Influenza antiviral drugs: Use them, then lose them

By the time you read this editorial, the United States will have experienced a biologic attack that likely will have killed at least 36,000 of our fellow countrymen and women.

The general public probably will not have heard much, if anything, about it. The biologic agent is influenza and the havoc that it wreaks each year is both predictable and unforgivable – predictable because of the thousands of Americans it kills annually and unforgivable because it can be prevented.

As is typical of the American health care system, management of influenza relies too much on support and treatment once someone is sick with the illness and too little on preventing the illness in the first place. The fallacy of the former approach is readily seen in the emergence of antiviral resistance that has been occurring over the past three years.

There currently are two classes of antiviral agents that are licensed for the treatment or prevention of influenza: the adamantanes, which consist of amantadine and rimantadine; and the neuraminidase inhibitors, which consist of oseltamivir and zanamivir.

Amantadine was first licensed by the FDA in 1966 and as such holds the unique distinction of being the oldest systemic antiviral drug. Rimantadine was licensed in 1993 and has the benefit of being severalfold more active than amantadine while having fewer central nervous system adverse events.

The viral target of the adamantanes is the influenza A virus M2 protein, which functions as a pH-activated ion channel that permits ions to enter the virion during the process of viral uncoating, resulting in destabilization of protein-protein bonds and allowing the viral nucleic acid to be transported into the nucleus of the newly-infected cell.

Both amantadine and rimantadine block the M2 ion channel and thereby interfere with influenza A virus replication. Since influenza B viruses do not have an M2 protein, amantadine and rimantadine have no antiviral activity against them. In contrast, the neuraminidase inhibitors, oseltamivir and zanamivir, are active against both influenza A and influenza B. Licensed in 1999, these two drugs inhibit the viral neuraminidase found in both influenza A and B and thus interfere with the de-aggregation and release of the viral progeny.

Adamantane resistance

Resistance to the adamantanes is conferred by mutations in the M2 protein, while resistance to the neuraminidase inhibitors is conferred by mutations in the neuraminidase enzyme. Adamantane resistance among circulating influenza A viruses has increased rapidly. The proportion of adamantane-resistant influenza A isolates worldwide increased from 0.4% during 1994-1995 to 12.3% during 2003-2004.

During the 2005-2006 influenza season, adamantane resistance rates skyrocketed to 92% of influenza A (H3N2) viruses, leading the CDC and the AAP to recommend in early 2006 that amantadine and rimantadine not be used for the treatment or prevention of influenza.

This left oseltamivir and zanamivir as the sole workhorses for the treatment of influenza disease. As with the adamantanes, resistance to the neuraminidase inhibitors initially was rare. From 1999 to 2002, only 0.3% of influenza isolates worldwide were oseltamivir-resistant. Even in Japan, where oseltamivir use is the highest in the world, resistance initially was not seen. Beginning with the 2005-2006 influenza season, though, things began to change. By the 2007-2008 season, 11.3% of influenza A (H1N1) isolates in the United States were resistant to oseltamivir, with some European countries reporting resistance rates of up to 70%. Preliminary data from the Southern Hemisphere during the 2008 influenza season suggested near-universal resistance to oseltamivir, among A (H1N1) viruses, even in countries that use relatively little oseltamivir such as South Africa.

On Dec. 19, 2008, the CDC released preliminary U.S. data on the antiviral sensitivities of 78 influenza viruses from 15 states. Of the 50 A (H1N1) viruses, 98% were oseltamivir-resistant but all were sensitive to zanamivir and the adamantanes. Of the eight A (H3N2) viruses, all were sensitive to oseltamivir and zanamivir but were resistant to amantadine and rimantadine. Of the 20 influenza B viruses, all were sensitive to the neuraminidase inhibitors. Thus, at the current time it looks like we have lost oseltamivir for the A (H1N1)s and we continue to not have the adamantanes for the A (H3N2)s, leaving zanamivir as the sole drug that can reasonably be expected to be active against all circulating strains of influenza.

With this in mind, the CDC released interim treatment recommendations, which are summarized in the following table:

Where all of this leads to next is unclear. Influenza viral replication is notoriously promiscuous, which is the reason that the circulating strains vary so much from year to year. It is possible that future strains will regain sensitivity to one or both classes of antiviral drugs. In the meantime, we are fortunate that oseltamivir and adamantane resistance is occurring in differing influenza strains, allowing for at least the theoretical prospect of dual therapy to cover all possible viruses causing a given person’s influenza illness. Zanamivir also remains a possible therapeutic agent, although its mode of delivery (inhalation) limits its use to older children and adults. If history is any guide, however, resistance will continue to worsen and in the not-too-distant future we could find ourselves again in the pre-1966 world of having no effective influenza antiviral drug to use.

In the midst of this doom and gloom, there is one very bright ray of hope. It is not sexy or flashy, but clearly represents our best option in the management of the inevitable annual influenza epidemics: vaccination.

Immunization

I would argue that the best influenza antiviral is an immune system already primed to prevent infection and disease. New production lines and techniques have increased our supply of influenza vaccine. While certain groups, such as the elderly, may not respond as robustly to influenza immunization, vaccinating entire communities can cocoon these especially vulnerable people by limiting influenza circulation.

For influenza immunization programs to be successful, though, the American people must decide to get vaccinated and access to vaccination sites must be without hindrance. We’ve got a long way to go. Only 20% to 40% of children aged 6 to 23 months at sentinel CDC sites are receiving one or two doses (as appropriate) of influenza vaccine. While about 70% of people aged older than 65 years are vaccinated for influenza annually, only about 40% of healthcare workers are vaccinated and 10% to 20% of pregnant women are vaccinated.

Perhaps most discouraging, these rates have not increased over the past several years.

The Advisory Committee on Immunization Practices recommended that all children aged 6 months to 18 years receive annual influenza vaccinations beginning with the 2009-2010 season. The logic is that bottom-up approaches in building infrastructure to improve vaccination rates have not worked and therefore a top-down approach in the form of expanded mandates is the next step. I hope that they are right.

The easy part is to make the recommendation; the hard part is to actually figure out how to implement it. Pediatricians will need to see every patient in their practice within a two to three month window of time during the school year, when availability to go to the doctor for a well-child visit is be limited. School-based immunization programs largely were disassembled years ago. Pharmacy-based immunization is allowed in some states but not others. And all of this is happening at a time when the country is experiencing its worst financial crisis in 70 years.

So what should be done? First, the principle of disease prevention should finally be weighted more heavily than the principle of disease treatment. Until the country and its populace truly embrace this concept and allocate resources accordingly, we will continue to pay the most for healthcare of any country in the world and yet receive less benefit than other countries for the dollars spent. Second, programs that promote influenza immunization must be expanded. Third, and perhaps most importantly, the country must rediscover the value of shared responsibility and the need to promote the public good. My children receiving the influenza vaccine could save the life of an elderly neighbor who is undergoing chemotherapy treatments for ovarian cancer. There is something bigger than me in this world and the me-generation(s) must discover this greater good.

David W. Kimberlin, MD, is Professor of Pediatrics in the Division of Pediatric Infectious Diseases at The University of Alabama at Birmingham.