JAC Advance Access originally published online on September 6, 2006
Journal of Antimicrobial Chemotherapy 2006 58(5):911-915; doi:10.1093/jac/dkl376
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Leading article |
Use of neuraminidase inhibitors to combat pandemic influenza
Infectious Diseases Unit, Leicester Royal Infirmary Leicester LE1 5WW, UK
*Corresponding author. Tel: +44-116-258-6952; Fax: +44-116-258-5067; E-mail: iain.stephenson{at}uhl-tr.nhs.uk
 |
Abstract |
|---|
 Top Abstract IntroductionAntiviral treatment of influenzaNeuraminidase inhibitorsCombating pandemic influenzaConcluding remarksTransparency declarationsReferences |
|---|
Since the last influenza pandemic in 1968, neuraminidase (NA) inhibitors have been licensed for the treatment and prophylaxis of seasonal influenza. Continuing outbreaks of highly pathogenic avian influenza H5N1 since 2004 have focused attention on the timing of the next pandemic and preparedness plans. Although immunization is the principal means of influenza prophylaxis, a well-matched efficacious vaccine is unlikely to be widely available for several months following the emergence of the pandemic strain. NA inhibitors could be used to contain and eliminate an emerging pandemic virus at source. If unsuccessful, they could still play a crucial role in reducing the medical impact of pandemic influenza as it spreads through countries. Accordingly, many authorities are creating stockpiles of NA inhibitors. However, the use of stockpiled drugs for treatment or prophylaxis, the rapid delivery to newly diagnosed cases and unknown characteristics of an emergent pandemic strain pose significant challenges to determining optimal use of stockpiles.
Keywords: resistance , treatment , prophylaxis
|
Introduction |
|---|
|
TopAbstractIntroductionAntiviral treatment of influenzaNeuraminidase inhibitorsCombating pandemic influenzaConcluding remarksTransparency declarationsReferences |
|---|
The world may be on the brink of the next influenza pandemic. Highly pathogenic avian influenza (H5N1) was first associated with severe respiratory disease among humans in Hong Kong during 1997.1 Although infrequent sporadic outbreaks of avian influenza have affected poultry flocks in several countries over many years, unprecedented multiple outbreaks of H5N1 have occurred since 2004 among poultry and migratory birds throughout Asia, and have recently extended their geographical range into Europe and Africa.2 More than 230 human infections have occurred during this outbreak, with more deaths in 2006 so far than the whole of 2005.2 Molecular analyses of H5N1 viruses isolated since 2004 reveal at least two distinct sublineages.3 Clade 1 H5N1 viruses circulate in the Indochina peninsula, whereas isolates from Indonesia and some other countries belong to a more divergent clade 2 group. Recent human cases of H5N1 infection include viruses of both sublineages, with case-fatality rates exceeding 50%.2 The A/H1N1 influenza virus responsible for the 1918 pandemic was derived from an avian influenza virus,4 and with a case-fatality rate of 2–3% was responsible for up to 50 million deaths worldwide. An H5N1 pandemic could potentially be far worse.
When the next pandemic emerges, vaccination will play an important role. However, pandemic vaccine development has been slow.5 Although worldwide demand for seasonal influenza vaccine has never been higher, global vaccine manufacturing capacity is limited and is unlikely to meet the demands of a pandemic threat. Therefore, specific anti-influenza chemoprophylaxis and treatment are useful additions to vaccination that could reduce the medical and socioeconomic impact of pandemic influenza.
