HHS plan for hospitals to stockpile pandemic flu antivirals draws fire

Cost and a host of consequences are cited

With a matching vaccine not expected to be available for at least five months if and when pandemic influenza hits, hospitals should stockpile flu antivirals to protect their health care workers, the U.S. Department of Health and Human Services (HHS) recommends in recently issued draft guidance.1 Sounds straightforward enough, but the recommendations immediately drew strong reactions and raised thorny questions about health care worker willingness to take prolonged antiviral regimens, the potential for side effects and adverse reactions, and the cost and expiration dates of the products.

"We are very disappointed that the HHS hasn't placed more emphasis on personal protective equipment, covering coughs, hand hygiene, quarantine strategies, etc. — and less emphasis on antivirals," says Susan Kraska, RN, CIC, an ICP at Memorial Hospital of South Bend, IN. "In the end, wrapping your arms around an outbreak takes a lot more than the false sense of security prophylaxis offers. [Antiviral] stock rotation needs to occur, outdates and expirations need to be monitored, storage of stockpiles with temperature controls all take resources out of an already stressed health care system. This is not as simple as it may first appear."

The HHS calls for hospitals to provide antiviral regimens to health care workers during the duration of a pandemic outbreak in their community, which would typically translate to eight 10-dose regimens per worker over a 12-week period. The guidelines call for prophylaxis of hospital employees who are potentially exposed to patients, which HHS estimated to be about two-thirds of workers in any given facility. With the 10-dose regimens running in the $40-$50 range, the cost will not be inconsequential.

"The concept here is to protect people who are exposed to patients who may have influenza," says Ben Schwartz, MD, senior science adviser with the National Vaccine Program Office at the HHS. "We want to keep the people who are at high risk protected by giving them prophylaxis, and our estimate is that's about two-thirds of the population of health care workers."

The remaining one-third of workers should be considered for post-exposure prophylaxis (PEP) if they have close contact with an influenza patient, he tells Hospital Infection Control. "For those who are less likely to be exposed — who may never have an exposure or just have an infrequent exposure — PEP prophylaxis would be very effective," he says. "It also uses fewer antiviral drugs, so it is a more cost-effective approach."

The HHS draft recommendations make the assumption that there will not be a vaccine immediately available should a pandemic flu strain emerge, he adds, estimating 20 weeks from the appearance of a pandemic strain to creation of a matching vaccine. "Based on how quickly a pandemic may spread, we don't have confidence that a vaccine will be available at the beginning," Schwartz says. "Health care workers are recommended to be in the first group to receive vaccine once it is available; so by stockpiling antiviral drugs, it is in some ways a 'belt-and-suspenders' approach. It provides the confidence that hospitals will be able to protect their work force in a pandemic."

Whether it emerges via some mutation of avian influenza A H5N1, or some other strain, a fact not frequently noted is that even a perfectly matched vaccine will not provide immediate protection against a pandemic flu virus. "It takes two doses to stimulate immunity," he explains. "So after the health care worker gets the first dose, you need to wait either three or four weeks before giving the second dose, and then it may take another week or two before a good immune response develops. So even after the health care worker is vaccinated with that first dose, there is still a period of maybe five to six weeks in which they are vulnerable to getting infected. That is another reason that the antiviral drugs need to be available to protect these important workers."

Two FDA-approved influenza antiviral medications used in the United States are oseltamivir (Tamiflu®) and zanamivir (Relenza®). These neuraminidase inhibitors have activity against both influenza A and B viruses. While all bets are off if a pandemic flu strain emerges, advice distributed by the CDC during the 2007-2008 flu season underscores that using antivirals to stave off or lessen the severity of flu infections is not without risk. According to the CDC, "when considering use of influenza antiviral medications, clinicians must consider the patient's age, weight and renal function; presence of other medical conditions; indications for use (i.e., chemoprophylaxis or therapy); and the potential for interaction with other medications. The main side effects for oseltamivir are nausea or vomiting (10%). Rare cases of transient neuropsychiatric events (self-injury or delirium) have been reported during post-marketing surveillance among people taking oseltamivir, primarily in Japan. Zanamivir is not recommended for people with underlying airways disease (e.g., asthma or chronic obstructive pulmonary diseases)."2 Thus, administering antivirals to large groups of health care workers would require some level of screening and follow-up.

"Health histories on employees will become an issue regarding staff ability to take the drugs," says Katherine West, RN, MSEd, CIC, a consultant with Infection Control/Emerging Concepts in Manassas, VA. "Side effects of the drugs are an issue as well. Lessons should have been learned from the anthrax episode in 2001 [with widespread administration of ciprofloxacin]. No questions were being asked about pregnancy, other current meds, medical history or allergies."

