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1.
Malar J ; 20(1): 73, 2021 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-33549122

RESUMEN

BACKGROUND: The emergence and spread of multidrug resistance poses a significant risk to malaria control and eradication goals in the world. There has been no indigenous malaria cases reported in China since 2017, and China is approaching national malaria elimination. Therefore, anti-malarial drug resistance surveillance and tracking the emergence and spread of imported drug-resistant malaria cases will be necessary in a post-elimination phase in China. METHODS: Dried blood spots were obtained from Plasmodium falciparum-infected cases returned from Africa to China between 2012 and 2015, prior to anti-malarial drug treatment. Whole DNA were extracted and known polymorphisms relating to drug resistance of pfcrt, pfmdr1 gene, and the propeller domain of pfk13 were evaluated by nested PCR and sequencing. The haplotypes and prevalence of these three genes were evaluated separately. Chi-squared test and Fisher's exact test were used to evaluate differences among the different sub-regions of Africa. A P value < 0.05 was used to evaluate differences with statistical significance. The maps were created using ArcGIS. RESULTS: A total of 731 P. falciparum isolates were sequenced at the pfcrt locus. The wild type CVMNK was the most prevalent haplotype with prevalence of 62.8% and 29.8% of the isolates showed the triple mutant haplotype CVIET. A total of 434 P. falciparum isolates were successfully sequenced and pfmdr1 allelic variants were observed in only codons 86, 184 and 1246. Twelve haplotypes were identified and the prevalence of the wild type pfmdr1 NYD was 44.1%. The single mutant pfmdr1 in codons 86 and 184 was predominant but the haplotype NYY with single mutation in codon 1246 was not observed. The double mutant haplotype YFD was common in Africa. About 1,357 isolates were successfully sequenced of pfk13-propeller domain, the wild type was found in 1,308 samples (96.4%) whereby 49 samples (3.6%) had mutation in pfk13. Of 49 samples with pfk13 mutations, 22 non-synonymous and 4 synonymous polymorphic sites were confirmed. The A578S was the most common mutation in pfk13-propeller domain and three mutations associated with artemisinin resistance (M476I, R539T, P553L) were identified in three isolates. CONCLUSION: This study provides evidence that could give insight into potential issues with anti-malarial drug resistance to inform national drug policy in China in order to treat imported cases.

2.
Malar J ; 20(1): 32, 2021 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-33422080

RESUMEN

BACKGROUND: Malaria remains highly endemic in Cameroon. The rapid emergence and spread of drug resistance was responsible for the change from monotherapies to artemisinin-based combinations. This systematic review and meta-analysis aimed to determine the prevalence and distribution of Plasmodium falciparum drug resistance markers within an evolving efficacy of anti-malarial drugs in Cameroon from January 1998 to August 2020. METHODS: The PRISMA-P and PRISMA statements were adopted in the inclusion of studies on single nucleotide polymorphisms (SNPs) of P. falciparum anti-malarial drug resistance genes (Pfcrt, Pfmdr1, Pfdhfr, Pfdhps, Pfatp6, Pfcytb and Pfk13). The heterogeneity of the included studies was evaluated using the Cochran's Q and I2 statistics. The random effects model was used as standard in the determination of heterogeneity between studies. RESULTS: Out of the 902 records screened, 48 studies were included in this aggregated meta-analysis of molecular data. A total of 18,706 SNPs of the anti-malarial drug resistance genes were genotyped from 47,382 samples which yielded a pooled prevalence of 35.4% (95% CI 29.1-42.3%). Between 1998 and 2020, there was significant decline (P < 0.0001 for all) in key mutants including Pfcrt 76 T (79.9%-43.0%), Pfmdr1 86Y (82.7%-30.5%), Pfdhfr 51I (72.2%-66.9%), Pfdhfr 59R (76.5%-67.8%), Pfdhfr 108 N (80.8%-67.6%). The only exception was Pfdhps 437G which increased over time (30.4%-46.9%, P < 0.0001) and Pfdhps 540E that remained largely unchanged (0.0%-0.4%, P = 0.201). Exploring mutant haplotypes, the study observed a significant increase in the prevalence of Pfcrt CVIET mixed quintuple haplotype from 57.1% in 1998 to 57.9% in 2020 (P < 0.0001). In addition, within the same study period, there was no significant change in the triple Pfdhfr IRN mutant haplotype (66.2% to 67.3%, P = 0.427). The Pfk13 amino acid polymorphisms associated with artemisinin resistance were not detected. CONCLUSIONS: This review reported an overall decline in the prevalence of P. falciparum gene mutations conferring resistance to 4-aminoquinolines and amino alcohols for a period over two decades. Resistance to artemisinins measured by the presence of SNPs in the Pfk13 gene does not seem to be a problem in Cameroon. Systematic review registration PROSPERO CRD42020162620.

