Does Antiviral Therapy Prevent Lower Respiratory Tract Complications in Influenza Patients?
By Amesh A. Adalja, MD, June 24, 2011
Oseltamivir’s (Tamiflu®, Roche) efficacy in shortening the duration of influenza symptoms when administered promptly is widely accepted; however, the drug is also often used to prevent serious complications secondary to influenza, including bacterial pneumonia. This indication has not been definitively established in the scientific literature; however, a recent meta-analysis by Hernán and Lipsitch1 provides new support for this use of the antiviral.
Early Analyses Yield Conflicting Results
A 2003 pooled analysis by Kaiser and colleagues provided the original evidence to support use of oseltamivir to reduce the rate of influenza-related lower respiratory tract complications. That analysis, which included 10 Roche-funded trials (only 2 of which were published), computed a 55% reduction in influenza-related lower respiratory tract complications with the use of oseltamivir at the standard dose of 75 mg b.i.d. x 5 days.2 A 2006 Cochrane review that drew largely on the Kaiser study arrived at a similar conclusion.3
In 2009, however, Jefferson and colleagues revisited the issue with another review that excluded 8 of the 10 studies included by Kaiser because they were not published. In this iteration, it appeared that oseltamivir conferred no benefit in reducing lower respiratory tract complications.4
Subsequent to the publication of the 2009 Cochrane review, Roche asked Miguel Hernán and Marc Lipsitch of the Harvard School of Public Health to perform an independent data analysis with full access to efficacy and safety data from the 10 trials included in the Kaiser study, the results of which were recently published in Clinical Infectious Diseases.1
Four Years of Roche Data
Hernán and Lipsitch analyzed results from 11 trials, including 1 study by Roche that was previously unidentified and unpublished. They had full access to all of the trial data. All of the trials were conducted during influenza seasons from 1997-2001, and all compared adult and adolescent outpatients randomized to receive either oseltamivir 75 mg b.i.d. x 5 days or placebo. The primary endpoint of the studies was the rate of lower respiratory tract complications treated with antibiotics during 24 days of follow-up; gastrointestinal disorders, neuropsychiatric disorders, and headache were also included as endpoints. A subgroup analysis was also conducted to compare cases of confirmed influenza with those who had flu symptoms, but unconfirmed influenza. Of note, a true intention-to-treat analysis was performed and did not exclude from analysis patients who were excluded from the Kaiser study.1
Analysis Confirms Efficacy in Past Trials
In all, data from 3,908 patients were included in the final analysis, with 2,188 (56%) who received oseltamivir, and 1,720 (44%) who received placebo. Of these, 291 developed a lower respiratory tract complication requiring antibiotics—130 (6%) in the oseltamivir arm and 161 (9%) in the placebo arm. The calculated risk ratio for oseltamivir being protective against lower respiratory tract complications requiring antibiotics was 0.72.
Of the 3,908 patients included in the analysis, 2,570 were confirmed for influenza infection. When unconfirmed cases were excluded from the analysis, oseltamivir was shown to have a risk ratio of 0.63 on complications, and, as expected, it had no effect on complications in those who did not have influenza.1
A safety analysis indicated that oseltamivir use was associated with side effects that included nausea, vomiting, diarrhea, and headache, but neuropsychiatric disorders were not significantly associated with its use.1
Strong Evidence of Efficacy; More Data Still Needed
While Hernán and Lipsitch have provided a substantive defense of the use of oseltamivir to reduce complications from influenza, further research is needed to understand the full benefit of antiviral treatment of influenza. As the authors note, oseltamivir’s efficacy in hospitalized patients has not been tested in placebo-controlled studies, and may never be, because current guidelines strongly recommend antiviral treatment for hospitalized patients. Also, since the studies that provided the basis for this analysis were conducted a decade or more ago, it is not known if the results are fully applicable to currently circulating strains of influenza, including 2009 H1N1. Nevertheless, in the absence of resistance, oseltamivir is generally recommended for patients who are hospitalized for, or who are otherwise at high-risk for developing, an influenza-related lower respiratory tract complication.
- Hernán MA, Lipsitch M. Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials. Clin Infect Dis 2011; http://cid.oxfordjournals.org/content/early/2011/06/14/cid.cir400.abstract. Accessed June 20, 2011.
- Kaiser L, Wat C, Mills T, et al. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 2003;163:1667-72.
- Jefferson TO, Demicheli V, Di Pietrantonj C, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database Syst Rev 2006;3:CD001265.
- Jefferson T, Jones M, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ 2009;339:b5106.