The Tamiflu trials
BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g2630 (Published 09 April 2014) Cite this as: BMJ 2014;348:g2630
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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The Table shows a summary of published and unpublished clinical trials of laninamivir and peramivir for influenza in healthy adults in Japan and other East Asian countries [4-7].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
Competing interests: The authors' department has received research funding from Dainippon Sumitomo Pharma, Taisho Toyama Pharmaceutical, and Pfizer.
I am concerned that the BMJ is conflating the Tamiflu RCT data with their admirable aim of supporting open access to all trials data. The potential benefits of early treatment of influenza have become the first casualty in this "political" war, and I am afraid that patients who are eligible for treatment will wrongly be denied treatment with neuraminidase inhibitors as a result, to their significant potential detriment.
Those who are genuinely interested in considering evidence from all sources should read what the CDC have announced following publication of the Cochrane review (1). It clearly indicates the role that these drugs have in reducing mortality in severe influenza.
1. http://www.cdc.gov/media/haveyouheard/stories/Influenza_antiviral2.html
Competing interests: No competing interests
Re: The Tamiflu trials
I blow my whistle, listen carefully, it is a sort of S.O.S:
“ - Tamiflu antiviral treatment is unscientific alternative chelating medicine -”
The so-called neuraminidase inhibitor Tamiflu is meant to inhibit the enzymatic activity of neuraminidase in cellular reproduction of virus. Since about 50 years, neuraminidase inhibitors are known to chelate trace metals. Reason enough to describe Tamiflu as chelating agent.
Up to now there are no reliable scientific clinical trials that tested the hypothesis that Tamiflu can safely and effectively be used for treatment of viral disease. As long as that is the case tamiflu antiviral treatment can best be regarded as unscientific alternative chelation treatment.
Hora est: EBM is in danger, the time has come to counter-attack those who endanger free evidence based patient oriented clinical decision making and to fight against market oriented so-called experts who have underreported about the dangers of chelating agents like the neuraminidase inhibitor Tamiflu.
Dare to be wise (Aude sapere): Listen to your conscience. Do not just follow the rules but ask for the evidence and data they are based on.
This rapid response aims at warning you:
- Beware of chelating agents
- Beware of market oriented expert opinions
- Beware of underreported data
References: see: BMJ/critical thinking/ tjaard; BMJ/diabetes expert/tjaard; BMJ/ Alzheimer/zinc/tjaard.
Competing interests: No competing interests