|
Antiviral treatment of influenza |
|---|
|
TopAbstractIntroductionAntiviral treatment of influenzaNeuraminidase inhibitorsCombating pandemic influenzaConcluding remarksTransparency declarationsReferences |
|---|
There are two classes of specific antiviral agents against influenza: M2 channel inhibitors (rimantadine and amantadine) and neuraminidase (NA) inhibitors (zanamivir and oseltamivir). M2 inhibitors are limited in clinical practice by their toxicity, lack of activity against influenza B and rapid emergence of drug resistance.6 Drug-resistant variants appear following 48–72 h of treatment, and transmission of drug-resistant virus from treated index cases to close contacts is responsible for failure of chemoprophylaxis during outbreaks. Rates of M2 inhibitor resistance among community isolates of A/H3N2 viruses have increased recently and exceeded 70% in China and Asia during 2004,7 and over 90% in the US during 2005–06.8 In addition, most of the recent H5N1 virus isolates from humans and birds exhibit genotypic resistance to M2 inhibitors.2,3 Thus, they are likely to be of limited use in an evolving H5 pandemic.
|
Neuraminidase inhibitors |
|---|
|
TopAbstractIntroductionAntiviral treatment of influenzaNeuraminidase inhibitorsCombating pandemic influenzaConcluding remarksTransparency declarationsReferences |
|---|
Mechanism of action
The NA is a good target for drug action, as it is essential for virus infectivity and has a highly conserved active site across influenza A and B viruses. Several highly selective competitive NA inhibitors have been developed that bind tightly to the active site. They inhibit release of new virion progeny from an infected cell, prevent digestion of neuraminic acid in mucus and reduce the ability of the virus to spread through the respiratory epithelium. Zanamivir, a dehydrated sialic acid derivative, and oseltamivir, the oral prodrug of the active oseltamivir carboxylate containing a cyclohexane ring structure, both entered clinical practice in 1999. Peramivir, a cyclopentane NA inhibitor, is currently in clinical development.
Spectrum of activity
NA inhibitors are effective against human and non-human subtypes of influenza A and B including the 1918 pandemic virus, amantadine-resistant strains and circulating highly pathogenic H5N1 isolates. In mouse studies, oseltamivir has a dose-dependent antiviral effect against H5N1 infection.9 However, higher doses and longer duration of treatment with oseltamivir are needed to treat mice infected with more recent human H5N1 isolates from 2004 compared with 1997 human H5N1 isolates.9 In vitro and animal studies using peramivir show its potential in inhibiting some zanamivir- and oseltamivir-resistant strains.10
Drug formulation and adverse effects
Zanamivir has poor bioavailability and must be administered directly into the respiratory tract via an inhalation device, posing concern in those who have poor inhaler technique, and in H5N1-infected patients where extrapulmonary virus replication has been detected. Side effects are rare, although it has been associated with bronchospasm. As oseltamivir is available as an oral formulation, it is a more attractive agent in pandemic planning, although uncertainties exist regarding absorption in critically ill patients. It is generally well tolerated, with its principal adverse reaction being minor gastrointestinal disturbance in <10% recipients.
Clinical use in seasonal influenza
Systematic review of randomized controlled trials,6,11 primarily recruiting healthy adults and children, supports the use of NA inhibitors in the treatment and prophylaxis of influenza A and B infections.
In acute influenza, treatment within 36–48 h of symptom onset with NA inhibitors is associated with significant reductions in median times to alleviation of symptoms and return to normal activities.11 Treatment of confirmed influenza among community-living patients significantly reduces the risk of lower respiratory complications, hospitalizations and related antibiotic use by 55%, 59% and 27%, respectively, when compared with placebo.12 In addition, treatment of community-dwelling and hospitalized patients with influenza with oseltamivir significantly reduces risk of death by 68–91%.13 The use of NA inhibitors in treatment does not impair induction of influenza-specific antibody responses.
