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Rapid Responses: Rapid Responses published:
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Antiviral stockpiles in the UK
- Wei Shen Lim, Jonathan Van Tam (10 February 2007)
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Fashion in treatment
- howard james rose, tr115nl (11 February 2007)
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Re: Antiviral stockpiles in the UK
- Sotirios Tsiodras, John D. Mooney and Angelos Hatzakis (11 February 2007)
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Pandemic stockpiling of amantadine
- John W Barber (12 February 2007)
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The need to look at all the evidence
- Tom Jefferson (22 February 2007)
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Re: The need to look at all the evidence
- Sotirios Tsiodras, John D Mooney, Angelos Hatzakis (3 March 2007)
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The need to look at all the evidence
- John W Barber (12 March 2007)
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Wei Shen Lim, Consultant Respiratory Physician Nottingham University Hospitals, City Hospital Campus, NG5 1PB, Jonathan Van Tam
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The analysis paper by Tsiodras et al states that the UK is stockpiling ion channel inhibitors in addition to neuraminidase inhibitors in its preparations for an influenza pandemic. No reference is given for this statement. Unfortunately, this statement is not correct: the UK maintains a small, historical, stockpile of amantadine, but in relation to current preparations for an influenza pandemic, the UK policy has been to stockpile oseltamivir, and this is reflected in current guidelines. At present, the UK has a stockpile of 14.6 million treatment courses of oseltamivir (Tamiflu). This represents enough oseltamivir to treat 25% of the population." Competing interests: None declared |
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howard james rose, retired 21 church road mylor falmouth, tr115nl
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Dear sir,Even when someone is ill with something like flu treatment is influenced by fashion.I was involved with investigating the effect of amantdineon acute aand b flu in the lat 1970s as i was a school medical officer.In those days the experts believed that a vaccine was the answer despite the common cold evadingcontrol by this approach i showed amantidine to be effective with only minimal side effects but this was ignored. Ibelieve amantidinehas gone on to be used as a prophylactic in the flocks of chickhens in the far east hence the emergence of resistence.It is reassuring to read sotirios Tsiodras article,we need two at least weapons to manage influenza,stockpile the cheapest,the tried and tested old drug not the new wonder drug.Hit the earlycases with both drugs and stop the emergence of resistance howard rose Competing interests: none |
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Sotirios Tsiodras, Lecturer in Internal Medicine and Infectious Diseases University of Athens Medical School, John D. Mooney and Angelos Hatzakis
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Antiviral stockpiles in the UK Our statement on UK's stockpiles of amantadine is based on a previous parliamentary publication (14 Mar 2005, Column WA121) available at : http://www.publications.parliament.uk/pa/ld200405/ldhansrd/pdvn/lds05/text/50314w06.htm We acknowledge that this refers to limited historical stockpiles and that it was incorrect to give the impression that the UK is actively stockpiling ion channel inhibitors. The authors regret this inaccuracy and we are grateful to Lim and Van Tam for clarification on this point. Competing interests: None declared |
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John W Barber, Director, Scientific Affairs Alliance Pharmaceuticals Ltd, Avonbridge House, Bath Road, Chippenham, Wiltshire, SN15 2BB
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Tsiodras et al make a number of significant statements regarding the management of pandemic influenza(1). In particular, they propose the stockpiling of M2 ion channel inhibitors for potential use in combination with neuraminidase inhibitors. This proposal echoes the findings of an assessment of the scientific evidence on the role of anti-influenzals conducted by the EMEA (European Medicines Agency) in 2005(2), which concluded that: Both the M2-inhibitors and the neuraminidase inhibitors are potentially useful in a pandemic situation. However, none of them provide an ideal solution to antiviral therapy of influenza. Thus, the availability of more than one agent would be useful in order to cope with special and unexpected circumstances, such as emergence of resistant strains. The dependence of [sic] only one