Will health care workers comply?

In addition — given the well-documented historical apathy of health care workers toward seasonal flu vaccination — it is not completely farfetched to ask whether they will comply with the antiviral recommendations even in the face of a pandemic. Kraska, who served on an Indiana state panel that looked at the role of antivirals in a pandemic, says the group came to a somewhat surprising conclusion.

"We looked at the issues surrounding mass prophylaxis and who should be included," she tells HIC. "Interestingly, we came to the conclusion that using antivirals for long periods wasn't acceptable to many health care workers. It is the uncertainty of how long? How effective? What is the impact on their health? To our knowledge, there are no studies that show the long-range effect of antivirals. Overall, we didn't feel it was more effective than preventing exposures in the first place [through barrier precautions and other infection control measures]."

The FDA has approved oseltamivir for a six-week prophylaxis course, Schwartz says, adding that ongoing studies may be able to extend the approved duration to 12 weeks. "In controlled trials with Tamiflu, there is some nausea and vomiting that may occur, but very rarely did someone receiving the drug need to stop taking it because of those side effects," he says. "In a pandemic, [health care workers] would recognize that they will be constantly exposed to patients with influenza. I think they would view this as an important way to protect themselves. Certainly, there would be noncompliance; people may forget to take it or stop taking it early. We see that with any drug in any population."

Another question is how quickly antiviral resistance will appear once mass prophylaxis programs begin. "We also need to consider emerging resistance of influenza A to existing antivirals," says Diana Carpal, RN, CIC, a member of the Indiana antiviral panel and infection control and prevention coordinator at Saint Joseph Regional Medical Center in South Bend. "Inappropriate or mass use could 'push' this even faster, leaving our stockpiled supplies mostly ineffective."

Ultimately, the Indiana panel decided using antivirals for post-exposure prophylaxis (PEP) of health care workers would be more effective than starting them on regimens as soon as a pandemic strain appears in the community. The HHS guideline concedes that PEP could be an alternative strategy, but the effect essentially may be the same. "Because exposure to ill persons during a pandemic outbreak will be frequent for health care workers and emergency service personnel with direct patient contact, post-exposure prophylaxis would be essentially equivalent to outbreak prophylaxis — as soon as one 10-day course of PEP ended, another would likely begin," the draft guidelines states.

A modification of the PEP strategy may be to dispense PEP only when "unprotected" exposures occur. "Potential concerns with this approach for those with frequent high-risk exposures include whether it would be sufficient to reduce absenteeism that may occur due to fear of occupational infection, whether unprotected exposures could be accurately identified and how frequently they would occur in a heavily exposed population," the HHS states. "In addition, there is a lack of data on the effectiveness of personal protective equipment measures in preventing influenza transmission. A hybrid strategy that includes outbreak prophylaxis for workers with frequent high-risk exposures and post-exposure prophylaxis when unprotected exposure occurs for those who have less frequent or intensive patient contact tailors the intervention to the level of risk and is the preference of the [HHS] working group."

Hold back until pandemic is local

Antiviral medications are 70%-90% effective in preventing influenza, but the drugs must be taken each day for the duration of potential exposure to influenza or until immunity after vaccination develops. The HHS is advising that even if a pandemic begins elsewhere, antivirals should be held back until it hits your local area. "You want to wait until it is in your community," Schwartz says. "The trigger for hospitals is when they are notified by their public health officials that a pandemic virus is in their area and an outbreak is beginning."

Though one certainly can argue that stocking antivirals is an investment in worker protection similar to the cost of vaccines for hepatitis B and other diseases, some hospitals may balk at such expenditure for a threat that is merely theoretical on the near horizon. A hospital with 2,400 employees, according to the HHS formula, would need to stockpile antivirals for 1,600 of them. At $400 per eight 10-pack doses, that translates to a $640,000 expenditure. With 7,000 employees, facilities such as the Marshfield (WI) Clinic are looking at much larger numbers. "For a system of our size, [this would require] a fairly significant outlay of cash," says Bruce E. Cunha, RN MS COHN-S, manager of employee health and safety at the clinic. "Given that the antivirals have expiration dates, I feel facilities are going to be reluctant to stockpile all that much."

The respective shelf-lives for Tamiflu and Relenza are seven years and five years if used in stockpiles, Schwartz says. "But the companies are continuing to test the potency of the drugs and they may in the future have longer [expiration dates] if it is FDA-approved," he adds.

