BUSINESS PLANNING SPECIAL
Antiviral drugs: essential info for business pandemic preparedness

NOTE: This article is reprinted from the April 5 CIDRAP Business Source Weekly Briefing as the first in a four-part series examining business-related stockpiling and use of antiviral medications. It demystifies the scientific aspects of antivirals and discusses what types the federal government is stockpiling and investigating. Other parts in the series look at distribution, ethical and legal concerns, and the role of antivirals in pandemic plans.

For access to the complete series, log on to the CIDRAP Business Source Web site to register for 2 weeks of free access to the entire Source content library, including all issues of the Weekly Briefing electronic newsletter.

 

May 11, 2007 (CIDRAP News) – At least 5 to 6 months into a pandemic, until a vaccine can be made and distributed, antiviral drugs for influenza (ie, antivirals) will be the only pharmacologic option for potentially preventing, shortening, or reducing the severity of illness among employees.

Given grim estimates of 30% absentee rates, offering employees antivirals as part of a prevention or treatment strategy could appear to be a cost-effective way of both reducing worker absenteeism and bolstering employees' confidence in their company. In a recent poll of 120 preparedness professionals attending the CIDRAP summit on business preparedness for pandemic influenza in February, 37% of the participants (many from Fortune 500 companies), said their firms had purchased or were planning to purchase antivirals for distribution to employees during a pandemic.

But what about the other 63%? Clearly, the decision about whether to stockpile and distribute antiviral drugs to employees is not a simple one. It is complicated by questions concerning:

Supply, distribution, and timing

• The government's ability to supply most Americans with antivirals
• Whether to distribute antivirals now or stockpile them for distribution during the pandemic
• Whether to use the entire stockpile during the first wave of a pandemic, when it is not known whether a second wave may be more—or less—deadly
• How state and selected local governments plan to distribute their stockpiles  (information that could help companies calculate how much of a stockpile they will need)
• The limited shelf life of antivirals

Effectiveness against a pandemic strain

• Viral resistance to the drugs

• Clinical investigations suggesting that higher doses of the drugs must be given over a longer period compared with seasonal influenza treatment
• Uncertainty about whether antivirals would be most efficiently used as pre-exposure prevention, postexposure prevention, or treatment of those already ill

Education, ethics, and usage

• How to educate employees about the potential for misuse with illnesses not caused by influenza

• Whether to provide enough antivirals for employees to share with their families
• Ethical concerns about who should have priority access to the drugs
• Availability of antivirals in other countries
• Distribution to overseas employees

Understanding the antiviral options
Two classes of antivirals, the adamantanes and the newer neuraminidase inhibitors, have been used to treat influenza A, the virus that has caused major past pandemics. The US federal stockpile of antivirals is largely made up of neuraminidase inhibitors. Adamantanes have been associated with rapid drug resistance (the acquired ability of an organism to withstand treatment to a certain drug) to the current seasonal flu virus (H3N2). However, the US Department of Health and Human Services (HHS) has stockpiled some adamantanes and has not ruled out their use in a pandemic. (See the sidebar article, "Adamantanes: What role will these antivirals have in a pandemic?")

The World Health Organization considers the neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza) the most important antivirals for the prevention and treatment of H5N1 infection (the infection currently of main concern in terms of a pandemic). Using them is much less likely to result in resistant virus strains than is use of adamantanes. No resistance against Relenza, a powder that is inhaled by mouth, has been detected in previously healthy patients, but H5N1 resistance to Tamiflu has been documented in several patients in Vietnam. The lack of Relenza resistance may be related to the relative lack of its use among H5N1-infected patients.

The goal for the national stockpile is to have a mix of roughly 80% Tamiflu and 20% Relenza, says Bruce Gellin, MD, director of the National Vaccine Program Office at HHS. "Having both drugs available is important, because they have slightly different molecular configurations; therefore, resistance to one doesn't necessarily mean resistance to the other," he says. This allows for a backup drug when treating a patient with a resistant virus. Tamiflu is the predominant drug in the stockpile because it is easier to use; it comes in capsule form, whereas Relenza must be delivered through an inhaler. In addition, the global manufacturing capacity of Tamiflu is currently much greater than that of Relenza.

Tamiflu and Relenza work by interfering with the release of influenza virus from infected human cells into the rest of the body. If the strain of pandemic influenza causes systemic disease (disease in other organs in addition to the lungs, which is currently seen with H5N1), Tamiflu will be the drug of choice, because it is absorbed and distributed throughout the body, according to a review article in the Jan 2006 issue of Emerging Infectious Diseases by Arnold Monto, MD, an epidemiologist from the University of Michigan School of Public Health, Ann Arbor. Relenza, on the other hand, may be useful in prevention, because it is delivered to the respiratory tract through an inhaler. The drug can stop infection from spreading from its point of entry (nasal passages or mouth).

