Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza - Randomized controlled trials for prevention and treatment

Context Influenza virus neuraminidase is thought to be essential for virus replication in humans; however, to date, available neuraminidase inhibitors are limited to zanamivir, which is topically administered. Objective To determine the safety, tolerability, and antiviral activity of oral neuraminidase inhibitor oseltamivir (GS4104/Ro64-0796) for prevention and the early treatment of influenza in experimentally infected humans. Design Two randomized, double-blind, placebo-controlled trials conducted be tween June and July 1997. Setting Individual hotel rooms; 2 large US university medical schools. Participants A total of 117 healthy adult volunteers (aged 18-40 years; med ian age, 21 years) who were susceptible (hemagglutination-inhibition antibo dy titer less than or equal to 1:8). Interventions All subjects were inoculated intranasally with influenza A/Te xas/36/91 (H1N1) virus. For the prophylaxis study, oral oseltamivir (100 mg once daily [n = 12], 100 mg twice daily [n = 12], or matching placebo [n = 13], starting 26 hours before virus inoculation) was administered. For the treatment study, the same drug was given (20 mg, 100 mg, or 200 mg twice d aily, 200 mg once daily, or matching placebo [n = 16], in each group starti ng 28 hours after inoculation). All regimens were continued for 5 days. Main Outcome Measures Comparing placebo groups with pooled treatment groups , for prophylaxis, outcomes included frequency of infection and viral shedd ing; for treatment, viral shedding in titers. Results In the prophylaxis study, 8 (67%) of 12 placebo and 8 (38%) of 21 o seltamivir recipients became infected (P = .16; efficacy, 61%); 6 (50%) pla cebo compared with 0 oseltamivir recipients shed virus (P<.001; efficacy, 1 00%), and 33% of placebo but no oseltamivir recipient had infection-related respiratory illness (P<.01). Among infected subjects in the treatment stud y (n = 69), the viral titer area under the curve of the combined oseltamivi r groups (n = 56) was lower (median [interquartile range {IQR}], 80 [23-151 ] vs 273 [79-306] log(10) tissue culture-infective doses(50) per milliliter x hour; P = .02) than the placebo group (n = 13), and the median (IQR) dur ation of viral shedding with therapy was reduced from 107 (83-131) to 58 (3 5-59) hours (P = .003). Oseltamivir treatment also reduced symptom scores ( median [IQR] score-hours, 225 [97-349] vs 400 [189-645]; P = .05), and nasa l proinflammatory cytokine levels. Transient mild to moderate nausea after dosing was observed in 15 (17%) of 88 oseltamivir and 2 (7%) of 29 placebo recipients (95% confidence interval for difference, -11% to 68%), which was largely prevented by ingestion with food. Conclusions In these trials, prophylaxis and early treatment with oral osel tamivir were both associated with significant antiviral and clinical effect s in experimental human influenza.