The antiviral drug Oseltamivir is very effective in treating uncomplicated cases associated with influenza A and influenza B viruses.[1] The drug can be used for the treatment of both adults and paediatric patients along with newborn babies and neonates less than 2 weeks old. Oseltamivir has been recommended as the drug of choice for the prophylactic treatment of influenza within 48 hours of the onset of symptoms in an infected person with significant comorbidities. However, Oseltamivir prophylaxis is recommended only for patients older than 1 year of age.
The World Health Organisation (WHO) and the Centers for Disease Control and Prevention (CDC) strongly recommend the use of Oseltamivir for the treatment and prophylaxis of disease resulting from avian influenza virus strains, including avian influenza A (H5N1).
Oseltamivir can be used for empirical treatment without confirmation of the disease and within 48 hours of the initiation of symptoms. This has been shown to reduce the duration of influenza in healthy people and hospitalised patients within 4-5 days of onset of symptoms. Oseltamivir is usually well-tolerated; however, the drug can produce certain adverse side effects like vomiting, nausea, abdominal pain, diarrhoea, insomnia, and vertigo in some cases.
Whereas the flu is self-limiting, the FDA’s capacity for bad decisions is not…
The recent decision by the FDA to approve the use of the antiviral drug Tamiflu for treating influenza in infants as young as two weeks old, belies an underlying trajectory within our regulatory agencies towards sheer insanity.
Tamiflu, known generically as oseltamivir, has already drawn international concern over its link with suicide deaths in children given the drug after its approval in 1999. In fact, in 2004, the Japanese pharmaceutical company Chugai added “abnormal behavior” as a possible side effect inside Tamiflu’s package. The FDA also acknowledged in its April, 2012 “Pediatric Postmarket Adverse Event Review” of Tamiflu that “abnormal behavior, delirium, including symptoms such as hallucinations, agitation, anxiety, altered level of consciousness, confusion, nightmares, delusions” are possible side effects.[i]
Recent animal research on Tamiflu has found that the infant brain absorbs the drug more readily than the adult brain,[ii][iii]lending a possible explanation for why neuropsychiatric side effects have been observed disproportionately in younger patients.
The very mechanism of Tamiflu’s anti-influenza action may hold the key to its well-known neurotoxicity. Known as a neuromindase inhibitor, the drug inhibits the key enzyme within the flu virus that enables it to enter through the membrane of the host cell. So fundamental is this enzyme that viruses are named after this antigenic characteristic. For instance, the “N” in H1N1 flu virus is named for type 1 viral neuromindase.
Mammals, however, also have neurimindase enzymes, known as ‘sialidase homologs,’ with four variations identified within the human genome so far; NEU1,NEU2,NEU3 and NUE4. These enzymes are important for neurological health. For example, the enzyme encoded by NEU3, is indispensable for the modulation of the ganglioside content of the lipid bilayer, which is found predominantly in the nervous system and constitutes 6% of all phospholipids in the brain.
It is therefore likely that neurimindase-targeted drugs like Tamiflu are simply not selective enough to inhibit only the enzymes associated with influenza viral infectivity. They likely also cross-react with those off-target neurimindase enzymes associated with proper neurological function within the host. This “cross reactivity” with self-structures may also explain why the offspring of pregnant women given Tamiflu have significantly elevated risk of birth defects (10.6%) relative to background rates (2-3%), according to a 2009 safety review by the European Medicines Agency.
Beyond the recognition of Tamiflu’s intrinsic toxicity, there are two additional problems with the use Tamiflu in infants:
Infants do not yet have a sufficiently developed blood-brain barrier capable of keeping the chemical out of their rapidly developing brains
Their detoxification systems are not sufficiently developed to remove the chemical rapidly enough to prevent harm
The FDA’s decision to include infants under one as treatable with Tamiflu is all the more disturbing when you consider that a 2010 study published in The Pediatric Infectious Disease Journal found that of 157 evaluable infants (mean age 6.3 months) treated for influenza with Tamiflu, complications due to the medication were found in the majority (54%) of the treated group.
According to the study
Complications were recorded in 84 patients (54%), the most serious of which were meningitis in 1 infant (1%), pneumonia in 9 (6%), and otitis media in 2 (1%).
Are meningitis, pneumonia and otitis media (ear infection) acceptable risks for treating influenza? Apparently for the FDA, it is.
How about death? Is that an acceptable risk of Tamiflu treatment for flu, a self-limiting disease?
These data suggest Tamiflu use could induce sudden deterioration leading to death especially within 12 hours of prescription. These findings are consistent with sudden deaths observed in a series of animal toxicity studies, several reported case series and the results of prospective cohort studies. From “the precautionary principle” the potential harm of Tamiflu should be taken into account and further detailed studies should be conducted.