Seasonal prophylaxis of 6–8 weeks duration with once daily oseltamivir or inhaled zanamivir is highly effective in preventing against influenza infection and illness in healthy adults, nursing home residents and immunocompromised children.6,11 When used for post-exposure prophylaxis for contacts in households with index cases of influenza, NA inhibitors reduce influenza infection by up to 90%, although the protective efficacy may be lower in younger children than adults.14
Resistance to NA inhibitors
NA inhibitors are less prone to selecting for drug resistance than M2 inhibitors, as the NA active site is highly conserved and essential for viral replication. Resistance has been studied in vitro by multiple passages of virus in tissue culture in the presence of drug. Two mechanisms of resistance have been identified: one involving NA mutations and the other involving mutations around the binding site of the viral haemagglutinin (HA). HA mutations decrease the binding of virus to host-cell sialic acid receptors, reducing dependency on NA activity necessary for release of new viruses from the cell. HA mutations are infrequent, and their clinical significance is unclear. NA resistance generally results from single amino acid changes in the active site. In order to accommodate the oseltamivir molecule, the active site undergoes rearrangement to create a pocket into which the drug will fit.15 Any of several mutations in the active site, typically R292K, N294S or H274Y, limit the formation of this pocket and prevents binding of oseltamivir. In contrast, zanamivir binds to the active site without the need for the formation of a pocket, so some oseltamivir-resistant strains remain susceptible to zanamivir. In animal models, viruses with NA mutations are associated with reduced infectivity and transmissibility compared with wild-type virus.16
To date, there is only one report of zanamivir resistance emerging with clinical use when an influenza B isolate with both HA and NA mutations was recovered from a paediatric bone marrow transplant recipient during 14 days of intravenous treatment.17 For oseltamivir, the frequency of drug resistance is higher. In treatment studies, the frequency of post-treatment viruses exhibiting resistance was greatest in children compared with adults, 
4% versus 0.4% of samples, respectively.18,19 However, worrying rates of resistance have been detected in Japanese children with A/H3N2 infection treated with oseltamivir.20 Of 50 children studied, nine (18%) had resistant viral clones mixed with wild-type virus detected after 4–6 days of oseltamivir. This may be related to suboptimal dosing as children in Japan receive 2 mg/kg of oseltamivir, in contrast to weight-tailored dosing (generally leading to higher doses) used elsewhere. During the 2003–04 influenza season in Japan, the country with the highest per capita use of oseltamivir, only 4 (0.4%) of 1180 A/H3N2 community isolates were shown to exhibit oseltamivir resistance, suggesting very low frequency of person-to-person transmission of drug-resistant viruses.21
Clinical use in avian influenza
Although the clinical benefits of treating seasonal influenza are established, care must be taken in extrapolating findings to those with primary H5N1 infection. With case-fatality rates exceeding 50%, H5N1 infection is clearly more aggressive than seasonal influenza. Clinical infection with H5N1 promotes excessive cytokine release and is associated with severe systemic disease including gastrointestinal symptoms, and there is evidence of extrapulmonary virus replication in mammals and humans.1,22–26 Intervention with standard doses of oseltamivir, if initiated late into the course of the illness, does not improve outcomes in patients with H5N1 infection.2,23 When administered within 48 h of symptom onset, six of eight Vietnamese patients with H5N1 infection achieved complete suppression of viral replication and survived.26 However, persistent viral replication was detected and drug-resistant H274Y variants were recovered from two patients, both of whom died, despite prompt oseltamivir treatment. The bioavailability and tissue penetration of oseltamivir administered to severely ill H5N1-infected patients is unknown. This has led to suggestions that increased doses and prolonged duration of oseltamivir for H5N1 infection should be considered.
Oseltamivir has been used as chemoprophylaxis against avian influenza among workers exposed during poultry farm A/H7 influenza outbreaks,27 although formal chemoprophylaxis studies have not been performed.
|
Combating pandemic influenza |
|---|
|
TopAbstractIntroductionAntiviral treatment of influenzaNeuraminidase inhibitorsCombating pandemic influenzaConcluding remarksTransparency declarationsReferences |
|---|
Faced with the H5N1 pandemic threat, strategies designed to contain an emerging pandemic should be considered a public health priority. The basic reproduction number R0 is the average number of secondary cases generated by an index case in a susceptible population. Disease spreads through a population if R0 > 1; the aim of intervention is to reduce R0 < 1 by disrupting transmission.
