Posts filed under ‘Antivirales no HIV’

Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil.

Sci Rep. June 25, 2018 V.8 N.1 P.9633.      doi: 10.1038/s41598-018-27890-4.

Omoto S1, Speranzini V2, Hashimoto T3, Noshi T3, Yamaguchi H3, Kawai M3, Kawaguchi K3, Uehara T3, Shishido T3, Naito A3, Cusack S4.

Author information

1 Shionogi & Co., Ltd., Osaka, Japan. shinya.oomoto@shionogi.co.jp

2 European Molecular Biology Laboratory, Grenoble Outstation, Grenoble, France.

3 Shionogi & Co., Ltd., Osaka, Japan.

4 European Molecular Biology Laboratory, Grenoble Outstation, Grenoble, France. cusack@embl.fr

Abstract

Baloxavir acid (BXA), derived from the prodrug baloxavir marboxil (BXM), potently and selectively inhibits the cap-dependent endonuclease within the polymerase PA subunit of influenza A and B viruses. In clinical trials, single doses of BXM profoundly decrease viral titers as well as alleviating influenza symptoms. Here, we characterize the impact on BXA susceptibility and replicative capacity of variant viruses detected in the post-treatment monitoring of the clinical studies. We find that the PA I38T substitution is a major pathway for reduced susceptibility to BXA, with 30- to 50-fold and 7-fold EC50 changes in A and B viruses, respectively.

The viruses harboring the I38T substitution show severely impaired replicative fitness in cells, and correspondingly reduced endonuclease activity in vitro. Co-crystal structures of wild-type and I38T influenza A and B endonucleases bound to BXA show that the mutation reduces van der Waals contacts with the inhibitor. A reduced affinity to the I38T mutant is supported by the lower stability of the BXA-bound endonuclease. These mechanistic insights provide markers for future surveillance of treated populations.

FULL TEXT

https://www.nature.com/articles/s41598-018-27890-4

PDF

https://www.nature.com/articles/s41598-018-27890-4.pdf

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June 30, 2018 at 5:47 pm

Approved: Baloxavir marboxil

WHO Drug Information 2018 V.32 N.1 P.32

One-dose treatment for influenza

Product name: Xofluza®

Dosage form: Tablet

Class: cap-dependent endonuclease inhibitor

Approval: Ministry of Health, Labour and Welfare (MHLW) of Japan

Use: Treatment of influenza types A and B

Benefits: Treatment requires only a single oral dose regardless of age.

Shionogi & Co. Ltd Press

PDF

http://www.who.int/medicines/publications/druginformation/issues/WHO_DI_32-1.pdf

 

June 30, 2018 at 5:45 pm

Westward Spread of Highly Pathogenic Avian Influenza A(H7N9) Virus among Humans, China

Emerging Infectious Diseases June 2018 V.24 N.6   

Yang et al.

Beijing Normal University, Beijing, China (Q. Yang, X. Tong, H. Tian); Shaanxi Provincial Centre for Disease Control and Prevention, Xi’an, China (W. Shi, L. Zhang, Y. Xu, J. Xu, S. Li, F. Liu, P. Yu); Xianyang Centre for Disease Control and Prevention, Xianyang, China (J. Zhang); Baoji Centre for Disease Control and Prevention, Baoji, China (K. Hu); Xi’an Centre for Disease Control and Prevention, Xi’an (C. Ma); Chinese Center for Disease Control and Prevention, Beijing (X. Zhao, X. Li); Chinese Academy of Forestry, Beijing (G. Zhang); University of Oxford, Oxford, UK (O.G. Pybus)

We report infection of humans with highly pathogenic avian influenza A(H7N9) virus in Shaanxi, China, in May 2017. We obtained complete genomes for samples from 5 patients and from live poultry markets or farms in 4 cities. Results indicate that H7N9 is spreading westward from southern and eastern China.

