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Accepted by Medicine June 4, 2015
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RECEIPT ACKNOWLEDGMENT
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Thank you for submitting your manuscript to Medicine®.
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May 31 2015 03:01AM
RE: "Prompt Oseltamivir Therapy Reduces Medical Care and Mortality for Patients with
Influenza Infection: An Asian Population Cohort Study"
MD-D-15-00900R1
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RE: MD-D-15-00900
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Prompt Oseltamivir Therapy Reduces Medical Care and Mortality for
Patients with Influenza Infection: An Asian Population Cohort Study
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Chang-Bi Wang, PhDa; Mu-Lin Chiu, MAa,b; Po-Chang Lin, MD, MSa,c;
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Wen-Miin Liang, PhDa,d; Chiu-Ying Chen, PhDa; Yu-Jun Chang, PhDa,e;
Trong-Neng Wu, PhDa; Jen-Hsien Wang, MD, PhDc; Fung-Chang Sung, PhD, MPHa,f
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Taiwan;
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Epidemiology and Biostatistics Center, Changhua Christian Hospital, Changhua, Taiwan;
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Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
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Department of Public Health, China Medical University, Taichung, Taiwan;
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Institute of Population Health Sciences, National Health Research Institutes, Zhunan,
Taiwan;
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Division of Infectious Diseases, Department of Internal Medicine, China Medical University
Hospital;
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Graduate Institute of Biostatistics, Biostatistics Center, China Medical University, Taichung,
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Short Title: Oseltamivir and Influenza
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Corresponding Author:
Fung-Chang Sung, PhD, MPH
Department of Public Health, China Medical University,
91 Hsueh Shih Road,
Taichung 40402, Taiwan.
Tel: 886-4-2205-4070, Fax: 886-4-2201-9901
E-mail: fcsung1008@yahoo.com
Word counts: 188 in abstract, 2236 in text, 4 Tables, 1 Figure and 33 references.
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Abbreviations:
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ICD-9-CM, the International Classification of Disease, Ninth Revision, Clinical
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Modification;
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OR and 95% CI, odds ratio and 95% confidence interval;
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USCDC, the US Centers for Disease Control and Prevention;
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WHO, the World Health Organization.
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Abstract
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BACKGROUND: There are limited population-based studies on the progress of oseltamivir
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therapy for influenza infection.
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METHODS: Using insurance claims data of 2005, 2009 and 2010, we established an
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"In-Time" cohort and a "Lag time" cohort representing influenza patients taking the medicine
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within and not within one week to examine the treatment progress. Incident outpatient visit,
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emergency care and hospitalization, and fatality were compared between the two cohorts in the
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first week and the second week of follow-up periods after the oseltamivir therapy.
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RESULTS: A total of 112,492 subjects diagnosed with influenza on oseltamivir therapy in
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2005, 2009 and 2010 were identified. The multivariate logistic regression analysis showed that
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the In-Time treatment was superior to the Lag-Time treatment with less repeat outpatient visits,
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hospitalizations and fatality. The overall corresponding In-Time treatment to Lag-Time
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treatment odds ratios were 0.50, 0.54 and 0.71(all p-value <0.05), respectively. The In-Time to
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Lag-Time odds ratios of all events were 0.50 in 2009 and 0.54 in 2010.
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CONCLUSIONS: Our study demonstrates that the in-time oseltamivir therapy leads to
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significantly better treatment outcomes. Oseltamivir should be administered as early as the
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onset of influenza symptoms appears.
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Key words: influenza, insurance claims data, oseltamivir, Tamiflu, treatment effectiveness
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Introduction
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Oseltamivir and zanamivirare drugs recommended by the World Health Organization (WHO)
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and the US Centers for Disease Control and Prevention (USCDC) are the first-line antiviral
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drug for patients infected with influenza A and B.1-3 The WHO guidelines recommended that
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patients with diagnosed or suspected influenza should be treated with antiviral medicine as
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soon as possible.2 The USCDC also recommended to treat patients with confirmed or
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suspected influenza with antiviral agents as soon as possible.3 Previous studies on the
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efficacy of antiviral medication used randomized controlled trials targeting patients with
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laboratory confirmed influenza infection.4-6. The study results consistently support that
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oseltamivir is clinically effective for the treatment of influenza and further for the prevention
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of pneumonia.4-6 Oseltamivir may provide symptomatic relief for patients with influenza
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infection, reduce viral excretion from the nose and interrupt the household viral transmission.