The effectiveness of interventions, including estimates of number of courses of drug required to contain pandemic influenza, can be assessed by modelling.28–32 Pandemic models are reliant on estimates of clinical parameters and assumptions (Table 1). Although the characteristics of a future pandemic virus are unknown, variables can be estimated by experience of previous pandemics and epidemics. Studies use a range of parameters to ensure that a spectrum of scenarios is considered.
|
Transmission may be broken by non-pharmaceutical measures, or reducing infectivity of infected persons and decreasing susceptibility of non-infected people with antivirals and vaccines. Non-pharmaceutical intervention includes restrictions on travel and mass gatherings including schools, and personal hygiene measures (e.g. masks).33 The benefits of such measures are unclear, but they are likely to be ineffective if used in isolation. Vaccination is the mainstay of prevention of seasonal influenza. However, global vaccine manufacturing capacity is unlikely to meet the demands of a pandemic threat. In addition, clinical trials of H5N1 candidate vaccines have proved disappointing, and the antigenic diversity of circulating H5N1 viruses means that stockpiled vaccines may be mismatched to an emergent strain.5 As efficacious vaccines are unlikely to be widely available during at least the first wave of pandemic influenza,32 NA inhibitors form critical components of preparedness plans.
Antiviral use in pandemic influenza
NA inhibitors offer advantages over vaccination including activity against antigenically diverse viral strains and subtypes, rapid onset of chemoprophylactic efficacy and therapeutic benefit in established infection. Potential roles for antivirals include post-exposure prophylaxis of those exposed to cases, long-term prophylaxis and early treatment. Although blanket prophylaxis of a population during a pandemic would afford best protection, this approach is impossible to achieve with limited drug availability and resources. Clearly, targeted antiviral strategies are needed to optimize use of available supplies. Limited chemoprophylaxis could protect key workers and minimize disruption to healthcare services. Early antiviral treatment of newly identified cases may reduce infectivity, interrupt transmission and lower morbidity and mortality.31,32
Owing to lengthy lead times in drug manufacture, it will not be feasible to respond to an emerging threat with surge capacity. Therefore, pre-pandemic stockpiling of drugs is necessary. Current 2006 global production capacity for oseltamivir is 190 million doses per year, and this will rise to 400 million doses in 2007. In addition, licences and technology transfer have been granted by Roche to a number of manufacturers for generic production in India, China and South Africa.
Containing an emerging pandemic at source
Models indicate that elimination of an emergent pandemic virus in south-east Asia is feasible using a combination of antiviral drugs and quarantining measures.29,30 Simply offering antiviral chemoprophylaxis to contacts exposed to influenza cases might not be successful in containment, as this strategy would require identification of cases, contact tracing and delivery of drugs more rapidly than logistically feasible. Therefore, ‘ring prophylaxis’ strategies that require less intense contact tracing, but increased numbers of drug doses particularly in urban settings, have been evaluated. Administration of antiviral prophylaxis to >90% of the population in a 5 km zone within 48 h of detecting illness in 20 people should contain a virus with R0 
1.5.30 However, when combined with quarantining and area-based school/workplace closures, ring prophylaxis carries a high probability of pandemic containment even if R0 approaches 2.
The WHO is creating stockpiles of at least 5 million oseltamivir treatment courses that can be rapidly delivered to the locality of an emergent virus. Although formidable obstacles to successful containment exist (rapid case identification, drug delivery, good compliance with treatment and quarantining) this approach offers the potential to prevent huge mortality and morbidity worldwide.
Impact of pandemic influenza in the United Kingdom
Models can estimate patterns of spread of novel influenza within a country. However, because the characteristics of a future pandemic virus are unknown, detailed epidemiological information must be collected early to allow interventions to be assessed in real time and policies reformulated for maximal impact on control of the actual strain. In particular, age-specific clinical attack rates and transmissibility within specific populations will be key factors.
