WHO Rapid Advice Guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus

Recent spread of avian infl uenza A (H5N1) virus to poultry and wild birds has increased the threat of human infectionswith H5N1 virus worldwide. Despite international agreement to stockpile antivirals, evidence-based guidelines for their use do not exist. WHO assembled an international multidisciplinary panel to develop rapid advice for the pharmacological management of human H5N1 virus infection in the current pandemic alert period. A transparent methodological guideline process on the basis of the Grading Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to develop evidence-based guidelines. Our development of specifi c recommendations for treatment and chemoprophylaxis of sporadic H5N1 infection resulted from the benefi ts, harms, burden, and cost of interventions in several patient and exposure groups. Overall, the quality of the underlying evidence for all recommendations was rated as very low because it was based on small case series of H5N1 patients, on extrapolation from preclinical studies, and high quality studies of seasonal infl uenza. A strong recommendation to treat H5N1 patients with oseltamivir was made in part because of the severity of the disease. Similarly, strong recommendations were made to use neuraminidase inhibitors as chemoprophylaxis in high-risk exposure populations. Emergence of other novel infl uenza A viral subtypes with pandemic potential, or changes in the pathogenicity of H5N1 virus strains, will require an update of these guidelines and WHO will be monitoring this closely.

# Introduction
Highly pathogenic avian infl uenza A (H5N1) virus causes rapid and fatal illness in many bird populations. Of all infl uenza A viruses circulating in birds, H5N1 is currently of greatest public-health concern because it has caused severe and fatal human infections with mortality ranging from 33% to over 50% since the fi rst known outbreak in Hong Kong in 1997. [bib_ref] Avian infl uenza A (H5N1) infection in humans, Beigel [/bib_ref] The spread of H5N1 in poultry and wild birds in many countries has raised concerns about the increased risk of transmission of H5N1 virus to human beings.
Clinicians, public-health offi cers, and policymakers worldwide are faced with uncertainty about the best pharmacological management options of human beings infected with H5N1 virus. In view of its mandate to provide international advice on public-health questions, WHO published interim clinical guidelines for the use of antivirals for H5N1 infection in February, 2004.These interim guidelines were updated in 2005 following an expert consultation [bib_ref] Avian infl uenza A (H5N1) infection in humans, Beigel [/bib_ref] and there has been general international agreement to stockpile antivirals for potential use during an infl uenza pandemic. [bib_ref] Preparing for pandemic infl uenza: should hospitals stockpile oseltamivir?, Cinti [/bib_ref] To provide evidence-based guidelines, [bib_ref] Practice guidelines: a new reality in medicine. I. Recent developments, Woolf [/bib_ref] WHO convened a rapid advice panel in March, 2006, on the pharmacological management of human infection with avian infl uenza A (H5N1) virus. Because of their publichealth implications, the full guidelines were initially made available on the internet by WHO on The guidelines are based on the current situation with sporadic H5N1 human infections and household clusters, and do not apply to a pandemic scenario.

# Methods
The methods used to develop these guidelines adhered to the suggested principles for developing transparent, evidence-based WHO guidelines. [bib_ref] Improving the use of research evidence in guideline development: introduction, Oxman [/bib_ref] [bib_ref] WHO: strengthening the road to renewal, Horton [/bib_ref] The decision to convene an international rapid advice guidelines panel for the treatment and chemoprophylaxis of H5N1 virus infection was made in January, 2006; review and preparation of the evidence summaries began in ; and the panel met on .

## Group composition
The group developing the guidelines included clinicians with experience in treating H5N1 patients, infectious disease experts, infl uenza specialists, basic scientists, public-health offi cers, and methodologists as shown in panel 1. 10

## Formulation of questions and rating the importance of outcomes
Questions were initially identifi ed by clinicians managing patients with H5N1 infections and refi ned by the panel members. An evidence profi le was prepared for each question using the Grading Recommendations Assessment, Development and Evaluation (GRADE) approach. [bib_ref] Grading quality of evidence and strength of recommendations, Atkins [/bib_ref] Eight potentially important outcomes were initially identifi ed by two reviewers (MK, ADO). This list was circulated to the panel chair (HJS), WHO staff , and the scientifi c reviewers by email for independent scoring of the relative importance of each outcome. Scores were rated on a scale from 1 to 9: a rating of 7-9 indicated the outcome was critical for a decision or Review recommendation, 4-6 indicated that it was important, and 1-3 indicated that it was not important. Because the relative importance of some outcomes depended on whether a drug was being used for treatment or chemoprophylaxis, these two methods were considered separately. For all ratings, the means of the panel members' ratings established the relative importance of the outcomes.
The Cochrane Consumers network was consulted and this generated four responses, but the ratings did not diff er substanially from those of the panel.

## Preparation of evidence profi les
A group of independent scientifi c reviewers (panel 1) with expertise in the conduct of systematic reviews of the literature and preparation of evidence summaries compiled the evidence (MK, RB, LS, GEV, ADO). The clinical and public-health questions covered by the guidelines were developed from suggestions by clinicians and public-health offi cers and are listed in panel 2. The underlying considerations included the selection of appropriate clinical outcomes, target populations, and dosing regimens for treatment and chemoprophylaxis.

