- Email: [email protected]
How should influenza be treated? Focus on antivirals
G Model
ARTICLE IN PRESS
JVAC-16722; No. of Pages 4
Vaccine xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Conference report How should influenza be treated? Focus on antivirals Is there a clear cut answer to the question: ‘Should antiviral drugs be used for seasonal influenza?’ It is reasonable to argue that antivirals are readily available, shorten illness and reduce the risk of complications, so why not use them? However, the use of antivirals is contentious and different countries adopt varying strategies. In particular, European doctors generally believe that antivirals should in general not be used in normal people with ordinary flu. It is remarkable that patients with flu care are more likely to be given antibiotics than antivirals. However, new in-depth reviews by the Post-pandemic Review of anti-Influenza Drug Effectiveness (PRIDE) and the Multiparty Group for Advice on Science (MUGAS) are set to change this policy. Both reviews clearly demonstrate the beneficial effect of antivirals and endorse the policy decision to stockpile antiviral drugs. Deploying resources against seasonal influenza Antiviral stockpiling behaviour has traditionally been (and still is) very different from country to country. Since 2009, European countries have hardly invested any money in replenishing or renewing their stockpiles of antiviral drugs. The attitude to antivirals mirrors, to some extent, the pattern of vaccination coverage. “Based on the same evidence, it seems that different countries make different decisions,” says Ted van Essen from the University Medical Center in Utrecht, the Netherlands. “The general idea in Europe is that you should’nt use antivirals unless there is an influenza crisis at hand. During the pandemic, for example, many European countries made large-scale use of oseltamivir. But since then, hardly anyone has prescribed antivirals. If you compare the use of antivirals and antibiotics, the overall use of antivirals remains very, very low. This European attitude is very different from the one prevailing in the US and in Japan, where we see very a high use of oseltamivir. After the pandemic, use levels grew even further.” In the absence of clear universal guidelines, different European countries adopt different positions – if they adopt a position at all. Van Essen discussed the situation in the Netherlands and the United Kingdom. In the UK, the NICE Guideline from 2009 is quite clear. Van Essen: “It recommends oseltamivir and zanamivir as a possible treatments, but with some conditions attached, all of which must be met: the person must be in a risk group and must be able to start the treatment within 48 h after the first signs of the flu-like symptoms becoming apparent, or 36 h for zanamivir treatment in children. The flu virus should also be known to be in circulation and there must be reasonable grounds to assume that the flu-like illness has been caused by this flu virus. If there is an outbreak of flu-like illness in a long-term residential or nursing home, oseltamivir and zanamivir may be offered to treat residents in ‘at risk’ groups who have
symptoms of flu. In these circumstances, the treatment can be given even if the flu virus is not in circulation in the wider community outside the home, but the healthcare team must be reasonably sure that the illness is indeed flu.” In the Netherlands, the dominant opinion on these matters was set down in the Dutch College of General Practitioners (DCGP) Guideline of 2008. Van Essen: “This guideline starts by saying that it has not been sufficiently demonstrated that neuraminidase inhibitors prevent influenza complications in at-risk patients. Consequently, antiviral medications can only be prescribed in those with strict medical indications and are subject to the limited evidence of being therapeutically beneficial for patients at very high risk, who are presumed to have influenza, who have not been vaccinated against influenza or for whom the vaccine is insufficiently effective. In other words, the patient almost has to be dead before you can start to use antivirals! You can also use antivirals as post exposure prophylaxis during a virologically confirmed influenza outbreak in a care home and for patients with a very high risk of contracting influenza complications (even those who are vaccinated) and during an (imminent) influenza pandemic.” For the purposes of comparison, Van Essen also presented the recent US antiviral guidelines, published in 2013. They are much simpler, easier to follow and much more complete. All the key risk groups are indicated: children younger than 2 years; people aged 65 years or over; persons with chronic pulmonary (including asthma), cardiovascular (excluding hypertension), renal, hepatic, haematological (including sickle cell disease) and metabolic disorders (including diabetes mellitus); persons with immunosuppression; women who are pregnant or postpartum; persons aged younger than 19 years who are receiving long-term aspirin therapy; persons who are morbidly obese (i.e., the BMI is 40 or greater); and residents of nursing homes and other chronic-care facilities. Europe lacks the same kind of comprehensive and clear advice on how to use flu antivirals. And according to Van Essen, there is more to this lack of urgency than post-pandemic flu fatigue – an opinion supported by many specialists in the field. The fuss caused by the supposed concealment of clinical trials; the Cochrane effect and the perception that antivirals only offer a 1-day reduction in sickness (and if it is the first or last day remains unclear!); the myth that influenza only presents a real risk to those in the risk groups: about half of all those hospitalized with flu have no known risk factors, and these opinions strengthen a certain unwillingness to take action to codify the guidelines. Van Essen: “The problem is that doctors are only interested in patients at risk and not in healthy patients. The recommendations say treatment with antivirals should start within the first 48 h of the flu symptoms occurring. But patients generally visit a doctor only after the first 48 h have passed. Most people’s first reaction is to try and ‘sit out’ the disease. There is a general belief among the public that flu is something you don’t need to bother the doctor about. It is only when things get
0264-410X/$ – see front matter http://dx.doi.org/10.1016/j.vaccine.2015.07.066
Please cite this article in press as: van Essen GA, et al. How should influenza be treated? Focus on antivirals. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.07.066
G Model JVAC-16722; No. of Pages 4
ARTICLE IN PRESS Conference report / Vaccine xxx (2015) xxx–xxx
2
worse that they finally decide to do something about it and by then using antivirals may have much less benefit.”