3.
PLoS Pathog ; 16(12): e1009133, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33320907

RESUMEN

The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical samples. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical samples from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants' genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1, ferredoxin, atg18 and pnp. These findings suggest that a P. falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites' drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance.


Asunto(s)
Antiinfecciosos , Artemisininas , Resistencia a Medicamentos/genética , Genes Protozoarios/genética , Plasmodium falciparum/genética , Antiinfecciosos/uso terapéutico , Artemisininas/uso terapéutico , Estudios Transversales , Humanos , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Mutación , Papúa Nueva Guinea
4.
PLoS One ; 15(10): e0240174, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33075062

RESUMEN

BACKGROUND: Mass drug administration (MDA) can rapidly reduce the burden of Plasmodium falciparum (Pf). However, concerns remain about its contribution to select for antimalarial drug resistance. METHODS: We used Sanger sequencing and real-time PCR to determine the proportion of molecular markers associated with antimalarial resistance (k13, pfpm2, pfmdr1 and pfcrt) in Pf isolates collected before (n = 99) and after (n = 112) the implementation of two monthly MDA rounds with dihydroartemisinin-piperaquine (DHAp) for two consecutive years in Magude district of Southern Mozambique. RESULTS: None of the k13 polymorphisms associated with artemisinin resistance were observed in the Pf isolates analyzed. The proportion of Pf isolates with multiple copies of pfpm2, an amplification associated with piperaquine resistance, was similar in pre- (4.9%) and post-MDA groups (3.4%; p = 1.000). No statistically significant differences were observed between pre- and post-MDA groups in the proportion of Pf isolates neither with mutations in pfcrt and pfmdr1 genes, nor with the carriage of pfmdr1 multiple copies (p>0.05). CONCLUSIONS: This study does not show any evidence of increased frequency of molecular makers of antimalarial resistance after MDA with DHAp in southern Mozambique where markers of antimalarial resistance were absent or low at the beginning of the intervention.

5.
Malar J ; 19(1): 334, 2020 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-32928233

RESUMEN

BACKGROUND: The emergence and spread of artemisinin resistance in Plasmodium falciparum poses a threat to malaria eradication, including China's plan to eliminate malaria by 2020. Piperaquine (PPQ) resistance has emerged in Cambodia, compromising an important partner drug that is widely used in China in the form of dihydroartemisinin (DHA)-PPQ. Several mutations in a P. falciparum gene encoding a kelch protein on chromosome 13 (k13) are associated with artemisinin resistance and have arisen spread in the Great Mekong subregion, including the China-Myanmar border. Multiple copies of the plasmepsin II/III (pm2/3) genes, located on chromosome 14, have been shown to be associated with PPQ resistance. METHODS: The therapeutic efficacy of DHA-PPQ for the treatment of uncomplicated P. falciparum was evaluated along the China-Myanmar border from 2010 to 2014. The dry blood spots samples collected in the efficacy study prior DHA-PPQ treatment and from the local hospital by passive detection were used to amplify k13 and pm2. Polymorphisms within k13 were genotyped by capillary sequencing and pm2 copy number was quantified by relative-quantitative real-time polymerase chain reaction. Treatment outcome was evaluated with the World Health Organization protocol. A linear regression model was used to estimate the association between the day 3 positive rate and k13 mutation and the relationship of the pm2 copy number variants and k13 mutations. RESULTS: DHA-PPQ was effective for uncomplicated P. falciparum infection in Yunnan Province with cure rates > 95%. Twelve non synonymous mutations in the k13 domain were observed among the 268 samples with the prevalence of 44.0% and the predominant mutation was F446I with a prevalence of 32.8%. Only one sample was observed with multi-copies of pm2, including parasites with and without k13 mutations. The therapeutic efficacy of DHA-PPQ was > 95% along the China-Myanmar border, consistent with the lack of amplification of pm2. CONCLUSION: DHA-PPQ for uncomplicated P. falciparum infection still showed efficacy in an area with artemisinin-resistant malaria along the China-Myanmar border. There was no evidence to show PPQ resistance by clinical study and molecular markers survey. Continued monitoring of the parasite population using molecular markers will be important to track emergence and spread of resistance in this region.