## Evidence summaries and quality ratings
The evidence summaries were based on systematic reviews supplemented with recent randomised trials for the treatment and chemoprophylaxis of any infl uenza virus infection; and case series, animal, and in-vitro studies for the treatment or chemoprophylaxis of H5N1 virus infection. The search strategy is described elsewhere. [bib_ref] Rapid Advice Guidelines on pharmacological management of humans infected with avian infl..., Who [/bib_ref] Original controlled studies not included in the systematic reviews and published before 2005 or after February, 2006, were not included. However, panel members were asked to identify relevant published studies that became available between February, 2006, and the meeting date and these were considered if provided in full to the panel 2 weeks before the meeting. Adverse event data from trials were supplemented by reports from the Uppsala Monitoring Centre and from manufacturers' reports.
Evidence summaries were created using the GRADE approach [bib_ref] Grading quality of evidence and strength of recommendations, Atkins [/bib_ref] with GRADE profi ler software (v1.12, http:// www.gradeworkingroup.org). Evidence is classifi ed as "high", "moderate", "low", or "very low" quality, based on its methodological characteristics for a specifi c healthcare problem. Assessments of the quality of evidence for each important outcome took into account the study design, limitations of the studies, consistency of the evidence across studies, the directness of the evidence, and the precision of the estimate. Based on the GRADE system the overall quality of evidence is determined by the lowest quality for critical outcomes, and thus the overall quality of evidence was very low for each of the clinical questions.

## Panel meeting
One meeting of the guideline panel, chaired by a clinical epidemiologist with experience in respiratory medicine, was held to discuss the results of the evidence review and to develop recommendations. WHO was represented at the group's meeting and provided scientifi c input and guidance. The panel agreed recommendations would be based on a consensus of the panel and that voting would be used if agreement could not be reached. Panel members declared their potential confl icts of interest according to WHO rules in writing before and verbally at the meeting as described elsewhere. [bib_ref] Rapid Advice Guidelines on pharmacological management of humans infected with avian infl..., Who [/bib_ref] [bib_ref] WHO Rapid Advice Guidelines: quick and transparent, Schunemann [/bib_ref] Balance of benefi ts, harms, burden, and cost and developing recommendations
Formulating the recommendations included explicit consideration of the quality of evidence, benefi ts, harms, burdens, costs, and values. A high value was placed on antiviral resistance to specifi c drugs for most questions. The panel considered several diff erent patient and exposure groups and assessed the balance of benefi ts and drawbacks of interventions for each group. Recommendations are classifi ed as "strong" or "weak" recommendations, as recommended by the GRADE working group. [bib_ref] Grading quality of evidence and strength of recommendations, Atkins [/bib_ref] [bib_ref] An offi cial ATS statement: grading the quality of evidence and strength..., Schunemann [/bib_ref] Agreement on the type and wording of the recommendations was also reached during the panel meeting by consensus. However, two recommendations required voting to decide the strength of the recommendation or whether the recommendation should be given at all.

# Results
Evidence profi les were prepared for each of the clinical questions shown in panel 2 and are available from the WHO website. [bib_ref] Rapid Advice Guidelines on pharmacological management of humans infected with avian infl..., Who [/bib_ref] disease was considered indirect, because the populations, viruses, and possibly even drug eff ects were diff erent. Therefore, the rating of quality of evidenceie, confi dence in the estimates of eff ect-for all important effi cacy outcomes was lowered by two quality levels. The rate and severity of adverse eff ects, however, were judged to be similar. Sparse data lowered the quality of evidence for some of the other critical outcomes (eg, lower respiratory tract infections) by another level.

## Treatment
For treatment of H5N1 infection, the fi nal list of critical outcomes comprised mortality, duration of hospitalisation, incidence of lower respiratory tract complications, antiviral drug resistance existing before treatment, and serious adverse events. The panel placed a low value on the potential of developing resistance during therapy, adverse outcomes, and cost. In judging strength of the recommendations, the panel considered the high case fatality and the paucity of possible pharmacological alternatives in all of the recommendations.

