Written as an editorial commentary regarding Martin AR, Collins CD, Otto M, Malani A, Cinti S. Peramivir on pages 11-15 of the journal.
Infection due to influenza virus is associated with significant morbidity and mortality especially in patients with severe disease.1 In 2009, the world was challenged with the first influenza virus pandemic in more than 40 years. This situation highlighted some of the difficulties clinicians face in treatment of severe influenza including resistance, limited treatment options, and current formulations of available agents. Influenza A (H1N1) virus was a newly isolated strain of influenza virus that was first identified in Mexico in early 2009 and within months spread to both the northern and southern hemispheres. The World Health Organization declared the 2009 H1N1 influenza outbreak a worldwide pandemic. As of August 1, 2010, more than 18,000 deaths among laboratory-confirmed cases have been reported to the World Health Organization.2,3 In the United States, laboratory-confirmed influenza-associated hospitalizations and deaths from August 30, 2009 to May 28, 2010, were 41,821 and 2117, respectively.4
Patients at risk of severe disease or complications of influenza include age younger than 5 years or 65 years or older, pregnancy, immunosuppression, morbid obesity, and underlying medical conditions (ie, pulmonary, cardiac, renal, hepatic disease, and diabetes).1,3 In contrast, during the recent pandemic, much of the severe disease occurred in younger adults (age, 18-64 years). The addition of antiviral therapy early in the course of the illness (ie, <48 hours after symptom onset) may reduce the severity, complications, and morbidity associated with influenza.1 The adamantanes and neuraminidase inhibitors are the 2 classes of anti-influenza medications approved by the Food and Drug Administration (FDA) and have been the mainstay of treatment for influenza. Issues with current antiviral therapy include the concerns for antiviral resistance because susceptibilities may evolve rapidly, and current agents are available as only an oral or inhaled formulation.1 These formulations do not offer an optimal method of delivery for all patients with severe influenza infection.
In this issue, Martin et al5 provides a detailed review of peramivir, an investigational antiviral agent. Peramivir was granted an Emergency Use Authorization (EUA) by the FDA on October 23, 2009, for emergency use to treat hospitalized adult and pediatric patients with suspected or laboratory-confirmed 2009 H1N1 influenza who met specified criteria. The EUA gave clinicians an alternative treatment option an intravenous (IV) formulation in peramivir for patients with severe influenza. The EUA granted by the FDA has since been terminated as of June 23, 2010.6
Peramivir is an investigational neuraminidase inhibitor and has demonstrated potent in vitro activity against influenza A and B. Similar to the other neuraminidase inhibitors, peramivir inhibits the neuraminidase subtypes important for cleaving sialic acid residue ultimately preventing the spread of virus. Peramivir was initially studied as an oral formulation; however, results were not promising due to low oral bioavailability.5 An IV formulation was later developed.
The authors provide a review for the clinical efficacy for peramivir to date. In a phase 2 randomized, double-blind, placebo-control trial peramivir at single IV doses of either 300 mg or 600 mg was compared to a single IV placebo dose in patients with acute uncomplicated influenza.5 Peramivir demonstrated a significant reduction in the time to alleviation of symptoms compared with placebo (P = 0.0046).5 A phase 3 clinical trial compared single doses of IV peramivir at either 300 mg or 600 mg with oral oseltamivir at 75 mg twice a day for 5 days.5 This study concluded a single dose of IV peramivir was noninferior to oseltamivir.5 Peramivir was also evaluated in a clinical trial for adults hospitalized with serious or life-threatening influenza. The study was multicenter, randomized controlled trial comparing IV peramivir at 200 mg daily, IV peramivir at 400 mg daily to oral oseltamivir at 75 mg twice daily for 5 days. Intravenous peramivir was found to demonstrate equivalent clinical efficacy and tolerability in comparison to oral oseltamivir.5 There are several ongoing clinical trials investigating the efficacy and safety of IV peramivir.7 One of these clinical studies is a multicenter, randomized, double blind, controlled study in adult and adolescent hospitalized patients with severe influenza evaluating peramivir at 600 mg IV daily in adults or peramivir at 10 mg/kg IV daily in adolescents for 5 days plus standard of therapy versus standard of therapy only.7
