Adamantane Resistance in Influenza A

Abstract

THE GLOBAL BURDEN OF INFLUENZA INFECTION IS STAGgering. In a typical year, approximately 20% of the world’s population is infected and more than a half million individuals die of influenza-associated complications. During influenza pandemics, morbidity and mortality are catastrophic—20 million to 100 million individuals died in the 1918 influenza pandemic, 2 million in the 1955 pandemic, and 1 million in the 1968 pandemic. Vaccination is the primary means for preventing influenza infections. In addition, 2 classes of drugs are currently available for treatment and prophylaxis: the adamantanes (amantadine and rimantadine) and the neuraminidase inhibitors (zanamivir and oseltamivir). Adamantanes are effective against susceptible strains of influenza A virus, whereas neuraminidase inhibitors are effective against susceptible strains of both A and B virus. All 4 agents can reduce the duration of infection by 1 to 2 days if treatment is initiated within 48 hours of symptom onset. Amantadine, rimantadine, and oseltamivir also have been approved by the US Food and Drug Administration (FDA) for prophylaxis and appear to be 70% to 90% effective at preventing symptomatic influenza infection. In the absence of protective humoral immunity from prior exposure to antigenically compatible virus or vaccine, these drugs are the only treatments available to mitigate or prevent illness. Adamantanes inhibit influenza propagation by blocking the viral M2 protein ion channel, which prevents fusion of the virus and host-cell membranes and release of viral RNA into the cytoplasm of infected cells. Approximately 30% of individuals treated with adamantanes for influenza virus infection excrete viruses resistant to these drugs. Resistance to adamantanes develops rapidly as a result of single amino acid substitutions at position 26, 27, 30, 31, or 34 within the transmembrane domain of the M2 protein. Adamantane-resistant mutants are not impaired in virulence, in vitro replication, or human-to-human transmission and maintain drug resistance for multiple generations in culture. Cross-resistance between amantadine and rimantadine is complete and adamantane-resistant virus can be shed for prolonged periods in immunocompromised patients. Nonetheless, through the mid-1990s the rate of resistance among untreated patients remained less than 1%. In this issue of JAMA, Bright and colleagues at the Centers for Disease Control and Prevention (CDC) report that the overwhelming majority of currently circulating influenza A(H3N2) viruses in the United States exhibit highlevel resistance to adamantanes due to an S31N (serine to asparagine at position 31) substitution in the viral M2 protein. Using the combination of 2 sequencing methods and a bioassay to confirm phenotypic resistance, Bright et al demonstrated resistance in 92% of 209 isolates submitted to the CDC during the first few months of the 2005-2006 influenza season. Based on an earlier analysis of 120 of these influenza A(H3N2) isolates, the CDC issued a Health Alert on January 14, 2006, and recommended that neither amantadine nor rimantadine should be used for the treatment or prophylaxis of influenza A infections in the United States for the remainder of the 2005-2006 influenza season. The resistance pattern they described extends beyond the United States: according to Bright et al, 43 of 47 isolates (91%) recently tested in Canada are resistant to adamantanes, and isolates from the 2004-2005 influenza season from some regions of Asia have shown high rates of resistance to adamantanes. The startling prevalence of resistance raises obvious questions: what happened, what does this mean, and what are physicians, other health care professionals, and public health officials, individually and collectively, going to do? The answers are in the epidemiology. The rate of adamantane resistance began to increase in Asia in the 1997-1998 influenza season and increased markedly in China to 57.5% in 2002-2003 and 73.8% in 2003-2004. Misuse of adamantanes most likely contributed to this rapid increase in resistance. In China, Russia, and some other countries, amantadine and rimantadine are both available without a prescription and are included in over-the-counter “antiflu” and “cold” preparations at a range of doses. In North America, the increase in resistance began about 5 years after the initial increase in Asia. In the United States, resis-