## Panel 2: clinical questions
- Should oseltamivir be used for treatment or prophylaxis? - Should zanamivir be used for treatment or prophylaxis?
- Should amantadine or rimantadine be used for treatment or prophylaxis? - Should ribavirin be used for treatment? - Should corticosteroids, immunoglobulin, or interferon be used for treatment? - Should broad-spectrum antibiotics be used for the prevention of secondary pneumonia? Direct data came from the most recent case series that described 37 H5N1 patients, of whom 25 were treated with oseltamivir (19 deaths) and 12 patients did not receive oseltamivir (nine deaths). [bib_ref] Avian infl uenza A (H5N1) infection in humans, Beigel [/bib_ref] Treatment regimens diff ered across these patients, beginning between days 4 to 22 of the illness. Three cases of resistance to oseltamivir developing after treatment of H5N1 patients have been published, one of whom received a prophylaxis dose. [bib_ref] Oseltamivir resistance during treatment of infl uenza A (H5N1) infection, De Jong [/bib_ref] [bib_ref] Avian fl u: isolation of drugresistant H5N1 virus, Le [/bib_ref] In fi ve similarly designed studies in otherwise healthy adults with seasonal infl uenza (n=1644), lower respiratory tract complications (including pneumonia) were reduced (relative risk [RR] 015, 95% CI 003-069) but there were only 11 events. [bib_ref] Impact of oseltamivir treatment on infl uenza-related lower respiratory tract complications and..., Kaiser [/bib_ref] This analysis also reported a signifi cant reduction (RR 040, 95% CI 018-088) in all-cause hospitalisations within 30 days of diagnosis in oseltamivir recipients compared with placebo. Rare cases of anaphylaxis and serious skin reactions were reported during post-marketing experience, and data from regulatory trials reported nausea and vomiting as the most frequent adverse event. [bib_ref] Safety and pharmacology of oseltamivir in clinical use, Dutkowski [/bib_ref] Even allowing for the sparse direct evidence, most panel members judged that oseltamivir should be used as treatment and made a strong recommendation (recommendation 1; see below) following a vote (one abstention and one vote for a weak recommendation out of 13 panel members). It was noted that even small relative risk reductions could lead to large net benefi t in mortality. Recommended treatment regimens are shown in the table. There were no clinical data to recommend higher drug doses or more prolonged treatment, but the panel noted that two-fold higher doses did not provide greater antiviral or clinical eff ects in adults with uncomplicated seasonal infl uenza. [bib_ref] Effi cacy and safety of oseltamivir in treatment of acute infl uenza:..., Nicholson [/bib_ref] [bib_ref] Effi cacy and safety of the oral neuraminidase inhibitor oseltamivir in treating..., Treanor [/bib_ref] Should H5N1 patients receive treatment with zanamivir?
Direct evidence for the use of zanamivir in H5N1 patients currently does not exist. Zanamivir is active in vitro and in vivo against H5N1 viruses including the oseltamivirresistant H5N1 virus that contains the H274Y mutation. 14 Indirect evidence derives from zanamivir studies for treatment of seasonal infl uenza, but there are too few events in these studies to provide evidence of a benefi t in terms of mortality or duration of hospitalisation. Lower respiratory tract complications were not signifi cantly reduced (odds ratio [OR] 083, 95% CI 024-226) in three trials (n=2299 patients with 46 events) that described this outcome in otherwise healthy adults with seasonal infl uenza. [bib_ref] Antivirals for infl uenza in healthy adults: systematic review, Jeff Erson [/bib_ref] [bib_ref] Zanamivir in the prevention of infl uenza among healthy adults: a randomized..., Monto [/bib_ref] [bib_ref] Zanamivir: a signifi cant reduction in viral load during treatment in military..., Puhakka [/bib_ref] An increased incidence of bronchospasm was reported particularly for patients with airway disease. [bib_ref] From the food and drug administration: revised labeling for zanamivir, Henney [/bib_ref] No information on resistance of H5N1 viruses to zanamivir exists.
There was uncertainty about the adequacy of drug delivery with the commercial formulation of inhaled zanamivir in patients with viral pneumonia or possible extra-pulmonary viral spread. Although there is limited evidence of a possible net clinical benefi t of inhaled zanamivir, because H5N1 infection is associated with a high case fatality the panel made a weak recommendation for the use of zanamivir in H5N1 patients (recommendation .

## Should h5n1 patients receive treatment with m2 ion channel inhibitors?
No controlled clinical trial has evaluated amantadine or rimantadine for the treatment of H5N1 infection, although there are published case study data for ten patients in whom amantadine was used as treatment. [bib_ref] Avian infl uenza A (H5N1) infection in humans, Beigel [/bib_ref] All four of the patients who received amantadine within 5 days of symptom onset survived, and two of the six patients who were treated after 5 days of illness survived. Six of eight patients who did not receive amantadine survived, but no conclusions can be drawn from these uncontrolled clinical data.
There is insuffi cient evidence in the studies on seasonal infl uenza to evaluate the eff ects of amantadine or rimantadine on mortality or duration of hospitalisation. A Cochrane review of M2 inhibitor treatment and chemoprophylaxis reports adverse eff ects (gastrointestinal and central nervous system) with both agents. [bib_ref] Amantadine and rimantadine for infl uenza A in adults, Jeff Erson [/bib_ref] Moderate to severe central nervous system side-eff ects appear to be more frequent with amantadine. [bib_ref] Amantadine and rimantadine for preventing and treating infl uenza A in adults, Jeff Erson [/bib_ref] [bib_ref] A controlled trial of amantadine and rimantadine in the prophylaxis of infl..., Dolin [/bib_ref] The development of antiviral resistance during treatment is a frequent problem with amantadine and rimantadine. Primary (pretreatment) resistance appears to be common in clade 1 H5N1 virus isolated from human beings in Thailand, Vietnam, and Cambodia, [bib_ref] Oseltamivir resistance during treatment of infl uenza A (H5N1) infection, De Jong [/bib_ref] [bib_ref] Avian fl u: isolation of drugresistant H5N1 virus, Le [/bib_ref] and resistance has occurred in some clade 2 H5N1 viruses, particularly those isolated in Indonesia. [bib_ref] Oseltamivir resistance during treatment of infl uenza A (H5N1) infection, De Jong [/bib_ref] [bib_ref] Avian fl u: isolation of drugresistant H5N1 virus, Le [/bib_ref] Resistance has been found in H1N1 viruses from the preamantadine era. [bib_ref] Generation and characterization of recombinant infl uenza A (H1N1) viruses harboring amantadine..., Abed [/bib_ref] Thus, amantadine or rimantadine do not off er greater net clinical benefi t as fi rst-line agents in the treatment of H5N1 infection compared with the neuraminidase inhibitors, and drug resistance is a major limitation. This assessment of possible net benefi t under certain circumstances led to conditional and weak recommendations only when neuraminidase inhibitors are not available (recommendations 4 and 6). The recommendation includes considerations of possible development of drug resistance and the incidence of toxic eff ects.

## Should h5n1 patients receive combination treatment of neuraminidase inhibitors and m2 ion channel inhibitors?
Insuffi cient data exist to assess the possible benefi t of combination treatment of neuraminidase inhibitors and M2 ion channel inhibitors on mortality, duration of hospitalisation, complications, or resistance emergence in either seasonal infl uenza or H5N1 infection. Without convincing evidence of clinical benefi t, combination therapy might be used only in the context of prospective Review data collection (recommendation 7) at the same time as doses described for monotherapy .

