Skip Navigation

Effects of Oseltamivir Treatment on Duration of Clinical Illness and Viral Shedding and Household Transmission of Influenza Virus

  1. Sophia Ng1,
  2. Benjamin J. Cowling1,
  3. Vicky J. Fang1,
  4. Kwok Hung Chan2,
  5. Dennis K. M. Ip1,
  6. Calvin K. Y. Cheng1,
  7. Timothy M. Uyeki3,
  8. Peter M. Houck4,
  9. J. S. Malik Peiris2, and
  10. Gabriel M. Leung1
  1. 1Department of Community Medicine, School of Public Health, Hong Kong, China
  2. 2Department of Microbiology, University of Hong Kong, Hong Kong, China
  3. 3Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
  4. 4Seattle Quarantine Station, Division of Global Migration and Quarantine, Centers for Disease Control and Prevention, National Center for Preparedness, Detection and Control of Infectious Diseases, Seattle, Washington
  1. Reprints or correspondence: Dr Benjamin J. Cowling, School of Public Health, University of Hong Kong, Units 624-7, Cyberport 3, Pokfulam, Hong Kong, China (bcowling{at}hku.hk).
 
Next Section

Abstract

Background. Large clinical trials have demonstrated the therapeutic efficacy of oseltamivir against influenza. We assessed the indirect effectiveness of oseltamivir in reducing secondary household transmission in an incident cohort of influenza index patients and their household members.

Methods. We recruited index outpatients whose rapid test results were positive for influenza from February through September 2007 and January through September 2008. Household contacts were followed up for 7–10 days during 3–4 home visits to monitor symptoms. Nose and throat swabs were collected and tested for influenza by reverse-transcription polymerase chain reaction or viral culture.

Results. We followed up 384 index patients and their household contacts. Index patients who took oseltamivir within 24 h of symptom onset halved the time to symptom alleviation (adjusted acceleration factor, 0.56; 95% confidence interval [CI], 0.42–0.76). Oseltamivir treatment was not associated with statistically significant reduction in the duration of viral shedding. Household contacts of index patients who had taken oseltamivir within 24 h of onset had a nonstatistically significant lower risk of developing laboratory-confirmed infection (adjusted odds ratio, 0.54; 95% CI, 0.11–2.57) and a marginally statistically significant lower risk of clinical illness (adjusted odds ratio, 0.52; 95% CI, 0.25–1.08) compared with contacts of index patients who did not take oseltamivir.

Conclusions. Oseltamivir treatment is effective in reducing the duration of symptoms, but evidence of household reduction in transmission of influenza virus was inconclusive.

Oseltamivir is a neuraminidase inhibitor used for the treatment of influenza virus infection, including 2009 pandemic influenza A (H1N1) virus, which emerged in 2009 [1–3], with well-established antiviral efficacies in reducing clinical illness and complications [4]. Large randomized controlled trials have confirmed that oseltamivir is also effective for chemoprophylaxis [5, 6]. However, less is known about the indirect benefit of oseltamivir treatment in reducing infectiousness [7]. Household transmission is thought to be responsible for approximately one-third of all influenza virus transmission in the community [8, 9]. A better understanding of the role of oseltamivir treatment in reducing household transmission will provide important insights into the value of antiviral use during pandemics and seasonal epidemics. We assessed the effectiveness of oseltamivir treatment of household index patients on reducing the duration of clinical illness and viral shedding and transmission to household contacts in studies conducted in Hong Kong in the 2007 and 2008 influenza seasons.

Previous SectionNext Section

Methods

Recruitment and follow-up of participants. The present study was a secondary analysis of data collected in a community-based randomized controlled trial of the use of facemasks and enhanced hand hygiene to prevent household transmission of influenza virus [10, 11]. We enrolled index patients who reported at least 2 symptoms of acute respiratory illness (ARI) with symptom onset within 48 h and lived with at least 2 other individuals, none of whom had reported ARI symptoms during the previous 14 days. Study participants were recruited from February through September 2007 and January through September 2008 from 45 public and private outpatient clinics in Hong Kong. Index patients who tested positive for influenza A or B virus infection (QuickVue Influenza A+B test; Quidel) and their household members were followed up for 7–10 days. Medications prescribed to index patients, including oseltamivir and drugs for symptomatic relief, were recorded at recruitment sites and confirmed at subsequent home visits. Oseltamivir treatment decisions were made at the discretion of the treating physician.

