scholarly journals A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Yeka Adoke ◽  
◽  
Rella Zoleko-Manego ◽  
Serge Ouoba ◽  
Alfred B. Tiono ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Single Dose ◽  
Drug Exposure ◽  
Negative Impact ◽  
Artemisinin Resistance ◽  
African Countries ◽  
Double Blind ◽  
Asian Patients ◽  
African Patients ◽  
Kelch 13

Abstract Background For uncomplicated Plasmodium falciparum malaria, highly efficacious single-dose treatments are expected to increase compliance and improve treatment outcomes, and thereby may slow the development of resistance. The efficacy and safety of a single-dose combination of artefenomel (800 mg) plus ferroquine (400/600/900/1200 mg doses) for the treatment of uncomplicated P. falciparum malaria were evaluated in Africa (focusing on children ≤ 5 years) and Asia. Methods The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged > 6 months to < 70 years, from six African countries and Vietnam. Patients were followed up for 63 days to assess treatment efficacy, safety and pharmacokinetics. The primary efficacy endpoint was the polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 28 in the Per-Protocol [PP] Set comprising only African patients ≤ 5 years. The exposure–response relationship for PCR-adjusted ACPR at Day 28 and prevalence of kelch-13 mutations were explored. Results A total of 373 patients were treated: 289 African patients ≤ 5 years (77.5%), 64 African patients > 5 years and 20 Asian patients. None of the treatment arms met the target efficacy criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%). PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged from 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in Vietnamese patients, ranging from 20 to 40%. A clear relationship was found between drug exposure (artefenomel and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher concentrations of both drugs resulting in higher efficacy. Six distinct kelch-13 mutations were detected in parasite isolates from 10/272 African patients (with 2 mutations known to be associated with artemisinin resistance) and 18/20 Asian patients (all C580Y mutation). Vomiting within 6 h of initial artefenomel administration was common (24.6%) and associated with lower drug exposures. Conclusion The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged ≤ 5 years, the population of interest, and vomiting most likely had a negative impact on efficacy. Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https://clinicaltrials.gov/ct2/show/NCT02497612?term=NCT02497612&draw=2&rank=1

scholarly journals Prevalence of Mutations in the pfcoronin Gene and Association with Ex Vivo Susceptibility to Common Quinoline Drugs against Plasmodium falciparum

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1273
Author(s):  
Océane Delandre ◽  
Mathieu Gendrot ◽  
Isabelle Fonta ◽  
Joel Mosnier ◽  
Nicolas Benoit ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Sanger Sequencing ◽  
Ex Vivo ◽  
Central Africa ◽  
Artemisinin Resistance ◽  
Current Data ◽  
Artemisinin Derivative ◽  
African Countries ◽  
Low Prevalence

Background: Artemisinin-based combination therapy (ACT) was recommended to treat uncomplicated falciparum malaria. Unlike the situation in Asia where resistance to ACT has been reported, artemisinin resistance has not yet emerged in Africa. However, some rare failures with ACT or patients continuing to be parasitaemic on day 3 after ACT treatment have been reported in Africa or in travellers returning from Africa. Three mutations (G50E, R100K, and E107V) in the pfcoronin gene could be responsible for artemisinin resistance in Africa. Methods: The aims of this study were first to determine the prevalence of mutations in the pfcoronin gene in African P. falciparum isolates by Sanger sequencing, by targeting the 874 samples collected from patients hospitalised in France after returning from endemic areas in Africa between 2018 and 2019, and secondly to evaluate their association with in vitro reduced susceptibility to standard quinoline antimalarial drugs, including chloroquine, quinine, mefloquine, desethylamodiaquine, lumefantrine, piperaquine, and pyronaridine. Results: The three mutations in the pfcoronin gene (50E, 100K, and 107V) were not detected in the 874 P. falciparum isolates. Current data show that another polymorphism (P76S) is present in many countries of West Africa (mean prevalence of 20.7%) and Central Africa (11.9%) and, rarely, in East Africa (4.2%). This mutation does not appear to be predictive of in vitro reduced susceptibility to quinolines, including artemisinin derivative partners in ACT such as amodiaquine, lumefantrine, piperaquine, pyronaridine, and mefloquine. Another mutation (V62M) was identified at low prevalence (overall prevalence of 1%). Conclusions: The 76S mutation is present in many African countries with a prevalence above 10%. It is reassuring that this mutation does not confer in vitro resistance to ACT partners.

