#NAIs and #Hospital Length of Stay: A Meta-analysis of Individual Participant Data to Determine #Treatment Effectiveness Among Patients Hospitalized With Nonfatal #H1N1pdm09 Virus Infection (J Infect Dis., abstract)

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

Neuraminidase Inhibitors and Hospital Length of Stay: A Meta-analysis of Individual Participant Data to Determine Treatment Effectiveness Among Patients Hospitalized With Nonfatal 2009 Pandemic Influenza A(H1N1) Virus Infection

Sudhir Venkatesan, Puja R Myles, Kirsty J Bolton, Stella G Muthuri, Tarig Al Khuwaitir, Ashish P Anovadiya, Eduardo Azziz-Baumgartner, Tahar Bajjou, Matteo Bassetti, Bojana Beovic, Barbara Bertisch, Isabelle Bonmarin, Robert Booy, Victor H Borja-Aburto, Heinz Burgmann, Bin Cao, Jordi Carratala, Tserendorj Chinbayar, Catia Cilloniz, Justin T Denholm, Samuel R Dominguez, Pericles A D Duarte, Gal Dubnov-Raz, Sergio Fanella, Zhancheng Gao, Patrick Gérardin, Maddalena Giannella, Sophie Gubbels, Jethro Herberg Anjarath, Lorena Higuera Iglesias, Peter H Hoeger, Xiao Yun Hu, Quazi T Islam, Mirela F Jiménez, Gerben Keijzers, Hossein Khalili, Gabriela Kusznierz, Ilija Kuzman, Eduard Langenegger, Kamran B Lankarani, Yee-Sin Leo, Romina P Libster, Rita Linko, Faris Madanat, Efstratios Maltezos, Abdullah Mamun, Toshie Manabe, Gokhan Metan, Auksė Mickiene, Dragan Mikić, Kristin G I Mohn, Maria E Oliva, Mehpare Ozkan Dhruv, Parekh Mical, Paul Barbara A Rath, Samir Refaey, Alejandro H Rodríguez, Bunyamin Sertogullarindan, Joanna Skręt-Magierło, Ayper Somer, Ewa Talarek, Julian W Tang, Kelvin To Dat Tran, Timothy M Uyeki, Wendy Vaudry, Tjasa Vidmar, Paul Zarogoulidis, PRIDE Consortium Investigators, Jonathan S Nguyen-Van-Tam

The Journal of Infectious Diseases, jiz152, https://doi.org/10.1093/infdis/jiz152

Published: 17 July 2019

 

Abstract

Background

The effect of neuraminidase inhibitor (NAI) treatment on length of stay (LoS) in patients hospitalized with influenza is unclear.

Methods

We conducted a one-stage individual participant data (IPD) meta-analysis exploring the association between NAI treatment and LoS in patients hospitalized with 2009 influenza A(H1N1) virus (A[H1N1]pdm09) infection. Using mixed-effects negative binomial regression and adjusting for the propensity to receive NAI, antibiotic, and corticosteroid treatment, we calculated incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Patients with a LoS of <1 day and those who died while hospitalized were excluded.

Results

We analyzed data on 18 309 patients from 70 clinical centers. After adjustment, NAI treatment initiated at hospitalization was associated with a 19% reduction in the LoS among patients with clinically suspected or laboratory-confirmed influenza A(H1N1)pdm09 infection (IRR, 0.81; 95% CI, .78–.85), compared with later or no initiation of NAI treatment. Similar statistically significant associations were seen in all clinical subgroups. NAI treatment (at any time), compared with no NAI treatment, and NAI treatment initiated <2 days after symptom onset, compared with later or no initiation of NAI treatment, showed mixed patterns of association with the LoS.

Conclusions

When patients hospitalized with influenza are treated with NAIs, treatment initiated on admission, regardless of time since symptom onset, is associated with a reduced LoS, compared with later or no initiation of treatment.

Neuraminidase inhibitors, pandemic influenza, IPD meta-analysis, length of stay, antivirals

Issue Section: Major Article

Keywords: Seasonal Influenza; H1N1pdm09; Antivirals; Oseltamivir.

——

Advertisements

Characterization of viral #genomic #mutations in novel #influenza A (#H7N9)-infected #patients: the association between #oseltamivir-resistant variants and viral shedding duration (Virus Genes., abstract)

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

Virus Genes. 2019 Jul 13. doi: 10.1007/s11262-019-01678-8. [Epub ahead of print]

Characterization of viral genomic mutations in novel influenza A (H7N9)-infected patients: the association between oseltamivir-resistant variants and viral shedding duration.

