Antiviral Research 49 (2001) 147–156 www.elsevier.com/locate/antiviral Review Position statement: global neuraminidase inhibitor susceptibility network Maria Zambon a,1, Frederick G. Hayden b,*,1 (On behalf of the Global Neuraminidase Inhibitor Susceptibility Network) a Public Health Laboratory Ser6ice, London, UK b Uni6ersity of Virginia Health Sciences Center, Box 800473, Department of Internal Medicine, Charlottes6ille, VA 22908, USA Received 21 December 2000; accepted 11 January 2001 1. Introduction of drug resistance in influenza viruses following the introduction of the influenza neuraminidase The global Neuraminidase Inhibitor Suscepti- inhibitor (NI) class of antiviral agents. The first bility Network (NISN) was established in 1999 to meeting was held on December 13, 1999, and address public health and regulatory concerns re- subsequent meetings were conducted on June 30, garding the potential emergence and consequences 2000 and September 23, 2000. The Network ini- tially included investigators and public health per- * Corresponding author. Tel.: +1-804-9245059; fax: +1- sons with demonstrated interest in neuraminidase 804-9249065. inhibitors or anti-viral resistance and has ex- E-mail address: [email protected] (F. G. Hayden). panded to include representatives of each of the 1 Other current Network members: Michele Aymard, Uni- four WHO global influenza reference laboratories versite Claude Bernard, Lyon, France; Alan Hay, National and scientists from regions of the world where Institute for Medical Research, Mill Hill, London, UK; Alan Hampson, WHO Collaborating Centre for Reference and increasing use of these drugs is anticipated. The Research on Influenza, Melbourne, Australia; Alexander Network’s activities are funded currently by two Klimov, Centers for Disease Control, Atlanta, GA; Jenny corporate sponsors, GlaxoSmithKline and Hoff- McKimm-Breschkin, Biomolecular Research Institute, Mel- man-LaRoche, and company representatives are bourne, Australia; Arnold Monto, University of Michigan, invited to attend meetings as observers. However, Ann Arbor, MI; Masato Tashiro, WHO Collaborating Center for Influenza, Tokyo, Japan; Robert Webster, St. Jude Chil- the deliberations and actions of the Network itself dren’s Research Hospital, Memphis, TN. Daniel Lavanchy, are intended to be independent of any company, Coordinator, Epidemic Disease Control, Department of Com- and the core working group of the Network is municable Disease Surveillance and Response, WHO, Geneva, composed of scientists drawn either from aca- Switzerland is an advisor to the Network. Pharmaceutical sponsor observers include Margaret Tisdale, Rob Fenton, and demic or public health sectors. The broad objec- Michael Elliot (GlaxoWellcome) and Noel Roberts, Emma tives of the Network are to: (1) provide a coherent Covington, and Penelope Ward (Hoffman-LaRoche). approach to global NI resistance monitoring from 0166-3542/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved. PII: S0166-3542(01)00124-3 148 M. Zambon, F. G. Hayden / Anti6iral Research 49 (2001) 147–156 both public health and research perspectives; (2) are rooted in the accumulated experiences with the examine data from the scientific literature and from first class of anti-influenza agents, the M2 protein specific monitoring programs to make recommen- inhibitors amantadine and rimantadine, resistance dations for appropriate general strategies and spe- to drugs for HIV infection, and on the significant cific assays for monitoring resistance; (3) conduct problems associated with the emergence of antimi- longitudinal prospective surveillance for resistance crobial resistance in non-viral pathogens (pyogenic emergence through a link with the existing WHO bacteria, tuberculosis, malaria). Indeed, the naivety Global Influenza Surveillance Network; and (4) of the mid 20th century towards the conquering of communicate this information to the scientific infectious diseases has been replaced by mature community. In particular, the Network will select realism and respect for the mutability of microbial appropriate monitoring assays, determine the NI pathogens. susceptibility of representative clinical isolates (\ The experience with the M2 inhibitors, aman- 1000) collected before introduction of these drugs, tadine and rimantadine, illustrates the potential of and continue surveillance for resistance emergence influenza A viruses to rapidly develop drug resis- on a sustained basis (\5 years). The four WHO tance in the clinical setting (reviewed in Hayden, Collaborating Centers for Reference and Research 1996). The basis of resistance is point mutations in on Influenza will continue to provide the Network the M gene with corresponding single amino acid with viruses isolated in the post-licensing