WHO downgrades status of oseltamivirBMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3266 (Published 12 July 2017) Cite this as: BMJ 2017;358:j3266
All rapid responses
To the Editor:
We strongly disagree with the interpretation of the evidence on antiviral treatment of influenza as described by Ebell in “WHO downgrades status of oseltamivir” , and we would like to clarify the fundamental issue of how to interpret the available data from studies of oseltamivir treatment of influenza patients. This is critically important to avert confusion among clinicians providing care for influenza patients worldwide. As representatives of public health and professional medical organizations, we continue to recommend use of neuraminidase inhibitor antiviral drugs, including oseltamivir, as soon as possible for treatment of influenza patients.
The WHO 2017 Expert Committee on the Selection and Use of Essential Medicines considered a proposal by the Cochrane Review acute respiratory infections group to delete oseltamivir from the Essential Medicines List (EML) and EML in children (EMLc) . The WHO EML and EMLc serve as guides for the development of national and institutional essential medicine lists worldwide. Oseltamivir was added to the EML and EMLc in 2011. Ebell wrote that “Removal of oseltamivir from the essential medicines list is better late than never.” In fact, importantly, the WHO did not remove oseltamivir from the EML. Rather, the “Committee recommended the listing of oseltamivir be amended and the medicine be moved from the core to the complementary list, and its use be restricted to severe illness due to confirmed or suspected influenza virus infection in critically ill hospitalized patients” .
The Cochrane review of oseltamivir, mentioned by Ebell, considered data only from randomized controlled trials (RCTs) of early oseltamivir treatment (generally started within 2 days of illness onset) versus placebo that were conducted mostly in otherwise healthy non-high risk outpatients with mild illness. These studies demonstrated modest benefit of early oseltamivir treatment in reducing the duration of illness . These trials were not intended or designed to assess complications, hospitalization or death, were therefore underpowered for these outcomes, and do not inform oseltamivir use in hospitalized influenza patients with more severe disease . In order to increase statistical power to detect such outcomes, studies with much larger sample size, including participants with chronic co-morbidities and those at higher risk for complications from influenza are needed, but do not exist; therefore, meta-analyses of pooled existing clinical trial and observational data can be informative. Ebell did not mention the meta-analysis of RCTs in outpatients published by Dobson et al. that reported oseltamivir treatment of adults with laboratory-confirmed influenza versus placebo was associated with a reduction in clinician-diagnosed lower respiratory tract complications requiring antibiotics more than 48 hours after randomization, and fewer hospital admissions for any cause .
Post-licensure, non-randomized studies can also provide important insights into protection against more severe clinical end-points. For example, data from an observational study in China where persons with mild-to-moderate illness caused by laboratory-confirmed influenza A(H1N1)pdm09 virus infection were isolated in hospitals at the beginning of the 2009 H1N1 pandemic provided an opportunity to assess the effect of oseltamivir treatment in preventing complications. Oseltamivir treatment started 2 or more days after illness onset compared with no antiviral treatment was associated with reduced risk of developing radiographically confirmed pneumonia . Furthermore, an individual patient data meta-analysis of more than 3000 outpatients with laboratory-confirmed influenza concluded that neuraminidase inhibitor (NAI) antiviral drug treatment significantly reduced the likelihood of hospital admission .
Ebell and others, including the Cochrane review of oseltamivir RCTs [3,8], commonly report results for the “intention-to-treat (ITT)” population, of which many participants had negative influenza testing results, but had overlapping signs and symptoms of the syndrome of ”influenza-like illness” that can be caused by influenza viruses and multiple other respiratory pathogens. Because oseltamivir and other NAI antiviral drugs only have activity against influenza viruses, but not other pathogens, the reporting of ITT results is misleading and biased toward not finding benefit. Rather, what is most important is whether oseltamivir treatment is beneficial to patients with illness caused by influenza virus infection, the “intention-to-treat-infected” (ITTi) study population. For example, the Cochrane review reported that in adult outpatients with influenza-like illness, oseltamivir treatment significantly reduced the time from first alleviation of symptoms by 16.7 hours versus placebo , whereas in the Dobson et al meta-analysis, oseltamivir treatment of adult outpatients with laboratory-confirmed influenza significantly reduced the time to alleviation of all symptoms by 25 hours versus placebo .
We take strong exception to Ebell’s statement “Of course, what really matters is how the drug performs for patients with influenza-like illness since near patient tests for influenza lack sensitivity and are little used in most European countries”. Antimicrobial stewardship includes selection of the optimal antimicrobial drug regimen for treatment of an infectious disease. Oseltamivir and other NAI antiviral drugs block the release of influenza viral particles from infected cells, but have no effect and provide no benefit to patients with signs and symptoms of influenza-like illness caused by non-influenza pathogens. Therefore, it is important for clinicians to properly and promptly diagnose influenza in order to prescribe antiviral medications for influenza patients who can benefit, particularly those who are at increased risk for influenza complications or with severe illness. Influenza tests, for example during a respiratory illness outbreak or with an out-of-season case, along with local influenza surveillance data on the level of influenza activity in the community and thus the likelihood that an individual has influenza, are critical to inform clinical decision-making. Recently, rapid molecular assays with high accuracy have become available for use in outpatient settings .