So, how did the FDA justify its decision to consider Tamiflu safe in infants under one year? Did it use controlled, randomized, placebo-controlled trials to ascertain safety? Of course not. Testing drugs on infants is unethical, and no parent in their right mind would enroll their newborn in such a trial. Lacking definitive evidence of safety, the FDA’s expanded approval in children younger than one year was based on extrapolation of data from previous results in adults and older children.[iv] This, of course, is inappropriate as it denies the aforementioned differences in the susceptibility to drug toxicity and neurotoxicity between infants and older individuals. It also avoids proper consideration of the studies in the biomedical literature indicating its potential for severe, if not life-threatening toxicity to infants, children and adults alike.
Another concern, not addressed in the FDA announcement, is that as of Dec. 15th, 2010, the World Health Organization has acknowledged that, based on over 300 tested worldwide samples of the 2009 pandemic H1N1 flu, resistance to Tamiflu is growing.[v] Therefore, treating an infant with Tamiflu-resistant influenza would not only do nothing to combat the infection, but would poison that child and further disable their natural immune response.
The clear winner in the FDA’s decision will be the bottom line of Roche, the manufacturer of this patented chemical. How much longer can the FDA continue to expect those subject to its regulatory decisions to maintain the illusion that it is interested in the public welfare?
We must remember that infants do not get sick from the flu as a result of Tamiflu deficiency, or flu vaccine deficiency for that matter. They do get sick from the immune-disrupting effects of synthetic chemicals completely foreign to human physiology (such as Tamiflu), and lack of vital hormone modulating compounds that result from adequate sunlight exposure (vitamin D3), and good nutrition.
[i] Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology, Pediatric Postmarket Adverse Event Review on Tamiflu, April, 2012.
It’s a particularly nasty flu season, right – what should we do??
Last week, a student in my daughter’s elementary school died. An apparently healthy, active, and vital 10-year old child suddenly departed. Despite an initial announcement of “cause unknown,” the administrators followed up with a suddenly clear pronouncement that he died “from the flu.” Looking beyond the fact that now even school administrators feel entitled to give clinical advice (“if you haven’t yet received your flu shot, please do”), I was interested to see that this child’s flu vaccine status was not mentioned. I wondered if he had received the flu shot or taken Tamiflu – especially since both have been associated with sudden death in the pediatric population. 1
It’s a “deadly” flu season, and the pharmaceutically-funded media would have you believe that you must head on over to CVS and get your flu shot to make it through the year. And if the flu shot doesn’t work – even the CDC estimates its effectiveness around 39%2 – well then, just head to your doctor and get treated with Tamiflu!
But is it really that simple? Is it possible that we are bumping up against the glass ceiling of the Simple Solution for Sickness? Many of us are rolling our eyes at the “10% off your shopping order!” flu shot incentives, and our sniffles don’t send us running to the doctor for antibiotics “just in case.” As our own memories tell a different story from the scary stories on TV (wait…the chicken pox and the flu are deadly? Mom, Dad…didn’t you both have Measles and live to tell the tale?), we are becoming less and less susceptible to fabricated lore. We are harder to scare into action. We are beginning to accept that the magic pill is a fantasy, and that this crisis of confidence in our medical system is no small hurdle to overcome. It is an initiation into a new belief system.
I believe that this initiation begins with information and understanding. This understanding leads to informed choices. These empowered choices lead to a new experience of trust in your bodyand in the natural world.
Let’s bring this back to earth with an example. Let’s look at the Simple Solution for the flu: Tamiflu.
Conventional medicine tells us that you can pull one thread of the spider web without impacting the whole design. So, is it possible that Tamiflu can enter your system, kill those nasty flu germs, and quietly exit without harming any innocents?
What is Tamiflu, and how does it work?
Tamiflu (oseltamivir) is prescription medication that is FDA-approved for anyone 2 weeks of age and older.3 It is designed to prevent the influenza virus from replicating and invading other cells. The pharmaceutical company that developed Tamiflu, Roche (also called Hoffmann–LaRoche), claims that Tamiflu can protect against getting the flu and reduce the severity of flu symptoms. Roche cites studies like a 1999 article in JAMA, in which authors write that Tamiflu “…provided significant antiviral, biochemical, and clinical effects in experimental human influenza virus infection. Prophylactic administration either once or twice daily completely protected against viral recovery in the upper respiratory tract and against infection-associated respiratory tract illness.” 4
Well that sounds good, right? In 1999, Roche presented this study, along with two clinical trials involving 1,358 patients,5 to an FDA committee of medical advisors – but the committee declined to approve Tamiflu due to a lack of convincing data.
Let’s dive a bit deeper to see if the data are indeed unconvincing (the full-text of this article is free!). This study involved 117 young adults (median age was 21), split into several groups that ranged from 11 to 64 subjects. Any scientist or statistician will immediately warn you that those group sizes (called sample sizes) are too small to draw statistically significant conclusions. With that in mind, let’s continue unpacking this study…
To measure the prophylactic effects of Tamiflu, researchers gave 12 people a placebo pill, and they gave 21 people various doses of Tamiflu before they stuck influenza virus into their noses. Flu-like symptoms were measured after viral inoculation, and people who had received Tamiflu were rated to exhibit lower symptom scores. From this experiment (based on a paltry 33 subjects), researchers concluded that Tamiflu indeed protects against getting the flu.