Historical evidence suggests that, without interventions, R0 of pandemic influenza will average 1.4–1.8.31,32 It has been suggested that although most people will be susceptible, 50% of those infected may be symptomatic, resulting in a cumulative attack rate of 25% of the population over one or more waves of infection. By using these assumptions, specific models have suggested that an excess of 1.5 million primary care consultations, 750 000 emergency department attendances, 82 500 excess hospitalizations and 56 000 deaths could occur during the first wave.31,32 Many national authorities including the United Kingdom have planned or established stockpiles to treat 25% of the population.
Strategies for containing pandemic influenza in the United Kingdom
Once a novel virus arrives in the United Kingdom, repeat seeding will occur at ports of entry, so interventions aimed at elimination will be unfeasible.30–32 Long-term prophylaxis would require a prohibitively large drug stockpile, rapidly deplete stocks and postpone the outbreak by the period for which prophylaxis is provided. As influenza-infected patients display greatest infectivity shortly after onset of symptoms, the most efficient use of antivirals would be early treatment to reduce disease severity, and possibly overall attack rates. One model, for a virus of high transmissibility, suggests that treatment of 90% cases within 24 h of symptoms would reduce the cumulative population clinical attack rate from 34% to 29%, and peak daily attack rates from 1.9% to 1.6%.31 A stockpile sufficient to treat 25% of the population is needed to implement this policy. If access to treatment is delayed by 1 day, its impact is reduced and greater stockpiles are needed. In practice, combinations of control measures will be applied, and models can predict their impact (Table 2).31 While non-pharmaceutical measures have value if compliance is high, targeted post-exposure prophylaxis could provide significant benefits, but this strategy requires much greater stockpiles than currently provisioned.
|
Significant threats to the effectiveness of antiviral treatment policies exist. If there are higher clinical attack rates (>50% of infections causing clinical illness), treatment may need to be prioritized.31,32 Antiviral prophylaxis of essential workers and/or their contacts would have a high cost on stockpiles but could be considered if absence rates rise unexpectedly.
Additionally, the emergence of transmissible drug-resistant variants would have a serious impact. Although transmissible strains have not been detected, emergence of resistant clones following oseltamivir treatment of seasonal influenza in children20 and H5N1 infection26 are concerning. Virological monitoring during the pandemic would be essential. If resistance emerges, temporary cessation of antiviral therapy might allow wild-type virus to re-establish itself before further use of treatment.
Regardless of the level of stockpile, the provision of safe storage and rapid access to drugs form key elements of planning, and could be challenging issues.34 In the United Kingdom, primary care trusts must develop arrangements to ensure rapid access to drugs whilst allowing hospitals and general practitioners to focus on clinical needs. This may include telephone diagnosis and remote prescribing, pharmacist-led prescribing, use of walk-in centres, home-visiting teams and designated influenza centres.
|
Concluding remarks |
|---|
|
TopAbstractIntroductionAntiviral treatment of influenzaNeuraminidase inhibitorsCombating pandemic influenzaConcluding remarksTransparency declarationsReferences |
|---|
WHO has declared that the world is as close as ever to the next pandemic.2 For the first time during an inter-pandemic period, effective treatment and prophylaxis with NA inhibitors is available. Antiviral stockpiling to allow ring prophylaxis around infected cases emerging at source could eliminate a pandemic virus. If this fails, antivirals will play a crucial role in reducing its impact as it spreads through countries. Accordingly, many authorities including the United Kingdom have stockpiled sufficient antiviral therapy to treat 25% of the population. Although models show that this strategy could successfully reduce disease severity and transmission, it remains possible that this will not be enough. Identification and rapid delivery to newly diagnosed cases remains a formidable logistic challenge and it remains unclear how this is to be implemented in practice. A pandemic virus of high transmissibility or the emergence of oseltamivir resistance would significantly reduce the impact of any stockpile; the current planned number of doses allow for little flexibility. The French authorities have increased investment in their antiviral stockpile of both oseltamivir and zanamivir to levels in excess of 50% population treatment doses so as to allow greater flexibility in responding.35 The characteristics of the next pandemic cannot be predicted. Enormous effort and resources have gone into preparedness plans. The millions who died during the 1918 Spanish influenza pandemic, the greatest outbreak of infectious disease in history, would consider this effort worthwhile, whilst hoping that the plans in place are not tested.
