Elsevier

The Lancet

Volume 366, Issue 9492, 1–7 October 2005, Pages 1175-1181
The Lancet

Articles
Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern

https://doi.org/10.1016/S0140-6736(05)67338-2Get rights and content

Summary

Background

Adamantanes have been used to treat influenza A virus infections for many years. Studies have shown a low incidence of resistance to these drugs among circulating influenza viruses; however, their use is rising worldwide and drug resistance has been reported among influenza A (H5N1) viruses isolated from poultry and human beings in Asia. We sought to assess adamantane resistance among influenza A viruses isolated during the past decade from countries participating in WHO's global influenza surveillance network.

Methods

We analysed data for influenza field isolates that were obtained worldwide and submitted to the WHO Collaborating Center for Influenza at the US Centers for Disease Control and Prevention between Oct 1, 1994, and Mar 31, 2005. We used pyrosequencing, confirmatory sequence analysis, and phenotypic testing to detect drug resistance among circulating influenza A H3N2 (n=6524), H1N1 (n=589), and H1N2 (n=83) viruses.

Findings

More than 7000 influenza A field isolates were screened for specific aminoacid substitutions in the M2 gene known to confer drug resistance. During the decade of surveillance a significant increase in drug resistance was noted, from 0·4% in 1994–1995 to 12·3% in 2003–2004. This increase in the proportion of resistant viruses was weighted heavily by those obtained from Asia with 61% of resistant viruses isolated since 2003 being from people in Asia.

Interpretation

Our data raise concerns about the appropriate use of adamantanes and draw attention to the importance of tracking the emergence and spread of drug-resistant influenza A viruses.

Introduction

Adamantane derivatives, such as amantadine and rimantadine, have been used successfully for the prevention and treatment of influenza A virus infection for more than 30 years.1, 2, 3 These drugs, known as M2 channel blockers, inhibit influenza A virus replication by blocking the M2 protein ion channel thereby preventing fusion of the virus and host-cell membranes and the release of viral RNA into the cytoplasm of infected cells.4 The prophylactic effect of these drugs varies between 80% and 90%, and the drugs can reduce the duration of illness by about 1·5 days if given within 48 h of infection.5, 6, 7

Human and animal studies have shown the frequent occurrence of amantadine-resistant influenza viruses after exposure to the drug, and drug-resistant viruses can be transmitted from one person to another without apparent loss of pathogenicity.1, 8, 9, 10, 11 Additionally, complete cross-resistance between amantadine and rimantadine has been shown.1 The genetic basis for resistance to these drugs has been well characterised and is associated with an aminoacid substitution at position 26, 27, 30, 31, or 34 in the transmembrane region of the M2 protein.1, 12 Most drug-resistant influenza viruses contain one of these aminoacid changes, but variants with dual mutations have also been described.1, 9 Resistance to adamantanes has been reported predominantly in people in semi-closed settings (eg, nursing home facilities, paediatric wards, and family households) where antiviral treatment was used.8, 13, 14, 15, 16, 17, 18, 19, 20

Since 1991, drug-susceptibility surveillance has been undertaken routinely in the characterisation of influenza virus isolates submitted to the WHO Collaborating Center for Influenza at the US Centers for Disease Control and Prevention. Previous surveillance studies have identified a low incidence of resistance to amantadine and rimantadine (approximately 1%) among circulating influenza viruses. However, 10 years have elapsed since the last comprehensive global study of resistance to these drugs was published.21, 22, 23, 24 Furthermore, influenza A (H5N1) viruses isolated from both human beings and avian sources in southeast Asia since 2003 have an S31N aminoacid substitution in the M2 protein and, thus, are resistant to amantadine and rimantadine.25, 26 In this study we report results of a surveillance study for resistance to adamantanes among circulating influenza viruses collected worldwide between Oct 1, 1994, and Mar 31, 2005.

Section snippets

Viruses

Worldwide data for influenza field isolates that were obtained and submitted to the WHO Collaborating Center for Influenza at the US Centers for Disease Control and Prevention (CDC) between Oct 1, 1994, and Mar 31, 2005, were included in this study. Viruses were identified from individuals of various age, sex, and geographic groups around the world without any demographic specification or bias from the CDC. The selection of samples submitted or screened for drug resistance was random and

Results

In all, 6524 influenza A (H3N2) viruses were screened for specific mutations known to correlate with resistance to amantadine and rimantadine (table 1). All M2 sequences were typical for human influenza viruses and different from sequences known for avian or swine viruses. Overall, 392 (6%) H3N2 viruses contained an aminoacid substitution in the M2 protein that correlates with drug resistance: L26F: 3 (0·8%); V27A: 3 (0·8%); A30T: 1 (0·2%); and S31N: 385 (98·2%). 84% of resistant viruses were

Discussion

This study reveals an alarming increase in the incidence of amantadine-resistant and rimantadine-resistant H3N2 influenza A viruses over the past decade. Our study, which assessed more than 7000 influenza A viruses obtained worldwide, is the largest and most comprehensive report on adamantane resistance to date. The last major surveillance study by Ziegler and co-workers23 showed a drug-resistance frequency of 0·8% among H1N1 and H3N2 viruses and identified only 16 drug-resistant viruses

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