Amid Controversy about the Efficacy of Oseltamivir, Experts Recommend Antiviral Treatment for Patients with Influenza

Although some meta-analyses have called into question the efficacy of antiviral treatment, the Centers for Disease Control recommends empirical use of antiviral medications patients with symptoms suggestive of influenza.

Currently, influenza is widespread in 46 states, and the predominant circulating strain—H3N2—is not covered by this year’s vaccine. In a press conference held on Friday, January 9, 2015, Centers for Disease Control (CDC) officials advised physicians to prescribe a course of the antiviral oseltamivir (Tamiflu) for patients with flu-like symptoms, even in the absence of confirmatory testing for the virus.^1,2

According to a statement from Peter Doshi, assistant professor at the University of Maryland School of Pharmacy, and associate editor of the British Medical Journal, the CDC should not support antiviral treatment unless strong evidence supports that they prevent hospitalizations and complications of influenza.²

In a 2014 meta-analysis on which Doshi was an author, treatment with oseltamivir was found to be effective in reducing the duration of influenza symptoms, but only by approximately half a day (16.8 hours; 95% CI: 8.4 to 24.1; P<.001). Similar results were reported in otherwise healthy children, with oseltamivir treatment inducing symptom reduction 29 hours sooner (95% CI: 12 to 47 hours, P =.001). However, treatment was associated with some side effects, notably nausea (number needed to harm [NNH] = 28) and vomiting (NNH = 22 in adults, 19 in children).³

Although this systematic review calls into question the efficacy of oseltamivir on the narrow criterion of symptom reduction, abundant evidence supports the efficacy of oseltamivir in prior outbreaks.

For instance, in a study funded by Hoffmann-La Roche, using data from a total of 29,234 patients collected from 78 studies, investigators conducted a systematic review and meta-analysis the efficacy of neuraminidase inhibitors in reducing mortality rates in patients hospitalized with the 2009 pandemic H1N1 influenza A. Researchers measured a significant 19% reduction in mortality risk in patients receiving neuraminidase inhibitors versus no treatment (adjusted odds ratio: 0.81; 95% CI: 0.70 to 0.93; P = .0024).⁴

Retrospective studies also show the benefits of using oseltamivir. In a population-based cohort study, investigators in British Columbia, Canada, analyzed rates of all-cause hospitalization within 14 days of receiving an outpatient influenza diagnosis. Hospitalization rates were compared for a total of 304 patients who received a neuraminidase inhibitor on the same day of symptom onset and 245 patients who did not receive a neuraminidase inhibitor on the same day of symptom onset.

After adjustment for baseline differences in patient populations using propensity score matching, investigators found that all-cause hospitalization rates were significantly reduced by 16% (95% CI 2% to 28%) in patients receiving early treatment with a neuraminidase inhibitor versus patients receiving no treatment.⁵

However, consistent with the Cochrane metaanalysis, studies evaluating the symptomatic benefits of oseltamivir in relatively healthy patients seem to show less dramatic benefits than those observed in patients with more severe illness. For instance:

• A 2012 metaanalysis of 3 published and 8 unpublished studies showed that use of oseltamivir reduced the duration of symptoms by an average of 20.7 hours (95% CI: 13.1 to 28.0 hours), but did not affect hospitalization rates.⁶
• In patients 162 patients aged 15 years and older treated with oseltamivir or symptomatic management, median illness duration were not statistically different between groups (6.50 days with oseltamivir versus 7.04 days with symptomatic treatment).⁷
• In a total of 408 children aged 1 to 3 with influenza with either oseltamivir (n = 203) or placebo (n = 205) over 2 flu seasons (2007 to 2009), oseltamivir use in patients with influenza A receiving oseltamivir within 24 hours of symptom onset experienced a median 3.5-day reduction in the duration of illness (3.0 versus 6.5 days; P = .006), and parents missed 3 fewer days of work, although no improvement was observed in children with influenza B.⁸

With many studies and several metaanalyses published related to the efficacy of neuraminidase inhibitors, investigators in Antwerp, Belgium sought an even higher level of evidence—a meta-analysis of meta-analyses evaluating the efficacy of neuraminidase inhibitors.⁹

In the meta-meta-analysis, Michiels and colleagues analyzed the value of neuraminidase inhibitors for the treatment and prevention of seasonal influenza using data from a total of 9 systematic reviews deemed by 2 reviewers to meet quality standards. Investigators found moderate to low evidence, based on GRADE criteria, that neuraminidase inhibitors were effective for prophylaxis of seasonal influenza, and found moderate- to high-quality evidence that neuraminidase inhibitor use yields clinically relevant benefits in healthy adults and children with influenza-like illness. One of the 9 systematic reviews found that oseltamivir use reduced rates of antibiotic use in health adults with influenza-like illness.⁹

The CDC recommendation is not support by studies evaluating the use of oseltamivir for its symptomatic benefits in relatively healthy individuals. But, considering other evidence, the use of oseltamivir is reasonable considering past experience in other epidemic conditions. For instance, during the 2009 H1N1 influenza outbreak, a metaanalysis found a 19% reduction in mortality risk with prompt oseltamivir treatment,⁴ and a retrospective study of data collected during the same outbreak indicates a 16% reduction in the risk of hospitalization with outpatient treatment.⁴Considering this evidence, and the current epidemic conditions, the CDC’s latest recommendationis logical and responsible.

References

1. Grady D. The New York Times. http://www.nytimes.com/2015/01/10/health/a-bad-flu-season-hits-the-halfway-mark-cdc-says.html. Published January 9, 2015. Accessed January 12, 2015.

2. Stobbe M. The Associated Press. http://hosted2.ap.org/APDEFAULT/386c25518f464186bf7a2ac026580ce7/Article_2015-01-09-US-MED--Flu%20Season/id-f1324345528844929a305b35a3c1ced1. Accessed January 12, 2014.

3. Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ.2014;348:g2545.

4. Muthuri SG, Venkatesan S, Myles PR, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med. 2014;2(5):395-404.

5. Marra F, Chong M, Henry B, Patrick DM, Kendall P. Effectiveness of neuraminidase inhibitors in preventing hospitalization during the H1N1 influenza pandemic in British Columbia, Canada. J AntimicrobChemother. 2014;69(5):1397-1406.

6. Ebell MH, Call M, Shinholser J. Effectiveness of oseltamivir in adults: a meta-analysis of published and unpublished clinical trials. FamPract. 2013;30(2):125-133

7. Lee JS, Park SY, Kim JS, You JY, Ju YS, Eom JS. The clinical effectiveness of oseltamivir in mild cases of pandemic influenza A H1N1 2009 infection. Scand J Infect Dis. 2012;44(8):595-599.

8. Heinonen S, Silvennoinen H, Lehtinen P, et al. Early oseltamivir treatment of influenza in children 1-3 years of age: a randomized controlled trial. Clin Infect Dis. 2010;51(8):887-894.

9. Michiels B, Van Puyenbroeck K, Verhoeven V, Vermeire E, Coenen S. The value of neuraminidase inhibitors for the prevention and treatment of seasonal influenza: a systematic review of systematic reviews. PLoS One. 2013;8(4):e60348.