## Chemoprophylaxis
For chemoprophylaxis, the critical outcomes were infl uenza cases, outbreak control, drug resistance, and serious adverse events. The panel developed risk categorisations for exposure to assist countries in prioritising use of antivirals where availability is limited and to avoid chemoprophylaxis of individuals not considered at risk (panel 3).

## Should oseltamivir be used for the chemoprophylaxis of h5n1 infection?
Although oseltamivir has been used in the fi eld for chemoprophylaxis of H5N1 infection, there are no controlled human studies. For seasonal infl uenza, two systematic reviews and health technology assessments have reported eff ects of oseltamivir (for 1-6 weeks) as chemoprophylaxis. [bib_ref] Antivirals for infl uenza in healthy adults: systematic review, Jeff Erson [/bib_ref] [bib_ref] Systematic review and economic decision modelling for the prevention and treatment of..., Turner [/bib_ref] Three randomised controlled trials of the eff ect of oral oseltamivir on post-exposure infl uenza incidence found large reductions in laboratoryconfi rmed infl uenza (RR reductions of 50% to 89%). [bib_ref] Antivirals for infl uenza in healthy adults: systematic review, Jeff Erson [/bib_ref] No diff erences in prophylactic effi cacy were found between 75 mg once-daily and 75 mg twice-daily dosing in seasonal infl uenza in adults. Two trials found that oseltamivir was also eff ective for chemoprophylaxis of household contacts of infl uenza cases, when taken for 7-10 days after exposure to an index case. [bib_ref] Management of infl uenza in households: a prospective, randomized comparison of oseltamivir..., Hayden [/bib_ref] [bib_ref] Eff ectiveness of oseltamivir in preventing infl uenza in household contacts: a..., Welliver [/bib_ref] Overall the evidence for pharmacological chemoprophylaxis of H5N1 infection with oseltamivir was rated as very low quality and indirect. However, oseltamivir has shown large eff ects on infl uenza incidence as post-exposure chemoprophylaxis for seasonal infl uenza and is active as pre-exposure prophylaxis in animal models of H5N1 infection. [bib_ref] Antivirals for infl uenza in healthy adults: systematic review, Jeff Erson [/bib_ref] Oselta mivir might eff ectively provide an important reduction in H5N1 virus transmission. The panel, therefore, recom mended that chemoprophylaxis courses should begin as soon as possible after exposure status is known and be used continuously for 7-10 days after the last known exposure (recommendations 8 to 11), but the strength of the recommendation diff ers by risk group.

## Should zanamivir be used for the chemoprophylaxis of h5n1 infection?
Two randomised controlled trials investigating the eff ect of inhaled zanamivir on post-exposure infl uenza incidence in healthy adults found large reductions in laboratory-confi rmed seasonal infl uenza (OR 019, 95% CI 009-038). [bib_ref] Systematic review and economic decision modelling for the prevention and treatment of..., Turner [/bib_ref] A similar eff ect was seen in two trials of seasonal chemoprophylaxis. [bib_ref] Systematic review and economic decision modelling for the prevention and treatment of..., Turner [/bib_ref] Trials assessing the combination of both intranasal (not commercially available) and inhaled zanamivir in healthy adults,and in elderly and high-risk adults showed no additive benefi t for any critical outcome. 31

## Panel 3: risk stratifi cation for the provision of chemoprophylaxis of h5n1 virus infection
Antiviral chemoprophylaxis should generally be considered according to the risk stratifi cation described below. It is based on observational data for reported cases of human infection with avian infl uenza A (H5N1) virus and on high quality data from studies of seasonal human infl uenza virus infection.
High-risk exposure groups are currently defi ned as:
- Household or close family contacts* of a strongly suspected or confi rmed H5N1 patient, because of potential exposure to a common environmental or poultry source as well as exposure to the index case
Moderate-risk exposure groups are currently defi ned as:
- Individuals with unprotected and very close direct exposure  to sick or dead H5N1 infected animals or to particular poultry that have been implicated directly in human cases - Persons involved in handling sick animals or decontaminating known infected animals or environments, if personal protective equipment might not have been used properly - Health-care personnel in close contact with strongly suspected or confi rmed H5N1 patients, for example during intubation or performing tracheal suctioning, or delivering nebulised drugs, or handling inadequately screened/sealed body fl uids without any, or with insuffi cient, personal protective equipment. This also includes laboratory personnel who might have an unprotected exposure to virus-containing samples  Low-risk exposure groups are currently defi ned as:
- Health-care workers not in close contact (distance greater than 1 m or no direct contact with infectious material) with a strongly suspected or confi rmed H5N1 patient - Health-care workers who used appropriate personal protective equipment during exposure to H5N1 patients - Personnel involved in culling non-infected or likely noninfected animal populations to prevent viral spread - Personnel involved in handling sick animals or decontaminating known infected animals or environments, who used proper personal protective equipment
In the absence of sustained human-to-human transmission, the general population is currently not considered at risk.
*A close contact may be defi ned as an individual sharing a household with, or remaining unprotected while within speaking distance (<1 m) of, or in the care of, a patient with confi rmed or strongly suspected H5N1 infection. Examples of high-risk exposure based on confi rmed transmission to humans include: unprotected exposure to infected animal products such as consumption of blood from H5N1 infected ducks, preparation of food from infected animals (eg, plucking feathers), or prolonged exposure to infected birds in a confi ned space, such as playing with pets. This defi nition of moderate risk is based on very few cases recognised under these situations to date. Because circumstances could change rapidly, it would be reasonable to consider the moderate and high-risk groups together for prophylaxis decisions. If a particular patient has been implicated in possible human-to-human transmission, then these examples of exposures could be defi ned as high risk.