had a front-page feature accusing the planners of irresponsibility in not vaccinating all children!” Endorsing stockpiling
The UK experience In Europe, the country with the largest antiviral stockpiles in terms of the percentage of total population covered is the UK. In 2009 the target coverage increased to 80% and the stockpile has been renewed and replenished since. Peter Openshaw, from Imperial College London, who was part of the UK Pandemic Influenza Committee, offered a personal account of what happened in the UK before, during and after the H1N1 pandemic. Openshaw: “We had a comprehensive plan in place prior to the 2009 pandemic. This was in response to concern about H5N1 or other highly pathogenic strains of flu. The pandemic plan was in part driven by sophisticated epidemiological models and had three phases: (1) Preparation, getting ready by stockpiling antivirals and putting plans in place for accelerated vaccine delivery with advance purchase agreements; (2) Containment, with an emphasis on early diagnosis and treatment. This was designed to slow the speed, blunt the peak and buy time. The UK was unusual in investing heavily in contact prophylaxis, self-isolation and early school closures. We also knew, of course, that at some point we would have to move on to phase (3): Treatment.” “We went for a widespread prophylaxis. This can be seen as an excessive response now that we know how mild most cases of pH1N1 were, but at the time you have to remember that we just did not know how severe the disease was on average. It was quite frightening at the time and we were getting reports of numerous hospitalizations. But we had no real idea about case severity. We thought we might be in the midst of an outbreak of a highly pathogenic virus and that the only responsible thing to do was to do everything to limit spread.” In the UK, there were two very distinct pandemic waves. The first one happened in Spring and the second in Autumn of 2009 in the run up to Christmas. “It was all very different from the single wave the modellers had predicted,” says Openshaw. “During the second wave, we saw more hospitalizations and fewer GP consultations. One of the reasons for this was the UK’s national pandemic flu phone service. If you reached out to the call centre and gave the right answers, you were given an electronic voucher which entitled you to obtain antivirals directly from pharmacies without a prescription. Over a million courses of antivirals were distributed in this way. But the proportion of people who developed flu probably was’nt very high. Only about a quarter of the 2.7 million people who phoned the emergency line were referred to GPs.” Early in 2010 the pandemic was declared to be over. Despite the careful management of publicity and communication, the press was highly critical of the UK response. For example, on 5 February 2010, The Daily Mail wrote: ‘Billions of pounds have been wasted on swine flu vaccines that will never be used’ and listed that 342 million vaccine doses were ordered, 4.25 million people were offered vaccine, £13.5 million was spent on the flu phone-line, approximately 1 million courses of oseltamivir were issued. With all this cost and effort, ‘only’ 411 people died. Openshaw: “By the time the third (post-pandemic) wave hit the UK in November 2010, things had changed. We had moved away from the advice that antivirals should be widely used and reverted to the policy that antivirals should only be used under very strict conditions. As a result, the use of antivirals in the third wave had dropped to almost nothing. There was a big increase in the number of inpatients with confirmed influenza, outnumbering those admitted in the first and second wave combined. And what happened then? The same Daily Mail
In order to get antivirals more widely accepted and make them an integral part of influenza policies, ongoing misunderstandings and popular misconceptions regarding the efficacy and safety of these medicines need to be dealt with effectively. Puja Myles from the University of Nottingham in the UK presented the results of the Post-pandemic Review of anti-Influenza Drug Effectiveness (PRIDE) review of anti-influenza effectiveness during the 2009 flu pandemic. Until now, little pre-pandemic evidence existed relating to the effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza. Most of the evidence came from observational studies of the treatment of seasonal influenza, often in highly specific risk groups. Some studies suggested antivirals were of benefit in restricting serious