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Effectiveness of Oseltamivir in Preventing
Influenza in Household Contacts
A Randomized Controlled Trial
Context Influenza virus is easily spread among the household contacts of an in-
fected person, and prevention of influenza in household contacts can control spread Objective To investigate the efficacy of oseltamivir in preventing spread of influ-
enza to household contacts of influenza-infected index cases (ICs).
Design and Setting Randomized, double-blind, placebo-controlled study con-
ducted at 76 centers in North America and Europe during the winter of 1998-1999.
Participants Three hundred seventy-seven ICs, 163 (43%) of whom had laboratory-
confirmed influenza infection, and 955 household contacts (aged Ն12 years) of all
ICs (415 contacts of influenza-positive ICs).
Interventions Household contacts were randomly assigned by household cluster to
take 75 mg of oseltamivir (n=493) or placebo (n=462) once daily for 7 days within48 hours of symptom onset in the IC. The ICs did not receive antiviral treatment.
Main Outcome Measure Clinical influenza in contacts of influenza-positive ICs,
confirmed in a laboratory by detection of virus shedding in nose and throat swabs or
a 4-fold or greater increase in influenza-specific serum antibody titer between base- line and convalescent serum samples.
Results In contacts of an influenza-positive IC, the overall protective efficacy of
oseltamivir against clinical influenza was 89% for individuals (95% confidence interval [CI], 67%-97%; PϽ.001) and 84% for households (95% CI, 49%-95%; PϽ.001). In contacts of all ICs, oseltamivir also significantly reduced incidence of clinical influenza, with 89% protective efficacy (95% CI, 71%-96%; PϽ.001). Viral shedding was inhibited in contacts taking oseltamivir, with 84% protective efficacy (95% CI, 57%-95%; PϽ.001). All virus isolates from oseltamivir recipients retained sensitivity to the active metabolite. Oseltamivir was well tolerated; gastrointestinal tract effects were reported with similar frequency in oseltamivir (9.3%) and placebo Conclusion In our sample, postexposure prophylaxis with oseltamivir, 75 mg once
daily for 7 days, protected close contacts of influenza-infected persons against influ- enza illness, prevented outbreaks within households, and was well tolerated.
opment of resistance and, for amanta-dine, poor tolerance.10-13 In addition, Author Affiliations: Children’s Hospital, Buffalo, NY
London, England (Dr Oxford). Dr Carewicz is in pri- these agents have no activity against in- (Dr Welliver); University of Michigan School of Pub- vate practice in Heidelberg, Germany, and Dr Schatte- lic Health, Ann Arbor (Dr Monto); Comprehensive man is in private practice in Drogen, Ghent, Belgium.
Clinical Research, Berlin, NJ (Dr Hassman); Kentucky A list of the members of the Oseltamivir Post Expo- a new class of anti-influenza agents that Pediatric and Adult Research, Bardstown, Ky (Dr Hed- sure Prophylaxis Investigator Group and Financial Dis- rick); Roche Global Development, Welwyn, England closures appear at the end of this article.
(Drs Jackson, Huson, and Ward); and St Bartho- Corresponding Author and Reprints: John S. Oxford,
lomew’s and Royal London Hospital School of Medi- PhD, The Medical Building, 327 Mile End Rd, London, cine and Dentistry, and Retroscreen Virology Ltd, England E1 4NS (e-mail: [email protected]).
748 JAMA, February 14, 2001—Vol 285, No. 6 (Reprinted)
2001 American Medical Association. All rights reserved.
CONTROL OF THE SPREAD OF INFLUENZA IN HOUSEHOLDS vitro.15 Oseltamivir is the first orally ad- gible. Elderly subjects (Ն65 years) were cal influenza but a subset had laboratory- Study Procedures
Index Cases. Nose and throat swabs
Laboratory Confirmation
of Influenza Infection
ficacy of oseltamivir in prevention of the ther by isolation of influenza virus from Contacts. Before the first dose of
hold contacts of influenza-infected cases.
local institutional review boards or eth- Study Drug
Study Population
or matching placebo once daily for 7 days participating clinics and from local press structed to take 1 capsule with water and Identification of Clinical Influenza
Clinical influenza was defined as an oral Influenza Neuraminidase
sal congestion, or sore throat) and at least Sensitivity
aches/pains, chills/sweats, or fatigue) oc- influenza virus–positive culture super- Roche, Basel, Switzerland, data on file).
