Investigation of Markers of Artemisinin Resistance at Selected Intervals during the 72 h Period after Artemisinin based Combination Therapy Dosing in Kisumu Western Kenya

2018 ◽  
Vol 06 (02) ◽  
Author(s):  
Apollo Asenath ◽  
Lorna J Chebon ◽  
Keneth Mitei ◽  
Benjamin Opot ◽  
Dennis W Juma ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Artemisinin Resistance ◽  
Western Kenya

scholarly journals Evidence of interaction between humoral immunity and drug half-life in determining treatment outcome for artemisinin combination therapy in high transmission settings in western Kenya

2020 ◽  
Author(s):  
Ben Andagalu ◽  
Pinyi Lu ◽  
Irene Onyango ◽  
Elke Bergmann-Leitner ◽  
Ruth Wasuna ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Combination Therapy ◽  
Humoral Immunity ◽  
Artemisinin Combination Therapy ◽  
Western Kenya ◽  
Humoral Immune ◽  
High Transmission ◽  
Humoral Immune Responses ◽  
Applied Machine Learning ◽  
Study Participants

AbstractThe role of humoral immunity on the efficacy of artemisinin combination therapy (ACT) has not been investigated, yet naturally acquired immunity is key determinant of antimalarial therapeutic response. We conducted a therapeutic efficacy study in high transmission settings of western Kenya, which showed artesunate-mefloquine (ASMQ) and dihydroartemisinin-piperaquine (DP) were more efficacious than artemether-lumefantrine (AL). To investigate the underlying prophylactic mechanism, we compared a broad range of humoral immune responses in cohort I study participants treated with ASMQ or AL, and applied machine-learning (ML) models using immunoprofile data to analyze individual participants’ treatment outcome. We showed ML models could predict treatment outcome for ASMQ but no AL with high (72-92%) accuracy. Simulated PK profiling provided evidence demonstrating specific humoral immunity confers protection in the presence of sub-therapeutic residual mefloquine concentration. We concluded patient humoral immunity and partner drug interact to provide long prophylactic effect of ASMQ.

scholarly journals Novel pfkelch13 Gene Polymorphism Associates With Artemisinin Resistance in Eastern India

2018 ◽  
Vol 69 (7) ◽  
pp. 1144-1152 ◽  
Author(s):  
Sabyasachi Das ◽  
Subhankar Manna ◽  
Bhaskar Saha ◽  
Amiya Kumar Hati ◽  
Somenath Roy
Keyword(s):  
Combination Therapy ◽  
Treatment Failure ◽  
Ex Vivo ◽  
Artemisinin Combination Therapy ◽  
Gene Mutations ◽  
Artemisinin Resistance ◽  
Parasite Clearance ◽  
World Health ◽  
Ring Stage ◽  
Self Medication

Abstract Background Artesunate-sulfadoxine-pyrimethamine (ASSP) is the frontline artemisinin combination therapy (ACT) in India. Random, irrational, subtherapeutic artemisinin doses and self-medication with ACT along with predominance of sulfadoxine-pyrimethamine resistance parasite invoked a strong possibility of emerging artemisinin-resistant malaria parasites. Methods This study involved 226 patients with uncomplicated Plasmodium falciparum infection who had successfully completed the 42 days follow-up after ASSP combination therapy from April 2014 to January 2016. We assessed the ASSP treatment efficacy by evaluating parasite clearance half-life, pfkelch13, and other (pfdhfr, pfdhps, pfmdr1, pfcrt) gene mutations and survival of parasites as detected by an ex vivo ring-stage survival assay (RSA). Findings Slow-clearing infections with longer parasite clearance half-lives (>5 hours) were observed in 12% isolates. Cure rate after ASSP treatment was declining to about 84.1%. ASSP failure was recorded in 15.9% (early treatment failure, 7.9%; late treatment failure, 7.9%) of isolates. In sum, 24 patients (10.6%) had parasite clearance half-lives greater than 5 hours with pfkelch13 polymorphism after 441 codon; in 15 of those patients (6.6%), parasites had not cleared by 72 hours after initiation of therapy. Median ex vivo ring-stage survival rate of these isolates was very high (12.2%; 95% confidence interval [CI], 10.9–13.8) from that of cured patients (0.9%; 95% CI, 0.09–1.07). Of these 15 patients, 13 patients had pfkelch13 G625R polymorphism, whereas 2 patients contained R539T polymorphism. As per the World Health Organization guideline, these 15 isolates were true artemisinin-resistant isolates. Interpretation Identification of artemisinin-resistant isolates in India together with new mutations and increasing combination therapy failures blow alarms for urgent malaria control.

scholarly journals Sustained Ex Vivo Susceptibility of Plasmodium falciparum to Artemisinin Derivatives but Increasing Tolerance to Artemisinin Combination Therapy Partner Quinolines in The Gambia

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Alfred Amambua-Ngwa ◽  
Joseph Okebe ◽  
Haddijatou Mbye ◽  
Sukai Ceesay ◽  
Fatima El-Fatouri ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Combination Therapy ◽  
Genomic Sequence ◽  
Sequence Data ◽  
Ex Vivo ◽  
Artemisinin Combination Therapy ◽  
Artemisinin Resistance ◽  
The Gambia ◽  
Microsatellite Variation