6.
Nat Med ; 26(10): 1602-1608, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32747827

RESUMEN

Artemisinin resistance (delayed P. falciparum clearance following artemisinin-based combination therapy), is widespread across Southeast Asia but to date has not been reported in Africa1-4. Here we genotyped the P. falciparum K13 (Pfkelch13) propeller domain, mutations in which can mediate artemisinin resistance5,6, in pretreatment samples collected from recent dihydroarteminisin-piperaquine and artemether-lumefantrine efficacy trials in Rwanda7. While cure rates were >95% in both treatment arms, the Pfkelch13 R561H mutation was identified in 19 of 257 (7.4%) patients at Masaka. Phylogenetic analysis revealed the expansion of an indigenous R561H lineage. Gene editing confirmed that this mutation can drive artemisinin resistance in vitro. This study provides evidence for the de novo emergence of Pfkelch13-mediated artemisinin resistance in Rwanda, potentially compromising the continued success of antimalarial chemotherapy in Africa.

7.
Am J Trop Med Hyg ; 103(3): 1088-1093, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32524960

RESUMEN

Four single-arm, prospective, clinical studies of pyronaridine-artesunate efficacy in uncomplicated Plasmodium falciparum or Plasmodium vivax malaria were conducted in Myanmar between 2017 and 2019. Eligible subjects were aged at least 6 years, with microscopically confirmed P. falciparum (n = 196) or P. vivax mono-infection (n = 206). Patients received pyronaridine-artesunate once daily for 3 days with follow-up until day 42 for P. falciparum or day 28 for P. vivax. For the primary efficacy analysis, adequate clinical and parasitological response (ACPR) in the per-protocol population at day 42 for P. falciparum malaria was 100% (88/88; 95% CI: 95.9, 100) in northern Myanmar (Kachin State and northern Shan State), and 100% (101/101; 95% CI: 96.4, 100) in southern Myanmar (Tanintharyi Region and Kayin State). Plasmodium falciparum day-3 parasite clearance was observed for 96.9% (190/196) of patients. Mutations in the P. falciparum Kelch propeller domain (K13) were detected in 39.0% (69/177) of isolates: F446I (14.7% [26/177]), R561H (13.0% [23/177]), C580Y (10.2% [18/177]), and P574L (1.1% [2/177]). For P. vivax, the day-28 ACPR was 100% (104/104; 95% CI: 96.5, 100) in northern Myanmar and 100% (97/97; 95% CI: 96.3, 100) in southern Myanmar. Across both P. vivax studies, 100% (206/206) of patients had day-3 parasite clearance. There were no adverse events. Pyronaridine-artesunate had excellent efficacy in Myanmar against P. falciparum and P. vivax and was well tolerated. This study supports the inclusion of pyronaridine-artesunate in national malaria treatment guidelines for Myanmar.


Asunto(s)
Antimaláricos/uso terapéutico , Artesunato/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Malaria Vivax/tratamiento farmacológico , Naftiridinas/uso terapéutico , Plasmodium falciparum/efectos de los fármacos , Plasmodium vivax/efectos de los fármacos , Adolescente , Adulto , Niño , Quimioterapia Combinada , Femenino , Humanos , Malaria Falciparum/parasitología , Malaria Vivax/parasitología , Masculino , Persona de Mediana Edad , Mianmar , Estudios Prospectivos , Adulto Joven
8.
Elife ; 92020 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-32394893

RESUMEN

Antimalarial drug resistance has historically arisen through convergent de novo mutations in Plasmodium falciparum parasite populations in Southeast Asia and South America. For the past decade in Southeast Asia, artemisinins, the core component of first-line antimalarial therapies, have experienced delayed parasite clearance associated with several pfk13 mutations, primarily C580Y. We report that mutant pfk13 has emerged independently in Guyana, with genome analysis indicating an evolutionary origin distinct from Southeast Asia. Pfk13 C580Y parasites were observed in 1.6% (14/854) of samples collected in Guyana in 2016-2017. Introducing pfk13 C580Y or R539T mutations by gene editing into local parasites conferred high levels of in vitro artemisinin resistance. In vitro growth competition assays revealed a fitness cost associated with these pfk13 variants, potentially explaining why these resistance alleles have not increased in frequency more quickly in South America. These data place local malaria control efforts at risk in the Guiana Shield.

