Oseltamivir, zanamivir and amantadine in the prevention of influenza: A systematic review

Published:November 08, 2010DOI:https://doi.org/10.1016/j.jinf.2010.10.003

      Summary

      Objective

      To systematically review evidence relating to the clinical efficacy of oseltamivir, zanamivir and amantadine in the prevention of influenza.

      Methods

      RCTs evaluating these interventions in seasonal prophylaxis and post-exposure prophylaxis were identified using electronic bibliographic databases and handsearching of retrieved articles.

      Results

      Oseltamivir was effective in preventing symptomatic laboratory-confirmed influenza (SLCI) in seasonal prophylaxis in healthy adults and at-risk elderly subjects and in post-exposure prophylaxis within households of mixed composition. Post-exposure prophylaxis using oseltamivir for paediatric contacts was observed to prevent SLCI. Zanamivir prevented SLCI in seasonal prophylaxis in healthy adults, at-risk adults and adolescents and in post-exposure prophylaxis within mixed households, with a trend for seasonal and post-exposure preventative effects in elderly subjects. Evidence for amantadine prophylaxis across subgroups was very limited. However, amantadine prevented SLCI in seasonal prophylaxis in healthy adults and in outbreak control amongst adolescent subjects. Interventions were reported to be well tolerated by subjects, with a relatively low proportion of subjects experiencing drug-related adverse events and drug-related withdrawals.

      Conclusions

      Evidence was identified for the efficacy of oseltamivir and zanamivir in preventing influenza in a range of population subgroups. The evidence base for amantadine was considerably more limited.

      Keywords

      Introduction

      Influenza is a contagious, acute febrile respiratory infection caused by the influenza virus. Influenza A and B are responsible for nearly all influenza illness, with influenza A accounting for approximately 80% of outbreaks.
      • Douglas R.G.
      Prophylaxis and treatment of influenza.
      The level of influenza in a community is measured via a combination of the consultation rate for influenza-like illness (ILI) and the laboratory-based identification of influenza virus in samples from individuals with ILI.

      Health Protection Agency. 18-12-2007.

      Seasonal influenza generally occurs during the winter months in the northern hemisphere.
      • Nicholson K.G.
      Human influenza.
      Worldwide pandemics occur infrequently when a new influenza subtype of avian or porcine origin crosses the species barrier, is transmissible from person-to-person, and differs antigenically from recently circulating human strains of influenza, so the population has little or no immunity to the new virus.
      In healthy adults, seasonal influenza is often self-limiting and does not require treatment. However, complications such as pneumonia and exacerbations of asthma and chronic bronchitis can occur. Serious influenza-related complications are more common in individuals who are aged 65 years or over, who live in long-stay residential care facilities, or who have certain co-morbidities, including chronic respiratory, cardiovascular, renal, hepatic or neurological disease, diabetes, or immunosuppression.
      • Nicholson K.G.
      Human influenza.
      Complications may require antibiotic treatment, hospitalisation, and are associated with increased mortality. Estimated numbers of deaths that occur each year in the UK due to influenza have ranged between 12,000 and 13,800 deaths, mainly among the elderly and individuals with co-morbidities.
      • Tillett H.E.
      • Smith J.W.G.
      • Gooch C.D.
      Excess deaths attributable to influenza in England and Wales: age at death and certified cause.
      ,
      • Nicholson K.G.
      Impact of influenza and respiratory syncitial virus on mortality in England and Wales from January 1975 to December 1990.
      ,
      • Fleming D.M.
      The contribution of influenza to combined acute respiratory infections, hospital admissions, and deaths in winter.
      The objective of this systematic review, commissioned by the National Institute for Health and Clinical Excellence (NICE) as an update to previous guidance

      National Institute for Health and Clinical Excellence. Oseltamivir and amantadine for the prophylaxis of influenza. Technology Appraisal Guidance 67, 2003.

      , was to evaluate the performance of the neuraminidase inhibitors oseltamivir and zanamivir and the M2 inhibitor amantadine in influenza prophylaxis. The scope of the NICE assessment covered two prophylactic circumstances: i) post-exposure prophylaxis and ii) seasonal prophylaxis. The populations analysed included children, adults and older people, with each group being further sub-divided into healthy individuals or those at-risk of developing complications of influenza. The review findings, together with a related health economic decision model, were used to inform the current NICE guidance on the use of antiviral drugs in seasonal and post-exposure influenza prophylaxis.

      National Institute for Clinical Excellence. Oseltamivir, amatadine (review) and zanamivir for the prophylaxis of influenza. Technology Appraisal Guidance 158, 2008.

      • Tappenden P.
      • Jackson R.
      • Cooper K.
      • Rees A.
      • Simpson E.
      • Read R.
      • et al.
      Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation.

      Methods

       Identification of evidence

      A review protocol outlining the planned approaches to the review was developed and adhered to throughout the conduct of the review. The search strategy consisted of the following approaches: searching of electronic databases (searched August 2007 and updated in August 2009); contact with topic experts; and handsearching of bibliographies of retrieved papers. Searches were performed in electronic databases including Medline, Medline in Process, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, BIOSIS, CINAHL, DARE, NHS EED and HTA databases, OHE HEED, NRR (National Research Register), Science Citation Index, Current Controlled Trials, Clinical Trials.gov. The search strategies included subject headings and free text terms, combined using Boolean logic, to identify all published and unpublished data relating to the clinical effectiveness of oseltamivir, zanamivir and amantadine in the prevention of influenza. Searches for the clinical effectiveness review were limited by publication type to controlled clinical trials, and systematic reviews. Searches were not restricted by the date of publication or by language. Published findings identified during this assessment are presented in this publication.

       Study selection

      Studies were considered eligible for inclusion if they related to the use of oseltamivir, zanamivir or amantadine administered in line with current UK marketing authorisations.

      British National Formulary. 2007.

      Population groups considered were children, adults and the elderly (see Table 1, Table 2, Table 3 for age composition of study populations), with each group being further sub-divided into healthy individuals or those at-risk of developing complications of influenza. Two prophylactic situations were assessed: i) seasonal prophylaxis, and ii) post-exposure prophylaxis. Interventions were compared against each other and against no prophylaxis (whereby subjects received any of the following: placebo, no treatment or expectant treatment following onset of symptomatic influenza). The number of influenza cases prevented was measured in terms of symptomatic, laboratory-confirmed influenza (SLCI) or, in the absence of this outcome, acute respiratory illness or influenza-like illness and/or confirmed influenza infection. Other outcomes of interest included complications prevented, hospitalisations prevented, length of influenza illness, time to return to normal activities, mortality, health-related quality of life, and adverse events. The following exclusion criteria were applied: intervention medications not used in accordance with their licensed indications, and studies only published in languages other than English. Studies based on experimentally-induced influenza are not described in this report due to limited generalisability to clinical practice. Based on the above inclusion/exclusion criteria, study selection was undertaken by one reviewer (RJ), with involvement of a second reviewer (KC/ES) when necessary to provide consensus on inclusion or exclusion of studies.
      Table 1Characteristics of included oseltamivir prophylaxis trials.
      Trial and reference detailsPopulation characteristicsInterventions (no. of patients in each arm)Preventative strategyProphylaxis duration
      WV15825; Peters et al., 2001
      • Peters P.H.
      • Gravenstein S.
      • Norwood P.
      • De Bock V.
      • Van Couter A.
      • Gibbens M.
      • et al.
      Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population.
      De Bock et al., 2000
      • De Bock V.
      • Peters P.
      • Von Planta T.-A.
      • Gibbens M.
      • Ward P.
      Oral oseltamivir for prevention of influenza in the frail elderly.
      At-risk elderly subjects living in a residential home (Mean age = 81–82 yrs across treatment arms age 81 yr) (98% with concomitant disease in each group),

      Intervention arm: 80.4% vaccinated

      Placebo arm: 80.1% vaccinated
      Intervention arm: Oseltamivir 75 mg once daily n = 276

      Placebo arm: n = 272
      Seasonal6 weeks
      WV15673; Hayden et al., 1999
      • Hayden F.G.
      • Atmar R.L.
      • Schilling M.
      • Johnson C.
      • Poretz D.
      • Paar D.
      • et al.
      Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.
      Healthy unvaccinated adults aged 18–65 yrs living in the community.

      Conducted at study sites in Virginia, USA
      Intervention arm: Oseltamivir 75 mg once daily n = 268

      Placebo arm: n = 268
      Seasonal6 weeks
      WV15697; Hayden et al., 1999
      • Hayden F.G.
      • Atmar R.L.
      • Schilling M.
      • Johnson C.
      • Poretz D.
      • Paar D.
      • et al.
      Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.
      Healthy unvaccinated adults aged 18–65 yrs living in the community.

      Conducted at study sites in Texas and Kansas City, USA
      Intervention arm: Oseltamivir 75 mg once daily n = 252

      Placebo arm: n = 251
      Seasonal6 weeks
      WV15799;

      Welliver et al., 2001

      Welliver R, Monto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA;285(6):748–754.

      Subjects of mixed age and health status living in households.

      Adults and children aged 12 years and above (as contacts),Contacts of all index cases:

      Intervention arm: 11.4% vaccinated.

      Placebo arm: 13.9% vaccinated

      Index cases did not receive treatment.
      Intervention arm: Oseltamivir 75 mg once daily n = 493

      Placebo arm: n = 462
      Post-exposure prophylaxis7 days
      WV16193;

      Hayden et al., 2004
      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
      ;

      Hayden et al., 2002
      • Hayden F.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Small I.
      • Hughes C.
      • et al.
      Oral oseltamivir prevents the spread of influenza between children in households.
      ; Belshe et al., 2001
      • Belshe R.
      • Hayden F.
      • Carewicz O.
      • Lanno R.
      • Martin C.
      • Hughes C.
      • et al.
      Effectiveness of oral oseltamivir in preventing spread of influenza-like illness in households with proven influenza.
      Subjects of mixed age and health status. Adults and children aged 1 year and above.

      Contacts:

      Oseltamivir prophylaxis arm: 8% vaccinated

      Expectant treatment arm: 7% vaccinated

      Index cases in both arms received treatment with oseltamivir 75 mg twice daily for 5 days.
      Oseltamivir: prophylaxis (PEP) vs. treatment on influenza onset (expectant treatment); index cases in both groups received treatment.

      Oseltamivir prophylaxis arm: Oseltamivir 75 mg daily for 10 days, n = 410

      Expectant treatment arm: Oseltamivir treatment on influenza onset 75 mg twice daily for 5 days (less in children), n = 402

      Subjects reported as ≤ 12 years

      Oseltamivir prophylaxis arm: n = 69,

      Expectant treatment arm: n = 65
      Post-exposure prophylaxis10 days
      Table 2Characteristics of included zanamivir prophylaxis trials.
      Trial and reference detailsPopulation characteristicsInterventions

      (no. of patients in each arm)
      Preventative strategyProphylaxis duration
      NAIA3005;

      Monto et al., 1999
      • Monto A.S.
      • Robinson D.P.
      • Louise M.
      • James H.
      • Hinson M.
      • Elliott M.J.
      • et al.
      Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial.
      Healthy adults (aged 18–64 years) from University communities,

      Intervention arm: 14% vaccinated

      Placebo arm: 14% vaccinated
      Intervention arm: Zanamivir 10 mg once daily n = 553

      Placebo arm: n = 554
      Seasonal28 days
      NAI30034;

      LaForce et al., 2007
      • LaForce C.
      • Man C.Y.
      • Henderson F.W.
      • McElhaney J.E.
      • Hampel Jr., F.C.
      • Bettis R.
      • et al.
      Efficacy and safety of inhaled zanamivir in the prevention of influenza in community-dwelling, high-risk adult and adolescent subjects: a 28-day, multicenter, randomized, double-blind, placebo-controlled trial.
      At-risk adolescents and adults (aged 12 yrs and above). High-risk defined as age 65 yrs and above or having chronic disorders of pulmonary or cardiovascular system or diabetes mellitus.

