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What pharmacological therapy should be selected for patients with suspected oseltamivir-resistant influenza A (H1N1)?

Introduction

Influenza activity during the 2008-2009 is lower than usual, but activity is starting to increase toward the end of the season.¹ Every year, about 5% to 20% of the population within the United States is infected with the influenza virus.² Twenty thousand of these individuals are hospitalized for complications, and about 36,000 individuals die from causes related to influenza. The influenza virus is subdivided into 3 types: influenza A, influenza B, and influenza C. Influenza A is further subdivided into 2 subtypes: influenza A (H1N1) and influenza A (H3N2). Influenza A and B are major causes of human illness associated with an influenza infection. In contrast, influenza C will present as a less severe form of infection.³ The influenza virus infects the epithelium of the respiratory tract resulting in an acute illness involving fever, malaise, and cough.^3,4 The virus is transmitted via the droplets formed when an infected person coughs or sneezes. Inadvertently, these droplets can be spread through casual forms of human contact or inanimate objects. Thus, the influenza virus can easily infect a large number of individuals in a relatively short period of time.

The influenza virus can be detected through a variety of testing methods that may be available depending on a healthcare professional’s practice setting. It can be isolated through nasal swab specimens, throat swab specimens, a combination of nasal and throat swab specimens, or nasal washes.⁴ There are a number of rapid testing products that can detect both influenza A and influenza B within a relatively short period of time. In order to detect the influenza virus, a sample of a respiratory secretion is treated with a mucolytic agent and is exposed to antibodies that react with the antigens presented in the respiratory sample. Thus, if the influenza virus is present, the testing device will change color to show that the antibody on the testing device has reacted with the antigen in the sample. However, there are several limitations to rapid antigen testing. The sensitivity of these tests can vary due to the type of respiratory sample that is used in the testing. Also, the age of the patient can also affect the sensitivity of the test. Young children shed a larger amount of the virus in their nasal secretions than adults; therefore, a larger quantity of antigens are available in their testing samples. A major disadvantage of the rapid antigen tests is their inability to distinguish between the 2 influenza A subtypes.⁵ There are other tests available to distinguish between influenza subtypes, but these tests are not readily accessible to healthcare professionals within the ambulatory setting, and the results of the test are not evident for several days. Therefore, it is even more imperative that a healthcare professional is able to select a pharmacological agent based on objective data available.

Treatment of influenza

An annual influenza vaccination is the most optimal therapeutic intervention to prevent influenza infection and complications related to infection. However, for patients who are infected with influenza, there are particular pharmacological agents that assist in their recovery. The Centers for Disease Control and Prevention (CDC) sets forth recommendations for antiviral use for each influenza season depending on the susceptibility of the virus within the population to the available antiviral agents. In general, antiviral therapy is recommended for anyone with laboratory confirmed influenza who presents for care within 48 hours of symptom onset who express the desire for treatment in order to reduce severity or duration of symptoms or to prevent transmission to high-risk contacts.⁶ Treatment initiated within the appropriate timeframe is especially important for hospitalized patients, patients with influenza pneumonia, influenza with bacterial coinfection, and patients at high risk for complications.

Due to the increased incidence of oseltamivir-resistance influenza A (H1N1), for the 2008-2009 influenza season, the CDC has made adjustments to its antiviral guidance recommendations.^5,7 Selection of antiviral therapy should be based on viral surveillance data and resistance patterns in the community. Healthcare providers can contact the state public health department to obtain information related to local influenza activity. Specific recommendations are summarized in the table below.

Table 1. Recommendation for antiviral treatment based on test results and viral surveillance data.^5,7

The 2 main antiviral drug classes available to treat influenza are the adamantanes (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir). It is recommended that treatment be initiated within 48 hours of the presentation of symptoms. Zanamivir is considered the preferred therapeutic option for patients residing in communities with unknown or influenza A (H1N1) predominant viral infections based on viral surveillance. Yet, zanamivir should not be used in children less than five years old due to inadequate inhalation of the medication via the inhaler.⁸ Zanamivir should also be avoided in patients with a history of respiratory disease due the risk of serious adverse effects and the lack of efficacy in this particular special population. Based on the CDC recommendations, amantadine may be substituted for rimantadine as an alternative treatment option for patients with suspected or documented influenza A (H1N1). However, amantadine has increased risk of adverse events specifically, central nervous system disturbances (i.e. anxiety, hallucinations, depression). Thus, a comprehensive review of the local viral surveillance and the patient’s medical history should be evaluated prior to initiating pharmacological therapy for the treatment of influenza.

