Comment
Fighting influenza—a new weapon in the armoury? preparation stage, we will probably have to wait some time to understand the full public health relevance of this drug. In what other ways might the new treatment hold promise? These preliminary findings suggest an effect size that is comparable to that achieved with existing drugs; neuraminase inhibitors also typically reduce symptom duration by a little less than a day,2 but the introduction of a new drug class could be a valuable instrument against the threat of resistant virus. Haffizulla and colleagues3 report no development of nitazoxanide resistance in the few samples cultured from swabs taken 5 days into treatment, but acknowledge the need for future studies to assess more comprehensively the potential for resistance. Another intriguing finding was the drug’s apparent efficacy in around half of trial patients in whom no influenza virus was ultimately identified; even in those with no identifiable virus at all, median symptom duration was reduced by roughly 17 h. This reduction suggests a potential broader role for nitazoxanide in treatment of influenzalike illness. Finally, could nitazoxanide have a role in combination antiviral therapy? The ongoing phase 3 trial (NCT01610245) of combined nitazoxanide and oseltamivir versus each drug given as monotherapy will help to answer this question. The early findings and data presented by Haffizulla and colleagues3 are interesting and suggest that nitazoxanide is worth pursuing for its potential. But we must bear in mind the caveats that come with this
www.thelancet.com/infection Published online May 20, 2014 http://dx.doi.org/10.1016/S1473-3099(14)70769-8
Lancet Infect Dis 2014 Published Online May 20, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70769-8 See Online/Articles http://dx.doi.org/10.1016/ S1473-3099(14)70717-0
Tim Vernon, LTH NHS Trust/Science Photo Library
The search for treatments to reduce the effect of influenza dates back decades and even centuries. In March, 1899, Charles Graham Grant wrote to the British Medical Journal with substantial excitement about a promising new use of cinnamon: ‘‘I was anything but prepared to find the extraordinary influence it seemed to exert when I began to use it in cases of influenza in, I believe, the 1891 epidemic.’’1 Sadly, cinnamon did not live up to this early promise, and today, despite decades of endeavour we still have at our disposal only a handful of treatments for influenza—mainly, the neuraminadase inhibitors oseltamavir and zanamavir. An updated Cochrane review concludes that although these drugs slightly shorten the time to alleviation of symptoms of influenza in adults, their ability to prevent complications such as pneumonia is unclear.2 In The Lancet Infectious Diseases, Jason Haffizulla and colleagues3 report a welcome attempt to broaden the available options. Their small phase 2b/3 placebo-controlled trial suggests a modest benefit of nitazoxanide—a drug first discovered in the 1980s and already an established treatment for diarrhoea caused by Cryptosporidium parvum and Giardia lamblia infections. In individuals aged 12–65 years with uncomplicated disease, nitazoxanide reduced the median duration of influenza symptoms by around 21 h. Reducing the misery endured by otherwise healthy adults and adolescents unlucky enough to come down with influenza is attractive, but must be weighed up against the risk of side-effects (for which the trial data are reassuring) and costs of treatment. However, present guidelines do not usually consider such individuals a priority for treatment.4,5 The real prize is surely to reduce complications and mortality in the more vulnerable patients and those presenting with severe influenza, and the trial gives us no information about whether nitazoxanide can achieve this. Most deaths from seasonal influenza occur in older individuals and those with other morbidities.6,7 In this trial, the investigators crucially recruited only adolescents and adults aged 65 years and younger, and excluded those with severe disease or at risk of complications. This recruitment was understandable for an early-stage placebo-controlled study, but because at present trials of high-risk individuals are only at the
1
Comment
early-stage research. Will there ultimately be a role for this drug in treatment of influenza, or will we look back on this small trial as showing early promise that was not ultimately realised? At this stage it is impossible to say. At the close of the 19th century, Grant’s enthusiasm for cinammon as a breakthrough in influenza treatment proved somewhat premature. In 2014, we must calibrate our expectations, temper optimism with caution, and await further evidence. *Krishnan Bhaskaran, Sara L Thomas Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK (KB, SLT) [email protected] We declare no competing interests.
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Grant CG. Correspondence: cinnamon in influenza. BMJ 1899; 1: 763. Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2014; 4: CD008965. Haffizulla J, Hartman A, Hoppers M, et al. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2B/3 trial. Lancet Infect Dis 2014; published online May 20. http://dx.doi.org/10.1016/S1473-3099(14)70717-0. Fiore AE, Fry A, Shay D, et al. Antiviral agents for the treatment and chemoprophylaxis of influenza - recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2011; 60: 1–24. National Institute for Health and Clinical Excellence. NICE technology appraisal guidance 168: Amantadine, oseltamivir and zanamivir for the treatment of influenza, 2009 http://www.nice.org.uk/nicemedia/ live/11774/43268/43268.pdf (accessed March 25, 2014). Dawood FS, Iuliano AD, Reed C, et al. Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a modelling study. Lancet Infect Dis 2012; 12: 687–95. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003; 289: 179–86.
