scholarly journals Persistence of High In Vivo Efficacy and Safety of Artesunate–Amodiaquine and Artemether–Lumefantrine as the First- and Second-Line Treatments for Uncomplicated Plasmodium falciparum Malaria 10 Years After Their Implementation in Gabon

2019 ◽  
Vol 64 (4) ◽  
pp. 898-902
Author(s):  
Jacques M. Ndong Ngomo ◽  
Guy J. Ondzagha Megnie ◽  
Bridy Moutombi Ditombi ◽  
Jeanne V. Koumba Lengongo ◽  
Noé P. M’Bondoukwé ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Adverse Events ◽  
Uncomplicated Malaria ◽  
Plasmodium Falciparum Malaria ◽  
Parasite Resistance ◽  
Serious Adverse Events ◽  
Uncomplicated Plasmodium Falciparum Malaria ◽  
Who 2008

Abstract Purpose Artesunate–amodiaquine (AS–AQ) and artemether–lumefantrine (AL) have been widely used for the treatment of uncomplicated Plasmodium falciparum malaria since 2005 in Gabon. Since 2011, a rebound of malaria morbidity has been observed in this country, while no survey evaluating ACT efficacy was performed. During the same period, parasite resistance against artemisinin has been reported in Asia. The aim of this study was to assess the efficacy and tolerability of these two drugs in two sentinel sites of Gabon 10 years after their implementation. Methods Children aged from 12 to 144 months with uncomplicated malaria were recruited at the Regional Hospital of Melen, Libreville and in the Urban Health Center of Franceville between March 2014 and September 2015. The therapeutic efficacy was evaluated according to the WHO 2008 protocol of 28-day follow-up and PCR-uncorrected/corrected treatment outcomes were assessed. Results One hundred and eighty-five children (98 ASAQ and 89 AL) were followed up until day 28. The PCR-corrected ACPR was 98.9% for AS–AQ and 96.4% for AL. Late therapeutic failure rate was 3.6% and 1.1% for AL and AS–AQ, respectively (p = 0.2). Adverse events and serious adverse events were rarely observed with both treatments. Conclusion AS–AQ and AL are still efficacious and well-tolerated for the treatment of uncomplicated malaria in Gabonese children.

scholarly journals Efficacy of sulfadoxine/pyrimethamine for uncomplicated Plasmodium falciparum malaria in a small sample of Sudanese children

2004 ◽  
Vol 10 (3) ◽  
pp. 309-314
Author(s):  
I. Adam ◽  
M. H. Ibrahim ◽  
I. A. Aelbasit ◽  
M. I. El Bashir
Keyword(s):  
Plasmodium Falciparum ◽  
Falciparum Malaria ◽  
Plasmodium Falciparum Malaria ◽  
Small Sample ◽  
In Vivo Efficacy ◽  
Late Treatment ◽  
High Level ◽  
Uncomplicated Plasmodium Falciparum Malaria

A prospective clinical trial was carried out to determine in vivo efficacy of sulfadoxine/pyrimethamine for the treatment of uncomplicated Plasmodium falciparum malaria in children in New Halfa. Forty patients were enrolled; 31 completed the 28-day follow-up. Six [19.4%] patients showed recurrence of parasitaemia during follow-up, while the rest [80.6%] cleared the parasites and responded fully to treatment. All the failures were late treatment failures. Parasite genotyping showed that 1 [16.7%] of the 6 cases of late parasitaemia was due to reinfection while the rest [83.4%] were due to true recrudescence. During the follow-up period 22.6% of patients showed gametocytaemia. The high level of treatment failure as well as gametocytaemia necessitates the introduction of artesunate in this combination therapy

scholarly journals Therapeutic efficacy of artemether–lumefantrine and artesunate–amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Mali, 2015–2016

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Youssouf Diarra ◽  
Oumar Koné ◽  
Lansana Sangaré ◽  
Lassina Doumbia ◽  
Dade Bouye Ben Haidara ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Uncomplicated Malaria ◽  
Artemisinin Resistance ◽  
National Malaria Control Programme ◽  
Plasmodium Falciparum Malaria ◽  
Control Programme ◽  
Malaria Control Programme ◽  
Pre Treatment ◽  
Better Than

