Intravenous Peramivir for Treatment of Influenza in Hospitalized Patients

Abstract

Background

Influenza causes over 200,000 hospitalizations a year in the United States, but few antiviral treatment studies have focused on patients hospitalized with influenza. This open-label, randomized study was initiated during the 2009 H1N1 pandemic to help assess the antiviral activity, safety and tolerability of 5–10 days treatment with two different dosing regimens of the intravenous neuraminidase inhibitor, peramivir, in hospitalized subjects with influenza.

Methods

Quantitative virology was done on nasopharyngeal swab specimens from subjects ≥6 years of age to measure change from baseline in tissue culture infective dose (primary end point) and quantitative viral RNA levels by real-time PCR. Clinical end points included time to clinical resolution, a composite end point of four vital signs and oxygen saturation.

Results

A total of 234 hospitalized patients were randomized to peramivir 300 mg twice daily or 600 mg once daily; 127 had laboratory confirmed influenza. In those with detectable virus at baseline, viral titres declined without differences between regimens. There were no significant differences in clinical or virological end points between treatment arms, and apparent differences were explained by baseline disease severity differences in the groups. Peramivir was generally safe and well tolerated for treated patients hospitalized with pandemic influenza with outcomes similar to those described in the literature.

Conclusions

This open-label trial of intravenous peramivir in subjects hospitalized predominantly with 2009 influenza A (H1N1) demonstrated that once- or twice-daily administration was associated with decreases in viral shedding and clinical improvement. ClinicalTrials.gov number NCT00957996.

References

Thompson

W.W.

, Shay

D.K.

, Weintraub

Influenza-associated hospitalizations in the United States. JAMA 2004; 292: 1333–1340.

Thompson

W.W.

, Weintraub

, Dhankhar

Estimates of US influenza-associated deaths made using four different methods. Influenza Other Respir Viruses 2009; 3: 37–49.

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 2010; 362: 1708–1719.

Shrestha

S.S.

, Swerdlow

D.L.

, Borse

R.H.

Estimating the burden of 2009 pandemic influenza A (H1N1) in the United States (April 2009-April 2010). Clin Infect Dis 2011; 52 Suppl 1: S75–S82.

Viboud

, Miller

, Olson

, Osterholm

, Simonsen

Preliminary estimates of mortality and years of life lost associated with the 2009 A/H1N1 pandemic in the US and comparison with past influenza seasons. PLoS Curr 2010; 2: RRN1153.

Hernandez

J.E.

, Grainger

, Simonsen

, Collis

, Edelman

, Sheridan

W.P.

Impact of the 2009/2010 influenza A (H1N1) pandemic on trends in influenza hospitalization, diagnostic testing, and treatment. Influenza Other Respir Viruses 2012; 6: 305–308.

Lee

, Ison

M.G.

Diagnosis, management and outcomes of adults hospitalized with influenza. Antivir Ther 2012; 17: 143–157.

Deyde

V.M.

, Xu

, Bright

R.A.

Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. J Infect Dis 2007; 196: 249–257.

Dharan

N.J.

, Gubareva

L.V.

, Meyer

J.J.

Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States. JAMA 2009; 301: 1034–1041.

10.

Hurt

A.C.

, Holien

J.K.

, Parker

, Kelso

, Barr

I.G.

Zanamivir-resistant influenza viruses with a novel neuraminidase mutation. J Virol 2009; 83: 10366–10373.

11.

Kohno

, Kida

, Mizuguchi

Intravenous peramivir for treatment of influenza A and B virus infection in high-risk patients. Antimicrob Agents Chemother 2011; 55: 2803–2812.

12.

Kohno

, Kida

, Mizuguchi

, Shimada

Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection. Antimicrob Agents Chemother 2010; 54: 4568–4574.

13.

Kohno

, Yen

M.Y.

, Cheong

H.J.

Phase III randomized, double-blind study comparing single-dose intravenous peramivir with oral oseltamivir in patients with seasonal influenza virus infection. Antimicrob Agents Chemother 2011; 55: 5267–5276.

14.

Ison

M.G.

, Hui

D.S.

, Clezy

A clinical trial of intravenous peramivir compared with oral oseltamivir for the treatment of seasonal influenza in hospitalized adults. Antivir Ther 2012; 18: 651–661.

15.

Boivin

, Goyette

Susceptibility of recent Canadian influenza A and B virus isolates to different neuraminidase inhibitors. Antiviral Res 2002; 54: 143–147.

16.

Boltz

D.A.

, Aldridge

J.R.

Jr. , Webster

R.G.

, Govorkova

E.A.

Drugs in development for influenza. Drugs 2010; 70: 1349–1362.

17.

Hernandez

J.E.

, Adiga

, Armstrong

Clinical experience in adults and children treated with intravenous peramivir for 2009 influenza A (H1N1) under an Emergency IND program in the United States. Clin Infect Dis 2011; 52: 695–706.

18.