Next, to determine if Tamiflu reduced the severity of flu symptoms, researchers infected 80 people with the influenza virus (again in their noses). They gave Tamiflu to 56 people and a placebo to the rest. Then, researchers washed out people’s noses and measured the number of virus particles in their mucus. They reported that Tamiflu treatment reduced the number of viral copies in people’s nasal passages.
Quantifying the number of viral particles in people’s noses – after the flu virus was stuck into people’s noses – does not tell us anything about how the flu virus is spreading throughout the body. Anyway, for whatever reasons (you can use your imagination), FDA administrators overruled the medical expert committee’s suggestion and approved Tamiflu in October 1999. 6 But the FDA hedged a bit and required the drugmaker to issue the following statement:
“Tamiflu has not been proven to have a positive impact on the potential consequences (such as hospitalizations, mortality, or economic impact) of seasonal, avian, or pandemic influenza.” 7
Since its FDA approval, clinical trials touting the effectiveness of Tamiflu have been published – though a look at the authors and footnotes of these studies may give you pause. For example, Penelope Ward, MD has authored dozens of scientific studies that support Tamiflu,8 including the 1999 JAMA study we just deconstructed, a 2001 JAMA study with similar methods and conclusions,9 study of Tamiflu a mechanistic study of Tamiflu,10 and an oft-cited 1999 study in the New England Journal of Medicine (NEJM) entitled ‘Use of the Selective Oral Neuraminidase Inhibitor Oseltamivir to Prevent Influenza’ – and she served as the Head of Clinical Development for Hoffman-LaRoche.11 Actually, let’s look at the footnote of the 1999 NEJM study:12
Interesting…
Overall, it appears that all the studies that support the efficacy of Tamiflu are funded by the pharmaceutical companies that stand to profit from its sales.
Fortunately, a group of unbiased medical experts at the US Cochrane Center13 re-analyzed data from 20 clinical trials like these, reporting their results in a 2009 BMJ article. Their meta-analysis showed that there was no significant evidence that Tamiflu reduced influenza symptoms or complications – the only possible positive association was that Tamiflu might decrease the length of time people exhibited symptoms by a few hours.14 Further, the reanalysis found that Tamiflu increased nausea.
As an interesting aside, Cochrane Center researchers noted that it took years-long concerted efforts to obtain clinical data from drugmakers.15 Along these lines, investigative articles published in The Atlantic in 200916 and 201317 suggest that political and financial motivations (to the tune of billions of dollars) underpin this Tamiflu delusion.
So where does this leave us? Perhaps Tamiflu doesn’t work that well, but is there any harm in taking it anyway, just to be safe?
Is Tamiflu safe?
A 2007 scientific report18 suggests that Tamiflu is in fact exceedingly dangerous. In the 6 years that Tamiflu was marketed in Japan, the Japanese Ministry of Health Labour and Welfare received 1377 reports of adverse reactions. Approximately half of these reactions were serious neuropsychiatric cases, including delirium, convulsions, and encephalitis. Eighty deaths were reported, though only 71 were considered to be directly related to Tamiflu. Two of the most alarming deaths were suicides by 14-year-old teens on Tamiflu.19
As such, Japanese authorities advised against Tamiflu for adolescents, and the National Institute for Health and Clinical Excellence (the UK’s version of the FDA) recommends against Tamiflu as a preventative strategy in healthy people.20 Yet, American agencies like the CDC and FDA continue to push Tamiflu in spite of its documented side effects of hallucinations.21
Several recent news stories have highlighted these side effects of Tamiflu. For example, on January 15, 2018 a 6-year-old Texan girl took Tamiflu, hallucinated, and tried to jump out of a window22. About a week later, another Texan child, this time a two-year-old boy, suffered from hallucinations that caused him to repeatedly slap his mother.23
In a news article from January 24, 2018, the mother of a five-year-old girl who experienced severe hallucinations and seizure-like symptoms stated, “The flu is bad, it’s horrible, you feel helpless your child’s sick…I would take that a hundred times over the reaction she had to the Tamiflu.”24Perhaps most telling is an article in Time entitled ‘Tamiflu Made My Kid Hallucinate. I Think the Flu is Preferable to Delirium.’25
Very sadly, a 6-year old girl named Emily Muth from North Carolina died this week – three days after being given Tamiflu.26 According to her mother, Emily suffered from labored breathing (a known side effect of Tamiflu) right before her tragic passing.
Emily Muth
Unfortunately, Tamiflu is neither safe nor effective. I hope that presenting the terrible experiences of the children and families mentioned in this article will serve as a warning to prevent more tragedies.
Fighting won’t win this fight
When you understand that the preschool analogy of foreign invaders (germs) fighting your inner soldiers (immune system) has been rendered obsolete by our awareness of the microbiome(including the virome!), and the poetic reality that we are made up of the very organisms we thought that we were fighting…well, then pharmaceutical medicine seems something like cutting off your nose to spite your face.
