- Email: [email protected]
Optimum timing of oseltamivir: lessons from Bangladesh
Comment
Optimum timing of oseltamivir: lessons from Bangladesh Widespread resistance in currently circulating influenza A viruses has reduced the options for antiviral therapy against influenza.1,2 Neuraminidase inhibitors, including laninamivir, oseltamivir, peramivir, and zanamivir, are the only approved anti-influenza drugs that have proven activity against circulating strains of influenza A and B viruses worldwide.3 Oseltamivir is available in both pill and oral suspension formulations that can be given safely to patients of any age.4–7 Furthermore, oseltamivir has been the most widely used antiviral drug for the treatment of influenza in all patient populations, including ambulatory adults and children and patients with complicated influenza who need hospital admission. The optimum timing of antiviral therapy in patients infected with influenza has been studied in various settings. Most randomised clinical trials of oseltamivir in ambulatory adults have been limited to patients presenting within 48 h of symptom onset.6–9 The interval between symptom onset and initiation of oseltamivir treatment in ambulatory adults is predictive of the effect of therapy: early treatment, within 6 h of symptom onset, is associated with the greatest reduction in the duration of fever, severity of symptoms, and time to return to baseline activity.9 In patients with compromised immunity and those who need to be admitted to hospital, observational data suggest that antiviral therapy is associated with clinical benefit beyond
Published Online November 22, 2013 http://dx.doi.org/10.1016/ S1473-3099(13)70287-1
Ap Pasieka/Science Photo Library
See Articles page 109
88
48 h.10,11 Similarly to ambulatory patients, hospitalised and immunocompromised patients seem to gain the greatest benefit when treatment is initiated early in the course of illness.10,12–14 Although the available evidence supports early initiation of antiviral therapy to maximise the clinical effect of oseltamivir treatment in patients with influenza infection, health care-seeking behaviour and access to medical care often results in delayed presentation for treatment. Insufficient data have been available to provide information about the role of oseltamivir in patients, especially those who do not need hospital admission, who present 48 h or longer after symptom onset. Furthermore, scarce data exist for the efficacy of oseltamivir in developing countries where malnutrition and other comorbidities can result in more severe or progressive influenza infections in ambulatory adults and children. This fact is of particular importance because the burden of influenza in such less developed regions is likely to be substantial.15 In The Lancet Infectious Diseases, Alicia Fry and colleagues16 present data from a randomised placebocontrolled trial of patients diagnosed with influenza within 5 days of symptom onset. Eligible participants were randomly allocated to 5 days of oseltamivir or placebo; pregnant women, children younger than 1 year of age, and those with a history of seizure were excluded. Participants were visited by research assistants until 7 consecutive days after symptom resolution and nasal washes were collected at enrolment and at days 2, 4, and 7 after enrolment. 1190 patients were enrolled in the study, 67% (794) of whom began treatment within 48 h of symptom onset. Most of the patients (89%) were children and there was an almost even distribution of influenza subtypes in the study: 35% influenza A H3N2, 11% seasonal influenza A H1N1, 18% influenza A H1N1 pdm09, and 33% influenza B. All seasonal A H1N1 viruses had the His275Tyr mutation in the neuraminidase gene. In this study, oseltamivir treatment was associated with a 1 day reduction in the duration of major symptoms and significantly reduced detection of virus by PCR and culture at days 2, 4, and 7. Notably, treatment that was started up to 72 h after illness onset was associated with significantly reduced virus isolation on days 2 and 4, and a reduced duration of major symptoms compared with placebo. www.thelancet.com/infection Vol 14 February 2014
Comment
Treatment was generally well tolerated with a low frequency of vomiting, which was higher in the patients given oseltamivir. Moreover, few isolates developed oseltamivir resistance during the study. This study is especially important because it is one of the first to present data for oseltamivir treatment in a controlled study in ambulatory patients who began treatment more than 48 h after symptom onset. Since most of these patients presented on day 3 after symptom onset and still achieved clinical and virological benefit from oseltamivir, this study questions the existing idea that treatment started after 48 h is of low benefit. Perhaps most importantly, virus shedding was reduced by a similar amount with oseltamivir, irrespective of whether treatment