#Oseltamivir #resistance in #severe #influenza A #H1N1pdm09 #pneumonia and #ARDS: a #French multicenter observational cohort study (Clin Infect Dis., abstract)

[Source: Clinical Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Clin Infect Dis. 2019 Sep 20. pii: ciz904. doi: 10.1093/cid/ciz904. [Epub ahead of print]

Oseltamivir resistance in severe influenza A(H1N1)pdm09 pneumonia and acute respiratory distress syndrome: a French multicenter observational cohort study.

Behillil S1, May F2,3, Fourati S4, Luyt CE5, Chicheportiche T5, Sonneville R6, Tandjaoui-Lambiotte Y7, Roux D8, Guérin L9, Mayaux J10, Maury E11, Ferré A12, Georger JF13, Voiriot G14, Enouf V1, van der Werf S1, Dessap AM2,3, de Prost N2,3.

Author information: 1 Unité de Génétique Moléculaire des Virus à ARN et Centre National de Référence des Virus des Infections Respiratoires (dont la grippe), Institut Pasteur, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. 2 Service de Réanimation Médicale, Hôpitaux Universitaires Henri Mondor-Albert Chenevier, Assistance Publique-Hôpitaux de Paris, Créteil, France. 3 Groupe de Recherche Clinique CARMAS, Université Paris-Est Créteil, IMRB, Créteil,  France. 4 Département de Microbiologie, Hôpitaux Universitaires Henri Mondor-Albert Chenevier, Assistance Publique-Hôpitaux de Paris, Créteil, France. 5 Service de Médecine Intensive Réanimation, Hôpital de La Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 6 Service de Médecine Intensive Réanimation, Hôpital Bichat Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris, France. 7 Service de Réanimation médico-chirurgicale, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Bobigny, France. 8 Service de réanimation médico-chirurgicale, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes,  France; IAME, Université Paris Diderot, Paris, France. 9 Service de réanimation médicale, Hôpital Bicètre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicètre, France. 10 Service de Réanimation Médicale et Pneumologie, Hôpital de La Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 11 Service de Réanimation Médicale, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France. 12 Service de Réanimation, Centre hospitalier de Versailles, Le Chesnay, France. 13 Service de Réanimation, Centre hospitalier Intercommunal de Villeneuve Saint-Georges, Villeneuve Saint-Georges, France. 14 Service de Réanimation Médicale, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France.

 

Abstract

In a multicenter cohort study including 22 oseltamivir-treated patients with influenza A(H1N1)pdm09 acute respiratory distress syndrome, prevalence of the H275Y substitution in the neuraminidase, responsible for highly reduced sensitivity to oseltamivir, was 23%. Patients infected with the H275Y mutant virus had higher day-28 mortality than others (80% vs 12%; p=0.011).

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

KEYWORDS: Influenza A Virus, H1N1 Subtype; Oseltamivir; Pneumonia, Viral; Respiratory Distress Syndrome, Adult

PMID: 31538643 DOI: 10.1093/cid/ciz904

Keywords: Seasonal Influenza; H1N1pdm09; Antivirals; Drugs Resistance; Oseltamivir; Pneumonia; ARDS; France.

——

Advertisements

#Growth activation of #influenza virus by #trypsin and effect of T-705 (#favipiravir) on trypsin-optimized growth condition (Acta Virol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Acta Virol. 2019;63(3):309-315. doi: 10.4149/av_2019_311.

Growth activation of influenza virus by trypsin and effect of T-705 (favipiravir) on trypsin-optimized growth condition.

Daikoku T, Okuda T, Kawai M, Morita N, Tanaka T, Takemoto M, Fukuda Y, Takahashi K, Nomura N, Shiraki K.

