Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection

Abstract

Zanamivir is a potent inhibitor of influenza A and B virus neuraminidases and is active topically in experimental and natural human influenza. We conducted this double-blinded, placebo-controlled study to evaluate the safety and efficacy of intravenously administered zanamivir. Susceptible volunteers were randomized to receive either saline or zanamivir (600 mg) intravenously twice daily for 5 days beginning 4 h prior to intranasal inoculation with approximately 10(5) 50% tissue culture infectious doses (TCID50) of influenza A/Texas/36/91 (H1N1) virus. Reductions in the frequency of viral shedding (0% versus 100% in placebo, P < 0.005) and seroconversion (14% versus 100% in placebo, P < 0.005) and decreases in viral titer areas under the curve (0 versus 11.6 [median] log10 TCID50. day/ml in placebo, P < 0.005) were observed in the zanamivir group, as were reductions in fever (14% versus 88% in placebo, P < 0.05), upper respiratory tract illness (0% versus 100% in placebo, P < 0.005), total symptom scores (1 versus 44 [median] in placebo, P < 0.005), and nasal-discharge weight (3.9 g versus 17.5 g [median] in placebo, P < 0.005). Zanamivir was detectable in nasal lavage samples collected on days 2 and 4 (unadjusted median concentrations, 10.5 and 12.0 ng/ml of nasal wash, respectively). This study demonstrates that intravenously administered zanamivir is distributed to the respiratory mucosa and is protective against infection and illness following experimental human influenza A virus inoculation.

FIG. 1

Titers of influenza A virus in nasal washes collected from volunteers experimentally infected with influenza A/Texas/36/91 virus following administration of intravenous zanamivir or placebo twice daily. Drug administration began 4 h prior to inoculation on day 0 and continued for 5 days. There was a significant difference in the AUC values for viral titers between the placebo (11.6 log₁₀ TCID₅₀ · day/ml) and zanamivir (0) (P < 0.005) groups.

FIG. 2

Daily symptom scores of volunteers experimentally infected with influenza A/Texas/36/91 virus following administration of intravenous zanamivir or placebo twice daily. Drug administration began 4 h prior to inoculation on day 0 and continued for 5 days. There was a significant difference in median total symptom scores between the zanamivir (1 point) and placebo (44 points) groups (P < 0.05).