Faculty Opinions recommendation of Host immunity to Plasmodium falciparum and the assessment of emerging artemisinin resistance in a multinational cohort.

Artemisinin-resistant falciparum malaria, defined by a slow-clearance phenotype and the presence of kelch13 mutants, has emerged in the Greater Mekong Subregion. Naturally acquired immunity to malaria clears parasites independent of antimalarial drugs. We hypothesized that between- and within-population variations in host immunity influence parasite clearance after artemisinin treatment and the interpretation of emerging artemisinin resistance. Antibodies specific to 12 Plasmodium falciparum sporozoite and blood-stage antigens were determined in 959 patients (from 11 sites in Southeast Asia) participating in a multinational cohort study assessing parasite clearance half-life (PCt1/2) after artesunate treatment and kelch13 mutations. Linear mixed-effects modeling of pooled individual patient data assessed the association between antibody responses and PCt1/2.P. falciparum antibodies were lowest in areas where the prevalence of kelch13 mutations and slow PCt1/2 were highest [Spearman ρ = −0.90 (95% confidence interval, −0.97, −0.65), and Spearman ρ = −0.94 (95% confidence interval, −0.98, −0.77), respectively]. P. falciparum antibodies were associated with faster PCt1/2 (mean difference in PCt1/2 according to seropositivity, −0.16 to −0.65 h, depending on antigen); antibodies have a greater effect on the clearance of kelch13 mutant compared with wild-type parasites (mean difference in PCt1/2 according to seropositivity, −0.22 to −0.61 h faster in kelch13 mutants compared with wild-type parasites). Naturally acquired immunity accelerates the clearance of artemisinin-resistant parasites in patients with falciparum malaria and may confound the current working definition of artemisinin resistance. Immunity may also play an important role in the emergence and transmission potential of artemisinin-resistant parasites.

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Predictors of treatment failures of plasmodium falciparum malaria in Vietnam: a 4-year single‐centre retrospective study

Malaria Journal ◽

10.1186/s12936-021-03720-3 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Minh Cuong Duong ◽

Oanh Kieu Nguyet Pham ◽

Phong Thanh Nguyen ◽

Van Vinh Chau Nguyen ◽

Phu Hoan Nguyen

Keyword(s):

Plasmodium Falciparum ◽

Treatment Failure ◽

Severe Malaria ◽

Falciparum Malaria ◽

Control Strategies ◽

Artemisinin Resistance ◽

Plasmodium Falciparum Malaria ◽

Molecular Technique ◽

Drug Resistant ◽

Public Health Burden

Abstract Background Drug-resistant falciparum malaria is an increasing public health burden. This study examined the magnitude of Plasmodium falciparum infection and the patterns and predictors of treatment failure in Vietnam. Methods Medical records of all 443 patients with malaria infection admitted to the Hospital for Tropical Diseases between January 2015 and December 2018 were used to extract information on demographics, risk factors, symptoms, laboratory tests, treatment, and outcome. Results More than half (59.8%, 265/443, CI 55.1–64.4%) of patients acquired Plasmodium falciparum infection of whom 21.9% (58/265, CI 17.1–27.4%) had severe malaria, while 7.2% (19/265, CI 4.6–10.9%) and 19.2% (51/265, CI 14.7–24.5%) developed early treatment failure (ETF) and late treatment failure (LTF) respectively. Among 58 patients with severe malaria, 14 (24.1%) acquired infection in regions where artemisinin resistance has been documented including Binh Phuoc (11 patients), Dak Nong (2 patients) and Gia Lai (1 patient). Under treatment with intravenous artesunate, the median (IQR) parasite half-life of 11 patients coming from Binh Phuoc was 3 h (2.3 to 8.3 h), two patients coming from Dak Nong was 2.8 and 5.7 h, and a patient coming from Gia Lai was 6.5 h. Most patients (98.5%, 261/265) recovered completely. Four patients with severe malaria died. Severe malaria was statistically associated with receiving treatment at previous hospitals (P < 0.001), hepatomegaly (P < 0.001) and number of inpatient days (P < 0.001). Having severe malaria was a predictor of ETF (AOR 6.96, CI 2.55–19.02, P < 0.001). No predictor of LTF was identified. Conclusions Plasmodium falciparum remains the prevalent malaria parasite. Despite low mortality rate, severe malaria is not rare and is a significant predictor of ETF. To reduce the risk for ETF, studies are needed to examine the effectiveness of combination therapy including parenteral artesunate and a parenteral partner drug for severe malaria. The study alerts the possibility of drug-resistant malaria in Africa and other areas in Vietnam, which are known as non-endemic areas of anti-malarial drug resistance. A more comprehensive study using molecular technique in these regions is required to completely understand the magnitude of drug-resistant malaria and to design appropriate control strategies.

