# 271
Yesterday (Jan 1st), the British medical journal The Lancet published a review of the current WHO (World Health Organization) recommendations for the use of antivirals when treating sporadic cases of H5N1 Avian Flu in humans. Entitled WHO Rapid Advice Guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus, it is available online here for registered members of the Lancet.
Basically a panel of doctors and scientists was convened to review the meager scientific evidence gathered to date on the efficacy of various treatments for the H5N1 virus, and based on factors such as the high mortality rate of the virus, the low incidence of side effects of medications, and the risk factors of various groups, they have come up with recommendations for treatment and chemoprophylaxis using Tamiflu, Relenza, Amantadine, and Rimantadine.
Spoiler: For those who like to read the last page of a mystery novel first, the big surprise in all of this is: there is no recommendation to increase the dosage or duration of the administration of Tamiflu (Oseltamevir). The `seasonal flu’ course of treatment, 10 pills over 5 days, is maintained despite rumblings for months in the medical community that `double the dose for double the duration’ might be needed.
A cynic might point out that increasing the recommended course from 10 pills to as many as 40, could effectively reduce each nation’s stockpile by up to 75% (in terms of the number of patients that could be treated), and would open up a public relations can of worms, but in all fairness, there are other plausible explanations. They may simply have too little data on too few patients to make solid recommendations at this time.
It is unlikely that any doctor treating an H5N1 patient would withhold essential treatment after the fifth day if the patient still showed signs of infection, so the five-day recommendation is unlikely to cause patients any harm. This will, however, become a major issue that must be addressed if we ever move beyond `sporadic' cases.
Moving on.
The authors cite that most of their clinical data on H5N1 cases are derived 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).1 Treatment regimens differed 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.”
A good deal of their data was derived from studies on the use of antivirals against regular seasonal flu. The amount of real data available on the use of various antivirals when used against the H5N1 virus is pretty small, and often treatment didn’t begin until very late in the course of the illness. This panel was therefore forced to make difficult decisions based on less than ideal data.
Tamiflu was strongly endorsed by this panel as the first line of defense against the H5N1 virus. Quoting from the study:
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).
Relenza (Zanamivir) received a weak recommendation from the panel, based on the lack of any direct evidence that it is effective against the H5N1 virus (no studies) and concerns over the delivery system (inhaled).
Amantadine and Rimantadine, both M2 ion channel inhibitors, received weak conditional recommendations by the panel. Quoting:
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.1 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.
Early reports of Amantadine resistance in the H5N1 virus Clade I, combined with a higher risk of CNS (central nervous system) side effects from these drugs, make them less desirable than Tamiflu. The panel concludes:
This assessment of possible net benefit 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 effects.
A nice way of saying, if you can’t get Tamiflu, they are likely better than nothing.
The panel also addresses chemoprophylaxis, or the administration of antivirals to those persons presumed to be exposed, but not yet showing symptoms of infection. They have divided those exposed into 3 groups, as defined below.
High-risk exposure groups are currently defined as:
•Household or close family contacts**A close contact may be defined 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 confirmed or strongly suspected H5N1 infection.of a strongly suspected or confirmed 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 defined as:
•Individuals with unprotected and very close direct exposure††Examples of high-risk exposure based on confirmed 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 confined space, such as playing with pets.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 confirmed H5N1 patients, for example during intubation or performing tracheal suctioning, or delivering nebulised drugs, or handling inadequately screened/sealed body fluids without any, or with insufficient, personal protective equipment. This also includes laboratory personnel who might have an unprotected exposure to virus-containing samples‡‡This definition 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 defined as high risk.
Low-risk exposure groups are currently defined 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 confirmed H5N1 patient
•Health-care workers who used appropriate personal protective equipment during exposure to H5N1 patients
•Personnel involved in culling non-infected or likely non-infected 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.
Based on these risk groups, the panel recommends that Tamiflu or Relenza:
Should be administered to High Risk groups for 7-10 days after their last exposure
Might be administered to Moderate Risk Groups for 7-10 days after their last exposure.
Probably should not be administered to Low Risk Groups.
The M2 ion channel inhibitors (Amantadine and Rimantadine) received weak and highly conditional recommendations for chemoprophylaxis. The likelihood of side effects is seen as higher, as are the odds of the virus developing resistance.
All totaled there are 23 recommendations in this study, and the entire article is worth reading.
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