 

Abstract

Influenza virus is activated by proteolytic cleavage of hemagglutinin by trypsin. After determining the optimal trypsin concentration, intracellular and extracellular influenza A/PR/8/34 (H1N1) and A/Victoria/361/2011 (H3N2) virus productions were compared in cultures treated with T-705 (favipiravir) and GS 4071 (an active form of oseltamivir). Although both drugs efficiently inhibited extracellular viral RNA release in a dose-dependent manner, T-705 inhibited it to the level of the inoculum without trypsin treatment, while GS 4071 inhibited it to a final level 10 times higher than that without trypsin. T-705 inhibited intracellular viral RNA production to the level of input virus in both trypsin-treated and untreated cells. In contrast, GS 4071 dose-dependently inhibited intracellular viral RNA production in cells treated with trypsin but allowed viral RNA synthesis. The level of maximum inhibition by GS 4071 was 10 times higher than that of cells without trypsin and 1,000 times greater than the inoculum titer in cells without trypsin. T-705 inhibited both intracellular and extracellular virus production 1,000 and 10 times more strongly, respectively, than GS 4071. T-705 has powerful anti-influenza activity in the absence of trypsin and even in the trypsin-optimized growth condition, suggesting the therapeutic advantage in treatment of influenza complicated with bacterial pneumonia.

Keywords: influenza; T-705; Tamiflu; trypsin; bacterial trypsin-like protease.

PMID: 31507197 DOI: 10.4149/av_2019_311

Keywords: Influenza A; H1N1; H3N2; Antivirals; Favipiravir; Oseltamivir.

——

A study of the #relationship between #human #infection with #avian #influenza a (#H5N6) and environmental avian influenza viruses in #Fujian, #China (BMC Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

BMC Infect Dis. 2019 Sep 2;19(1):762. doi: 10.1186/s12879-019-4145-6.

A study of the relationship between human infection with avian influenza a (H5N6) and environmental avian influenza viruses in Fujian, China.

Chen P1, Xie JF1,2, Lin Q2, Zhao L2, Zhang YH2, Chen HB2, Weng YW1,2, Huang Z2, Zheng KC3,4.

Author information: 1 College of Public Health, Fujian Medical University, No. 88, Jiaotong Road, Taijiang District, Fuzhou, 350000, China. 2 Fujian Center for Disease Control and Prevention, Fujian Provincial Key Laboratory of Zoonosis Research, Fuzhou, 350001, China. 3 College of Public Health, Fujian Medical University, No. 88, Jiaotong Road, Taijiang District, Fuzhou, 350000, China. kingdadi9909@126.com. 4 Fujian Center for Disease Control and Prevention, Fujian Provincial Key Laboratory of Zoonosis Research, Fuzhou, 350001, China. kingdadi9909@126.com.

 

Abstract

BACKGROUND:

Avian influenza A (H5N6) virus poses a great threat to the human health since it is capable to cross the species barrier and infect humans. Although human infections are believed to largely originate from poultry contaminations, the transmissibility is unclear and only limited information was available on poultry environment contaminations, especially in Fujian Province.

METHODS:

A total of 4901 environmental samples were collected and tested for Avian Influenza Virus (AIV) from six cities in Fujian Province through the Fujian Influenza Surveillance System from 2013 to 2017. Two patient-related samples were taken from Fujian’s first confirmed H5N6 human case and his backyard chicken feces in 2017. Chi-square test or Fisher’s exact probability test was used to compare the AIV and the viral subtype positive rates among samples from different Surveillance cities, surveillance sites, sample types, and seasons. Phylogenetic tree analysis and molecular analysis were conducted to track the viral transmission route of the human infection and to map out the evolutions of H5N6 in Fujian.

RESULTS:

The overall positive rate of the H5 subtype AIVs was 4.24% (208/4903). There were distinctive differences (p < 0.05) in the positive rates in samples from different cities, sample sites, sample types and seasons. The viruses from the patient and his backyard chicken feces shared high homologies (99.9-100%) in all the eight gene segments. Phylogenetic trees also showed that these two H5N6 viruses were closely related to each other, and were classified into the same genetic clade 2.3.4.4 with another six H5N6 isolates from the environmental samples. The patient’s H5N6 virus carried genes from H6N6, H5N8 and H5N6 viruses originated from different areas. The R294K or N294S substitution was not detected in the neuraminidase (NA). The S31 N substitution in the matrix2 (M2) gene was detected but only in one strain from the environmental samples.