Birnkrant

, Cox

The emergency use authorization of peramivir for treatment of 2009 H1N1 influenza. N Engl J Med 2009; 361: 2204–2207.

19.

Bantia

, Kellog

, Parker

, Upshaw

, Illyushina

N.A.

, Babu

Y.S.

A single intramuscular injection of neuraminidase inhibitor peramivir demonstrates antiviral activity against novel pandemic A/California/04/2009 (H1N1) influenza virus infection in mice. Antiviral Res 2011; 90: 17–21.

20.

Gubareva

L.V.

, Trujillo

A.A.

, Okomo-Adhiambo

Comprehensive assessment of 2009 pandemic influenza A (H1N1) virus drug susceptibility in vitro. Antivir Ther 2010; 15: 1151–1159.

21.

Rhodin

M.M.

, Anderson

B.J.

, Peters

A.M.

Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol 2009; 24: 67–76.

22.

Wetherall

N.T.

, Trivedi

, Zeller

Evaluation of neuraminidase enzyme assays using different substrates to measure susceptibility of influenza virus clinical isolates to neuraminidase inhibitors: report of the neuraminidase inhibitor susceptibility network. J Clin Microbiol 2003; 41: 742–750.

23.

Bazan

J.A.

, Bauer

K.A.

, Hollister

A.S.

Peramivir pharmacokinetics in two critically ill adults with 2009 H1N1 influenza A concurrently receiving continuous renal replacement therapy. Pharmacotherapy 2010; 30: 1016–1020.

24.

Halm

E.A.

, Fine

M.J.

, Marrie

T.J.

Time to clinical stability in patients hospitalized with community-acquired pneumonia: implications for practice guidelines. JAMA 1998; 279: 1452–1457.

25.

Jain

, Kamimoto

, Bramley

A.M.

Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009. N Engl J Med 2009; 361: 1935–1944.

26.

Skarbinski

, Jain

, Bramley

Hospitalized patients with 2009 pandemic influenza A (H1N1) virus infection in the United States–September-October 2009. Clin Infect Dis 2011; 52 Suppl 1: S50–S59.

27.

Centers for Disease Control and Prevention. Update: influenza activity - United States, 2009-10 season. MMWR Morb Mortal Wkly Rep 2010; 59: 901–908.

28.

Ison

M.G.

, Riordan

, Elder

, Collis

P.J.

, Hernandez

J.E.

Comparison of tissue culture infective dose (TCID50) and quantitative PCR (QPCR) for diagnosis and follow up of influenza in hospitalized subjects. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy. 17–20 September 2011, Chicago, IL, USA. Abstract V-1556.

29.

Ison

M.G.

, de Jong

M.D.

, Gilligan

K.J.

End points for testing influenza antiviral treatments for patients at high risk of severe and life-threatening disease. J Infect Dis 2010; 201: 1654–1662.

30.

Lee

, Chan

P.K.

, Wong

C.K.

Viral clearance and inflammatory response patterns in adults hospitalized for pandemic 2009 influenza A(H1N1) virus pneumonia. Antivir Ther 2011; 16: 237–247.

31.

Petersen

, Keld

D.B.

, Ellermann-Eriksen

Failure of combination oral oseltamivir and inhaled zanamivir antiviral treatment in ventilator- and ECMO-treated critically ill patients with pandemic influenza A (H1N1)v. Scand J Infect Dis 2011; 43: 495–503.

32.

Sorbello

, Jones

S.C.

, Carter

Emergency use authorization for intravenous peramivir: evaluation of safety in the treatment of hospitalized patients infected with 2009 H1N1 Influenza A virus. Clin Infect Dis 2012; 55: 1–7.

33.

Louie

J.K.

, Yang

, Yen

, Acosta

, Schechter

, Uyeki

T.M.

Use of intravenous peramivir for treatment of severe influenza A(H1N1)pdm09. PLoS One 2012; 7: e40261.

34.

Sugaya

, Kohno

, Ishibashi

, Wajima

, Takahashi

Efficacy, safety, and pharmacokinetics of intravenous peramivir in children with 2009 pandemic H1N1 influenza A virus infection. Antimicrob Agents Chemother 2012; 56: 369–377.

35.

Thomas

, Hollister

A.S.

, Muczynski

K.A.

Peramivir clearance in continuous renal replacement therapy. Hemodial Int 2010; 14: 339–340.

36.

Beigel

, Harman

L.A.

, Collis

Pharmacokinetic and safety evaluations of escalating doses of peramivir administered intravenously in healthy volunteers. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. 17–20 September 2007, Chicago, IL, USA. Abstract A-1408.

37.

US Food and Drug Administration. Emergency use authorization of peramivir IV fact sheet for health care providers. US Department of Health and Human Services. (Accessed 26 May 2014.) Available from http://www.fda.gov/downloads/Drugs/DrugSafety/PostMarketDrugSafetyInformationforPatientsandProviders/UCM187811.pdf.