Treatment comes first in HHS antiviral guidance

Editor's note: This story was revised Dec 17 to include an item that was mistakenly left out of the list of five main recommendations on antiviral use in a pandemic.

Dec 16, 2008 (CIDRAP News) – A revised federal guidance document on the use of antiviral drugs in an influenza pandemic reaffirms that public supplies of the drugs should be reserved mainly for treating the sick and that preventive treatment for high-risk workers should rely on private supplies.

The Department of Health and Human Services (HHS) issued its draft guidance on the topic in June. A revision released yesterday includes no major changes but does have some new material added in response to comments, particularly on implementation problems and risks and uncertainties.

HHS also released a separate document summarizing the 28 comments it received on the draft version and presenting responses to them. At the same time, HHS released a revision of its guidance on employer stockpiling of antivirals, with no major changes.

The thrust of the general guidance is that, in a pandemic, antivirals should primarily be used to treat the sick, but they should also be used to prevent illness in high-risk healthcare and emergency workers and to both prevent and treat illness in the context of initial outbreaks both in the Untied States and overseas. The guidance pertains mainly to the two licensed neuraminidase inhibitors, oseltamivir (Tamiflu) and zanamivir (Relenza).

The five main recommendations are unchanged in the revised guidance. It calls for using antivirals for the following purposes:

  • Containing or suppressing initial pandemic outbreaks overseas and in the United States with treatment and postexposure prophylaxis (PEP) among individuals identified as exposed to pandemic flu and for geographically targeted prophylaxis in areas where exposure may occur
  • Reducing introduction of infection into the United States early in an influenza pandemic as part of a risk-based policy at US borders
  • Treating people with pandemic flu who present for care early during their illness and would benefit from such treatment
  • Prophylaxis of high-risk healthcare and emergency services personnel for the duration of community pandemic outbreaks
  • Prophylaxis of healthcare and emergency services workers who are not at high exposure risk, people with compromised immune systems who are less likely to be protected by pandemic vaccination, and people living in group settings such as nursing homes and prisons if outbreaks occur in their facilities

HHS is buying antiviral drugs for the Strategic National Stockpile, and states are stockpiling the drugs with a 25% federal subsidy. The overall goal for public stockpiles is 81 million treatment courses, including 75 million courses for treatment and 6 million for containment and for delaying the spread of pandemic flu into the United States.

About 73 million courses are currently in federal and state stockpiles, according to HHS's response to comments on the guidance. It also says "many federal agencies" are "acquiring additional stockpiles to support prophylaxis as recommended in the guidance," but it does not list the amounts of these supplies.

Like the draft version, the revised guidance says that antivirals for preventive treatment of healthcare workers and others will have to come mostly from supplies bought by private organizations and businesses for their employees.

HHS says the 28 comments it received on the draft guidance came from public health workers, healthcare providers, healthcare organizations, the pharmaceutical industry, business associations, public health organizations, and labor groups, among others.

The agency added two significant pieces to the guidance in response to comments. One addresses implementation difficulties, mainly concerning barriers to the stockpiling of antivirals for health and emergency workers; the other deals with risks and uncertainties, such as antiviral resistance and treatment effectiveness.

Lowering barriers to implementation
Several commentators said private organizations are unlikely to buy antivirals for their employees because of the cost, and several suggested that the federal government should buy the additional supplies needed to implement the guidance, according to HHS. Others said more information and materials were needed to support implementation.

The revised guidance says that barriers to antiviral stockpiling for healthcare workers include not only the cost, but also drug shelf-life, the potential for seizure of private stockpiles by state health departments, and liability concerns. These problems were identified in the stakeholder meetings conducted in developing the guidance.

The problems of cost and limited shelf-life may be reduced through programs recently announced by the antiviral manufacturers, whereby organizations can reserve an up-to-date supply of the drugs by paying a small annual per-regimen fee, the revised guidance says. At the time of a pandemic, organizations could pay for the drugs and receive them within 48 hours.

As for the possibility of government seizure of private antiviral supplies, the revised guidance says this would be very unlikely. Health officials who participated in a working group convened by the Association of State and Territorial Health Officials (ASTHO) "recognized the benefits of enhanced preparedness and coordination between public and private sectors and emphasized that this authority would be very unlikely to be used," HHS says.