CONCLUSIONS:

The H5 subtype of AIVs has started circulating in the poultry environments in Fujian Province. The patient’s viral strain originated from the chicken feces in his backyard. Genetic reassortment in H5N6 viruses in Fujian Province was indicated. The H5N6 viruses currently circulating in Fujian Province were still commonly sensitive to Oseltamivir and Zanamivir, but the resistance against Amantadine has emerged.

KEYWORDS: Avian influenza a (H5N6) virus; Environmental contamination; Phylogenetic analysis

PMID: 31477028 DOI: 10.1186/s12879-019-4145-6

Keywords: Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Amantadine; H5N6; H6N6; H5N8; Reassortant strain; Avian Influenza; Human; Fujian; China.

—–

#Genetic characterisation of #influenza A #H1N1pdm09 viruses circulating in #Assam, Northeast #India during 2009-2015 (Indian J Med Microbiol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Indian J Med Microbiol. 2019 Jan-Mar;37(1):42-49. doi: 10.4103/ijmm.IJMM_18_416.

Genetic characterisation of influenza A(H1N1)pdm09 viruses circulating in Assam, Northeast India during 2009-2015.

Biswas D1, Dutta M1, Sarmah K1, Yadav K1, Buragohain M1, Sarma K1, Borkakoty B1.

Author information: 1 Division of Virology, ICMR-Regional Medical Research Centre, N.E. Region, Dibrugarh, Assam, India.

 

Abstract

INTRODUCTION:

Influenza A(H1N1)pdm09 virus, since its identification in April 2009, has continued to cause significant outbreaks of respiratory tract infections including pandemics in humans. In the course of its evolution, the virus has acquired many mutations with an ability to cause increased disease severity. A regular molecular surveillance of the virus is essential to mark the evolutionary changes that may cause a shift to the viral behavior.

MATERIALS AND METHODS:

Samples of Throat/Nasal swabs were collected from a total of 3715 influenza-like illness cases and screened by Real-time Reverse Transcription-Polymerase Chain Reaction for influenza viruses. Nucleotide sequence analysis was done to identify changes in antigenicity of the virus strains.

RESULTS:

The present study describes the molecular characteristics of influenza A(H1N1)pdm09 viruses detected in Assam of Northeast India during 2009-2015. Influenza A viruses were detected in 11.4% (425/3715), of which influenza A(H1N1)pdm09 viruses were detected in 41.4% (176/425). The nucleotide sequencing of influenza A(H1N1)pdm09 viruses revealed a total of 17 and 22 amino acid substitutions in haemagglutinin (HA) and neuraminidase (NA) genes of the virus, respectively, compared to contemporary vaccine strain A/California/07/2009. The important mutations detected in HA genes of A/Assam(H1N1)pdm09 strains included E391K, K180Q and S202T. Mutation ‘N248D’ which has an ability to develop oseltamivir resistance was also detected in NA gene of A/Assam(H1N1)pdm09 strains.

CONCLUSIONS:

Regular molecular surveillance of influenza A(H1N1)pdm09 is important to monitor the viral behavior in terms of increase virulence, drug resistance pattern and emergence of novel strains.

KEYWORDS: Haemagglutinin; Northeast India; influenza A(H1N1)pdm09; neuraminidase; pandemic

PMID: 31424009 DOI: 10.4103/ijmm.IJMM_18_416

Keywords: Seasonal Influenza; H1N1pdm09; Assam; India; Antivirals; Drugs Resistance; Oseltamivir.

——

The #evolution and characterization of #influenza A(#H7N9) virus under the selective #pressure of #peramivir (Virology, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Virology. 2019 Aug 6;536:58-67. doi: 10.1016/j.virol.2019.08.004. [Epub ahead of print]

The evolution and characterization of influenza A(H7N9) virus under the selective pressure of peramivir.

Ge Y1, Chi Y2, Min X3, Zhao K2, Wu B2, Wu T2, Zhu X2, Shi Z2, Zhu F2, Cui L4.