This is when you can graduate to a deeper sense that illness is purposeful, that the body recalibrates through fever, and that we are simply here to support the body’s innate wisdom…the less fear, the better.
There are many evidence-based tools for supporting your body’s detoxification process including vitamins A and D, herbs like ginseng, elderberry, and ginger, and food-derived compounds like AHCC and beta glucan, and, my favorite in this case, homeopathy (Oscillococcinum).27 Take the cue to stop, rest, and just be – while your body does its wise work.
Despite recent controversies about its effectiveness, clinicians should not forget about using the antiviral, oseltamivir (Tamiflu), to help shorten the course of influenza among patients during the coming flu season. In this exclusive MedPage Today video, Arnold Monto, MD, of the University of Michigan School of Public Health in Ann Arbor, discusses how antivirals may be more important than ever this flu season — both in adult and pediatric populations — with an influenza vaccine that may not be as effective.
Following is a transcript of his remarks:
What’s happening is that we are about to have an influenza outbreak, or it’s already starting. We know that this influenza outbreak in the U.S. is mainly H3N2, which is the one that’s the most severe in terms of causing severe morbidity and mortality.
We also know that the vaccine doesn’t work as well against this kind of influenza, and what we really need to remember is that we should be using Tamiflu as the one licensed antiviral that we have which is commonly available. We have others that are a little harder to get a hold of, but they will shorten the duration of illness and prevent complications. We should not hesitate to use what we’ve got because these drugs are not super drugs.
We know that we need better antivirals, and there are new ones in the pipeline, but they are not currently available. The CDC is very strong in their recommendation in certain risk groups that the antivirals — mainly oseltamivir, Tamiflu — be used in the appropriate situations.
I think the CDC has spoken — as have various other organizations like the Infectious Diseases Society, pediatric groups — [about] appropriate use of antivirals, and we need to remember to use them during the coming flu season because we expect the vaccine to work, but not as well as we would like.
There has been controversy between two journals in terms of how they view Tamiflu, which is very strange because we are all science-based and we should really go on the evidence.
We published an article in Lancet looking at the clinical trials of Tamiflu, and we are now about to publish a paper in Clinical and Infectious Diseases that looks at the effect of Tamiflu in pediatrics. We find that it not only shortens the duration of influenza, but also prevents complications [like] otitis media, which is an important complication that occurs after a case of influenza.
To compare pregnancy outcome between women exposed and unexposed to oseltamivir during pregnancy.
Design
A comparative observational cohort study of women exposed to oseltamivir during pregnancy.
Setting
A French prescription database (EFEMERIS) that includes data for pregnant women was used. EFEMERIS records prescribed and dispensed reimbursed drugs during pregnancy and pregnancy outcomes in Haute-Garonne, South West France.
Population
Women who delivered from 1 July 2004 to 31 December 2010.
Methods
The study compared exposed and unexposed pregnant women. Two women unexposed to oseltamivir were individually matched, by maternal age, month, and year of delivery, with one women exposed to oseltamivir. Multivariable conditional logistic regression and multivariable Cox proportional hazards regression were used to evaluate associations between each outcome and exposure to oseltamivir during pregnancy.
Main outcome measures
Pregnancy loss for any cause, preterm delivery, low birthweight, neonatal pathology, and congenital malformation.
Results
A cohort of 337 (0.58% of women included in EFEMERIS) women exposed to oseltamivir were compared with 674 unexposed women. The risk for pregnancy loss (HR 1.52; 95 % CI 0.80–2.91), for preterm birth (adjusted OR 0.64; 95% CI 0.31–1.27), and for neonatal pathology (adjusted OR 0.62; 95% CI 0.23–1.54) did not differ between exposed and unexposed groups. When exposure during organogenesis was considered, one case of congenital anomaly (2.0%) among 49 exposed women and one case (1.0%) among 99 unexposed women were observed (crude OR 2.00; 95% CI 0.13–32.00).
Conclusions
There was no significant association between adverse pregnancy outcomes and exposure to oseltamivir during pregnancy.
Jonathan Nguyen-Van-Tam, virologist and researcher from the University of Nottingham, told a group of triallists and virologists last week “we must remember why we’re here—because of the controversies. The clinical world doesn’t believe that Tamiflu works. We should assess whether the regulatory approval/product insert for Tamiflu is valid.”
That group, the MUltiparty Group for Advice on Science (MUGAS) was at a workshop in Brussels on 18 June organised by the European Scientific Working group on Influenza (ESWI) and supported by an unrestricted grant from Roche. Led by several of the original Tamiflu regulatory triallists, the workshop heard plenty of evidence to challenge current claims about Tamiflu’s effects. MUGAS decided to plan and conduct individual participant data (IPD) meta-analyses of the randomised trial data—and observational data. That’s quite a remarkable turnaround, given the strength of claims made by some of the same people over the past decade.