## Review
Although the evidence for chemoprophylaxis of H5N1 infection with zanamivir is of very low quality and indirect, trials in seasonal infl uenza [bib_ref] Antivirals for infl uenza in healthy adults: systematic review, Jeff Erson [/bib_ref] have shown quite large reductions in the incidence of infl uenza cases. On the basis of extrapolation from these trials, zanamivir might provide reductions in cases of H5N1 infection (recommendations 12 to 15).

## Should m2 ion channel inhibitors be used for the chemoprophylaxis of h5n1 infection?
No direct data on the use of M2 ion channel inhibitors in human H5N1 virus infection exist.
11 randomised controlled trials investigating the eff ect of oral amantadine on seasonal infl uenza A incidence in healthy adults found large reductions in laboratoryconfi rmed infl uenza A (RR reductions of 61%, 95% CI 35-76). [bib_ref] Antivirals for infl uenza in healthy adults: systematic review, Jeff Erson [/bib_ref] Eff ects on mortality were not reported. High quality evidence for the use of amantadine as postexposure chemoprophylaxis for H5N1 infection in any population does not exist.
The eff ect of oral rimantadine in reducing laboratoryconfi rmed cases of infl uenza A in healthy adults in three randomised placebo controlled trials was not signifi cant (RR 028, 95% CI 008-108), but head to head trials against amantadine showed no diff erence between the two active treatments. [bib_ref] Antivirals for infl uenza in healthy adults: systematic review, Jeff Erson [/bib_ref] Overall, amantadine and rimantadine appear not to be of greater net clinical benefi t as a fi rst-line agent for chemoprophylaxis of H5N1 infection compared with the neuraminidase inhibitors. However, based on extrapolation from trials in seasonal infl uenza, amantadine and rimantadine might have net clinical benefi t as a fi rst-line agent for chemoprophylaxis of H5N1 infection when neuraminidase inhibitors are not available and the virus is known or likely to be susceptible (recommendations 17 and 21).

## Recommendations for treatment of patients with confi rmed or strongly suspected infection with avian infl uenza a (h5n1) in a non-pandemic situation

## Recommendation 1
In patients with confi rmed or strongly suspected H5N1 infection, clinicians should administer oseltamivir treatment as soon as possible (strong recommendation, very low quality evidence).

## Remarks
This recommendation places a high value on the prevention of death in an illness with a high case fatality. It places relatively low values on adverse reactions, the development of resistance, and costs of treatment. Despite the lack of controlled treatment data for H5N1, this is a strong recommendation, in part, because there is a lack of known eff ective alternative pharmacological interventions at this time. The recommendation applies to adults, including pregnant women and children. Until further information becomes available, the current treatment regimen for H5N1 is as recommended for early treatment of adults, special patient groups (eg, those with renal insuffi ciency), and children with seasonal infl uenza.

## Recommendation 2
In patients with confi rmed or strongly suspected infection with avian infl uenza A (H5N1) virus, clinicians might administer zanamivir (weak recommendation, very low quality evidence).

## Remarks
This recommendation places a high value on the prevention of death in an illness with high case fatality. It places a relatively low value on adverse eff ects (including bronchospasm), the potential development of resistance, and costs of treatment. The bioavailability of zanamivir outside of the respiratory tract is lower than that of oseltamivir. Zanamivir might be active against some strains of oseltamivir-resistant H5N1 virus. The recommendation applies to adults, including pregnant women, and children. Use of zanamivir requires that patients are able to use the diskhaler device. Until further information becomes available, the current treatment regimen for H5N1 infection is the same as recommended for early treatment of adults and children with seasonal infl uenza.
Although the quality of evidence when considered on a continuum is lower for the use of zanamivir compared with oseltamivir, the overall quality of evidence in the fourcategory grading system is very low for both interventions.

## Recommendation 3
If neuraminidase inhibitors are available, clinicians should not administer amantadine alone as a fi rst-line treatment to patients with confi rmed or strongly suspected human infection with avian infl uenza H5N1 (strong recommendation, very low quality evidence).

## Remarks
Although recognising that the illness is severe, this recommendation places a high value on the potential development of resistance and avoiding adverse eff ects. This is a strong recommendation in part, because of the availability of other options for treatment that might be more eff ective.

## Recommendation 4
If neuraminidase inhibitors are not available and especially if the virus is known or likely to be susceptible, clinicians might administer amantadine as a fi rst-line treatment to patients with confi rmed or strongly suspected infection with avian infl uenza A (H5N1) virus (weak recommendation, very low quality evidence).

## Remarks
This recommendation places a high value on the prevention of death in an illness with a high case fatality.

## Review
It places a relatively low value on adverse eff ects and the development of resistance in a situation without alternative pharmacological treatment. Until further infor mation becomes available, the current treatment regimen for (H5N1) infection is the same as recommended for early treatment of adults and children with seasonal infl uenza. The use of amantadine should be guided by knowledge about local resistance patterns, and special consideration of the benefi ts and harms to patients at higher risk for adverse outcomes (eg, pregnant patients).

## Recommendation 5
If neuraminidase inhibitors are available, clinicians should not administer rimantadine alone as a fi rst-line treatment to patients with confi rmed or strongly suspected infection with avian infl uenza A (H5N1) virus (strong recommendation, very low quality evidence).