      Intervention arm: 67% vaccinated

      Placebo arm: 68% vaccinated
      Intervention arm: Zanamivir 10 mg once daily n = 1678 randomised, n = 1595 completed study

      Placebo arm: n = 1685 randomised, n = 1594 completed study

      Aged ≥65 years n = 946
      Seasonal28 days
      NAI30031;

      Monto et al., 2002
      • Monto A.S.
      • Pichichero M.E.
      • Blanckenberg S.J.
      • Ruuskanen O.
      • Cooper C.
      • Fleming D.M.
      • et al.
      Zanamivir prophylaxis: an effective strategy for the prevention of influenza types A and B within households.
      Subjects of mixed age and health status. Adults and children aged 5 years and above (as contacts).

      Index cases: Intervention arm: 8% vaccinated, Placebo arm: 5% vaccinated,

      Contact cases:

      Intervention arm: 11% vaccinated, Placebo arm: 10% vaccinated

      Index cases did not receive treatment.
      Intervention arm: Zanamivir 10 mg once daily n = 661

      Placebo arm: n = 630
      Post-exposure prophylaxis10 days
      NAI30010;

      Hayden et al., 2000
      • Hayden F.G.
      • Gubareva L.V.
      • Monto A.S.
      • Klein T.C.
      • Elliott M.J.
      • Hammond J.M.
      • et al.
      Inhaled zanamivir for the prevention of influenza in families.
      Subjects of mixed age and health status. Adults and children aged 5 years and above.

      Contacts: Intervention arm: 14% vaccinated, Placebo arm: 18% vaccinated

      Index cases were randomised to zanamivir twice daily or placebo.
      Intervention arm: Zanamivir inhaled 10 mg daily n = 414

      Placebo arm: n = 423
      Post-exposure prophylaxis10 days
      NAIA2009,

      NAIB2009;

      Kaiser et al., 2000
      • Kaiser L.
      • Henry D.
      • Flack N.P.
      • Keene O.
      • Hayden F.G.
      Short-term treatment with zanamivir to prevent influenza: Results of a placebo-controlled study.
      Subjects of mixed age and health status. Unvaccinated adults and children aged 13–65 years (as contacts).

      Index cases did not receive treatment.
      Intervention arm: Zanamivir 10 mg inhaled daily n = 144

      Placebo arm: n = 144
      Post-exposure prophylaxis5 days
      NAIA3004;

      Ambrozaitis et al., 2005
      • Ambrozaitis A.
      • Gravenstein S.
      • Van Essen G.A.
      • Rubinstein E.
      • Balciuniene L.
      • Stikleryte A.
      • et al.
      Inhaled zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population.
      ;

      Ambrozaitis et al., 2001
      • Ambrozaitis A.
      • VanEssen G.
      • Rubinstein E.
      • Balciuiene L.
      • Stikleryte A.
      • Gravenstein S.
      • et al.
      Inhaled zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population (NAIA3004).
      At-risk elderly subjects in long-term care (mean age Intervention arm = 66.8 yrs, Placebo arm = 67.2 yrs) (84–85% at-risk of complications)

      Intervention arm: 9.6% vaccinated, Placebo arm: 8.8% vaccinated
      Intervention arm: Zanamivir once daily n = 242

      Placebo arm: n = 252
      Outbreak control14 days
      NAIA3003;

      Gravenstein et al., 2005
      • Gravenstein S.
      • Drinka P.
      • Osterweil D.
      • Schilling M.
      • Krause P.
      • Elliott M.
      • et al.
      Inhaled zanamivir versus rimantadine for the control of influenza in a highly vaccinated long-term care population.
      At-risk elderly subjects in long-term care (mean age Intervention arm = 76.3 yrs, Placebo arm = 74.8 yrs) (96–100% at-risk of complications)

      Intervention arm: 99% vaccinated, Placebo arm: 92% vaccinated
      Intervention arm: Zanamivir 10 mg once daily n = 12 for influenza B outbreak

      Placebo arm: Placebo n = 13 for influenza B outbreak
      Outbreak control14 days
      Table 3Characteristics of included amantadine prophylaxis trials.
      Trial and reference detailsPopulation characteristicsInterventions

      (no. of patients in each arm)
      Preventative strategyProphylaxis duration
      Reuman et al., 1989
      • Reuman P.D.
      • Bernstein D.I.
      • Keefer M.C.
      • Young E.C.
      • Sherwood J.R.
      • Schiff G.M.
      Efficacy and safety of low dosage amantadine hydrochloride As prophylaxis for influenza A.
      Healthy unvaccinated adults aged 18–55 years living in the communityIntervention arm: Amantadine 100 mg/day n = 159

      Placebo arm: n = 159
      SeasonalPresumed 6 weeks
      Aoki et al., 1986
      • Aoki F.Y.
      • Stiver H.G.
      • Sitar D.S.
      • Hammond G.W.
      • Milley E.V.
      • Vermeersch C.
      • et al.
      Potential of influenza vaccine and amantadine to prevent influenza A illness in Canadian forces personnel 1980-1983.
      Healthy adults in a military setting, (age not defined)

      6–8 individuals in each study year immunised against influenza in previous years
      Intervention arm: Amantadine 100 mg/day, 1980–1981 n = 74, 1981–1982: under 28 yrs n = 21, over 29 yrs n = 29, 1982–1983 n = 46

      Placebo arm: 1980–1981 n = 48, 1981–1982: under 28 yrs n = 16, over 29 yrs n = 18, 1982–1983 n = 33
      Seasonal39 days (1980–1981)

      32 days (1982–1983)
      Pettersson et al., 1980
      • Pettersson R.F.
      • Hellström P.E.
      • Penttinen K.
      • Pyhälä R.
      • Tokola O.
      • Vartio T.
      • et al.
      Evaluation of amantadine in the prophylaxis of influenza A (H1N1) virus infection: a controlled field trial among young adults and high-risk patients.
      Elderly subjects (mean ages Intervention arm = 77.4 yrs, Placebo arm = 79.0 yrs) living in a residential home, vaccination status unclear, but discussion states no adequate vaccine availableIntervention arm: Amantadine 100 mg/day, randomised n = 94, completing study n = 89

      Placebo arm: randomised n = 101, completing study n = 99
      Seasonal9 weeks
      Payler & Purdham, 1984
      • Payler D.K.
      • Purdham P.A.
      Influenza A prophylaxis with amantadine in a boarding school.
      Adolescent males (13–19 yrs old) in boarding school setting, 87% vaccinatedIntervention arm: Amantadine 100 mg/day randomised n = 299, final analysis n = 267

      Comparison arm: No specific treatment randomised n = 307, final analysis n = 269
      Outbreak control14 days
      Smorodintsev et al., 1970a, b
      • Smorodintsev A.
      • Karpuchin G.
      • Zlydnikov D.
      The prospect of amantadine for prevention of influenza A in humans (effectiveness of amantadine during influenza A2/Hong Kong epidemics in January-February 1969 in Leningrad.
      • Smorodintsev A.A.
      • Karapuhi G.I.
      • Zlydniko D.M.
      • Malyseva A.M.
      • Svecova E.G.
      • Burov S.A.
      • et al.
      Prophylactic effectiveness of amantadine hydrochloride in an epidemic of Hong-Kong influenza in Leningrad in 1969.
      Male adults (recruitment pool aged 18–30 yrs) (presumed healthy) in semi-isolated engineering school populationsIntervention arm: Amantadine 100 mg/day (50.7% of 10,053), assigned to group n = 5092, onset of influenza prior to dosing n = 441, n = 4559 regularly or irregularly taking amantadine.

      Placebo arm: (31.6% of 10,053), assigned to group n = 3175, onset of influenza prior to dosing n = 307, n = 2804 receiving placebo (3175 minus 307 = 2868, 2804 included in analysis.

      Internal control arm: individuals at the same engineering schools as the amantadine and placebo groups, but living at home rather than at the school; received no prophylaxis (10.0% of 10,053) n = 1011

      External control: individuals at an 8th engineering school; received no prophylaxis (7.7% of 10,053), assigned to group n = 775
      Outbreak control5 of 7 populations dosed for 30 days, 2 populations dosed for 12 days

       Data abstraction

      Data was extracted by one reviewer (RJ) using a form developed for this purpose. All data abstraction was checked and confirmed by a second reviewer (KC).

       Quality assessment

      The quality of included randomised controlled studies was assessed using quality criteria based on those developed by the NHS Centre for Reviews and Dissemination.

      NHS Centre for Reviews and Dissemination. Report 4: Undertaking systematic reviews on effectiveness; CRDs guidance for those carrying out or commissioning reviews. 2001.

      Quality assessment was confirmed by a second reviewer (KC).

       Data synthesis

      Data were presented within a narrative synthesis. Where quantitative synthesis was considered to be appropriate, statistical meta-analysis was undertaken using a random effects model within Review Manager (RevMan) software (version 4.2.10, The Cochrane Collaboration) in order to calculate pooled estimates for relative risks for outcomes of interest. Efficacy data were presented as relative risks (RR) and protective efficacy (PE = 1 minus RR, expressed as a percentage) with associated 95% confidence intervals (95% CI).
      The methods and findings of this review have been reported based on the PRISMA standards for systematic reviews and meta-analyses.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      for the PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.