Chen R1, Zou Q2,3, Xie G2,3, Yu F2,3, Yang X2,3, Cao L1, Huo Z4, Zheng S5,6.

Author information: 1 Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China. 2 Center of Clinical Laboratory, First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China. 3 Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, People’s Republic of China. 4 Experimental Teaching Center, School of Basic Medical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, People’s Republic of China. zxhuo@zju.edu.cn. 5 Center of Clinical Laboratory, First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China. zsfzheng@zju.edu.cn. 6 Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, People’s Republic of China. zsfzheng@zju.edu.cn.

 

Abstract

Since February 2013, human infections with the novel influenza A H7N9 virus have occurred in eastern China. It is important to detect mutations in viral genes and analyze the clinical features of patients and viral shedding duration related to neuraminidase inhibitor (NAI) resistance. We collected clinical specimens from 31 hospitalized H7N9 patients and sequenced NA, PB2, HA, and M gene fragments. Of the 31 identified patients, 7 (22.6%) carried the R292K substitution in NA, 30 (96.8%), 3 (9.7%), and 5 (16.1%) carried E627K, Q591K, and D701N mutations in PB2, respectively, and 2 (6.5%) carried both E627K and D701N mutations in PB2. All 26 identified patients harbored Q226L mutations and possessed only a single arginine (R) at cleavage sites in the HA and a S31N mutation in M2. Among 7 NA-R292K mutated patients, 3 died and 4 were discharged. There was no significant difference in the days that patients started oseltamivir treatment after symptom onset between NA-R292K mutant and NA-R292 wild-type patients (median days, 7 vs 6, P = 0.374). NA-R292K mutant patients had a significantly longer duration of viral shedding than NA-R292 wild-type patients after oseltamivir treatment (median days, 10 vs 5, P = 0.022). The mutation of R292K in NA conferring the potential ability of oseltamivir resistance resulted in prolonged viral duration and poor outcome and should be taken into consideration in the clinical management of infected patients.

KEYWORDS: Influenza A (H7N9); Mutation; Neuraminidase (NA); Oseltamivir resistance; Viral duration

PMID: 31302878 DOI: 10.1007/s11262-019-01678-8

Keywords: Avian Influenza; H7N9; Antivirals; Drugs Resistance; Oseltamivir; China; Human.

——

#Baloxavir and #Treatment-Emergent #Resistance: #PublicHealth Insights and Next Steps (J Infect Dis., summary)

[Source: Journal of Infectious Diseases, full page: (LINK). Summary, edited.]

Baloxavir and Treatment-Emergent Resistance: Public Health Insights and Next Steps

Larisa V Gubareva, Alicia M Fry

The Journal of Infectious Diseases, jiz245, https://doi.org/10.1093/infdis/jiz245

Published: 16 July 2019

Issue Section: Editorial Commentary

___

Summary

Drug resistance is a topic of significant concern in the treatment of infectious diseases caused by rapidly evolving RNA viruses that can persist (eg, human immunodeficiency virus and hepatitis C virus) or reinfect (eg, influenza virus). Combination drug therapy is standard of care for the treatment of infections by rapidly mutating RNA viruses [1, 2]. However, it is not a common approach for treating influenza virus infections, partly because of the limited number of anti-influenza drugs and drug targets. We now know that all of the classes of anti-influenza drugs—M2 blockers, neuraminidase inhibitors (NAIs), and the newly licensed cap-dependent endonuclease inhibitor (baloxavir marboxil)—have low genetic barriers to resistance: 1 or 2 amino acid substitutions are sufficient to gain resistance [3, 4].

(…)

___

Notes

Disclaimer.

The statements and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Financial support.

This work was supported by the Centers for Disease Control and Prevention.

Potential conflicts of interest.

Both authors: No reported conflicts. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Keywords: Antivirals; Drugs Resistance; Oseltamivir; Baloxavir; Seasonal Influenza.

——

A novel I117T #substitution in #neuraminidase of highly pathogenic #avian #influenza #H5N1 virus conferring reduced susceptibility to #oseltamivir and #zanamivir (Vet Microbiol., abstract)

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

Vet Microbiol. 2019 Jun 5;235:21-24. doi: 10.1016/j.vetmic.2019.06.005. [Epub ahead of print]

A novel I117T substitution in neuraminidase of highly pathogenic avian influenza H5N1 virus conferring reduced susceptibility to oseltamivir and zanamivir.

Kode SS1, Pawar SD2, Tare DS1, Keng SS1, Hurt AC3, Mullick J1.