Participating households were visited within 48 h of index patient recruitment, and an additional 2 or 3 visits were scheduled during the subsequent 7 days in 2007 and 10 days in 2008. A digital tympanic thermometer was provided, and all household members were requested to record their body temperature and any systemic and respiratory signs and symptoms in symptom diaries once daily until the final home visit. During each home visit, nasal and throat swabs were collected from all household members (regardless of illness) for laboratory testing by viral culture (in 2007) or reverse-transcription polymerase chain reaction (RT-PCR) (in 2008). Further technical details of the laboratory methods have been published elsewhere [10, 11].

Written consent was obtained from all participants 18 years or older, and proxy written consent for participants younger than 18 years was obtained from their parents or legal guardians. Additional verbal assent was obtained from participants aged 8–17 years. The study protocol was approved by the institutional review board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster.

Statistical analysis. Time to alleviation of influenza symptoms and signs in index patients was determined from analysis of symptom diaries. The respiratory symptom score was the sum of the presence (vs absence) of sore throat, cough, coryza, and phlegm and ranged from 0 to 4. The total symptoms score comprised the respiratory symptom score plus the presence (vs absence) of temperature ⩾37.8°C, headache, and myalgia and ranged from 0 to 7. We defined the time to alleviation of respiratory (total) symptoms as the time from symptom onset to the first day on which the respiratory (total) symptom score was 0. The time to alleviation was right censored at the last follow-up date if symptoms persisted throughout follow-up. We analyzed the time to alleviation of symptoms using Kaplan-Meier estimates and lognormal and Weibull accelerated failure time regression models, which allow explanatory variables (including oseltamivir use; age; sex; vaccination history; baseline symptom score; type of influenza virus; underlying chronic health conditions; use of antibiotics, antipyretics, and steroids; and study year) to proportionally increase (decelerate) or decrease (accelerate) the time to the end point [12]. We used the Akaike Information Criterion (AIC) to compare alternative regression models [13]. In analyses of time to symptom resolution, we only included individuals who reported the relevant symptoms at recruitment.

The time at which viral shedding ceased was defined as occurring within the interval between the last positive laboratory result and the first negative laboratory result. The time from symptom onset to cessation of viral shedding was analyzed using nonparametric estimates [14] and lognormal and Weibull accelerated failure time regression models, allowing for the interval censoring [15, 16]. Explanatory variables included oseltamivir use, age, sex, vaccination history, baseline symptom score, and type of influenza virus. Regression models were compared with the AIC. Analyses of time to cessation of viral shedding were stratified by year to allow for potential differences in duration of shedding detected by culture (2007) and RT-PCR (2008).

We defined the secondary attack ratio (SAR) as the proportion of household contacts who developed influenza virus infection during the follow-up period. We used a laboratory definition of ⩾1 nose and throat swabs positive for influenza viruses by viral culture or RT-PCR. We also used a clinical definition of influenza in household contacts, which was at least 2 signs or symptoms of temperature ⩾37.8°C, cough, headache, sore throat, and/or aches or pains in muscles or joints on ⩾1 days during follow-up [10, 11]. We calculated 95% confidence intervals (CIs) for the crude SARs using the exact binomial method. We estimated adjusted odds ratios (ORs) of laboratory-confirmed and clinical influenza in household contacts using logistic regression with generalized estimating equations adjusting for index and household contact characteristics, including age, sex, vaccination history, type of influenza virus, use of nonpharmaceutical interventions, study year, and within-household clustering [17, 18]. Households where ⩾1 household contacts had laboratory-confirmed influenza virus infection by viral culture or RT-PCR at the baseline home visit (i.e., a potential coindex patient) were excluded from these analyses.

All statistical analyses were performed with R, version 2.7.2 (R Development Core Team). Raw data from the study and R syntax to permit reproducible statistical analyses are available on the authors' Web site (http://www.hku.hk/bcowling/HK_NPI_study.htm).

Previous SectionNext Section

Results

In 2007 and 2008, a total of 3695 outpatients were recruited, and 568 (15%) had a positive influenza rapid test result. We were able to successfully schedule home visits for 450 index patients and their household members. Influenza virus infection could not be confirmed by RT-PCR or viral culture in 53 index patients. Thirteen index patients were prescribed antiviral medications other than oseltamivir (10 amantadine, 2 zanamivir, and 1 ribavirin). These 66 index patients were excluded, and 384 remain for analysis of cessation of symptoms and viral shedding. Among the remaining 384 index patients, 90 (23%) were treated with oseltamivir.