scholarly journals Expansion of the Plasmodium falciparum Kelch 13 R622I mutation in Northwest Ethiopia

2021 ◽  
Author(s):  
Aberham A. Alemayehu ◽  
Daniel Castaneda-Mogollon ◽  
Habtie Tesfa ◽  
Sisay Getie ◽  
Abu Naser Mohon ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Artemisinin Resistance ◽  
Northwest Ethiopia ◽  
Efficacy Trial ◽  
North West ◽  
North West Ethiopia ◽  
Parasitological Response ◽  
Kelch 13

Abstract According to the WHO, almost two thirds of the Ethiopian population are at risk of contracting malaria, where infection with Plasmodium falciparum accounts for approximately 60% of cases today. The risk of artemisinin resistance spreading from SE Asia to Africa is a major concern. We conducted a 28-day in vivo efficacy trial of Artemether-Lumefantrine (Co-Artem) for treatment of uncomplicated malaria (n = 97) in the Gondar Region, North West Ethiopia in 2017–2018. Our results confirmed 100% adequate clinical and parasitological response (ACPR) with no parasites observed at day 3 by microscopy. Further analysis of day 0 samples showed the expansion of a kelch13 mutation R622I to 9.5% from 2.4% of isolates reported three years earlier. Closer examination of the R622I mutation in vitro is warranted.

scholarly journals Dose-Dependent Infectivity of Aseptic, Purified, Cryopreserved Plasmodium falciparum 7G8 Sporozoites in Malaria-Naive Adults

2019 ◽  
Vol 220 (12) ◽  
pp. 1962-1966 ◽  
Author(s):  
Matthew B Laurens ◽  
Andrea A Berry ◽  
Mark A Travassos ◽  
Kathy Strauss ◽  
Matthew Adams ◽  
...  
Keyword(s):  
United States ◽  
Plasmodium Falciparum ◽  
Malaria Infection ◽  
The United States ◽  
Infection Rates ◽  
African Countries ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Controlled Human Malaria Infection ◽  
Dose Dependent

Abstract Direct venous inoculation of 3.2 × 103 aseptic, purified, cryopreserved, vialed Plasmodium falciparum (Pf) strain NF54 sporozoites, PfSPZ Challenge (NF54), has been used for controlled human malaria infection (CHMI) in the United States, 4 European countries, and 6 African countries. In nonimmune adults, this results in 100% infection rates. We conducted a double-blind, randomized, dose-escalation study to assess the infectivity of the 7G8 clone of Pf (PfSPZ Challenge [7G8]). Results showed dose-dependent infectivity from 43% for 8 × 102 PfSPZ to 100% for 4.8 × 103 PfSPZ. PfSPZ Challenge (7G8) will allow for more complete assessment by CHMI of antimalarial vaccines and drugs.

scholarly journals Polymorphisms in Plasmodium falciparum Kelch 13 and P. vivax Kelch 12 Genes in Parasites Collected from Three South Pacific Countries Prior to Extensive Exposure to Artemisinin Combination Therapies

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Karryn Gresty ◽  
Karen Anderson ◽  
Cielo Pasay ◽  
Norman C. Waters ◽  
Qin Cheng
Keyword(s):  
Plasmodium Falciparum ◽  
Papua New Guinea ◽  
Solomon Islands ◽  
Artemisinin Resistance ◽  
South Pacific ◽  
New Guinea ◽  
Combination Therapies ◽  
Baseline Information ◽  
Artemisinin Combination Therapies ◽  
Kelch 13