Abstract Background The current first-line treatments for uncomplicated malaria recommended by the National Malaria Control Programme in Mali are artemether–lumefantrine (AL) and artesunate–amodiaquine (ASAQ). From 2015 to 2016, an in vivo study was carried out to assess the clinical and parasitological responses to AL and ASAQ in Sélingué, Mali. Methods Children between 6 and 59 months of age with uncomplicated Plasmodium falciparum infection and 2000–200,000 asexual parasites/μL of blood were enrolled, randomly assigned to either AL or ASAQ, and followed up for 42 days. Uncorrected and PCR-corrected efficacy results at days 28 and 42. were calculated. Known markers of resistance in the Pfk13, Pfmdr1, and Pfcrt genes were assessed using Sanger sequencing. Results A total of 449 patients were enrolled: 225 in the AL group and 224 in the ASAQ group. Uncorrected efficacy at day 28 was 83.4% (95% CI 78.5–88.4%) in the AL arm and 93.1% (95% CI 89.7–96.5%) in the ASAQ arm. The per protocol PCR-corrected efficacy at day 28 was 91.0% (86.0–95.9%) in the AL arm and 97.1% (93.6–100%) in the ASAQ arm. ASAQ was significantly (p < 0.05) better than AL for each of the aforementioned efficacy outcomes. No mutations associated with artemisinin resistance were identified in the Pfk13 gene. Overall, for Pfmdr1, the N86 allele and the NFD haplotype were the most common. The NFD haplotype was significantly more prevalent in the post-treatment than in the pre-treatment isolates in the AL arm (p < 0.01) but not in the ASAQ arm. For Pfcrt, the CVIET haplotype was the most common. Conclusions The findings indicate that both AL and ASAQ remain effective for the treatment of uncomplicated malaria in Sélingué, Mali.

scholarly journals Efficacy and Safety of Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine for The Treatment of Uncomplicated Plasmodium Falciparum Malaria and Prevalence of Molecular Markers Associated With Artemisinin and Partner Drug Resistance in Uganda

2021 ◽  
Author(s):  
Chris Ebong ◽  
Asadu Sserwanga ◽  
Jane Frances Namuganga ◽  
James Kapisi ◽  
Arthur Mpimbaza ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Markers ◽  
Falciparum Malaria ◽  
Uncomplicated Malaria ◽  
Plasmodium Falciparum Malaria ◽  
Pharmacokinetic Studies ◽  
Efficacy And Safety ◽  
Open Label ◽  
Serious Adverse Events ◽  
Line Therapy

Abstract Background In Uganda, artemether-lumefantrine (AL) is the first-line therapy and dihydroartemisinin-piperaquine (DP) the second-line therapy for the treatment of uncomplicated malaria. We evaluated the efficacy and safety of AL and DP in the management of uncomplicated Plasmodium falciparum malaria and measured the prevalence of molecular markers of resistance in three sentinel sites from 2018–2019 in Uganda. Methods This was a randomized, open-label, phase IV clinical trial. Children aged 6 months to 10 years with uncomplicated falciparum malaria were randomly assigned to treatment with AL or DP and followed for 28 and 42 days, respectively. Genotyping was used to distinguish recrudescence from new infection, and a Bayesian algorithm was used to assign each treatment failure a posterior probability of recrudescence. For monitoring resistance, Pfk13 and Pfmdr1 genes were Sanger sequenced and plasmepsin-2 copy number was assessed by qPCR. Results There were no early treatment failures. The uncorrected 28-day cumulative efficacy of AL ranged from 41.2–71.2% and the PCR-corrected cumulative 28-day efficacy of AL ranged from 87.2–94.4%. The uncorrected 28-day cumulative efficacy of DP ranged from 95.8–97.9% and the PCR-corrected cumulative 28-day efficacy of DP ranged from 98.9–100%. The uncorrected 42-day efficacy of DP ranged from 73.5–87.4% and the PCR-corrected 42-day efficacy of DP ranged from 92.1–97.5%. There were no reported serious adverse events associated with any of the regimens. No resistance-associated mutations in the Pfk13 gene were found in the successfully sequenced samples. In the AL arm, the NFD haplotype (N86Y, Y184F, D1246Y) was the predominant Pfmdr1 haplotype, present in 78 of 127 (61%) and 76 of 110 (69%) of the day 0 and day of failure samples, respectively. All the day 0 samples in the DP arm had one copy of the plasmepsin-2 gene. Conclusions DP remains highly effective and safe for the treatment of uncomplicated malaria in Uganda. Recurrent infections with AL were common. In Busia and Arua, the 95% confidence interval for PCR-corrected AL efficacy fell below 90%. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended. Trial registration: The trail was also registered with the ISRCTN registry with study Trial no PACTR201811640750761.