9.
Clin Infect Dis ; 2020 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-32459308

RESUMEN

BACKGROUND: Artesunate-amodiaquine is a potential therapy for uncomplicated malaria in Cambodia. METHODS: Between September 2016 and January 2017, artesunate-amodiaquine efficacy and safety were evaluated in a prospective, open-label, single-arm observational study at health centers in Mondulkiri, Pursat and Siem Reap Provinces, Cambodia. Adults and children with microscopically-confirmed Plasmodium falciparum malaria received oral artesunate-amodiaquine once daily for three days plus single-dose primaquine, with follow-up on Days 7, 14, 21 and 28. The primary outcome was Day-28 PCR-adjusted adequate clinical and parasitological response (ACPR). An amodiaquine parasite survival assay (AQSA) was developed and applied to whole genome sequencing results to evaluate potential amodiaquine resistance molecular markers. RESULTS: In 63 patients, Day-28 PCR-adjusted ACPR was 81.0% (95% confidence interval [CI], 68.9-88.7). Day 3 parasite positivity rate was 44.4% (28/63; 95%CI, 31.9-57.5). All 63 isolates had the K13(C580Y) marker for artemisinin resistance; 79.4% (50/63) had Pfpm2 amplification. The AQSA resistance phenotype (≥45% parasite survival) was expressed in 36.5% (23/63) of isolates and was significantly associated with treatment failure (P = 0.0020). Pfmdr1 mutant haplotypes were N86/184F/D1246 and Pfcrt was CVIET or CVIDT at positions 72-76. Additional Pfcrt mutations were not associated with amodiaquine resistance, but the G353V mutant allele was associated with ACPR compared to Pfmdr1 haplotypes harboring F1068L or S784L/R945P mutations (P = 0.030 and P = 0.0004, respectively). CONCLUSIONS: For uncomplicated falciparum malaria in Cambodia, artesunate-amodiaquine had inadequate efficacy owing to amodiaquine-resistant P. falciparum. Amodiaquine resistance was not associated with previously identified molecular markers.

10.
Clin Infect Dis ; 70(10): 2187-2195, 2020 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-31251812

RESUMEN

BACKGROUND: Multidrug-resistant Plasmodium falciparum undermines the efficacy of currently deployed antimalarial therapies in southern Viet Nam. METHODS: Between May 2017 and December 2018, this prospective, open-label, single-arm, observational clinical trial, conducted in Binh Phuoc, Dak Nong, Gia Lai, Khanh Hoa, and Ninh Thuan provinces, evaluated the safety and efficacy of oral pyronaridine-artesunate once daily for 3 consecutive days in adults and children with microscopically confirmed P. falciparum malaria. Patients were treated as inpatients for Days 0-3, with follow-up visits on Days 7, 14, 21, 28, 35, and 42. The primary outcome was the proportion of polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 42. RESULTS: The cumulative incidence of PCR-adjusted ACPR at Day 42 was 96.1% (95% confidence interval [CI] 91.4-98.2; Kaplan-Meier). In the per-protocol analysis, the proportion of patients with Day 42 PCR-adjusted ACPR was 96.1% (147/153; 95% CI 91.7-98.5). The proportion of patients with parasitemia at Day 3 was 24.0% (40/167; 95% CI 17.7-31.2). The prevalences of the Kelch13 (C580Y) mutation were: in Binh Phuoc, 97.7% (43/44); in Dak Nong, 96.2% (25/26); in Gia Lai, 57.8% (37/64); in Khanh Hoa, 66.6% (6/9); and in Ninh Thuan, 3.6% (1/28). The majority of artemisinin-resistant isolates also had increased plasmepsin2 copy number (75.9%; 85/112). There was 1 isolate (Binh Phuoc) that had Kelch13 (C580Y) plus increased plasmepsin2 and Pfmdr1 copy numbers. Asymptomatic transient increases in alanine transaminase and aspartate transaminase were observed at Day 7, resolving by Day 28. CONCLUSIONS: Pyronaridine-artesunate can be used to diversify antimalarial therapy in areas of artemisinin-resistant P. falciparum in Viet Nam. CLINICAL TRIALS REGISTRATION: ACTRN12618001274268.

