The Tamiflu trials

To the Editor:
 
The updated Cochrane review concluded that oseltamivir and zanamivir reduce the duration of influenza symptoms but do not reduce influenza-related complications and hospital admissions [1-3]. Although the Cochrane review authors did not review efficacy of newer neuraminidase inhibitors (NIs), they stated, "laninamivir and peramivir may be more potent as NIs, because their bioavailability is far higher than zanamivir and may affect the host’s endogenous neuraminidase [1]."
 
The Table shows a summary of published and unpublished clinical trials of laninamivir and peramivir for influenza in healthy adults in Japan and other East Asian countries [4-7]. All of these trials were conducted in two consecutive influenza seasons before the 2009 pandemic. Although both laninamivir and peramivir demonstrated a significant reduction in symptom duration, without increasing the risk of adverse events, no data supported the superiority of the newer NIs over oseltamivir, including limited information of physician-diagnosed influenza-related complications; the risks of complications in the 300-mg- and 600-mg-peramivir groups did not significantly differ from that in the oseltamivir-group (2.7%, 2.5%, and 3.3%, respectively) [7].
 
Japan is the leading NI-consuming country and has prescribed 75% of all oseltamivir worldwide [8 9]. Laninamivir and preramivir were first approved in Japan in 2010 and have already been widely marketed there [10 11]. A recent report showed that in the 2012-13 influenza season, Japanese clinicians prescribed laninamivir for 42% of adult influenza patients, oseltamivir for 41%, peramivir for 12%, and zanamivir for 5% [12]. The Cochrane review reminded us of the importance of having independent scrutiny of data contained in clinical study reports. Such an evaluation should help provide further information to answer the question of whether the newer NIs are truly more potent or not.

 
References:
1. Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2014;4:CD008965
2. Jefferson T, Jones M, Doshi P, et al. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014;348:g2545
3. Heneghan CJ, Onakpoya I, Thompson M, et al. Zanamivir for influenza in adults and children: systematic review of clinical study reports. BNJ 2014;348:g2547
4. CS-8958 Taiwan Phase 2 study: A randomized double-blind placebo-controlled, multicenter phase 2 study for the evaluation of efficacy and safety of CS-8958 in patients with influenza virus infection. 2011. http://www.clinicaltrials.jp/user/ctrDetail_e.jsp?resultId=296.
5. Kohno S, Kida H, Mizuguchi M, et al. Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection. Antimicrobial agents and chemotherapy 2010;54(11):4568-74.
6. Watanabe A, Chang SC, Kim MJ, et al. Long-acting neuraminidase inhibitor laninamivir octanoate versus oseltamivir for treatment of influenza: A double-blind, randomized, noninferiority clinical trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2010;51(10):1167-75.
7. Kohno S, Yen MY, Cheong HJ, et al. Phase III randomized, double-blind study comparing single-dose intravenous peramivir with oral oseltamivir in patients with seasonal influenza virus infection. Antimicrobial agents and chemotherapy 2011;55(11):5267-76.
8. Tashiro M, McKimm-Breschkin JL, Saito T, et al. Surveillance for neuraminidase-inhibitor-resistant influenza viruses in Japan, 1996-2007. Antiviral therapy 2009;14(6):751-61.
9. USFDA. Tamiflu (oseltamivir phosphate) Pediatric Safety Update: Background Summary and Review of Clinical Review Team Activities, 2007 to Present. 2012. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMateria....
10. Sunagawa S, Higa F, Cash HL, et al. Single-dose inhaled laninamivir: registered in Japan and its potential role in control of influenza epidemics. Influenza and other respiratory viruses 2013;7(1):1-3.
11. Sugaya N. Widespread use of neuraminidase inhibitors in Japan. Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 2011;17(5):595-601.
12. Japan Physicians Association. Influenza Clinical Practice Guideline 2013-14 season. Japan: Japan Physicians Association, 2013.

 
Authors
Motoi Suzuki, MD, MSc, PhD
Assistant Professor
Department of Clinical Medicine,
Institute of Tropical Medicine, Nagasaki University, Japan
 
Konosuke Morimoto, MD, PhD
Associate Professor
Department of Clinical Medicine,
Institute of Tropical Medicine, Nagasaki University, Japan
 
Koya Ariyoshi, MD, MSc, PhD
Professor
Department of Clinical Medicine,
Institute of Tropical Medicine, Nagasaki University, Japan