scholarly journals Influence of Cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate-amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar

2021 ◽  
Author(s):  
Leyre Pernaute-Lau ◽  
Ulrika Morris ◽  
Mwinyi Msellem ◽  
Andreas Mårtensson ◽  
Anders Björkman ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cytochrome P450 ◽  
Adverse Events ◽  
Randomized Clinical Trials ◽  
Plasmodium Falciparum Malaria ◽  
Serious Adverse Events ◽  
Exact Test ◽  
Genotype Frequencies ◽  
Significant Difference ◽  
Minor Alleles

Abstract BackgroundThe antimalarial drug amodiaquine, a commonly used long acting partner drug in artemisinin-based combination therapy, is metabolized to active desethyl-amodiaquine (DEAQ) by cytochrome P450 2C8 (CYP2C8). The CYP2C8 gene carries several polymorphisms including the more frequent minor alleles CYP2C8*2 and CYP2C8*3. These minor alleles have been associated with decreased enzymatic activity, slowing the amodiaquine biotransformation towards DEAQ. This study aimed to assess the influence of these CYP2C8 polymorphisms on the efficacy and tolerability of artesunate-amodiaquine treatment for uncomplicated Plasmodium falciparum malaria in Zanzibar.MethodsWe analysed data from 618 children under 5 years of age with uncomplicated P. falciparum malaria enrolled in two randomized clinical trials comparing artesunate-amodiaquine and artemether-lumefantrine in 2002-2005 in Zanzibar. CYP2C8*2 and CYP2C8*3 genotype frequencies were determined by PCR-restriction fragment length polymorphism. Statistical associations between CYP2C8*2 and/or CYP2C8*3 allele carriers and treatment outcome or occurrence of adverse events were assessed by Fisher’s Exact test.ResultsThe allele frequencies of CYP2C8*2 and CYP2C8*3 were 17.5% (95% CI 15.4-19.7%) and 2.7% (95% CI 1.8-3.7%), respectively. There was no significant difference in the proportion of subjects carrying either CYP2C8*2 or CYP2C8*3 alleles amongst those with reinfections (44.1%; 95% CI 33.8-54.8) or those with recrudescent infections (48.3%; 95% CI 29.4-67.5), compared to those with an adequate clinical and parasitological response (36.7%; 95% CI 30.0-43.9) (P = 0.25 and P = 0.31, respectively). However, patients carrying either the CYP2C8*2 or CYP2C8*3 alleles were significantly associated with an increased occurrence of non-serious adverse events, when compared with CYP2C8 *1/*1 wildtype homozygotes (44.9%; 95% CI 36.1-54.0 versus 28.1%; 95% CI 21.9-35.0, respectively; P = 0.003). ConclusionsCYP2C8 genotypes did not influence treatment efficacy directly, but the tolerability to AS-AQ may be reduced in subjects carrying the CYP2C8*2 and CYP2C8*3 alleles. The importance of this non-negligible association with regards to amodiaquine-based malaria chemotherapy warrants further investigation.