      Results

      A total of 1010 citations were identified and, following removal of duplicate records, were screened for inclusion in the review.
      Seven citations were excluded, since the full text article was not available in English.
      • Hess P.
      Amantadine and rimantadine in the prophylaxis of influenza A.
      • Plesnik V.
      • Heinz F.
      • Bindas B.
      • Cechova D.
      • Eliasova J.
      • Galetkova A.
      • et al.
      Controlled study of influenza prophylaxis by VUFB amantadin.
      • Quilligan Jr., J.J.
      • Hirayama M.
      • Baernstein Jr., H.D.
      The prevention of A2-influenza in children by chemoprophylaxis with amantadine hydrochloride.
      • Smorodintsev A.A.
      • Zlydnikov D.M.
      • Romanov I.
      • Rumovski V.I.
      • Smorodintsev A.A.
      • Zlydnikov D.M.
      • et al.
      Effectiveness of amantadine hydrochloride (midantane) in prevention of artificially induced influenza.
      • Kashiwagi S.
      • Kudoh S.
      • Watanabe A.
      • Yoshimura I.
      Efficacy and safety of the selective oral neuraminidase inhibitor oseltamivir for prophylaxis against influenza–placebo-controlled double-blind multicenter phase III trial.
      • Shinjoh M.
      • Sato S.
      • Sugaya N.
      • Mitamura K.
      • Takeuchi Y.
      • Kosaki K.
      • et al.
      Effect of post-exposure prophylaxis with oseltamivir for those in contacts with influenza patients in pediatric wards.
      • Diaz-Pedroche C.
      • Lizasoain M.
      • Lopez-Medrano F.
      • Escalante F.
      • Lumbreras C.
      • Folgueira D.
      • et al.
      Nosocomial outbreak of influenza in high-risk hematological patients. Efficacy of control measures and the use of zanamivir.
      Thirty nine studies were excluded as they related to the use of intervention medications not in accordance with their UK licensed indications. The majority of these were specific to the use of amantadine,
      • Aoki F.Y.
      • Stiver H.G.
      • Sitar D.S.
      • Boudreault A.
      • Ogilvie R.I.
      • Aoki F.Y.
      • et al.
      Prophylactic amantadine dose and plasma concentration-effect relationships in healthy adults.
      • Bryson Y.J.
      • Monahan C.
      • Pollack M.
      • Shields W.D.
      A prospective double-blind study of side effects associated with the administration of amantadine for influenza A virus prophylaxis.
      • Callmander E.
      • Hellgren L.
      Amantadine hydrochloride as a prophylactic in respiratory infections. A double-blind investigation of its clinical use and serology.
      • Cohen A.
      • Togo Y.
      • Khakoo R.
      • Waldman R.
      • Sigel M.
      Comparative clinical and laboratory evaluation of the prophylactic capacity of ribavirin, amantadine hydrochloride, and placebo in induced human influenza type A.
      • Dawkins A.T.
      • Gallager L.R.
      • Togo Y.
      • Hornick R.B.
      • Harris B.A.
      Studies on induced influenza in man. II. Double-blind study designed to assess the prophylactic efficacy of an analogue of amantadine hydrochloride.
      • Dolin R.
      • Reichman R.C.
      • Madore H.P.
      • Maynard R.
      • Linton P.N.
      • Webber-Jones J.
      A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection.
      • Finklea J.F.
      • Hennessy A.V.
      • Davenport F.M.
      A field trial of amantadine prophylaxis in naturally-occurring acute respiratory illness.
      • Galbraith A.W.
      • Oxford J.S.
      • Schild G.C.
      • Watson G.I.
      Protective effect of 1-adamantanamine hydrochloride on influenza A2 infections in the family environment: a controlled double-blind study.
      • Galbraith A.W.
      • Oxford J.S.
      • Schild G.C.
      • Watson G.I.
      Study of 1-adamantanamine hydrochloride used prophylactically during the Hong Kong influenza epidemic in the family environment.
      • Galbraith A.W.
      • Oxford J.S.
      • Schild G.C.
      • Potter C.W.
      • Watson G.I.
      Therapeutic effect of 1-adamantanamine hydrochloride in naturally occurring influenza A2-Hong Kong infection. A controlled double-blind study.
      • Hayden F.
      • Gwaltney J.M.
      • Van de Castle R.L.
      • Adams K.F.
      • Giordani B.
      Comparative toxicity of amantadine hydrochloride and rimantadine hydrochloride in healthy adults.
      • Jackson G.G.
      • Muldoon R.L.
      • Akers L.W.
      Serological evidence for prevention of influenzal infection in volunteers by an anti-influenzal drug adamantanamine hydrochloride.
      • Kantor R.J.
      • Stevens D.
      • Potts D.W.
      • Noble G.R.
      Prevention of influenza A/USSR/77 (H1N1): an evaluation of the side effects and efficacy of amantadine in recruits at Fort Sam Houston.
      • Leeming J.T.
      Amantidine hydrochloride and the elderly.
      • Leung P.
      • McIntosh K.
      • Chai H.
      Amantadine prophylaxis against influenza A/USSR in children with chronic asthma.
      • Máté J.
      • Simon M.
      • Juvancz I.
      • Takátsy G.
      • Hollós I.
      • Farkas E.
      Prophylactic use of amantadine during Hong Kong influenza epidemic.
      • Millet V.M.
      • Dreisbach M.
      • Bryson Y.J.
      Double-blind controlled study of central nervous system side effects of amantadine, rimantadine and chlorpheniramine.
      • Monto A.S.
      • Gunn R.A.
      • Bandyk M.G.
      • King C.L.
      Prevention of Russian influenza by amantadine.
      • Muldoon R.L.
      • Stanley E.D.
      • Jackson G.G.
      Use and withdrawal of amantadine chemoprophylaxis during epidemic influenza A.
      • Nafta I.
      • TTurcanu A.G.
      • Braun I.
      • Companetz W.
      • Simionescu A.
      • Birt E.
      • et al.
      Administration of amantadine for the prevention of Hong Kong influenza.
      • O’Donoghue J.M.
      • Ray C.G.
      • Terry D.W.
      • Beaty H.N.
      Prevention of Nosocomial influenza infection with amantadine.
      • Oker-Blom N.
      • Hovi T.
      • Leinikki P.
      • Palosuo T.
      • Pettersson R.
      • Suni J.
      Protection of man from natural infection with influenza A2 Hong Kong virus by amantadine: a controlled field trial.
      • Peckinpaugh R.O.
      • Askin F.B.
      • Pierce W.E.
      • Edwards E.A.
      • Johnson D.P.
      • Jackson G.G.
      Field studies with amantadine: acceptability and protection.
      • Quarles J.M.
      • Couch R.B.
      • Cate T.R.
      • Goswick C.B.
      Comparison of amantadine and rimantadine for prevention of type A (Russian) influenza.
      • Quilligan J.J.
      • Hirayama M.
      • Baernstein H.D.
      The suppression of A2 influenza in children by the chemoprophylactic use of Amantadine.
      • Schapira M.
      • Oxford J.
      • Galbraith W.
      A study of adamantamine hydrochloride during the 1970 Hong Kong influenza epidemic.
      • Stanley E.D.
      • Muldoon R.E.
      • Akers L.W.
      • Jackson G.G.
      Evaluation of antiviral drugs: the effect of amantadine on influenza in volunteers.
      • Togo Y.
      • Hornick R.B.
      • Dawkins A.T.
      Studies on induced influenza in man. I. Double-blind studies designed to assess prophylactic efficacy of amantadine hydrochloride against a2/Rockville/1/65 strain.
      • Tyrell D.A.J.
      • Bynoe M.L.
      • Dawkins A.T.
      Studies on the antiviral activity of 1-adamantanamine.
      • Wendel H.A.
      • Snyder M.T.
      • Pell S.
      Trial of amantadine in epidemic influenza.
      • Wright P.F.
      • Khaw K.T.
      • Oxman M.N.
      • Shwachma H.
      Amantadine for prophylaxis of influenza in patients with cystic-fibrosis.
      • Wright P.F.
      • Khaw K.T.
      • Oxman M.N.
      • Shwachman H.
      Evaluation of the safety of amantadine-HC1 and the role of respiratory viral infections in children with cystic fibrosis.
      whilst six were studies of zanamivir
      • Calfee D.P.
      • Peng A.W.
      • Hussey E.K.
      • Lobo M.
      • Hayden F.G.
      Safety and efficacy of once daily intranasal zanamivir in preventing experimental human influenza A infection.
      • Calfee D.P.
      • Peng A.W.
      • Cass L.M.
      • Lobo M.
      • Hayden F.G.
      Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection.
      • Cass L.M.R.
      • Gunawardena K.A.
      • MacMahon M.M.
      • Bye A.
      Pulmonary function and airway responsiveness in mild to moderate asthmatics given repeated inhaled doses of zanamivir.
      • Hayden F.G.
      • Treanor J.J.
      • Betts R.F.
      • Lobo M.
      • Esinhart J.D.
      • Hussey E.K.
      Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza.
      • Schilling M.
      • Povinelli L.
      • Krause P.
      • Gravenstein M.
      • Ambrozaitis A.
      • Jones H.
      • et al.
      Efficacy of zanamivir for chemoprophylaxis of nursing home influenza outbreaks.
      • Walker J.B.
      • Hussey E.K.
      • Treanor J.J.
      • Montalvo Jr., A.
      • Hayden F.G.
      Effects of the neuraminidase inhibitor zanamivir on otologic manifestations of experimental human influenza.
      and one related to oseltamivir.
      • Hayden F.G.
      • Treanor J.J.
      • Fritz R.S.
      • Lobo M.
      • Betts R.F.
      • Miller M.
      • et al.
      Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment.
      Evidence for amantadine prophylaxis in children under 10 years is not presented in this systematic review, as such data were excluded as amantadine dosage is not established in this age group according to licensed indications.
      Twenty two published reports of 18 RCTs were included. Seven references comprising four full papers and three abstracts were identified for five RCTs describing the prophylactic use of oseltamivir (Table 1). For zanamivir, nine published reports of eight RCTs were identified, including seven full papers and two abstracts (see Table 2). We identified six papers reporting five RCTs evaluating the use of amantadine in the prevention of influenza (Table 3).
      The quality of the oseltamivir prophylaxis evidence was considered robust in terms of study design and reporting. However, randomisation methods used and concealment of allocation were unclear in two study reports.

      Welliver R, Monto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA;285(6):748–754.

      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
      All oseltamivir studies were judged to have achieved baseline comparability amongst subjects. Four study reports listed potentially confounding co-interventions, including vaccination status

      Welliver R, Monto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA;285(6):748–754.

      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
      • Peters P.H.
      • Gravenstein S.
      • Norwood P.
      • De Bock V.
      • Van Couter A.
      • Gibbens M.
      • et al.
      Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population.
      • Hayden F.G.
      • Atmar R.L.
      • Schilling M.
      • Johnson C.
      • Poretz D.
      • Paar D.
      • et al.
      Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.
      , recent use of antivirals
      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
      • Peters P.H.
      • Gravenstein S.
      • Norwood P.
      • De Bock V.
      • Van Couter A.
      • Gibbens M.
      • et al.
      Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population.
      and antibiotics.
      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
      For some studies, it was unclear whether outcome assessors,

      Welliver R, Monto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA;285(6):748–754.

      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
      • Peters P.H.
      • Gravenstein S.
      • Norwood P.
      • De Bock V.
      • Van Couter A.
      • Gibbens M.
      • et al.
      Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population.
      • Hayden F.G.
      • Atmar R.L.
      • Schilling M.
      • Johnson C.
      • Poretz D.
      • Paar D.
      • et al.
      Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.
      intervention providers

      Welliver R, Monto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA;285(6):748–754.

      • Peters P.H.
      • Gravenstein S.
      • Norwood P.
      • De Bock V.
      • Van Couter A.
      • Gibbens M.
      • et al.
      Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population.
      or participants were blinded to treatment allocation,

      Welliver R, Monto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA;285(6):748–754.