BMJ readers will already be very familiar with growing concerns about oseltamivir’s effectiveness. Earlier this year Professor Harlan Krumholz and co-authors concluded in an editorial in theBMJthat “Despite government claims, we should acknowledge the uncertainty surrounding oseltamivir’s effectiveness and the gaps in publicly available evidence. On the basis of the available data, at best the drug shortens symptoms by about a day when used within the first two days of symptoms, but it has no effect on hospital admissions. In addition, trial data from which to draw conclusions about complications and transmission of flu are lacking.”
WHO made particularly firm claims about oseltamivir in August 2009 during the swine flu (H1N1) pandemic. WHO then stated that, “The guidelines represent the consensus reached by an international panel of experts who reviewed all available studies on the safety and effectiveness of these drugs…Evidence reviewed by the panel indicates that oseltamivir, when properly prescribed, can significantly reduce the risk of pneumonia (a leading cause of death for both pandemic and seasonal influenza) and the need for hospitalization.”
That expert panel advising WHO was anonymous: all its members had signed a confidentiality agreement. But at least one member was identified later as Professor Arnold Monto of the University of Michigan, who coauthored several trials of neuraminidase inhibitors back in the 1990s. The same Professor Monto is one of the four convenors of MUGAS, along with Professor Ab Osterhaus (of Erasmus MC University in Rotterdam, a scientific advisor to Roche, another oseltamivir triallist), Professor Menno de Jong (of Academic Medical Center Amsterdam, virologist and researcher) and Professor Rich Whitley (of University of Alabama at Birmingham, professor of pediatric infectious diseases and an adviser on flu to the Obama administration).
Barry Clinch, Principal Clinical Scientist at F. Hoffmann-La Roche, presented at the MUGAS workshop an overview of all studies in the company’s oseltamivir research programme. His slides showed that in all, 18,928 patients had taken part in trials, observational studies of treatment, and studies of prophylaxis; around 11,500 of them treated with oral oseltamivir. Randomised controlled trials (RCTs) had included 4799 adults and 1368 children and, along with some open label studies, a total of 8078 patients had taken part. All but one of the 12 RCTs took place in the late 1990s. Roche’s lab researchers had also done experimental flu studies and clinical pharmacology studies.
Clinch confirmed that investigators were told to always report admissions to hospital during the Roche trials, but warned that “caution should be exercised in interpreting results on hospitalisation.” This is because there were such low event rates: for example in trial WV15671 just 1 of 201 participants was hospitalised. The main intention to treat analyses in the 12 Roche RCTs (for all patients enrolled with flu-like illness and who had at least 1 dose of trial medication) failed to find statistically significant evidence that hospitalisation rates were reduced by oseltamivir when compared against placebo. For the ITTI population (the subset with flu confirmed by culture or >4 fold rise in antibody titre) the overall P value was 0.06 but this was grossly underpowered.
Presenting the key oseltamivir trials that yielded data on flu complications, Clinch explained that a standard case report form was used to collected data on “Secondary illness.” “We didn’t ask physicians to actively look for complications,” he said. “They simply reported them if they thought patients had, for example, sinusitis, otitis media, bronchitis, pneumonia or other chest infections.” Clinicians could also say if patients needed antibiotics or X rays—thereby implying that there might be some secondary illness—but there was no requirement to confirm diagnoses without anything more than a clinical diagnosis. “To be honest, we weren’t that stringent at the time,” acknowledged Clinch. (And, of course, at that time Roche was testing oseltamivir primarily as another antiviral for seasonal flu, not as a lifesaver in a pandemic.) Only two trial protocols required reporting of clinically diagnosed complications (coded as bronchitis, pneumonia, lower respiratory tract complication, or antibiotic prescription occurring >48h after start of treatment with oseltamivir) as a formal secondary endpoint: those among older and at risk participants. Statistical analyses of these outcomes were exploratory, said Clinch.
The ensuing questions and discussion among the MUGAS review board members (some of whom co-authored some of the trials in question) confirmed that “secondary illness” was indeed only a clinical diagnosis, that in most of the trials its reporting was ad hoc, and that Roche does not know the extent of any missing data. Decisions to give antibiotics were made for nonspecified clinical reasons, and, as someone pointed out, antibiotic usage rates will have varied a lot from site to site because of geographical variations in prescribing behaviour.
However, some of the MUGAS virologists said we know from Roche’s original observational studies and from subsequent case series from the H1N1 pandemic that oseltamivir does reduce complications. Do we? Not yet, although Professor Van Tam’s group has conducted a systematic review and IPD meta-analysis of published andunpublished observational study data during the H1N1 pandemic that will be submitted soon for publication. This study was sponsored by Roche but Professor Van Tam said the data agreement gives Roche no access to the data. The authors plan, however, to share the data with other investigators on request.
When asked what proportion of the original Roche oseltamivir research programme had results in the public domain, Clinch said “about 90% in one form or another.” Virologist Fred Hayden, co-author of several Roche trials, asked: “the contentious area is the 8-10 unpublished trials done some time ago. Are there any plans to publish those?” Clinch replied “it’s a good question…we’d like MUGAS to discuss that. Roche has no objection to that.” Professor Osterhaus said that MUGAS wants to analyse the IPD from those trials and to publish the resulting papers in peer reviewed journals.