BLOOD FOLATE CONCENTRATIONS AND IN VIVO SULFADOXINE-PYRIMETHAMINE FAILURE IN MALAWIAN CHILDREN WITH UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA

2005 ◽  
Vol 72 (3) ◽  
pp. 267-272 ◽  
Author(s):  
FRACTION K. DZINJALAMALA ◽  
KAREN I. BARNES ◽  
CHRISTOPHER V. PLOWE ◽  
TERRIE E. TAYLOR ◽  
MALCOM E. MOLYNEUX ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Falciparum Malaria ◽  
Plasmodium Falciparum Malaria ◽  
Uncomplicated Plasmodium Falciparum Malaria

scholarly journals In vivo Efficacy and Safety of Artemether-Lumefantrine and Amodiaquine-Artesunate for Uncomplicated Plasmodium Falciparum Malaria in Mozambique, 2018

2021 ◽  
Author(s):  
Abel Nhama ◽  
Lidia Nhamussua ◽  
Eusébio Macete ◽  
Quique Bassat ◽  
Crizolgo Salvador ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Combination Therapy ◽  
Falciparum Malaria ◽  
Therapeutic Efficacy ◽  
Plasmodium Falciparum Malaria ◽  
Molecular Testing ◽  
Recommended Treatment ◽  
Recurrent Malaria ◽  
Uncomplicated Plasmodium Falciparum Malaria

Abstract Background : Artemisinin-based combination therapy has been the recommended treatment for uncomplicated malaria in Mozambique since 2006, with artemether-lumefantrine (AL) and amodiaquine-artesunate (AS-AQ) as first-line treatments. To assess efficacy of currently used artemisinin-based combination therapy, an in vivo therapeutic efficacy study was conducted. Methods : The study was conducted in four sentinel sites: Montepuez, Moatize, Mopeia and Massinga. Patients between 6 to 59 months old with uncomplicated Plasmodium falciparum malaria (2,000–200,000 parasites/µl) were enrolled between February and September of 2018, assigned to either an AL or AS-AQ treatment arm, and monitored for 28 days. A Bayesian algorithm was applied to differentiate recrudescence from new infection using genotyping data of seven neutral microsatellites. Uncorrected and PCR-corrected efficacy results at day 28 were calculated. Results : Totals of 368 and 273 patients were enrolled in the AL and AS-AQ arms, respectively. Of these, 9.5% (35/368) and 5.1% (14/273) were lost to follow-up in the AL and AS-AQ arms, respectively. There were 48 and 3 recurrent malaria infections (late clinical and late parasitological failures) in the AL and AS-AQ arms, respectively. The day 28 uncorrected efficacy was 85.3% (95% CI: 81.1–88.9%) for AL and 98.8% (95% CI: 96.7–99.8%) for AS-AQ, whereas day 28 PCR-corrected efficacy was 97.9% (95% CI: 95.6–99.2%) for AL and 99.6 % (95% CI: 97.9–100%) for AS-AQ. Molecular testing confirmed that 87.4% (42/48) and 33.3% (1/3) of participants with a recurrent malaria infection in the AL and AS-AQ arms were new infections; an expected finding in a high malaria transmission area. Adverse events were documented in less than 2% of participants for both drugs. Conclusion : Both AL and AS-AQ have therapeutic efficacies well above the 90% WHO recommended threshold and remain well-tolerated in Mozambique. Routine monitoring of therapeutic efficacy should continue to ensure the treatments remain efficacious. Trial registration: Clinicaltrials.gov: NCT04370977

scholarly journals Serious antimalaria resistance, genetic markers of Kelch 13, plasmepsine 2 CNV associated with dihydroartemisinine-piperaquine phosphate resistance in Plasmodium falciparum population in malaria hyperendemic zone of Dak Lak Province (2019-2020)

2020 ◽  
Vol 8 (1) ◽  
pp. 246-253
Author(s):  
Huynh Hong Quang ◽  
Chau Van Khanh ◽  
Phạm Thanh Hien ◽  
Nguyen Thanh Thuy Nhien ◽  
Do Van Nguyen ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Markers ◽  
Study Design ◽  
Plasmodium Falciparum Malaria ◽  
Parasite Clearance ◽  
Controlled Study ◽  
In Vivo Test ◽  
Number Variation

