Prevention and Control of Influenza, Recommendations of the Advisory Committee on Immunization Practices (ACIP)

Nicole M. Smith, PhD; Joseph S. Bresee, MD; David K. Shay, MD; Timothy M. Uyeki, MD; Nancy J. Cox, PhD; Raymond A. Strikas, MD


Morbidity and Mortality Weekly Report. 2006;55(27):1-41. 

In This Article

Antiviral Drug-Resistant Strains of Influenza Virus

CDC recently reported 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.[23,24] In addition, two of eight influenza A (H1N1) viruses tested were resistant.[24] Canadian health authorities also have reported the same mutation in a comparable proportion of isolates recently tested.[284] Until these findings, previous screenings of epidemic strains of influenza A viruses found few amantadine- and rimantadine-resistant viruses.[290,291,292]

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.[293,294] Drug-resistant viruses can emerge in approximately one third of patients when either amantadine or rimantadine is used for therapy.[293,295,296] During the course of amantadine or rimantadine therapy, resistant influenza strains can replace susceptible strains within 2-3 days of starting therapy.[290,297] Resistant viruses have been isolated from persons who live at home or in an institution in which other residents are taking or have taken amantadine or rimantadine as therapy;[298,299] however, the frequency with which resistant viruses are transmitted and their effect on efforts to control influenza are unknown.

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.[295]

Resistance to zanamivir and oseltamivir can be induced in influenza A and B viruses in vitro[300,301,302,303,304,305,306,307]i>, but induction of resistance usually requires multiple passages in cell culture. By contrast, resistance to amantadine and rimantadine in vitro can be induced with fewer passages in cell culture.[308,309] Development of viral resistance to zanamivir and oseltamivir during treatment has been identified but does not appear to be frequent.[310,311,312,313,314] In one pediatric study, 5.5% of patients treated with oseltamivir had posttreatment isolates that were resistant to neuraminidase inhibitors. One small study of Japanese children treated with oseltamivir reported a high frequency of resistant viruses.[315] However, no transmission of neuraminidase inhibitor-resistant viruses in humans has been documented to date. No isolates with reduced susceptibility to zanamivir have been reported from clinical trials, although the number of posttreatment isolates tested is limited,[316] and the risk for emergence of zanamivir-resistant isolates cannot be quantified.[317] Only one clinical isolate with reduced susceptibility to zanamivir, obtained from an immunocompromised child on prolonged therapy, has been reported.[312] Available diagnostic tests are not optimal for detecting clinical resistance to the neuraminidase inhibitor antiviral drugs, and additional tests are being developed.[316,318] Postmarketing surveillance for neuraminidase inhibitor-resistant influenza viruses is being conducted.[319]


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