So, of course, does the Cochrane Acute Respiratory Infections Group, which has been struggling for years to get the unpublished trial data from Roche. That data release has now begun, and the Cochrane group is poring over the partly redacted Clinical Study Reports right now.
So it’s from famine to feast, with two different groups working towards meta-analyses of the unpublished patient-level data on the effects of oseltamivir in flu. Will they come to the same conclusions?
Objective To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza.
Setting Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam.
ParticipantsPatients aged ≥1 year admitted to hospital with confirmed severe influenza.
Interventions Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent).
Main outcome measure Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five.
Results Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (−5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found.
Conclusions There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital.
Discussion
In this large randomised controlled trial of antiviral treatment in patients with severe influenza we found that double dose oseltamivir was well tolerated but did not confer additional virological or clinical benefits over standard dose treatment in patients in South East Asia. There were no differences between the treatment arms in detection of viral RNA or infectious virus on day five, and there were also no differences in clinical failure rates, mortality in hospital, or rates of adverse events between the dose regimens on day five. We enrolled a heterogeneous population that included mostly children and also those infected with avian H5N1 or H1N1-pdm09 viruses. While subgroup analyses based on age cohorts, virus type and subtype, and time to treatment did not suggest additional virological efficacy of double dose oseltamivir in any subgroup, these results should be interpreted with caution as the study was not powered for these analyses.
Our patients presented relatively late after the onset of illness, a median of five days overall (seven days for H5N1). Despite administration of oseltamivir, about 30% of those enrolled remained positive for viral RNA (the primary endpoint) after five days of treatment. Timing of oseltamivir treatment is important as several studies have shown that early treatment confers greater virological and clinical benefits.456323334 In particular, later viral clearance has been noted with delayed treatment with oseltamivir compared with treatment within two to three days after onset of symptoms in observational reports from patients with H1N1-pdm09, especially those with severe illness.353637383940 In the current trial, 73 (22.4%) patients presented within three days of illness, but even in this subpopulation, double dose oseltamivir was not associated with more rapid viral RNA clearance. Over a quarter of patients received neuraminidase inhibitors before enrolment, which could have influenced the effect size and contributed to the low proportion of patients shedding virus at day five in both treatment groups.
Although viral RNA detection in samples from the upper respiratory tract might not accurately reflect viral replication in the lower respiratory tract, especially in those with severe illness,39 prolonged viral RNA detection in upper respiratory tract samples has been shown to correlate with inpatient morbidity and prolonged hospital stay. In our study viral detection on day five was observed at about twofold the frequency in those meeting the criteria for clinical failure, although lack of clinical failure was not a surrogate for cessation of viral detection. Thus in our study the delays in starting treatment with oseltamivir also probably contributed to the substantial rates of admission to intensive care (18%), use of supplemental oxygen (30%), mechanical ventilation (12%), and mortality in hospital of 6.4%. Although our study was not placebo controlled for ethical reasons, other studies indicate that early oseltamivir treatment in people with severe influenza is associated with both clinical benefits and more rapid viral clearance from upper respiratory tract samples.
Possible reasons for findings
It is unclear why double dose oseltamivir does not seem to offer benefit over standard dose in patients with severe influenza. Blood trough concentrations of oseltamivir carboxylate from 75 mg or 150 mg twice daily in influenza exceed the IC50 (inhibitory concentration) of influenza viruses.4243 Inhibition of viral neuraminidase by oseltamivir might be a saturable process, and maximal inhibition might be achieved with a standard dose; exceeding these concentrations might not produce an additional clinical or virological effect. In this regard, a randomised oseltamivir controlled study of intravenous peramivir (BioCryst Pharmaceuticals, Durham, NC), which reaches over 20-fold higher peak blood concentrations of active metabolite than oseltamivir carboxylate, found similar viral reductions in patients with influenza A virus admitted to hospital.44 Further studies of peramivir and other intravenous neuraminidase inhibitors currently in progress should provide additional evidence regarding this hypothesis.