Dihydroartemisinin-piperaquine (DHA-PPQ) is a current frontline drug recommended in global by WHO for the treatment of Plasmodium falciparum malaria (WHO, 2015), but is now failing in Vietnam’s provinces where border Cambodia, and has emerged and spread. The purpose of this study was to evaluate the efficacy and molecular markers of DHA-PPQ failures in Dak Lak province. Methods: A study design of non-randomized controlled study design for the 42 day-course follow-up in vivo test, and the molecular markers analysis. Findings: The data showed that adequate clinical and parasitological response was sharply declined to 12,1%, the proportion of late clinical failure was 51.5%, and 36.4% of patients had late parasitological. The proportion of positive parasitemia at D3 was 37%, the slope half-life was 5.36 hrs, and the progressive parasite clearance (PC) PC50, PC75, PC 90, PC95, and PC99 were 13.24; 19.29; 25.69; 29.97 and 39.15 hours, respectively. Molecular markers of C580Y Kelch mutation were observed in 100% (50/50) of the patients, the increased of Plasmepsine 2 copy number variation (CNV) was 72% (36/50), and the proportion of patients who had both K13 and increased Plasmepsine 2 CNV was 72% (36/50). Conclusions: The DHA-PPQ efficacy severely decreased to 12.1%, overall treatment failure was 87.9% with the prominent C580Y mutant plus increased Plasmepsine 2 CNV in delayed asexual P. falciparum parasite clearance. These obvious data suggest the urgency to change antimalarial policy in DHA-PPQ resistance zones, especially in Dak Lak province.

scholarly journals Artemether–lumefantrine and dihydroartemisinin–piperaquine treatment outcomes among children infected with uncomplicated Plasmodium falciparum malaria in Mwanza, Tanzania

2021 ◽  
Vol 49 (1) ◽  
Author(s):  
Karol J. Marwa ◽  
Eveline T. Konje ◽  
Anthony Kapesa ◽  
Erasmus Kamugisha ◽  
Stanley Mwita ◽  
...  
Keyword(s):  
Adverse Events ◽  
Treatment Outcomes ◽  
Antimalarial Drug ◽  
Uncomplicated Malaria ◽  
Cumulative Risk ◽  
Plasmodium Falciparum Malaria ◽  
Parasite Clearance ◽  
Rapid Decline ◽  
First Line

Abstract Background Artemisinin based combination therapies (ACTs) have been a cornerstone in the treatment of malaria in the world. A rapid decline in dihydroartemisinin piperaquine (DHP) and artemether lumefantrine (ALU) efficacies has been reported in some parts of South East Asia, the historical epicenter for the antimalarial drug resistance. Prolonged drug use is associated with selection of resistant parasites due to exposure to inadequate drug levels hence effects on treatment outcomes in malaria. ALU and DHP are used as first line and alternative first line, respectively, in Tanzania. This study was carried in Igombe, Tanzania to assess the efficacies of ALU and DHP in routine treatment of uncomplicated malaria among children. Methods This was a prospective study involving children up to 10 years and followed up for 28 and 35 days as per the WHO protocol, 2015 for monitoring antimalarial drug efficacy. The primary end points were crude and adjusted Adequate Clinical and Parasitological Response (ACPR), parasite clearance rate and reported adverse events. Results A total of 205 children with uncomplicated malaria were enrolled. One hundred and sixteen participants were treated with ALU, while 89 participants were treated with DHP. Two participants in the ALU group were lost within the 24 h of follow-up. The PCR unadjusted ACPR was108 (94.7%) for ALU and 88 (98.9%) for DHP, while the PCR adjusted ACPR was 109(95.6%) and 88(98.9%) for ALU and DHP, respectively, at 28 day follow-up. No treatment failure was observed in both groups. Cumulative risk of recurrent parasitemia was similar in both groups (p = 0.32). Age and parasite density were strong predictors for persistent day 1 parasitemia (p = 0.034 and 0.026, respectively). Nausea and vomiting, abdominal pain and headache were the most clinical adverse events reported in both groups of patients. Conclusion The present study shows that ALU and DHP are still efficacious after more than a decade of use with PCR corrected efficacies greater than 95% implying a failure rate less than 5% which is below the WHO minimum threshold requirement for recommendation of a change in the treatment policy. Both drugs were well tolerated with no major adverse events reported.

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