ABSTRACT & COMMENTARY
Efficacy of Higher-dose Oseltamivir in Adults with Influenza A and B
By Richard R. Watkins, MD, MS, FACP
Division of Infectious Diseases, Akron General Medical Center, Akron, OH; Associate Professor of Internal
Medicine, Northeast Ohio Medical University, Rootstown, OH.
Dr. Watkins reports no financial relationships in this field of study.
This article originally appeared in the January 2014 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, FIDSA, and peer reviewed by Timothy Jenkins, MD. Dr. Deresinki is Clinical Professor of Medicine, Stanford University, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, and Dr. Jenkins is Assistant Professor of Medicine, University of Colorado, Denver Health Medical Center. Dr. Deresinski does research for the National Institutes of Health, and is an advisory board member and consultant for Merck, and Dr. Jenkins reports no financial relationships relevant to this field of study.
Synopsis: In a prospective, open-label, intervention study conducted over four influenza seasons, higher dose oseltamivir compared to standard dose produced no additional benefits in patients with influenza A infection. It did lead to improved virologic response in those with influenza B, but this did not reach statistical significance.
Source: Lee N, et al. A Prospective Intervention Study on Higher-Dose Oseltamivir Treatment in Adults Hospitalized with Influenza A and B infections. Clin Infect Dis 2013; 57:1511-1519.
A common affliction during the winter months, influenza is most often managed with supportive therapy. However, neuraminidase inhibitors like oseltamivir are frequently prescribed to patients with more serious illness including those who require hospitalization. The efficacy of the standard regimen of oseltamivir, 75 mg twice a day for 5 days, has been questioned especially for those who are seriously ill. Lee et al. aimed to determine if a higher dose of oseltamivir (150 mg twice a day) would be more effective in adults hospitalized with laboratory-confirmed influenza A or B compared to standard-dose therapy.
The study was a prospective, open-label, interventional trial conducted at two hospitals in Hong Kong during four influenza seasons. Inclusion criteria included age ≥ 18 years, hospitalization for laboratory-confirmed influenza A or B infection, presentation within 96 hours from the onset of symptoms, and provision of informed consent. The two study arms included standard therapy, defined as oseltamivir 75 mg twice daily for 5 days, and the comparator therapy, defined as oseltamivir 150 mg twice daily for 5 days or 75 mg twice daily for 5 days in patients with a creatinine clearance of 40-60 mL/minute. Study arms were allocated by hospital site and not individually. In all, 157 patients were randomized, with 87 in the standard therapy arm and 70 in the comparator therapy arm. There were no significant differences between the arms in demographic characteristics, underlying medical conditions and severity of illness at enrollment. A median of 6 nasopharyngeal swabs were collected from each patient between days 0 to 5 after starting oseltamivir.
The investigators found no significant difference in viral RNA negativity at day 5 between the two treatment arms (44.7 % in the comparator group vs. 40.2% in the standard group; P = .634). They did observe a nonsignificant trend toward more frequent day 5 RNA negativity for the comparator therapy arm vs. the standard therapy arm in influenza B patients (80% vs. 57.1%; P = .214) but not in those with influenza A (32.1% vs. 35.2%). Moreover, another nonsignificant trend was found for the comparator therapy being associated with a faster rate of viral DNA decline for influenza B but not A (P = .051). After univariate and multivariate analysis there were no significant differences in clinical outcomes between the two groups, including duration of hospitalization, time to discontinuation of supplemental oxygen and time to fever resolution. More adverse events were noted in patients who received the 150 mg twice daily dose (22.0%) compared to those who received the 75 mg twice daily dose (5.3%; P = .004). All of the events were described as mild to moderate.
The main finding of the study, that high-dose oseltamivir did not produce a clear benefit in adults with influenza, is not surprising since it agrees with previously reported data.1 While a trend toward faster viral clearance in patients with influenza B was observed, it did not reach statistical significance. This latter result is interesting because some data suggest influenza B is less susceptible to standard dose oseltamivir.2 However, it is worth emphasizing that influenza B cannot be differentiated from influenza A infection by presenting clinical signs and symptoms.3 By day 5 in the present study about half of the cases still had a detectable viral load. This suggests that the standard 5-day course of therapy might not be adequate for all patients, such as those with prolonged symptoms or who require intensive care.
There are several limitations to the study that deserve comment. The patients were not randomized individually, which may have led to unforeseen confounding. The number of patients in the two arms was relatively small and could have made the study underpowered to detect significant differences in virologic and clinical outcomes. Finally, there were very few patients with severe illness, so the results might not be generalizable to this population.
The take-home message from this study is that high-dose oseltamivir did not show any significant benefit on the course of influenza A compared to standard-dose therapy. It is uncertain if high-dose oseltamivir is useful for influenza B and this hypothesis requires further clinical investigation. I suggest that clinicians continue to use standard-dose oseltamivir until data showing clear benefit from higher-dose therapy are available.
- Yang SG, et al. Antiviral therapy and outcomes of patients with pneumonia caused by influenza A pandemic (H1N1) virus. PLoS One 2012;7:e29652.
- Kawai N, et al. A comparison of the effectiveness of oseltamivir for the treatment of influenza A and influenza B: A Japanese multicenter study of the 2003-2004 and 2004-2005 influenza seasons. Clin Infect Dis 2006;43:439-44.
- Daley AJ, et al. Comparison of influenza A and influenza B virus infection in hospitalized children. J Paediatr Child Health 2000;36:332-5.