|
Transparency declarations |
|---|
|
TopAbstractIntroductionAntiviral treatment of influenzaNeuraminidase inhibitorsCombating pandemic influenzaConcluding remarksTransparency declarationsReferences |
|---|
I. S. has received grants for scientific research, speaker honoraria and travel to international meetings from pharmaceutical industry including Roche and GSK who manufacture NA inhibitors. J. D. and M. P. have no conflicts of interest.
|
References |
|---|
|
TopAbstractIntroductionAntiviral treatment of influenzaNeuraminidase inhibitorsCombating pandemic influenzaConcluding remarksTransparency declarationsReferences |
|---|
1 Yuen KY, Chan PKS, Peiris MK, et al. (1998) Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet 351:467–71.[CrossRef][ISI][Medline]
2 Epidemic and Pandemic Alert and Response (EPR). Avian Influenza. http://www.who.int/csr/disease/avian_influenza/en/ (16 August 2006, date last accessed).
3 The World Health Organization Global Influenza Program Surveillance Network. (2005) Evolution of H5N1 avian influenza viruses in Asia. Emerg Infect Dis 11:1515–22.[ISI][Medline]
4
Tumpey TM, Basler CF, Aguilar PV, et al. (2005) Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 310:77–80.
5 Fedson DS. (2006) Vaccine development for an imminent pandemic. Human Vaccines 2:38–42.[Medline]
6 Gubareva LV and Hayden FG. (2006) M2 and neuraminidase inhibitors: anti-influenza activity, mechanisms of resistance and clinical effectiveness. In Kawaoka Y (Ed.). Influenza Virology: Current Topics(Caister Press, UK) pp. 169–202.
7 Bright RA, Medina MJ, Xu X, et al. (2005) Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet 366:1175–82.[CrossRef][ISI][Medline]
8
Bright RA, Shay DK, Shu B, et al. (2006) Adamantane resistance among influenza A viruses isolated early during the 2005–2006 influenza season in the United States. JAMA 295:934–6.
9 Yen HL, Monto AS, Webster RG, et al. (2005) Virulence may determine the necessary duration and dosage of oseltamivir treatment for highly pathogenic A/Vietnam/1203/04 influenza virus in mice. J Infect Dis 192:665–72.[CrossRef][ISI][Medline]
10 Bantia S, Arnold CS, Parker CD, et al. (2006) Anti-influenza virus activity of peramivir in mice with single intramuscular injection. Antiviral Res 69:39–45.[CrossRef][ISI][Medline]
11
Cooper NJ, Sutton AJ, Abrams KR, et al. (2003) Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomized controlled trials. BMJ 326:1235–43.
12
Kaiser L, Wat C, Mills T, et al. (2003) Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 163:1667–72.
13
Smith JR and Dutkowski R. (2005) Roche clarifies data for improved mortality with oseltamivir. BMJ 331:1203.