Table 1 gives the characteristics of the index patients. The baseline total symptoms scores of index patients were comparable between the oseltamivir and no antiviral groups. There were more febrile patients and fewer patients prescribed antihistamines or antipyretics in the oseltamivir group. There were more males in the oseltamivir group, whereas other index characteristics were not statistically significantly different. Household contacts of the 2 groups were generally similar.

Figure 1
View larger version:
Figure 1

Kaplan-Meier curves of time to resolution of all symptoms (A; n=384), fever (B; n=321), and respiratory symptoms (C; n=379) in index patients.

Figure 2
View larger version:
Figure 2

Kaplan-Meier curves of time to cessation of viral shedding in index patients (n=392).

Table 1
View larger version:
Table 1

Characteristics of Index Patients at Baseline

Duration of illness. The Kaplan-Meier curves in Figure 1 show the proportions of index patients with unresolved signs or symptoms through the follow-up period. The median duration of illness was 9 days for the oseltamivir group and 11 days for those who did not receive antiviral treatment. A persistently smaller proportion of index patients in the oseltamivir group had unresolved respiratory symptoms and total symptoms from day 1 onward. Index patients who had taken oseltamivir within 24 h of symptom onset experienced a 44% reduction in time to alleviation of all signs and symptoms, with an adjusted acceleration factor of alleviation of 0.56 (95% CI, 0.42–0.76) compared with index patients who did not take any antiviral (Table 2). Results were similar for time to alleviation of fever and time to alleviation of respiratory symptoms (Table 2). Analysis based on the lognormal distribution yielded estimates similar to those based on the Weibull distribution, whereas the lognormal fit was inferior according to the AIC for duration of all symptoms and respiratory symptoms and vice versa for fever (data not shown).

Table 2
View larger version:
Table 2

Factors that Affect Time to Alleviation of All Symptoms, Fever, and Respiratory Symptoms in Index Patients

Duration of viral shedding. The median duration of viral shedding after symptom onset was 6 days, and viral shedding resolved sooner in individuals prescribed oseltamivir within 24 h of onset (Figure 2). Some of the index patients who had not taken any antiviral medication continued to shed virus 12 days after illness onset. After adjustment in a lognormal model with stratification by year (table 3), index patients who took oseltamivir within 48 h of onset had nonstatistically significant reductions in duration of viral shedding in year 2007 (acceleration factor, 0.76; 95% CI, 0.51–1.14) and 2008 (acceleration factor, 0.99; 95% CI, 0.83–1.17) compared with index patients who did not take any antiviral medication. Analysis based on the Weibull distribution yielded estimates similar to those based on the lognormal distribution, whereas the Weibull fit was inferior according to the AIC (data not shown).

Table 3
View larger version:
Table 3

Factors That Affect Time to Cessation of Viral Shedding

Table 4
View larger version:
Table 4

Factors That Affect Transmission of Influenza Virus Infection from Index Patients to Household Contacts

Household transmission. We identified 53 households that included ⩾1 household contacts with detectable viral shedding by RT-PCR or viral culture at the initial home visit [10, 11]. These households with potential coindex patients were excluded from our analysis of household transmission. The baseline characteristics of index patients and their household contacts included in the analysis of household transmission were similar to these in the main analyses.

Among the 331 households with a single index patient, influenza virus infection was confirmed by RT-PCR or viral culture in 80 of 989 household contacts, corresponding to an overall SAR of 8.1% (95% CI, 6.5%-10%). Stratifying by groups, the SAR was 4.7% (95% CI, 1.0%-13%), 6.0% (95% CI, 2.5%-12%), and 7.0% (95% CI, 1.5%-19%) in household contacts of index patients who had taken oseltamivir within 24 h, 24–48 h, and >48 h after symptom onset, respectively, compared with 8.7% (95% CI, 6.8%-11%) in the no antiviral group (P for trend < .01). The unadjusted protective effectiveness (1- SAR 1 /SAR 0 ) of oseltamivir treatment initiated within 24 h or at 24–48 h after symptom onset was 46% and 31%, respectively.