ABSTRACT The South Pacific countries Solomon Islands, Vanuatu, and Papua New Guinea (PNG) adopted artemisinin-based combination therapies (ACTs) in 2008. We examined Kelch 13 and Kelch 12 genes in parasites originating from these countries before or at ACT introduction. Four Kelch 13 and two Kelch 12 novel sequence polymorphisms, not associated with artemisinin resistance, were observed in parasites from Solomon Islands and Vanuatu. No polymorphisms were observed in PNG parasites. The findings provide useful baseline information.

scholarly journals Continued Sensitivity of Plasmodium falciparum to Artemisinin in Guyana, With Absence of Kelch Propeller Domain Mutant Alleles

2016 ◽  
Vol 3 (3) ◽  
Author(s):  
Reyaud Rahman ◽  
Maria Jesus Sanchez Martin ◽  
Shamdeo Persaud ◽  
Nicolas Ceron ◽  
Dwayne Kellman ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Confidence Interval ◽  
Clearance Rate ◽  
Artemisinin Resistance ◽  
Parasite Clearance ◽  
Wild Type ◽  
Resistance Monitoring ◽  
Mining Areas ◽  
Widespread Availability ◽  
Kelch 13

Abstract Because of concerns about possible emergence of artemisinin resistance strains of Plasmodium falciparum in mining areas of the interior of Guyana, a 7-day artesunate trial was conducted from March to December 2014. The day-3 parasite clearance rate, the efficacy of artesunate at day 28, and polymorphism of Kelch 13 (PfK13)—the marker of artemisinin resistance—were assessed. The study confirmed the continued sensitivity of P falciparum to artemisinin. A 7-day course of artesunate was 100% efficacious with only 2% (95% confidence interval, .1%–10.9%) of enrolled subjects positive at day 3. All day-0 parasite samples were wild type. Continued resistance monitoring is nevertheless recommended, given the widespread availability and uncontrolled use of artemisinin drugs in mining areas of Guyana.

scholarly journals Significant Efficacy of a Single Low Dose of Primaquine Compared to Stand-Alone Artemisinin Combination Therapy in Reducing Gametocyte Carriage in Cambodian Patients with Uncomplicated Multidrug-Resistant Plasmodium falciparum Malaria

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Amélie Vantaux ◽  
Saorin Kim ◽  
Eakpor Piv ◽  
Sophy Chy ◽  
Laura Berne ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Low Dose ◽  
Negative Impact ◽  
Controlled Trial ◽  
Artemisinin Combination Therapy ◽  
Artemisinin Resistance ◽  
Multidrug Resistant ◽  
Transmission Blocking ◽  
Content Type ◽  
Gametocyte Carriage

ABSTRACT Since 2012, a single low dose of primaquine (SLDPQ; 0.25 mg/kg of body weight) with artemisinin-based combination therapies has been recommended as the first-line treatment of acute uncomplicated Plasmodium falciparum malaria to interrupt its transmission, especially in low-transmission settings of multidrug resistance, including artemisinin resistance. Policy makers in Cambodia have been reluctant to implement this recommendation due to primaquine safety concerns and a lack of data on its efficacy. In this randomized controlled trial, 109 Cambodians with acute uncomplicated P. falciparum malaria received dihydroartemisinin-piperaquine (DP) alone or combined with SLDPQ on the first treatment day. The transmission-blocking efficacy of SLDPQ was evaluated on days 0, 1, 2, 3, 7, 14, 21, and 28, and recrudescence by reverse transcriptase PCR (RT-PCR) (gametocyte prevalence) and membrane feeding assays with Anopheles minimus mosquitoes (gametocyte infectivity). Without the influence of recrudescent infections, DP-SLDPQ reduced gametocyte carriage 3-fold compared to that achieved with DP. Of 48 patients tested on day 0, only 3 patients were infectious to mosquitoes (∼6%). Posttreatment, three patients were infectious on day 14 (3.5%, 1/29) and on the 1st and 7th days of recrudescence (8.3%, 1/12 for each); this overall low infectivity precluded our ability to assess its transmission-blocking efficacy. Our study confirms the effective gametocyte clearance of SLDPQ when combined with DP in multidrug-resistant P. falciparum infections and the negative impact of recrudescent infections due to poor DP efficacy. Artesunate-mefloquine (ASMQ) has replaced DP, and ASMQ-SLDPQ has been deployed to treat all patients with symptomatic P. falciparum infections to further support the elimination of multidrug-resistant P. falciparum in Cambodia. (This study has been registered at ClinicalTrials.gov under identifier NCT02434952.)