Studies have shown that when Relenza or Tamiflu is administered within 2 days of illness onset to otherwise healthy adults, the drugs can reduce the duration of influenza A and B (seasonal flu) by about 1 day compared with placebo when the patient has no other accompanying disease.

It's important to note, however, that a drug's effectiveness against seasonal flu does not mean it will have the same result when used against H5N1 avian influenza or another pandemic strain. H5N1 is a particularly deadly strain that has killed about 60% of the people infected with it from late 2003 to now. For comparison, the case-fatality rate for the 1918 influenza pandemic has been estimated at about 2.5%.

To date, most patients with H5N1 have been treated with Tamiflu. Studies of Tamiflu for use in H5N1 influenza have produced varying results. Two studies of patients with H5N1 influenza in 2004 and 2005 revealed no difference in outcome between those who received Tamiflu and those who did not. However, some of the patients received an antiviral only later in the disease, and the studies were not large enough to produce meaningful conclusions.

"The numbers are so small that it's hard to know whether Tamiflu is efficacious at mitigating disease, but it's all we have, so it's worth trying because it has very limited toxicity [poisonous effects]," says Stephanie Black, MD, assistant professor of medicine in the section of infectious diseases at Rush University Medical Center in Chicago. Studies in mice have demonstrated a protective and therapeutic benefit of Tamiflu against the 2004 Vietnam strain of H5N1. However, this efficacy does not guarantee the same result in humans or with a pandemic strain.

A 2007 study of the effectiveness of Tamiflu in improving the survival rate of ferrets exposed to the H5N1 virus found that giving the drug within 4 hours of exposure (ie, before illness) resulted in 100% survival. When the treatment was delayed 24 hours after exposure, a higher dose was needed to achieve the same result. (H5N1 follows a similar course in ferrets and humans.)

Researchers have discovered that giving higher doses of Tamiflu for a longer period extended the survival of mice infected with H5N1. In a 2-year clinical trial beginning in May and run by the Southeast Asia Influenza Clinical Research Network, doctors in Asia and the United States will give patients with seasonal flu or H5N1 infection a double dose of the drug for twice the normal course (150 mg twice daily for 10 days rather than 75 mg twice daily for 5 days) to see if they can produce the same result in humans.

Exploring other antiviral avenues
HHS wants to add other options to its antiviral resources, Gellin says. While adamantanes are no longer used against seasonal flu because of evidence of drug resistance, HHS has stockpiled some to use if a pandemic strain proves to be susceptible to the drug. "We're monitoring [resistance] for H5N1," he says. "While some [strains] have developed resistance, some have not. This is part of a current assessment of our antiviral policy."

HHS is investing in another neuraminidase inhibitor called peramivir, an investigational drug developed by BioCryst Pharmaceuticals, Inc., Birmingham, Ala. According to the company's Web site, peramivir has "outstanding broad-spectrum potency against multiple strains of influenza, including the avian strain H5N1. In addition, peramivir retains activity [does not become resistant] against nearly all Tamiflu-resistant strains of influenza that have been identified to date."

BioCryst is focusing on developing two injectable forms of the drug, including an intramuscular form and an intravenous formulation. Gellin says HHS is particularly interested in the latter, because it would offer an alternative delivery method. Peramivir is in early clinical trials.

The National Institutes of Health is monitoring the development of two other drugs that work through different mechanisms, Gellin says. "We're interested to see, based on how the virus works, if we can head it off on a molecular basis," he says. One drug, which is being developed under the trade name Fludase by NexBio, Inc., San Diego, "potentially confers broad-spectrum protection against all subtypes and strains of influenza viruses (including the potential pandemic virus H5N1)," according to the company's Web site. Clinical trials on Fludase have not yet begun.

The second drug, an early investigational compound—one not yet in the drug pipeline—that goes by the moniker T-705, is being studied for its ability to inhibit the influenza virus, including strains that are resistant to neuraminidase inhibitors, Gellin says. However, these drugs will not be available in large volume for public use for at least several years.

Don't rely on antivirals alone
Gellin cautions that antivirals are but one option. "When we started our discussions on pandemic preparedness a long time ago, we had to say 'preparedness is not equal to Tamiflu,' " he says. "Tamiflu was something that was tangible. You could see it. You could hold it in your hand, and you could count on it. However, the HHS strategy included antivirals as one part of a broader strategy that includes enhanced domestic and international surveillance, improved diagnostic tests, vaccines, local preparedness, and the importance of a communication strategy prior to and during a pandemic."

Cautioning that what works in animal models does not necessarily work in humans, Gellin says: "Antivirals are potentially important, but we have to admit that we don't know how well [antivirals] might work against this [H5N1] virus."

—Mary Van Beusekom, CIDRAP Source Staff Writer