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December 2015

Treating Influenza With Neuraminidase Inhibitors: What Is the Evidence?

Author Affiliations
  • 1Division of Infectious Diseases, Department of Medicine, University of California, San Francisco
  • 2Division of Infectious Diseases, Department of Medicine, San Francisco VA Health Care System, University of California, San Francisco
JAMA Intern Med. 2015;175(12):1899-1900. doi:10.1001/jamainternmed.2015.5747

The approaching influenza season will likely bring renewed debate about the usefulness of the neuraminidase inhibitors, a class of antiviral drugs approved for the chemoprophylaxis and treatment of influenza. The available approved formulations include oral oseltamivir (Tamiflu; Roche Pharmaceuticals), inhaled zanamivir (Relenza; GlaxoSmithKline), and intravenous peramivir (Rapivab; BioCryst Pharmaceuticals). All 3 drugs are perceived to have comparable efficacy, although because of its ease of administration, oseltamivir has been the best studied and is the most aggressively marketed and prescribed neuraminidase inhibitor in the United States and worldwide.

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    2 Comments for this article
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    Concerns about this article
    Peter Doshi, Tom Jeferson | University of Maryland School of Pharmacy
    Dear editor, we are writing with concerns about what we think are inaccurate and misleading statements in the Viewpoint on influenza antivirals by Louie and Lampiris (Louie 2015). We summarize our concerns below.

    Louie and Lampiris define “high risk” populations as including young children and the elderly, and state that randomized controlled trials (RCTs) have not been carried out in high-risk populations. This is false. Multiple RCTs analyzed in our Cochrane review (Jefferson 2014) were in such populations (e.g. trials WV15708, WV15825, WV15758, and WV15759/WV15871). In addition, elderly patients participated in trials such as M76001.
    Based on RCTs alone, Roche wrote in 2003 that oseltamivir treatment reduces complications and hospitalizations in “at-risk” adults (Kaiser 2003).

    Louie and Lampiris describe a Roche funded study published in 2015. They note: “Of the four authors, one reported receiving fees from Roche and another company outside the submitted work, and another reported receiving travel funding from Roche.” This is incomplete. In fact, not two but all four authors have financial conflicts of interest. One author (RJW) does not inform readers that Gilead Sciences is the patent holder for oseltamivir; another (JD) declares \"no competing interests” but her salary was supported by Roche while she carried out the analysis; a third (SP) declares “no competing interests” but Stuart Pocock told The BMJ (Lenzer 2015) that he received research funds from Gilead and Genentech. These facts have been documented for months in the following places:


    http://www.cebm.net/dobson-lancet-tamiflu-re-analysis-independent-review-group-really/
    http://blogs.bmj.com/bmj/2015/02/05/paul-roblin-on-dobson-et-als-lancet-tamiflu-re-analysis-independent-review-group-really/
    http://www.bmj.com/content/350/bmj.h658.full
    http://www.healthnewsreview.org/2015/02/conflicting-study-reports-tamiflu-and-unquestioning-news-reporting/

    Louie and Lampiris write, “The overall conclusions of the 2006 and 2014 Cochrane studies were very similar.” This is obviously a subjective characterization and open to debate, but it does not follow from the previous paragraph in which the authors stated that the 2006 Cochrane review found oseltamivir prevented lower respiratory tract infections and the 2014 Cochrane review found no benefit for prevention of pneumonia. They write: “In 2006, the reasons to treat patients with oseltamivir were bolstered when a Cochrane Collaboration meta-analysis concluded that early treatment also prevented lower respiratory tract infections … [In 2014,] No benefit was found for the prevention of pneumonia, but the studies were not designed for this outcome (for example, the definitions of pneumonia did not include radiographic confirmation).”

    Louie and Lampiris focus entirely on the evidence base for potential benefit. They do not discuss potential harms. Presenting one side of the story (benefits) does not support evidence based decision making.

    Louie’s and Lampiris’s characterization of our 2014 review as “very similar” to our 2006 review suggests we did not identify new evidence. However we have shown the effect of oseltamivir on antibody production, on the renal and neuropsychiatric systems and its lack of efficacy in children with asthma and the frail elderly. The manufacturer’s use of a ghost writer to develop oseltamivir papers was also undocumented until 2009. In 2014, we also documented the lack of convincing evidence on interruption of transmission as well as extensive publication and reporting bias in oseltamivir trials which continues to this day. None of these were identified in our 2006 review.