outcomes, but the surveys were too small to be able to demonstrate statistically significant results. Myles: “For us, the question was this: was there good enough evidence to convince countries to replenish their stocks? This prompted us to systematically review the literature and the available studies, in the hope of arriving at a standardized answer.” The PRIDE review involved 80 research groups from 38 countries. The total sample size was nearly 170,000 patients, including almost 30,000 patients (across all age ranges) admitted to hospital between 2 January 2009 and 14 March 2011. The PRIDE findings indicated that patients hospitalised with H1N1 influenza during the 2009–2010 pandemic were 18% less likely to die if they were given neuraminidase inhibitors. The risk of death was halved (52%) when treatment was started within 2 days of the onset of the illness, in comparison with people who received later antiviral treatment or no antiviral treatment at all. It was therefore clear that early treatment is essential if optimal results are to be obtained. If the clinical suspicion of influenza is high, Myles advocates not waiting for laboratory confirmation before starting treatment. The data also suggest that even when the 48-h mark following symptom onset has passed, treatment might nonetheless confer mortality benefits to critically ill patients. As a result, the review clearly endorses the policy decision to stockpile and use antivirals in treating hospitalised patients during the 2009–2010 pandemic. Providing more evidence Any unsolved scientific matters that hamper proper and effective public guidance in relation to the stockpiling and use of antivirals need to be resolved. In April 2014, the Cochrane Collaboration published a review of clinical study data to assess the effectiveness of the neuraminidase inhibitor oseltamivir (Tamiflu) against influenza. In its conclusions, Cochrane said these medicines are of little value and advised governments not to stockpile neuraminidase inhibitors for use in pandemics, suggesting that this is a waste of taxpayers’ money. The lack of a consensus on the effectiveness of oseltamivir inspired MUGAS Foundation, the Multiparty Group for Advice on Science, to clarify the evidence once and for all. The group unanimously agreed that a more in-depth analysis was needed in order to provide proper medical evidence on which to base reliable findings. In their opinion, reviewing published results from randomized controlled trial data was insufficient to resolve the issues regarding the efficacy and safety of oseltamivir. A deeper analysis of the oseltamivir individual patient data was essential. MUGAS therefore arranged a complete and detailed re-analysis by a statistical group
Please cite this article in press as: van Essen GA, et al. How should influenza be treated? Focus on antivirals. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.07.066
G Model JVAC-16722; No. of Pages 4
ARTICLE IN PRESS Conference report / Vaccine xxx (2015) xxx–xxx
led by Professor Stuart Pollock of the London School of Hygiene and Tropical Medicine. Roche provided MUGAS and Stuart Pollock’s team with all the requested reports and datasets, as well as the necessary individual patient data (IPD), via a secure data room. MUGAS member Arnold Monto, from the University of Michigan, presented the outcome of the re-analysis. “Adult and paediatric trials were meta-analysed separately. The outcomes of greatest interest were time to alleviation, prevention of complications and safety. The meta-analysis was restricted to the licensed 75 mg dose of Tamiflu. The prophylactic studies were not part of the analysis. The preliminary results of the statistical analysis of the oseltamivir data indicate a highly significant reduction in the time to alleviation for the major symptoms of influenza. The results also demonstrate a highly significant reduction in the number of lower respiratory infections requiring antibiotics. The wellknown side-effects of nausea and vomiting were confirmed, but not diarrhoea.” Cochrane’s pronouncements that ‘antivirals are of little value’ and that ‘the harm caused by Tamiflu exceeds the benefits’ have gained momentum in both the public and the political debate, reducing the use of antivirals and jeopardizing the future willingness of governments to stockpile antivirals in preparation for the treatment of pandemics. For the first time, the MUGAS review and the statistical analysis of the oseltamivir data provides meticulous, complete and sustainable evidence of the benefits of antivirals.
