Alternative Therapeutic Options for Pandemic Influenza A H1N1

Abstract & Commentary

By Pamela Tien, PharmD Candidate, Jonathan Nieh, PharmD Candidate, Jessica C. Song, MA, PharmD

Pamela Tien and Jonathan Nieh are PharmD Candidates at the University of the Pacific, and Jessica C. Song, PharmD, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA, Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.

They report no financial relationships relevant to this field of study.

Since April 2009, pandemic influenza a (H1N1) virus isolates have been tested for resistance to adamantanes (amantadine, rimantadine) and have demonstrated 100% resistance to this class of antiviral agents. In contrast, susceptibility rates of 2009 influenza A (H1N1) viruses to the neuraminidase inhibitor oseltamivir have exceeded 99%, with a total of 14 cases of oseltamivir-resistant isolates identified in the United States since April 2009.1 In addition, a recently published case report2 has highlighted the use of intravenous zanamivir (available for compassionate use) in a patient failing to respond to oseltamivir therapy.

On October 23, 2009, due to the severity of the 2009-2010 influenza A (H1N1) season, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the intravenous neuraminidase inhibitor peramivir (BioCryst Pharmaceuticals).1

The purpose of this article is to describe cross-resistance among neuraminidase inhibitors, to summarize therapeutic options available for oseltamivir-resistant and for oseltamivir-refractory 2009 influenza A (H1N1), and to discuss the use of combination antiviral regimens.

Neuraminidase-Inhibitor Resistance

At present, neuraminidase-inhibitor resistance patterns of the pandemic influenza A (H1N1) virus have not been fully elucidated. However, structural comparisons between the active sites of the enzymes of seasonal and pandemic influenza A (H1N1) have shown great similarities and, hence, resistance patterns of pandemic influenza A (H1N1) may parallel those of seasonal influenza A (H1N1). A single nucleotide mutation (cytosine to thymine) at position 823 of the pandemic neuraminidase gene can lead to a histidine to tyrosine substitution at position 275 (H275Y mutation).3 Of note, the Centers for Disease Control and Prevention (CDC) reported the emergence of a second type of mutation (I223V) in two young females infected with oseltamivir-resistant 2009 influenza A (H1N1) virus following chemoprophylaxis. The functional significance of the mutation could not be determined since neuraminidase-inhibitory assays were not performed.4

Leung et al reported the resistance patterns of neuraminidase inhibitors over a two-month period (May-June 2009) in Hong Kong, and found that of 200 influenza A (H1N1) isolates, one strain (A/Hong Kong/2369/2009 [H1N1]) was resistant to oseltamivir. The 50% inhibition concentration (IC50) of zanamivir was approximately 200-fold lower compared with oseltamivir, demonstrating a lack of cross-resistance between the two neuraminidase inhibitors.5 In the United States, of the 14 tested oseltamivir-resistant 2009 influenza A (H1N1) viruses, all isolates retained sensitivity to zanamivir.1

To date, no clinical data are available on resistance rates of 2009 influenza A (H1N1) to the neuraminidase inhibitor peramivir. Cross-resistance between peramivir and oseltamivir have been observed in other influenza viruses. Neuraminidase assay analysis of the oseltamivir resistance-associated substitutions E119V (A/H3N2), D198N (B), H275Y (A/H1N1), and R292(K) revealed 1-, 4.8-, 100-, and 80-fold reductions in susceptibility to peramivir, respectively. In addition, zanamivir resistance-associated mutations E119A (H4N2), E119D (H4N2), E119G (H4N2), and R152K (B) resulted in 1-, 33-, 2-, and 400-fold reductions in susceptibility to peramivir, respectively. Consequently, patients with documented oseltamivir-resistant 2009 influenza A (H1N1) virus should not receive peramivir as an alternative antiviral treatment option.6

Alternative Therapies

The CDC currently recommends the use of oral oseltamivir or inhaled zanamivir for the treatment of hospitalized patients with 2009 influenza A (H1N1) infection.7 Peramivir, the only intravenous neuraminidase inhibitor available for use in the United States, serves as another option for patients who cannot take oral (including enteral oseltamivir) or inhaled medications.7 Recently, it has become available through EUA, provided that the patient fulfills at least one of the following conditions: 1) insufficient clinical response to oral or inhaled antiviral therapy, 2) intravenous route is the only feasible treatment approach, and/or 3) physician's professional judgment deems its use necessary (in the adult population only). Based on the EUA, peramivir should not be used for the treatment of patients infected with seasonal influenza A or B virus, and this agent should not be used for chemoprophylaxis.6 Table 1 summarizes key pharmacologic properties of the three neuraminidase inhibitors.6-9 Table 2