14 Hayden FG, Belshe R, Viilanueva C, et al. (2004) Management of influenza in households: a prospective randomised comparison of oseltamivir treatment with or without post-exposure prophylaxis. J Infect Dis 189:440–9.[CrossRef][ISI][Medline]
15 McKimm-Breschkin JL. (2000) Resistance of influenza virus to neuraminidase inhibitors: a review. Antiviral Res 47:1–17.[CrossRef][ISI][Medline]
16 Herlocher ML, Truscon R, Elias S, et al. (2004) Influenza viruses resistant to the antiviral drug oseltamivir: transmission studies in ferrets. J Infect Dis 190:1627–30.[CrossRef][ISI][Medline]
17 Gubareva LV, Matrosovich MN, Brenner MK, et al. (1998) Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis 178:1257–62.[CrossRef][ISI][Medline]
18 Nicholson KG, Aoki FY, Osterhaus ADME, et al. (2000) Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Lancet 355:1845–50.[CrossRef][ISI][Medline]
19 Whitley RJ, Hayden FG, Reisinger KS, et al. (2001) Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 20:127–33.[ISI][Medline]
20 Kiso M, Mitamura K, Sakai-Tagawa YS, et al. (2005) Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 364:759–67.
21 NISN. (2005) Use of influenza antivirals during 2003–2004 and monitoring of neuraminidase inhibitor resistance. Wkly Epidemiol Rec 80:156.[Medline]
22 Peiris JSM, Yu WC, Leung CW, et al. (2004) Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet 363:617–9.[CrossRef][ISI][Medline]
23
Hien TT, Liem NT, Dung NT, et al. (2004) Avian influenza (H5N1) in 10 patients in Vietnam. N Engl J Med 350:1179–88.
24
Rimmelzwaan GF, van Riel D, Baars M, et al. (2006) Influenza A virus (H5N1) infection in cats causes systemic disease with potential novel routes of virus spread within and between hosts. Am J Pathol 168:176–83.
25
de Jong MD, Bach VC, Phan TQ, et al. (2005) Fatal avian influenza A (H5N1) in a child presenting with diarrhoea followed by coma. New Eng J Med 352:686.
26
de Jong MD, Thanh TT, Khanh TH, et al. (2005) Oseltamivir resistance during treatment of influenza A (H5N1) infection. New Eng J Med 353:2667–75.
27 Koopmans M, Wilbrink B, Conyn M, et al. (2004) Transmission of H7N7 avian influenza A virus to human beings during a large outbreak in commercial poultry farms in the Netherlands. Lancet 363:587–93.[CrossRef][ISI][Medline]
28 Gani R, Hughes H, Fleming D, et al. (2005) Potential impact of antiviral drug use during influenza pandemic. Emerg Infect Dis 11:1355–62.[ISI][Medline]
29
Longini IM, Nizam A, Xu S, et al. (2005) Containing pandemic influenza at the source. Science 309:1083–7.
30 Ferguson NM, Cummings DAT, Cauchemez S, et al. (2005) Strategies for containing an emerging influenza pandemic in Southeast Asia. Nature 437:209–14.[CrossRef][Medline]
31 Ferguson NM, Cummings DAT, Fraser C, et al. (2006) Strategies for mitigating an influenza pandemic. Nature 442:448–52.[CrossRef][Medline]
32 Health Protection Agency. Influenza Pandemic Contingency Plan http://www.hpa.org.uk/infections/topics_az/influenza/pandemic/fluplan.htm (17 August 2006, date last accessed).
33 World Health Organization Writing Group. (2006) Non-pharmaceutical interventions for pandemic influenza, national and community measures. Emerg Infect Dis 12:88–94.[ISI][Medline]
34 Department of Health. UK Operational Framework for Stockpiling, Distributing and Using Antiviral Medicines in the Event of Pandemic Influenza. http://www.dh.gov.uk/PublicationsAndStatistics/Publications/PublicationsPolicyAndGuidance/PublicationsPolicyAndGuidanceArticle/fs/en?CONTENT_ID=4119491&chk=T/Iaww (17 August 2006, date last accessed).
35 French updated plan to combat the avian influenza pandemic. ((2006)) www.info-france-usa.org/news/statmnts/2006/avianflu.pdf (16 August 2006, date last accessed).
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||