The future of antivirals As a last speaker during this SPI Track, Erhard van der Vries from the Department of Viroscience at the Erasmus Medical Centre in Rotterdam, the Netherlands, discussed the future of influenza antivirals. Van der Vries focused on the different windows of opportunity for inhibiting virus replication in influenza-infected patients. The strength of current therapies is their ability to reduce severe clinical outcomes, such as mortality. Van der Vries: “I think new strategies should focus on early treatment and reducing the risk of developing severe influenza infections, especially for patients with a high-risk of contracting such infections. Currently, there are two types of approved influenza antiviral drugs: the M2-channel inhibitors and the neuraminidase inhibitors. The M2channel inhibitors, amantadine and rimantadine, have been around since the 1960s. However, they are only active against the A virus and not the B virus. They also have considerable side-effects and the viruses become easily resistant to the drugs. The neuraminidase inhibitors were designed to be active against both influenza A and B viruses and to have a high barrier of resistance. And although antiviral resistance to this type of drug has also emerged in the past, the level of global incidence is so far low.” Within the last 15 years a number of events have refocused attention on the neuraminidase inhibitors. “Three of these events were of particular importance,” says van der Vries. “First of all, the occasional outbreaks of the highly pathogenic avian virus H5N1 have alerted public health authorities to the possibility of a major pandemic, which has contributed to the stockpiling of these drugs at national level. The recent H7N9 outbreak in China is yet another example of this phenomenon. The second event was the emergence of seasonal influenza viruses with adamantane and oseltamivir resistance. In particular, the emergence of oseltamivir resistant viruses in 2007 and 2008 was surprising. These viruses had inherited oseltamivir resistance with no loss of pathogenicity or ability to spread. The third event, of course, was the outbreak of the 2009 influenza pandemic.” A rapid start to therapy is crucial when treating influenza. Van der Vries: “And in a situation where the immune response
3
is inadequate, the antiviral benefits can be much greater. This can make all the difference in patients with prolonged infection, such as very young children, immuno-compromised patients and the elderly. These strategies do not necessarily mean having to develop new antivirals. Why not start antiviral therapy in a hospital setting before the influenza diagnosis is confirmed, especially for patients at risk? The recommended 5-day regime seems reasonable for adults with an adequate immune response, but what about immuno-compromised patients, where replication can regularly persist for 14 days or even up to a year in extreme cases of immuno-deficiency? Levels of mortality and the emergence of resistant viruses are high in these immuno-compromised groups. Consequently, there needs to be a special focus on strategies that involve reducing the time for starting therapy and treating complicated infections. Oseltamivir resistance emerged in nearly 50% of the cases in the immuno-deficient group and it is expected that the number of patients with an impaired immune system or a high risk of severe influenza, such as obese patients, will further increase in the coming decades.” So what is the pipeline like for new influenza therapies? The most promising antivirals intervene during the first stage of infection, when the virus binds to the receptor or during transcription of the virus genome. Van der Vries: “Monoclonal antibodies have been developed to interact with the receptor binding site or at the stem of the protein, which destabilizes its conformation. DAS181 is a sialidase and strips the virus receptors from the human epithelial cells to prevent virus binding. Currently, a promising candidate is T-705 or favipiravir. This inhibitor is a nucleoside analogue of the influenza RNA polymerase. An advantage of this inhibitor is that it is not only active against influenza, but also targets a broad range of RNA viruses, including the Ebola virus.”
SPI lessons learned Europe lacks consistent guidelines on how best to use antivirals. Moreover, antiviral stockpiling behaviour has been (and still is) very variable in different countries. The PRIDE review clearly endorses the policy decisions taken to stockpile and early use antivirals to reduce mortality during influenza outbreaks. The MUGAS review and the statistical analysis of the oseltamivir data provides solid evidence to support the benefits of early use of antivirals. New Europe-wide antiviral strategies for influenza should be developed based on comprehensive evidence with respect to existing drugs, taking into account drugs that are currently under development.
Conflict of interest Van Essen: None declared. Openshaw: None declared. Myles: • Funded via an unrestricted educational grant from F. HoffmannLa Roche. – The study is being undertaken fully independently of the company, which has had/will have: • no input to the project design; • no access to any of the data; • no role in analysis or data interpretation; • no preview of the study results; • no opportunity to preview or comment on this presentation or any manuscripts arising from the work.