FULL TEXT

https://wwwnc.cdc.gov/eid/article/24/6/17-1135_article

PDF

https://wwwnc.cdc.gov/eid/article/24/6/pdfs/17-1135.pdf

May 22, 2018 at 7:41 am

Is cytomegalovirus reactivation increasing the mortality of patients with severe sepsis?

Crit Care. 2011;15(2):138.

Kalil AC1, Florescu DF.

Author information

1 Department of Internal Medicine, University of Nebraska Medical Center, 985400 Nebraska Medical Center, Omaha, NE 68198, USA. akalil@unmc.edu

Abstract

Cytomegalovirus (CMV) is a ubiquitous virus present in approximately two-thirds of the healthy population.

This virus rarely causes an active disease in healthy individuals, but it is among the most common opportunistic infections in immunocompromised patients such as solid organ transplant recipients, patients receiving chemotherapy for cancer or patients with human immunodeficiency virus.

Critically ill patients who are immunocompetent before intensive care unit admission may also become more prone to develop active CMV infection if they have prolonged hospitalizations, high disease severity, and severe sepsis.

The development of active CMV infection in these critically ill patients has been associated with a significantly higher risk of death in several previous studies.

The present issue of Critical Care brings a new study by Heininger and colleagues in which the authors found that patients with severe sepsis who developed active CMV infection had significantly longer intensive care unit and hospital stays, prolonged mechanical ventilation, but no changes in mortality compared to patients without CMV infection.

We discuss the possible reasons for their findings (for example, selection bias and low (20%) statistical power to detect mortality endpoints), and also perform an update of our previous meta-analysis with the addition of Heininger and colleagues’ study to verify whether the higher mortality rate with CMV holds.

Our updated meta-analysis with approximately 1,000 patients shows that active CMV infection continues to be associated with a significant 81% higher mortality rate than that in critically ill patients without active CMV infection.

PDF

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219353/pdf/cc10093.pdf

March 24, 2018 at 10:58 am

Adenovirus Type 4 Respiratory Infections among Civilian Adults, Northeastern United States, 2011–2015

Emerg Infect Dis. 2018 V.24 N.2 P.201-209

Adriana E. KajonComments to Author , Daryl M. Lamson, Camden R. Bair, Xiaoyan Lu, Marie L. Landry, Marilyn Menegus2, Dean D. Erdman, and Kirsten St. George

Author affiliations: Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA (A.E. Kajon, C.R. Bair); New York State Department of Health, Albany, New York, USA (D.M. Lamson, K. St. George); Centers for Disease Control and Prevention, Atlanta, Georgia, USA (X. Lu, D.D. Erdman); Yale University School of Medicine, New Haven, Connecticut, USA (M.L. Landry); University of Rochester Medical Center, Rochester, New York, USA (M. Menegus)

Abstract

Human adenovirus type 4 (HAdV-4) is most commonly isolated in military settings. We conducted detailed molecular characterization on 36 HAdV-4 isolates recovered from civilian adults with acute respiratory disease (ARD) in the northeastern United States during 2011–2015.

Specimens came from college students, residents of long-term care facilities or nursing homes, a cancer patient, and young adults without co-morbidities.

HAdV-4 genome types 4a1 and 4a2, the variants most frequently detected among US military recruits in basic training before the restoration of vaccination protocols, were isolated in most cases.

Two novel a-like variants were recovered from students enrolled at a college in Tompkins County, New York, USA, and a prototype-like variant distinguishable from the vaccine strain was isolated from an 18-year-old woman visiting a physician’s office in Ulster County, New York, USA, with symptoms of influenza-like illness. Our data suggest that HAdV-4 might be an underestimated causative agent of ARD among civilian adults.

FULL TEXT

https://wwwnc.cdc.gov/eid/article/24/2/17-1407_article

PDF

https://wwwnc.cdc.gov/eid/article/24/2/pdfs/17-1407.pdf

 

 

February 9, 2018 at 6:47 pm

Infectious virus in exhaled breath of symptomatic seasonal influenza cases from a college community.