      whilst one study was described as being open-label in design.
      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
      All oseltamivir trials retained at least 80% of randomised subjects for analysis. The identified evidence for the use of zanamivir in prophylaxis against influenza had a lack of detail on methods of randomisation
      • Monto A.S.
      • Pichichero M.E.
      • Blanckenberg S.J.
      • Ruuskanen O.
      • Cooper C.
      • Fleming D.M.
      • et al.
      Zanamivir prophylaxis: an effective strategy for the prevention of influenza types A and B within households.
      • Hayden F.G.
      • Gubareva L.V.
      • Monto A.S.
      • Klein T.C.
      • Elliott M.J.
      • Hammond J.M.
      • et al.
      Inhaled zanamivir for the prevention of influenza in families.
      • Kaiser L.
      • Henry D.
      • Flack N.P.
      • Keene O.
      • Hayden F.G.
      Short-term treatment with zanamivir to prevent influenza: Results of a placebo-controlled study.
      and allocation concealment.
      • Hayden F.G.
      • Gubareva L.V.
      • Monto A.S.
      • Klein T.C.
      • Elliott M.J.
      • Hammond J.M.
      • et al.
      Inhaled zanamivir for the prevention of influenza in families.
      • Kaiser L.
      • Henry D.
      • Flack N.P.
      • Keene O.
      • Hayden F.G.
      Short-term treatment with zanamivir to prevent influenza: Results of a placebo-controlled study.
      • Ambrozaitis A.
      • Gravenstein S.
      • Van Essen G.A.
      • Rubinstein E.
      • Balciuniene L.
      • Stikleryte A.
      • et al.
      Inhaled zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population.
      All zanamivir studies included over 80% of randomised subjects in analyses. Several limitations in the quality of the included studies relating to the prophylactic use of amantadine were noted. A lack of detail on methods of randomisation,
      • Payler D.K.
      • Purdham P.A.
      Influenza A prophylaxis with amantadine in a boarding school.
      • Smorodintsev A.
      • Karpuchin G.
      • Zlydnikov D.
      The prospect of amantadine for prevention of influenza A in humans (effectiveness of amantadine during influenza A2/Hong Kong epidemics in January-February 1969 in Leningrad.
      • Smorodintsev A.A.
      • Karapuhi G.I.
      • Zlydniko D.M.
      • Malyseva A.M.
      • Svecova E.G.
      • Burov S.A.
      • et al.
      Prophylactic effectiveness of amantadine hydrochloride in an epidemic of Hong-Kong influenza in Leningrad in 1969.
      blinding,
      • Reuman P.D.
      • Bernstein D.I.
      • Keefer M.C.
      • Young E.C.
      • Sherwood J.R.
      • Schiff G.M.
      Efficacy and safety of low dosage amantadine hydrochloride As prophylaxis for influenza A.
      • Aoki F.Y.
      • Stiver H.G.
      • Sitar D.S.
      • Hammond G.W.
      • Milley E.V.
      • Vermeersch C.
      • et al.
      Potential of influenza vaccine and amantadine to prevent influenza A illness in Canadian forces personnel 1980-1983.
      • Payler D.K.
      • Purdham P.A.
      Influenza A prophylaxis with amantadine in a boarding school.
      • Smorodintsev A.
      • Karpuchin G.
      • Zlydnikov D.
      The prospect of amantadine for prevention of influenza A in humans (effectiveness of amantadine during influenza A2/Hong Kong epidemics in January-February 1969 in Leningrad.
      • Smorodintsev A.A.
      • Karapuhi G.I.
      • Zlydniko D.M.
      • Malyseva A.M.
      • Svecova E.G.
      • Burov S.A.
      • et al.
      Prophylactic effectiveness of amantadine hydrochloride in an epidemic of Hong-Kong influenza in Leningrad in 1969.
      and concealment of treatment allocation was observed.
      • Aoki F.Y.
      • Stiver H.G.
      • Sitar D.S.
      • Hammond G.W.
      • Milley E.V.
      • Vermeersch C.
      • et al.
      Potential of influenza vaccine and amantadine to prevent influenza A illness in Canadian forces personnel 1980-1983.
      • Payler D.K.
      • Purdham P.A.
      Influenza A prophylaxis with amantadine in a boarding school.
      • Smorodintsev A.
      • Karpuchin G.
      • Zlydnikov D.
      The prospect of amantadine for prevention of influenza A in humans (effectiveness of amantadine during influenza A2/Hong Kong epidemics in January-February 1969 in Leningrad.
      • Smorodintsev A.A.
      • Karapuhi G.I.
      • Zlydniko D.M.
      • Malyseva A.M.
      • Svecova E.G.
      • Burov S.A.
      • et al.
      Prophylactic effectiveness of amantadine hydrochloride in an epidemic of Hong-Kong influenza in Leningrad in 1969.
      Five study reports described co-interventions with the potential to affect outcomes, such as vaccination.
      • Reuman P.D.
      • Bernstein D.I.
      • Keefer M.C.
      • Young E.C.
      • Sherwood J.R.
      • Schiff G.M.
      Efficacy and safety of low dosage amantadine hydrochloride As prophylaxis for influenza A.
      • Aoki F.Y.
      • Stiver H.G.
      • Sitar D.S.
      • Hammond G.W.
      • Milley E.V.
      • Vermeersch C.
      • et al.
      Potential of influenza vaccine and amantadine to prevent influenza A illness in Canadian forces personnel 1980-1983.
      • Payler D.K.
      • Purdham P.A.
      Influenza A prophylaxis with amantadine in a boarding school.
      • Smorodintsev A.
      • Karpuchin G.
      • Zlydnikov D.
      The prospect of amantadine for prevention of influenza A in humans (effectiveness of amantadine during influenza A2/Hong Kong epidemics in January-February 1969 in Leningrad.
      • Smorodintsev A.A.
      • Karapuhi G.I.
      • Zlydniko D.M.
      • Malyseva A.M.
      • Svecova E.G.
      • Burov S.A.
      • et al.
      Prophylactic effectiveness of amantadine hydrochloride in an epidemic of Hong-Kong influenza in Leningrad in 1969.

       Prevention of symptomatic, laboratory-confirmed influenza

      The primary outcome reported in most included trials related to cases of influenza prevented as measured in terms of the incidence of SLCI. Key findings are summarised in Table 4, Table 5.
      Table 4Efficacy of interventions in seasonal prevention of symptomatic, laboratory-confirmed influenza.


      Prophylactic strategy
      Relative risk of developing symptomatic, laboratory-confirmed influenza (95%C.I.)
      AmantadineOseltamivirZanamivir
      Seasonal prophylaxis in healthy childrenDosage not established in childrenNDANDA
      Seasonal prophylaxis in at-risk childrenDosage not established in childrenNDANDA
      Seasonal prophylaxis in healthy adults0.40 (0.08–2.03) (Reuman et al., 1989)
      • Reuman P.D.
      • Bernstein D.I.
      • Keefer M.C.
      • Young E.C.
      • Sherwood J.R.
      • Schiff G.M.
      Efficacy and safety of low dosage amantadine hydrochloride As prophylaxis for influenza A.


      From 1 trial
      0.24 (0.09–0.54) (Hayden et al., 1999)
      • Hayden F.G.
      • Atmar R.L.
      • Schilling M.
      • Johnson C.
      • Poretz D.
      • Paar D.
      • et al.
      Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.


      From 2 trials
      0.32 (calculated by assessment group) (0.17–0.63) (Monto et al., 1999)
      • Monto A.S.
      • Robinson D.P.
      • Louise M.
      • James H.
      • Hinson M.
      • Elliott M.J.
      • et al.
      Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial.


      From 1 trial
      Seasonal prophylaxis in at-risk adults and adolescentsNDANDA0.17 (0.07–0.44) (LaForce et al., 2007)
      • LaForce C.
      • Man C.Y.
      • Henderson F.W.
      • McElhaney J.E.
      • Hampel Jr., F.C.
      • Bettis R.
      • et al.
      Efficacy and safety of inhaled zanamivir in the prevention of influenza in community-dwelling, high-risk adult and adolescent subjects: a 28-day, multicenter, randomized, double-blind, placebo-controlled trial.


      From 1 trial
      Seasonal prophylaxis in healthy elderly subjectsNo data reported (Pettersson et al., 1980)
      • Pettersson R.F.
      • Hellström P.E.
      • Penttinen K.
      • Pyhälä R.
      • Tokola O.
      • Vartio T.
      • et al.
      Evaluation of amantadine in the prophylaxis of influenza A (H1N1) virus infection: a controlled field trial among young adults and high-risk patients.
      NDA0.20 (0.02–1.72) (LaForce et al., 2007)
      • LaForce C.
      • Man C.Y.
      • Henderson F.W.
      • McElhaney J.E.
      • Hampel Jr., F.C.
      • Bettis R.
      • et al.
      Efficacy and safety of inhaled zanamivir in the prevention of influenza in community-dwelling, high-risk adult and adolescent subjects: a 28-day, multicenter, randomized, double-blind, placebo-controlled trial.


      From 1 trial
      Seasonal prophylaxis in at-risk elderly subjectsNo data reported (Pettersson et al., 1980)
      • Pettersson R.F.
      • Hellström P.E.
      • Penttinen K.
      • Pyhälä R.
      • Tokola O.
      • Vartio T.
      • et al.
      Evaluation of amantadine in the prophylaxis of influenza A (H1N1) virus infection: a controlled field trial among young adults and high-risk patients.
      0.08 (0.01–0.63) (Peters et al., 2001)
      • Peters P.H.
      • Gravenstein S.
      • Norwood P.
      • De Bock V.
      • Van Couter A.
      • Gibbens M.
      • et al.
      Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population.


      (98% subjects with concomitant disease)

      From 1 trial
      0.20 (0.02–1.72) (LaForce et al., 2007)
      • LaForce C.
      • Man C.Y.
      • Henderson F.W.
      • McElhaney J.E.
      • Hampel Jr., F.C.
      • Bettis R.
      • et al.
      Efficacy and safety of inhaled zanamivir in the prevention of influenza in community-dwelling, high-risk adult and adolescent subjects: a 28-day, multicenter, randomized, double-blind, placebo-controlled trial.


      From 1 trial
      (NDA indicates subgroup categories for which no data were available).
      Table 5Efficacy of interventions in post-exposure prevention of symptomatic, laboratory-confirmed influenza.


      Prophylactic strategy
      Relative risk of developing symptomatic, laboratory-confirmed influenza (95%C.I.)
      AmantadineOseltamivirZanamivir
      Post-exposure prophylaxis in mixed householdsNDA0.19 (0.08–0.45) (Hayden et al., 2004)
      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
      ; Welliver et al., 2001)

      Welliver R, Monto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA;285(6):748–754.



      From 2 trials
      0.21 (0.13–0.33) (Hayden et al., 2000;
      • Hayden F.G.
      • Gubareva L.V.
      • Monto A.S.
      • Klein T.C.
      • Elliott M.J.
      • Hammond J.M.
      • et al.
      Inhaled zanamivir for the prevention of influenza in families.
      Kaiser et al., 2000;
      • Kaiser L.
      • Henry D.
      • Flack N.P.
      • Keene O.
      • Hayden F.G.
      Short-term treatment with zanamivir to prevent influenza: Results of a placebo-controlled study.
      Monto et al., 2002)
      • Monto A.S.
      • Pichichero M.E.
      • Blanckenberg S.J.
      • Ruuskanen O.
      • Cooper C.
      • Fleming D.M.
      • et al.
      Zanamivir prophylaxis: an effective strategy for the prevention of influenza types A and B within households.


      From 4 trials
      Post-exposure prophylaxis in healthy childrenDosage not established in children0.36 (0.15–0.84) (Hayden et al., 2004)
      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.


      From 1 trial
      NDA
      Post-exposure prophylaxis in at-risk childrenDosage not established in childrenNDA (subjects with a number of chronic conditions excluded) (Hayden et al., 2004)
      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
      NDA
      Post-exposure prophylaxis in healthy adults and adolescents0.10 (0.03–0.34) (Payler & Purdham, 1984)
      • Payler D.K.
      • Purdham P.A.
      Influenza A prophylaxis with amantadine in a boarding school.


      From 1 trial
      NDANDA
      Post-exposure prophylaxis in at-risk adults and adolescentsNDANDANDA
      Post-exposure prophylaxis in healthy elderly subjectsNDANDANDA
      Post-exposure prophylaxis in at-risk elderly subjectsNDANDA0.68 (0.33–1.27) (Ambrozaitis et al., 2005)
      • Ambrozaitis A.
      • Gravenstein S.
      • Van Essen G.A.
      • Rubinstein E.
      • Balciuniene L.
      • Stikleryte A.
      • et al.
      Inhaled zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population.
      (calculated by assessment group)

      (Subjects 85% at-risk of complications)
      (NDA indicates subgroup categories for which no data were available).

       Use of oseltamivir in seasonal prophylaxis

      Oseltamivir was efficacious in seasonal prophylaxis against SLCI in healthy adults (RR = 0.24, 95% CI 0.09–0.54, pooled estimate from two trials reported as a single publication).
      • Hayden F.G.
      • Atmar R.L.
      • Schilling M.
      • Johnson C.
      • Poretz D.
      • Paar D.
      • et al.
      Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.
      A protective effect of oseltamivir in seasonal prophylaxis against SLCI was notable in one trial amongst the frail elderly living in residential care (98% with concomitant disease) (RR = 0.08, 95% CI 0.01–0.63).
      • Peters P.H.
      • Gravenstein S.
      • Norwood P.
      • De Bock V.
      • Van Couter A.
      • Gibbens M.
      • et al.
      Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population.

       Use of oseltamivir in post-exposure prophylaxis

      Oseltamivir conveyed a protective efficacy of 81% against SLCI in household contacts of mixed composition (adults and children aged 1 year and above, and adults and children aged 12 years and above) (RR = 0.19, 95% CI 0.08–0.45) (pooled estimate from two trials).

      Welliver R, Monto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA;285(6):748–754.

      ,
      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
      Only one RCT
      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
      in which data relating specifically to children aged 1–12 years were presented was identified. Post-exposure prophylaxis in paediatric contacts (aged 1 year and above) was demonstrated to have a preventative effect against SLCI in this trial (RR = 0.36, 95% CI 0.15–0.84).