Author information: 1 Institute of Pathogenic Microbiology, NHC Key Laboratories of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, 210009, China. Electronic address: geyiyue@163.com. 2 Institute of Pathogenic Microbiology, NHC Key Laboratories of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, 210009, China. 3 Department of Geriatric Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. 4 Institute of Pathogenic Microbiology, NHC Key Laboratories of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, 210009, China. Electronic address: lbcui@jscdc.cn.

 

Abstract

Human infection with H7N9 virus has provoked global public health concern due to the substantial morbidity and mortality. Neuraminidase inhibitors (NAIs) are used as first-line drugs to treat the infection. However, virus quasispecies can evolve rapidly under drug pressure, which may alter various biological characteristics of virus. Using an in vitro evolution platform and next-generation sequencing, we found the presence of peramivir led to changes to the dominant populations of the virus. Two important amino acid substitutions were identified in NA, I222T and H274Y, which caused reduced susceptibilities to oseltamivir or both oseltamivir and peramivir as confirmed by enzyme- and cell-based assays. The NA-H274Y variant showed decreased replicative fitness at the early stage of infection accompanied with impaired NA function. The quasispecies evolution of H7N9 virus and the potential emergence of these two variants should be closely monitored, which may guide the adjustment of antiviral strategies.

Copyright © 2019 Elsevier Inc. All rights reserved.

KEYWORDS: Evolution; H7N9; Influenza virus; Mutation; Neuraminidase; Peramivir; Quasispecies; Selective pressure

PMID: 31400550 DOI: 10.1016/j.virol.2019.08.004

Keywords: Avian Influenza; Antivirals; Drugs Resistance; H7N9; Peramivir; Oseltamivir.

——

A randomized controlled study of #peramivir, #oseltamivir and placebo in #patients with mild #influenza (Zhonghua Nei Ke Za Zhi, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Zhonghua Nei Ke Za Zhi. 2019 Aug 1;58(8):560-565. doi: 10.3760/cma.j.issn.0578-1426.2019.08.003.

[A randomized controlled study of peramivir, oseltamivir and placebo in patients with mild influenza].

[Article in Chinese; Abstract available in Chinese from the publisher]

Fan HW1, Han Y1, Liu W2, Li XW3, Li LZ4, Yao HY4, Wang Y4, Su ZQ4, Ye WX5, Huang J6, Lu WZ7, Li GW8, Li HL9, Wang SY10, Wu H11, Lu QF12, Zhu GF13, Liu SM14, Chen G15, Zhang WH16, Li TS1.

Author information: 1 Department of Infectious Disease, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China. 2 Department of Respiratory, Liuzhou Worker’s Hospital, Liuzhou 545005, China. 3 Department of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China. 4 Pude Pharmaceutical Company Limited, Datong 037000, China. 5 Department of Respiratory, Guizhou Provincial People’s Hospital, Guiyang 550002, China. 6 Department of Respiratory, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China. 7 Department of Respiratory, PLA 303 Hospital, Nanning 530021, China. 8 Department of Emergency, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China. 9 Department of Respiratory, Shanghai Yangpu District Central Hospital, Shanghai 200090, China. 10 Department of Infectious Disease, 900 Hospital of the Joint Logistics Team, PLA, Fuzhou 350025, China. 11 Department of Infectious Disease, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China. 12 Department of Respiratory, Puai Hospital, Wuhan 430032, China. 13 Department of Infectious Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China. 14 Department of Respiratory, First Affiliated Hospital of Ji’nan University, Guangzhou 510632, China. 15 Department of Respiratory, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, China. 16 Department of Infectious Disease, Huashan Hospital, Fudan University, Shanghai 200040, China.

 

Abstract in English, Chinese

Objectives:

To evaluate the effectiveness and safety of peramivir trihydrate in patients with influenza.