was initiated within 48 h or 72 h after illness onset. Furthermore, a 1 day reduction in major symptoms occurred in patients given oseltamivir, whether 48 h or 72 h after illness onset. Since most of the patients were children and had positive rapid antigen tests, this finding might indicate a benefit of treatment in patients with higher baseline viral loads. Patients with higher baseline viral loads and children generally have a longer duration of viral shedding and therefore could potentially benefit from antiviral therapy started more than 48 h after symptom onset. Although time since symptom onset is easy to measure in the clinic, it could be imprecise. As we develop more robust ways to measure quantitative or semiquantitative viral load monitoring for influenza, baseline viral load might be more predictive of benefit from antiviral therapy than time since onset of symptoms.17 However, for now we must rely on the time from symptom onset, particularly in resource-poor settings. This study enrolled patients from a crowded, lowincome community. Such patients might have been malnourished or had other disorders that resulted in more prolonged viral shedding, which could partly explain the study’s findings.18 Nonetheless, this study suggests that patients with ongoing viral replication and clinical symptoms up to day 3 after symptom onset would benefit from oseltamivir treatment. Future studies should investigate whether later onset therapy results in similar positive outcomes in mainly adult patients and those from more developed regions. These findings will help to inform guidelines for the treatment of influenza and should spur research to better define the optimum timing of antiviral therapy in a range of clinical settings. www.thelancet.com/infection Vol 14 February 2014
Most importantly, this study raises the idea that some ambulatory patients could benefit from clinical therapy beyond 48 h after symptom onset. Michael G Ison Divisions of Infectious Diseases and Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA [email protected] MGI has received research support (paid to Northwestern University) from Anolinx, Cellex, Chimerix, Crucell, GlaxoSmithKlein, NexBio, and ViroPharma. He has acted as a paid consultant for Alios, Abbott, Crucell, and Genentech/Roche, and as an unpaid consultant for BioCryst, Biota, Cellex, Clarassance, GlaxoSmithKline, Toyama/MediVector, NexBio, Theraclone, Vertex, and Visterra. He has participated in Data and Safety Monitoring Boards for Biota and NexBio. 1
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Deyde VM, Xu X, Bright RA, et al. Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. J Infect Dis 2007; 196: 249–57. Bright RA, Medina MJ, Xu X, et al. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet 2005; 366: 1175–81. Ison MG. Clinical use of approved influenza antivirals: therapy and prophylaxis. Influenza Other Respi Viruses 2013; 7 (suppl 1): 7–13. Kimberlin DW, Acosta EP, Prichard MN, et al. Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza. J Infect Dis 2013; 207: 709–20. Acosta EP, Jester P, Gal P, et al. Oseltamivir dosing for influenza infection in premature neonates. J Infect Dis 2010; 202: 563–66. Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 2001; 20: 127–33. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA 2000; 283: 1016–24. Nicholson KG, Aoki FY, Osterhaus AD, et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Lancet 2000; 355: 1845–50. Aoki FY, Macleod MD, Paggiaro P, et al. Early administration of oral oseltamivir increases the benefits of influenza treatment. J Antimicrob Chemother 2003; 51: 123–29. Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clin Infect Dis 2012; 55: 1198–204. Adisasmito W, Chan PK, Lee N, et al. Strengthening observational evidence for antiviral effectiveness in influenza A (H5N1). J Infect Dis 2011; 204: 810–11. Lee N, Choi KW, Chan PK, et al. Outcomes of adults hospitalised with severe influenza. Thorax 2010; 65: 510–15. Reid G, Huprikar S, Patel G, et al. A multicenter evaluation of pandemic influenza A/H1N1 in hematopoietic stem cell transplant recipients. Transpl Infect Dis 2013; 15: 487–92. Kumar D, Michaels MG, Morris MI, et al. Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study. Lancet Infect Dis 2010; 10: 521–26. Nair H, Brooks WA, Katz M, et al. Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis. Lancet 2011; 378: 1917–30. Fry AM, Goswami D, Nahar K, et al. Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomised placebo-controlled trial. Lancet Infect Dis 2013; published online Nov 22. http://dx.doi. org/10.1016/S1473-3099(13)70267-6. Lee N, Chan PK, Rainer TH, Hui D, Choi KW, Cockram CS. Influenza virus load in hospitalised patients. Hong Kong Med J 2013; 19 (suppl 4): 15–18. Taylor AK, Cao W, Vora KP, et al. Protein energy malnutrition decreases immunity and increases susceptibility to influenza infection in mice. J Infect Dis 2013; 207: 501–10.