    Louie and Lampiris describe Kaiser et al. as a “manufacturer-sponsored meta-analysis of 10 studies,” but it was a pooled analysis. It was also co-authored by the manufacturer, not only sponsored (Kaiser 2003).

    Louie and Lampiris write, “Many of these [observational] studies have shown that morbidity and mortality are reduced in hospitalized and critically ill patients, and that the ‘window of benefit’ for starting treatment is significantly longer than would have been anticipated from the RCTs performed in healthy outpatients.” They offer two citations. One is a Roche funded observational study, a fact they do not mention despite commenting on the funding of other studies. The other is not a study, but rather a CDC webpage containing information for clinicians about influenza antivirals.

    Louie and Lampiris write, “However, the [2014] Cochrane findings are difficult to interpret with regard to treating patients with severe illness who are hospitalized or patients infected with novel influenza strains.” We agree that the randomized trials were not in hospitalized patients, but the presumption that the trials do not provide evidence for how the drugs will work in treating novel influenza strains requires justification as it goes against the drug’s mechanism of action and regulation. Neuraminidase inhibitors work on neuraminidase. Trial populations were infected with influenza A/H3N2 and A/H1N1, as well as influenza B. All epidemics and pandemics of influenza have been associated with these neuraminidase subtypes of influenza A (A/H1N1 in 1918 “Spanish flu”, A/H2N2 in 1957 “Asian flu”, A/H3N2 in 1968 “Hong Kong flu”). Furthermore, the FDA and other regulators approved the drugs for treatment and prophylaxis of influenza A and B. The approval is not limited to certain subtypes or strains.

    We also note that Louie is a frequent co-author with the CDC on papers about the management of influenza. We would like understand why that was not reported as a conflict of interest.


    Peter Doshi
    Assistant professor
    University of Maryland School of Pharmacy
    Baltimore, MD 21201

    Tom Jefferson
    Honorary Research Fellow
    Centre for Evidence Based Medicine
    Oxford OX2 6GG
    United Kingdom

    References

    Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD008965 DOI: 10.1002/14651858.CD008965.pub4.

    Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med. 2003 Jul 28;163(14):1667–72.

    Lenzer J. Why aren’t the US Centers for Disease Control and Food and Drug Administration speaking with one voice on flu? BMJ. 2015 Feb 5;350:h658.

    Louie JK, Lampiris H. Treating Influenza With Neuraminidase Inhibitors: What Is the Evidence? JAMA Internal Medicine. 2015 Oct 19;1. DOI:10.1001/jamainternmed.2015.5747
    CONFLICT OF INTEREST: PD and TJ were co-recipients of a UK National Institute for Health Research grant (HTA – 10/80/01 Update and amalgamation of two Cochrane Reviews: neuraminidase inhibitors for preventing and treating influenza in healthy adults and children—http://www.nets.nihr.ac.uk/projects/hta/108001), the 2014 Cochrane review mentioned above.  TJ was a co-author of the 2006 review.  In addition: PD received €1500 from the European Respiratory Society in support of his travel to the society’s September 2012 annual congress in Vienna, where he gave an invited talk on oseltamivir. PD gratefully acknowledges the American Association of Colleges of Pharmacy for its funding support ($10,000) for a study to analyze written medical information regarding the possible harms of statins.  TJ receives royalties from his books published by Blackwells and Il Pensiero Scientifico Editore, Rome. TJ is occasionally interviewed by market research companies for anonymous interviews about Phase 1 or 2 pharmaceutical products. In 2011-2013, TJ acted as an expert witness in a litigation case related to oseltamivir phosphate; Tamiflu [Roche] and in a labour case on influenza vaccines in healthcare workers in Canada. In 1997-99 TJ acted as a consultant for Roche, in 2001-2 for GSK, and in 2003 for Sanofi-Synthelabo for pleconaril (an anti-rhinoviral, which did not get approval from the Food and Drug Administration). TJ was a consultant for IMS Health in 2013, and in 2014 was retained as a scientific adviser to a legal team acting on the drug Tamiflu (oseltamivir, Roche). In 2014-15 TJ was a member of two advisory boards for Boerhinger and is in receipt of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews. TJ has a potential financial conflict of interest in the investigation of the drug oseltamivir. TJ is acting as an expert witness in a legal case involving the drug oseltamivir (Roche). TJ is a member of an Independent Data Monitoring Committee for a Sanofi Pasteur clinical trial. None of the organizations mentioned above had any involvement with this letter.
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    The devil is in the details - A closer examination of the evidence surrounding oseltamivir in treating influenza
    Martin Mayer | Clinical Assistant Professor, Department of Physician Assistant Studies, College of Allied Health Sciences, East Carolina University, Greenville, NC 27858
    Dear Editor:

    Several aspects of Louie and Lampiris’ discussion of the evidence surrounding neuraminidase inhibitors in treating influenza[1] require attention.

