Research Article: What Is the Optimal Therapy for Patients with H5N1 Influenza?

Date Published: June 23, 2009

Publisher: Public Library of Science

Author(s): Nicholas J. White, Robert G. Webster, Elena A. Govorkova, Timothy M. Uyeki

Abstract: Background to the debateIn a 2007 article in PLoS Medicine[10], Holger J. Schünemann and colleagues described a new process used by the World Health Organization for rapidly developing clinical management guidelines in emergency situations. These situations include outbreaks of emerging infectious diseases. The authors discussed how they developed such a “rapid advice” guideline for the pharmacological management of avian influenza A (H5N1) virus infection. The guideline recommends giving the antiviral drug oseltamivir at a dose of 75 mg twice daily for five days. In this Debate, Nicholas White argues that such dosing is inadequate, Robert Webster and Elena Govorkova say that combination antiviral therapy should be used, and Tim Uyeki reminds us that clinical care of patients with H5N1 entails much more than antiviral treatment. These issues may also apply to therapy of patients hospitalized with severe disease due to novel swine-origin influenza A (H1N1) virus infection.

Partial Text: Nature has again sent a message to scientists and public health officials concerned with the current pharmacological treatment of humans with a potential pandemic influenza virus. The message is loud and clear that the strategy of relying on single anti-influenza drug treatment is wrong. The rapid emergence of seasonal influenza A (H1N1) viruses resistant to oseltamivir in Scandinavia at the end of 2007 (where little or no anti-influenza drugs are used) was unexpected [16]. These resistant viruses contain the His274Tyr neuraminidase mutation and have remarkable fitness; they spread globally in less than a year [17]. While the oseltamivir-resistant influenza A (H1N1) viruses are still susceptible to the neuraminidase inhibitor zanamivir (Relenza), it would be foolish to continue being complacent and rely on monotherapy. Influenza viruses have a segmented RNA genome that is error-prone during replication and lacks proofreading mechanisms. This fundamental property of influenza viruses guarantees that resistant variants will emerge. Such resistance may occur spontaneously and naturally (without drug intervention) but would be facilitated by the use of single-agent chemotherapy with oseltamivir alone.

The emergence of a new respiratory infection that can cause rapid severe outcomes, including death, presents major challenges for identifying optimal clinical management and treatment. For example, early in the severe acute respiratory syndrome (SARS) epidemic, oral or intravenous ribavirin was administered to patients with SARS on the assumption that this antiviral medication would have activity against a suspected respiratory viral pathogen. Unfortunately, it is unclear if ribavirin was beneficial for treatment of patients with SARS, and hemolytic anemia occurred in some treated patients [30],[31]. Methylprednisolone was also administered widely to patients with SARS, and higher doses were associated with avascular necrosis among survivors [32],[33]. To date, no definitive treatment exists for human infection with SARS-associated coronavirus (SARS-CoV), and there are still challenges in collecting data from controlled clinical treatment trials of novel pathogens [34].



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