period. changes in the M2 protein that confer high level The current position paper of the Network covers cross-resistance between the drugs in vitro (Hay, the rationale, mechanisms of NI resistance includ- 1992; Belshe et al., 1988). Rarely, amantadine-resis- tant variants predominate in clinical isolates. How- ing phenotypic and genotypic characterization, ever, resistant variants are present in low currently recommended approaches and assays, concentration in virus samples and emerge within and future directions for neuraminidase inhibitor 2 to 5 days of initiating drug therapy in 30% of resistance monitoring in influenza viruses. This treated immunocompetent adults and children consensus statement derives from deliberations of (Belshe et al., 1988; Hayden et al., 1991; Hall et al., the group over the past 18 months and is intended 1987). More prolonged virus replication, as seen in to provide the foundation for subsequent commu- immunocompromised hosts, is associated with high nications which will deal with assay selection and frequencies of resistance emergence (Englund et al., validation, statistical considerations, baseline sus- 1998). Amantadine-resistant variants are geneti- ceptibility results, and surveillance data. cally stable, are not reduced in infectivity or viru- lence in animal models, cause typical influenza illness in humans, and are transmissible from 2. Antimicrobial resistance person to person under conditions of close contact. Spread of these resistant variants has caused fail- The emergence and societal implications of an- ures of drug prophylaxis in households and nursing timicrobial resistance has received increasing atten- homes (Hayden et al., 1989; Degelau et al., 1992; tion in recent years. The development of effective Mast et al., 1991). Thus, amantadine/rimantadine- antiviral drugs is an important scientific achieve- resistant variants possess the biological properties ment and has led to the licensing and use of over associated with clinically, and possibly epidemio- two dozen specific antiviral drugs in the developed logically, important drug resistance. To date the use world in the last two decades. The most recently of amantadine and rimantadine has been relatively licensed class of antiviral compounds, the neu- limited and has been associated uncommonly (B raminidase inhibitors of influenza viruses 1%) with recovery of resistant variants in the (zanamivir [Relenza™, GlaxoSmithKline] and os- general population (Ziegler et al., 1999). eltamivir [Tamiflu™, Roche]) has sparked opti- In part because of this experience, the introduc- mism but also controversy. Inevitably, the licensing tion of the neuraminidase inhibitors (NI) requires of new antiviral drugs provokes concerns about the the establishment of longitudinal surveillance to development of antiviral resistance. Such concerns determine the possible emergence, clinical impor- M. Zambon, F. G. Hayden / Anti6iral Research 49 (2001) 147–156 149 tance, and epidemiological consequences of resis- technical problems which limit the usefulness of tant strains, particularly in patient populations many current assays (e.g. cell culture-based phe- under-represented in clinical trials. This necessity notypic assays). may be translated into regulatory requirements Clearly, there is a need to determine the poten- following the introduction of new antiviral drugs. tial for development of resistance to NIs during Although there has been limitation on public sec- wide spread use for the treatment of acute influ- tor prescription of NIs in several European coun- enza, and the possible consequences should resis- tries because of reimbursement issues (NICE, tance develop. Key questions include the 1999), there was extensive prescribing in primary frequency and rapidity of resistance development; care in the USA and to a lesser extent in western the genetic stability, virulence and transmissibility Europe during the 1999–2000 influenza season. of any resistant strains; and whether alterations in Thus the possibility of emergence of antiviral drug susceptibility result in antigenic changes in resistance is realised for the first time as the drugs circulating strains. Answers to these questions are used outside of the clinical trials setting. With may be technically challenging to achieve. Assess- the anticipated extension of NI availability to ment of NI resistance should therefore include: other countries and increased awareness of their Use of suitable, validated assays for resistance value, it is expected that use will continue to testing with appropriate controls. Currently, increase, and with it the potential for drug pres- measuring inhibition of NA enzymatic activity sure to select resistant variants. in vitro is the most sensitive and