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Optimum timing of oseltamivir: lessons from Bangladesh Widespread resistance in currently circulating influenza A viruses has reduced the options for antiviral therapy against influenza.1,2 Neuraminidase inhibitors, including laninamivir, oseltamivir, peramivir, and zanamivir, are the only approved anti-influenza drugs that have proven activity against circulating strains of influenza A and B viruses worldwide.3 Oseltamivir is available in both pill and oral suspension formulations that can be given safely to patients of any age.4–7 Furthermore, oseltamivir has been the most widely used antiviral drug for the treatment of influenza in all patient populations, including ambulatory adults and children and patients with complicated influenza who need hospital admission. The optimum timing of antiviral therapy in patients infected with influenza has been studied in various settings. Most randomised clinical trials of oseltamivir in ambulatory adults have been limited to patients presenting within 48 h of symptom onset.6–9 The interval between symptom onset and initiation of oseltamivir treatment in ambulatory adults is predictive of the effect of therapy: early treatment, within 6 h of symptom onset, is associated with the greatest reduction in the duration of fever, severity of symptoms, and time to return to baseline activity.9 In patients with compromised immunity and those who need to be admitted to hospital, observational data suggest that antiviral therapy is associated with clinical benefit beyond
Published Online November 22, 2013 http://dx.doi.org/10.1016/ S1473-3099(13)70287-1
Ap Pasieka/Science Photo Library
See Articles page 109
88
48 h.10,11 Similarly to ambulatory patients, hospitalised and immunocompromised patients seem to gain the greatest benefit when treatment is initiated early in the course of illness.10,12–14 Although the available evidence supports early initiation of antiviral therapy to maximise the clinical effect of oseltamivir treatment in patients with influenza infection, health care-seeking behaviour and access to medical care often results in delayed presentation for treatment. Insufficient data have been available to provide information about the role of oseltamivir in patients, especially those who do not need hospital admission, who present 48 h or longer after symptom onset. Furthermore, scarce data exist for the efficacy of oseltamivir in developing countries where malnutrition and other comorbidities can result in more severe or progressive influenza infections in ambulatory adults and children. This fact is of particular importance because the burden of influenza in such less developed regions is likely to be substantial.15 In The Lancet Infectious Diseases, Alicia Fry and colleagues16 present data from a randomised placebocontrolled trial of patients diagnosed with influenza within 5 days of symptom onset. Eligible participants were randomly allocated to 5 days of oseltamivir or placebo; pregnant women, children younger than 1 year of age, and those with a history of seizure were excluded. Participants were visited by research assistants until 7 consecutive days after symptom resolution and nasal washes were collected at enrolment and at days 2, 4, and 7 after enrolment. 1190 patients were enrolled in the study, 67% (794) of whom began treatment within 48 h of symptom onset. Most of the patients (89%) were children and there was an almost even distribution of influenza subtypes in the study: 35% influenza A H3N2, 11% seasonal influenza A H1N1, 18% influenza A H1N1 pdm09, and 33% influenza B. All seasonal A H1N1 viruses had the His275Tyr mutation in the neuraminidase gene. In this study, oseltamivir treatment was associated with a 1 day reduction in the duration of major symptoms and significantly reduced detection of virus by PCR and culture at days 2, 4, and 7. Notably, treatment that was started up to 72 h after illness onset was associated with significantly reduced virus isolation on days 2 and 4, and a reduced duration of major symptoms compared with placebo. www.thelancet.com/infection Vol 14 February 2014
Comment
Treatment was generally well tolerated with a low frequency of vomiting, which was higher in the patients given oseltamivir. Moreover, few isolates developed oseltamivir resistance during the study. This study is especially important because it is one of the first to present data for oseltamivir treatment in a controlled study in ambulatory patients who began treatment more than 48 h after symptom onset. Since most of these patients presented on day 3 after symptom onset and still achieved clinical and virological benefit from oseltamivir, this study questions the existing idea that treatment started after 48 h is of low benefit. Perhaps most importantly, virus shedding was reduced by a similar amount with oseltamivir, irrespective of whether treatment was initiated within 48 h or 72 h after illness