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In addition, oseltamivir reduces the duration of symptoms and related antibiotic uses
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associated with flu, the risk of bronchitis, pneumonia and death.7-13 The oseltamivir treatment
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may reduce near 60% of secondary spread of influenza in family contact members.14
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An estimated 45 million patients have received the antiviral treatment worldwide by
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2013 since 2005.15 A retrospective cohort study using a large health data of the US found
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oseltamivir treatment twice daily could reduce pneumonia risk by 32%.14 Hospital based
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study has proved that the oseltamivir treatment effectiveness for patients receiving treatment
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in time is superior to patients with delayed antiviral administration.16
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Although oseltamivir is known as an effective medicine for influenza treatment,
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comparing outcomes and adverse responses between prompt initiation and delayed antiviral
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administration of this medicine has not been well examined for Asian population. This study
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took the advantage of population data available in the Taiwan's National Health Insurance to
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perform a retrospective cohort study. We evaluated the efficacy of oseltamivir therapy for
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patients diagnosed with influenza infection. Patients with oseltamivir therapy within 1 week
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were compared to those with the therapy beyond 1 week for treatment progress, evaluated by
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additional outpatient visits, emergency uses, hospitalization and mortality during a 2-week
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follow-up period.
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Methods
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Database
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This study used claims data of the National Health Insurance Research Dataset (NHIRD)
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from 2000 to 2010, provided by the National Health Research Institutes in Taiwan. This large
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and comprehensive population-based health data set covers over 23,275,000
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Taiwan. The diagnoses were coded with the International Classification of Disease, Ninth
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Revision, Clinical Modification (ICD-9-CM) for insurance claims registered. This study was
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approved by the research ethics committee at China Medical University and Hospital.
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Study cohorts and outcomes observation
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We identified all adult patients with the principal diagnosis of influenza (ICD-9-CM480-487)
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and prescription of oseltamivir during influenza seasons in 2005, 2009 and 2010 (Figure 1).
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This medicine was used in 2005 for an influenza prevention trial mainly for the elderly
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diagnosed with influenza, and has been implemented for all eligible patients since 2009.
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From the prescription records available in the claims data, we ascertained the usage of
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oseltamivir for the specific date, dose, and route of every prescription in years 2005, 2009
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and 2010. The date a patient initiated with the oseltamivir prescription was designated as the
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index day. Patients clinically newly diagnosed with influenza by physician and initiated the
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oseltamivir prescription within one week were designated into the In-Time cohort. Patients
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who were diagnosed with influenza and started taking oseltamivir beyond one week of the
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diagnosis were designated as the Lag-Time cohort. We traced all patients prescribed with
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oseltamivir for a 2-week follow-up period, to observe the treatment progress, using additional
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people in
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outpatient visit, emergency use, hospitalization and death as study outcomes. The first period
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(week 1) was from the 8th day to the 14th day following the oseltamivir prescription. The
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week 2 period began immediately after the completion of the preceding week 1 follow-up
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(i.e. from the 15th day to 21st day). A 2-week follow-up period was designed to observe a
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short-term progress of the treatments. Patients who had taken oseltamivir and sought further
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medical services, including outpatient visit, emergency use or hospitalization, or had
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encountered death were identified weekly from the claims data during the 2-week follow-up
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period. These events were designated as adverse progressions.