       Use of zanamivir in seasonal prophylaxis

      Data were obtained from one trial demonstrating a protective efficacy of 68% for seasonal prophylaxis using zanamivir in healthy adults (RR = 0.32, 95% CI 0.17–0.63) (calculated by assessment group).
      • Monto A.S.
      • Robinson D.P.
      • Louise M.
      • James H.
      • Hinson M.
      • Elliott M.J.
      • et al.
      Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial.
      A further trial showed zanamivir to be effective in seasonal prophylaxis in at-risk adolescents and adults (RR = 0.17, 95% CI 0.07–0.44), with a non-significant preventative effect in older people (1/946 in zanamivir arm, 5/950 in placebo arm) (RR = 0.20, 95% CI 0.02–1.72).
      • LaForce C.
      • Man C.Y.
      • Henderson F.W.
      • McElhaney J.E.
      • Hampel Jr., F.C.
      • Bettis R.
      • et al.
      Efficacy and safety of inhaled zanamivir in the prevention of influenza in community-dwelling, high-risk adult and adolescent subjects: a 28-day, multicenter, randomized, double-blind, placebo-controlled trial.

       Use of zanamivir in post-exposure prophylaxis

      Post-exposure prophylaxis using zanamivir was effective in preventing transmission of SLCI in households of mixed composition (adults and children aged 5 years and above,
      • Monto A.S.
      • Pichichero M.E.
      • Blanckenberg S.J.
      • Ruuskanen O.
      • Cooper C.
      • Fleming D.M.
      • et al.
      Zanamivir prophylaxis: an effective strategy for the prevention of influenza types A and B within households.
      • Hayden F.G.
      • Gubareva L.V.
      • Monto A.S.
      • Klein T.C.
      • Elliott M.J.
      • Hammond J.M.
      • et al.
      Inhaled zanamivir for the prevention of influenza in families.
      unvaccinated adolescents and adults aged 13–65 years)
      • Kaiser L.
      • Henry D.
      • Flack N.P.
      • Keene O.
      • Hayden F.G.
      Short-term treatment with zanamivir to prevent influenza: Results of a placebo-controlled study.
      based on three publications (RR = 0.21, 95% CI 0.13–0.33).
      • Monto A.S.
      • Pichichero M.E.
      • Blanckenberg S.J.
      • Ruuskanen O.
      • Cooper C.
      • Fleming D.M.
      • et al.
      Zanamivir prophylaxis: an effective strategy for the prevention of influenza types A and B within households.
      • Hayden F.G.
      • Gubareva L.V.
      • Monto A.S.
      • Klein T.C.
      • Elliott M.J.
      • Hammond J.M.
      • et al.
      Inhaled zanamivir for the prevention of influenza in families.
      • Kaiser L.
      • Henry D.
      • Flack N.P.
      • Keene O.
      • Hayden F.G.
      Short-term treatment with zanamivir to prevent influenza: Results of a placebo-controlled study.
      Evidence for outbreak control in the elderly in long-term care was more limited, with a non-significant protective effect against SLCI demonstrated (RR = 0.68, 95% CI 0.33–1.27), whereby all cases occurred in unvaccinated subjects (calculated by assessment group).
      • Ambrozaitis A.
      • Gravenstein S.
      • Van Essen G.A.
      • Rubinstein E.
      • Balciuniene L.
      • Stikleryte A.
      • et al.
      Inhaled zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population.
      Data for zanamivir versus placebo were limited in the study reported by Gravenstein et al.
      • Gravenstein S.
      • Drinka P.
      • Osterweil D.
      • Schilling M.
      • Krause P.
      • Elliott M.
      • et al.
      Inhaled zanamivir versus rimantadine for the control of influenza in a highly vaccinated long-term care population.
      since no subjects developed influenza during the study period and data were excluded from analysis in the published report.

       Use of amantadine in seasonal prophylaxis

      Owing to low attack rates during study periods, evidence for the use of amantadine against SLCI in seasonal prophylaxis was limited. One trial demonstrated a non-significant preventative effect among healthy adults in seasonal prophylaxis (RR = 0.40, 95% CI 0.08–2.03).
      • Reuman P.D.
      • Bernstein D.I.
      • Keefer M.C.
      • Young E.C.
      • Sherwood J.R.
      • Schiff G.M.
      Efficacy and safety of low dosage amantadine hydrochloride As prophylaxis for influenza A.
      The use of amantadine in seasonal prophylaxis in healthy adults appeared to result in no difference in the incidence of acute respiratory illness between treatment groups.
      • Aoki F.Y.
      • Stiver H.G.
      • Sitar D.S.
      • Hammond G.W.
      • Milley E.V.
      • Vermeersch C.
      • et al.
      Potential of influenza vaccine and amantadine to prevent influenza A illness in Canadian forces personnel 1980-1983.
      No data were available relating to the efficacy or effectiveness of amantadine in seasonal prophylaxis in elderly subjects, since there was no evidence of an influenza epidemic among this group during the period of study.
      • Pettersson R.F.
      • Hellström P.E.
      • Penttinen K.
      • Pyhälä R.
      • Tokola O.
      • Vartio T.
      • et al.
      Evaluation of amantadine in the prophylaxis of influenza A (H1N1) virus infection: a controlled field trial among young adults and high-risk patients.

       Use of amantadine in post-exposure prophylaxis

      A study of outbreak control in a boarding school setting showed that amantadine was effective in preventing SLCI in healthy adolescents (RR = 0.10, 95% CI 0.03–0.34).
      • Payler D.K.
      • Purdham P.A.
      Influenza A prophylaxis with amantadine in a boarding school.
      Only very limited evidence was available in the publications reported by Smorodintsev et al. (1970),
      • Smorodintsev A.
      • Karpuchin G.
      • Zlydnikov D.
      The prospect of amantadine for prevention of influenza A in humans (effectiveness of amantadine during influenza A2/Hong Kong epidemics in January-February 1969 in Leningrad.
      • Smorodintsev A.A.
      • Karapuhi G.I.
      • Zlydniko D.M.
      • Malyseva A.M.
      • Svecova E.G.
      • Burov S.A.
      • et al.
      Prophylactic effectiveness of amantadine hydrochloride in an epidemic of Hong-Kong influenza in Leningrad in 1969.
      which indicated the role of amantadine in preventing (RR = 0.59, 95% CI 0.49–0.70) and shortening the duration (p < 0.05) and severity (p < 0.01) of clinical influenza. However, the reporting of this study was unclear.

       Secondary outcomes

      Limited data were reported relating to complications prevented, hospitalisations prevented, length of influenza illness and time to return to normal activities.

       Use of oseltamivir in seasonal prophylaxis

      One study
      • Peters P.H.
      • Gravenstein S.
      • Norwood P.
      • De Bock V.
      • Van Couter A.
      • Gibbens M.
      • et al.
      Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population.
      described the impact of oseltamivir prophylaxis on secondary complications of influenza (including bronchitis, pneumonia and sinusitis) and demonstrated that oseltamivir seasonal prophylaxis was associated with a non-statistically significant 78% relative reduction in secondary complications (no further details presented) among at-risk elderly subjects with laboratory-confirmed influenza (P = 1.14, as reported).

       Use of oseltamivir in post-exposure prophylaxis

      In a study of post-exposure prophylaxis reported by Hayden et al.
      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
      and conducted in a population of mixed composition (adults and children aged 1 year and above), the proportion of contacts with laboratory-confirmed influenza with at least one secondary complication (including bronchitis, pneumonia, lower respiratory tract infection, otitis media or sinusitis) was broadly equivalent among post-exposure group subjects and those in the control arm who received expectant treatment upon the onset of influenza-like illness (7% (3/46) versus 5% (4/75)); however the more severe respiratory complications (bronchitis and pneumonia) occurred among the expectant treatment group.
      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
      The median duration of illness in contacts was shorter in the oseltamivir post-exposure prophylaxis group (n = 10) versus those receiving treatment on influenza onset (n = 33) (5.5 h (range 0–87) versus 39.8 h (range 0–627) (P = 0.103)).
      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
      Similarly, fewer contacts with laboratory-confirmed influenza in the oseltamivir post-exposure prophylaxis group were bed-bound compared with subjects in those receiving treatment on influenza onset (7% (3/46) versus 28% (21/75)), demonstrating a milder form of disease.
      • Hayden F.G.
      • Belshe R.
      • Villanueva C.
      • Lanno R.
      • Hughes C.
      • Small I.
      • et al.
      Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.

       Use of zanamivir in seasonal prophylaxis

      A conference abstract provided additional data on the impact of zanamivir seasonal prophylaxis on secondary outcomes.
      • Monto A.S.
      • Robinson D.
      • Griffin A.D.
      • Edmundson S.
      The effects of zanamivir on productivity in the prevention of influenza among healthy adults.
      Significantly less work absence was reported among subjects who received zanamivir as seasonal prophylaxis versus control group subjects (mean hours lost 0.6 vs 1.4, P = 0.001). Total productive time lost was also less in the zanamivir group (1.8 vs. 3.0 h, P = 0.001).

       Use of zanamivir in post-exposure prophylaxis

      Significantly fewer households randomised to zanamivir post-exposure prophylaxis reported a contact developing a complication of laboratory-confirmed influenza (2% vs. 6%, P = 0.01).
      • Monto A.S.
      • Pichichero M.E.
      • Blanckenberg S.J.
      • Ruuskanen O.
      • Cooper C.
      • Fleming D.M.
      • et al.
      Zanamivir prophylaxis: an effective strategy for the prevention of influenza types A and B within households.
      Complications of SLCI (defined as adverse events consistent with complications of influenza among subjects with SLCI) during the first 28 days following post-exposure prophylaxis initiation were slightly lower among the zanamivir-treated subjects versus placebo, although this difference was not statistically significant (5% vs. 6%, P = 0.653).
      • Ambrozaitis A.
      • Gravenstein S.
      • Van Essen G.A.
      • Rubinstein E.
      • Balciuniene L.
      • Stikleryte A.
      • et al.
      Inhaled zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population.
      This study was powered for the primary outcome of protective efficacy, rather than such secondary outcomes. The proportion of cases with complications requiring antibiotics was marginally lower among subjects receiving zanamivir post-exposure prophylaxis compared with placebo (5% vs. 8%, statistical significance not reported).
      • Hayden F.G.
      • Gubareva L.V.
      • Monto A.S.
      • Klein T.C.
      • Elliott M.J.
      • Hammond J.M.
      • et al.
      Inhaled zanamivir for the prevention of influenza in families.
      Furthermore, among household contacts with laboratory-confirmed influenza, the median time to alleviation of symptoms without use of medication was 5.5 days in the prophylaxis and 8.0 days in the placebo groups (statistical significance not reported).
      • Hayden F.G.
      • Gubareva L.V.
      • Monto A.S.
      • Klein T.C.
      • Elliott M.J.
      • Hammond J.M.
      • et al.
      Inhaled zanamivir for the prevention of influenza in families.
      Mean duration of significant influenza-like symptoms was also observed to be shorter in the zanamivir post-exposure prophylaxis versus placebo group (0.2 vs. 0.6 days, P = 0.016).
      • Kaiser L.
      • Henry D.
      • Flack N.P.
      • Keene O.
      • Hayden F.G.
      Short-term treatment with zanamivir to prevent influenza: Results of a placebo-controlled study.

       Use of amantadine in seasonal prophylaxis

      No secondary outcomes were described relating to the use of amantadine in seasonal prophylaxis.

