Why carry out this study?
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Influenza in hospitalized patients in the ICU with acute respiratory failure is associated with overall 25% mortality, despite timely oseltamivir treatment. |
What was learned from the study?
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Systemic administration of neuraminidase inhibitor regimens to treat hospitalized patients with influenza infections are equally safe but do not modify meaningful clinical outcomes when compared with orally administered oseltamivir 75 mg tid. |
For hospitalized patients with influenza H1N1, H3N2, or B, higher doses of neuraminidase inhibitors compared to standard of care (oral oseltamivir therapy or intravenous peramivir therapy) do not modify meaningful clinical outcomes when compared with the standard dose. |
Introduction
Methods
Protocol and Registration
Data Sources
Data Extraction and Study Selection Process
Definitions and Outcomes
Quality Assessment
Data Analysis
Results
Interventions
Study | Country | Characteristics | Study period | Intent-to-treat population (ITT) | Influenza-positive population (IPP) | Intervention | Comparator | Treatment duration |
---|---|---|---|---|---|---|---|---|
Oseltamivir trials | ||||||||
Lee et al. [12] | China | Phase lV Open-label Multicenter | 01/2010–06/2012 | 155 | 155 | Oseltamivir oral 150 mg twice daily | Oseltamivir oral 75 mg twice daily | 5 days |
South East Asia infectious Disease Clinical Research Network [13] | Indonesia, Singapore, Taiwan, Vietnam | Phase II Double-blind Multicenter | 07/2007–02/2012 | 326 | 313 | Oseltamivir oral 150 mg twice daily | Oseltamivir oral 75 mg twice daily | 5–10 days |
Zanamivir trials | ||||||||
Marty et al. [14] | USA, Spain, India, France, Australia, UK, Belgium, Mexico, Czech Republic | Phase III Double-blind Multicenter | 01/2011–02/2015 | 615 | 488 | Zanamivir intravenous 600 mg twice daily + oral placebo Zanamivir intravenous 300 mg twice daily + oral placebo | Oseltamivir oral 75 mg twice daily + intravenous placebo | 5–10 days |
Peramivir trials | ||||||||
Ison et al. [15] | Australia, Canada, Hong Kong, New Zealand, Singapore, South Africa, USA | Phase III Double-blind Multicenter | 07/2007–09/2008 | 137 | 122 | Peramivir intravenous 400 mg once daily + oral placebo Peramivir intravenous 200 mg once daily + oral placebo | Oseltamivir oral 75 mg twice daily + intravenous placebo | 5 days |
Lee et al. [16] | Hong Kong | Phase ll–lll Open-label Single center | 2011–2014 | 70 | 70 | Peramivir intravenous 600 mg once daily Peramivir intravenous 300 mg once daily | Oseltamivir oral 75 mg twice daily | 5 days |
Kohno et al. [17] | Japan | Phase III Double-blinded Multicenter | 01/2009–05/2009 | 42 | 37 | Peramivir intravenous 300 mg once daily | Peramivir intravenous 600 mg once daily | 5 days |
Ison et al. [18] | USA, Canada, Mexico, New Zealand, and Australia | Phase III Open label Multicenter | 10/2009–10/2010 | 234 | 127 | Peramivir intravenous 300 mg twice daily | Peramivir intravenous 600 mg once daily | 5–10 days |
Patient Characteristics
Study | Age | Inclusion criteria | Influenza diagnosis | Type of influenza | Intensive care unit | Previous antiviral treatment | Comorbidities | Vaccine |
---|---|---|---|---|---|---|---|---|
Oseltamivir trials | ||||||||
Lee et al. [12] | ≥ 18 years | Presentation within 96 h from illness onset, and provision of written informed consent | Laboratory confirmed (PCR or immunofluorescence) | AH1N1pdm09: 22 (34/155) AH3N2: 54.8 (85/155) Influenza B: 23.2 (36/155) | 1.3 (2/155) | Patients excluded: receipt of any antiviral for influenza before presentation | Patients excluded Severe renal impairment (CrCl < 40 ml/min), hepatic failure Baseline characteristics Systemic comorbidities: 48.4 (75/155) Chronic lung disease: 33.5 (52/155) | 18.7 (29/155) |