    They do not mention the Cochrane review on oseltamivir[2,3] actually reviewed not just “summary data from the RCTs”[1] (suggesting typical meta-analysis), but the actual clinical study reports (CSRs) from Roche, which were only made available after years of Roche unacceptably delaying access.[2-4] (See also the correspondence with Roche: http://www.bmj.com/tamiflu/roche and The BMJ’s “Tamiflu timeline”: http://goo.gl/UaLByd.) Additionally, the Cochrane review authors requested individual patient data (IPD), but Roche never supplied this in a format permitting meaningful use despite the authors’ follow-up correspondence;
    while the appendices of the CSRs contained printed tables of patient-level data, this is not a realistic format for meaningful use, and Roche has supplied electronic IPD (which is realistically-useable) to other researchers, so it remains unclear why the same was not done for the Cochrane review authors (see the “Rapid Responses” to the abridged version of the Cochrane review published in The BMJ,[3] as well as the aforementioned Roche correspondence).

    Louie and Lampiris also say the Lancet individual-patient-data meta-analysis (IPDMA)[5] provides evidence “in contrast to the findings of the Cochrane meta-analysis,”[1] but they do not discuss these meta-analyses in sufficient detail (and although space limitations often require curtailing detailed examinations, it seems inappropriate and misleading to present these meta-analyses in the manner they did). Among patients with confirmed influenza infection (PWCIIs) in the Lancet IPDMA, 27 would have to be treated with oseltamivir to prevent one lower respiratory tract complication (LRTC) “requiring” antibiotics (number needed to treat to benefit [NNTB], 27; 95% CI, 20 to 46; absolute risk difference [ARD], 3.83%; 95% CI, 2.18% to 5.05%; risk ratio [RR], 0.56; 95% CI, 0.42 to 0.75; P = 0.0001). However, 81.71% of the events in this outcome were cases of acute bronchitis, a condition where antibiotics are not indicated unless the cause is Bordetella pertussis (which is relatively uncommon and not addressed in the IPDMA). Also reported was a lower rate of pneumonia in PWCIIs receiving oseltamivir (NNTB, 101; 95% CI, 75 to 376; ARD, 1.00%; 95% CI, 0.27% to 1.35%; RR, 0.40; 95% CI, 0.19 to 0.84; P = 0.015), but cases were based only on “participant report and the investigator’s clinical judgment” without radiographic confirmation.[5,p1731] In fact, all lower respiratory tract complications were based solely on participant report and the investigator’s clinical judgment. Additionally reported was a lower rate of hospitalization in PWCIIs receiving oseltamivir (NNTB, 94; 95% CI, 72 to 312; ARD, 1.06%; 95% CI, 0.32% to 1.40%; RR, 0.37; 95% CI, 0.17 to 0.81; P = 0.013), but the reasons for hospitalization were reportedly too varied to detect any pattern.[5]

    However, as the Cochrane reviewers note, analysis limited to PWCIIs is likely problematic, introducing bias (from demonstrated imbalances in the treatment groups when analyzing only PWCIIs) and potentially limiting generalizability (from variable availability of influenza tests, which themselves can suffer from variable accuracy).[2,3] What, then, of the full intention-to-treat (ITT) population in the Lancet IPDMA? For prevention of LRTCs “requiring” antibiotics, the NNTB in the full ITT population was 34 (95% CI, 25 to 61; ARD, 2.98%; 95% CI, 1.65% to 4.00%; RR, 0.62; 95% CI, 0.49 to 0.79; P = 0.0001), but here as well, 79.76% of the outcomes were cases of acute bronchitis. The NNTB for prevention of pneumonia in the full ITT population – with the same aforementioned limitations surrounding diagnosis – was 89 (95% CI, 72 to 163; ARD, 1.13%; 95% CI, 0.62% to 1.40%; RR, 0.34; 95% CI, 0.18 to 0.64; P = 0.0009). Rates of hospitalization were not statistically significantly different between oseltamivir and placebo recipients in the ITT population.