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Statistical Analysis
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Based on dates with influenza diagnosed and oseltamivir prescribed, patients were divided
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into “In-time” and “Lag-time” cohorts, by the study year of 2005, 2009, and 2010. To
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determine whether patient characteristics were similar between the two prescription times for
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oseltamivir, we compared distributions of sex and age. The 2-week follow-up period-specific
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frequencies of outpatient visit, emergency use, hospitalization and death were calculated for
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oseltamivir users in the In-time cohort and the Lag-time cohort by study year. We used the
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Mantel-Haenszel method to calculate the In-time cohort to Lag-time cohort odds ratio (OR)
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and 95% confidence interval (CI) of each event. We further used the multivariable logistic
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regression model to estimate the ORs of repeat outpatients visits, hospitalization and death
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associated with In-Time and Lag-Time treatments by age and sex in all three years combined.
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Similar data analysis method was also performed to estimate ORs of all events combined for
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2009 and 2010 to evaluate whether the treatment effectiveness changed in 2010. The SAS
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software for Windows, Version 9.3(SAS Institute Inc., Cary, NC, USA) was used for data
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analyses with the two-sided p value of 0.05 considered statistical significance.
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Results
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Among patients clinically diagnosed with influenza, there were 998 cases in 2005, 96093
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cases in 2009 and 15401 cases in 2010 on the oseltamivir therapy (Table 1). Influenza cases
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in 2005 were much older than those in 2009 and 2010. There were more In-Time therapy
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cases than Lag-Time therapy cases in 2005, but not in 2009 and 2010. After taking the
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medicine, outpatient visits declined weekly. The outpatient visits in week 1 follow-up were
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3.2-fold more frequent in the Lag-Time cohort than in the In-Time cohort (32.3 vs. 9.98%) in
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2005. The difference in outpatient visits between the Lag-Time cohort and the In-time cohort
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was reduced in 2009 (26.3 vs. 15.4%, respectively) and in 2010 (28.8 vs. 17.9%,
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respectively). Similar trends remained in week 2 follow-up. The incidence of hospitalization
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and the mortality were lower in the In-Time cohort than in the Lag-Time cohort over the
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2-week periods. The hospitalization rate and mortality were greater in 2005.
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Among patients with oseltamivir therapy in the 3 years combined, 9502 (18.0%) in the
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In-Time cohort and 18174 (30.4%) in the Lag-Time cohort had repeat outpatient visits (Table
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2). The Cochran-Mantel-Haenszel analysis estimated overall OR of repeat outpatient visits in
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patients with In-Time therapy was 0.50 (95% CI = 0.49-0.52, p < 0.0001), comparing to
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Lag-Time therapy. The corresponding ORs of hospitalization and death for patients with
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In-Time therapy were 0.54 (95% CI = 0.37-0.62, p < 0.0001) and 0.71(95% CI = 0.56-0.91, p
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< 0.0001), respectively. The oseltamivir therapy was consistently superior in the In-Time
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cohort than in the Lag-Time cohort among study years, age groups and both sexes. The
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age-specific results showed that the OR decreased as age increased, from 0.60 (95% CI =
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0.58-0.63, p < 0.0001) in 20-29 years old to 0.34 (95% CI = 0.29-0.41, p < 0.0001) in 70-79
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years old. However, the age-specific OR pattern of repeat outpatient visits did not appear in
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hospitalization and death. The reduction in hospitalization risk remained significant for most
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age groups. Reductions in outpatient visits and hospitalization were similar in males and
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females, while the reduction in mortality risk was significant for males, but not for females.
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Table 3 shows In-Time relative to Lag-Time ORs of repeat outpatient visits,
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hospitalization and death associated with age and sex. The risk of repeat outpatient visits,
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hospitalization or death increased with age. Compared to patients 20-29 years old, the OR of
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death was increased to 307 (95% CI = 154-611, p <0.0001) in patients aged 80 years and
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above. Males were at lower risk of repeat outpatient visits (OR = 0.84, 95% CI = 0.82-0.86)
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but at higher risk of hospitalization (OR = 1.39, 95% CI = 1.1-1.77) or death (OR = 1.83,
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95% CI = 1.41-2.36). Table 4 shows that the superior effectiveness of the In-Time oseltamivir
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therapy relative to Lag-Time for all events changed slightly between 2009 and 2010, with
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overall ORs of 0.50 (95% CI = 0.49-0.52) and 0.54(95% CI = 0.50-0.58), respectively.
