 |
|
The Evolution of Influenza Resistance and Treatment
David M. Weinstock, MD;
Gianna Zuccotti, MD
JAMA. 2009;301(10):(doi:10.1001/jama.2009.324).
In February 2006, the US Centers for Disease Control and Prevention (CDC) reported that 92.3% of the circulating influenza A(H3N2) at that time was resistant to the adamantanes (amantadine and ramantidine), 1 of 2 pharmacological classes available for the treatment of influenza.1 The resistant viruses harbored an S31N amino acid substitution in the influenza M2 protein that confers resistance but does not affect virulence. Although resistance to adamantanes increased to 14.5% in the prior year,2 the dramatic increase in 2005-2006 came as a shock to both the medical and scientific communities and the public.3
At the time, it was confidently held that influenza was unlikely to develop similar resistance to neuraminidase inhibitors (oseltamivir and zanamivir), the second class of influenza-directed agents.4-5 The neuraminidase inhibitors were designed with an understanding of the structural interaction between neuraminidase and its natural substrate sialic acid. Because these antivirals closely resemble sialic acid, any mutation within neuraminidase that reduced affinity for the pharmacological inhibitors was believed to invariably compromise viral fitness.
The available evidence supported this notion. In vitro selection of neuraminidase inhibitor–resistant mutants is generally difficult, which argues that resistance-associated mutations compromise viability. In a 2002 study,5 the H274Y (histidine-to-tyrosine at codon 274 in N2 nomenclature) mutation in neuraminidase significantly reduced the replication of H1N1 strains and their virulence in mice and ferrets, regardless of whether the mutation was derived by site-directed mutagenesis, through serial passage in culture under drug pressure or during treatment in humans. In clinical trials of oseltamivir, resistance was relatively rare (0.32% in adults and 4.1% in children)4 and the few oseltamivir-resistant isolates recovered during treatment seemed clinically unimportant. As recently as the 2006-2007 influenza season, transmission of oseltamivir-resistant influenza was exceedingly uncommon.6-7
Nevertheless, studies by Dharan et al8 and Gooskens et al9 in this issue of JAMA demonstrate that change was in the air. On December 19, 2008, the CDC reported that nearly all cases of influenza A(H1N1), the predominant circulating strain for the season thus far, are resistant to oseltamivir.10 Dharan et al8 expand that analysis to 268 H1N1 isolates, of which 264 (98.5%) are oseltamivir resistant. Of all influenza isolates typed by the CDC this season, approximately 55% are oseltamivir-resistant H1N1.11 These isolates carry the neuraminidase H274Y mutation that confers resistance to oseltamivir but does not affect susceptibility to zanamivir. The oseltamivir-resistant H1N1, which is now circulating on all major continents,12 is similar to the A/Brisbane/59/2007 strain that circulated during the 2007-2008 season13 and is included in the 2008-2009 influenza vaccines.
The studies by Dharan et al8 and Gooskens et al9 dispel the notion that oseltamivir resistance compromises virulence. Four of the 142 patients (2.8%) with oseltamivir-resistant H1N1 isolates submitted to the CDC during the 2007-2008 influenza season died of influenza. In a comparison between 99 oseltamivir-resistant cases and 182 matched oseltamivir-susceptible cases, there were no discernible differences in the predisposing factors, clinical symptoms, or complications related to influenza infection.
Gooskens et al9 describe a typical nosocomial outbreak of influenza at their center during the 2007-2008 season with an alarming new wrinkle—the outbreak strain was oseltamivir-resistant H1N1. At least 3 patients who were immunocompromised acquired influenza from the index case, each developed pneumonia and 2 died. Five health care workers also developed an influenza-like illness but were not tested for H1N1.