Please cite this article in press as: van Essen GA, et al. How should influenza be treated? Focus on antivirals. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.07.066
G Model JVAC-16722; No. of Pages 4
ARTICLE IN PRESS Conference report / Vaccine xxx (2015) xxx–xxx
4
Monto:
Peter Openshaw Imperial College London, London, UK
• Funded via an unrestricted educational grant from F. HoffmannLa Roche. – The study is being undertaken fully independently of the company, which has had/will have: • no input to the project design; • no access to any of the data; • no role in analysis or data interpretation; • no preview of the study results; • no opportunity to preview or comment on this presentation or any manuscripts arising from the work. Van der Vries: None declared. G(errit) A. van Essen ∗ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
Puja Myles University of Nottingham, Nottingham, UK Arnold Monto University of Michigan School of Public Health, Ann Arbor, MI, USA Erhard van der Vries Erasmus MC, Rotterdam, The Netherlands ∗ Corresponding
author at: Paladijnenweg 30, 3813 DJ Amersfoort, The Netherlands. E-mail address: [email protected] (G.A. van Essen) Available online xxx
Please cite this article in press as: van Essen GA, et al. How should influenza be treated? Focus on antivirals. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.07.066
ARTICLE IN PRESS
JVAC-16722; No. of Pages 4
Vaccine xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Conference report How should influenza be treated? Focus on antivirals Is there a clear cut answer to the question: ‘Should antiviral drugs be used for seasonal influenza?’ It is reasonable to argue that antivirals are readily available, shorten illness and reduce the risk of complications, so why not use them? However, the use of antivirals is contentious and different countries adopt varying strategies. In particular, European doctors generally believe that antivirals should in general not be used in normal people with ordinary flu. It is remarkable that patients with flu care are more likely to be given antibiotics than antivirals. However, new in-depth reviews by the Post-pandemic Review of anti-Influenza Drug Effectiveness (PRIDE) and the Multiparty Group for Advice on Science (MUGAS) are set to change this policy. Both reviews clearly demonstrate the beneficial effect of antivirals and endorse the policy decision to stockpile antiviral drugs. Deploying resources against seasonal influenza Antiviral stockpiling behaviour has traditionally been (and still is) very different from country to country. Since 2009, European countries have hardly invested any money in replenishing or renewing their stockpiles of antiviral drugs. The attitude to antivirals mirrors, to some extent, the pattern of vaccination coverage. “Based on the same evidence, it seems that different countries make different decisions,” says Ted van Essen from the University Medical Center in Utrecht, the Netherlands. “The general idea in Europe is that you should’nt use antivirals unless there is an influenza crisis at hand. During the pandemic, for example, many European countries made large-scale use of oseltamivir. But since then, hardly anyone has prescribed antivirals. If you compare the use of antivirals and antibiotics, the overall use of antivirals remains very, very low. This European attitude is very different from the one prevailing in the US and in Japan, where we see very a high use of oseltamivir. After the pandemic, use levels grew even further.” In the absence of clear universal guidelines, different European countries adopt different positions – if they adopt a position at all. Van Essen discussed the situation in the Netherlands and the United Kingdom. In the UK, the NICE Guideline from 2009 is quite clear. Van Essen: “It recommends oseltamivir and zanamivir as a possible treatments, but with some conditions attached, all of which must be met: the person must be in a risk group and must be able to start the treatment within 48 h after the first signs of the flu-like symptoms becoming apparent, or 36 h for zanamivir treatment in children. The flu virus should also be known to be in circulation and there must be reasonable grounds to assume that the flu-like illness has been caused by this flu virus. If there is an outbreak of flu-like illness in a long-term residential or nursing home, oseltamivir and zanamivir may be offered to treat residents in ‘at risk’ groups who have
symptoms of flu. In these circumstances, the treatment can be given even if the flu virus is not in circulation in the wider community outside the home, but the healthcare team must be reasonably sure that the illness is indeed flu.” In the Netherlands, the dominant opinion on these matters was set down in the Dutch College of General Practitioners (DCGP) Guideline of 2008. Van Essen: “This guideline starts by saying that it has not been sufficiently demonstrated that neuraminidase inhibitors prevent influenza complications in at-risk patients. Consequently, antiviral medications can only be prescribed in those with strict medical indications and are subject to the limited evidence of being therapeutically beneficial for patients at very high risk, who are presumed to have influenza, who have not been vaccinated against influenza or for whom the vaccine is insufficiently effective. In other words, the patient almost has to be dead before you can start to use antivirals! You can also use antivirals as post exposure prophylaxis during a virologically confirmed influenza outbreak in a care home and for patients with a very high risk of contracting influenza complications (even those who are vaccinated) and during an (imminent) influenza pandemic.” For the purposes of comparison, Van Essen also presented the recent US antiviral guidelines, published in 2013. They are much simpler, easier to follow and much more complete. All the key risk groups are indicated: children younger than 2 years; people aged 65 years or over; persons with chronic pulmonary (including asthma), cardiovascular (excluding hypertension), renal, hepatic, haematological (including sickle cell disease) and metabolic disorders (including diabetes mellitus); persons with immunosuppression; women who are pregnant or postpartum; persons aged younger than 19 years who are receiving long-term aspirin therapy; persons who are morbidly obese (i.e., the BMI is 40 or greater); and residents of nursing homes and other chronic-care facilities. Europe lacks the same kind of comprehensive and clear advice on how to use flu antivirals. And according to Van Essen, there is more to this lack of urgency than post-pandemic flu fatigue – an opinion supported by many specialists in the field. The fuss caused by the supposed concealment of clinical trials; the Cochrane effect and the perception that antivirals only offer a 1-day reduction in sickness (and if it is the first or last day remains unclear!); the myth that influenza only presents a real risk to those in the risk groups: about half of all those hospitalized with flu have no known risk factors, and these opinions strengthen a certain unwillingness to take action to codify the guidelines. Van Essen: “The problem is that doctors are only interested in patients at risk and not in healthy patients. The recommendations say treatment with antivirals should start within the first 48 h of the flu symptoms occurring. But patients generally visit a doctor only after the first 48 h have passed. Most people’s first reaction is to try and ‘sit out’ the disease. There is a general belief among the public that flu is something you don’t need to bother the doctor about. It is only when things get
0264-410X/$ – see front matter http://dx.doi.org/10.1016/j.vaccine.2015.07.066
Please cite this article in press as: van Essen GA, et al. How should influenza be treated? Focus on antivirals. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.07.066
G Model JVAC-16722; No. of Pages 4
ARTICLE IN PRESS Conference report / Vaccine xxx (2015) xxx–xxx
2
worse that they finally decide to do something about it and by then using antivirals may have much less benefit.”