2001 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 14, 2001—Vol 285, No. 6 749
CONTROL OF THE SPREAD OF INFLUENZA IN HOUSEHOLDS Figure. Flow Diagram of Enrolled Household Contacts
contacts of all ICs (99%) in 371 house-
holds (FIGURE). The 7 excluded per-
sons did not take any trial medication.
lower frequency of infection than ob-served during oseltamivir treatmentstudies (60%); however, in those stud-ies the case definition also includedbody temperature of 38°C or higher.16 was 27 years (range, 1-76 years). Tenpercent (16/163) were children younger years), 33% (54/163) were adoles-cents (12-17 years), and the remain- ing the recruitment focus on familieswith teenage siblings (Ն12 years).
households in which the IC had labo-ratory-confirmed influenza infection (Figure, TABLE 1). This subset of con-
already shedding influenza virus atbaseline. Five of these were asymptom- Asterisk indicates all randomized contacts regardless of whether they took any medication.
Statistical Analyses
␹2 tests and test-based confidence in- did not meet the case definition at en- ing the case definition during the study.
populations: contacts of all ICs and con- Other Analyses. Other analyses com-
admitted in violation of the protocol.
families used Fisher exact test. The level ized, had efficacy data, received at least Primary End Point. The primary ef-
contacts of an influenza-positive IC with 750 JAMA, February 14, 2001—Vol 285, No. 6 (Reprinted)
2001 American Medical Association. All rights reserved.
CONTROL OF THE SPREAD OF INFLUENZA IN HOUSEHOLDS Table 1. Contacts Receiving Oseltamivir or Placebo With Laboratory-Confirmed Clinical
Figure. In both analysis populations (con- Percentage With
tacts of all ICs and contacts of an influ- No./ Total (%)
Protective Efficacy
(95% Confidence
P
Oseltamivir
Interval)
cally and in immune status (TABLE 2).
dence of infection with influenza A.
*All randomized contacts with any efficacy data who received 1 or more doses of study medication.
Efficacy
Protective efficacy of oseltamivir was de-
Table 2. Demographic Data for Contacts of All Index Cases and Contacts of an
Oseltamivir
all ICs (Table 1). Protective efficacy in Contacts of All Index Cases
this situation was very high, 89% for in- dividuals (95% CI, 71%-96%; PϽ.001) 95%; PϽ.001) (Table 1). The minor dif- single households. In the contacts of all Contacts of an Influenza-Positive Index Case
Infected index cases with Ͼ48-hour delay forded by the second household case.
infected ICs. In this population, the in- *Values are expressed as number (percentage) unless otherwise indicated. HAI indicates hemagglutinin inhibition holds receiving oseltamivir during the7-day prophylaxis period was reducedby 89% (95% CI, 67%-97%; PϽ.001) and 84% (95% CI, 49%-95%; PϽ.001), ferent from that detected in the IC.
contacts of all ICs was 78.5% (P = .02).
2001 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 14, 2001—Vol 285, No. 6 751
CONTROL OF THE SPREAD OF INFLUENZA IN HOUSEHOLDS Table 3. Contacts Receiving Oseltamivir or Placebo With Symptomatic or Asymptomatic
Laboratory-Confirmed Influenza Infection* No./ Total (%)
Oseltamivir
P Value
Contacts of an influenza-positive index case fected. In this study, the risk of infec- Contacts of an influenza-negative index case *All randomized contacts with efficacy data who received 1 or more doses of study medication.
ing in the community, so new intro-ductions of infection into families are viduals. In this analysis, 24 (12%) of 200 63% (95% CI, 40%-80%; P = .003) was 2 (1%) of 205 oseltamivir recipients.