www.thelancet.com/infection Published online May 20, 2014 http://dx.doi.org/10.1016/S1473-3099(14)70769-8
Fighting influenza—a new weapon in the armoury? preparation stage, we will probably have to wait some time to understand the full public health relevance of this drug. In what other ways might the new treatment hold promise? These preliminary findings suggest an effect size that is comparable to that achieved with existing drugs; neuraminase inhibitors also typically reduce symptom duration by a little less than a day,2 but the introduction of a new drug class could be a valuable instrument against the threat of resistant virus. Haffizulla and colleagues3 report no development of nitazoxanide resistance in the few samples cultured from swabs taken 5 days into treatment, but acknowledge the need for future studies to assess more comprehensively the potential for resistance. Another intriguing finding was the drug’s apparent efficacy in around half of trial patients in whom no influenza virus was ultimately identified; even in those with no identifiable virus at all, median symptom duration was reduced by roughly 17 h. This reduction suggests a potential broader role for nitazoxanide in treatment of influenzalike illness. Finally, could nitazoxanide have a role in combination antiviral therapy? The ongoing phase 3 trial (NCT01610245) of combined nitazoxanide and oseltamivir versus each drug given as monotherapy will help to answer this question. The early findings and data presented by Haffizulla and colleagues3 are interesting and suggest that nitazoxanide is worth pursuing for its potential. But we must bear in mind the caveats that come with this
www.thelancet.com/infection Published online May 20, 2014 http://dx.doi.org/10.1016/S1473-3099(14)70769-8
Lancet Infect Dis 2014 Published Online May 20, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70769-8 See Online/Articles http://dx.doi.org/10.1016/ S1473-3099(14)70717-0
Tim Vernon, LTH NHS Trust/Science Photo Library
The search for treatments to reduce the effect of influenza dates back decades and even centuries. In March, 1899, Charles Graham Grant wrote to the British Medical Journal with substantial excitement about a promising new use of cinnamon: ‘‘I was anything but prepared to find the extraordinary influence it seemed to exert when I began to use it in cases of influenza in, I believe, the 1891 epidemic.’’1 Sadly, cinnamon did not live up to this early promise, and today, despite decades of endeavour we still have at our disposal only a handful of treatments for influenza—mainly, the neuraminadase inhibitors oseltamavir and zanamavir. An updated Cochrane review concludes that although these drugs slightly shorten the time to alleviation of symptoms of influenza in adults, their ability to prevent complications such as pneumonia is unclear.2 In The Lancet Infectious Diseases, Jason Haffizulla and colleagues3 report a welcome attempt to broaden the available options. Their small phase 2b/3 placebo-controlled trial suggests a modest benefit of nitazoxanide—a drug first discovered in the 1980s and already an established treatment for diarrhoea caused by Cryptosporidium parvum and Giardia lamblia infections. In individuals aged 12–65 years with uncomplicated disease, nitazoxanide reduced the median duration of influenza symptoms by around 21 h. Reducing the misery endured by otherwise healthy adults and adolescents unlucky enough to come down with influenza is attractive, but must be weighed up against the risk of side-effects (for which the trial data are reassuring) and costs of treatment. However, present guidelines do not usually consider such individuals a priority for treatment.4,5 The real prize is surely to reduce complications and mortality in the more vulnerable patients and those presenting with severe influenza, and the trial gives us no information about whether nitazoxanide can achieve this. Most deaths from seasonal influenza occur in older individuals and those with other morbidities.6,7 In this trial, the investigators crucially recruited only adolescents and adults aged 65 years and younger, and excluded those with severe disease or at risk of complications. This recruitment was understandable for an early-stage placebo-controlled study, but because at present trials of high-risk individuals are only at the
1
Comment
early-stage research. Will there ultimately be a role for this drug in treatment of influenza, or will we look back on this small trial as showing early promise that was not ultimately realised? At this stage it is impossible to say. At the close of the 19th century, Grant’s enthusiasm for cinammon as a breakthrough in influenza treatment proved somewhat premature. In 2014, we must calibrate our expectations, temper optimism with caution, and await further evidence. *Krishnan Bhaskaran, Sara L Thomas Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, UK (KB, SLT) [email protected] We declare no competing interests.
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Grant CG. Correspondence: cinnamon in influenza. BMJ 1899; 1: 763. Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 2014; 4: CD008965. Haffizulla J, Hartman A, Hoppers M, et al. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2B/3 trial. Lancet Infect Dis 2014; published online May 20. http://dx.doi.org/10.1016/S1473-3099(14)70717-0. Fiore AE, Fry A, Shay D, et al. Antiviral agents for the treatment and chemoprophylaxis of influenza - recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2011; 60: 1–24. National Institute for Health and Clinical Excellence. NICE technology appraisal guidance 168: Amantadine, oseltamivir and zanamivir for the treatment of influenza, 2009 http://www.nice.org.uk/nicemedia/ live/11774/43268/43268.pdf (accessed March 25, 2014). Dawood FS, Iuliano AD, Reed C, et al. Estimated global mortality associated with the first 12 months of 2009 pandemic influenza A H1N1 virus circulation: a modelling study. Lancet Infect Dis 2012; 12: 687–95. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003; 289: 179–86.
www.thelancet.com/infection Published online May 20, 2014 http://dx.doi.org/10.1016/S1473-3099(14)70769-8