Table 3 indicates that household contacts of index patients who took oseltamivir within 24 h of first symptoms had a nonstatistically significant lower risk of developing influenza virus infection confirmed by RT-PCR or viral culture (adjusted OR, 0.54; 95% CI, 0.11–2.57), clinical influenza (adjusted OR, 0.52; 95% CI, 0.25–1.08), and clinical influenza confirmed by RT-PCR or viral culture (adjusted OR, 0.47; 95% CI, 0.05–4.03). The risk reduction was attenuated for the contacts of index patients who had taken oseltamivir later than 24 h after symptom onset (the P value for trend in risk of transmission for oseltamivir administered by time since onset was .09 for laboratory-confirmed influenza and .41 for clinical influenza). Household contacts were at lower risk of illness from influenza virus infection if they had been vaccinated, if they were older, or if their corresponding index patient was older. Results for the year 2008 separately were similar, whereas the sample size was insufficient to analyze data from 2007 separately.

Previous SectionNext Section

Discussion

Our results confirm the effectiveness of early oseltamivir treatment of uncomplicated influenza virus infections in terms of reducing duration of illness. When treatment was given within 24 h of symptom onset, our results were also suggestive of an indirect benefit to household members. A study by Halloran et al [7] investigated the indirect effect of oseltamivir treatment in reducing transmission to household contacts by analyzing pooled data from 2 randomized controlled trials of prophylaxis, one of which provided oseltamivir treatment to all index patients within 48 h of onset and another of which did not, and estimated the unadjusted antiviral efficacy to be 16% [7]. However, other differences between the 2 trials might have confounded the comparison. In our study, we found that the earlier after illness onset oseltamivir was taken, the quicker the resolution of symptoms and by implication infectiousness. This finding is consistent with the trends in odds of household transmission, where the point estimates for the odds of transmission were lowest when treatment was given earliest.

In 2007, influenza A (H3N2) predominated, whereas in 2008 influenza A (H1N1), A (H3N2), and B cocirculated. Although oseltamivir resistance among seasonal H1N1 strains became a concern in 2008–2009, during our study period in Hong Kong resistance was rare in 2007, and a small proportion (12.5%) of influenza A (H1N1) virus isolates were resistant to oseltamivir in 2007–2008 [19]. Although no resistance has yet been reported in influenza B virus or other subtypes of human influenza A viruses and only sporadically in novel influenza A (H1N1) to date, early oseltamivir treatment is likely to continue to be effective in reducing the duration of clinical illness and viral shedding associated with influenza virus infections [4].

A meta-analysis of randomized controlled trials showed that early oseltamivir treatment reduced time to alleviation of symptoms by 1–2 days [20]. Our study provides additional information on how other factors affect the duration of illness and viral shedding. Our results indicate that those who were administered oseltamivir within 24 h of symptom onset, took antipyretics, were older than 18 years, were vaccinated against influenza in the past year, and were infected with influenza A experienced shorter duration of illness. Use of antibiotics, steroids, and antihistamines did not significantly shorten the duration of illness (Table 3).

Symptoms and signs typically lasted longer than viral shedding, and approximately half of the patients continued to show symptoms 10 days after onset, whereas fever had subsided in all patients by day 6. After adjustment, those who had taken oseltamivir within 48 h experienced a nonstatistically significant 24% reduction in time to cessation of viral shedding in 2007 (Table 3). Children shed virus for ∼40%–80% longer than adults, depending on their age and year of study (Table 3). The most likely explanation for the lower effectiveness against viral shedding in 2008 is that RT-PCR is more sensitive than viral culture, particularly later in illness [21], whereas RT-PCR measures RNA load and may not distinguish between viable and inactivated influenza virions. One other possibility is the presence of oseltamivir-resistant influenza A (H1N1) virus infections in 2008, when ∼50% of influenza A virus infections were associated with the H1N1 subtype and resistance had begun to emerge [19, 22].

After adjusting for potential confounding factors, the effectiveness of oseltamivir treatment in reducing secondary infection of household contacts approached 50% if treatment was initiated within 24 h of onset and approached the null if treatment was initiated later, although with wide CIs indicate substantial uncertainty, particularly for laboratory-confirmed secondary infection. Household contacts of index patients younger than 18 years and unvaccinated contacts had a higher risk of laboratory-confirmed secondary infection. Our findings suggest that treating index patients with oseltamivir may confer some degree of protection to their household contacts. Although previous studies on the cost-effectiveness of oseltamivir treatment have focused on reduction of morbidity in the treated individuals, a reevaluation that incorporates the potential indirect benefits of protection to household contacts may be warranted [23].