The widespread belief that oseltamivir would retain activity against epidemic influenza strains has crumbled, but this should come as no surprise. Global and regional surveillance networks have tracked the incidence of neuraminidase-inhibitor resistance among circulating influenza for several years. The available epidemiology indicated that oseltamivir resistance was increasing on a trajectory that precisely paralleled the surge of adamantane resistance 3 years earlier (Figure). During the 2007-2008 season, 10.9% of H1N1 viruses tested in the United States were oseltamivir resistant.13 Even higher rates were reported elsewhere, including Canada (26%), Europe (25%), and Hong Kong (12%).14 The highest rate of oseltamivir resistance (67.3%) was in Norway, a country where oseltamivir can only be acquired with a prescription and is rarely used.14 In a study of the cases in Norway, oseltamivir resistance did not affect the phenotype of influenza infection,15 similar to the study by Dharan et al.8 During the summer of 2008, H1N1 strains related to A/Brisbane/59/2007 predominated in the Southern hemisphere and 100% of the H1N1 isolates in South Africa were resistant to oseltamivir.14
|
|
|
|
Figure. Frequency of Resistance to Adamantane Among Influenza A(H1N1) Isolates and Oseltamivir Among Influenza A(H3N2) Isolates Submitted to the Centers for Disease Control and Prevention in the United States
Frequency of resistance among isolates submitted to the US Centers for Disease Control and Prevention.1-2,7-8,11, 13 NA indicates not available. The number of H1N1 isolates tested for oseltamivir resistance in 2005-2006 and the number of adamantane resistant H3N2 isolates in 2006-2007 were not available. The oseltamivir resistance before the 2007-2008 influenza season was less than 1%.
|
|
|
If the epidemiology was not sufficiently compelling, newer studies of H1N1 virulence have confirmed that H274Y does not necessarily compromise substrate binding, enzyme activity, viral replication, or virulence in animal models.16-18 Binding of neuraminidase to oseltamivir involves a conformational change in the side chain of the glutamic acid residue at codon 276 (E276). Importantly, the same conformational change is not required for zanamivir binding. Substitution of a tyrosine, which is bulkier than histidine, at codon 274 pushes the carboxyl group of E276 further into the binding site.18 Group 1 neuraminidases (N1, N4, N5, N8) have another tyrosine below the active site at codon 252. The combination of the 2 tyrosines (Y252 and Y274) disrupts the pocket that normally accommodates oseltamivir. In contrast, group 2 neuraminidases (N2, N3, N6, N7, N9) have a smaller threonine at codon 252 and can still accommodate oseltamivir in the binding pocket in the presence of Y274.18
The structural study offers several insights. First, resistance to oseltamivir among strains with group 1 neuraminidases was predictable. Second, this resistance was less likely to affect strains with group 2 neuraminidases, consistent with the complete susceptibility of H3N2 strains to oseltamivir this season.11 Third, zanamivir will maintain activity against some oseltamivir-resistant strains. Fourth, new inhibitors can be intelligently crafted to overcome specific mutations within neuraminidase.19 Fifth, oseltamivir resistance is likely to develop during the treatment of other N1-containing strains, including avian influenza A(H5N1).20 Thus, stockpiles to mitigate an influenza pandemic should not be limited to oseltamivir.
For an influenza strain to achieve global predominance, it must outcompete other strains. A study by Rameix-Welti et al16 supports the intriguing notion that the H274Y mutation provides a competitive advantage to the circulating H1N1 strain that is completely independent of its effect on oseltamivir. The neuraminidase from this strain is distinguished by a unique combination of at least 8 amino acid substitutions, exclusive of H274Y. Both the enzymatic activity and substrate affinity of this neuraminidase (with or without H274Y) are significantly higher compared with neuraminidase proteins from strains that circulated during previous years, although the affinity is reduced somewhat by the H274Y mutation.16 The latter point is especially noteworthy. The "fitness" of an influenza strain is affected by the functional balance between its hemagglutinin and neuraminidase proteins. The additional mutations within the circulating H1N1 strain greatly enhance neuraminidase function, which may throw off the balance. The H274Y mutation, by attenuating neuraminidase substrate affinity, could bring the relative activities of hemagglutinin and neuraminidase back into balance, thereby enhancing the strain's overall fitness.16
In an accompanying editorial to the 2006 report of adamantane resistance, we stated that "an axiom of good infectious disease practice [is that] inappropriate use of anti-infectives invariably results in resistance."3 But if drug-resistant strains can outcompete susceptible ones in the absence of anti-infective pressure, it follows that for this organism and this agent, the most basic "truth" about anti-infective resistance may be wrong.