South East Asia infectious Disease Clinical Research Network [13] | ≥ 1 year | Severe influenza was defined as admission to hospital and one of the following: new infiltrate on chest x-ray; tachypnea (respiratory rate ≥ 30 for ages ≥ 12, ≥ 40 for ages 6–11, ≥ 45 for ages 3–5, ≥ 50 for ages 1–2); dyspnea; or hypoxia (arterial oxygen saturation ≤ 92% on room air) Duration of symptoms ≤ 10 days | Laboratory confirmed | AH1N1pdm09: 22 (72/326) AH3N2: 40.8 (133/326) Influenza B: 15.9 (53/326) AH5N1a: 5.2 (17/326) | 17.5 (57/326) | Baseline characteristics: antivirals before enrollment: 23.3 (76/326) | Patients excluded Severe renal impairment (CrCl < 10 ml/min) Baseline characteristics Diabetes mellitus: 0.3 (1/326) Asthma: 7.3 (24/326) | NR |
Zanamivir trials | ||||||||
Marty et al. [14] | ≥ 16 years | Onset of symptoms within 6 days of study enrollment; had experienced fever within 24 h or feverishness within 48 h of starting study treatment; and had two or more of four severity criteria (oxygen saturation < 95%, or need for oxygen supplementation or ventilator support; respiratory rate > 24 breaths per min; heart rate > 100 beats per min; systolic blood pressure < 90 mmHg) | Suspected or laboratory confirmed | AH1N1pdm09: 37.6 (185/491) AH3N2: 58.6 (228/491) Influenza B: 15.8 (78/491) | 40 (244/615) | Patients excluded Taken any approved anti-influenza treatment for longer than 3 days in the period between onset of symptoms and enrollment Baseline characteristics Permitted prior to study drug initiation: (49% [299/615] had received oseltamivir) | Patients excluded Expected to survive < 48 h from baseline, with severe acute liver injury or chronic liver disease with evidence of server liver impairment, CrCl < 10 ml/min or treated with renal replacement therapy or required hemodialysis Baseline characteristics All illnesses: 76 (468/615) Diabetes: 25 (153/615) COPD: 21 (130/615) Asthma: 15 (90/615) | 11 (67/615) |
Peramivir trials | ||||||||
Ison et al. [15] | ≥ 18 years | Influenza-like illness within the previous 72 h with fever or feverishness, ≥ 1 respiratory symptom (cough, sore throat or nasal congestion), ≥ 1 constitutional symptom (headache, myalgia, feverishness, or malaise/fatigue), and positive RAT for influenza A or B from a nasopharyngeal swab performed at screening. In addition, ≥ 1 of the following conditions: age ≥ 60 years, COPD or other chronic lung disease, NYHA class I or II congestive heart failure or angina, diabetes mellitus, transcutaneous oxygen saturation < 94% without supplemental oxygen or in the investigator’s judgment a medically significant decrease in oxygen saturation from a know baseline value, or systolic blood pressure < 90 mmHg | Laboratory confirmed (RAT) | AH1N1: 18 (22/122) AH3N2: 55.3 (68/122) Influenza B: 26.3 (32/122) | NR | Patients excluded if they have received any antiviral treatment for influenza | Patients excluded Moderate or severe renal impairment, acute ischemia or significant dysrhythmia, required outpatients oxygen therapy, required ventilatory support, received an organ transplantation or cancer chemotherapy in the previous 12 months, HIV with most known recent CD4 T cells < 350/μL Baseline characteristics Diabetes: 13.9 (17/122) COPD/chronic lung disease: 19.7 (24/122) | NR |
Lee et al. [16] | ≥ 18 years | Symptoms/signs of influenza and confirmation of LRTC (e.g., radiographic pneumonia, dyspnea caused by acute exacerbation of underlying airway diseases, bronchitis, or their combinations) | Laboratory confirmed (PCR or immunofluorescence) | AH1N1pdm09: 21.4 (15/70) AH3N2: 60 (42/70) Influenza B: 18.6 (13/70) | NR | Other antivirals, if given, were discontinued | Patients excluded Hemodynamic instability, hepatic/renal failure, dialysis, immunosuppression Baseline characteristics Comorbidity systemic: 55.7 (39/70) COPD: 44.3 (31/70) | 18.5 (13/70) |
