#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




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


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.


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.


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.



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.



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



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].





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.


#Treatment-Emergent #Influenza Variant Viruses With Reduced #Baloxavir Susceptibility: Impact on #Clinical and Virologic #Outcomes in Uncomplicated Influenza (J Infect Dis., abstract)

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

Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza

Takeki Uehara, Frederick G Hayden, Keiko Kawaguchi, Shinya Omoto, Aeron C Hurt, Menno D De Jong, Nobuo Hirotsu, Norio Sugaya, Nelson Lee, Keiko Baba, Takao Shishido, Kenji Tsuchiya, Simon Portsmouth, Hiroshi Kida

The Journal of Infectious Diseases, jiz244, https://doi.org/10.1093/infdis/jiz244

Published: 16 July 2019




Single-dose baloxavir rapidly reduces influenza virus titers and symptoms in patients with uncomplicated influenza, but viruses with reduced in vitro susceptibility due to amino acid substitutions at position 38 of polymerase acidic protein (PA/I38X) sometimes emerge.


We evaluated the kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses.


Viruses containing PA/I38X substitutions were identified 3–9 days after baloxavir treatment in 9.7% (36/370) of patients, of whom 85.3% had transient virus titer rises. Median time to sustained cessation of infectious virus detection was 192, 48, and 96 hours in the baloxavir recipients with PA/I38X-substituted viruses, without PA/I38X-substituted viruses, and placebo recipients, respectively. The corresponding median times to alleviation of symptoms were 63.1, 51.0, and 80.2 hours, respectively. After day 5, symptom increases occurred in 11.5%, 8.0%, and 13.0%, respectively, and in 8.9% of oseltamivir recipients. Variant virus emergence was associated with lower baseline neutralizing antibody titers.


The emergence of viruses with PA/I38X substitutions following baloxavir treatment was associated with transient rises in infectious virus titers, prolongation of virus detectability, initial delay in symptom alleviation, and uncommonly with symptom rebound. The potential transmissibility of PA/I38X-substituted viruses requires careful study.

Clinical Trial Registration NCT02954354.

antiviral susceptibility, baloxavir marboxil, cap-dependent endonuclease, influenza, polymerase acidic protein

Issue Section: Major Article

Keywords: Influenza A; Antivirals; Drugs Resistance; Baloxavir Marboxil.


#Repurposing #Quinacrine Against #Ebola Virus Infection In vivo (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Repurposing Quinacrine Against Ebola Virus Infection In vivo

Thomas R. Lane, Jason E. Comer, Alexander N. Freiberg, Peter B. Madrid, Sean Ekins

DOI: 10.1128/AAC.01142-19



Quinacrine hydrochloride is a small-molecule, orally bioavailable drug that has been used clinically as an antimalarial and for many other applications. A machine learning model trained on Ebola virus (EBOV) screening data identified quinacrine as a potent (nM) in vitro inhibitor. Quinacrine (25 mg/kg) was shown in the current study to protect 70% of mice (statistically significant) from a lethal challenge with mouse-adapted EBOV (maEBOV) with once daily intraperitoneal (i.p.) dosing for 8 days.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antivirals; Ebola; Quinacrine; Animal models.


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.



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.


Characterisation of #infectious #Ebola virus from the ongoing #outbreak to guide #response activities in the #DRC: a #phylogenetic and in vitro analysis (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Characterisation of infectious Ebola virus from the ongoing outbreak to guide response activities in the Democratic Republic of the Congo: a phylogenetic and in vitro analysis

Laura K McMullan, PhD, Mike Flint, PhD, Ayan Chakrabarti, MS, Lisa Guerrero, MPH, Michael K Lo, PhD, Danielle Porter, PhD, Stuart T Nichol, PhD, Christina F Spiropoulou, PhD, César Albariño, PhD

Published: July 09, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30291-9




The ongoing Ebola virus outbreak in the Ituri and North Kivu Provinces of the Democratic Republic of the Congo, which began in July, 2018, is the second largest ever recorded. Despite civil unrest, outbreak control measures and the administration of experimental therapies and a vaccine have been initiated. The aim of this study was to test the efficacy of candidate therapies and diagnostic tests with the outbreak strain Ituri Ebola virus. Lacking a virus isolate from this outbreak, a recombinant Ituri Ebola virus was compared with a similarly engineered Makona virus from the 2013–16 outbreak.


Using Ebola virus sequences provided by organisations in DR Congo and a reverse genetics system, we generated an authentic Ebola virus from the ongoing outbreak in Ituri and North Kivu provinces. To relate this virus to other Ebola viruses in DR Congo, we did a phylogenetic analysis of representative complete Ebola virus genome sequences from previous outbreaks. We evaluated experimental therapies being tested in clinical trials in DR Congo, including remdesivir and ZMapp monoclonal antibodies, for their ability to inhibit the growth of infectious Ituri Ebola virus in cell culture. We also tested diagnostic assays for detection of the Ituri Ebola virus sequence.


The phylogenetic analysis of whole-genome sequences from each Ebola virus outbreak suggests there are at least two Ebola virus strains in DR Congo, which have independently crossed into the human population. The Ituri Ebola strain initially grew slower than the Makona strain, yet reached similar mean yields of 3 × 10 7 50% tissue culture infectious dose by 72 h infection in Huh-7 cells. Ituri Ebola virus was similar to Makona in its susceptibility to inhibition by remdesivir and to neutralisation by monoclonal antibodies from ZMapp and other monoclonal antibodies. Remdesivir inhibited Ituri Ebola virus at a 50% effective concentration (EC 50) of 12nM (with a selectivity index of 303) and Makona Ebola virus at 13nM (with a selectivity index of 279). The Zmapp monoclonal antibodies 2G4 and 4G7 neutralised Ituri Ebola virus with a mean EC 50 of 0·24 μg/mL and 0·48 μg/mL, and Makona Ebola virus with a mean EC 50 of 0·45 μg/mL and 0·2 μg/mL. The Xpert Ebola and US Centers for Disease Control and Prevention real-time RT-qPCR diagnostic assays detected Ituri and Makona Ebola virus sequences with similar sensitivities and efficiencies, despite primer site binding mismatches in the Ituri Ebola virus.


Our findings provide a rationale for the continued testing of investigational therapies, confirm the effectiveness of the diagnostic assays used in the region, and establish a paradigm for the use of reverse genetics to inform response activities in an outbreak.


US Centers for Disease Control and Prevention.

Keywords: Ebola; Ebola-Makona; Ebola-Ituri; Antivirals; Monoclonal Antibodies; Zmapp; Remdesivir; DRC.