Methods:

This was a randomized, double-blind, double-dummy, placebo and positive control, multicenter clinical trial, comparing peramivir trihydrate with oseltamivir and placebo. The inclusive criteria were 15-70 years old, onset within 48 h, positive rapid influenza antigen test, and febrile (>38℃) accompanied with at least two associated symptoms. The severe cases complicated with chronic pulmonary and cardiac diseases, malignancies, organ transplantation, hemodialysis, uncontrolled diabetes, immunocompromised status, pregnancy and coexistence of bacterium infections were excluded. All patients were randomized 2∶2∶1 to receive peramivir, oseltamivir and placebo respectively. The primary endpoint was the disease duration, the secondary endpoints included time to normal axillary temperature and normal living activities, viral response, and adverse effects.

Results:

Following informed consent, 133 patients were included in this study. Four patients were exclude due to missing medical records, not fitting inclusion or exclusion criteria and poor compliance. A total of 129 patients were finally analyzed, including 49 cases, 54 cases and 26 cases in peramivir group, oseltamivir group and placebo group. The median disease duration were 96 (76, 120) hours, 105 (90,124) hours, and 124 (104, 172) hours in three groups respectively (P>0.05) . The time to normal axillary temperature, normal living activities and viral response were not significantly different in three groups (P>0.05) .

Conclusion:

The value of antiviral therapy in patients with mild influenza needs to be further determined.

KEYWORDS: Influenza; Oseltamivir; Peramivir

PMID: 31365976 DOI: 10.3760/cma.j.issn.0578-1426.2019.08.003

Keywords: Seasonal Influenza; Antivirals; Oseltamivir; Peramivir.

—–

The Val430Ile #neuraminidase (NA) #substitution, identified in #influenza B virus isolates, impacts the catalytic 116Arg residue causing reduced susceptibility to NA #inhibitors (Antiviral Res., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Antiviral Res. 2019 Jul 16:104561. doi: 10.1016/j.antiviral.2019.104561. [Epub ahead of print]

The Val430Ile neuraminidase (NA) substitution, identified in influenza B virus isolates, impacts the catalytic 116Arg residue causing reduced susceptibility to NA inhibitors.

Abed Y1, Fage C2, Checkmahomed L2, Begin G3, Carbonneau J2, Lague P3, Boivin G4.

Author information: 1 Research Center in Infectious Diseases of the CHU of Québec and Laval University, Québec City, Québec, Canada. Electronic address: yacine.abed@crchul.ulaval.ca. 2 Research Center in Infectious Diseases of the CHU of Québec and Laval University, Québec City, Québec, Canada. 3 Proteo and IBIS, Department of Biochemistry, Microbiology and Bioinformatics, Faculty of Science and Engineering, Laval University, Québec City, QC, Canada. 4 Research Center in Infectious Diseases of the CHU of Québec and Laval University, Québec City, Québec, Canada. Electronic address: guy.boivin@crchul.ulaval.ca.

 

Abstract

As part of a 2015-2018 clinical trial of peramivir treatment for acute influenza infections in the elderly, an influenza B/Yamagata/16/1988-like isolate harbouring a Val430Ile neuraminidase (NA) substitution was recovered from a single patient. This substitution was detected in respiratory samples collected before and during peramivir treatment. In NA inhibition assays, oseltamivir, zanamivir and peramivir IC50s of the Val430Ile isolate were 4-, 15- and 16-fold higher compared to a wild-type (WT) strain. In reverse genetics experiments, the Ile430Val reversion restored the drug susceptible phenotype. The Val430Ile mutant and the WT strain had comparable replication kinetics in ST6GalI-MDCK cells and the NA mutation was stable after four passages in that cell line. Molecular dynamics simulations suggested that Val430Ile impacts the NA binding through a mechanism involving the catalytic Arg116 residue. The potential of some NA mutations not part of the active site to alter the susceptibility to NA inhibitors highlights the need to develop novel antiviral strategies against influenza B infections.

Copyright © 2019. Published by Elsevier B.V.

KEYWORDS: Influenza B; Mutation; Neuraminidase; Peramivir; Resistance; Val430Ile

PMID: 31323237 DOI: 10.1016/j.antiviral.2019.104561

Keywords: Seasonal Influenza; Influenza B; Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Peramivir.

——