Trends 2007-present

Within the past couple of years, the influenza virus has been showing resistance to the pharmacological agents available for the treatment of influenza. At the beginning to 2006, the CDC stated that a particular subtype of influenza was over 90% resistant to the adamantane medication class (amantadine and rimantadine).⁹ However, the resistance that was seen with the adamantine medication class was not thought to occur with neuraminidase inhibitors (oseltamivir and zanamivir).¹⁰

In fact, the incidence of oseltamivir-resistance in clinical trials was less than 1% in adults and less than 5% in children.¹⁰ However, as time has progressed, the incidence of oseltamivir resistance has increased. In the 2007-2008 influenza season, oseltamivir resistance was detected in 10.9% of the H1N1 viruses tested within the United States.¹¹ Other geographic regions were not immune to the prevalence of oseltamivir resistance. Within in Canada and Europe, the percentage of oseltamivir resistance was reported as 26% and 25%, respectively.¹² Also, the reporting of oseltamivir resistance does not correlate with the use of the medication within a particular region. For example, in Japan, the incidence of oseltamivir-resistance is fairly low at 3% of H1N1 strains showing oseltamivir-resistance. However, Japan has the highest per capita oseltamivir use in comparison to other countries. Thus, the resistance pattern that is being observed may not be linked to the use of oseltamivir within the general population.

The trend of oseltamivir-resistance that was detected 1 year ago continues to be present at a staggering rate. Surprisingly, recent data show that the frequency of oseltamivir-resistance detected in influenza A (H1N1) has increased to 98.5% during the early 2008-2009 influenza season.¹³ The resistance pattern of a subtype of influenza A allows healthcare professionals to select therapeutic options that would be most effective against the resistant virus. A recent clinical study conducted by Dharan was a descriptive study that described the risk factors for infection with oseltamivir-resistant viruses. Public health laboratories in the US voluntarily submitted influenza A (H1N1) virus isolates and samples of other virus types and subtypes. The demographic characteristics and clinical symptoms were compared between patients with oseltamivir-resistant and oseltamivir-susceptible influenza A (H1N1) infections. The study showed that the demographic characteristics and clinical symptoms were similar between patients who were infected with susceptible and resistant strains. Significant limitations to this study were the small number of influenza A (H1N1) samples and the passive nature in which the analyzed samples were obtained. However, the large increase in the incidence of oseltamivir-resistant strains is alarming. Thus, with the increasing emergence of oseltamivir-resistant influenza, the selection of an appropriate therapeutic agent is even more important in order to resolve symptoms secondary to infection with influenza.

Conclusion

The increased incidence of oseltamivir-resistant influenza A (H1N1) has caused the CDC to update treatment recommendations. Healthcare professionals should select the pharmacological agent for treatment of the infection based on local viral surveillance. Thus, knowledge of the most likely type and subtype of influenza causing a patient’s infection and the selection of the appropriate therapy would aid in relieving symptoms.

References

1. Centers for Disease Control and Prevention. Questions & Answers about the 2008-2009 flu season. http://www.cdc.gov/flu/2008-09_flu_qa.htm. Accessed March 9, 2009.
2. Centers for Disease Control and Prevention. Influenza: the disease. http://www.cdc.gov/flu/about/disease/ . Accessed March 9, 2009.
3. Dolin R. Influenza. In: Braunwald E, Fauci AS, Kasper DL, Hause SL, Longo DL, Jameson JL. Harrison’s Principles of Internal Medicine. 15^th ed. New York, NY: McGraw-Hill; 2001:1125-1135.
4. Treano JJ. Influenza virus. In: Mandell GL, Bennett JE, Dolin R. Principles and Practice of Infectious Diseases. 6^th ed. Philadelphia, PA: Elsevier; 2005:2060-2085.
5. Centers for Disease Control and Prevention. Additional considerations to the interim recommendations for the use of influenza antiviral medications in the setting of oseltamivir resistance among circulating influenza A (H1N1) viruses, 2008-2009 influenza season. http://www.cdc.gov/flu/professionals/antivirals/additional_considerations.htm. Accessed March 9, 2009.
6. Fiore AE, Shay DK, Broder K, et al. Prevention and control of influenza: recommendations of the advisory committee on immunization practices (ACIP), 2008. MMWR. 2008;57(RR07):1-60.
7. Centers for Disease Control and Prevention. Health care providers: monitor influenza activity in your area and review CDC’s Interim antiviral Guidance. http://www.cdc.gov/features/dsFluView2009/. Accessed March 11, 2009.
8. Lacy CF, Armstong LL, Goldman MP, Lance LL. Drug Information Handbook. 15^th ed. Hudson, OH: Lexi-Comp; 2007.
9. Bright RA, Shay DK, Shu B, Cox NJ, Klimov AI. Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States. JAMA. 2006;295(8):891-894.
10. Aoki FY, Boivin G, Roberts N. Influenza virus susceptibility and resistance to oseltamivir. Antivir Ther. 2007;12(4 pt B):603-616.
11. Centers for Disease Control and Prevention (CDC). Influenza activity-united States and worldwide. 2007-2008 season. MMWR Morb Mortal Wkly Rep. 2008;57(25):692-697.
12. World Health Organization. Table: Influenza A (H1N1) virus resistance to oseltamivir: Last quarter 2007 to 2 June 2008 (Update 13 June 2008). http://www.who.int/csr/disease/influenza/H1N1webupdate20082008_kf.pdf. Accessed March 12, 2009.
13. Dharan NJ, Gubareva LV, Meyer JJ, et al. Infections with oseltamivir-resistant influenza A (H1N1) virus in the United States. JAMA. 2009;301(10): 1034-1041.

By Tonya Crawford, PharmD