Since no randomized controlled efficacy trials of NAI antiviral drugs versus placebo for treatment of hospitalized influenza patients exist, assessment of available data on the “real-world” effectiveness of oseltamivir treatment from observational studies is relevant and appropriate, despite the well-recognized inherent limitations of observational data. A recent review assessed the strengths and limitations of a variety of study designs and concluded that different study designs can provide “actionable data that are sufficient for clinical and public health action” to inform health decision-making . Furthermore, a Cochrane review found “little evidence for significant effect estimate differences between observational studies and RCTs, regardless of specific observational study design, heterogeneity, or inclusion of studies of pharmacological interventions” . Just as the quality of RCTs may vary, observational studies that have attempted to reduce biases and confounding are better than studies that did not.
Ebell also did not mention a very large meta-analysis of individual patient-level data from more than 29,000 hospitalized patients (86% with laboratory-confirmed influenza, 14% clinically diagnosed with influenza) from 38 countries that reported survival benefit of NAI treatment (primarily oseltamivir) in adults compared with no treatment, with significantly greater survival benefit with early (within 2 days of illness onset) compared with later initiation (>2 days after onset) of NAI treatment . NAI treatment (including started >2 days after onset) versus no treatment also had significant survival benefit in critically ill adults and in pregnant women . In response to concerns raised after publication, the authors performed additional analyses utilizing other methodologies to address different biases and suggested that the association of NAI treatment with survival benefit remained . This study, together with the Cochrane review and the review by Dobson et al were recently reviewed by the European Centre for Disease Prevention and Control and an assembled independent expert group in order to form a balanced expert opinion of available data on the effectiveness of NAIs . They concluded that “available evidence provides support for the use of NAIs as prophylaxis and treatment and thus they can be considered a reasonable public health measure during seasonal influenza outbreaks, pandemics and zoonotic outbreaks caused by susceptible influenza” .
Clinicians managing influenza patients should consider whether the potential benefits of oseltamivir treatment outweigh any possible adverse effects. Ebell referred to oseltamivir adverse effects of nausea, vomiting and “psychiatric events” identified by the Cochrane review. However, it is notable that in their meta-analysis of RCTs in adults, Dobson et al did not find any effect on neurological or psychiatric disorders or serious adverse events . Furthermore, it is well-established that there is a wide spectrum of neurologic complications associated with influenza virus infection of the respiratory tract [15-17]. Dobson et al and others have reported an increased risk of nausea and vomiting with oseltamivir treatment versus placebo. In the Cochrane review, the risk difference identified in adults treated with oseltamivir versus placebo was 3.66% for nausea, and 4.56% for vomiting [3,8]. Such risks seem low and should be weighed against the fact that influenza results in direct medical and opportunity costs from staying home from school or work. The burden of severe disease is high, particularly in the elderly and those with underlying chronic co-morbidities, and for persons with severe disease, the risks of gastrointestinal symptoms are unlikely to be relevant.
The purported “psychiatric events” identified by the Cochrane review were not statistically significant in recipients of oseltamivir treatment compared with placebo. The only significant finding of “psychiatric events” was not during exposure to oseltamivir for treatment (twice daily dosing) or chemoprophylaxis (once daily dosing), but late events after the drug was no longer being taken - only in a small number of participants who had received chemoprophylaxis when the observation period was extended to days when no drug was received (off drug periods) [3,8]. Additionally, a large administrative database study of outpatients with clinically diagnosed or laboratory-confirmed influenza found no evidence of an increased risk of neuropsychiatric or other adverse events with oseltamivir treatment compared with no treatment . It should also be noted that a large multinational European registry of pregnant women who received NAIs (oseltamivir or zanamivir) during pregnancy found no increased risks of adverse neonatal outcomes or congenital malformations compared with infants without NAI exposure in utero . This is particularly important for clinicians to understand because influenza virus infection of pregnant women can result in severe disease.
It is indisputable that seasonal influenza epidemics cause substantial public health impact in terms of medical visits, hospitalizations, and deaths worldwide. During 2002-2008, an estimated 40,880-160,270 influenza-associated deaths occurred in 35 Latin American countries . During 2010-2015, the CDC estimated that 140,000-710,000 hospitalizations and 12,000-56,000 deaths were associated with influenza each year in the U.S. . Early estimates suggest that in 19 European countries at least 137 excess deaths per 100 000 population were attributable to influenza during the 2016-17 season .