Kohno et al. [17] | ≥ 20 years | RAT positive and had ≥ 1 risk factor, had experienced onset of influenza symptoms within the previous 48 h, and showed ≥ 2 of 7 influenza symptoms of moderate or greater severity. Influenza symptoms included headache, muscle or joint pain, fever or chills, fatigue, cough, sore throat, and nasal congestion. The onset of influenza symptoms was defined as the time at which body temperature rose ≥ 1 °C over the patient’s normal body temperature (≥ 37 °C) or the time at which the patient experienced the onset of ≥ 2 of the above-mentioned influenza symptoms | Laboratory confirmed (RAT) | AH1N1: 43.2 (16/37) AH3N2: 35.1 (13/37) Influenza B: 8.1 (3/37) | NR | NR | Patients excluded Chronic respiratory failure requiring artificial ventilation; diabetes with HbA1c > 10%; organ transplant or hematopoietic stem cell transplant within the previous 12 months; requirement for dialysis or presence of nephropathy (CrCl < 50 ml/min); presence of congestive heart failure as a complication; presence of ischemic heart disease or serious arrhythmia; bradycardia; presence of major circulatory system disease, central nervous system disease, metabolic disease, cancer, hepatitis, or liver cirrhosis Baseline characteristics Poorly controlled diabetes: 10.8 (4/37) Respiratory tract disease on treatment: 78.4 (29/37) Use of immunosuppressant drugs: 24.3 (9/37) | 51.4 (19/37) |
Ison et al. [18] | ≥ 6 years | Symptoms/signs of influenza, temperature ≥ 38 °C (oral) or ≥ 38.6 °C (rectal or tympanic), and recent onset of respiratory symptoms, with severity of illness requiring hospitalization as judged by the investigator | Suspected influenza | AH1N1pdm09: 74 (94/127) Influenza B: 2 (3/127) | 17 (39/234) | Baseline characteristics Treatment with other antivirals was permitted prior to study drug initiation: 73% [170/234] had received oseltamivir (ITT) | Patients excluded Peritoneal dialysis, altered neurological status, systemic chemotherapy or radiotherapy, recent hematopoietic or solid organs transplant, uncontrolled HIV, pre-existing chronic infection, cystic fibrosis Baseline characteristics Moderate renal impairment: 9 (21/234) | 33 (77/234) |
Outcomes
Study | TTCR, median days (IQR) | Mortality, % (n) | Viral clearance, % (n) | Drug-related AEs, % (n) | SAEs, % (n) |
---|---|---|---|---|---|
Oseltamivir trials | |||||
Lee et al. [12] | Oseltamivir 75 mg: 1.0 (1.0–2.0) Oseltamivir 150 mg: 2.0 (0.0–3.0) | Oseltamivir 75 mg: 0.9 (1/114) Oseltamivir 150 mg: 2.4 (1/41) | Oseltamivir 75 mg: 40.2 (46/114) Oseltamivir 150 mg: 44.7(18/41) | Oseltamivir 75 mg: 5.3 (6/114) Oseltamivir 150 mg: 22 (9/41) | NR |
South East Asia infectious Disease Clinical Research [13] | NR | aOseltamivir 75 mg: 5.8 (9/153) Oseltamivir 150 mg: 7.6 (12/156) | Oseltamivir 75 mg: 68.2 (105/154) Oseltamivir 150 mg: 72.3 (115/159) | Oseltamivir 75 mg: 5.6 (9/161) Oseltamivir 150 mg: 3 (5/165) | Oseltamivir 75 mg: 0.6 (1/161) Oseltamivir 150 mg: 0 (0/165) |
Zanamivir trials | |||||
Marty et al. [14] | Zanamivir 300 mg: 5.8 (NR) Zanamivir 600 mg: 5.1 (NR) Oseltamivir 75 mg: 5.7 (NR) | Zanamivir 300 mg: 7 (15/201) Zanamivir 600 mg: 7 (15/209) Oseltamivir 75 mg: 5 (11/205) | NR | Zanamivir 300 mg: 12 (25/201) Zanamivir 600 mg: 11 (22/209) Oseltamivir 75 mg: 17 (35/205) | Zanamivir 300 mg: 19 (38/201) Zanamivir 600 mg: 16 (33/209) Oseltamivir 75 mg: 19 (38/205) |
Peramivir trials | |||||
Ison et al. [15] | Peramivir 200 mg: 1.3 (0.6–2.0) Peramivir 400 mg: 1.0 (0.6–2.7) Oseltamivir 75 mg: 1.5 (0.9–2.3) | Peramivir 200 mg: 0 (0/45) Peramivir 400 mg: 2 (1/46) Oseltamivir 75 mg: 0 (0/46) | NR | NR | Peramivir 200 mg: 4 (2/45) Peramivir 400 mg: 17 (8/46) Oseltamivir 75 mg: 9 (4/46) |
Lee et al. [16] | NR | Overall: 1.4 (1/70) | Overall peramivir: 43.8 (7/16) Oseltamivir: 39 (21/54) | Overall: 20 (14/70) | NR |
