1185. Virologic Analysis of Influenza Viruses after Therapy with a Single Intramuscular (IM) Dose of the Neuraminidase Inhibitor (NAI) Peramivir (PVR) Versus Placebo (PBO) in Patients with Influenza in the Outpatient (OP) Setting
Session: Poster Abstract Session: New Approaches to Anti-Viral Therapy
Saturday, October 22, 2011
Room: Poster Hall B1
Background:Concerns about NAI resistance have been raised. We assessed resistance development using virology from a phase 2 study comparing IM PVR to PBO in OP subjects.

Methods: Virus was collected from NP swabs. RT PCR, culture or serology confirmed influenza A subtype and B infection, and TCID50 quantified virus from BL through day 9. Phenotypes using MUNANA were done at BL and post-treatment. Two genotyping (GT) subsets were defined: paired isolates with NAI IC50s > BL mean + 2 SD, and subjects culture positive at day 9.

Results:

318 subjects enrolled in 7 countries in 2 seasons (2006/2007), (82 A/H1N1, 162 A/H3N2, 65 B and 7 A ind.) and received PBO (109), single dose IM PVR 150mg (104) or IM PVR 300mg (105). TCID50/mL (BL to 48 hr) was Δ by a median of -3.00 logs (PVR 150), -3.25 logs (PVR 300), & -2.75 logs (PBO, p<0.001). The table shows BL IC50 by type and NAI and Δ in IC50 (BL to last + culture). Paired GTs in the IC50 > mean + 2 SD subset (n=20 [7.5%]) found 2 subjects with emergent H275Y mutation (1 in each PVR dose); the subset with delayed viral clearance (n=18 [5.7%]) saw no emerging NA resistance.

Virus

Subjects

 

BL IC50 nM  Mdn (Min, Max)

PVR

OSE

ZAN

A/H1N1

n = 68

0.1 (0.01,  5.5)

1.0 (0.03, 64.4)

0.6 (0.02, 42.3)

A/H3N2

n = 136

0.1 (0.01,  3.4)

0.4 (0.03, 31.7)

0.4 (0.01,  6.5)

B

n = 56

2.4 (0.04, 10.3)

15.4 (0.05, 80.5)

3.7 (0.03, 14.3)

 

Virus

Group

Mdn (Min, Max) IC50 Fold Δ from BL

 

PVR

OSE

ZAN

 

A/H1N1 WT,  n = 64

PBO,  n=27

0.6 (0.04, 14.0)

1.0 (0.2,  7.9)

1.0 (0.1, 14.0)

 

PVR 150,  n=18

2.0 (0.2, 69.5)

1.1 (0.1, 28.8)

0.7 (0.1, 14.6)

 

PVR 300,  n=19

1.1 (0.04, 29.3)

1.4 (0.3, 36.9)

1.1 (0.5, 23.5)

 

A/H3N2,  n = 121

PBO,  n=44

1.1 (0.2, 18.0)

1.0 (0.2, 23.6)

1.2 (0.1, 25. 4)

 

PVR 150,  n=37

1.2 (0.1, 53.0)

1.0 (0.1, 6.2)

1.3 (0.2,  6.0)

 

PVR 300,  n=40

1.4 (0.3, 37.7)

1.2 (0.3, 36.4)

1.4 (0.1, 36.1)

 

B,  n= 51

PBO,  n=18

1.1 (0.5,  3.0)

1.1 (0.2,  2.5)

1.0 (0.3,  2.4)

 

PVR 150,  n=14

1.0 (0.2,  2.1)

1.0 (0.2,  1.2)

1.1 (0.7,  2.7)

 

PVR 300, n=19

0.9 (0.03,  1.9)

1.0 (0.1,  1.4)

1.0 (0.4,  3.1)

Conclusion:BL IC50s for influenza A & B were: PVR < ZAN < OSE. PVR significantly decreased influenza titers. Little Δ in IC50s post BL was seen. Few subjects shed virus at day 9; few paired isolates had post-BL > 2 SD Δ in IC50.  GTs could not be obtained in all specimens, but only 2 viruses (IC50 > mean + 2 SD subset) for which the GT was determined had an emergent known resistance mutation.


Subject Category: V. Virology including clinical and basic studies of viral infections, including hepatitis

George Atiee, MD1, Allan Laughlin, MD2, Guy Tellier, MD3, Phil Collis, PhD4, William Alexander, MD4, John Wise, MD5, Amy Flynt, PhD6 and Jaime Hernandez, MD7, (1)HealthCare Discoveries, LLC, San Antonio, TX, (2)Merrylands Medical Centre, Merrylands, Australia, (3)Omnispec Clin. Res., Inc., , Mirabel, QC, Canada, (4)BioCryst Pharmaceuticals, Durham, NC, (5)Bozeman Urgent Care Center, Bozeman, MT, (6)PharPoint Research, Wilmington, NC, (7)Clinical Development, BioCryst Pharmaceuticals, Inc., Durham, NC

Disclosures:

G. Atiee, BioCryst Pharmaceuticals: Investigator, Research grant

A. Laughlin, BioCryst Pharmaceuticals: Investigator, Research grant

G. Tellier, BioCryst Pharmaceuticals: Investigator, Research grant

P. Collis, BioCryst Pharmaceuticals: Employee and Shareholder, Salary

W. Alexander, BioCryst Pharmaceuticals: Consultant and Shareholder, Consulting fee

J. Wise, BioCryst Pharmaceuticals: Investigator, Research grant

A. Flynt, BioCryst Pharmaceuticals: Consultant, Consulting fee

J. Hernandez, BioCryst Pharmaceuticals: Employee and Shareholder, Salary

Findings in the abstracts are embargoed until 12:01 a.m. EST Thursday, Oct. 20 with the exception of research findings presented at IDSA press conferences.