Infection with avian H5N1 virus, higher baseline viral load, and severity of disease were independently associated with longer viral RNA detection. The association between avian H5N1, severe illness, and prolonged shedding has been well described.14 The clearance kinetics of influenza viruses, both without antiviral treatment and with oseltamivir treatment,3241 could explain longer viral RNA detection with higher baseline viral loads. It is unclear whether the independent association with disease severity might be related to impaired mechanisms of viral clearance or higher intrinsic rates of viral replication or both in these patients. Severe chronic comorbidities are seen commonly in industrialised countries and are related to prolonged viral shedding but most of our patients lacked these comorbidities.4041
The heterogeneous population characteristics, geographical differences in recruitment (most patients were from Vietnam but there were no significant differences between Vietnam and other sites), and the variety of infecting viruses in our trial reflect the clinical circumstances in South East Asia during our study but might be viewed as a limitation. Most of these patients were children and had low or normal BMI, and for all patients only about a fifth reported a chronic underlying medical condition. Thus, our findings are applicable primarily to the region where the study was conducted and other settings with similar characteristics of influenza epidemiology. We did not have many adults in our study and results were inconclusive but indicate no difference in efficacy between the two oseltamivir regimens. We would caution the extension of our results to, for example, morbidly obese adults with severe influenza and those who could have underlying chronic illnesses. We conducted several statistical comparisons and inevitably subgroup analyses involved small numbers; thus power was limited and some significant results could have resulted by chance. Additionally, as all patients were randomised to an active treatment, our study was not designed to evaluate the efficacy of oseltamivir in severe influenza nor in H5N1 infections. This large randomised trial did, however, examine an important clinical and public health question and showed a lack of a clinical or virological benefit of double dose compared with standard dose oseltamivir in patients admitted to hospital with severe influenza. Our results and other observational reports from avian H5N110 and H1N1-pdm091136 infections do not support routine use of double dose oseltamivir to treat severe influenza. These findings have implications for both clinical management and pandemic preparedness including during the current H7N9 epidemic.161718
What is already known on this topic
Clinical trials in patients with uncomplicated influenza have shown that treatment with oseltamivir has clinical and virological benefit when administered within 48 hours of onset of symptoms
Observational studies in severe influenza have shown that oseltamivir treatment, if given early, is associated with reduced mortality and shorter length of hospital stay. Reduced mortality has also been reported for patients with H5N1 influenza treated with oseltamivir
Several authorities have suggested the use of double dose oseltamivir for severe influenza, although there is no clinical evidence to support this
In the largest randomised trial on the treatment of severe influenza, no clinical or virological benefit of double dose oseltamivir over standard dose was found
These findings have implications for both clinical management of severe influenza and for pandemic preparedness of emerging influenza viruses including the current H7N9 epidemic
Objective To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza.
Setting Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam.
ParticipantsPatients aged ≥1 year admitted to hospital with confirmed severe influenza.
Interventions Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent).
Main outcome measure Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five.
Results Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (−5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found.
Conclusions There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital.
Discussion
In this large randomised controlled trial of antiviral treatment in patients with severe influenza we found that double dose oseltamivir was well tolerated but did not confer additional virological or clinical benefits over standard dose treatment in patients in South East Asia. There were no differences between the treatment arms in detection of viral RNA or infectious virus on day five, and there were also no differences in clinical failure rates, mortality in hospital, or rates of adverse events between the dose regimens on day five. We enrolled a heterogeneous population that included mostly children and also those infected with avian H5N1 or H1N1-pdm09 viruses. While subgroup analyses based on age cohorts, virus type and subtype, and time to treatment did not suggest additional virological efficacy of double dose oseltamivir in any subgroup, these results should be interpreted with caution as the study was not powered for these analyses.
Our patients presented relatively late after the onset of illness, a median of five days overall (seven days for H5N1). Despite administration of oseltamivir, about 30% of those enrolled remained positive for viral RNA (the primary endpoint) after five days of treatment. Timing of oseltamivir treatment is important as several studies have shown that early treatment confers greater virological and clinical benefits.456323334 In particular, later viral clearance has been noted with delayed treatment with oseltamivir compared with treatment within two to three days after onset of symptoms in observational reports from patients with H1N1-pdm09, especially those with severe illness.353637383940 In the current trial, 73 (22.4%) patients presented within three days of illness, but even in this subpopulation, double dose oseltamivir was not associated with more rapid viral RNA clearance. Over a quarter of patients received neuraminidase inhibitors before enrolment, which could have influenced the effect size and contributed to the low proportion of patients shedding virus at day five in both treatment groups.
Although viral RNA detection in samples from the upper respiratory tract might not accurately reflect viral replication in the lower respiratory tract, especially in those with severe illness,39 prolonged viral RNA detection in upper respiratory tract samples has been shown to correlate with inpatient morbidity and prolonged hospital stay. In our study viral detection on day five was observed at about twofold the frequency in those meeting the criteria for clinical failure, although lack of clinical failure was not a surrogate for cessation of viral detection. Thus in our study the delays in starting treatment with oseltamivir also probably contributed to the substantial rates of admission to intensive care (18%), use of supplemental oxygen (30%), mechanical ventilation (12%), and mortality in hospital of 6.4%. Although our study was not placebo controlled for ethical reasons, other studies indicate that early oseltamivir treatment in people with severe influenza is associated with both clinical benefits and more rapid viral clearance from upper respiratory tract samples.4814363738394041
Possible reasons for findings
It is unclear why double dose oseltamivir does not seem to offer benefit over standard dose in patients with severe influenza. Blood trough concentrations of oseltamivir carboxylate from 75 mg or 150 mg twice daily in influenza exceed the IC50 (inhibitory concentration) of influenza viruses.4243 Inhibition of viral neuraminidase by oseltamivir might be a saturable process, and maximal inhibition might be achieved with a standard dose; exceeding these concentrations might not produce an additional clinical or virological effect. In this regard, a randomised oseltamivir controlled study of intravenous peramivir (BioCryst Pharmaceuticals, Durham, NC), which reaches over 20-fold higher peak blood concentrations of active metabolite than oseltamivir carboxylate, found similar viral reductions in patients with influenza A virus admitted to hospital.44 Further studies of peramivir and other intravenous neuraminidase inhibitors currently in progress should provide additional evidence regarding this hypothesis.