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Therapeutic efficacy of artesunate-amodiaquine and artemether-lumefantrine and polymorphism in Plasmodium falciparum kelch13-propeller gene in Equatorial Guinea

Malaria Journal ◽

10.1186/s12936-021-03807-x ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Matilde Riloha Rivas ◽

Marian Warsame ◽

Ramona Mbá Andeme ◽

Salomón Nsue Esidang ◽

Policarpo Ricardo Ncogo ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Artemisinin Resistance ◽

Parasite Clearance ◽

Equatorial Guinea ◽

Inclusion Criteria ◽

Treatment Groups ◽

Three Samples ◽

Cure Rates ◽

Al Treatment ◽

Parasitological Response

Abstract Background Artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are the currently recommended first- and second-line therapies for uncomplicated Plasmodium falciparum infections in Equatorial Guinea. This study was designed to evaluate the efficacy of these artemisinin-based combinations and detect mutations in P. falciparum kelch13-propeller domain gene (Pfkelch13). Methods A single-arm prospective study evaluating the efficacy of ASAQ and AL at three sites: Malabo, Bata and Ebebiyin was conducted between August 2017 and July 2018. Febrile children aged six months to 10 years with confirmed uncomplicated P. falciparum infection and other inclusion criteria were sequentially enrolled first in ASAQ and then in AL at each site, and followed up for 28 days. Clinical and parasitological parameters were assessed. The primary endpoint was PCR-adjusted adequate clinical and parasitological response (ACPR). Samples on day-0 were analysed for mutations in Pfkelch13 gene. Results A total 264 and 226 patients were enrolled in the ASAQ and AL treatment groups, respectively. Based on per-protocol analysis, PCR-adjusted cure rates of 98.6% to 100% and 92.4% to 100% were observed in patients treated with ASAQ and AL, respectively. All study children in both treatment groups were free of parasitaemia by day-3. Of the 476 samples with interpretable results, only three samples carried non-synonymous Pfkelch13 mutations (E433D and A578S), and none of them is the known markers associated with artemisinin resistance. Conclusion The study confirmed high efficacy of ASAQ and AL for the treatment of uncomplicated falciparum infections as well as the absence of delayed parasite clearance and Pfkelch13 mutations associated with artemisinin resistance. Continued monitoring of the efficacy of these artemisinin-based combinations, at least every two years, along with molecular markers associated with artemisinin and partner drug resistance is imperative to inform national malaria treatment policy and detect resistant parasites early. Trial registration ACTRN12617000456358, Registered 28 March 2017; http://www.anzctr.org.au/trial/MyTrial.aspx

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

Malaria Journal ◽

10.1186/s12936-021-03760-9 ◽

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.

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Implicating extracellular vesicles in Plasmodium falciparum artemisinin resistance development

Traffic ◽

10.1111/tra.12787 ◽

2021 ◽

Author(s):

Kwesi Z. Tandoh ◽

Michael D. Wilson ◽

Neils B. Quashie ◽

Nancy O. Duah‐Quashie

Keyword(s):

Plasmodium Falciparum ◽

Extracellular Vesicles ◽

Artemisinin Resistance ◽

Resistance Development

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A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria

Nature ◽

10.1038/nature14412 ◽

2015 ◽

Vol 520 (7549) ◽

pp. 683-687 ◽

Cited By ~ 320

Author(s):

Alassane Mbengue ◽

Souvik Bhattacharjee ◽

Trupti Pandharkar ◽

Haining Liu ◽

Guillermina Estiu ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Molecular Mechanism ◽

Falciparum Malaria ◽

Artemisinin Resistance ◽

Plasmodium Falciparum Malaria

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Emergence and Spread of kelch13 Mutations Associated with Artemisinin Resistance in Plasmodium falciparum Parasites in 12 Thai Provinces from 2007 to 2016

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02141-17 ◽

2018 ◽

Vol 62 (4) ◽

Cited By ~ 10

Author(s):

Theerayot Kobasa ◽

Eldin Talundzic ◽

Rungniran Sug-aram ◽

Patcharida Boondat ◽

Ira F. Goldman ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Gene Mutations ◽