Between 2002 and 2007, the antigenic and genetic evolution of influenza A(H3N2) at distant locations around the world was remarkably homogenous.21 This homogeneity supports a model in which epidemic viruses circulate globally rather than persisting within a region and evolving locally. In fact, there is a continuous network of temporally overlapping H3N2 epidemics in East and Southeast Asia. The epidemics within temperate regions are seeded from this network, generally first in Oceania, North America and Europe, and then later in South America.21 Reseeding back into East and Southeast Asia is uncommon, such that once H3N2 strains leave East and Southeast Asia they rarely contribute to viral evolution. If the global dissemination of H1N1 follows similar patterns to those for H3N2, the widespread use of oseltamivir is not the cause of widespread resistance. Instead, oseltamivir use outside of East and Southeast Asia, appropriate or not, is unlikely to affect the epidemics within East and Southeast Asia, and thus the next wave of global dissemination.
This new understanding of influenza dynamics helps to explain the discordance between regional frequencies of oseltamivir resistance and oseltamivir use during the 2007-2008 influenza season. For example, oseltamivir resistance among H1N1 strains was 67.3% in Norway, where oseltamivir is rarely used, but was only 3% in Japan, the country with the highest per capita oseltamivir use.14
While rates of oseltamivir-resistant H1N1 remain high, patients who are candidates for influenza treatment or chemoprophylaxis should receive either zanamivir or the combination of oseltamivir and rimantidine (or amantidine, if rimantidine is not available).10 Essentially all influenza A(H3N2) strains circulating this year are resistant to adamantanes but susceptible to both neuraminidase inhibitors. Thus, single-agent oseltamivir is only appropriate for the rare patient with infection that is known to be caused by influenza A(H3N2) or influenza B.
Considering the need for dual-therapy or inhaled zanamivir, which can be difficult to administer and tolerate, the risk/benefit calculus for empirically treating a healthy adult with an influenza-like illness needs to be assessed on a case-by-case basis. Rapid assays to diagnose influenza are insensitive, so the decision should primarily rest on the patient's risk for influenza-related complications and the local influenza epidemiology.
Vaccination remains the cornerstone of global efforts to control the dissemination of influenza. A study by Wang et al22 provides some additional insight into the absolute and relative benefits of the trivalent inactivated vaccine (TIV) and live attenuated influenza vaccine (LAIV). The authors reviewed the health care encounters for influenza and pneumonia among more than a million active-duty members of the US military between 2004 and 2007. In this young healthy population with annual vaccination rates between 50% and 80%, TIV was associated with reduced influenza and pneumonia encounters by 30% to 55% compared with placebo. Those outcomes were similar to previous studies and were better than LAIV, which only outperformed placebo for vaccinees who were relatively vaccine-naive.
The authors speculate that because the attenuated vaccine strains in LAIV must replicate within the recipient to effectively stimulate influenza-specific immunity, the presence of neutralizing antibodies from either previous vaccination or natural infection may prevent this replication and thereby compromise the efficacy of LAIV. Both a randomized study23-24 and a meta-analysis25 have compared TIV with LAIV in adults and both reported an advantage for TIV. Not surprisingly, LAIV is equally or possibly more efficacious in children, who presumably lack preexisting influenza-specific immunity.26-27
How these new findings by Wang et al22 will affect recommendations for influenza vaccination remain to be seen. During typical influenza seasons, it may be prudent to use TIV in patients who were vaccinated at least once in the previous 2 years. On the other hand, live attenuated vaccines against pandemic strains may be more effective than inactivated vaccines, as the population will presumably lack preexisting immunity.
The understanding of influenza biology and epidemiology has advanced markedly; however, the global dissemination of oseltamivir-resistant influenza came as a great surprise. Undoubtedly, new surprises await in the perpetual struggle with influenza as one thing is certain—the organism will continue to evolve. Anticipating the rapid and endless changes in influenza biology and dynamics will require faster diagnostics to molecularly characterize specimens, extensive surveillance among humans and animals, and more rapid and malleable systems for translating basic and epidemiological discoveries into clinically applicable interventions. For now, the best tools to mitigate influenza infection are tried-and-true—vaccination, social distancing, hand washing, and common sense.