67%; P = .007) for contacts of all ICs tors), efficacy in preventing clinical in- (TABLE 3).
venting initial viral infection (63%).
71%-98%; PϽ.001) for prevention of Tolerability
daily for 7 days was well tolerated. Gas- virus and therefore more likely to trans- early following infection effectively pre- 95%; PϽ.001). No isolates from patients sensitivity to the active metabolite of os- 752 JAMA, February 14, 2001—Vol 285, No. 6 (Reprinted)
2001 American Medical Association. All rights reserved.
CONTROL OF THE SPREAD OF INFLUENZA IN HOUSEHOLDS ing exposure of contacts to influenza.
the manuscript for important intellectual content, andprovided statistical expertise.
Dr Carewicz participated in acquisition of data, analy- 13 years at the time it was conducted.
sis and interpretation of data, critical revision of the manu- script for important intellectual content, provided sta-tistical expertise, and supervised conduct of the study.
Dr Schatteman participated in acquisition of data, analysis and interpretation of data, critical revision ofthe manuscript for important intellectual content, and provided administrative, technical, or material sup- Dr Hassman participated in acquisition of data, criti-cal revision of the manuscript for important intellec- of the isolates were resistant to the car- tual content, and provided administrative, technical, or material support.
Dr Hedrick participated in analysis and interpretation 12 years suggests that the protective ef- of data, drafting of the manuscript, and provided ad- ministrative, technical, or material support.
Dr Jackson participated in study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, provided administrative, technical, or material support, and supervised con-duct of the study.
Dr Huson participated in study concept and design, analysis and interpretation of data, drafting of themanuscript, critical revision of the manuscript for im- ruses that retain full infectivity,26 re- portant intellectual content, and provided statistical fold less infectious than wild-type virus Dr Ward participated in study concept and design, ac-quisition of data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manu- script for important intellectual content, and super-vised conduct of the study.
Dr Oxford participated in study concept and design, analysis and interpretation of data, drafting of themanuscript, critical revision of the manuscript for im- portant intellectual content, and supervised conduct Full Access to Data: Dr Oxford had full access to all data
in this study and has taken responsibility for the integ-
rity of data collection and accuracy of data analysis.
Funding/Support: This study was funded by Hoff-
mann-La Roche.
Financial Disclosure: Dr Hassmann has done clinical
research with Roche Pharmaceuticals and has givenseveral lectures and presentations on influenza and ing close contacts against influenza ill- treatment with oseltamivir. Dr Oxford has received honoraria, traveling expenses to scientific meetings, and research funding support from Hoffmann-LaRoche.
Oseltamivir Post Exposure Prophylaxis Investigator
mivir effectively prevented further trans- Group: Belgium: Moorsel: N. Van Mulders; Tes-
senderlo: A. Ceulemans. Canada: British Columbia: Co-
quitlam: D. Shu; Vancouver: P. Vohora; Winnipeg, Manitoba: F. Y. Aoki, G. W. Hammond, P. H. Orr, and J. N. Simonsen; Ontario: Mississauga: P. Patel; Os-hawa: P. Whitsitt; Ottawa: F. Diaz-Mitoma; Toronto: E. Wang; Quebec: Montreal: B. Pynn; St Jerome: G.
Tellier; Ste-Foy: S. Trottier; Regina, Saskatchewan: G.
Achyuthan. Denmark: Lyngby: L. Hergel. Finland: Es- poo: O. Amzil and T. Aronkyto¨; Pori: E. Karra; Salo: S. Junnila; Vantaa: J. Anttila and K. Piispanen. Ger-many: Bechhofen: R. Lebmeier; Deggingen: T. Jung; of transmission. Use of oseltamivir short- Gau-Algesheim: C. Raddatz; Goch: T. Menke; Her- maringen: R. Fuchs. the Netherlands: Castricum: P. of influenza in those likely to have been Buitenhuis; Losser: A. J. M. Boermans; Nijverdal: J.