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Discussion
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Oral oseltamivir is a well-tolerated and effective antiviral drug for influenza patients of all
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ages, even for those with comorbidities of respiratory diseases and/or chronic cardiac
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disease.17 Population-based study on antiviral efficacy has been limited to retrospective
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cohort study because it is difficult to perform a randomized population trial.14-16 Our study
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used insurance claims data to performed another retrospective cohort study. The results
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showed that oseltamivir treatment was also effective for Asian patients with influenza
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infection of all ages in 2005, 2009, or 2010. Previous studies emphasized in evaluating
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whether the oseltamivir treatment reduced lower respiratory tract complications, antibiotic
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use and/or hospitalization, alleviated symptoms, or reduced mortality.18-22 An earlier double
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blind prospective trial involving 3564 flu patients concluded that the oseltamivir treatment
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could reduce lower respiratory tract complications, antibiotic use, and hospitalization.18
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Studies recommended early treatment with oseltamivir for patients with influenza A
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(H1N1 and H5N1).22-24 Delayed oseltamivir treatment increases the lung involvement.25 An
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UK study found that influenza patients treated with oseltamivir 75 mg within 24 hours of
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symptom onset, the duration of symptoms was 43 hours shorter than placebo controls.19 A
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Japanese study found that paediatric patients with 2009 H1N1 infection treated within 48
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hours of symptom onset with neuraminidase inhibitors, primarily oseltamivir, could reduce
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case fatality to 0.1%.22 Nursing home and hospital studies on oseltamivir therapy also showed
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the in-time treatment reduced the disease spread, duration of illness, level of viral shedding
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and respiratory failure.26-31
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Our study defined oseltamivir treatment within one week of symptom onset as the prompt
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In-Time treatment. The In-Time treatment was consistently superior to the Lag-Time
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treatment in the reduction of adverse events; there were overall 50% (OR = 0.50) reduction in
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repeat outpatient visits, 46% (OR = 0.54) reduction in hospitalization and 29% (OR = 0.71)
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reduction in mortality within the 2-week follow-up period (Table 2). The superior effects of
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the In-Time treatment appeared in each study year, each age group, males and females
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However, the stratified analysis showed that the fatality reduction was significant only in
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2009 and for males. We were unable to observe a significant trend for the emergency
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admission due to small sample size.
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Studies have reported that the 2008-2009 influenza A (H1N1) viruses exhibited
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decreased susceptibility to oseltamivir.31-33 Using influenza surveillance network laboratories
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study of the Taiwan Centers for Disease Control, Yang et al. found that the
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oseltamivir-resistant influenza virus had developed in Taiwan during the pandemic
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outbreak.31,33 The trend of oseltamivir resistance also appeared noticeable in our study results
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of 2009 and 2010. Our data showed that the outpatient visit, hospitalization and mortality
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were higher in 2010, especially for the patients receiving delayed oseltamivir treatment. We
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conducted a further analysis to compared the all events using the study year as a covariate.
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Compared to 2005, the adjusted ORs of having adverse events were 1.81(95% CI =
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1.55-2.11) in 2009 and 2.04(95% CI = 1.74-2.38) in 2010 (data not shown). However, the
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overall In-Time to Lag-Time treatment OR of all events changed slightly from 0.50 in 2009
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to 0.54 in 2010, indicating that the early oseltamivir treatment remains an effective choice for
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interrupting seasonal influenza. The oseltamivir-resistant virus might be slightly happening in
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2010 in Taiwan's population.
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This study is an example using population-based insurance claims data to evaluate the
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treatment progress of prompt initiation of oseltamivir therapy for reducing repeat outpatient
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visits, hospitalizations, and mortality in an Asian population. In addition to a large number of
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study population, we examined a wide range of age groups, including the elderly. Unlike
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clinical trials, this natural history study was able to demonstrate that an earlier antiretroviral
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administration reduced near half of odds for outpatient visits and hospitalization.