In any case, hospitals should make the purchase to safeguard their workers, even if they have to make it again if the stockpile sits unused past the expiration period, Schwartz argues. "If a pandemic does not occur within the seven-year licensed shelf life, then they would need to repurchase their antiviral drugs — so this would represent a recurring cost," he says. "There is currently not a federal program that would purchase the drugs for prophylaxis of private sector health care workers."

The hospital stockpiles are not intended for treatment of infected patients, which would be covered by state and federal sources during a pandemic, Schwartz adds. Neither are the hospital stockpiles earmarked for family members of health care workers, though pandemic planners have warned that staff may not show up unless they believe their families are safe. "The [HHS guidelines] do not include a recommendation for family members, though a hospital could certainly choose to stockpile drugs for the family members as well as the health care workers," he says. "But given the burden and expense of protecting their health care work force, I think it's unlikely that hospitals would also choose to protect family members."

That said, health care workers receiving prophylaxis would pose no threat to their families, who would receive antivirals for treatment as needed from community sources, Schwartz emphasizes. "Recognizing that the way influenza is transmitted is by respiratory droplets, if you protect the health care worker then they would not be at risk to bring the infection home to their family," he says. "So one important thing to emphasize in the education that should be provided is that families of health care workers are not at increased risk compared to other families. That should reassure them they do not need special prophylaxis."

Indeed, the HHS draft guidelines argue essentially that prophylaxing health care workers may be the best strategy to get them to stay on the job. "The health care sector will face a massively increased burden while coping with a work force diminished by illness and possibly other causes of absenteeism — for example, caring for an ill family member or due to fear of becoming infected in the workplace," the guidelines state. ". . . [A]ntiviral prophylaxis may reduce absenteeism both by preventing illness and by improving perceptions of safety in the workplace."

Uncharted territory

The HHS guidelines concede the health benefits of this ambitious prophylactic strategy cannot be easily quantified. Several studies suggest that health care workers who have patient exposure have increased rates of seasonal influenza infections, the guidelines note.3,4 In addition to the direct effect of reducing pandemic influenza illness and its consequences, prophylaxis also would reduce the risk of transmission to family members, co-workers, and to patients, the guidelines state. Influenza prevention by vaccination of health care workers has been shown to reduce nosocomial infection in acute care hospitals and mortality in long-term care facilities for the elderly.5,6

Nevertheless, given the litany of concerns, the HHS may face formidable opposition to its guidelines and compliance problems if they are finalized as drafted. Ultimately, the specter of pandemic flu may stand as its own best argument for preparation. It is oft described as something that must be faced eventually, a "when-not-if" biological disaster that could all but shut down the health system. And H5N1 is conceivably but a few fateful mutations away from becoming easily transmissible among humans.

"Part of the planning for hospitals is acquiring the materials, whether it be masks or respirators or antiviral drugs that will protect their health care workers and maintain operations during a pandemic," Schwartz says. "One cannot predict whether H5N1 is going to ever cause a pandemic. It certainly is the greatest pandemic threat that is out there. The continued circulation of this virus in poultry and the occasional infection of people certainly raise the risk that such a mutation could occur. Whether it does or not is totally unpredictable."

(Editor's note: The HHS issued a notice regarding the guidelines and a comment period in the June 3, 2008, Federal Register. The guidelines are posted at http://aspe.hhs.gov. The comment period ends July 3, 2008.)

References

  1. Department of Health and Human Services. Proposed Guidance on Antiviral Drug Use during an Influenza Pandemic, 2008. Available at: http://aspe.hhs.gov.
  2. Centers for Disease Control and Prevention. Influenza Antiviral Medications: Summary for Clinicians, 2007. Available at: www.cdc.gov.
  3. Elder AG, O'Donnell B, McCruden EAB, et al. Incidence and recall of influenza in a cohort of Glasgow healthcare workers during the 1993-4 epidemic: Results of serum testing and questionnaire. BMJ 1996; 313:1,241-1,242.
  4. Kawana A, Teruya K, Kirikae T, et al. Syndromic surveillance within a hospital for the early detection of a nosocomial outbreak of acute respiratory illness. Jpn J Infect Dis 2006; 59:377-379.
  5. Salgado CD, Giannetta ET, Hayden FG, et al. Preventing nosocomial influenza by improving the vaccine acceptance rate of clinicians. Inf Cont Hosp Epidemiol 2004; 25:923-928.
  6. Carman WF, Elder AG, Wallace LA, et al. Effects of influenza vaccination of healthcare workers on mortality of elderly people in long-term care: A randomized controlled trial. Lancet 2000; 355:93-97.