       Use of amantadine in post-exposure prophylaxis

      Limited evidence was identified for milder influenza illness of shorter duration as a result of the use of amantadine in post-exposure prophylaxis.
      • Smorodintsev A.
      • Karpuchin G.
      • Zlydnikov D.
      The prospect of amantadine for prevention of influenza A in humans (effectiveness of amantadine during influenza A2/Hong Kong epidemics in January-February 1969 in Leningrad.
      • Smorodintsev A.A.
      • Karapuhi G.I.
      • Zlydniko D.M.
      • Malyseva A.M.
      • Svecova E.G.
      • Burov S.A.
      • et al.
      Prophylactic effectiveness of amantadine hydrochloride in an epidemic of Hong-Kong influenza in Leningrad in 1969.
      Of 400 randomly selected participants, the severity of symptoms was reported as 56.0% mild and 9.0% severe in the amantadine group, and 38.0% mild and 19.0% severe in the placebo group (p < 0.01 for severe symptoms, p < 0.001 for mild symptoms (no further details presented on classification of severity of illness). Mean duration of illness was found to be shorter in the amantadine group versus the placebo group (p < 0.05).
      No evidence relating to health-related quality of life or mortality could be identified for oseltamivir, zanamivir or amantadine.

       Adverse events

      The measurement and reporting of adverse events varied considerably between included trials and precluded the use of meta-analysis. No strong evidence for a higher incidence of adverse events in treatment groups than in control groups was identified for oseltamivir, zanamivir or amantadine. Few serious drug-related adverse events and drug-related withdrawals were reported.
      The study by Peters et al. (2001)
      • Peters P.H.
      • Gravenstein S.
      • Norwood P.
      • De Bock V.
      • Van Couter A.
      • Gibbens M.
      • et al.
      Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population.
      demonstrated a slightly higher incidence of headaches (8.3% vs. 5.5%) and gastrointestinal (GI) adverse events (14.9% vs. 12.9%) (statistical significance not reported) in frail, elderly individuals receiving oseltamivir than among placebo group subjects. Two studies reported that GI adverse effects were marginally higher amongst the oseltamivir-treated subjects, with GI adverse events being reported in 9.3% and 7.2% of oseltamivir and placebo group subjects respectively

      Welliver R, Monto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA;285(6):748–754.

      and a higher proportion of subjects in the oseltamivir arm experiencing upper GI adverse events (specifically nausea) (12.1% vs. 7.1%, a difference of 5.0%, 95% CI 1.4–8.6) and vomiting (2.5% vs. 0.8%, a difference of 1.7%, 95% CI 0.2–3.3).
      • Hayden F.G.
      • Atmar R.L.
      • Schilling M.
      • Johnson C.
      • Poretz D.
      • Paar D.
      • et al.
      Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.
      Adverse events were similar in both treatment arms and across all studies of zanamivir prophylaxis. Withdrawals due to adverse events and illness were similar in amantadine and placebo groups, whilst adverse effects were similar in both groups, with the exception of limited data from the trial reported by Smorodintsev et al.
      • Smorodintsev A.
      • Karpuchin G.
      • Zlydnikov D.
      The prospect of amantadine for prevention of influenza A in humans (effectiveness of amantadine during influenza A2/Hong Kong epidemics in January-February 1969 in Leningrad.
      • Smorodintsev A.A.
      • Karapuhi G.I.
      • Zlydniko D.M.
      • Malyseva A.M.
      • Svecova E.G.
      • Burov S.A.
      • et al.
      Prophylactic effectiveness of amantadine hydrochloride in an epidemic of Hong-Kong influenza in Leningrad in 1969.
      from a subset of non-ill subjects (n = 1825) questioned from the amantadine and treatment groups, which indicated a non-significant 2.1% excess in adverse events in the amantadine group (7.2%, 94/1313) vs placebo group (5.1%, 26/512), with statistically significant (p < 0.05) excesses in dyspepsia (1.72%) and sleep disturbances (1.14%).

       Vaccination status

      Details of the vaccination status of study populations are presented in Table 1, Table 2, Table 3 where available. The protective efficacy of oseltamivir in elderly subjects in seasonal prophylaxis when analysed among vaccinated subjects only was found to be comparable with the protective efficacy among the study population as a whole (protective efficacies of 91% and 92% respectively).
      • Peters P.H.
      • Gravenstein S.
      • Norwood P.
      • De Bock V.
      • Van Couter A.
      • Gibbens M.
      • et al.
      Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population.
      The use of zanamivir in seasonal prophylaxis in healthy adults aged 18–64 years yielded a 68% (calculated by assessment group) protective efficacy against SLCI (95% CI 37%, 83%).
      • Monto A.S.
      • Robinson D.P.
      • Louise M.
      • James H.
      • Hinson M.
      • Elliott M.J.
      • et al.
      Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial.
      Among unvaccinated subjects, the protective efficacy appeared to be marginally lower at 60% (95% CI 24%–80%). For the use of zanamivir in seasonal prophylaxis in at-risk adults and adolescents, comparable effects were observed, with relative risks of 0.17 (95% CI 0.02–1.41) and 0.17 (95% CI 0.05–0.58) of developing SLCI in vaccinated and unvaccinated subjects respectively.
      • LaForce C.
      • Man C.Y.
      • Henderson F.W.
      • McElhaney J.E.
      • Hampel Jr., F.C.
      • Bettis R.
      • et al.
      Efficacy and safety of inhaled zanamivir in the prevention of influenza in community-dwelling, high-risk adult and adolescent subjects: a 28-day, multicenter, randomized, double-blind, placebo-controlled trial.
      Of the cases of SLCI that were observed in a trial
      • Ambrozaitis A.
      • Gravenstein S.
      • Van Essen G.A.
      • Rubinstein E.
      • Balciuniene L.
      • Stikleryte A.
      • et al.
      Inhaled zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population.
      of zanamivir in outbreak control all occurred in unvaccinated subjects.
      Limited evidence was identified relating to the impact of vaccination status on the efficacy of amantadine prophylaxis. The study by Payler and Purdham
      • Payler D.K.
      • Purdham P.A.
      Influenza A prophylaxis with amantadine in a boarding school.
      (in which the study population was 87% vaccinated) demonstrated that, of the three subjects developing SLCI in the amantadine-treated arm, two were vaccinated whilst one subject was reported as unvaccinated. No information was given for the control arm.

       Antiviral resistance

      No evidence of reduced sensitivity of tested viral isolates to oseltamivir or zanamivir was obtained in included studies. None of the amantadine prophylaxis trials included in this review reported the assessment of sensitivity of influenza isolates to amantadine.

      Discussion

      Oseltamivir was demonstrated to prevent SLCI in seasonal prophylaxis in healthy adults and at-risk elderly subjects and in post-exposure prophylaxis within households of mixed composition. Post-exposure prophylaxis using oseltamivir for paediatric contacts was also shown to be effective in preventing influenza. Evidence relating to the efficacy of zanamivir in preventing SLCI was observed in trials of seasonal prophylaxis in healthy adults, at-risk adults and adolescents, and in post-exposure prophylaxis in households of mixed composition, with a trend for seasonal and post-exposure preventative effects among elderly subjects. Whilst the evidence for amantadine prophylaxis across subgroups was very limited, the effectiveness of amantadine in preventing SLCI in seasonal prophylaxis in healthy adults and in outbreak control amongst adolescent subjects was reported.
      Very limited data were identified relating to the benefits of the interventions in preventing complications and hospitalisations and in minimising length of illness and return to normal activities. No data could be identified concerning health-related quality of life or mortality outcomes.
      No trials were identified to evaluate the efficacy of amantadine in seasonal prophylaxis in at-risk adults and adolescents, post-exposure prophylaxis in households of mixed composition, or post-exposure prophylaxis in at-risk adults and adolescents or elderly subjects. No evidence was found relating to the use of oseltamivir in seasonal prophylaxis in at-risk adults and adolescents, seasonal prophylaxis in healthy elderly subjects, or post-exposure prophylaxis in elderly subjects. Furthermore, no trials were available for the evaluation of zanamivir in seasonal or post-exposure prophylaxis in children, post-exposure prophylaxis in adults and adolescents, or healthy elderly subjects.

       Strengths and limitations of review

      The scope of this review was comprehensive, covering the use of three antiviral interventions in two prophylactic strategies across a broad range of population subgroups. The methods used for reviewing the evidence were comprehensive and rigorous. However, a limitation of the review relates to the limiting of included studies by language. Searches were not restricted by language, but studies other than those published in the English language were excluded. Seven citations were excluded as the full text was not available in English.
      • Hess P.
      Amantadine and rimantadine in the prophylaxis of influenza A.
      • Plesnik V.
      • Heinz F.
      • Bindas B.
      • Cechova D.
      • Eliasova J.
      • Galetkova A.
      • et al.
      Controlled study of influenza prophylaxis by VUFB amantadin.
      • Quilligan Jr., J.J.
      • Hirayama M.
      • Baernstein Jr., H.D.
      The prevention of A2-influenza in children by chemoprophylaxis with amantadine hydrochloride.
      • Smorodintsev A.A.
      • Zlydnikov D.M.
      • Romanov I.
      • Rumovski V.I.
      • Smorodintsev A.A.
      • Zlydnikov D.M.
      • et al.
      Effectiveness of amantadine hydrochloride (midantane) in prevention of artificially induced influenza.
      • Kashiwagi S.
      • Kudoh S.
      • Watanabe A.
      • Yoshimura I.
      Efficacy and safety of the selective oral neuraminidase inhibitor oseltamivir for prophylaxis against influenza–placebo-controlled double-blind multicenter phase III trial.
      • Shinjoh M.
      • Sato S.
      • Sugaya N.
      • Mitamura K.
      • Takeuchi Y.
      • Kosaki K.
      • et al.
      Effect of post-exposure prophylaxis with oseltamivir for those in contacts with influenza patients in pediatric wards.
      • Diaz-Pedroche C.
      • Lizasoain M.
      • Lopez-Medrano F.
      • Escalante F.
      • Lumbreras C.
      • Folgueira D.
      • et al.
      Nosocomial outbreak of influenza in high-risk hematological patients. Efficacy of control measures and the use of zanamivir.
      It should also be noted that none of the included studies investigated the efficacy of antiviral prophylaxis against pandemic strains of influenza.

       Comparison with related literature

      Our review provides an update of the previous assessment of the use of oseltamivir and zanamivir in the prevention of influenza reported by Cooper et al. (2003).
      • Cooper N.J.
      • Sutton A.J.
      • Abrams K.R.
      • Wailoo A.
      • Turner D.A.
      • Nicholson K.G.
      Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials.
      Whilst our review includes additional evidence published subsequent to the searches conducted by Cooper et al. (search end date of December 2001), our conclusions are similar in that, whilst oseltamivir and zanamivir appear to be effective in the prevention of influenza, evidence is lacking for some patient populations and prophylactic strategies. Our review also included all of the trials of the efficacy of neuraminidase inhibitors in the prevention of influenza that were described in the systematic review of the effects of neuraminidase inhibitors as prophylaxis in children reported by Shun-Shin et al. (2009)
      • Shun-Shin M.
      • Thompson M.
      • Heneghan C.
      • Perera R.
      • Harnden A.
      • Mant D.
      Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials.
      (NAI30010; NAI30031; WV16193) and our findings support their conclusion that post-exposure prophylaxis with neuraminidase inhibitors may reduce the risk of developing SLCI among paediatric subjects. Jefferson et al.
      • Jefferson T.
      • Jones M.
      • Doshi P.
      • Del M.C.
      Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis.
      conducted a systematic review of neuraminidase inhibitors in the prevention of influenza in healthy adults. Our review contained the same prophylaxis studies as the Jefferson review, with the exception of the report by Kashiwagi et al. (2000),
      • Kashiwagi S.
      • Kudoh S.
      • Watanabe A.
      • Yoshimura I.
      Efficacy and safety of the selective oral neuraminidase inhibitor oseltamivir for prophylaxis against influenza–placebo-controlled double-blind multicenter phase III trial.
      which was not available in full in English and was therefore excluded from this review. Our review concurs with their conclusion that current evidence indicates that neuraminidase inhibitors are effective in post-exposure prophylaxis against SLCI but that further research is required to address evidence gaps.