AUTHOR INFORMATION
Corresponding Author: David M. Weinstock, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, DA510B, Boston, MA 02115 (davidm_weinstock{at}dfci.harvard.edu).
Published Online: March 2, 2009 (doi:10.1001/jama.2009.324).
Financial Disclosures: None reported.
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
Author Affiliations: Department of Medical Oncology, Dana-Farber Cancer Institute (Dr Weinstock); Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital (Dr Zuccotti); and Harvard Medical School (Drs Weinstock and Zuccotti), Boston, Massachusetts. Dr Zuccotti is Contributing Editor, JAMA, Chicago, Illinois.
REFERENCES
|
1. Bright RA, Shay DK, Shu B, Cox NJ, Klimov AI. Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States. JAMA. 2006;295(8):891-894.
FREE FULL TEXT
2. Bright RA, Medina MJ, Xu X; et al. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet. 2005;366(9492):1175-1181.
PUBMED
3. Weinstock DM, Zuccotti G. Adamantane resistance in influenza A. JAMA. 2006;295(8):934-936.
FREE FULL TEXT
4. Aoki FY, Boivin G, Roberts N. Influenza virus susceptibility and resistance to oseltamivir. Antivir Ther. 2007;12(4 pt B):603-616.
PUBMED
5. Ives JA, Carr JA, Mendel DB; et al. The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo. Antiviral Res. 2002;55(2):307-317.
PUBMED
6. Monto AS, McKimm-Breschkin JL, Macken C; et al. Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use. Antimicrob Agents Chemother. 2006;50(7):2395-2402.
FREE FULL TEXT
7. Sheu TG, Deyde VM, Okomo-Adhiambo M; et al. Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008. Antimicrob Agents Chemother. 2008;52(9):3284-3292.
FREE FULL TEXT
8. Dharan NJ, Gubareva LV, Meyer JJ; et al, Oseltamivir-Resistance Working Group. Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States. JAMA. 2009;301(10):(doi:10.1001/jama.2009.294).9. Gooskens J, Jonges M, Claas ECJ, Meijer A, van den Broek PJ, Kroes ACM. Morbidity and mortality associated with nosocomial transmission of oseltamivir-resistant influenza A(H1N1) virus. JAMA. 2009;301(10):(doi:10.1001/jama.2009.297).10. Centers for Disease Control and Prevention. CDC Issues Interim Recommendations for the Use of Influenza Antiviral Medications in the Setting of Oseltamivir Resistance among Circulating Influenza A(H1N1) Viruses, 2008-09 Influenza Season. http://www2a.cdc.gov/HAN/ArchiveSys/ViewMsgV.asp?AlertNum=00279. Accessed February 12, 2009.11. Centers for Disease Control and Prevention. FluView: 2008-2009 Influenza Season Week ending January 31, 2009. http://www.cdc.gov/flu/weekly/.12. World Health Organization. Influenza A(H1N1) virus resistance to oseltamivir–2008/2009 influenza season, 22 January 2009. http://www.who.int/csr/disease/influenza/H1N120090122_final.pdf. Accessed February 12, 2009.13. Centers for Disease Control and Prevention (CDC). Influenza activity—United States and worldwide, 2007-08 season. MMWR Morb Mortal Wkly Rep. 2008;57(25):692-697.
PUBMED
14. World Health Organization. Table: Influenza A(H1N1) Virus Resistance to Oseltamivir: Last Quarter 2007 to 2 June 2008 (Update 13 June 2008). http://www.who.int/csr/disease/influenza/ResistanceTable200806013.pdf. Accessed February 12, 2009.15. Hauge SH, Dudman S, Borgen K, Lackenby A, Hungnes O. Oseltamivir-resistant influenza viruses A (H1N1), Norway, 2007-08. Emerg Infect Dis. 2009;15(2):155-162.