had a front-page feature accusing the planners of irresponsibility in not vaccinating all children!” Endorsing stockpiling
The UK experience In Europe, the country with the largest antiviral stockpiles in terms of the percentage of total population covered is the UK. In 2009 the target coverage increased to 80% and the stockpile has been renewed and replenished since. Peter Openshaw, from Imperial College London, who was part of the UK Pandemic Influenza Committee, offered a personal account of what happened in the UK before, during and after the H1N1 pandemic. Openshaw: “We had a comprehensive plan in place prior to the 2009 pandemic. This was in response to concern about H5N1 or other highly pathogenic strains of flu. The pandemic plan was in part driven by sophisticated epidemiological models and had three phases: (1) Preparation, getting ready by stockpiling antivirals and putting plans in place for accelerated vaccine delivery with advance purchase agreements; (2) Containment, with an emphasis on early diagnosis and treatment. This was designed to slow the speed, blunt the peak and buy time. The UK was unusual in investing heavily in contact prophylaxis, self-isolation and early school closures. We also knew, of course, that at some point we would have to move on to phase (3): Treatment.” “We went for a widespread prophylaxis. This can be seen as an excessive response now that we know how mild most cases of pH1N1 were, but at the time you have to remember that we just did not know how severe the disease was on average. It was quite frightening at the time and we were getting reports of numerous hospitalizations. But we had no real idea about case severity. We thought we might be in the midst of an outbreak of a highly pathogenic virus and that the only responsible thing to do was to do everything to limit spread.” In the UK, there were two very distinct pandemic waves. The first one happened in Spring and the second in Autumn of 2009 in the run up to Christmas. “It was all very different from the single wave the modellers had predicted,” says Openshaw. “During the second wave, we saw more hospitalizations and fewer GP consultations. One of the reasons for this was the UK’s national pandemic flu phone service. If you reached out to the call centre and gave the right answers, you were given an electronic voucher which entitled you to obtain antivirals directly from pharmacies without a prescription. Over a million courses of antivirals were distributed in this way. But the proportion of people who developed flu probably was’nt very high. Only about a quarter of the 2.7 million people who phoned the emergency line were referred to GPs.” Early in 2010 the pandemic was declared to be over. Despite the careful management of publicity and communication, the press was highly critical of the UK response. For example, on 5 February 2010, The Daily Mail wrote: ‘Billions of pounds have been wasted on swine flu vaccines that will never be used’ and listed that 342 million vaccine doses were ordered, 4.25 million people were offered vaccine, £13.5 million was spent on the flu phone-line, approximately 1 million courses of oseltamivir were issued. With all this cost and effort, ‘only’ 411 people died. Openshaw: “By the time the third (post-pandemic) wave hit the UK in November 2010, things had changed. We had moved away from the advice that antivirals should be widely used and reverted to the policy that antivirals should only be used under very strict conditions. As a result, the use of antivirals in the third wave had dropped to almost nothing. There was a big increase in the number of inpatients with confirmed influenza, outnumbering those admitted in the first and second wave combined. And what happened then? The same Daily Mail
In order to get antivirals more widely accepted and make them an integral part of influenza policies, ongoing misunderstandings and popular misconceptions regarding the efficacy and safety of these medicines need to be dealt with effectively. Puja Myles from the University of Nottingham in the UK presented the results of the Post-pandemic Review of anti-Influenza Drug Effectiveness (PRIDE) review of anti-influenza effectiveness during the 2009 flu pandemic. Until now, little pre-pandemic evidence existed relating to the effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza. Most of the evidence came from observational studies of the treatment of seasonal influenza, often in highly specific risk groups. Some studies suggested antivirals were of benefit in restricting serious