Our study has several limitations. Our evaluation of the effects of oseltamivir treatment is based on nonrandomized allocation to treatment, and our findings may be affected by unobserved confounders or insufficient adjustment for observed confounders. Our study was not planned in advance in our study protocol because we had not anticipated such substantial use of oseltamivir in local outpatient care. The sample size of our study was relatively small, although larger than that of the previous study on effects of oseltamivir treatment in reducing household transmission [7]. Households with individuals concurrently infected with influenza as confirmed by RT-PCR or culture at first home visit were excluded from the study. This may lead to exclusion of patients who were infected with more transmissible strains that secondary infection might have had occurred before the first visit.

Findings from this study suggest that early oseltamivir treatment of index patients is effective in reducing duration of illness and could provide some degree of protection to their household contacts. Our results may be useful when considering the allocation of oseltamivir in mitigating influenza epidemics and pandemics. Pandemic plans should consider the feasibility and logistics required to efficiently distribute antiviral treatment to patients either by ensuring that sufficient stockpiles are available at local clinics or pharmacies or perhaps by predispensing antivirals to households that include individuals at higher risk of severe illness [24]. Our estimation of the plausible size of indirect benefits may also be useful for planning further studies of antiviral treatment [7].

Previous SectionNext Section

Acknowledgments

We thank all the physicians, nurses, and staff of the participating centers for facilitating recruitment and Rita Fung, Lai-Ming Ho, Conrad Lam, Joey Sin, Winnie Wai, and Eileen Yeung for research support.

Financial support. This work received financial support from the Centers for Disease Control and Prevention (grant 1 U01 CI000439–02), the Research Fund for the Control of Infectious Disease, Food and Health Bureau, Government of the Hong Kong SAR (grant 08070632), US National Institutes of Health (cooperative agreement 5 U01 GM076497, Models of Infectious Disease Agent Study), and the Area of Excellence Scheme of the Hong Kong University Grants Committee (grant AoE/M-12/06).

Manuscript preparation. The funding agencies had no role in data collection and analysis or the decision to publish, but the Centers for Disease Control and Prevention was involved in study design and preparation of the manuscript. This work represents the views of the authors and not their institutions, including the Centers for Disease Control and Prevention.

Potential conflicts of interest. All authors: no conflicts.

