-1 D1246 allele (79.8%), with only 12 (6.38%) specimens with the D1246Y mutant allele and 26 (13.8%) with mixed alleles. All the samples had a single copy of the Pfmdr-1 gene (mean of 0.907 ؎ 0.141 copies). None of the sequenced parasites had mutations in K13. Our results suggest that artemisinin is likely to remain highly efficacious and that CQ sensitivity appears to be on the rise in western Kenya.A ntimalarial drug resistance has hampered progress in malaria control and has led to several changes in drug policies over time. To minimize the potential emergence of drug resistance, the World Health Organization (WHO) recommends the use of artemisinin-based combination therapy (ACT), which consists of an artemisinin derivative coformulated with another class of antimalarial (1). In Kenya, the use of chloroquine (CQ) as the first line of malaria treatment was discontinued in the late 1990s due to a high percentage of treatment failures. CQ was replaced by sulfadoxinepyrimethamine (SP) as the first line of treatment, with amodiaquine (AQ) as a second choice. However, the use of SP was shortlived, as the majority of circulating parasites rapidly developed resistance to SP (reviewed in reference 2). Therefore, in April 2004, the ACT artemether-lumefantrine (AL; Coartem) was recommended as the first-line therapy for the treatment of uncomplicated Plasmodium falciparum malaria in Kenya, although this was not fully implemented until late 2006, when the country was finally able to undertake delivery of large quantities of the drug. Thus, between 2004 and 2006, AQ was briefly used as the first-line treatment for malaria in Kenya. Dihydroartemisinin-piperaquine (DHAP) is the current second-line antimalarial drug treatment, while artesu...

show abstract

Section: Discussionmentioning

confidence: 99%

In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity

Lucchi

Komino

Okoth

et al. 2015

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…Samples used in this study were collected prior to treatment. Samples from Ghana were collected between 1999 and 2010, samples from Tanzania in 2011, and samples from Angola in 2013 [30]. Electronic supplementary material, figure S1, shows study locations and malaria prevalence.…”

Section: (B) Sample Collection and Processingmentioning

confidence: 99%

Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum

et al. 2016

Self Cite

View full text Add to dashboard Cite

Infections with the malaria parasite Plasmodium falciparum typically comprise multiple strains, especially in high-transmission areas where infectious mosquito bites occur frequently. However, little is known about the dynamics of mixed-strain infections, particularly whether strains sharing a host compete or grow independently. Competition between drug-sensitive and drug-resistant strains, if it occurs, could be a crucial determinant of the spread of resistance. We analysed 1341 P. falciparum infections in children from Angola, Ghana and Tanzania and found compelling evidence for competition in mixed-strain infections: overall parasite density did not increase with additional strains, and densities of individual chloroquine-sensitive (CQS) and chloroquine-resistant (CQR) strains were reduced in the presence of competitors. We also found that CQR strains exhibited low densities compared with CQS strains (in the absence of chloroquine), which may underlie observed declines of chloroquine resistance in many countries following retirement of chloroquine as a first-line therapy. Our observations support a key role for within-host competition in the evolution of drug-resistant malaria. Malaria control and resistance-management efforts in high-transmission regions may be significantly aided or hindered by the effects of competition in mixed-strain infections. Consideration of within-host dynamics may spur development of novel strategies to minimize resistance while maximizing the benefits of control measures.

show abstract

“…The second source of data is a set of 24 treatment failures from a 2013 in vivo therapeutic efficacy study of AL and dihydroartemisin-piperaquine (DP) in children with uncomplicated P. falciparum malaria in Zaire and Uíge provinces in Angola (14). There were 24 late treatment failures observed in three of the study arms: AL in Zaire, AL in Uíge, and DP in Zaire.…”

Section: Methodsmentioning

confidence: 99%

“…Samples from day 0 and the day of treatment failure for each treatment failure had been genotyped using seven neutral microsatellites. In addition to the previously published microsatellite data from the treatment failures, all remaining day-0 samples from all 398 enrolled patients in both Angolan sites using six of the seven original loci were analyzed, following the methods from the original paper (14).…”

Section: Methodsmentioning

confidence: 99%

Robust Algorithm for Systematic Classification of Malaria Late Treatment Failures as Recrudescence or Reinfection Using Microsatellite Genotyping

Pluciński

Morton

Bushman

et al. 2015

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Routine therapeutic efficacy monitoring to measure the response to antimalarial treatment is a cornerstone of malaria control. To correctly measure drug efficacy, therapeutic efficacy studies require genotyping parasites from late treatment failures to differentiate between recrudescent infections and reinfections. However, there is a lack of statistical methods to systematically classify late treatment failures from genotyping data. A Bayesian algorithm was developed to estimate the posterior probability of late treatment failure being the result of a recrudescent infection from microsatellite genotyping data. The algorithm was implemented using a Monte Carlo Markov chain approach and was used to classify late treatment failures using published microsatellite data from therapeutic efficacy studies in Ethiopia and Angola. The algorithm classified 85% of the Ethiopian and 95% of the Angolan late treatment failures as either likely reinfection or likely recrudescence, defined as a posterior probability of recrudescence of <0.1 or >0.9, respectively. The adjusted efficacies calculated using the new algorithm differed from efficacies estimated using commonly used methods for differentiating recrudescence from reinfection. In a high-transmission setting such as Angola, as few as 15 samples needed to be genotyped in order to have enough power to correctly classify treatment failures. Analysis of microsatellite genotyping data for differentiating between recrudescence and reinfection benefits from an approach that both systematically classifies late treatment failures and estimates the uncertainty of these classifications. Researchers analyzing genotyping data from antimalarial therapeutic efficacy monitoring are urged to publish their raw genetic data and to estimate the uncertainty around their classification. P rompt and effective treatment for malaria is one of the pillars of malaria control, the global effort to reduce the burden of this parasitic disease responsible for 627,000 deaths annually (1). However, the malaria parasite has historically shown a tendency to develop resistance to antimalarial drugs. The emergence of resistance to virtually all antimalarial drugs, including quinine, chloroquine, sulfadoxine-pyrimethamine, mefloquine, and recently, artemisinins, has been documented (2-4). As a result, the World Health Organization (WHO) recommends that all countries in which malaria is endemic routinely retest the efficacy of first-and second-line antimalarials to monitor for early signs of resistance and to aid in the development of revised treatment guidelines (5).The main tool for surveillance of antimalarial resistance is the biennial in vivo therapeutic efficacy study that follows a standard WHO protocol (5). These are typically small clinical outcome studies that administer directly observed therapy of an antimalarial agent to patients presenting to health facilities with uncomplicated malaria. Patients not adequately clearing the infection within 4 days are classified as early treatment failures. If cl...

show abstract

Efficacy of Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine for Treatment of Uncomplicated Malaria in Children in Zaire and Uíge Provinces, Angola

Cited by 87 publications

References 34 publications

In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity

In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity

Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum

Robust Algorithm for Systematic Classification of Malaria Late Treatment Failures as Recrudescence or Reinfection Using Microsatellite Genotyping

Contact Info

Product

Resources

About