outcomes, but the surveys were too small to be able to demonstrate statistically significant results. Myles: “For us, the question was this: was there good enough evidence to convince countries to replenish their stocks? This prompted us to systematically review the literature and the available studies, in the hope of arriving at a standardized answer.” The PRIDE review involved 80 research groups from 38 countries. The total sample size was nearly 170,000 patients, including almost 30,000 patients (across all age ranges) admitted to hospital between 2 January 2009 and 14 March 2011. The PRIDE findings indicated that patients hospitalised with H1N1 influenza during the 2009–2010 pandemic were 18% less likely to die if they were given neuraminidase inhibitors. The risk of death was halved (52%) when treatment was started within 2 days of the onset of the illness, in comparison with people who received later antiviral treatment or no antiviral treatment at all. It was therefore clear that early treatment is essential if optimal results are to be obtained. If the clinical suspicion of influenza is high, Myles advocates not waiting for laboratory confirmation before starting treatment. The data also suggest that even when the 48-h mark following symptom onset has passed, treatment might nonetheless confer mortality benefits to critically ill patients. As a result, the review clearly endorses the policy decision to stockpile and use antivirals in treating hospitalised patients during the 2009–2010 pandemic. Providing more evidence Any unsolved scientific matters that hamper proper and effective public guidance in relation to the stockpiling and use of antivirals need to be resolved. In April 2014, the Cochrane Collaboration published a review of clinical study data to assess the effectiveness of the neuraminidase inhibitor oseltamivir (Tamiflu) against influenza. In its conclusions, Cochrane said these medicines are of little value and advised governments not to stockpile neuraminidase inhibitors for use in pandemics, suggesting that this is a waste of taxpayers’ money. The lack of a consensus on the effectiveness of oseltamivir inspired MUGAS Foundation, the Multiparty Group for Advice on Science, to clarify the evidence once and for all. The group unanimously agreed that a more in-depth analysis was needed in order to provide proper medical evidence on which to base reliable findings. In their opinion, reviewing published results from randomized controlled trial data was insufficient to resolve the issues regarding the efficacy and safety of oseltamivir. A deeper analysis of the oseltamivir individual patient data was essential. MUGAS therefore arranged a complete and detailed re-analysis by a statistical group
Please cite this article in press as: van Essen GA, et al. How should influenza be treated? Focus on antivirals. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.07.066
G Model JVAC-16722; No. of Pages 4
ARTICLE IN PRESS Conference report / Vaccine xxx (2015) xxx–xxx
led by Professor Stuart Pollock of the London School of Hygiene and Tropical Medicine. Roche provided MUGAS and Stuart Pollock’s team with all the requested reports and datasets, as well as the necessary individual patient data (IPD), via a secure data room. MUGAS member Arnold Monto, from the University of Michigan, presented the outcome of the re-analysis. “Adult and paediatric trials were meta-analysed separately. The outcomes of greatest interest were time to alleviation, prevention of complications and safety. The meta-analysis was restricted to the licensed 75 mg dose of Tamiflu. The prophylactic studies were not part of the analysis. The preliminary results of the statistical analysis of the oseltamivir data indicate a highly significant reduction in the time to alleviation for the major symptoms of influenza. The results also demonstrate a highly significant reduction in the number of lower respiratory infections requiring antibiotics. The wellknown side-effects of nausea and vomiting were confirmed, but not diarrhoea.” Cochrane’s pronouncements that ‘antivirals are of little value’ and that ‘the harm caused by Tamiflu exceeds the benefits’ have gained momentum in both the public and the political debate, reducing the use of antivirals and jeopardizing the future willingness of governments to stockpile antivirals in preparation for the treatment of pandemics. For the first time, the MUGAS review and the statistical analysis of the oseltamivir data provides meticulous, complete and sustainable evidence of the benefits of antivirals.