       Implications for practice

      A number of issues relating to the external validity of the included studies should be taken into consideration during interpretation of the evidence base. Subjects who were unable to understand study personnel were excluded from trial participation in the zanamivir trials reported by Ambroizaitis et al. and Gravenstein et al. Peters et al. and Welliver et al. excluded individuals scoring below 7 on a mental status questionnaire from study participation.
      None of the amantadine prophylaxis trials included in this review reported the assessment of sensitivity of influenza isolates to amantadine. However, the development of amantadine-resistant influenza A strains presents a significant challenge to the use of amantadine in prophylaxis against influenza and must be taken into consideration. No evidence of reduced sensitivity of viral isolates to oseltamivir or zanamivir was obtained in the studies included in this review. However, Health Protection Agency surveillance data

      Health Protection Agency. HPA weekly national influenza report. 15-4-2009.

      from within the UK indicated variable levels of resistance to antivirals. In the 2008 to 2009 season, of 91 influenza A (H1N1) isolates tested, 90 (99%) were resistant to oseltamivir but retained sensitivity to zanamivir and amantadine. For the same period, all of 231 influenza A (H3) isolates were resistant to amantadine, but not oseltamivir or zanamivir. Similarly, of 44 influenza B isolates tested, none were resistant to oseltamivir or zanamivir. The evidence for the use of antivirals in prophylaxis against influenza should therefore be interpreted in light of the potential for emerging resistance. The potential generation of antiviral resistance as a result of the use of the interventions during the H1N1 pandemic that began in 2009 should also be carefully monitored. As of July 2010, the WHO stated that a cumulative total of 298 cases of oseltamivir-resistant pandemic influenza A (H1N1) 2009 viruses had been reported, all but one of which had the H275Y substitution and were assumed to retain sensitivity to zanamivir.

      World Health Organisation. Weekly update on oseltamivir resistance to pandemic influenza A (H1N1) 2009 viruses. 2010 Jul 7

      It should also be noted that antivirals were administered to study participants within the appropriate timeframe stated in the licensed indications for each intervention and, therefore, timely patient presentation and prescription of antivirals would be integral to effective prophylaxis in clinical practice.

       Areas for future research

      Whilst a considerable amount of evidence was identified relating to the use of antiviral prophylaxis of influenza, a number of areas warrant further research. Further studies among those population groups considered at higher risk of influenza-associated complications are necessary to strengthen the evidence base for efficacy in the most clinically relevant subgroups. There is a particular requirement for further evidence relating to the clinical effectiveness of antivirals in post-exposure prophylaxis amongst elderly subjects, particularly in long-term care settings, since subjects over 65 years of age were not well represented within the post-exposure prophylaxis trials. Further evidence gaps (see Table 4, Table 5) were also noted in which further studies may be of value. Studies of influenza antiviral prophylaxis in which the effect of the confounding variable of vaccination is further explored are recommended.

      Role of the funding source

      This review was performed as part of a Health Technology Assessment commissioned by the National Coordinating Centre for Health Technology Assessment (NCCHTA) on behalf of the National Institute for Health and Clinical Excellence (NICE) and was funded by the NIHR Health Technology Assessment programme. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Department of Health.

      Acknowledgements

      We would like to thank Myfanwy Lloyd-Jones and Eva Kaltenthaler for methodological advice and Andrea Shippam for providing administrative support.

      References

        • Douglas R.G.
        Prophylaxis and treatment of influenza.
        N Engl J Med. 1990; 322: 443-450
      1. Health Protection Agency. 18-12-2007.

        • Nicholson K.G.
        Human influenza.
        in: Nicholson K.G. Webster R.G. Hay A.J. Textbook of influenza. Blackwell Science, Oxford1998
        • Tillett H.E.
        • Smith J.W.G.
        • Gooch C.D.
        Excess deaths attributable to influenza in England and Wales: age at death and certified cause.
        Int J Epidemiol. 1983; 12: 344-352
        • Nicholson K.G.
        Impact of influenza and respiratory syncitial virus on mortality in England and Wales from January 1975 to December 1990.
        Epidemiol Infect. 2009; 116: 51-63
        • Fleming D.M.
        The contribution of influenza to combined acute respiratory infections, hospital admissions, and deaths in winter.
        Commun Dis Public Health. 2000; 3: 32-38
      2. National Institute for Health and Clinical Excellence. Oseltamivir and amantadine for the prophylaxis of influenza. Technology Appraisal Guidance 67, 2003.

      3. National Institute for Clinical Excellence. Oseltamivir, amatadine (review) and zanamivir for the prophylaxis of influenza. Technology Appraisal Guidance 158, 2008.

        • Tappenden P.
        • Jackson R.
        • Cooper K.
        • Rees A.
        • Simpson E.
        • Read R.
        • et al.
        Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation.
        Health Technol Assess. 2009 Feb; 13 (iii, ix-iii): 246
      4. British National Formulary. 2007.

      5. NHS Centre for Reviews and Dissemination. Report 4: Undertaking systematic reviews on effectiveness; CRDs guidance for those carrying out or commissioning reviews. 2001.

        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        • for the PRISMA Group
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        BMJ. 2009; 339: 332-336
        • Hess P.
        Amantadine and rimantadine in the prophylaxis of influenza A.
        Med Hyg. 1982; 40: 3496
        • Plesnik V.
        • Heinz F.
        • Bindas B.
        • Cechova D.
        • Eliasova J.
        • Galetkova A.
        • et al.
        Controlled study of influenza prophylaxis by VUFB amantadin.
        Cesk Epidemiol Mikrobiol Imunol. 1977; 26: 216-226
        • Quilligan Jr., J.J.
        • Hirayama M.
        • Baernstein Jr., H.D.
        The prevention of A2-influenza in children by chemoprophylaxis with amantadine hydrochloride.
        Schweiz Med Wochenschr. 1966 Dec 17; 96 (Journal Suisse de Medecine): 1689-1692
        • Smorodintsev A.A.
        • Zlydnikov D.M.
        • Romanov I.
        • Rumovski V.I.
        • Smorodintsev A.A.
        • Zlydnikov D.M.
        • et al.
        Effectiveness of amantadine hydrochloride (midantane) in prevention of artificially induced influenza.
        Vopr Virusol. 1972 Mar; 17: 152-156
        • Kashiwagi S.
        • Kudoh S.
        • Watanabe A.
        • Yoshimura I.
        Efficacy and safety of the selective oral neuraminidase inhibitor oseltamivir for prophylaxis against influenza–placebo-controlled double-blind multicenter phase III trial.
        Kansenshogaku Zasshi. 2000; 74: 1062-1076
        • Shinjoh M.
        • Sato S.
        • Sugaya N.
        • Mitamura K.
        • Takeuchi Y.
        • Kosaki K.
        • et al.
        Effect of post-exposure prophylaxis with oseltamivir for those in contacts with influenza patients in pediatric wards.
        Kansenshogaku Zasshi. 2004; 78: 262-269
        • Diaz-Pedroche C.
        • Lizasoain M.
        • Lopez-Medrano F.
        • Escalante F.
        • Lumbreras C.
        • Folgueira D.
        • et al.
        Nosocomial outbreak of influenza in high-risk hematological patients. Efficacy of control measures and the use of zanamivir.
        Enferm Infecc Microbiol Clin. 2006 Jan; 24: 10-13
        • Aoki F.Y.
        • Stiver H.G.
        • Sitar D.S.
        • Boudreault A.
        • Ogilvie R.I.
        • Aoki F.Y.
        • et al.
        Prophylactic amantadine dose and plasma concentration-effect relationships in healthy adults.
        Clin Pharmacol Ther. 1985 Feb; 37: 128-136
        • Bryson Y.J.
        • Monahan C.
        • Pollack M.
        • Shields W.D.
        A prospective double-blind study of side effects associated with the administration of amantadine for influenza A virus prophylaxis.
        J Infect Dis. 1980; 141: 543-547
        • Callmander E.
        • Hellgren L.
        Amantadine hydrochloride as a prophylactic in respiratory infections. A double-blind investigation of its clinical use and serology.
        J Clin Pharmacol J New Drugs. 1968; 8: 186-189
        • Cohen A.
        • Togo Y.
        • Khakoo R.
        • Waldman R.
        • Sigel M.
        Comparative clinical and laboratory evaluation of the prophylactic capacity of ribavirin, amantadine hydrochloride, and placebo in induced human influenza type A.
        J Infect Dis. 1976; 133
        • Dawkins A.T.
        • Gallager L.R.
        • Togo Y.
        • Hornick R.B.
        • Harris B.A.
        Studies on induced influenza in man. II. Double-blind study designed to assess the prophylactic efficacy of an analogue of amantadine hydrochloride.
        JAMA. 1968; 203: 1095-1099
        • Dolin R.
        • Reichman R.C.
        • Madore H.P.
        • Maynard R.
        • Linton P.N.
        • Webber-Jones J.
        A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection.
        N Engl J Med. 1982; 307: 580-584
        • Finklea J.F.
        • Hennessy A.V.
        • Davenport F.M.
        A field trial of amantadine prophylaxis in naturally-occurring acute respiratory illness.
        Am J Epidemiol. 1967; 85: 403-412
        • Galbraith A.W.
        • Oxford J.S.
        • Schild G.C.
        • Watson G.I.
        Protective effect of 1-adamantanamine hydrochloride on influenza A2 infections in the family environment: a controlled double-blind study.
        Lancet. 1969; 2: 1026-1028
        • Galbraith A.W.
        • Oxford J.S.
        • Schild G.C.
        • Watson G.I.
        Study of 1-adamantanamine hydrochloride used prophylactically during the Hong Kong influenza epidemic in the family environment.
        Bull World Health Organ. 1969; 41: 677-682
        • Galbraith A.W.
        • Oxford J.S.
        • Schild G.C.
        • Potter C.W.
        • Watson G.I.
        Therapeutic effect of 1-adamantanamine hydrochloride in naturally occurring influenza A2-Hong Kong infection. A controlled double-blind study.
        Lancet. 1971; 2: 113-115
        • Hayden F.
        • Gwaltney J.M.
        • Van de Castle R.L.
        • Adams K.F.
        • Giordani B.
        Comparative toxicity of amantadine hydrochloride and rimantadine hydrochloride in healthy adults.
        Antimicrob Agents Chemother. 1981; 19: 226-233
        • Jackson G.G.
        • Muldoon R.L.
        • Akers L.W.
        Serological evidence for prevention of influenzal infection in volunteers by an anti-influenzal drug adamantanamine hydrochloride.
        Antimicrob Agents Chemother. 1963; 161: 703-707
        • Kantor R.J.
        • Stevens D.
        • Potts D.W.
        • Noble G.R.
        Prevention of influenza A/USSR/77 (H1N1): an evaluation of the side effects and efficacy of amantadine in recruits at Fort Sam Houston.
        Mil Med. 1980; 145: 312-315
        • Leeming J.T.
        Amantidine hydrochloride and the elderly.
        BMJ. 1969; 1: 313-314
        • Leung P.
        • McIntosh K.
        • Chai H.
        Amantadine prophylaxis against influenza A/USSR in children with chronic asthma.
        J Allergy Clin Immunol. 1979; 63: 140
        • Máté J.
        • Simon M.
        • Juvancz I.
        • Takátsy G.
        • Hollós I.
        • Farkas E.
        Prophylactic use of amantadine during Hong Kong influenza epidemic.
        Acta Microbiol Acad Sci Hung. 1970; 17: 285-296
        • Millet V.M.
        • Dreisbach M.
        • Bryson Y.J.
        Double-blind controlled study of central nervous system side effects of amantadine, rimantadine and chlorpheniramine.
        Antimicrob Agents Chemother. 1982; 21: 1-4
        • Monto A.S.
        • Gunn R.A.
        • Bandyk M.G.
        • King C.L.
        Prevention of Russian influenza by amantadine.
        JAMA. 1979; 241: 1003-1007
        • Muldoon R.L.
        • Stanley E.D.
        • Jackson G.G.
        Use and withdrawal of amantadine chemoprophylaxis during epidemic influenza A.
        Am Rev Respir Dis. 1976; 113: 487-491
        • Nafta I.
        • TTurcanu A.G.
        • Braun I.
        • Companetz W.
        • Simionescu A.
        • Birt E.
        • et al.
        Administration of amantadine for the prevention of Hong Kong influenza.
        Bull World Health Organ. 1970; 42: 423-427
        • O’Donoghue J.M.
        • Ray C.G.
        • Terry D.W.
        • Beaty H.N.
        Prevention of Nosocomial influenza infection with amantadine.
        Am J Epidemiol. 1973; 97: 276-282
        • Oker-Blom N.
        • Hovi T.
        • Leinikki P.
        • Palosuo T.
        • Pettersson R.
        • Suni J.
        Protection of man from natural infection with influenza A2 Hong Kong virus by amantadine: a controlled field trial.
        BMJ. 1970; 3: 676-678
        • Peckinpaugh R.O.
        • Askin F.B.
        • Pierce W.E.
        • Edwards E.A.
        • Johnson D.P.
        • Jackson G.G.
        Field studies with amantadine: acceptability and protection.
        Ann N Y Acad Sci. 1970; 173: 62-73
        • Quarles J.M.
        • Couch R.B.
        • Cate T.R.
        • Goswick C.B.
        Comparison of amantadine and rimantadine for prevention of type A (Russian) influenza.
        Antiviral Res. 1981; 1: 149-155
        • Quilligan J.J.
        • Hirayama M.
        • Baernstein H.D.
        The suppression of A2 influenza in children by the chemoprophylactic use of Amantadine.
        J Pediatr. 1966; 69: 572-575
        • Schapira M.
        • Oxford J.
        • Galbraith W.
        A study of adamantamine hydrochloride during the 1970 Hong Kong influenza epidemic.
        J R Coll Gen Pract. 1971; 21: 695-697
        • Stanley E.D.
        • Muldoon R.E.
        • Akers L.W.
        • Jackson G.G.
        Evaluation of antiviral drugs: the effect of amantadine on influenza in volunteers.
        Ann N Y Acad Sci. 1965; 130: 44-51
        • Togo Y.
        • Hornick R.B.
        • Dawkins A.T.
        Studies on induced influenza in man. I. Double-blind studies designed to assess prophylactic efficacy of amantadine hydrochloride against a2/Rockville/1/65 strain.
        JAMA. 1968; 203: 1089-1094
        • Tyrell D.A.J.
        • Bynoe M.L.
        • Dawkins A.T.
        Studies on the antiviral activity of 1-adamantanamine.
        Br J Exp Pathol. 1965; 46: 375
        • Wendel H.A.
        • Snyder M.T.
        • Pell S.
        Trial of amantadine in epidemic influenza.
        Clin Pharmacol Ther. 1966; 7: 38-43
        • Wright P.F.
        • Khaw K.T.
        • Oxman M.N.
        • Shwachma H.
        Amantadine for prophylaxis of influenza in patients with cystic-fibrosis.
        Pediatr Res. 1974; 8: 430
        • Wright P.F.
        • Khaw K.T.
        • Oxman M.N.
        • Shwachman H.
        Evaluation of the safety of amantadine-HC1 and the role of respiratory viral infections in children with cystic fibrosis.
        J Infect Dis. 1976; 134: 144-149
        • Calfee D.P.
        • Peng A.W.
        • Hussey E.K.
        • Lobo M.
        • Hayden F.G.
        Safety and efficacy of once daily intranasal zanamivir in preventing experimental human influenza A infection.
        Antivir Ther. 1999; 4: 143-149
        • Calfee D.P.
        • Peng A.W.
        • Cass L.M.
        • Lobo M.
        • Hayden F.G.
        Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection.
        Antimicrob Agents Chemother. 1999; 43: 1616-1620
        • Cass L.M.R.
        • Gunawardena K.A.
        • MacMahon M.M.
        • Bye A.
        Pulmonary function and airway responsiveness in mild to moderate asthmatics given repeated inhaled doses of zanamivir.
        Respir Med. 2000; 94: 166-173
        • Hayden F.G.
        • Treanor J.J.
        • Betts R.F.
        • Lobo M.
        • Esinhart J.D.
        • Hussey E.K.
        Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza.
        JAMA. 1996; 275: 295-299
        • Schilling M.
        • Povinelli L.
        • Krause P.
        • Gravenstein M.
        • Ambrozaitis A.
        • Jones H.
        • et al.
        Efficacy of zanamivir for chemoprophylaxis of nursing home influenza outbreaks.
        Vaccine. 1998; 16: 1771-1774
        • Walker J.B.
        • Hussey E.K.
        • Treanor J.J.
        • Montalvo Jr., A.
        • Hayden F.G.
        Effects of the neuraminidase inhibitor zanamivir on otologic manifestations of experimental human influenza.
        J Infect Dis. 1997; 176: 1417-1422
        • Hayden F.G.
        • Treanor J.J.
        • Fritz R.S.
        • Lobo M.
        • Betts R.F.
        • Miller M.
        • et al.
        Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment.
        JAMA. 1999; 282: 1240-1246
      6. Welliver R, Monto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA;285(6):748–754.