## Remarks
Although recognising that the illness is severe, this recommendation places a high value on the potential development of resistance and avoiding adverse eff ects. This is a strong recommendation in part, because of the availability of other options for treatment that might be more eff ective.

## Recommendation 6
If neuraminidase inhibitors are not available and especially if the virus is known or likely to be susceptible, clinicians might administer rimantadine as a fi rstline treatment to patients with confi rmed or strongly suspected infection with avian infl uenza A (H5N1) virus (weak recommendation, very low quality evidence).

## Remarks
This recommendation places a high value on the prevention of death in an illness with a high case fatality. It places a relatively low value on adverse eff ects and the development of resistance. The use of rimantadine should be guided by knowledge about local antiviral resistance patterns, and special consideration of the benefi ts, harms, burdens, and cost in patients at higher risk for adverse outcomes. Rimantadine has generally a more favourable side-eff ect profi le than amantadine.

## Recommendation 7
If neuraminidase inhibitors are available and especially if the virus is known or likely to be susceptible, clinicians might administer a combination of neuraminidase inhibitor and M2 inhibitor to patients with confi rmed or strongly suspected infection with avian infl uenza A (H5N1) virus (weak recommendation, very low quality evidence). This should only be done in the context of prospective data collection.

## Remarks
This recommendation places a high value on the prevention of death in an illness with a high case fatality. It places a relatively low value on adverse eff ects, the potential development of resistance, and costs associated with therapy. The use of combination therapy should be guided by knowledge about local antiviral resistance patterns under special consideration for the benefi ts and shortcomings in patients at higher risk for adverse outcomes. Combination therapy should only be done if detailed and standardised clinical and virological data collection is in place at the start of therapy (prospective data collection). Clinicians should carefully establish which patients (eg, severely ill patients) could receive combination therapy.

## Recommendations for chemoprophylaxis of avian infl uenza a (h5n1)
For antiviral chemoprophylaxis, the panel devised an exposure-based assessment of risk (panel 3) developed from observational data for reported cases of H5N1 infection. These categories of risk were based on expert interpretation of existing evidence of the current situation with sporadic H5N1 infections in the prepandemic era. Decisions to initiate antiviral chemoprophylaxis should generally be guided by this risk stratifi cation and specifi c recommendations for chemoprophylaxis are shown below.

## Recommendation 8
In high-risk exposure groups oseltamivir should be administered as chemoprophylaxis continuing for 7-10 days after the last known exposure (strong recommendation, very low quality evidence).

## Remarks
This recommendation places a high value on preventing an illness with high case fatality. It places a relatively low value on adverse eff ects, development of resistance, and cost. Administration of chemoprophylaxis should begin as soon as possible after exposure status is known and be used continuously for 7-10 days after last known exposure. Oseltamivir has been used for as long as 8 weeks for chemoprophylaxis of seasonal infl uenza. The dose of oseltamivir for H5N1 chemoprophylaxis should be that used in seasonal infl uenza. This recommendation also applies to pregnant women in the high-risk exposure group.

## Recommendation 9
In moderate-risk exposure groups oseltamivir might be administered as chemoprophylaxis, continuing for 7-10 days after the last known exposure (weak recommendation, very low quality evidence).

## Remarks
This recommendation places a high value on preventing an illness with high case fatality. It places a relatively low Review value on adverse eff ects, development of resistance, and cost. Administration of chemoprophylaxis should begin as soon as possible after exposure status is known and be used continuously for 7-10 days after last known exposure. Oseltamivir has been used for as long as 8 weeks for chemoprophylaxis of seasonal infl uenza. The dose of oseltamivir for H5N1 chemoprophylaxis should be that used in seasonal infl uenza. This recommendation applies to pregnant women in the moderate-risk exposure group.

## Recommendation 10
In low-risk exposure groups oseltamivir should probably not be administered for chemoprophylaxis (weak recommendation, very low quality of evidence).

## Remarks
This recommendation places a high value on avoiding adverse eff ects and cost. It places a lower value on preventing the low risk of H5N1 disease.

## Recommendation 11
Pregnant women in the low exposure risk groups should not receive oseltamivir for chemoprophylaxis (strong recommendation, very low quality of evidence).

## Remarks
This recommendation places a high value on avoiding possible but uncertain harm associated with oseltamivir chemoprophylaxis during pregnancy. It places a lower value on preventing the low risk of H5N1 disease.

## Recommendation 12
In high-risk exposure groups zanamivir should be administered as chemoprophylaxis continuing for 7-10 days after the last known exposure (strong recommendation, very low quality evidence).

## Remarks
This recommendation places a high value on preventing an illness with high case fatality. It places a relatively low value on adverse eff ects, development of resistance, and cost. Administration of chemoprophylaxis should begin as soon as possible after exposure status is known and be used continuously for 7-10 days after last known exposure. The dose of zanamivir should be that used for the chemoprophylaxis of seasonal infl uenza. The bioavailability of zanamivir outside of the respiratory tract is lower than that of oseltamivir. Zanamivir might be active against some strains of oseltamivir-resistant H5N1 virus. Consequently, it might be a reasonable choice for healthcare workers with a high-risk exposure to an oseltamivirtreated H5N1 patient. This recommendation also applies to pregnant women who have high-risk exposure.

## Recommendation 13
In moderate-risk exposure groups, zanamivir might be administered as chemoprophylaxis continuing for 7-10 days after the last known exposure (weak recommendation, very low quality evidence).