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Our study has a number of limitations. First, the nature of retrospective study has an
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inherent limitation of selection bias. Patients administered with oseltamivir usually suffered
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from severe influenza symptoms. Thus, our study results may not be applicable to patients
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with mild symptoms. Second, Taiwan government provided free oseltamivir to patients only
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in 2005, 2009 and 2010, we therefore constrained the present study using data available for
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these three years. Nevertheless, our study results show that oseltamivir is effective and useful
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to relieve influenza symptoms, especially for the In-Time cohort. The clinical features show
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that patients in the In-Time cohort usually suffer from more severe symptoms at the onset of
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influenza than those who are in the Lag-Time cohort. If early oseltamivir treatment is more
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effective for patients with severe symptoms than those with mild symptoms, such treatment
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should be more significant for patients with severe symptoms. Third, some personal factors
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such as body mass index, lifestyle, and family medical history were not considered in our
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study because of a lack of related information. Finally, we only identified the patients
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infected with influenza, but we did not analyze the subtype to which the influenza belonged
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to. Future studies can be conducted to examine the treatment effectiveness of oseltamivir on
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the subtypes of influenza.
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Conclusion
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Oseltamivir therapy was initiated with a small size trial for mainly patients of the elderly in
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2005 in Taiwan, which resulted successful effectiveness on reducing outpatient visit,
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hospitalization, and mortality. Oseltamivir also exhibits superior effectiveness in reducing
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outpatient visit, hospitalization, and mortality when the much larger sizes of patients were
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treated promptly in 2009 and 2010. Although, minor variant in drug resistance was noted
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from 2009 to 2010.This national data with large sample size obviously shows that oseltamivir
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is an effective medicine until now, especially in reducing the re-outpatient visit rates for
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patients of all ages.
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ARTICLE INFORMATION
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Author Contributions: Sung FC had full access to all of the data in the study and takes
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responsibility for the integrity of the data and the accuracy of the data analysis.
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Study concept and design: Wang CB, Chiu ML, Lin PC, Chang YJ, Sung FC.
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Acquisition of data: Chen CY, Wu TN, Sung FC.
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Analysis and interpretation of data: Wang CB, Chiu ML, Lin PC, Liang WM, Wang JH,
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Sung FC.
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Drafting of the manuscript: Wang CB, Chiu ML, Lin PC, Sung FC.
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Critical revision of the manuscript for important intellectual content: Wang CB, Chiu ML,
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Lin PC, Sung FC.
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Statistical analysis: Wang CB, Liang WM, Chang YJ, Sung FC.
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Administrative, technical, or material support: Wang CB, Chiu ML, Lin PC, Liang WM,
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Chang YJ, Sung FC.
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Study supervision: Wang CB, Lin PC, Liang WM, Chen CY, Wu TN, Wang JH, Sung FC.
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Wang CB and Chiu ML have equal contribution.
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Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE
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Form for Disclosure of Potential Conflicts of Interest and none were reported.
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Funding/Support: The present study was supported by the National Sciences Council,
Executive Yuan (grant numbers NSC 100-2621-M-039-001), China Medical University
Hospital (grant number 1MS1), Taiwan Ministry of Health and Welfare Clinical Trial and
Research Center of Excellence (MOHW104-TDU-B-212-113002). China Medical University
Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM104010092);
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NRPB Stroke Clinical Trial Consortium (MOST 103-2325-B-039 -006); Tseng-Lien Lin
Foundation, Taichung, Taiwan; Taiwan Brain Disease Foundation, Taipei, Taiwan; Katsuzo
and Kiyo Aoshima Memorial Funds, Japan; and Health, and welfare surcharge of tobacco
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products, China Medical University Hospital Cancer Research Center of Excellence
(MOHW104-TDU-B-212-124-002, Taiwan)..
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Role of the Sponsor: None of the funders had a role in the study design, data collection
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and analysis, decision to publish, or preparation of the manuscript.
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Disclaimer: The content is solely the responsibility of the authors and does not necessarily
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represent the official views of the Taiwan National Health Research Institutes.
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Additional Contributions: All authors would like to thank the Taiwan National Health
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Research Institutes for providing the NHI database. The institute had no role in study design,
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data collection and analysis, decision to publish, or preparation of the manuscript.
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Figure legend
Figure 1. Study Flow chart of study design.
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