Proc Natl Acad Sci U S A 2018 Jan; 115:1081.

Yan J et al

Significance

Lack of human data on influenza virus aerosol shedding fuels debate over the importance of airborne transmission. We provide overwhelming evidence that humans generate infectious aerosols and quantitative data to improve mathematical models of transmission and public health interventions. We show that sneezing is rare and not important for—and that coughing is not required for—influenza virus aerosolization. Our findings, that upper and lower airway infection are independent and that fine-particle exhaled aerosols reflect infection in the lung, opened a pathway for a deeper understanding of the human biology of influenza infection and transmission. Our observation of an association between repeated vaccination and increased viral aerosol generation demonstrated the power of our method, but needs confirmation.

Abstract

Little is known about the amount and infectiousness of influenza virus shed into exhaled breath. This contributes to uncertainty about the importance of airborne influenza transmission. We screened 355 symptomatic volunteers with acute respiratory illness and report 142 cases with confirmed influenza infection who provided 218 paired nasopharyngeal (NP) and 30-minute breath samples (coarse >5-µm and fine ≤5-µm fractions) on days 1–3 after symptom onset. We assessed viral RNA copy number for all samples and cultured NP swabs and fine aerosols. We recovered infectious virus from 52 (39%) of the fine aerosols and 150 (89%) of the NP swabs with valid cultures. The geometric mean RNA copy numbers were 3.8 × 104/30-minutes fine-, 1.2 × 104/30-minutes coarse-aerosol sample, and 8.2 × 108 per NP swab. Fine- and coarse-aerosol viral RNA were positively associated with body mass index and number of coughs and negatively associated with increasing days since symptom onset in adjusted models. Fine-aerosol viral RNA was also positively associated with having influenza vaccination for both the current and prior season. NP swab viral RNA was positively associated with upper respiratory symptoms and negatively associated with age but was not significantly associated with fine- or coarse-aerosol viral RNA or their predictors. Sneezing was rare, and sneezing and coughing were not necessary for infectious aerosol generation. Our observations suggest that influenza infection in the upper and lower airways are compartmentalized and independent.

FULL TEXT

http://www.pnas.org/content/115/5/1081

PDF

http://www.pnas.org/content/pnas/115/5/1081.full.pdf

February 8, 2018 at 8:40 pm

IDSA/AASLD Response to Cochrane Review on Direct-Acting Antivirals for Hepatitis C

Clinical Infectious Diseases December 2017 V.65 N.11

EDITOR’S CHOICE

William G Powderly; Susanna Naggie; Arthur Y Kim; Hugo E Vargas; Raymond T Chung …

A recent Cochrane Review with the stated objective to assess the benefits and harms of direct-acting antiviral (DAA) therapy for people with chronic hepatitis C virus (HCV) infection raised alarms within the hepatology and infectious diseases communities because the authors concluded that there was insufficient evidence to confirm or reject an effect of DAA therapy on HCV-related morbidity (cirrhosis, hepatic decompensation, or hepatocellular carcinoma) or all-cause mortality [1]. The authors also concluded that the clinical relevance of sustained virological response (SVR) obtained with DAAs is questionable, as it is a nonvalidated surrogate outcome. The Review further stated that because all DAA trials and outcome results were at high risk of bias, their results presumably overestimated benefit and underestimated harm. Indeed, the plain language summary stated that the lack of valid evidence and the possibility of potentially harming people with chronic hepatitis should be considered before treating people with hepatitis C using DAAs. Based on the findings of this Review, the authors concluded that additional randomized clinical trials are needed to assess the long-term clinical effects of DAAs…

PDF (hacer CLIC en PDF)

https://academic.oup.com/cid/article/65/11/1773/3965298

November 29, 2017 at 8:21 am

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