11.
Am J Trop Med Hyg ; 102(3): 598-604, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31833468

RESUMEN

The emergence of artemisinin-resistant Plasmodium falciparum in the Greater Mekong Subregion threatens both the efficacy of artemisinin-based combination therapy (ACT), the first-line treatment for malaria, and prospects for malaria elimination. Monitoring of ACT efficacy is essential for ensuring timely updates to elimination policies and treatment recommendations. In 2014-2015, we assessed the therapeutic efficacies of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) for the treatment of uncomplicated P. falciparum at three study sites in Rakhine, Shan, and Kachin states in Myanmar. Patients presenting with uncomplicated P. falciparum malaria were enrolled, treated, and followed up for 28 days for AL or 42 days for DP. Both AL and DP demonstrated good therapeutic efficacy at all three study sites. The 28-day cure rate for AL was > 96% across all study sites, and the 42-day cure rate for DP was 100%. Parasitemia on day 3 was detected in 0%, 3.3%, and 3.6% of participants treated with AL at the Rakhine, Shan, and Kachin sites, respectively. No participants treated with DP were parasitemic on day 3. No evidence of P. falciparum k13 mutations was found at the Rakhine study site. A high prevalence of k13 mutations associated with artemisinin resistance was observed at the Kachin and Shan state study sites. These results confirm that ACT efficacy has been resilient in therapeutic efficacy study (TES) sentinel sites in Myanmar, despite the presence at some sites of k13 mutations associated with resistance. Studies are ongoing to assess whether this resilience persists.


Asunto(s)
Combinación Arteméter y Lumefantrina/uso terapéutico , Artemisininas/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Quinolinas/uso terapéutico , Adolescente , Adulto , Antimaláricos/administración & dosificación , Antimaláricos/uso terapéutico , Artemisininas/administración & dosificación , Niño , Combinación de Medicamentos , Femenino , Genotipo , Humanos , Malaria Falciparum/epidemiología , Masculino , Persona de Mediana Edad , Mianmar/epidemiología , Plasmodium falciparum/genética , Quinolinas/administración & dosificación , Adulto Joven
12.
IDCases ; 18: e00607, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31700799

RESUMEN

Introduction: Artemisinin-based combination therapy (ACT) is recommended by the World Health Organization as first-line treatment of uncomplicated Plasmodium falciparum malaria. ACT treatments failures among travellers returning from Africa to non-endemic countries are considered to be caused by resistance. Case presentation: We report on a case of artemether-lumefantrine treatment failure in a Turkish traveller with uncomplicated P. falciparum malaria returning from Bamako, Mali. Conclusions: Information on returning travellers, includes ensuring that the patients receive supervised treatment with the recommended dose of a quality controlled medicine, routine follow-up of all cases, assessment of adequate absorption of the drug, and/or testing the prevalence of molecular markers of drug resistance if validated, can be an important source of an early warning system for emerging resistance.

14.
Acta Parasitol ; 64(4): 898-902, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31512064

RESUMEN

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.


Asunto(s)
Amodiaquina/uso terapéutico , Combinación Arteméter y Lumefantrina/uso terapéutico , Artemisininas/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Amodiaquina/efectos adversos , Combinación Arteméter y Lumefantrina/efectos adversos , Artemisininas/efectos adversos , Niño , Preescolar , Combinación de Medicamentos , Gabón , Humanos , Lactante , Estudios Prospectivos , Vigilancia de Guardia , Resultado del Tratamiento
15.
J Antimicrob Chemother ; 74(11): 3240-3244, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31518407