Author information: 1 Avian Influenza Group, Microbial Containment Complex, ICMR-National Institute of Virology, 130/1, Sus Road, Pashan, Pune 411021, India. 2 Avian Influenza Group, Microbial Containment Complex, ICMR-National Institute of Virology, 130/1, Sus Road, Pashan, Pune 411021, India. Electronic address: shaileshpawarniv@gmail.com. 3 WHO Collaborating Centre for Reference and Research on Influenza (VIDRL), Peter Doherty Institute for Infection and Immunity, 792 Elizabeth Street, Melbourne, VIC 3000, Australia.

 

Abstract

Occurrence of avian influenza (AI) with Neuraminidase (NA) mutations which confer reduced neuraminidase inhibitor (NAI) susceptibility has remained a cause of concern. The susceptibility to NAIs of 67 highly pathogenic avian influenza H5N1 viruses isolated during 2006-2012 in India was tested in phenotypic fluorescence-based NA inhibition assay, sequence analysis and in ovo. One isolate showed a novel NA I117T amino acid substitution (N2 numbering) and eight isolates showed previously known NAI-resistance marker mutations (I117V, E119D, N294S, total 9/67). The overall incidence of resistant variants was 13.4%. The novel I117T substitution reduced oseltamivir susceptibility by 18.6-fold and zanamivir susceptibility by 11.8-fold, compared to the wild type AI H5N1virus, thus showed cross-resistance to both oseltamivir and zanamivir in NA inhibition assays. However, the other two isolates with I117V substitution were sensitive to both the NAIs. In addition, the comparison of growth of the I117T and I117V variants in presence of NAI’s in the in ovo assays exhibited difference in growth levels. The present study reports the natural occurrence of a novel I117T mutation in AI H5N1 virus conferring cross-resistance to oseltamivir and zanamivir highlighting the urgent need of antiviral surveillance of AI viruses.

Copyright © 2019 Elsevier B.V. All rights reserved.

KEYWORDS: Antiviral resistance; H5N1; I117T substitution; In ovo assay; Oseltamivir; Zanamivir

PMID: 31282375 DOI: 10.1016/j.vetmic.2019.06.005

Keywords: Avian Influenza; H5N1; Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; India.

——

Susceptibility of #Influenza A, B, C, and D Viruses to #Baloxavir (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 10—October 2019 / Dispatch

Susceptibility of Influenza A, B, C, and D Viruses to Baloxavir

Vasiliy P. Mishin, Mira C. Patel, Anton Chesnokov, Juan De La Cruz, Ha T. Nguyen, Lori Lollis, Erin Hodges, Yunho Jang, John Barnes, Timothy Uyeki, Charles T. Davis, David E. Wentworth, and Larisa V. Gubareva

Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA (V.P. Mishin, M.C. Patel, A. Chesnokov, J. De La Cruz, H.T. Nguyen, L. Lollis, E. Hodges, Y. Jang, J. Barnes, T. Uyeki, C.T. Davis, D.E. Wentworth, L.V. Gubareva); Battelle Memorial Institute, Atlanta (M.C. Patel, J. De La Cruz, H.T. Nguyen, L. Lollis)

 

Abstract

Baloxavir showed broad-spectrum in vitro replication inhibition of 4 types of influenza viruses (90% effective concentration range 1.2–98.3 nmol/L); susceptibility pattern was influenza A ˃ B ˃ C ˃ D. This drug also inhibited influenza A viruses of avian and swine origin, including viruses that have pandemic potential and those resistant to neuraminidase inhibitors.

Keywords: Antivirals; Drugs Resistance; Oseltamivir; Favipiravir; Baloxavir; Influenza A; Influenza B; Influenza C; Influenza D; H1N1pdm09; H3N2; H7N9.

——

Highly pathogenic #avian #influenza #H7N9 viruses with reduced susceptibility to #neuraminidase #inhibitors showed comparable #replication capacity to their sensitive counterparts (Virol J., abstract)

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

Virol J. 2019 Jul 2;16(1):87. doi: 10.1186/s12985-019-1194-9.

Highly pathogenic avian influenza H7N9 viruses with reduced susceptibility to neuraminidase inhibitors showed comparable replication capacity to their sensitive counterparts.

Tang J1, Zhang J1, Zhou J1, Zhu W1, Yang L1, Zou S1, Wei H1, Xin L1, Huang W1, Li X1, Cheng Y1, Wang D2.

Author information: 1 National Institute for Viral Disease Control and Prevention Chinese Centers for Disease Control and Prevention Key Laboratory for Medical Virology, National Health Commission, NO.155 Changbai road, Changping District, Beijing, 102206, People’s Republic of China. 2 National Institute for Viral Disease Control and Prevention Chinese Centers for Disease Control and Prevention Key Laboratory for Medical Virology, National Health Commission, NO.155 Changbai road, Changping District, Beijing, 102206, People’s Republic of China. dayanwang@cnic.org.cn.