        • Hayden F.G.
        • Belshe R.
        • Villanueva C.
        • Lanno R.
        • Hughes C.
        • Small I.
        • et al.
        Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis.
        J Infect Dis. 2004; 189: 440-449
        • Peters P.H.
        • Gravenstein S.
        • Norwood P.
        • De Bock V.
        • Van Couter A.
        • Gibbens M.
        • et al.
        Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population.
        J Am Geriatr Soc. 2001; 49: 1025-1031
        • Hayden F.G.
        • Atmar R.L.
        • Schilling M.
        • Johnson C.
        • Poretz D.
        • Paar D.
        • et al.
        Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.
        N Engl J Med. 1999; 341: 1336-1343
        • Monto A.S.
        • Pichichero M.E.
        • Blanckenberg S.J.
        • Ruuskanen O.
        • Cooper C.
        • Fleming D.M.
        • et al.
        Zanamivir prophylaxis: an effective strategy for the prevention of influenza types A and B within households.
        J Infect Dis. 2002; 186: 1582-1588
        • Hayden F.G.
        • Gubareva L.V.
        • Monto A.S.
        • Klein T.C.
        • Elliott M.J.
        • Hammond J.M.
        • et al.
        Inhaled zanamivir for the prevention of influenza in families.
        N Engl J Med. 2000; 343: 1282-1289
        • Kaiser L.
        • Henry D.
        • Flack N.P.
        • Keene O.
        • Hayden F.G.
        Short-term treatment with zanamivir to prevent influenza: Results of a placebo-controlled study.
        Clin Infect Dis. 2000; 30: 587-589
        • Ambrozaitis A.
        • Gravenstein S.
        • Van Essen G.A.
        • Rubinstein E.
        • Balciuniene L.
        • Stikleryte A.
        • et al.
        Inhaled zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population.
        J Am Med Dir Assoc. 2005; 6: 367-374
        • Payler D.K.
        • Purdham P.A.
        Influenza A prophylaxis with amantadine in a boarding school.
        Lancet. 1984; 1: 502-504
        • Smorodintsev A.
        • Karpuchin G.
        • Zlydnikov D.
        The prospect of amantadine for prevention of influenza A in humans (effectiveness of amantadine during influenza A2/Hong Kong epidemics in January-February 1969 in Leningrad.
        Ann N Y Acad Sci. 1970; 173: 44-73
        • Smorodintsev A.A.
        • Karapuhi G.I.
        • Zlydniko D.M.
        • Malyseva A.M.
        • Svecova E.G.
        • Burov S.A.
        • et al.
        Prophylactic effectiveness of amantadine hydrochloride in an epidemic of Hong-Kong influenza in Leningrad in 1969.
        Bull World Health Organ. 1970; 42: 865-872
        • Reuman P.D.
        • Bernstein D.I.
        • Keefer M.C.
        • Young E.C.
        • Sherwood J.R.
        • Schiff G.M.
        Efficacy and safety of low dosage amantadine hydrochloride As prophylaxis for influenza A.
        Antiviral Res. 1989; 11: 27-40
        • Aoki F.Y.
        • Stiver H.G.
        • Sitar D.S.
        • Hammond G.W.
        • Milley E.V.
        • Vermeersch C.
        • et al.
        Potential of influenza vaccine and amantadine to prevent influenza A illness in Canadian forces personnel 1980-1983.
        Mil Med. 1986 Sep; 151: 459-465
        • Monto A.S.
        • Robinson D.P.
        • Louise M.
        • James H.
        • Hinson M.
        • Elliott M.J.
        • et al.
        Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial.
        JAMA. 1999; 282: 31-35
        • LaForce C.
        • Man C.Y.
        • Henderson F.W.
        • McElhaney J.E.
        • Hampel Jr., F.C.
        • Bettis R.
        • et al.
        Efficacy and safety of inhaled zanamivir in the prevention of influenza in community-dwelling, high-risk adult and adolescent subjects: a 28-day, multicenter, randomized, double-blind, placebo-controlled trial.
        Clin Ther. 2007; 29: 1579-1590
        • Gravenstein S.
        • Drinka P.
        • Osterweil D.
        • Schilling M.
        • Krause P.
        • Elliott M.
        • et al.
        Inhaled zanamivir versus rimantadine for the control of influenza in a highly vaccinated long-term care population.
        J Am Med Dir Assoc. 2005; 6: 359-366
        • Pettersson R.F.
        • Hellström P.E.
        • Penttinen K.
        • Pyhälä R.
        • Tokola O.
        • Vartio T.
        • et al.
        Evaluation of amantadine in the prophylaxis of influenza A (H1N1) virus infection: a controlled field trial among young adults and high-risk patients.
        J Infect Dis. 1980; 142: 377-383
        • Monto A.S.
        • Robinson D.
        • Griffin A.D.
        • Edmundson S.
        The effects of zanamivir on productivity in the prevention of influenza among healthy adults.
        J Antimicrob Chemother. 1999; 44
        • Cooper N.J.
        • Sutton A.J.
        • Abrams K.R.
        • Wailoo A.
        • Turner D.A.
        • Nicholson K.G.
        Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials.
        BMJ. 2003; 326: 1235-1239
        • Shun-Shin M.
        • Thompson M.
        • Heneghan C.
        • Perera R.
        • Harnden A.
        • Mant D.
        Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials.
        BMJ. 2009; 339: b3172
        • Jefferson T.
        • Jones M.
        • Doshi P.
        • Del M.C.
        Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis.
        BMJ. 2009; 339: b5106
      7. Health Protection Agency. HPA weekly national influenza report. 15-4-2009.

      8. World Health Organisation. Weekly update on oseltamivir resistance to pandemic influenza A (H1N1) 2009 viruses. 2010 Jul 7

        • De Bock V.
        • Peters P.
        • Von Planta T.-A.
        • Gibbens M.
        • Ward P.
        Oral oseltamivir for prevention of influenza in the frail elderly.
        Clin Microbiol Infect. 2000; 6: 140
        • Hayden F.
        • Belshe R.
        • Villanueva C.
        • Lanno R.
        • Small I.
        • Hughes C.
        • et al.
        Oral oseltamivir prevents the spread of influenza between children in households.
        Abstr Intersci Conf Antimicrob Agents Chemother. 2002; 42
        • Belshe R.
        • Hayden F.
        • Carewicz O.
        • Lanno R.
        • Martin C.
        • Hughes C.
        • et al.
        Effectiveness of oral oseltamivir in preventing spread of influenza-like illness in households with proven influenza.
        Abstr Intersci Conf Antimicrob Agents Chemother. 2001; 41
        • Ambrozaitis A.
        • VanEssen G.
        • Rubinstein E.
        • Balciuiene L.
        • Stikleryte A.
        • Gravenstein S.
        • et al.
        Inhaled zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population (NAIA3004).
        J Am Geriatr Soc. 2001; 49: S130-S131