The recommended dose of peramivir during the FDA EUA in adult patients was 600 mg IV daily in patients with normal renal function.5 In patients with moderate to severe renal impairment, it is recommended to decrease the dose of peramivir. There is limited data available regarding the dose of peramivir in patients undergoing continuous renal replacement therapy, although a recent report by Thomas et al8 suggests a daily dose of 600 mg may be more appropriate for patients on daily continuous hemodialysis. An ongoing clinical study assessing the pharmacokinetics of peramivir in hospitalized patients undergoing continuous renal replacement therapy will hopefully provide some answers.7
For the past several years, reports of antiviral resistance to neuraminidase inhibitors have increased.1 Data from the 2008-2009 influenza seasons identified oseltamivir resistance among 264 (98.5%) of 268 seasonal influenza A (H1N1) viruses tested.9 A number of these oseltamivir resistant isolates contain either the H274Y or H275Y mutation in the neuraminidase gene, which confers reduced susceptibility to oseltamivir. These strains have shown to retain susceptibility to zanamivir.1 As for peramivir, several studies have demonstrated that clinical isolates of influenza A resistant to oseltamivir also express resistance to peramivir.5 In addition, recent reports have described the emergence of resistance to peramivir. The first report by Memoli et al10 described an immunocompromised individual with persistence of influenza A (H1N1) infection despite treatment with oseltamivir initially and then peramivir. The authors reported there was a 50-fold change in the IC50 of the viral isolates to peramivir indicating a significant loss of susceptibility to peramivir. The second report described an immunocompromised patient who developed influenza A (H1N1) infection that conferred resistance to oseltamivir, zanamivir, and peramivir.11 The increased antiviral resistance highlights an important issue that clinicians face today. The role of peramivir in the setting of oseltamivir remains unclear and warrants further investigation.
The 2009 H1N1 influenza virus pandemic highlighted the limited number of antiviral agents to treat influenza especially in patients with severe disease. The neuraminidase inhibitors were considered a first-line treatment option in the treatment of 2009 Influenza H1N1 virus pandemic. Currently, oseltamivir and zanamivir are the 2 neuraminidase inhibitors available in the United States. These agents have limitations in the treatment of severe influenza infections where oral or inhaled route may not be the most optimal method of administration. The EUA declared by the FDA allowed for peramivir, an IV neuraminidase inhibitor, as an alternative option for clinicians to consider in patients who met specific criteria.
Peramivir has shown potent in vitro against both influenza A and B. In clinical studies, IV peramivir has demonstrated equivalent clinical efficacy and tolerability compared to oseltamivir. The increase in oseltamivir resistance and limited data available showing potential cross resistance to peramivir highlights a concern regarding the utility of peramivir in oseltamivir resistant isolates. Further investigations will continue to help define the role of peramivir. The development and investigations into an IV antiviral therapy is a small step in the right direction and hope to provide clinicians with additional treatment options in patients with serious influenza infection.
1. Harper SA, Bradley JS, Englund JA, et al. Seasonal influenza in adults and children-diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases of Society of America. Clin Infect Dis
3. Bautista E, Chotpitayasunondh T, Gao Z, et al. Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med
5. Martin AR, Collins C, Otto M, et al. Peramivir: a new drug for influenza. Infect Dis Clin Practice
. 2010. In press.
6. Centers for Disease Control and Prevention. Hamburg MA. Termination of Declarations of Emergency Justifying Emergency Use Authorization of Certain Antiviral Drugs - Zanamivir, Oseltamivir Phosphate, an Peramivir. Available at: http://www.cdc.gov/H1N1flu/EUA/pdf/Antivirals.pdf
. Accessed October 12, 2010.
8. Thomas B, Hollister AS, Muczynski KA. Peramivir clearance in continuous renal replacement therapy. Hemodial Int
9. Dharan NJ, Gubareva LV, Meyer JJ, et al. Infections with oseltamivir-resistant influenza A (H1N1) virus in the United States. JAMA
10. Memoli M, Hrabal RJ, Hassantoufighi A, et al. Rapid selection of oseltamivir and peramivir-resistant pandemic H1N1 virus during therapy in 2 immunocompromised hosts. Clin Infect Dis
11. van der Vries E, Stelma FF, Boucher CA. Emergence of multidrug-resistance pandemic influenza A (H1N1) virus. N Engl J Med