 

Abstract

BACKGROUND:

Human infection with avian influenza H7N9 virus was first reported in 2013. Since the fifth epidemic, a highly pathogenic avian influenza (HPAI) H7N9 virus has emerged and caused 33 human infections. Several potential NAI resistance sites have been found in human cases. However, the drug susceptibility and replication ability of HPAI H7N9 virus with such substitutions have not yet been studied.

METHODS:

Thirty-three HPAI H7N9 virus strains were isolated from human cases in China, and then sequences were analyzed to identify potential NAI resistance sites. Recombinant influenza viruses were generated to evaluate the effect of NA amino acid substitutions on NAI (oseltamivir or zanamivir) susceptibility and viral replication efficiency in MDCK cells.

RESULTS:

Four potential NAI resistance sites, R292 K, E119V, A246T or H274Y, were screened. All four substitutions conferred either reduced or highly reduced susceptibility to oseltamivir or zanamivir. 292 K not only highly reduced the susceptibility of HPAI H7N9 to oseltamivir but also induced an increase in the IC50 of zanamivir. 119 V or 274Y conferred reduced susceptibility of HPAI H7N9 to oseltamivir. Additionally, 246 T conferred reduced susceptibility to zanamivir. All tested NAI-resistant viruses were capable of replication in MDCK cells. The virus yields of rg006-NA292K were lower than those of rg006-NA292R at 24, 48, 72 and 96 h postinfection (P<0.05). Rg006-NA119V, rg006-NA246T or rg006-NA274Y showed comparable replication capacity to wild-type virus (except for rg006-NA274Y at 96 h, P<0.05).

CONCLUSIONS:

All 4 amino acid substitutions (R292 K, E119V, A246T or H274Y) in NA reduced the susceptibility of HPAI H7N9 to NAIs. The NAI-resistant mutations in HPAI H7N9, in most cases, did not reduce the replication ability of the virus in mammalian cells. Special attention needs to be paid to these mutations, and the development of new anti-H7N9 drugs is of great importance.

KEYWORDS: Drug resistance; Highly pathogenic avian influenza H7N9; Influenza virus; Neuraminidase; Replication capacity; Reverse genetics

PMID: 31266524 DOI: 10.1186/s12985-019-1194-9

Keywords: Avian Influenza; H7N9; Human; Antivirals; Drugs Resistance; Oseltamivir; Zanamivir.

——

#Combination #Therapy With #Neuraminidase and #Polymerase #Inhibitors in Nude Mice Infected With #Influenza Virus (J Infect Dis., abstract)

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

J Infect Dis. 2018 Mar 5;217(6):887-896. doi: 10.1093/infdis/jix606.

Combination Therapy With Neuraminidase and Polymerase Inhibitors in Nude Mice Infected With Influenza Virus.

Kiso M1, Lopes TJS1,2, Yamayoshi S1, Ito M1, Yamashita M1, Nakajima N3, Hasegawa H3, Neumann G2, Kawaoka Y1,2,4.

Author information: 1 Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan. 2 Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison. 3 Department of Pathology, National Institute of Infectious Diseases, Tokyo. 4 ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan.

 

Abstract

BACKGROUND:

Treatment of immunocompromised, influenza virus-infected patients with the viral neuraminidase inhibitor oseltamivir often leads to the emergence of drug-resistant variants. Combination therapy with compounds that target different steps in the viral life cycle may improve treatment outcomes and reduce the emergence of drug-resistant variants.

METHODS:

Here, we infected immunocompromised nude mice with an influenza A virus and treated them with neuraminidase (oseltamivir, laninamivir) or viral polymerase (favipiravir) inhibitors, or combinations thereof.

RESULTS:

Combination therapy for 28 days increased survival times compared with monotherapy, but the animals died after treatment was terminated. Mono- and combination therapies did not consistently reduce lung virus titers. Prolonged viral replication led to the emergence of neuraminidase inhibitor-resistant variants, although viruses remained sensitive to favipiravir. Overall, favipiravir provided greater benefit than neuraminidase inhibitors.

CONCLUSIONS:

Collectively, our data demonstrate that combination therapy in immunocompromised hosts increases survival times, but does not suppress the emergence of neuraminidase inhibitor-resistant variants.

PMID: 29186472 DOI: 10.1093/infdis/jix606 [Indexed for MEDLINE]

Keywords: Antivirals; Drugs Resistance; Oseltamivir; Laninamivir; Favipiravir; Influenza A; Animal models.

——-