## Remarks
This recommendation places a high value on preventing an illness with high case fatality. It places a relatively low value on adverse eff ects, development of resistance, and cost. Administration of chemoprophylaxis should begin as soon as possible after exposure status is known and be continued for 7-10 days after the last known exposure. The bioavailability of zanamivir outside of the respiratory tract is lower than that of oseltamivir. Zanamivir might be active against some strains of oseltamivir-resistant H5N1 virus. This recommendation also applies to pregnant women in the moderate-risk exposure group.

## Recommendation 14
In low-risk exposure groups, zanamivir should probably not be administered for chemoprophylaxis (weak recommendation, very low quality of evidence).

## Remarks
This recommendation places a high value on avoiding adverse eff ects, possible development of resistance, and cost. It places a lower value on preventing the low risk of H5N1 disease.

## Recommendation 15
Pregnant women in the low-risk exposure group should not receive zanamivir for chemoprophylaxis (strong recommendation, very low quality of evidence).

## Remarks
This recommendation places a high value on avoiding possible but uncertain harm associated with zanamivir during pregnancy. It places a lower value on preventing the low risk of H5N1 disease.

## Recommendation 16
If the virus is known or likely to be an M2 inhibitorresistant H5N1 virus, amantadine should not be administered as chemoprophylaxis against human infection with avian infl uenza A (H5N1) virus (strong recommendation, very low quality evidence).

## Remarks
This recommendation places a high value on avoiding adverse eff ects in a situation when no drug effi cacy would be expected.

## Recommendation 17
If neuraminidase inhibitors are not available and especially if the virus is known or likely to be susceptible, amantadine might be administered as chemoprophylaxis against human infection with avian infl uenza A (H5N1) virus in high or moderate-risk exposure groups (weak recommendation, very low quality evidence).

## Review

## Remarks
This recommendation does not apply to pregnant women, the elderly, people with impaired renal function, and individuals receiving neuropsychiatric medication, or with neuropsychiatric or seizure disorders. It places a high value on preventing an illness with high case fatality. It places a relatively low value on adverse eff ects, development of resistance, and cost. Administration of chemoprophylaxis should begin as soon as possible after exposure status is known and be continued for 7-10 days after the last known exposure. Amantadine has been used for as long as 6 weeks for chemoprophylaxis of seasonal infl uenza A. This recommendation applies when neuraminidase inhibitors are not available or have limited availability.

## Recommendation 18
If neuraminidase inhibitors are not available and even if the virus is known or likely to be susceptible, amantadine should probably not be administered as chemoprophylaxis against human infection with avian infl uenza A (H5N1) virus in low-risk exposure groups (weak recommendation, very low quality evidence).

## Remarks
This recommendation places a high value on avoiding adverse events, development of resistance, and cost. It places a lower value on preventing the low risk of H5N1 disease.

## Recommendation 19
In pregnant women, the elderly, people with impaired renal function, and individuals receiving neuropsychiatric medication or with neuropsychiatric or seizure disorders amantadine should not be administered as chemoprophylaxis against human infection with avian infl uenza A (H5N1) virus (strong recommendation, very low quality of evidence).

## Recommendation 20
If the H5N1 virus is known or likely to be M2 inhibitorresistant, rimantadine should not be administered as chemoprophylaxis against human infection with avian infl uenza A (H5N1) virus (strong recommendation, very low quality evidence).

## Remarks
This recommendation places a high value on avoiding adverse eff ects in a situation when no drug effi cacy would be expected.

## Recommendation 21
If neuraminidase inhibitors are not available and especially if the virus is known or likely to be susceptible, rimantadine might be administered as chemoprophylaxis against human infection with avian infl uenza A (H5N1) virus in high or moderate-risk exposure groups (weak recommendation, very low quality evidence).

## Remarks
This recommendation places a high value on preventing an illness with high case fatality. It places a relatively low value on adverse eff ects, development of resistance, and cost. Administration of chemoprophylaxis should begin as soon as possible after exposure status is known and be continued for 7-10 days after the last known exposure. Rimantadine has been used for as long as 7 weeks for chemoprophylaxis of seasonal infl uenza A. This recommendation applies when neuraminidase inhibitors are not available or have limited availability. This recommendation does not apply to pregnant women.

## Recommendation 22
If neuraminidase inhibitors are not available and even if the virus is known or likely to be susceptible, rimantadine should probably not be administered as chemoprophylaxis against human infection with avian infl uenza A (H5N1) virus in low-risk exposure groups (weak recommendation, very low quality evidence).

## Remarks
This recommendation places a high value on avoiding adverse events, development of resistance, and cost. It places a lower value on preventing the low risk of H5N1 disease.

## Recommendation 23
In pregnant women rimantadine should not be administered for chemoprophylaxis of human infection with avian infl uenza A (H5N1) virus (strong recommendation, very low quality of evidence).
The recommended dose and duration of treatment and chemoprophylaxis are shown in the table.

## Other recommendations
In addition to the recommendations of antiviral use, the panel evaluated other pharmacological management options but made only one detailed recommendation (strong recommendation based on very low quality evidence against the use of ribavirin in pregnancy because of known adverse eff ects). Recommendations relating to antibiotic use are provided on the WHO website. 7 A number of research recommendations including the need for detailed prospective data collection on all H5N1 cases, exploration of combination therapy, and parenteral administration modes were also made. 7

# Discussion
This review summarises the clinical recommendations from the WHO Rapid Advice Guidelines on pharmacological management of human beings infected with avian infl uenza A (H5N1) virus. [bib_ref] Rapid Advice Guidelines on pharmacological management of humans infected with avian infl..., Who [/bib_ref] These guidelines were developed by a panel involving relevant stakeholders including clinicians who cared for patients with H5N1 disease.

