A Review of the Antiviral Susceptibility of Human and Avian Influenza Viruses over the Last Decade

Abstract

Antivirals play an important role in the prevention and treatment of influenza infections, particularly in high-risk or severely ill patients. Two classes of influenza antivirals have been available in many countries over the last decade (2004–2013), the adamantanes and the neuraminidase inhibitors (NAIs). During this period, widespread adamantane resistance has developed in circulating influenza viruses rendering these drugs useless, resulting in the reliance on the most widely available NAI, oseltamivir. However, the emergence of oseltamivir-resistant seasonal A(H1N1) viruses in 2008 demonstrated that NAI-resistant viruses could also emerge and spread globally in a similar manner to that seen for adamantane-resistant viruses. Previously, it was believed that NAI-resistant viruses had compromised replication and/or transmission. Fortunately, in 2013, the majority of circulating human influenza viruses remain sensitive to all of the NAIs, but significant work by our laboratory and others is now underway to understand what enables NAI-resistant viruses to retain the capacity to replicate and transmit. In this review, we describe how the susceptibility of circulating human and avian influenza viruses has changed over the last ten years and describe some research studies that aim to understand how NAI-resistant human and avian influenza viruses may emerge in the future.

Interpreting Thermodynamic Profiles of Aminoadamantane Compounds Inhibiting the M2 Proton Channel of Influenza A by Free Energy Calculations

“…Such a decomposition allows linking thermodynamic profiles from ITC with structural causes and, thus, is very helpful for guiding decision making in lead optimization. As an example, we found that compound 8 is optimal with respect to Amt (1), rimantadine (2), and compound 7 in terms of its configurational entropy contribution to binding; however, it is unsatisfactory in terms of its van der Waals energies with respect to 7. We therefore predicted profiles for compounds with smaller ring moieties, i.e., cyclopropyl or cyclobutyl substituents, at position 2 of the adamantane core.…”

Emerging infectious diseases: Focus on infection control issues for novel coronaviruses (Severe Acute Respiratory Syndrome-CoV and Middle East Respiratory Syndrome-CoV), hemorrhagic fever viruses (Lassa and Ebola), and highly pathogenic avian influenza viruses, A(H5N1) and A(H7N9)

“…123,124 Currently, circulating influenza A strains are susceptible to the neuraminidase inhibitors, including A(H5N1). 125 However, because circulating strains of A(H1N1) in 2008 exhibited resistance, one must be concerned that in the future, circulating influenza strains may develop resistance to neuraminidase inhibitors. Vaccines are available for A(H5N1) but not for A(H7N9).…”

Japanese Surveillance Systems and Treatment for Influenza

“…The M2 inhibitor, amantadine (Symmetrel®) is effective only for influenza A. However, the dug is rarely used in Japan in recent years because of the universal resistance among influenza A(H1N1)pdm09 and A(H3N2) attributed to an amino acid mutation serine to asparagine at position 31 in the M2 protein [39–42]. Thus, NAIs, which are effective against both influenza A and B, are now the drugs of choice for clinicians [3, 41] A newly developed RNA polymerase inhibitor, favipiravir (Avigan®), was approved in Japan in 2014, but the use is highly restricted due to its potential adverse effects [7, 9, 43].…”