Antiviral Drug-Resistant Strains of Influenza Virus

Adamantane resistance among circulating influenza A viruses has increased rapidly worldwide over the past several years. The proportion of influenza A viral isolates submitted from throughout the world to the World Health Organization Collaborating Center for Surveillance, Epidemiology, and Control of Influenza at CDC that were adamantane-resistant increased from 0.4% during 1994-1995 to 12.3% during 2003-2004 (378). During the 2005-06 influenza season, CDC determined that 193 (92%) of 209 influenza A (H3N2) viruses isolated from patients in 26 states demonstrated a change at amino acid 31 in the M2 gene that confers resistance to adamantanes (367,368). In addition, two (25%) of eight influenza A (H1N1) viruses tested were resistant (368). All 2005-06 influenza season isolates in these studies remained sensitive to neuraminidase inhibitors (367-369). Preliminary data from the 2006-07 influenza season indicates that resistance to adamantanes remains high among influenza A isolates, but resistance to neuraminidase inhibitors is extremely uncommon (<1% of isolates) (CDC, unpublished data, 2007). Amantadine or rimantidine should not be used for the treatment or prevention of influenza in the United States until evidence of susceptibility to these antiviral medications has been reestablished among circulating influenza A viruses.

Influenza A viral resistance to adamantanes can emerge rapidly during treatment because a single point mutation at amino acid positions 26, 27, 30, 31, or 34 of the M2 protein can confer cross resistance to both amantadine and rimantadine (379,380). Adamantane-resistant influenza A virus strains can emerge in approximately one third of patients when either amantadine or rimantadine is used for therapy (379,381,382). Resistant influenza A virus strains can replace susceptible strains within 2-3 days of starting amantadine or rimantadine therapy (383,384). Resistant influenza A viruses have been isolated from persons who live at home or in an institution in which other residents are taking or have recently taken amantadine or rimantadine as therapy (385,386). Persons who have influenza A virus infection and who are treated with either amantadine or rimantadine can shed susceptible viruses early in the course of treatment and later shed drug-resistant viruses, including after 5-7 days of therapy (381).

Resistance to zanamivir and oseltamivir can be induced in influenza A and B viruses in vitro (387-394), but induction of resistance typically requires multiple passages in cell culture. By contrast, resistance to amantadine and rimantadine in vitro can be induced with fewer passages in cell culture (395,396). Development of viral resistance to zanamivir or oseltamivir during treatment has been identified but does not appear to be frequent (397-401). One limited study reported that oseltamivir-resistant influenza A viruses were isolated from nine (18%) of 50 Japanese children during treatment with oseltamivir (402). Transmission of neuraminidase inhibitor-resistant influenza B viruses between humans is rare but has been documented (403). No isolates with reduced susceptibility to zanamivir have been reported from clinical trials, although the number of posttreatment isolates tested is limited (404,405). Only one clinical isolate with reduced susceptibility to zanamivir, obtained from an immunocompromised child on prolonged therapy, has been reported (405).

Laboratory studies suggest that influenza viruses with oseltamivir resistance have diminished replication competence and infectivity. However, prolonged shedding of oseltamivir- or zanamivir-resistant virus by severely immunocompromised patients, even after cessation of oseltamivir treatment, has been reported (406-407). Tests that can detect clinical resistance to the neuraminidase inhibitor antiviral drugs are being developed (404,408), and postmarketing surveillance for neuraminidase inhibitor-resistant influenza viruses is being conducted. Among 2,287 isolates obtained from multiple countries during 1999-2002, only eight (0.33%) had a greater-than-tenfold decrease in susceptibility to oseltamivir, and two (25%) of these eight also were resistant to zanamivir (409).

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