Veerman. Norway: Oslo: H. Gjessing; Sorum: R. Hel- lebo. Switzerland: Gene`ve: D. Lew, J. Garbino, and group at particularly high risk of devel- S. Huget. United Kingdom: Buckinghamshire: W. I. C.
Clark; Cornwall: R. C. Cook; Hants: M. MacLeod; Perth: F. Currie; Plymouth: C. P. Fletcher and K. Gillespie; Plympton: A. Golding-Cook; Sheffield: M. Davidson; Author Contributions: Dr Welliver participated in ac-
United States: Birmingham, Ala: S. Touger; Tempe, quisition of data, critical revision of the manuscript for Ariz: T. Fiel; California: Buena Park: W. Jannetti and important intellectual content, and provided admin- D. J. Sunga; Carmichael: J. Champlin; Chico: M. Vi- istrative, technical, or material support.
chare; Fresno: J. McCarty; La Mesa: M. Nosan; Or- Dr Monto participated in study concept and design, ange: S. Galant; San Diego: D. Brandon and H. Hass- analysis and interpretation of data, critical revision of man; Miami, Fla: H. Schwartz; Augusta, Ga: A. Carr; 2001 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 14, 2001—Vol 285, No. 6 753
CONTROL OF THE SPREAD OF INFLUENZA IN HOUSEHOLDS New Orleans, La: W. Smith; Duluth, Minn: I. Abol- ride on influenza A2 infections in the family environ- tal human influenza: randomized controlled trials for nik; St Louis, Mo: R. Barbarash; Missoula, Mon: C.
ment: a controlled double-blind study. Lancet. 1969; prevention and treatment. JAMA. 1999;282:1240- Cone; Papillon, Neb: T. Casale; Winston Salem, NC: T. Littlejohn; Cincinnati, Ohio: M. Noss; Pennsylva- 10. Degelau J, Somani SK, Cooper SL, Guay DR, Cross-
20. Hayden FG, Atmar RL, Schilling M, et al. Use of the
nia: Downingtown: L. Alwine; Philadelphia: V. Bralow; ley KB. Amantadine-resistant influenza A in a nursing selective oral neuraminidase inhibitor oseltamivir to pre- Pittsburgh: K. Reisinger; Memphis, Tenn: D. Peter- facility. Arch Intern Med. 1992;152:390-392.
vent influenza. N Engl J Med. 1999;341:1336-1343.
son; Houston, Tex: C. McKeever; Vienna, Va: R.
11. Hayden FG, Gwaltney JM Jr, van de Castle RL,
21. World Medical Association Declaration of Hel-
Schwartz; and Washington: Edmonds: R. Bettis; Spo- Adams KF, Giordani B. Comparative toxicity of aman- sinki: recommendations guiding physicians in bio- tadine hydrochloride and rimantadine hydrochloride medical research involving human subjects. JAMA.
in healthy adults. Antimicrob Agents Chemother. 1981; 22. Wilson LA, Brass W. Brief assessment of the men-
REFERENCES
12. Hayden FG, Belshe RB, Clover RD, Hay AJ, Oakes
tal state in geriatric domiciliary practice: the useful- 1. Human influenza. In: Nicholson KG, Webster RG,
MG, Soo W. Emergence and apparent transmission ness of the Mental Status Questionnaire. Age Age- Hay AJ, eds. Textbook of Influenza. Oxford, En- of rimantadine-resistant influenza A virus in families.
gland: Blackwell Science; 1998:219-264.
N Engl J Med. 1989;321:1696-1702.
