The antiviral resistance of influenza virus

The last pandemic has prompted the use of neuraminidase inhibitors (NAIs) against influenza virus infection and highlighted the problem of the resistance of influenza viruses to antiviral agents. Before NAI, amantadine and rimantadine were used to treat influenza A infections but adamantane derivatives are no longer recommended. From 2005 to 2006 there was an important increase in the resistance to adamantanes and in 2010–2011 most of the A(H1N1) and A(H3N2) circulating viruses were adamantane-resistant. The NAIs oseltamivir and zanamivir were introduced into clinical practice between 1999 and 2002 and are the current antiviral agents used against influenza. Peramivir and laninamivir are more recent NAIs. Peramivir is approved in Japan and South Korea and laninamivir is approved in Japan. The susceptibility to NAI of isolates recovered from 1996 to 1999 did not reveal any resistance to NAI in any of the isolates tested [1,2]. After 3 years of NAI use (from 1999 to 2002), 0.33% of viruses with a decrease in susceptibility to oseltamivir were isolated at a population level from various parts of the world [3]. Between 2004 and 2007, the percentage of NAI-resistant viruses remained low [4,5]. However, higher rates of oseltamivir resistance were described in isolates collected from NAI-treated patients, in particular from children. In this population, mutations responsible for resistance to NAI were detected in 5% [6], 18% [7] and 8.3% [8] of oseltamivir-treated children, respectively. These high rates of resistance could be explained by a prolonged and higher viral excretion in children as compared with adults. In addition, the NAI dose used in these children in Japan was suboptimal and could explain the rapid selection of resistant variants. Indeed, for children, oseltamivir is given at the dose of 2 mg/kg twice daily in Japan whereas in other countries, it is given according to weight groups (e.g., ≤15 kg, 30 mg twice daily; 15–23 kg, 45 mg twice daily; 23–40 kg, 60 mg twice daily; >40 kg, 75 mg twice daily). For example, a child weighing 10 kg will receive 40 mg/day in Japan and 60 mg/day in other countries [7]. In immunocompromised patients, influenza can become a chronic infection. The prolonged influenza virus shedding in the presence of drug treatment may lead to the selection of drug-resistant viruses in immunocompromised patients. These data suggested that the problem of NAI resistance mainly concerned treated children and/or immunocompromised patients. In 2007–2008, seasonal oseltamivir-resistant A(H1N1) viruses emerged and became predominant the following winter season. These oseltamivir-resistant A(H1N1) viruses predominantly occurred in individuals who were not under treatment. The emergence and dissemination of this virus was unexpected as it was thought that oseltamivir-resistant viruses had an impaired fitness as compared with oseltamivir-sensitive ones. The 2009 pandemic confirmed the increasing role antiviral treatment plays in influenza disease management in severe cases. In the 1960s adamantane derivatives were developed and used to treat influenza A virus infections. However, their limitations emphasized the need for the development of new classes of antivirals, such as neuraminidase inhibitors. Nowadays, different licensed neuraminidase inhibitors are available, but we still need new drugs in the anti-influenza pharmacopea. This article will provide the explanation of the mode of action of two classes of antivirals against influenza viruses, describe the mechanisms of resistance that viruses have developed against these products, and explain the evolution of the susceptibility of the influenza virus subtypes and types against these antivirals. We shall also address the expected evolution of the susceptibility of the viruses, the perspectives regarding new therapeutic options that have been used and/or new drugs that may be available in the near future.