Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice

Abstract

The replication efficiency and multi-organ dissemination of some influenza A (H5N1) viruses requires a rapid re-evaluation of the available antiviral strategies. We assessed five regimens of the neuraminidase (NA) inhibitor peramivir in mice inoculated with H5N1 virus. The regimens differed by: (1) frequency of administration on first day (once vs twice); (2) duration of administration (1 day vs 8 days); (3) route of administration (intramuscular [IM] injection alone or followed by oral administration). In all regimens, BALB/c mice were administered 30 mg/kg peramivir IM 1 h after lethal challenge with 5 MLD(50) of A/Vietnam/1203/04 (H5N1) influenza virus. When given only on the day of inoculation, a single IM injection produced a 33% survival rate, which increased to 55% with two injections. Eight-day regimens significantly increased survival; two IM injections followed by seven daily IM injections was the most effective regimen (100% survival; inhibition of replication in lungs and brain). When this 8-day regimen began at 24h after inoculation, 78% of mice survived; 56% survived when treatment began at 48 hours. Anti-HA antibody titer differed with the peramivir regimen and corresponded to the severity of disease. Overall, our results demonstrate that IM administration of peramivir is effective in promoting the survival of mice infected with systemically replicating H5N1 virus.

Figure 1

Experimental design. BALB/c mice were administered peramivir by intramuscular injection (arrows) or by oral gavage (circles).

Figure 2

Effect of 1- and 8-day peramivir regimens on mouse survival. BALB/c mice were administered peramivir for 1 day (A) or for 8 days (B). The Kaplan-Meier method was used to estimate the probability of survival, which expressed as survival distribution function. 1- probability of 100% survival.

Figure 3

Effect of peramivir regimens on virus titers in internal organs. Virus titers were determined at 3, 6, and 9 days p.i. (dpi) in the lungs (A) and brain (B). Each data point represents the mean virus titer ± SD (log₁₀EID₅₀/ml) from the lungs or brains of 3 mice. Dotted line indicates minimum level of detection (0.75 log₁₀EID₅₀/ml). * indicate P < 0.05.

Figure 4

Serum antibody responses in mice inoculated with A/Vietnam/1203/04 (H5N1) virus and treated with peramivir. Hemagglutination inhibition (HI) titers were tested by using A/Vietnam/1203/04 (H5N1) and A/Hong Kong/213/03 (H5N1) viruses. Drug regimens are shown as mg/kg (see Figures 1 and 2). Sera were obtained 21 days p.i. Values are mean HI titers (log₂) ± SE.