    Although IPDMA is indeed a powerful analytical modality preferable to meta-analyzing summary metrics when all other things are equal, the Lancet IPDMA only shows small and uncertain effects,[5] is lacking in transparency and thoroughness compared to the Cochrane review with respect to methodology/protocol,[2,3,5] and includes analyses with potential bias or limited generalizability due to being limited to PWCIIs.[2,3] Additionally, although Louie and Lampiris note some of the financial conflicts of interest of the Lancet IPDMA authors, they do not note one of the authors is on the Board of Directors of Gilead Sciences (which holds the patent on oseltamivir, which is not disclosed in the Lancet IPDMA).[5]

    As previously noted, the Cochrane review was not based on individual patient data, but the authors asked for such. Despite not having realistically-usable IPD, the Cochrane review had more transparent and thorough methods/protocols. The Cochrane review authors analyzed the ITT population due to the aforementioned issues in limiting analysis to PWCIIs, and in their ITT analysis, no benefit on hospitalization or other complications was noted. The NNTB for prevention of pneumonia – again with the same limitations in case definition as in the Lancet IPDMA – was 100 (95% CI, 67 to 451; ARD, 1.00%; 95% CI, 0.22% to 1.49%; RR, 0.55; 95% CI, 0.33 to 0.90; P = 0.017); additionally, in an analysis limited to more detailed documentation of pneumonia (which had considerably less overall data, and which still did not utilize radiography to confirm the diagnosis), no statistically significant benefit was found for preventing pneumonia.[2]

    Thus, Louie and Lampiris’ characterization of the Lancet IPDMA as providing findings in contrast to the Cochrane meta-analysis with respect to lower respiratory tract infections and hospitalizations is not incorrect per se, but such a characterization is definitely misleadingly oversimplified and does not do the topic justice. They do not discuss important particulars of the findings, and in the same sentence where they suggest contrasting findings, Louie and Lampiris also make note of the Lancet meta-analysis being based on IPD and the Cochrane meta-analysis not being based on IPD, which may be interpreted by some as a suggestion of superiority of the Lancet IPDMA. In the end, providers will have to choose which review they feel is more reliable and what the overall data really show when considered carefully, but IPDMA does not in and of itself render an analysis better or more reliable (analogously, it would be imprudent to purchase one car over another based solely on the fact that one has a nicer coat of paint).

    Lastly, rather contrary to their suggestion of ethical concerns, the degree of relative clinical equipoise Louie and Lampiris admit to when considering high-risk and hospitalized patients (“the evidence to treat high-risk or hospitalized patients is inadequate and does not meet the highest level of evidence”)[1] is precisely what justifies conducting trials in these populations. It would seem entirely possible to conduct trials of sufficient power in these populations given the burden of influenza, and in the setting of such clinical equipoise brought about by limitations in the available data, the CDC and WHO endorsing utilization in high-risk and hospitalized patients neither obviates the need for further study nor introduces ethical concerns for pursuing such (and to suggest otherwise seems to rely on argumentum ad verecundiam). Indeed, although there are some trial data on the treatment of children and prophylaxis in the elderly (which are covered in the Cochrane review), one could readily argue what truly introduces ethical concerns is continuing to ignore limitations in the data surrounding high-risk and hospitalized patients.

    With best regards,

    Martin Mayer
    Clinical Assistant Professor
    Department of Physician Assistant Studies
    College of Allied Health Sciences
    East Carolina University
    Greenville, NC 27858 

    References:
    1. Louie JK, Lampiris H. Treating influenza with neuraminidase inhibitors: What is the evidence? JAMA Int Med. Published Online: October 19, 2015. doi:10.1001/jamainternmed.2015.5747.
    2. 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 Apr 10;4:CD008965. doi: 10.1002/14651858.CD008965.pub4.
    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 Apr 9;348:g2545. doi: 10.1136/bmj.g2545.
    4. Payne D. Tamiflu: The battle for secret drug data. BMJ. 2012;345:e7303. doi: 10.1136/bmj.e7303.
    5. Dobson J, Whitley RJ, Pocock S, Monto AS. Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials. Lancet. 2015 May 2;385(9979):1729-37. doi: 10.1016/S0140-6736(14)62449-1. Epub 2015 Jan 30.
    CONFLICT OF INTEREST: I am a member of the U.S. Board of BMJ Fellows. I do not receive any compensation from The BMJ or anyone else as a result of this. I disclose this here since I cite works published in The BMJ and activities of The BMJ pertaining to the controversy surrounding oseltamivir.
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