  • Received July 25, 2009.
  • Accepted November 2, 2009.
Previous Section
 

References

  1. ↵
    World Health Organization. Acute respiratory infections (update February 2009). http://www.who.int/vaccine_research/diseases/ari/en/print.html. Accessed 5 April 2009.
  2. Centers for Disease Control and Prevention. CDC issues interim recommendations for the use of influenza antiviral medications in the setting of oseltamivir resistance among circulating influenza A (H1N1) viruses, 2008–09 influenza season. http://www2a.cdc.gov/HAN/ArchiveSys/ViewMsgV.asp?AlertNum=00279. Accessed 5 April 2009.
  3. ↵
    Centers for Disease Control and Prevention. Interim guidance on antiviral recommendations for patients with novel influenza A (H1N1) virus infection and their close contacts. http://cdc.gov/h1n1flu/recommendations.htm. Accessed 26 June 2009.
  4. ↵
    1. Jefferson TO,
    2. Demicheli V,
    3. Di Pietrantonj C,
    4. Jones M,
    5. Rivetti D
    . Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database Syst Rev 2006;3:CD001265.
    Medline
  5. ↵
    1. Welliver R,
    2. Monto AS,
    3. Carewicz O,
    4. et al
    . Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA 2001;285:748-54.
    Abstract/FREE Full Text
  6. ↵
    1. Hayden FG,
    2. Belshe R,
    3. Villanueva C,
    4. et al
    . Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis. J Infect Dis 2004;189:440-9.
    Abstract/FREE Full Text
  7. ↵
    1. Halloran ME,
    2. Hayden FG,
    3. Yang Y,
    4. Longini IM Jr,
    5. Monto AS
    . Antiviral effects on influenza viral transmission and pathogenicity: observations from household-based trials. Am J Epidemiol 2007;165:212-21.
    Abstract/FREE Full Text
  8. ↵
    1. Cauchemez S,
    2. Carrat F,
    3. Viboud C,
    4. Valleron AJ,
    5. Boelle PY
    . A Bayesian MCMC approach to study transmission of influenza: application to household longitudinal data. Stat Med 2004;23:3469-87.
    CrossRefMedlineWeb of Science
  9. ↵
    1. Ferguson NM,
    2. Cummings DA,
    3. Cauchemez S,
    4. et al
    . Strategies for containing an emerging influenza pandemic in Southeast Asia. Nature 2005;437:209-14.
    CrossRefMedline
  10. ↵
    1. Cowling BJ,
    2. Fung ROP,
    3. Cheng CKY,
    4. et al
    . Preliminary findings of a randomized trial of non-pharmaceutical interventions to prevent influenza transmission in households. PLoS One 2008;3:e2101.
    CrossRefMedline
  11. ↵
    1. Cowling BJ,
    2. Chan KH,
    3. Fang VJ,
    4. et al
    . Face masks and hand hygiene to prevent influenza transmission in households: a cluster randomized, controlled trial. Ann Intern Med 2009;151:437-46.
    Abstract/FREE Full Text
  12. ↵
    1. Collett D
    . Modelling survival data in medical researc. 2nd ed. Boca Raton, FL: Chapman & Hall/CRC; 2003.
  13. ↵
    1. Akaike H
    . A new look at the statistical model identification. IEEE Trans Automat Contr 1974;19:716-23.
    CrossRef
  14. ↵
    1. Turnbull BW
    . The empirical distribution function with arbitrarily grouped, censored and truncated data. J R Stat Soc Ser B 1976;38:290-5.
  15. ↵
    1. Cowling BJ,
    2. Muller MP,
    3. Wong IO,
    4. et al
    . Alternative methods of estimating an incubation distribution: examples from severe acute respiratory syndrome. Epidemiology 2007;18:253-9.
    CrossRefMedlineWeb of Science
  16. ↵
    1. Lindsey JC
    . Tutorial in biostatistics methods for interval censored data. Stat Med 1998;17:219-38.
    CrossRefMedlineWeb of Science
  17. ↵
    1. Liang KY,
    2. Zeger SL
    . Longitudinal data analysis using generalized linear models. Biometrika 1986;73:13-22.
    Abstract/FREE Full Text
  18. ↵
    1. Donner A,
    2. Klar N
    . Design and analysis of cluster randomization trials in health research. London: Arnold; 2000.
  19. ↵
    1. Cheng PK,
    2. Leung TW,
    3. Ho EC,
    4. et al
    . Oseltamivir- and amantadine-resistant influenza viruses A (H1N1). Emerg Infect Dis 2009;15:966-8.
    CrossRefMedlineWeb of Science
  20. ↵
    1. Cooper NJ,
    2. Sutton AJ,
    3. Abrams KR,
    4. Wailoo A,
    5. Turner D,
    6. Nicholson KG
    . 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.
    Abstract/FREE Full Text
  21. ↵
    1. Lee N,
    2. Chan PK,
    3. Hui DS,
    4. et al
    . Viral loads and duration of viral shedding in adult patients hospitalized with influenza. J Infect Dis 2009;200:492-500.
    CrossRefMedlineWeb of Science
  22. ↵
    1. Kawai N,
    2. Ikematsu H,
    3. Iwaki N,
    4. et al
    . Clinical effectiveness of oseltamivir for influenza A(H1N1) virus with H274Y neuraminidase mutation. J Infect 2009;59:207-12.
    CrossRefMedlineWeb of Science
  23. ↵
    1. Beutels P,
    2. Scuffham PA,
    3. MacIntyre CR
    . Funding of drugs: do vaccines warrant a different approach? Lancet Infect Dis 2008;8:727-33.
    CrossRefMedline
  24. ↵
    1. Wu JT,
    2. Riley S,
    3. Fraser C,
    4. Leung GM
    . Reducing the impact of the next influenza pandemic using household-based public health interventions. PLoS Med 2006;3:e361.
    CrossRefMedline
| Table of Contents

This Article

  1. Clin Infect Dis. (2010) 50 (5): 707-714. doi: 10.1086/650458
  1. AbstractFree
  2. » Full Text (HTML)Free
  3. Full Text (PDF)Free

Classifications

Share

  1. Email this article

Navigate This Article

Current Issue

  1. March 1, 2012 54 (5)
  1. Clinical Infectious Diseases
  1. Alert me to new issues

Most