provider makes the pandemic plans vulnerable These findings were submitted to all EU Member States to aid their pandemic planning but whilst the UK has had a stockpile of amantadine since the mid 1990s, no other EU country, with the known exceptions of Greece and Sweden, are known to be stockpiling more than oseltamivir alone. However, the UK stockpile of amantadine equates to only 0.5 million treatment courses compared with the 14.6 million treatment courses of oseltamivir held and there is no evidence that the UK government is planning to increase its stockpile of amantadine. The authors suggest that the low cost of M2 ion channel blockers could be a disincentive for the pharmaceutical industry to invest in conducting clinical trials on combination therapy. In reality, however, the greater disincentives are the focus on the stockpiling of just one anti-influenzal, oseltamivir (Tamiflu, Roche), the push for a vaccine for the pandemic strain which is as yet unknown, and the lack of endorsement of the use of anti-influenzals during normal, interpandemic outbreaks(3). It should be remembered that amantadine is used not just for the management of influenza A, its main therapeutic use is in Parkinson’s disease. There is a legitimate concern that, if stocks of amantadine are suddenly diverted into a pandemic stockpile, the continuity of supply to Parkinson’s disease patients may be severely disrupted. If governments are to consider stockpiling amantadine for an influenza pandemic, planning should commence immediately and not be delayed until just before the pandemic strikes. (1) Tsiodras S, Mooney JD, Hatzakis A. Role of combination antiviral therapy in pandemic influenza and stockpiling implications. BMJ 2007; 334(7588):293-294. (2) Summary report. Review on influenza antiviral medicinal products for potential use during pandemic. EMEA/CHMP/339972/2005, 2005. European Medicines Agency (EMEA). (3) Guidance on the use of zanamivir, oseltamivir and amantadine in the treatment of influenza. 58. 2003. National Institue for Clinical Excellence. Technology Appraisal Guidance. Competing interests: Alliance Pharmaceuticals is the UK MAH for Symmetrel Capsules (amantadine 100mg), Symmetrel Syrup (amantadine 50mg/5ml) and Lysovir Capsules (amantadine 100mg |
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Tom Jefferson, Cochrane Acute Respiratory Infections Group Anguillara Sabazia, 00061, Italy
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I believe that any paper, be it original research, an analysis, editorial or comment that draws inductive conclusions should be based on evidence drawn from systematic reviews of the topic. When these are not available, the evidence base should come from systematic, reproducible and explicit searches of evidence unlikely to be tainted by the play of confounders. The analysis by Tsiodras, Mooney and Hatzakis is a good example of the pitfalls of not following a systematic method. The authors propose testing Amantadine to see if any benefits could accrue in combination with Neuraminidase Inhibitors. The principal attraction appears to be low cost. Although they quote resistance and harms as well as lack of "any demonstrable reduction in transmissibility or pathogenicity" this does not seem to deter them from their proposal. Had the authors consulted the Cochrane Library, they would have discovered that Amantadine (the only adamantane for which we have a reasonable knowledge base) relieves or suppresses symptoms if taken within 48 hours, but does not prevent infection with influenza A viruses, nor does it stop their nasal excretion. This is the key finding in a pandemic situation as apparently healthy individuals devoid of symptoms and feeling good because they have taken "the pill" would actually be spreading influenza viruses in the community, through contact and droplets. Amantadine suppresses symptoms but not infection, it does not prevent or even diminish the risk of influenza communication, it causes unacceptable harms, resistance to it is widespread and swiftly induced: it is a very dangerous drug, especially in a pandemic (1). My second point is that the authors have obviously never been in a situation where soldiers or policemen have to mount armed guard on essential supplies, or perform the million and one task of the military aid to a civilian power which will be their lot in the case of a pandemic. Would the authors give prophylactic amantadine to essential workers knowing it causes gastrointestinal symptoms (mainly nausea, OR 2.56; 95% CI 1.37 to 4.79) insomnia and hallucinations (OR 2.54; 95% CI 1.50 to 4.31) and caused withdrawals from the trials because of adverse events (2.54; 95% CI 1.60 to 4.06) (1)? Would they give it to ambulance drivers, train conductors and helicopter pilots? The article contains dangerous half-truths based on a partial reading of the evidence. If pharmacological intervention is required to help contain a pandemic, then neuraminidase inhibitors are far safer and more effective than adamantanes (2). No benefit, but a lot of harm will accrue with continued use of Amantadine. That is what all available comparative evidence shows. Bibliography 1. T Jefferson, V Demicheli, C Di Pietrantonj, D Rivetti. Amantadine and rimantadine for influenza A in adults. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD001169. DOI: 10.1002/14651858.CD001169.pub3. 2. TO Jefferson, V Demicheli, C Di Pietrantonj, M Jones, D Rivetti. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD001265. DOI: 10.1002/14651858.CD001265.pub2. Competing interests: I am the first author of both relevant Cochrane Reviews. I hold no stock or shares nor have I received any fees in the last 5 years from any organisation which could benefit or be harmed by my contribution. |
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Sotirios Tsiodras, Lecturer, University of Athens Medical School 12462, Athens Greece, John D Mooney, Angelos Hatzakis
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We thank Dr Jefferson for his comments(1). In response to his call to look at all the evidence, we wholeheartedly agree that any recommendations for a particular therapy or intervention should be based on the best quality evidence available. It is for this reason that the central message of our article(2) was to highlight the need for an improved evidence base on which to decide whether there is a genuine case to made for re- examining a role for ion channel inhibitors for pandemic influenza, and in particular for their potential role in combination therapy with the newer antivirals, the neuraminidase inhibitors (oseltamivir and zanamivir). With reference to the findings of Dr Jefferson’s two cited Cochrane reviews (3, 4) we would also certainly not contest that on the balance of available evidence, oseltamivir is the best monotherapeutic antiviral option in the event of a possible influenza pandemic. The review which deals with the neuraminidase inhibitors (NIs) however also highlights that this class of drugs are not devoid of the problems which beset amantadine(4). Firstly, like amantadine, they do not prevent infection; secondly higher prophylactic doses of oseltamivir (150mg) result in significant nausea (OR 2.29, 95% CI 1.34-3.92) comparable to the risk level quoted for amantadine prophylaxis and thirdly, resistance clearly cannot be ruled out when there is widespread use with one study in Japan reporting resistant isolates in 18% of 50 very young children after 4 days of treatment (A/H3N2) with prolonged viral excretion(5). Indeed the authors conclude that “the inability of NI’s to prevent infection and to suppress viral nasal excretion raises doubts as to their effectiveness in interrupting viral spread in a pandemic”. On the specific issue of side effects, research from nearly 20 years ago demonstrates that the adverse effects of amantadine, like those of oseltamivir, are strongly dose dependent with reductions to half the normal recommended dose (100mg/day compared to 200mg/day) resulting in a side effect profile statistically indistinguishable from placebo, while prophylactic efficacy was maintained(6). Concerns have also recently been raised about an increased risk of serious neuro-psychiatric symptoms (that have included self-injury) associated with the use of oseltamivir particularly in children and young adults(7, 8). Taking account of all the evidence presented in the reviews and in subsequent reports, it becomes apparent that neither class of antiviral drugs can be seen as a panacea. As Jefferson et al conclude in the NI review(4), anti-virals should only be considered as part of a wider package of measures and options to control the potential spread of pandemic influenza. If, as seems likely, there is a possibility that combination therapy could be used to strengthen the antiviral option by limiting side effects and the emergence of resistance, as has clearly been the case with other genetically versatile pathogens (most notably HIV), then we still feel that this may be an approach worthy of renewed attention. S Tsiodras, MD, MSc, PhD