Infection with avian H5N1 virus, higher baseline viral load, and severity of disease were independently associated with longer viral RNA detection. The association between avian H5N1, severe illness, and prolonged shedding has been well described.14 The clearance kinetics of influenza viruses, both without antiviral treatment and with oseltamivir treatment,3241 could explain longer viral RNA detection with higher baseline viral loads. It is unclear whether the independent association with disease severity might be related to impaired mechanisms of viral clearance or higher intrinsic rates of viral replication or both in these patients. Severe chronic comorbidities are seen commonly in industrialised countries and are related to prolonged viral shedding but most of our patients lacked these comorbidities.4041
The heterogeneous population characteristics, geographical differences in recruitment (most patients were from Vietnam but there were no significant differences between Vietnam and other sites), and the variety of infecting viruses in our trial reflect the clinical circumstances in South East Asia during our study but might be viewed as a limitation. Most of these patients were children and had low or normal BMI, and for all patients only about a fifth reported a chronic underlying medical condition. Thus, our findings are applicable primarily to the region where the study was conducted and other settings with similar characteristics of influenza epidemiology. We did not have many adults in our study and results were inconclusive but indicate no difference in efficacy between the two oseltamivir regimens. We would caution the extension of our results to, for example, morbidly obese adults with severe influenza and those who could have underlying chronic illnesses. We conducted several statistical comparisons and inevitably subgroup analyses involved small numbers; thus power was limited and some significant results could have resulted by chance. Additionally, as all patients were randomised to an active treatment, our study was not designed to evaluate the efficacy of oseltamivir in severe influenza nor in H5N1 infections. This large randomised trial did, however, examine an important clinical and public health question and showed a lack of a clinical or virological benefit of double dose compared with standard dose oseltamivir in patients admitted to hospital with severe influenza. Our results and other observational reports from avian H5N110 and H1N1-pdm091136 infections do not support routine use of double dose oseltamivir to treat severe influenza. These findings have implications for both clinical management and pandemic preparedness including during the current H7N9 epidemic.161718
What is already known on this topic
Clinical trials in patients with uncomplicated influenza have shown that treatment with oseltamivir has clinical and virological benefit when administered within 48 hours of onset of symptoms
Observational studies in severe influenza have shown that oseltamivir treatment, if given early, is associated with reduced mortality and shorter length of hospital stay. Reduced mortality has also been reported for patients with H5N1 influenza treated with oseltamivir
Several authorities have suggested the use of double dose oseltamivir for severe influenza, although there is no clinical evidence to support this
In the largest randomised trial on the treatment of severe influenza, no clinical or virological benefit of double dose oseltamivir over standard dose was found
These findings have implications for both clinical management of severe influenza and for pandemic preparedness of emerging influenza viruses including the current H7N9 epidemic
A double dose of oseltamivir (Tamiflu) offers no advantage over single-dose therapy among children and adults with severe influenza, according to a BMJ study.
Some 325 patients (three-quarters children) hospitalized with severe flu in Southeast Asia were randomized to either double-dose oseltamivir (150 mg twice daily, or pediatric equivalent) or standard treatment (75 mg twice daily, or equivalent). Detected viruses included various subtypes of seasonal influenza, 2009 pandemic flu, and avian flu.
The proportion of patients with no detectable viral RNA on day 5 did not differ between the groups (roughly 70%). In addition, the groups did not differ with respect to clinical failure or in-hospital mortality. Findings generally were consistent regardless of patient age or flu type.
The authors say their results “do not support routine use” of double-dose therapy in severe flu. Editorialists agree, adding that the results “could help to preserve oseltamivir stocks during a future pandemic.”
The novel influenza A virus H7N9 has shown a “concerning” ability to develop resistance to neuraminidase inhibitors such as Tamiflu (oseltamivir) and Relenza (zanamivir), according to a Lancet study.
Researchers studied 14 patients admitted to a Shanghai hospital with H7N9 influenza. In tracking patients’ viral loads, they noted that two showed persistently high loads after starting neuraminidase inhibitors. Both had also received steroid treatment. A mutation in the virus’s neuraminidase gene was associated with persistent high viral loads and poor clinical outcome.
The researchers wonder what, if any, role the steroid therapy had in the emergence of resistance. They advise early treatment with neuraminidase inhibitors.
Meanwhile, China has reported no new H7N9 cases for 2 weeks. The case count now stands at 131, with 32 deaths.
ARYAN'S BLOG 