scholarly journals Prevalence of Plasmodium falciparum Kelch 13 (PfK13) and Ubiquitin-Specific Protease 1 (pfubp1) Gene Polymorphisms in Returning Travelers from Africa Reported in Eastern China

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
He Yan ◽  
Xiangli Kong ◽  
Tao Zhang ◽  
Huihui Xiao ◽  
Xinyu Feng ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Markers ◽  
Eastern China ◽  
Parasite Clearance ◽  
African Countries ◽  
Content Type ◽  
Clinical Trial Research ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Kelch 13

ABSTRACT Delayed clearance of Plasmodium falciparum by artemisinin-based combination therapies (ACTs) has already been observed for African isolates. Here, we aimed to investigate the prevalence, among travelers returning from African countries, of polymorphisms in two genes correlated with delayed parasite clearance (encoding P. falciparum Kelch 13 [PfK13] and ubiquitin-specific protease 1 [pfubp1]) reported in eastern China and to provide baseline data for antimalarial drug resistance (ART) surveillance and evaluation. A total of 153 filter paper blood spots collected in 2017–2019 from patients with uncomplicated P. falciparum cases in Anhui and Shandong Provinces were included in this study. Among them, 3.3% (5/153) of the isolates carried PfK13 mutations, and 3 of them harbored the same synonymous mutation, C469C. A total of 13.1% (20/153) of the isolates were found to contain pfubp1 mutations, and all were nonsynonymous. The pfubp1 genotypes associated with ART that occurred in this study included E1528D (6.5% [10/153]) and D1525E (2.6% [4/153]). However, a high prevalence of the previously unreported mutation E1531D (5.9% [9/153]) was also detected. In addition, two types of deletions (encoding KID and KIE, respectively) and two types of insertions (encoding KYE and KYDKYD, respectively) were found in 16 isolates and 6 isolates, respectively. This study showed limited variation in PfK13 among travelers returning from African countries and suggested other potential molecular markers, such as pfubp1, for use in the surveillance of African isolates in ACT susceptibility studies. Further clinical trial research is under way to investigate these PfK13 and pfubp1 mutations, as well as other candidate molecular markers, and their roles in delaying parasite clearance.

scholarly journals Emergence of Mutations in the K13 Propeller Gene of Plasmodium falciparum Isolates from Dakar, Senegal, in 2013-2014

2015 ◽  
Vol 60 (1) ◽  
pp. 624-627 ◽  
Author(s):  
Agathe Boussaroque ◽  
Bécaye Fall ◽  
Marylin Madamet ◽  
Cheikhou Camara ◽  
Nicolas Benoit ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Artemisinin Resistance ◽  
Specific Domain ◽  
Content Type ◽  
Link Type ◽  
J 13 ◽  
Kelch 13

ABSTRACTThe kelch 13 (K13) propeller gene is associated with artemisinin resistance. In a previous work, there were no mutations found in 138Plasmodium falciparumisolates collected in 2012 and 2013 from patients residing in Dakar, Senegal (M. Torrentino-Madamet et al., Malar J 13:472, 2014,http://dx.doi.org/10.1186/1475-2875-13-472). However, the N554H, Q613H, and V637I mutations were identified in the propeller region of K13 in 92 (5.5%) isolates in 2013 and 2014. There were five polymorphisms identified in thePlasmodium/Apicomplexa-specific domain (K123R, N137S, N142NN/NNN, T149S, and K189T/N).

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