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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 between 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 ; median age , 21 years ) who were susceptible ( hemagglutination-inhibition antibody titer < or =1:8 ) . INTERVENTIONS All subjects were inoculated intranasally with influenza A/Texas/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 daily , 200 mg once daily , or matching placebo [ n = 16 ] , in each group starting 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 shedding ; for treatment , viral shedding in titers . RESULTS In the prophylaxis study , 8 ( 67 % ) of 12 placebo and 8 ( 38 % ) of 21 oseltamivir recipients became infected ( P = .16 ; efficacy , 61 % ) ; 6 ( 50 % ) placebo compared with 0 oseltamivir recipients shed virus ( P < .001 ; efficacy , 100 % ) , and 33 % of placebo but no oseltamivir recipient had infection-related respiratory illness ( P < .01 ) . Among infected subjects in the treatment study ( n = 69 ) , the viral titer area under the curve of the combined oseltamivir groups ( n = 56 ) was lower ( median [ interquartile range [ IQR ] ] , 80 [ 23-151 ] vs 273 [ 79-306 ] log10 tissue culture-infective doses50 per milliliter x hour ; P = .02 ) than the placebo group ( n = 13 ) , and the median ( IQR ) duration of viral shedding with therapy was reduced from 107 ( 83-131 ) to 58 ( 35-59 ) hours ( P = .003 ) . Oseltamivir treatment also reduced symptom scores ( median [ IQR ] score-hours , 225 [ 97-349 ] vs 400 [ 189-645 ] ; P = .05 ) , and nasal 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 oseltamivir were both associated with significant antiviral and clinical effects in experimental human influenza .
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Intervention_Pharmacological
neuraminidase inhibitor oseltamivir
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Intervention_Control
placebo-controlled
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Intervention_Other
inoculated intranasally with influenza A/Texas/36/91 ( H1N1 ) virus
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Intervention_Pharmacological
oral oseltamivir
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Intervention_Control
matching placebo
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Intervention_Control
placebo
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Outcome_Other
safety , tolerability , and antiviral activity
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Outcome_Other
frequency of infection and viral shedding
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Outcome_Physical
infected
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Outcome_Other
viral titer area under the curve
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Outcome_Other
median ( IQR ) duration of viral shedding
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Outcome_Physical
symptom scores
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Outcome_Physical
nasal proinflammatory cytokine levels
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Outcome_Adverse-effects
mild to moderate nausea
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Participant_Condition
influenza
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Participant_Sample-size
117
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Participant_Age
aged 18-40 years ; median age , 21 years
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Participant_Condition
influenza