Kohno et al. [17] | bPeramivir 300 mg: 4.7 (1.7–9.8) Peramivir 600 mg: 1.7 (1.3–3.5) | NR | NR | Peramivir 300 mg: 28.6 (6/21) Peramivir 600 mg: 38.1 (8/21) | NR |
Ison et al. [18] | Peramivir 300 mg: 1.9 (1.7–4.9) Peramivir 600 mg: 6.9 (3.5–11.4) | Peramivir 300 mg: 7 (8/114) Peramivir 600 mg: 12 (14/116) | Peramivir 300 mg: 62.2 (23/37) Peramivir 600 mg: 51 (25/49) | Peramivir 300 mg: 19 (22/114) Peramivir 600 mg: 16 (19/116) | Peramivir 300 mg: 18 (21/114) Peramivir 600 mg: 22 (26/116) |
Time to Clinical Resolution
Mortality
Viral Clearance
Drug-Related Adverse Events
Serious Adverse Events
Discussion
Drug | Agency | Year | Indications | Trade name | Hospitalized patients | Pediatric population | Dosage |
---|---|---|---|---|---|---|---|
Oseltamivir (oral) | FDA | 1999 | Treatment of acute, uncomplicated influenza A and B in patients 2 weeks of age and older who have been symptomatic for no more than 48 h Prophylaxis of influenza A and B in patients 1 year and older | TAMIFLU | NR | > 2 weeks | 75 mg twice/daily for 5 days (renal adjustment) Prophylaxis 75 mg once/daily for 10 days |
EMA | 2002 | Treatment of influenza in adults and children including full-term neonates who present with symptoms typical of influenza, when influenza virus is circulating in the community. Efficacy has been demonstrated when treatment is initiated within 2 days of first onset of symptoms Post-exposure prevention in individuals 1 year of age or older following contact with a clinically diagnosed influenza case | TAMIFLU | No information is available regarding the safety and efficacy of oseltamivir in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalization | Full-term neonates | 75 mg twice/daily for 5 days (renal adjustment) Prophylaxis 75 mg once/daily for 10 days | |
Zanamivir | FDA | Only inhaled 2000 | Treatment of acute, uncomplicated influenza type A and B infections in patients aged 7 years and older who have been symptomatic for no more than 2 days Prophylaxis of influenza in patients aged 5 years and older | RELENZA | > 7 years | ||
EMA | IV—2019 (2011a) | Treatment of complicated and potentially life-threatening influenza caused by either the influenza A or B virus in adults and children from 6 months of age. The medicine is used when the virus is resistant to other flu treatments or when other antiviral treatments, including inhaled zanamivir, are not suitable | DECTOVA | Complicated influenza is a severe flu infection that requires hospitalization of the patient | > 6 months | 600 mg twice/daily for 5–10 days | |
Peramivir (IV) | FDA | 2014 (2009a) | Treatment of acute uncomplicated influenza in patients 18 years and older who have been symptomatic for no more than 2 days | RAPIVAB | The efficacy of RAPIVAB could not be established in patients with serious influenza requiring hospitalization RAPIVAB was not shown to provide benefit in patients with serious influenza requiring hospitalization | > 18 years | 600 mg one dose (renal adjustment) (Compassionate use–hospitalized patients—600 mg twice/daily for 5 days) |
EMA | 2018 | Treat uncomplicated influenza in adults and children over 2 years | ALPIVAB | Uncomplicated means that the flu has typical features (such as fever, aches, cough, sore throat, and runny nose) and is not made worse by other conditions | > 2 years | 600 mg, one dose (renal adjustment) | |
Japan | 2009 | Treatment of uncomplicated seasonal influenza in adults Treatment of adult patient at high risk for complications associated with influenza | RAPIACTA | Treatment of adult patient at high risk for complications associated with influenza | NR | 300 mg, one dose (uncomplicated) 600 mg single dose Multiple doses (600 mg/daily) may be administered according to symptoms | |
South Korea | 2009 | NR | PERAMIFLU | NR | NR | NR | |
China | 2013 | NR | NR | NR | NR | NR |