While more effective influenza vaccines are needed to prevent influenza, especially in the elderly where disease burden is high, we also need much better therapies with different mechanisms of action than oseltamivir and other NAIs. In addition, the world needs to be much better prepared for the next influenza pandemic that could be much more severe than the 2009 H1N1 pandemic. Currently, avian influenza A(H7N9) virus poses the highest pandemic threat . Ebell mentions the issue of antiviral stockpiling for pandemic preparedness. The controversies in the interpretation of data on oseltamivir use for seasonal and pandemic influenza have been summarized well by Hurt and Kelly; they also highlighted the use of NAIs to control the impact of the 2009 H1N1 pandemic in Japan that was facilitated by the wide availability and access of NAIs for treatment of seasonal influenza . In the U.S., an annual review is conducted of available drugs for potential stockpiling for pandemic preparedness. In Europe, 27 of 28 countries with publicly available pandemic preparedness plans specifically include antiviral policy as part of the plans . A major gap is that no new drugs other than NAIs (zanamivir, peramivir) have been approved for treatment of influenza in the U.S. or the European Union since oseltamivir was approved in 1999. Until new therapies with different mechanisms of action are available, antiviral treatment of influenza patients worldwide will be based upon initiation of NAI treatment, including oseltamivir, as soon as possible, in addition to supportive management of the wide range of complications associated with influenza, and adherence to recommended infection prevention and control measures.
We agree with Ebell that data from “all trials be published, and that individual patient data be made available for independent re-analysis.” We also urge clinicians, public health colleagues, and decision-makers to understand all of the issues and details of the findings of the antiviral treatment studies (RCTs and observational studies), and to focus on outcomes for patients with laboratory-confirmed influenza. The U.S. Centers for Disease Control and Prevention, the European Centre for Disease Prevention and Control, Public Health England, the World Health Organization, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, the American Academy of Pediatrics, and the American College of Obstetricians and Gynecologists, all continue to recommend use of neuraminidase inhibitor antiviral drugs as soon as possible for influenza patients who are most likely to benefit from them: persons with suspected or confirmed influenza who have severe or progressive disease, are hospitalized, or are at high risk of complications from influenza.
Timothy Uyeki MD, MPH, MPP, Centers for Disease Control and Prevention
Pasi Penttinen MD, PhD, MPH, Mike Catchpole MB, European Centre for Disease Prevention and Control
Richard Pebody, MBChB, PhD, Maria Zambon PhD, FRCPath, F Med Sci, Jake Dunning MBBS, MRCP, PhD, Public Health England
John Watson MB BS, MSc, FRCP, FFPH, Department of Health, U.K.
Henry (Hank) Bernstein DO, MHCM, Flor M. Munoz MD, MSc, David W. Kimberlin MD, American Academy of Pediatrics
Richard Beigi MD, MSc, Laura E. Riley MD, American College of Obstetrics and Gynecology
Andy Pavia MD, William Powderly MD, Infectious Diseases Society of America
Paul Spearman MD, Pediatric Infectious Diseases Society
Nikki Shindo MD, PhD, World Health Organization, Geneva, Switzerland
Disclaimer: The views expressed are those of the authors and do not necessarily represent the official policy of the Centers for Disease Control and Prevention.
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Competing interests: None of the co-authors has any competing financial interests to declare with respect to oseltamivir or the content of our response. As stated in our response, all co-authors are representatives of organizations that provide recommendations for antiviral treatment of influenza or are supportive of such recommendations. Timothy M. Uyeki (on behalf of all co-authors) October 10, 2017
There is another way we must look at this problem. Taking the example of the Nicholson et al (2000) trial quoted in the article - "Duration of illness was significantly shorter by 29 h" - What was the lower limit of 95% CI for this difference? These results were not provided by the authors, but by looking at their results, we can say that the lower limit would be close to one hour! Even if statistically significant, this difference is not of major consequence.
We have argued that in superiority trials, like the one above, we should have a "superiorlty margin" like the inferiority trials (Shafiq N, Malhotra S. Superiority trials: raising the bar of null hypothesis statistical testing. Evid Based Med. 2015 Oct;20(5):154-5) and shown how small effect sizes are published as statistically significant findings even in the best of journals (Shafiq N, Malhotra S. Superiority trials: statistical trickery or mass blindness? Postgrad Med J. 2016 Feb;92(1084):118-9).
The meta-analysis quoted in the article (Jefferson et al, 2009) clearly shows what we are trying to point out - "The hazard ratios for time to alleviation of influenza-like illness symptoms were in favour of treatment: 1.20 (95% confidence interval 1.06 to 1.35) for oseltamivir". The lower limit of 1.06 for the hazard ratio is so close to 1.0, the level of no difference, that it is meaningless to give importance to such findings.