The future of antivirals As a last speaker during this SPI Track, Erhard van der Vries from the Department of Viroscience at the Erasmus Medical Centre in Rotterdam, the Netherlands, discussed the future of influenza antivirals. Van der Vries focused on the different windows of opportunity for inhibiting virus replication in influenza-infected patients. The strength of current therapies is their ability to reduce severe clinical outcomes, such as mortality. Van der Vries: “I think new strategies should focus on early treatment and reducing the risk of developing severe influenza infections, especially for patients with a high-risk of contracting such infections. Currently, there are two types of approved influenza antiviral drugs: the M2-channel inhibitors and the neuraminidase inhibitors. The M2channel inhibitors, amantadine and rimantadine, have been around since the 1960s. However, they are only active against the A virus and not the B virus. They also have considerable side-effects and the viruses become easily resistant to the drugs. The neuraminidase inhibitors were designed to be active against both influenza A and B viruses and to have a high barrier of resistance. And although antiviral resistance to this type of drug has also emerged in the past, the level of global incidence is so far low.” Within the last 15 years a number of events have refocused attention on the neuraminidase inhibitors. “Three of these events were of particular importance,” says van der Vries. “First of all, the occasional outbreaks of the highly pathogenic avian virus H5N1 have alerted public health authorities to the possibility of a major pandemic, which has contributed to the stockpiling of these drugs at national level. The recent H7N9 outbreak in China is yet another example of this phenomenon. The second event was the emergence of seasonal influenza viruses with adamantane and oseltamivir resistance. In particular, the emergence of oseltamivir resistant viruses in 2007 and 2008 was surprising. These viruses had inherited oseltamivir resistance with no loss of pathogenicity or ability to spread. The third event, of course, was the outbreak of the 2009 influenza pandemic.” A rapid start to therapy is crucial when treating influenza. Van der Vries: “And in a situation where the immune response
3
is inadequate, the antiviral benefits can be much greater. This can make all the difference in patients with prolonged infection, such as very young children, immuno-compromised patients and the elderly. These strategies do not necessarily mean having to develop new antivirals. Why not start antiviral therapy in a hospital setting before the influenza diagnosis is confirmed, especially for patients at risk? The recommended 5-day regime seems reasonable for adults with an adequate immune response, but what about immuno-compromised patients, where replication can regularly persist for 14 days or even up to a year in extreme cases of immuno-deficiency? Levels of mortality and the emergence of resistant viruses are high in these immuno-compromised groups. Consequently, there needs to be a special focus on strategies that involve reducing the time for starting therapy and treating complicated infections. Oseltamivir resistance emerged in nearly 50% of the cases in the immuno-deficient group and it is expected that the number of patients with an impaired immune system or a high risk of severe influenza, such as obese patients, will further increase in the coming decades.” So what is the pipeline like for new influenza therapies? The most promising antivirals intervene during the first stage of infection, when the virus binds to the receptor or during transcription of the virus genome. Van der Vries: “Monoclonal antibodies have been developed to interact with the receptor binding site or at the stem of the protein, which destabilizes its conformation. DAS181 is a sialidase and strips the virus receptors from the human epithelial cells to prevent virus binding. Currently, a promising candidate is T-705 or favipiravir. This inhibitor is a nucleoside analogue of the influenza RNA polymerase. An advantage of this inhibitor is that it is not only active against influenza, but also targets a broad range of RNA viruses, including the Ebola virus.”
SPI lessons learned Europe lacks consistent guidelines on how best to use antivirals. Moreover, antiviral stockpiling behaviour has been (and still is) very variable in different countries. The PRIDE review clearly endorses the policy decisions taken to stockpile and early use antivirals to reduce mortality during influenza outbreaks. The MUGAS review and the statistical analysis of the oseltamivir data provides solid evidence to support the benefits of early use of antivirals. New Europe-wide antiviral strategies for influenza should be developed based on comprehensive evidence with respect to existing drugs, taking into account drugs that are currently under development.
Conflict of interest Van Essen: None declared. Openshaw: None declared. Myles: • Funded via an unrestricted educational grant from F. HoffmannLa Roche. – The study is being undertaken fully independently of the company, which has had/will have: • no input to the project design; • no access to any of the data; • no role in analysis or data interpretation; • no preview of the study results; • no opportunity to preview or comment on this presentation or any manuscripts arising from the work.
Please cite this article in press as: van Essen GA, et al. How should influenza be treated? Focus on antivirals. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.07.066
G Model JVAC-16722; No. of Pages 4
ARTICLE IN PRESS Conference report / Vaccine xxx (2015) xxx–xxx
4
Monto:
Peter Openshaw Imperial College London, London, UK
• Funded via an unrestricted educational grant from F. HoffmannLa Roche. – The study is being undertaken fully independently of the company, which has had/will have: • no input to the project design; • no access to any of the data; • no role in analysis or data interpretation; • no preview of the study results; • no opportunity to preview or comment on this presentation or any manuscripts arising from the work. Van der Vries: None declared. G(errit) A. van Essen ∗ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
Puja Myles University of Nottingham, Nottingham, UK Arnold Monto University of Michigan School of Public Health, Ann Arbor, MI, USA Erhard van der Vries Erasmus MC, Rotterdam, The Netherlands ∗ Corresponding
author at: Paladijnenweg 30, 3813 DJ Amersfoort, The Netherlands. E-mail address: [email protected] (G.A. van Essen) Available online xxx
Please cite this article in press as: van Essen GA, et al. How should influenza be treated? Focus on antivirals. Vaccine (2015), http://dx.doi.org/10.1016/j.vaccine.2015.07.066