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Viral therapeutics

where we are and where we are going

Chemaly, Roy F.a; Clark, Tristan W.b,c,d

Current Opinion in Infectious Diseases: December 2018 - Volume 31 - Issue 6 - p 512–513
doi: 10.1097/QCO.0000000000000507
ANTIMICROBIAL AGENTS: VIRAL: Edited by Tristan W. Clark and Roy F. Chemaly
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aDepartment of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

bAcademic Unit of Clinical and Experimental Sciences, University of Southampton

cDepartment of Infection

dNIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK

Correspondence to Tristan W. Clark, MD, LF101, South Academic Block, Southampton General Hospital, Southampton, SO16 6YD, UK. Tel: +44(0)2381208410; e-mail: T.W.Clark@soton.ac.uk

This year marked the centenary of the 1918 influenza pandemic, one of the most destructive and deadly infectious diseases in human history, affecting 500 million people worldwide and killing over 50 million. Since this time we have made great strides in improving our understanding of pandemic and seasonal influenza and now have vaccines and antivirals that allow us to mitigate against its effects. Antivirals, however, are limited by the ability of influenza to rapidly develop resistance and so alternative agents are needed.

Almost 30 years ago, following the elucidation of the crystal structure of influenza neuraminidase, the first neuraminidase inhibitor (NAI), zanamivir, was developed. Zanamivir, an inhalational drug, was one of the first drugs to be developed using computer-assisted rational drug design and its development was shortly followed by the oral drug oseltamivir. Since this time, a new influenza pandemic (H1N1) has occurred and millions of people worldwide have been treated with NAIs – mainly with oseltamivir.

In our article in this edition [Beard et al. (pp. 514–519)], we review the evidence base for the treatment of influenza with NAIs, both in community dwelling patients and in those hospitalized with more severe disease. Although we acknowledge the absence of high-quality evidence for NAIs in many situations, we highlight the growing body of evidence from seasonal and pandemic studies, supporting their use in community dwelling patients and hospitalized adults.

Resistance to NAIs is a major concern, highlighted well by the rapid and widespread development of resistance to oseltamivir in seasonal H1N1 influenza in 2007–2008. Although this strain was subsequently replaced by the NAI-sensitive pandemic H1N1 strain in 2009, the potential development of resistance to this and other currently circulating seasonal strains remains a major risk. In his article Lee (pp. 520–526) reviews current levels of NAI resistance in seasonal and avian strains of influenza, risk factors for the development of resistance, and the importance of surveillance systems.

To improve outcomes for patients with influenza and mitigate against the development of NAI resistance, alternative therapeutic strategies are required. At the current time there is great optimism that new therapeutic options for influenza will become available in the near future as several promising novel antivirals are in the late stages of development. This includes several agents in the polymerase inhibitor class of antivirals including baloxavir, pimodivir, and favipiravir. Another type of anti-influenza therapeutic strategy is the use of passive antibody therapy, an intervention first used for influenza during the 1918 pandemic in the form of convalescent plasma. In his article Beigel (pp. 527–534) reviews the current evidence for polyclonal and monoclonal antibody therapy for influenza and notes that although well tolerated, the evidence of efficacy for these agents compared to NAIs, has been mixed to date.

Overall, much has happened since the influenza pandemic of 1918. We now have well tolerated and effective antiviral agents in the form of NAIs, although the potential for the development of class-wide resistance remains a great concern. Pending the results of ongoing trials, new antiviral agents and antibody therapy show great promise in improving the outcome of patient with influenza and mitigating against the risk of NAI resistance. We may be standing on the brink of a profound change in the management of patient with influenza.

Over the past decades, important advancements in diagnosis, prevention, and management of viral infections have improved outcomes in the general population and immunosuppressed patients, in particular. Specifically, the use of rapid molecular diagnosis provided early pathogen identification and subsequent prompt therapy or other interventions, when available.

Two main articles will cover immunocompromised patients with different type of viral infections. Hepatitis B or C viruses may lead to chronic infections and viral reactivation with adverse outcomes may occur in cancer patients on immunosuppressive therapy. In this special issue, a comprehensive review (pp. 535–541) on screening and management of Hepatitis B and C infections in cancer patients underscores the importance of universal screening, the type of the screening tests, the risk factors for viral reactivation, and the preventive strategies available including new antiviral agents. The review will also discuss the gaps in the lack of standardized definitions for Hepatitis B viral reactivation and its associated clinical outcomes.

Respiratory viruses (influenza, parainfluenza, respiratory syncytial virus, coronavirus, human metapneumovirus, and rhinovirus) represent the most common cause of respiratory infection in the immunocompromised patient. A review on paramyxoviral infections (pp. 542–552) (i.e., parainfluenza, respiratory syncytial virus, and human metapneumovirus) in hematopoietic cell transplant (HCT) recipients will focus on risk factors, diagnosis, and available management strategies. This review will also illustrate a new tool (i.e., an immunodeficiency scoring index) that can help stratify HCT recipients into low, moderate, to high-risk groups. Finally, it discusses in details the pipeline from new drugs to new vaccines under development.

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Acknowledgements

We would like to acknowledge and thank all the patients who have taken part in the trials reviewed in this article.

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Financial support and sponsorship

T.W.C. has acted as a Chief or Principal investigator in trials of antivirals sponsored by Gilead and Janssen. He has recruited patients into trials sponsored by Gilead, Janssen, GlaxoSmithKline, Novartis, and Baxter. He has acted as a paid consultant to Roche and Janssen and received speaker fees from BioMerieux and BioFire Diagnostics. He is the holder of a UK National Institute for Health Research (NIHR) personal fellowship. The views expressed here do not necessarily reflect those of the NIHR, NHS, or the UK department of health.

R.F.C. received research grants paid to his institution from Gilead, Ansun Pharmaceuticals, and Ablynx. He received honoraria from ADMA Biologics, Ablynx, Janssen, and Ansun Pharmaceuticals.

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Conflicts of interest

There are no conflicts of interest.

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