Oseltamivir dosing optimization for critically ill patients with influenza A (H1N1)

Oseltamivir is an orally available neuraminidase inhibitor that has antiviral activity against influenza A and influenza B viruses. It is FDA-approved for the treatment of uncomplicated acute influenza in patients aged 1 year and older who have been symptomatic for no more than 48 hours.

Oseltamivir (Tamiflu, Roche) was the primary antiviral agent of choice during the avian influenza A (H5N1) scare that occurred several years ago. It has once again emerged as the agent of choice for the treatment of novel influenza A (H1N1) infections in humans. The standard dose and duration of oseltamivir treatment (75 mg by mouth twice daily for five days in adults and adolescents aged 13 years and older) is derived from treatment studies of outpatients with uncomplicated seasonal influenza. This dosing regimen is also the currently recommended regimen for treatment of H1N1 influenza infections.

Recently, the FDA issued an emergency use authorization (EUA) for the use of oseltamivir in patients aged younger than 1 year with confirmed or suspected 2009 H1N1 influenza. In addition, the EUA is authorizing initiation of oseltamivir in patients with suspected influenza infection who have been symptomatic for more than 48 hours. The CDC also states that “hospitalized patients with severe [H1N1] infections — such as those with prolonged infection or who require intensive care unit admission — might require longer treatment courses.” CDC officials have said that the evidence supporting this recommendation is limited. Evidence showing mortality benefit when oseltamivir is used outside of its FDA-approved indication is limited to a cohort study reported out of Ontario, a brief report from Hong Kong and a case series from Indonesia. The available data provide little guidance to prescribers for treatment strategy. Clinicians are forced to make individual risk-benefit assessments regarding appropriate oseltamivir use. To make an appropriate assessment for extended oseltamivir treatment duration for H1N1 infections in the setting of limited evidence it requires a thorough understanding of the nature of the virus and of the drug itself.

Antiviral action

All influenza viruses bear two surface glycoproteins, a hemagglutinin and a neuraminidase. The hemagglutinin mediates entry of the virus into the target cell, and the neuraminidase mediates the release of newly formed viruses still bound to already infected host cells. The complete inhibition of neuraminidase would limit influenza infections to one round of replication. Therefore, it is by inhibition of viral replication that neuraminidase inhibitors, such as oseltamivir, exhibit their antiviral effects against influenza viruses.

Oseltamivir is most effective if treatment is initiated in conjunction when the virus is most rapidly replicating, which is within the first 48 hours after symptoms develop. In fact, the 2003 IMPACT study found a positive correlation between the time to initiation of oseltamivir therapy and the duration of illness and other efficacy measures in 1,426 patients ranging in age from 12 to 70 years. In this study, initiation of treatment within the first 12 hours after the onset of fever shortened the illness by more than three days, as compared with the one-to-two day reduction seen with treatment that was started at 48 hours. In addition, the IMPACT study found that the duration of fever, severity of symptoms, and time to return to normal activity also correlated with the earlier initiation of oseltamivir treatment.

Influenza A (H1N1) virus

The novel influenza A (H1N1) virus was first detected in people in the United States in April. CDC officials said they believe that the virus emerged as a result of viral reassortment, a process that occurs when two or more influenza viruses swap genetic information while infecting a single human or animal host. In this case, the reassortment appears to have occurred between influenza viruses common to North American pig herds and viruses common to Eurasian pig herds. This virus — influenza A (H1N1) — exhibited unique characteristics that left us with little to no protection from it.

The first cases of H1N1 influenza were initially reported from California, Texas and Mexico. Some of the first reports out of Mexico included reports of severe illness, including fatalities. Reports of confirmed cases next appeared in Kansas, Ohio and New York. On April 24, Margaret Chan, MD, the director-general of WHO, determined that the events surrounding influenza A (H1N1) constituted a public health emergency of international concern. Through November, approximately 99% of typed influenza viruses have been influenza A (H1N1). As of Dec. 19, there have been more than 60,000 confirmed cases of influenza A (H1N1) associated with more than 221 pediatric deaths. With the severity this illness has presented, vaccine development and administration, as well as antiviral treatment optimization have been critical.