onset. Furthermore, a 1 day reduction in major symptoms occurred in patients given oseltamivir, whether 48 h or 72 h after illness onset. Since most of the patients were children and had positive rapid antigen tests, this finding might indicate a benefit of treatment in patients with higher baseline viral loads. Patients with higher baseline viral loads and children generally have a longer duration of viral shedding and therefore could potentially benefit from antiviral therapy started more than 48 h after symptom onset. Although time since symptom onset is easy to measure in the clinic, it could be imprecise. As we develop more robust ways to measure quantitative or semiquantitative viral load monitoring for influenza, baseline viral load might be more predictive of benefit from antiviral therapy than time since onset of symptoms.17 However, for now we must rely on the time from symptom onset, particularly in resource-poor settings. This study enrolled patients from a crowded, lowincome community. Such patients might have been malnourished or had other disorders that resulted in more prolonged viral shedding, which could partly explain the study’s findings.18 Nonetheless, this study suggests that patients with ongoing viral replication and clinical symptoms up to day 3 after symptom onset would benefit from oseltamivir treatment. Future studies should investigate whether later onset therapy results in similar positive outcomes in mainly adult patients and those from more developed regions. These findings will help to inform guidelines for the treatment of influenza and should spur research to better define the optimum timing of antiviral therapy in a range of clinical settings. www.thelancet.com/infection Vol 14 February 2014
Most importantly, this study raises the idea that some ambulatory patients could benefit from clinical therapy beyond 48 h after symptom onset. Michael G Ison Divisions of Infectious Diseases and Organ Transplantation, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA [email protected] MGI has received research support (paid to Northwestern University) from Anolinx, Cellex, Chimerix, Crucell, GlaxoSmithKlein, NexBio, and ViroPharma. He has acted as a paid consultant for Alios, Abbott, Crucell, and Genentech/Roche, and as an unpaid consultant for BioCryst, Biota, Cellex, Clarassance, GlaxoSmithKline, Toyama/MediVector, NexBio, Theraclone, Vertex, and Visterra. He has participated in Data and Safety Monitoring Boards for Biota and NexBio. 1
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Deyde VM, Xu X, Bright RA, et al. Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. J Infect Dis 2007; 196: 249–57. Bright RA, Medina MJ, Xu X, et al. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet 2005; 366: 1175–81. Ison MG. Clinical use of approved influenza antivirals: therapy and prophylaxis. Influenza Other Respi Viruses 2013; 7 (suppl 1): 7–13. Kimberlin DW, Acosta EP, Prichard MN, et al. Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza. J Infect Dis 2013; 207: 709–20. Acosta EP, Jester P, Gal P, et al. Oseltamivir dosing for influenza infection in premature neonates. J Infect Dis 2010; 202: 563–66. Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 2001; 20: 127–33. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA 2000; 283: 1016–24. Nicholson KG, Aoki FY, Osterhaus AD, et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Lancet 2000; 355: 1845–50. Aoki FY, Macleod MD, Paggiaro P, et al. Early administration of oral oseltamivir increases the benefits of influenza treatment. J Antimicrob Chemother 2003; 51: 123–29. Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clin Infect Dis 2012; 55: 1198–204. Adisasmito W, Chan PK, Lee N, et al. Strengthening observational evidence for antiviral effectiveness in influenza A (H5N1). J Infect Dis 2011; 204: 810–11. Lee N, Choi KW, Chan PK, et al. Outcomes of adults hospitalised with severe influenza. Thorax 2010; 65: 510–15. Reid G, Huprikar S, Patel G, et al. A multicenter evaluation of pandemic influenza A/H1N1 in hematopoietic stem cell transplant recipients. Transpl Infect Dis 2013; 15: 487–92. Kumar D, Michaels MG, Morris MI, et al. Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study. Lancet Infect Dis 2010; 10: 521–26. Nair H, Brooks WA, Katz M, et al. Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis. Lancet 2011; 378: 1917–30. Fry AM, Goswami D, Nahar K, et al. Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomised placebo-controlled trial. Lancet Infect Dis 2013; published online Nov 22. http://dx.doi. org/10.1016/S1473-3099(13)70267-6. Lee N, Chan PK, Rainer TH, Hui D, Choi KW, Cockram CS. Influenza virus load in hospitalised patients. Hong Kong Med J 2013; 19 (suppl 4): 15–18. Taylor AK, Cao W, Vora KP, et al. Protein energy malnutrition decreases immunity and increases susceptibility to influenza infection in mice. J Infect Dis 2013; 207: 501–10.
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