References 1. Jefferson T. The need to look at all the evidence. Rapid Response to Tsiodras et al, (22 February 2007) 2. Tsiodras S, Mooney JD, Hatzakis A. Role of combination antiviral therapy in pandemic influenza and stockpiling implications. BMJ 2007; 334(7588):293-294. 3. T Jefferson, V Demicheli, C Di Pietrantonj, D Rivetti. Amantadine and rimantadine for influenza A in adults. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD001169. DOI: 10.1002/14651858.CD001169.pub3. 4. T Jefferson, V Demicheli, C Di Pietrantonj, M Jones, D Rivetti. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD001265. DOI: 10.1002/14651858.CD001265.pub2. 5. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C, Kimura K, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 2004;364:759-65. 6. Reuman PD, Bernstein DI, Keefer MC, Young EC, Sherwood JR, Schiff GM. Efficacy and safety of low dosage amantadine hydrochloride as prophylaxis for influenza A. Antiviral Res. 1989 Feb;11(1):27-40. 7. [No authors given]. Oseltamivir: cutaneous and neurological adverse effects in children. Prescrire Int. 2006 Oct;15(85):182-3. 8. Available at: http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006- 4254b_09_01_Tamiflu%20AE%20Review%202006%20Redacted_D060309_092.pdf Competing interests: None declared |
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John W Barber, Director, Scientific Affairs Alliance Pharmaceuticals Ltd, Avonbridge House, Bath Road, Chippenham, Wiltshire, SN15 2BB
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Jefferson is correct in his assertion that governments should look at all the evidence before stockpiling amantadine (1). It is unfortunate, however, in that citing only his Cochrane review he has ignored a whole body of other, equally relevant evidence. There is evidence that supports the use of combination therapy with amantadine and a neuraminidase inhibitor (NAI), such as oseltamivir, during an influenza outbreak. It is therefore possible that this should be a strategy to be used during a pandemic to reduce the risk of a pandemic strain arising that is resistant to either amantadine or the NAI. In the House of Lords report on pandemic influenza, a recommendation was made that the UK Department of Health consider a back up plan that could include combination use of oseltamivir and amantadine (2). At a conference on the threat of avian ‘flu (Retroscreen conference, 19-20 Jan 2006), a number of international experts agreed that combination therapy with oseltamivir and amantadine may have a role in the management of both emerging clinical cases of avian ‘flu and pandemic ‘flu. Two recent studies support the role of combination therapy during a pandemic (3,4). The first study looked at the effect of a combination of amantadine and oseltamivir on the emergence of resistant variants in vitro (3). Three strains were used in the study – H1N1, H3N2 and H5N1. Each strain was cultured for five sequential passages in varying concentrations of amantadine and/or oseltamivir. Whilst resistant variants were isolated for those strains cultured in amantadine alone and in oseltamivir alone, no resistant variants were isolated when they were cultured in the combination. The second study looked at the synergistic antiviral effect of a combination of rimantadine and oseltamivir in vivo (4). As amantadine and rimantadine are generally considered to be therapeutically equivalent, the conclusions from this study may therefore be extrapolated to amantadine. In this study, mice were infected with an H3N2 isolate and treated for five days with various concentrations of rimantadine and/or oseltamivir. The effect of the various treatments on survival and titres of lung virus were assessed. There were significant differences in the parameters assessed between the combination groups and those mice treated separately. In the combination groups, survival rates ranged form 34% to 87% whilst in the single treatment groups, survival rates ranged from 0% to 30%. There were also significant differences in survival time, being lengthened by 3.1-6.9 days in the combination groups and 0-1.9 days in the single treatment groups. The authors concluded that combination therapy had a synergistic, rather than just an additive effect. Such combination therapy may also allow lower doses of the individual anti-influenzal agents to be used. This may help avoid some of the adverse events associated with both agents and therefore aid compliance with therapy. Pandemic influenza will be an extraordinary event requiring extraordinary solutions. Stockpiling amantadine may well be one of those solutions. References 1. Jefferson T. Pandemic flu: Look at all the evidence before stockpiling amantadine. BMJ 2007;334(7591):439 2. House of Lords, Science and Technology Fourth Report. Pandemic Influenza. HL88.2005. 3. Ilyushina NA, Bovin NV, Webster RG, Govorkova EA. Combination chemotherapy, a potential strategy for reducing the emergence of drug- resistant influenza A variants. Antiviral Res 2006;70(3):121-31 4. Galabov AS, Simeonova L, Gegova G. Rimantadine and oseltamivir demonstrate synergistic combination effect in an experimental infection with type A (H3N2) influenza virus in mice. Antivir Chem Chemother 2006; 17(5):251-258. Competing interests: Competing interests: Alliance Pharmaceuticals is the UK MAH for Symmetrel Capsules (amantadine 100mg), Symmetrel Syrup (amantadine 50mg/5ml) and Lysovir Capsules (amantadine 100mg |
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