RESUMEN

BACKGROUND: Cambodia is the epicentre of resistance emergence for virtually all antimalarial drugs. Selection and spread of parasites resistant to artemisinin-based combination therapy (ACT) is a major threat for malaria elimination, hence the need to renew the pool of effective treatments. OBJECTIVES: To determine whether ACT resistance haplotypes could have an effect on ferroquine in vitro antimalarial activity. METHODS: In vitro susceptibility to ferroquine was measured for 80 isolates from Cambodia characterized for their molecular resistance profile to artemisinin, piperaquine and mefloquine. RESULTS: Among the 80 isolates tested, the overall median (IQR) IC50 of ferroquine was 10.9 nM (8.7-18.3). The ferroquine median (IQR) IC50 was 8.9 nM (8.1-11.8) for Pfk13 WT parasites and was 12.9 nM (9.5-20.0) for Pfk13 C580Y parasites with no amplification of Pfpm2 and Pfmdr1 genes. The median (IQR) IC50 of ferroquine for Pfk13 C580Y parasites with amplification of the Pfpm2 gene was 17.2 nM (14.5-20.5) versus 9.1 nM (7.9-10.7) for Pfk13 C580Y parasites with amplification of the Pfmdr1 gene. CONCLUSIONS: Ferroquine exerts promising efficacy against ACT-resistant isolates. Whereas Pfpm2 amplification was associated with the highest parasite tolerance to ferroquine, the susceptibility range observed was in accordance with those measured in ACT resistance-free areas. This enables consideration of ferroquine as a relevant therapeutic option against ACT-resistant malaria.


Asunto(s)
Aminoquinolinas/farmacología , Antimaláricos/farmacología , Artemisininas/farmacología , Resistencia a Medicamentos/genética , Compuestos Ferrosos/farmacología , Metalocenos/farmacología , Plasmodium falciparum/efectos de los fármacos , Cambodia , Quimioterapia Combinada , Humanos , Concentración 50 Inhibidora , Malaria Falciparum/parasitología , Pruebas de Sensibilidad Parasitaria
16.
Artículo en Inglés | MEDLINE | ID: mdl-31481442

RESUMEN

In South America, Plasmodium vivax resistance to chloroquine was recently reported in Brazil and Bolivia. The objective of this study was to collect data on chloroquine resistance in French Guiana by associating a retrospective evaluation of therapeutic efficacy with an analysis of recurrent parasitemia from any patients. Patients with P. vivax infection, confirmed by microscopy and a body temperature of ≥37.5°C, were retrospectively identified at Cayenne Hospital between 2009 and 2015. Follow-up and treatment responses were performed according to the World Health Organization protocol. Parasite resistance was confirmed after dosage of a plasma concentration of chloroquine and microsatellite characterization. The pvmdr1 and pvcrt-o genes were analyzed for sequence and gene copy number variation. Among the 172 patients followed for 28 days, 164 presented adequate clinical and parasitological responses. Eight cases of treatment failures were identified (4.7%; n = 8/172), all after 14 days. The therapeutic efficacy of chloroquine was estimated at 95.3% (95% confidence interval [CI], 92.5 to 98.1%; n = 164/172). Among the eight failures, five were characterized: two cases were true P. vivax chloroquine resistance (1.2%; 95% CI, 0 to 2.6%; n = 2/172), and three cases were found with subtherapeutic concentrations of chloroquine. No particular polymorphism in the Plasmodium vivax pvmdr1 and pvcrt-o genes was identified in the resistant parasites. This identified level of resistance of P. vivax to chloroquine in French Guiana does not require a change in therapeutic recommendations. However, primaquine should be administered more frequently to limit the spread of resistance, and there is still a need for a reliable molecular marker to facilitate the monitoring of P. vivax resistance to chloroquine.


Asunto(s)
Antimaláricos/uso terapéutico , Cloroquina/uso terapéutico , Malaria Vivax/tratamiento farmacológico , Plasmodium vivax/efectos de los fármacos , Adolescente , Adulto , Anciano , Antimaláricos/farmacología , Niño , Preescolar , Cloroquina/farmacología , Resistencia a Medicamentos , Femenino , Guyana Francesa/epidemiología , Humanos , Malaria Vivax/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
17.
Artículo en Inglés | MEDLINE | ID: mdl-31358594

RESUMEN

This single-arm trial (n = 104) in western Cambodia showed high efficacy for 3-day treatment with pyronaridine-artesunate plus single-dose primaquine in Plasmodium falciparum malaria. Day 42 PCR-adjusted adequate clinical and parasitological response (ACPR) was 98.3% (58/59) (95% confidence interval [CI], 90.9 to 100.0) in Trapeng Chau in Kampong Speu and 100% (41/41) (95% CI, 91.4 to 100) in Veal Veng in Pursat; 80.6% (83/103) of the patients had P. falciparum with drug resistance molecular markers. For Plasmodium vivax malaria, pyronaridine-artesunate day 28 ACPR was 98.3% (59/60) (95% CI, 91.1 to 100) and 100% (60/60) (95% CI, 94.0 to 100), respectively. (This study is registered in the Australian New Zealand Clinical Trials Registry [ANZCTR] under reference no. ACTRN12618001999224.).