Artemisinin Resistance ◽

Parasite Clearance ◽

Resistance Mutations ◽

Content Type ◽

Artemisinin Derivatives ◽

Reduced Ring ◽

Control And Prevention ◽

Greater Mekong Subregion

ABSTRACT Artemisinin-based combination therapy (ACT) is the most effective and widely used treatment for uncomplicated Plasmodium falciparum malaria and is a cornerstone for malaria control and prevention globally. Resistance to artemisinin derivatives has been confirmed in the Greater Mekong Subregion (GMS) and manifests as slow parasite clearance in patients and reduced ring stage susceptibility to artemisinins in survival assays. The P. falciparum kelch13 gene mutations associated with artemisinin-resistant parasites are now widespread in the GMS. We genotyped 277 samples collected during an observational study from 2012 to 2016 from eight provinces in Thailand to identify P. falciparum kelch13 mutations. The results were combined with previously reported genotyping results from Thailand to construct a map illustrating the evolution of P. falciparum kelch13 mutations from 2007 to 2016 in that country. Different mutant alleles were found in strains with different geographical origins. The artemisinin resistance-conferring Y493H and R539T mutations were detected mainly in eastern Thailand (bordering Cambodia), while P574L was found only in western Thailand and R561H only in northwestern Thailand. The C580Y mutation was found across the entire country and was nearing fixation along the Thai-Cambodia border. Overall, the prevalence of artemisinin resistance mutations increased over the last 10 years across Thailand, especially along the Thai-Cambodia border. Molecular surveillance and therapeutic efficacy monitoring should be intensified in the region to further assess the extent and spread of artemisinin resistance.

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Mutation in Plasmodium falciparum BTB/POZ domain of K13 protein confers artemisinin resistance

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01320-21 ◽

2021 ◽

Author(s):

Lucie Paloque ◽

Romain Coppée ◽

Barbara H. Stokes ◽

Nina F. Gnädig ◽

Karamoko Niaré ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Artemisinin Resistance ◽

Parasite Clearance ◽

West African ◽

Whole Genome Sequence ◽

Drug Pressure ◽

Synonymous Mutations ◽

Survival Assay ◽

One Year

Partial artemisinin resistance, defined in patients as a delayed parasite clearance following artemisinin-based treatment, is conferred by non-synonymous mutations in the Kelch beta-propeller domain of the Plasmodium falciparum k13 ( pfk13 ) gene. Here, we carried out in vitro selection over a one-year period on a West African P. falciparum strain isolated from Kolle (Mali) under a dose-escalating artemisinin regimen. After 18 cycles of sequential drug pressure, the selected parasites exhibited enhanced survival to dihydroartemisinin in the ring-stage survival assay (RSA 0-3h = 9.2%). Sanger and whole-genome sequence analyses identified the PfK13 P413A mutation, localized in the BTB/POZ domain, upstream of the propeller domain. This mutation was sufficient to confer in vitro artemisinin resistance when introduced into the PfK13 coding sequence of the parasite strain Dd2 by CRISPR/Cas9 gene editing. These results together with structural studies of the protein demonstrate that the propeller domain is not the sole in vitro mediator of PfK13-mediated artemisinin resistance, and highlight the importance of monitoring for mutations throughout PfK13.

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

Pharmaceutics ◽

10.3390/pharmaceutics13081273 ◽

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.

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Inhibitory Effect of Active Substances of Lollyfish (Holothuria atra) Against the Development of Plasmodium falciparum Based on In Silico Study

ILMU KELAUTAN Indonesian Journal of Marine Sciences ◽

10.14710/ik.ijms.25.4.135-142 ◽

2020 ◽

Vol 25 (4) ◽

pp. 135-142

Author(s):

Felly Moelyadi ◽

Prawesty Diah Utami ◽

Irmawati M. Dikman

Keyword(s):

Plasmodium Falciparum ◽

Antimalarial Drug ◽

In Silico ◽

Lethal Dose ◽

Artemisinin Resistance ◽

Inhibitory Effect ◽

In Silico Study ◽

Carbon Dioxide Co2 ◽

Holothuria Atra ◽

Active Substances

The high level of artemisinin resistance as the antimalarial drug makes the active substances found of lollyfish (Holothuria atra) become a very useful discovery as a new antimalarial drug. The purpose of this research is to find out the inhibitory effect of the active substances of lollyfish against the development of Plasmodium falciparum with in silico method. This is a one-shot experimental study research. Based on the test of potentially active substances of lollyfish through PubChem (https://pubchem.ncbi.nlm.nih.gov/), there are pyrogallol and catechin that have potential as the antimalarial drug. Pyrogallol, chlorogenic acid, catechin dan ascorbic acid have indirect inhibition to P. falciparum Orotidine 5-Monophosphate Decarboxylase (PfOMPDC) through carbon dioxide (CO2) and it is visualized by STITCH DB Version 5.0 (http://stitch.embl.de/). The binding affinity score of catechin, obtained from molecular docking, is higher than other substances and artemisinin. The Physicochemical and pharmacokinetic activity of the substance was predicted through SWISS ADME (http://www.swissadme.ch/index.php), while the toxicity was predicted through Pro-Tox (http://tox.charite.de/protox_II/). Catechin is a substance in lollyfish that is the safest because its lowest toxicity and very effective to be used as the antimalarial drug because of its high lethal dose 50 (LD50). Therefore, active substances in lollyfish have inhibitory effects against the development of P. falciparum based on in silico study.

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