Influenza virus drug resistance

It may be possible to increase the utility of our resources to treat influenza virus infection through combinations of antiviral agents with different modes of action (discussed in Cinatl et al. 2007a De Clercq and Neyts 2007). The sialidase inhibitors, for example, may be able to be used in conjunction with the adamantane-based M2 ion channel inhibitors (Govorkova et al. 2004 Ilyushina et al. 2006), with Ribavirin (Smee et al. 2002) or with non-influenza virus specific therapeutics such as anti-inflammatory drugs (Carter 2007). Combination therapy may also reduce the potential of resistance development (Ilyushina et al. 2006). 

Ison MG, Gubareva LV, Atmar RL, Treanor J, Hayden EG (2006a) Recovery of drug-resistant influenza virus from immunocompromised patients a case series, J Infect Dis 193 760-764 Ison MG, Mishin VP, Braciale TJ, Hayden EG, Gubareva LV (2006b) Comparative activities of oseltamivir and A-322278 in immunocompetent and immunocompromised murine models of influenza virus infection, J Infect Dis 193 765-772... 

Wang S-Q, Du Q-S, Chou K-C (2007) Study of drug resistance of chicken influenza A virus (H5N1) from homology-modeled 3D structures of neuraminidases. Biochem Biophys Res Commun 354 634-640... 

Drug resistance - In clinical studies of naturally acquired infection with influenza virus, 1.3% of posttreatment isolates in adults and adolescents, and 8.6% in children from 1 to 12 years of age showed emergence of influenza variants with decreased neuraminidase susceptibility to oseltamivir carboxylate. 

Currently, two classes of drugs are available with antiviral activity against influenza viruses inhibitors of the ion channel activity of the M2 membrane protein, amantadine and rimantadine, and the neuraminidase inhibitors oseltamivir, and zanamivir. H5N1 viruses isolated from poultry and humans in Thailand and Viet Nam in 2004 invariably showed an amantadine-resistance indicating that amantadine treatment is not an option during the ongoing outb-treak in South-East Asia. 

Influenza virus resistant to oseltamivir has not been found in naturally acquired isolates but has been isolated from influenza patients who have undergone treatment with this drug. These resistant strains contain mutations in the active site of neuraminidase and are generally less virulent and infective than nonresistant virus. In vitro passage of influenza virus in the presence of oseltamivir carboxylate can produce mutations in hemagglutinin that decrease the overall dependence of viral replication on neuraminidase however, the clinical relevance of this resistance mechanism is unknown. 

In the case of influenza virus, there have to date been no reports of drug resistance from field strains. However it has recently been reported [102,103]... 

The third major difficulty in developing cold cures arises from the fact that the HRVs are RNA viruses. When presented with any selective pressure, including chemotherapeutic or antibody challenge, RNA viruses mutate rapidly [9]. This ability to mutate is most clearly illustrated in influenza viruses (RNA viruses), where new strains continuously arise to circumvent immunity in a population. Influenza A viruses have been shown to mutate around the anti-influenza drug Amantadine, after a single passage through a susceptible human host. The mutated viruses shed from a host treated with Amantadine are now resistant to Amantadine. These mutated viruses appear to be as virulent as the parent strain of virus [10]. 

Therapies for typical human influenza viruses should work in treating avian influenza infection in humans however, influenza viruses can become resistant to drugs such as amantadine and rimantadine, decreasing their effectiveness. Currently no vaccine is available to protect humans against the H5N1 virus that causes... 

Mechanisms Amantadine and rimantadine inhibit the first steps in replication of the influenza A and rubella viruses (Figure 49-1). These steps involve viral adsorption to the host cell membrane, penetration into the cell via endocytosis. and viral particle uncapping. The inhibitory action of these drugs may be due to their alkaline reaction, which raises the endo-somal pH. At low concentrations, amantadine also binds to a specific protein in the surface coat of the influenza virus to prevent fusion. Drug-resistant influenza A virus mutants can emerge and infect contacts of patients in treatment. 

Rameix-Welti, M.-A., Munier, S., and Naffakh, N. (2012) Resistance development to influenza virus sialidase inhibitors, in Influenza Virus Sialidase A Drug Discovery Target (ed. M. von Itzstein), Springer, Basel, pp. 153-174. 

Viruses that contain amino acid substitutions in the sialidase that impart resistance to the developed inhibitors have been isolated from serial passage of virus in the presence of drug in cell culture and from the clinical setting (reviewed in McKimm-Breschkin 2000 Zambon and Hayden 2001 Cinatl et al. 2007a Reece 2007). In addition, influenza B virus variants with reduced drug sensitivity have been isolated from previously untreated patients (Hurt et al. 2006 Hatakeyama et al. 2007). The types of mutations that are observed are sub-type specific. The mutations present in variants isolated from clinical samples are shown in Table 1, and their locations within the sialidase active site are shown diagrammatically in Fig. 9. 

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