The Shionogi development program has enrolled a total of 1,891 patients who received peramivir (any dose, any formulation) in phase I, II, and III trials.6 Of the 1,891 patients, a total of 137 patients were enrolled in a Phase II efficacy and safety study of hospitalized adults infected with seasonal influenza virus. This double-dummy, randomized trial included patients who received intravenous peramivir 200 mg or 400 mg once daily for five days or oseltamivir (oral suspension) administered twice daily. Unfortunately, the results of this trial are difficult to interpret, given that the treatment effect of oseltamivir for the primary outcome of time to clinical efficacy has not been established in patients hospitalized for acute influenza infection. Furthermore, this trial did not show a dose-response effect for peramivir, and did not show superiority of peramivir (for both doses) over oseltamivir for the primary outcome.6 Other unresolved issues include the dosing of this agent in morbidly obese patients (body mass index ≥ 40 kg/m2) and the use of this drug in combination with other antiviral agents. A total of 847 patients have received ≥ 600 mg (intravenous or intramuscular route) peramivir and 33 patients have received 600 mg intravenous peramivir for at least five days.6

Intravenous zanamivir may be an option for patients who do not respond to oseltamivir treatment and who are unable to utilize the inhaled neuraminidase inhibitor, zanamivir. The intravenous formulation is currently offered under its manufacturer's (GlaxoSmithKline) compassionate use policy. Kidd et al reported the case of a neutropenic (post-chemotherapy for Hodgkin's disease) 22-year old female admitted to the intensive care unit (ICU) for laboratory-confirmed pandemic 2009 influenza A (H1N1) infection.2 The patient initially received six days of oseltamivir 75 mg, administered twice daily through her nasogastric tube, followed by nebulized zanamivir over the next eight days. Oseltamivir 150 mg, dosed twice daily, was added to nebulized zanamivir on days 13-16, with no clinical or virological response. On day 16, the combination regimen of nebulized zanamivir and high-dose oseltamivir was replaced by intravenous zanamivir, given as a twice-daily dose of 600 mg. The patient's condition improved within two days, and she received a total of 10 days of treatment with intravenous zanamivir.

Intravenous zanamivir has been combined with aerosolized ribavirin or oral ribavirin in oseltamivirresistant pandemic 2009 influenza A (H1N1) infection.10 The CDC reported the case of a female hematopoietic stem cell transplant patient (age ~ 40 years old) from Seattle, Washington, who failed to respond to combination treatment with high-dose oseltamivir (150 mg twice daily) and oral ribavirin 100 mg, given twice daily.10 During her 4-5 week course of combination therapy, the 2009 influenza A (H1N1) virus became resistant to oseltamivir, thereby prompting the attempted use of inhaled zanamivir, which was not tolerated by the patient. After the second failed attempt of administering inhaled zanamivir, the patient's therapeutic regimen was switched to a combination regimen of intravenous zanamivir (dose not specified) and aerosolized ribavirin. After nearly a week of receiving this combination regimen, aerosolized ribavirin was replaced by oral ribavirin, since the patient could not tolerate the aerosolized formulation. The CDC did not report whether this patient recovered from her infection.

Conclusion

Oseltamivir and inhaled zanamivir represent the two FDA-approved antivirals that can treat patients infected with pandemic 2009 influenza A (H1N1) virus. With the emergence of 2009 influenza A (H1N1) viruses that have become resistant to oseltamivir therapy, clinicians need to be aware of alternative treatment options for this potentially devastating infection. Moreover, since many patients may not respond to oseltamivir therapy and/or are unable to receive oral or inhaled therapy, healthcare providers must be informed of usage conditions applicable to intravenous peramivir. Future studies will hopefully address unresolved issues such as dosing of peramivir in morbidly obese patients, and the use of combination regimens consisting of two or more antiviral agents.

References

  1. Centers for Disease Control and Prevention. Fluview: a weekly surveillance report prepared by the influenza division. Atlanta, GA: US Department of Health and Human Services, CDC; 2009. Available at www.cdc.gov/flu/weekly/
  2. Kidd IM, et al. H1N1 pneumonitis treated with intravenous zanamivir. Lancet. 2009;374:1036.
  3. Van der Vries E, et al. Evaluation of a rapid molecular algorithm for deletion of pandemic influenza A (H1N1) 2009 virus and screening for a key oseltamivir resistance (H275Y) substitution in neuraminidase. J Clin Virol. 2009 [Epub ahead of print].
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  7. Centers for Disease Control and Prevention (CDC). Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza in the 2009-2010 season. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2009. Available at www.cdc.gov/h1n1flu/recommendations.htm
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  10. Centers for Disease Control and Prevention (CDC). Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunocompromised patients -Seattle, Washington, 2009. MMWR Morb Mortal Wkly Rep. 2009;58:890-896.