In addition, the guidance says that a recent declaration by HHS Secretary Mike Leavitt provides that state and local governments will be immune to liability related to the use of oseltamivir and zanamivir only to the extent the drugs are obtained by voluntary means, not confiscation. The Public Readiness and Emergency Preparedness (PREP) Act gives the HHS secretary the authority to do that, the document states.

Leavitt made the declaration on Oct 10 on grounds that governmental seizure of antivirals "would undermine national preparedness efforts and should be discouraged," it adds.

The PREP Act provides immunity from tort liability for both public and private groups that make, distribute, and administer antivirals in accordance with the HHS secretary's declaration, the guidance says.

Despite the various measures designed to facilitate implementation of the guidance, some organizations will probably not have "the capacity or willingness to comply," the document states. "In such settings, it is important to emphasize that antiviral drugs are only one component of a comprehensive program to protect workers and maintain essential services."

Risk of resistance
HHS also says that several comments focused on risks and uncertainties related to antiviral use, including the possibility of resistant viruses and adverse events.

"Antiviral resistance does represent a threat to the potential effectiveness of treatment and prophylaxis," HHS acknowledges in its responses to the comments. The emergence of oseltamivir resistance in some influenza A/H1N1 viruses last winter illustrated this. But there is no evidence that use of oseltamivir induced this resistance, and H1N1 and other seasonal flu viruses remain susceptible to zanamivir, the agency adds.

In addition, the guidance document says that mathematical modeling studies suggest that "antiviral treatment and prophylaxis would remain beneficial overall unless some of the pandemic viruses introduced into the U.S. at the beginning of a pandemic are both resistant and fully transmissible."

The guidance also states that the antivirals may be less effective if "the usual dose and duration of therapy are not optimal for a pandemic virus."

In the responses to comments, HHS says that side effects of oseltamivir and zanamivir are uncommon. However, the guidance says that widespread use of the drugs may lead to the identification of new side effects. It notes that neurobehavioral problems have been seen in a few people treated with oseltamivir

Despite the risks related to antiviral stockpiling, the working group that wrote the recommendations considers them appropriate and the pandemic threat great enough to justify the investment in the context of other preparedness measures, the document says.

In its responses to the comments, HHS also states that:

  • Its recommendations are just that—not standards of care or requirements
  • Providing antiviral prophylaxis to the families of healthcare and emergency workers is not recommended, because they have no greater risk of pandemic flu than the general population
  • In the revised guidance, school dormitories may be considered a "closed setting for post-exposure prophylaxis during an outbreak," if the students have not been dismissed
  • No members of the interagency working group that wrote the guidance had ties to the antiviral drug manufacturers, and the latter were not included or consulted in developing the guidance

In addition, in response to a suggestion that families should be able to stockpile antivirals, HHS says that any recommendations on home stockpiling will depend on the results of pending studies.

Roche and GlaxoSmithKline, the makers of oseltamivir and zanamivir, respectively, are developing home kits designed for stockpiling, HHS says. "Approval of these 'medkits' by the Food and Drug Administration will depend on studies showing that the kits can be appropriately maintained, the instructions understood, and the drug used appropriately at the correct time," the agency says. "Any HHS guidance on home stockpiling will depend on the results of these studies and FDA approval of these products."

Revised guidance for employers
The revised guidance on employer stockpiling of antivirals, like the draft released in June, recommends that businesses providing frontline healthcare and emergency services plan to provide preventive antivirals for employees who will be exposed to sick people in a pandemic. It also says that critical infrastructure employers should "strongly consider" providing antiviral prophylaxis for essential workers.

The revised version also reiterates that employers will have to acquire their own antiviral stockpiles for preventive use, since there are no plans for major expansion of public stockpiles.

In a separate document, HHS says it received comments on the draft employer guidance from 31 stakeholders, ranging from academics and labor unions to critical infrastructure companies and public health groups.

Several of the comments focused on whether antiviral stockpiling would be considered a "standard of care." In its response, HHS says its recommendations are only guidance and do not establish a requirement, but rather represent a prudent approach.

Some other comments addressed several of the same difficulties mentioned by those who commented on the general guidance: the cost of antivirals, limited shelf-life of the drugs, and the possibility of government confiscation. In its response, HHS makes generally the same points as in its response to comments on the general guidance.

See also:

HHS report "Considerations for Antiviral Drug Stockpiling by Employers in Preparation for an Influenza Pandemic"
http://www.flu.gov/planning-preparedness/business/antiviral_employer.pdf

Jun 3 CIDRAP News story "HHS offers pandemic guidance on masks, antivirals"

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