## Review
One of the strengths of these guidelines is the transparent, evidence-based development approach. Another strength is the explicit description of the values that infl uence the recommendations. The main weakness is the very limited amount of direct evidence pertaining to human H5N1 infections, and the lack of data on resource use, which render more detailed cost-eff ectiveness analyses infeasible.
Making strong recommendations-implying that they should be followed in most situations-in the face of evidence rated as very low quality demands explanation. First, the disease is deadly for a very high proportion of patients. Second, neuraminidase inhibitors are the most promising pharmacological treatments at present, despite the uncertainty about their effi cacy. However, even a hypothetical and small reduction in the relative risk of death in the order of 10% would require only 15-30 patients to be treated to prevent one H5N1 death. Third, in the absence of important adverse outcomes, the panel judged that the potential benefi ts clearly outweigh the associated harm, burden, and cost during the treatment of relatively few patients worldwide. Overall, these considerations highlight the importance of separating the rating of evidence from determining the strength of recommendations in any guideline process.
Prospective clinical research is needed to assess the effi cacy of neuraminidase and M2 ion channel inhibitors, the dose and duration, and the potential role of combination therapy for the treatment of H5N1 patients. The development of resistance to these drugs is a major concern and this aspect requires careful monitoring. The results of such work will help to establish whether these current recommendations will remain applicable. In view of the current uncertainty, clinicians will ask which other measures should be taken to treat H5N1 patients. Early antiviral treatment and supportive care remain key features in the management of H5N1 patients.Policymakers will ask whether the strong recommendation for treatment with oseltamivir leads to stockpiling. Because these recommendations were developed in the context of the current pandemic alert period without sustained human-to-human transmission, extrapolation to stockpiling decisions related to pandemic preparedness is limited, since diff erent criteria for judgment are likely to apply including changing estimates of benefi t and harm.
For chemoprophylaxis, resource considerations are of even greater concern. Users of these guidelines should apply the risk stratifi cation presented in these guidelines for allocation of oseltamivir. The panel strongly recommended chemoprophylaxis with neuraminidase inhibitors only for high-risk exposure groups and pointed out that chemoprophylaxis should be seen in the context of standard infection control measures including the proper use of adequate personal protective equipment. Zanamivir is listed as a reasonable alternative in view of the limited availability of oseltamivir and since the evidence base for chemoprophylaxis with zanamivir is stronger than for treatment with this agent. Moreover, in certain situations of limited or no availability of neuraminidase inhibitors clinicians might consider the use of M2 inhibitors (recommendations 4, 6, 17, and 21), although no activity would be expected for resistant viruses. Guideline users must be aware, however, that the risk stratifi cation is based on weak evidence from small observational studies as well as observations of expert clinicians.
These guidelines off er many advantages over previous advice because of the structured development process including explicit question formulation and evidence summaries. For example, the Health Evidence Network (HEN) reportprovides comprehensive, evidence-based information and recommendations ranging from vaccination to stockpiling antivirals, but the report does not provide the level of detail that clinicians and other decision makers need for making decisions about the pharmacological management in exposed or infected patients. [bib_ref] Pandemic infl uenza: using evidence on vaccines and antivirals for clinical decisions..., Granados [/bib_ref] The latter was not the mandate of the HEN report on avian infl uenza, and therefore the current document presents important new information.
These guidelines were developed with the aim of allowing simple implementation. The greatest barrier to implementation results from the limited availability of the neuraminidase inhibitors and the lack of resistance data. However, the clear description of the guiding principles of the panel's values and preferences will facilitate their application by clinicians treating H5N1 patients. In particular, weak recommendations will require careful evaluation of values and resources before they can be implemented. WHO will begin collecting feedback from user countries on the practicality of these guidelines. Emergence of novel human infl uenza A viral subtypes or a change in the pathogenicity or transmissibility of H5N1 virus strains, availability of new pharmacological agents, or important clinical research data on H5N1 will necessitate an update of these guidelines. In view of the potential for rapid change in the situation in relation to avian infl uenza, WHO will continue to monitor these factors carefully before deciding when to revise or update the recommendations.

## Confl icts of interest
This guideline project was funded by WHO. Panel members made the following declarations regarding possible confl icts of interest according to WHO rules for the period 2002-2006. JB declares no personal funding, but is an investigator (through the National Institutes of Health) on trials with Roche and Biocrest; CDM declares funding for trials in unrelated therapeutic area, not in the last 4 years; FGH declares receipt of research grants for trials of antivirals and vaccines from Roche, Abbotts, Biocrest and Merck; HJS declares no personal funding, but research grants and honoraria deposited into research accounts or received by a research group that he belongs to from Pfi zer, Amgen, Roche, and AstraZeneca for development or consulting regarding quality of life instruments for chronic respiratory diseases; NS declares receipt of travel grants from Roche to attend meetings on avian infl uenza; YY delares no personal funding, but is an investigator on trials with Tibotec Pharmaceutical, and has received travel grants from GlaxoSmithKline, Roche, Boehringer, Bristol-Myers Squibb, Pfi zer, Abbot, and Gilead to attend scientifi c meetings. All other members of the panel declare that they have no confl icts of interest.
[table] Table: The recommended dose and duration of treatment and chemoprophylaxis for management of human infection of avian infl uenza A (H5N1) virus [/table]