Oseltamivir treatment for H1N1

Since April, health care providers have not been hesitant to initiate oseltamivir treatment to patients presenting with flu-like symptoms, despite the length in time between the onset of symptoms and the patients’ clinical presentation. Patients in the critical care setting have also received oseltamivir treatment durations much longer than the standard five day course. This practice was earlier utilized by practitioners using oseltamivir for the treatment of avian influenza A (H5N1) virus.

Extended dosing oseltamivir for the treatment of the avian influenza (H5N1) virus was justified by evidence of higher levels and prolonged replication compared with seasonal influenza. There have been no reports suggesting similar replication patterns between the H1N1 influenza and the avian influenza (H5N1) viruses. It has become the clinical practice to err on the side of caution and treat more patients with oseltamivir therapy and to lengthen oseltamivir duration in the critically ill.

Lengthening oseltamivir therapy has been widely accepted, especially since there seems to be very little risk involved with drug exposure. Neuraminidase inhibitors, including oseltamivir, are associated with very little toxicity and are far less likely to promote the development of drug-resistant influenza. The most common adverse reactions to oseltamivir include nausea, vomiting and abdominal pain, all of which improve if therapy is administered in conjunction with food. Other less common but serious adverse reactions include: hypersensitivity reactions, dermatitis, elevated liver function tests, cardiac arrhythmias, seizures, delirium, aggravation of diabetes and hemorrhagic colitis. Although these side effects can be very serious, some may argue these are too infrequent to offset the potential benefit of reducing the severity of influenza illness in critically ill patients.

Unfortunately, the safety profile of extended oseltamivir has not been rigorously studied. The idea of prolonged oseltamivir therapy was considered for the avian influenza A (H5N1) “pandemic,” but we did not have to experience this first hand. That since has left a question of, is this treatment strategy appropriate and safe? Does long-term therapy affect clinical outcomes and adverse effects?

One strain of H1N1 influenza virus with more than 90% resistant to oseltamivir has already emerged. Although it may be prudent to continue current practice, it is important to realize that extended dosing oseltamivir has potential risks. As mentioned above, neuraminidase inhibitors are less likely to lead to drug-resistant influenza viruses, but we have yet to know the impact of prolonged drug exposure and resistance.

Practitioners should continue to follow treatment recommendations from CDC for updates on resistance patterns, empiric treatment recommendations and antiviral availability. Practitioners should also be aware of the serious adverse effects and monitor patients on the prolonged therapy for these adverse effects. Any suspected cases of adverse effects should be reported.

Learning from experience

The emergence of the novel influenza A (H1N1) virus created a true pandemic for the United States and much of the world. We know that oseltamivir is the first line drug of choice for treatment of influenza A (H1N1). Peramivir is also another treatment strategy for patients who are critically ill and have not responded to oral oseltamivir.

Clinicians will continue to make a judgment call as to what is best for patients based on the current evidence available and ongoing recommendations from CDC. Although we may not have enough evidence to support extended therapy oseltamivir for the current H1N1 influenza pandemic, there may be an opportunity to retrospectively look back at 2009 outcomes in patients who did receive extended dosing oseltamivir. This may also provide some insight for the future wave of influenza A (H1N1). We may have additional information on adverse effects or emergence of resistance that occurs when oseltamivir is used outside of its FDA-approved indication.

For more information:

• CDC. Emergency use authorization (EUA) review oseltamivir phosphate for swine influenza A. (Accessed 12/23/09, at http://www.cdc.gov/h1n1flu/eua/tamiflu.htm)
• CDC. Update interim Recommendations for the use of antiviral medication oseltamivir. (Accessed 12/27/09, at http://www.cdc.gov/H1N1flu/recommendations.htm)
• Intensive-Care patients with Severe Novel Influenza A (H1N1) Virus infection. June 2009. (Accessed 12/22/09, at http://www.cdc.gov/h1n1flu/ )
• Moscona, A. Neuraminidase inhibitors for influenza. N Engl J Med. 2005;353:1363-1373.
• Treanor JJ. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza-a randomized controlled trial. JAMA. 2000;283:1016-1023.
• Writing Committee of the Second World Health Organization Consultation on Clinical aspects of Human Infection with Avian Influenza A (H5N1) Virus. Update on Avian Influenza A (H5N1) virus infection in humans. N Engl J Med. 2008;258(3):261-273.