PUBMED
16. Rameix-Welti MA, Enouf V, Cuvelier F, Jeannin P, van der Werf S. Enzymatic properties of the neuraminidase of seasonal H1N1 influenza viruses provide insights for the emergence of natural resistance to oseltamivir. PLoS Pathog. 2008;4(7):e1000103.
PUBMED
17. Baz M, Abed Y, Nehme B, Boivin G. Activity of the oral neuraminidase inhibitor A-322278 against the oseltamivir-resistant H274Y (A/H1N1) influenza virus mutant in mice. Antimicrob Agents Chemother. 2009;53(2):791-793.
FREE FULL TEXT
18. Collins PJ, Haire LF, Lin YP; et al. Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants. Nature. 2008;453(7199):1258-1261.
PUBMED
19. Hayden F. Developing new antiviral agents for influenza treatment: what does the future hold? Clin Infect Dis. 2009;48(suppl 1):S3-S13.
PUBMED
20. Abdel-Ghafar AN, Chotpitayasunondh T, Gao Z; et al, Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection With Avian Influenza A (H5N1) Virus. Update on avian influenza A (H5N1) virus infection in humans. N Engl J Med. 2008;358(3):261-273.
FREE FULL TEXT
21. Russell CA, Jones TC, Barr IG; et al. The global circulation of seasonal influenza A (H3N2) viruses. Science. 2008;320(5874):340-346.
FREE FULL TEXT
22. Wang Z, Tobler S, Roayaei J, Eick A. Live attenuated or inactivated influenza vaccines and medical encounters for respiratory illnesses among US military personnel. JAMA. 2009;301(9):945-953.
FREE FULL TEXT
23. Ohmit SE, Victor JC, Rotthoff JR; et al. Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med. 2006;355(24):2513-2522.
FREE FULL TEXT
24. Ohmit SE, Victor JC, Teich ER; et al. Prevention of symptomatic seasonal influenza in 2005-2006 by inactivated and live attenuated vaccines. J Infect Dis. 2008;198(3):312-317.
PUBMED
25. Jefferson TO, Rivetti D, Di Pietrantonj C, Rivetti A, Demicheli V. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev. 2007;(2):CD001269.
PUBMED
26. Jefferson T, Rivetti A, Harnden A, Di Pietrantonj C, Demicheli V. Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev. 2008;(2):CD004879.
PUBMED
27. Belshe RB, Edwards KM, Vesikari T; et al, CAIV-T Comparative Efficacy Study Group. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med. 2007;356(7):685-696.
FREE FULL TEXT
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
RELATED ARTICLES
Infections With Oseltamivir-Resistant Influenza A(H1N1) Virus in the United States
Nila J. Dharan, Larisa V. Gubareva, John J. Meyer, Margaret Okomo-Adhiambo, Reginald C. McClinton, Steven A. Marshall, Kirsten St. George, Scott Epperson, Lynnette Brammer, Alexander I. Klimov, Joseph S. Bresee, Alicia M. Fry, and for the Oseltamivir-Resistance Working Group
JAMA. 2009;301(10):1034-1041.
ABSTRACT
| FULL TEXT
Morbidity and Mortality Associated With Nosocomial Transmission of Oseltamivir- Resistant Influenza A(H1N1) Virus
Jairo Gooskens, Marcel Jonges, Eric C. J. Claas, Adam Meijer, Peterhans J. van den Broek, and Aloys C. M. Kroes
JAMA. 2009;301(10):1042-1046.
ABSTRACT
| FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Influenza in long-term care facilities: Preventable, detectable, treatable
Mossad
Cleveland Clinic Journal of Medicine 2009;76:513-521.
ABSTRACT
| FULL TEXT
Forever Unprepared -- The Predictable Unpredictability of Pathogens
Sepkowitz
NEJM 2009;361:120-121.
FULL TEXT
Oseltamivir-Resistant Influenza A Virus
JWatch General 2009;2009:4-4.
FULL TEXT
Influenza: Problems with Prevention and Treatment
JWatch Infect. Diseases 2009;2009:1-1.
FULL TEXT
|