Therefore, even for the endpoint on which oseltamivir had some efficacy (duration of symptoms), the small effect size made the results clinically not too important.
Competing interests: No competing interests
Re: WHO downgrades status of oseltamivir. And we are happy that all is well in the World of Medicine?
Prof Ebell mentions deliberately withheld data.
The cost to the public purses is rather more than peanuts.
I do not blame the manufacturers at all - their job is to earn money, whatever the currency, whatever the cost to the innocent public.
1. A fraud has been perpetrated by one or more individuals.
2. Some individuals have been grossly negligent in their duties.
3. There is no evidence that anyone anywhere is investigating the crimes.
4. There is no evidence that any professional body has investigated any individual for either negligence or deliberate unethical actions.
Am I alone in wondering why there has been a collective hush in all the governments who look after PUBLIC MONEY and PUBLIC HEALTH?
Competing interests: No competing interests
Antiviral Agents For Influenza
At present vaccinations are the only preventive measures useful to prevent influenza . Influenza antiviral agents are an important adjunct to vaccinations.
The recommendations for using influenza antiviral medications are based on data from the randomized clinical trials as well as from observational studies of patients receiving treatment in practice. Early antiviral treatment in people with influenza can lessen the illness severity, shorten time of illness, and reduce the serious Influenza related complications such as pneumonia in outpatients and death in hospitalized patients.
There are three antiviral agents recommended for the treatment of influenza, they are oral oseltamivir, inhaled zanamivir, and intravenous peramivir. These neuraminidase inhibitors are chemically related and have activity against both influenza A and B viruses. Generic oseltamivir was approved by the US Food and Drug Administration (FDA) in August 2016 .
To treat influenza, oral oseltamivir and inhaled zanamivir are usually prescribed for 5 days, although hospitalized patients may receive treatment for longer. Intravenous peramivir is administered in a single infusion over 15-30 minutes. Peramivir is approved for treatment in adults, zanamivir for treatment of children 7 years or older, and oseltamivir for treatment even in infants.
Resistance to the circulating influenza viruses to any of the neuraminidase inhibitor antiviral agent is low at present.
Still more randomised control studies are required to confirm the effectiveness of antivirals in influenza viral infections
Competing interests: No competing interests
In practice it seemed useless at ameliorating flu severity or duration
Some people had significant adverse reactions
'Swine flu' with hindsight was no worse than 'ordinary flu' as per epidemic a few years prior.
Secondary infections in vulnerable more appropriately treated with antibiotics than relying on tamiflu
Again in hindsight a huge fuss over nothing and waste of money
Competing interests: No competing interests
“Man is so intelligent that he feels impelled to invent theories to account for what happens in the world. Unfortunately, he is not quite intelligent enough, in most cases, to find correct explanations. So that when he acts on his theories, he behaves very often like a lunatic.”
― Aldous Huxley
The global scare of a pandemic was an opportunity. It smoothly allowed a poorly studied research molecule into getting regulatory clearance in record-breaking style. No one since then has had the courage to revisit this mistake and make necessary corrections to disallow a dangerous precedence taking shape.
The sanctity of a well designed Randomised Controlled trial lies in the selection of a clinically valid outcome that truly represents a clinical need. How is it that evidence from a trial that just had the reduction in subjective "symptoms" for an arbitrary figure of "30 hours" become clinical evidence to get regulatory clearance and be permitted sales across the globe?
Regulatory processes need to give due credit to scientific research methodology that attempts at bringing out true pragmatic evidence for a treatment benefit. It SHOULD NOT just look for compliance with Good Clinical Practices and Good Manufacturing Practices; both creation of a dangerous pharma - policy maker - regulatory nexus.
Competing interests: No competing interests
Reminiscent of the Dutch tulip bulb frenzy. Don't forget how much money Canada wasted and may continue to waste on inefficient use of influenza vaccines. But at least it increased GDP substantially.
The most important costs are probably the lost opportunities to affect social determinants of health for people in poverty: housing, clean water, reasonable nutrition. It takes a lot of courage for elected representatives to ask the hard questions, even in the secrecy of a Cabinet meeting or the innermost counsels of governments. What about a new BMJ award for the rare ones who do?
Tom Perry MD
Competing interests: No competing interests
It is interesting to note that for a product with “$18bn in sales worldwide, half of it from governments stockpiling the drug”, in a disease that affects children, Roche has not yet completed the paediatric investigation plan, according to EMA records (http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/pips/EMEA-00...). This is after almost 8 years from the first agreement of the plan, during which Roche requested eight procedures of modification of the plan itself (http://www.ema.europa.eu/docs/en_GB/document_library/PIP_decision/WC5002...).
Competing interests: No competing interests