Intravenous Peramivir for Seasonal Influenza
Abstract & Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine Dr. Winslow is on the speaker's bureau for GSK and Cubist Pharmaceuticals, and is a consultant for Siemens Diagnostics. This article originally appeared in the December 2010 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, and peer reviewed by Timothy Jenkins, MD.
Synopsis: Outpatients with uncomplicated seasonal influenza were treated with single doses of IV peramivir 300 mg/kg, 600 mg/kg, or placebo. Peramivir significantly reduced the time to alleviation of symptoms at both doses compared with placebo. Peramivir was well-tolerated, and side effects were comparable to placebo.
Source: Kohno S, et al. Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection. Antimicrob Agents Chemother. 2010;54:4568-4574.
In this study, 296 previously healthy eligible adults ages 20-64 with onset of influenza-like symptoms within the previous 48 hours and a positive rapid antigen test were enrolled in a double-blind, placebo-controlled trial conducted at Nagasaki University. Patients were randomly assigned to receive a single dose of IV peramivir 300 mg/kg (n = 99), 600 mg/kg (n = 97), or matching placebo (n = 100). Influenza symptoms and body temperature were self-assessed for 14 days. Nasal and pharyngeal specimens were obtained, and influenza virus titers were determined. Peramivir at both doses was shown to significantly reduce (p = 0.0092) the median time to alleviation of symptoms compared with placebo (59.1 hours for 300 mg, 59.9 hours for 600 mg, and 81.8 hours for placebo). Efficacy was demonstrated against both A/H1 and A/H3 influenza virus subtypes. Virus titers in respiratory samples were significantly lower in both active treatment arms than in the placebo arm on both day 2 and day 3 of treatment. Adverse events observed with both doses of peramivir were similar to those reported in the placebo group.
Peramivir is an investigational sialic-acid analogue-neuraminidase inhibitor with potent in-vitro activity against influenza A and B viruses, and is available in an intravenous formulation. It has a strong affinity for influenza virus neuraminidase and a low off-rate, suggesting that infrequent dosing would be feasible. During the 2009-2010 season, a novel H1N1 strain became pandemic and displayed high mortality rates in both young and old patients. In critically ill patients, oral absorption of oseltamivir due to ileus or other factors and unreliable delivery to pulmonary tissue by inhalation route of zanamivir exist as major concerns to treating clinicians. Due to the lack of FDA-approved parenteral formulations of other neuraminidase inhibitors (oseltamivir and zanamavir), IV peramivir was released under a compassionate-use protocol for use in critically ill patients with confirmed pandemic H1N1 influenza. Formal analysis of the total experience of compassionate use of IV peramivir has yet to be published in the peer-reviewed literature, but smaller case series suggest that it showed significant efficacy and safety in many of these critically ill patients.
The impressive efficacy of single-dose IV peramivir in outpatients with uncomplicated influenza, and the clinical evidence for efficacy and safety in critically ill patients, support the effectiveness of this agent, as well as the need for additional randomized, controlled trials in larger numbers of patients and special populations (including children and immunocompromised patients).
One common misconception, which needs to be addressed, is the false belief that antiviral agents are not effective in patients who have duration of influenza symptoms of greater than 48 hours. It should be pointed out that while most antiviral agents studied over the last 40 years (amantadine, rimantadine, oseltamivir, zanamivir, and peramivir) seem to demonstrate greater relative efficacy vs. placebo when studied in clinical trials with duration of symptoms < 48 hours, as opposed to longer duration of symptoms, this result is, in part, due to the inclusion criteria of the trials themselves. Certainly, critically ill patients with influenza, especially those requiring mechanical ventilation or extra-corporeal membrane oxygenation, should not be denied antiviral therapy despite duration of symptoms > 48 hours.