ABSTRACT Antimalarial interventions have yielded a significant decline in malaria prevalence in The Gambia, where artemether-lumefantrine (AL) has been used as a first-line antimalarial for a decade. Clinical Plasmodium falciparum isolates collected from 2012 to 2015 were analyzed ex vivo for antimalarial susceptibility and genotyped for drug resistance markers (pfcrt K76T, pfmdr1 codons 86, 184, and 1246, and pfk13) and microsatellite variation. Additionally, allele frequencies of single nucleotide polymorphisms (SNPs) from other drug resistance-associated genes were compared from genomic sequence data sets from 2008 (n = 79) and 2014 (n = 168). No artemisinin resistance-associated pfk13 mutation was found, and only 4% of the isolates tested in 2015 showed significant growth after exposure to dihydroartemisinin. Conversely, the 50% inhibitory concentrations (IC50s) of amodiaquine and lumefantrine increased within this period. pfcrt 76T and pfmdr1 184F mutants remained at a prevalence above 80%. pfcrt 76T was positively associated with higher IC50s to chloroquine. pfmdr1 NYD increased in frequency between 2012 and 2015 due to lumefantrine selection. The TNYD (pfcrt 76T and pfmdr1 NYD wild-type haplotype) also increased in frequency following AL implementation in 2008. These results suggest selection for pfcrt and pfmdr1 genotypes that enable tolerance to lumefantrine. Increased tolerance to lumefantrine calls for sustained chemotherapeutic monitoring in The Gambia to minimize complete artemisinin combination therapy (ACT) failure in the future.

scholarly journals Plasmodium falciparum Genetic Diversity in Continental Equatorial Guinea before and after Introduction of Artemisinin-Based Combination Therapy

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Mónica Guerra ◽  
Rita Neres ◽  
Patrícia Salgueiro ◽  
Cristina Mendes ◽  
Nicolas Ndong-Mabale ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Combination Therapy ◽  
Microsatellite Loci ◽  
Point Mutations ◽  
Artemisinin Resistance ◽  
Equatorial Guinea ◽  
Content Type ◽  
Before And After

ABSTRACT Efforts to control malaria may affect malaria parasite genetic variability and drug resistance, the latter of which is associated with genetic events that promote mechanisms to escape drug action. The worldwide spread of drug resistance has been a major obstacle to controlling Plasmodium falciparum malaria, and thus the study of the origin and spread of associated mutations may provide some insights into the prevention of its emergence. This study reports an analysis of P. falciparum genetic diversity, focusing on antimalarial resistance-associated molecular markers in two socioeconomically different villages in mainland Equatorial Guinea. The present study took place 8 years after a previous one, allowing the analysis of results before and after the introduction of an artemisinin-based combination therapy (ACT), i.e., artesunate plus amodiaquine. Genetic diversity was assessed by analysis of the Pfmsp2 gene and neutral microsatellite loci. Pfdhps and Pfdhfr alleles associated with sulfadoxine-pyrimethamine (SP) resistance and flanking microsatellite loci were investigated, and the prevalences of drug resistance-associated point mutations of the Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps genes were estimated. Further, to monitor the use of ACT, we provide the baseline prevalences of K13 propeller mutations and Pfmdr1 copy numbers. After 8 years, noticeable differences occurred in the distribution of genotypes conferring resistance to chloroquine and SP, and the spread of mutated genotypes differed according to the setting. Regarding artemisinin resistance, although mutations reported as being linked to artemisinin resistance were not present at the time, several single nucleotide polymorphisms (SNPs) were observed in the K13 gene, suggesting that closer monitoring should be maintained to prevent the possible spread of artemisinin resistance in Africa.

scholarly journals Artemisinin resistance containment project in Thailand. II: responses to mefloquine-artesunate combination therapy among falciparum malaria patients in provinces bordering Cambodia

2012 ◽  
Vol 11 (1) ◽  
pp. 300 ◽  
Author(s):  
Wichai Satimai ◽  
Prayuth Sudathip ◽  
Saowanit Vijaykadga ◽  
Amnat Khamsiriwatchara ◽  
Surasak Sawang ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Falciparum Malaria ◽  
Artemisinin Resistance

scholarly journals Evaluation of the Combination of Azithromycin and Naphthoquine in Animal Malaria Models

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Zhu-Chun Bei ◽  
Guo-Fu Li ◽  
Jing-Hua Zhao ◽  
Min Zhang ◽  
Xiao-Guang Ji ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Synergistic Effects ◽  
Artemisinin Resistance ◽  
Optimal Dose ◽  
Dose Ratio ◽  
Content Type ◽  
Current State ◽  
Dosing Regimens ◽  
Further Development ◽  
Dose Dependent

ABSTRACT Combination therapy using drugs with different mechanisms of action is the current state of the art in antimalarial treatment. However, except for artemisinin-based combination therapies, only a few other combinations are now available. Increasing concern regarding the emergence and spread of artemisinin resistance in Plasmodium falciparum has led to a need for the development of new antimalarials. Moreover, the efficacy of current available chemoprophylaxis is compromised by drug resistance and noncompliance due to intolerable adverse effects or complicated dosing regimens. Therefore, new antimalarials that are more effective, safer, and more convenient are also urgently needed for malaria chemoprophylaxis. In this study, we assessed the combination of azithromycin and naphthoquine in animal malaria models. A dose-dependent interaction was observed in Peters’ 4-day suppressive test on P. berghei K173-infected mice. Moreover, at inhibition levels of ≥90%, synergistic effects were found for combinations at various ratios. At an optimal dose ratio of 1:1, the combination of azithromycin and naphthoquine acted synergistically even by 4 weeks after the first dose and provided a more effective and sustained prophylaxis than did naphthoquine alone in blood-stage P. berghei K173 and P. cynomolgi bastianelli L challenge models. The ability of the combination to delay and slow down resistance development in P. berghei K173 was also shown. These results showed clear evidence for the benefit of the combination therapy with azithromycin and naphthoquine in animal malaria models, providing some insight for further development of this therapy for malaria treatment and prophylaxis.

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