23. Donner A. Some aspects of the design and analy-
2. Stuart-Harris CH, Schild GC, Oxford JS. Influ-
13. Hayden FG, Sperber SJ, Belshe RB, Clover RD, Hay
sis of cluster randomization trials. Appl Stat. 1998;47: enza: The Viruses and the Disease. 2nd ed. London, AJ, Pyke S. Recovery of drug-resistant influenza A vi- rus during therapeutic use of rimantadine. Antimi- 24. De Bock V, Peters P, von Planta T-A, et al. Oral
3. Foy HM, Cooney MK, Allen I. Longitudinal stud-
crob Agents Chemother. 1991;35:1741-1747.
oseltamivir for prevention of influenza in the frail el- ies of types A and B influenza among Seattle school 14. Gubareva LV, Kaiser L, Hayden FG. Influenza vi-
derly. Clin Microbiol Infect. 2000;6(suppl 1):140.
children and families, 1968-1974. J Infect Dis. 1976; rus neuraminidase inhibitors. Lancet. 2000;355:827- 25. Gubareva LV, Matrosovich MN, Brenner MK, et
al. Evidence for zanamivir resistance in an immuno- 4. Fox JP, Hall CE, Cooney MK, Foy HM. Influenza
15. Kim CU, Lew W, Williams MA, et al. Influenza
compromised child infected with influenza B virus.
virus infections in Seattle families, 1975-1979. Am J neuraminidase inhibitors possessing a novel hydro- J Infect Dis. 1998;178:1257-1262.
phobic interaction in the enzyme active site: design, 26. Hayden FG, Hay AJ. Emergence and transmis-
5. Taber LH, Paredes A, Glezen WP, Couch RB. In-
synthesis, and structural analysis of carbocyclic sialic sion of influenza A viruses resistant to amantadine and fection with influenza A/Victoria virus in Houston fami- acid analogues with potent anti-influenza activity.
rimantadine. Curr Top Microbiol Immunol. 1992;176: lies, 1976. J Hyg. 1981;86:303-313.
J Am Chem Soc. 1997;119:681-690.
6. Longini IM, Koopman JS, Monto AS, Fox JP. Esti-
16. Treanor JJ, Hayden FG, Vrooman PS, et al. Effi-
27. Covington E, Mendel DB, Escarpe P, et al. Phe-
mating household and community transmission pa- cacy and safety of the oral neuraminidase inhibitor os- notypic and genotypic assay of influenza virus neur- rameters for influenza. Am J Epidemiol. 1982;115: eltamivir in treating acute influenza: a randomized con- aminidase indicates a low incidence of viral drug re- trolled trial. JAMA. 2000;283:1016-1024.
sistance during treatment with oseltamivir [abstract 7. Clover RD, Crawford SA, Abell TD, Ramsey CN Jr,
17. Mendel DB, Tai CY, Escarpe PA, et al. Oral ad-
P-326]. J Clin Virol. 2000;18:253.
Glezen WP, Couch RB. Effectiveness of rimantadine ministration of a prodrug of the influenza virus neur- 28. Hayden FG, Gubareva LV, Monto AS, et al. In-
prophylaxis of children within families. Am J Dis Child. aminidase inhibitor GS4071 protects mice and fer- haled zanamivir for the prevention of influenza in fami- rets against influenza infection. Antimicrob Agents lies. N Engl J Med. 2000;343:1282-1289.
8. Galbraith AW, Oxford JS, Schild GC, Watson GI.
29. Hurwitz ES, Haber M, Chang A, et al. Effective-
Study of 1-adamantanamine hydrochloride used pro- 18. Sidwell RW, Huffman JH, Barnard DL, et al. In-
ness of influenza vaccination of day care children in phylactically during the Hong Kong influenza epi- hibition of influenza virus infections in mice by GS4104, reducing influenza-related morbidity among house- demic in the family. Environ Bull WHO. 1969;41: an orally effective influenza virus neuraminidase in- hold contacts. JAMA. 2000;284:1677-1682.
hibitor. Antiviral Res. 1998;37:107-120.
30. Whitley RJ, Hayden FG, Reisinger KS, et al. Oral
9. Galbraith AW, Oxford JS, Schild GC, Watson GI.
19. Hayden FG, Treanor JJ, Fritz RS, et al. Use of the
oseltamivir treatment of influenza in children. Pedi- Protective effect of 1-adamantanamine hydrochlo- oral neuraminidase inhibitor oseltamivir in experimen- 754 JAMA, February 14, 2001—Vol 285, No. 6 (Reprinted)
2001 American Medical Association. All rights reserved.

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