Antiviral Resistance Has Emerged Among Seasonal Influenza Virus

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Flu vaccines are only 70-90% effective.229 Consequently, antiviral drugs have been developed for persons unable to develop a good immune response to the vaccine. Influenza viruses fall largely into two general types called A and B. (In the 2008-09 season, 77% were type A, 23% were type B.230) Two antibiotic classes have been used for influenza A. The adamantanes (amantadine, rimantadine) inhibit influenza virus membrane protein-2 (M2). This protein is part of a channel required for passage of protons that help uncoat the virus. The adamantanes prevent flu virus from taking over the host cell. These drugs, which have been available since 1964, are ineffective with influenza B because this virus lacks the M2 protein.230 The other antibiotic type, the neuraminidase inhibitors (zanamivir, oseltamivir [Tamiflu]), blocks the activity of the viral enzyme that breaks down glycolipids and glycoproteins. These agents prevent release of progeny virus from infected human cells. Neuraminidase inhibitors were designed for influenza A; influenza B tends to exhibit lower susceptibility. Zanamivir and oseltamivir target different sites on neuraminidase; consequently, the two drugs show little cross-resistance.231 Oseltamivir is taken orally and has been applied throughout the world; zanamivir has been used largely in Japan.

In principle, antibiotic resistance emerges as a direct result of selection pressure acting on spontaneous mutants. Resistance can then be maintained in the virus population either by continued antibiotic pressure due to treatment or by the resistance mutation being located near other viral mutations that confer an advantage to the virus.232 (Two mutations that are close to each other in a viral RNA segment tend to re-assort together and maintain a tight association.) In the latter case, resistant virus can spread to many persons who never receive antibiotic treatment.

In 2002-03, the circulating strains of seasonal influenza began to display adamantane resistance in Asia, perhaps stimulated by treatment of domestic birds.230, 232 The emergence of resistance was exacerbated when the agents were added to over-the-counter cold remedies in Russia and China.232 By 2005-06 amantidine resistance became extensive in the United States,232 and by 2008 the viruses displayed such a high prevalence of resistance that the compounds were no longer recommended for treatment.232

Resistance to the neuraminidase inhibitors has also been appearing, even though these drugs have not been used extensively for domestic birds.230 With clinical trials of oseltamivir, resistance was reported in 2% of treated patients (18% in treated children).233 Such high numbers indicated that resistance would arise readily if the drug were widely used. However, prior to 2007 oseltamivir in untreated patients was rare (less than 0.3%).

In the 2007-08 season, the worldwide prevalence of oseltamivir resistance rose to 15% among seasonal influenza A H1N1 isolates.231 (Subtypes are defined by differences in two viral proteins, hemagglutinin and neuraminidase, that are abbreviated by H and N, respectively.) Resistance was particularly evident in Norway (see Box 11-1). Later in 2008, resistant virus reached South Africa: Of 23 samples for which neuraminidase activity was tested, all exhibited oseltamivir resistance. Another 45 South African isolates were tested for a viral nucleotide sequence change associated with resistance. All tested positive for resistance. Because none of the South African patients had been treated with drug, spread of resistant virus appeared to be occurring. By late 2008, resistance was prevalent in the United States.230

In 2008-09, the common subtypes of seasonal influenza were H1N1, H1N2, and H3N2. These subtypes usually caused mild disease; consequently, antibiotic resistance was an issue mainly for immunocompromised persons and the elderly. However, understanding the emergence and transmission of resistance is important for managing more aggressive forms of the virus. One of the key points is that oseltamivir resistance in the seasonal H1N1 virus strain did not interfere with transmissibility nor did resistance correlate with treatment: Resistant mutants moved easily from person to person. Because new strains of seasonal flu appear each year, oseltamivir resistance may disappear when the current strain is replaced. However, it could reappear with little warning.

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