Asunto(s)
Artesunato/efectos adversos , Artesunato/uso terapéutico , Malaria/tratamiento farmacológico , Naftiridinas/efectos adversos , Naftiridinas/uso terapéutico , Primaquina/efectos adversos , Primaquina/uso terapéutico , Adolescente , Adulto , Antimaláricos/efectos adversos , Antimaláricos/uso terapéutico , Cambodia , Niño , Resistencia a Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Plasmodium vivax/efectos de los fármacos , Plasmodium vivax/patogenicidad , Adulto Joven
18.
Malar J ; 18(1): 231, 2019 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-31296223

RESUMEN

BACKGROUND: Artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA/PPQ) are the recommended first- and second-line treatments, respectively, for uncomplicated falciparum malaria in Somalia. The studies reported here were conducted to assess the efficacy of these artemisinin-based combinations and the mutations in Plasmodium falciparum K13-propeller (Pfk13) domain and amplification in Pfplasmepsin 2 (Pfpm2) gene in Somalia. METHODS: One-arm prospective studies were conducted to assess the clinical and parasitological responses to DHA/PPQ and AL at two sites in 2016 and 2017, respectively, using the standard WHO protocol. The patterns of molecular markers associated with artemisinin and PPQ resistance were investigated for the first time in Somalia. RESULTS: A total of 339 patients were enrolled with 139 for AL and 200 for DHA/PPQ. With AL, no parasite recurrence was observed among patients treated at either site, corresponding to 100% clinical and parasitological responses. For DHA-PPQ, an adequate clinical and parasitological response rate > 97% was observed. All study patients on both treatments at both sites were parasite-free on day 3. Of the 138 samples with interpretable results for the polymorphism in Pfk13, only one (0.7%), from Bosaso, contained a non-synonymous mutation (R622I), which is not one of the known markers of artemisinin resistance. No Pfpm2 amplification was observed among the 135 samples with interpretable results. CONCLUSIONS: AL and DHA/PPQ were highly effective in the treatment of uncomplicated falciparum malaria, and there was no evidence of resistance to artemisinin or PPQ. These two combinations are thus relevant in the chemotherapeutic strategy for malaria control in Somalia. Trial registration ACTRN12616001005448 (Jowhar DP study), ACTRN12616000553471 (Bosaso DP study), ACTRN12617001055392 (AL study in Bosaso and Jowhar).


Asunto(s)
Antimaláricos/uso terapéutico , Combinación Arteméter y Lumefantrina/uso terapéutico , Artemisininas/uso terapéutico , Malaria Falciparum/prevención & control , Plasmodium falciparum/efectos de los fármacos , Quinolinas/uso terapéutico , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Somalia , Adulto Joven
19.
Nat Commun ; 10(1): 2665, 2019 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-31209259

RESUMEN

Estimates of Plasmodium falciparum migration may inform strategies for malaria elimination. Here we elucidate fine-scale parasite population structure and infer recent migration across Southeast Asia using identity-by-descent (IBD) approaches based on genome-wide single nucleotide polymorphisms called in 1722 samples from 54 districts. IBD estimates are consistent with isolation-by-distance. We observe greater sharing of larger IBD segments between artemisinin-resistant parasites versus sensitive parasites, which is consistent with the recent spread of drug resistance. Our IBD analyses reveal actionable patterns, including isolated parasite populations, which may be prioritized for malaria elimination, as well as asymmetrical migration identifying potential sources and sinks of migrating parasites.


Asunto(s)
Resistencia a Medicamentos/genética , Monitoreo Epidemiológico , Genoma de Protozoos/genética , Malaria Falciparum/microbiología , Plasmodium falciparum/genética , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Artemisininas/farmacología , Artemisininas/uso terapéutico , Asia Sudoriental , Biodiversidad , Genotipo , Geografía Médica , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/prevención & control , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/aislamiento & purificación , Polimorfismo de Nucleótido Simple
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