- Email: [email protected]
Effective treatment of influenza with oral oseltamivir in a vaccinated population of high-risk patients
International Congress Series 1219 (2001) 813 – 816
Effective treatment of inf luenza with oral oseltamivir in a vaccinated population of high-risk patients M. Zauga,*, P. Mahoneyb, P. Wardb a
F. Hoffman-La Roche Ltd., PDC2 Bldg. 52/1115, CH-4070, Basel, Switzerland b Roche Global Development, Welwyn, UK
Abstract Background: Annual vaccination is recommended for patient groups considered at risk from significant morbidity and mortality from influenza, however, vaccination does not provide complete protection against influenza. Oral oseltamivir is effective for the treatment of influenza in healthy unvaccinated patients. We evaluated oseltamivir for the treatment of influenza in vaccinated ‘at-risk’ patients, including the elderly and patients with pre-existing cardiac and/or pulmonary disease. Methods: 226 vaccinated patients (>13 years) from a pooled dataset of 613 at-risk patients with acute febrile influenza ( 36 h duration) were randomized to receive oral oseltamivir 75 mg or placebo twice daily for 5 days. Influenza symptoms were recorded (0 = absent, 1 = mild, 2 = moderate, 3 = severe) in a diary twice daily. The primary endpoint was duration of illness (symptoms score 1 for 24 h). Results: 62% of vaccinated patients had confirmed influenza (placebo: n = 76, oseltamivir: n = 64). The median duration of illness was reduced by 1.8 days by oseltamivir compared with placebo (placebo: 8.2 days, oseltamivir: 6.4 days). Oseltamivir reduced individual influenza symptoms, secondary complications and viral shedding compared with placebo. Oseltamivir was well tolerated. Conclusions: Oral oseltamivir provides additional clinical benefit to vaccination for influenza-infected at-risk patients who develop the disease. D 2001 Elsevier Science B.V. All rights reserved. Keywords: Neuraminidase inhibitor; At-risk patients; Antiviral
*
Corresponding author. Tel. +41-61-688-7117; fax: +41-61-688-2790. E-mail address: [email protected] (M. Zaug).
0531-5131/01/$ – see front matter D 2001 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 3 6 0 - 0
814
M. Zaug et al. / International Congress Series 1219 (2001) 813–816
1. Introduction Vaccination against influenza infection is recommended for the elderly population and those considered at risk from the substantial morbidity and mortality associated with influenza infection (e.g. subjects with chronic cardiac and/or pulmonary disease) [1]. Death rates from influenza have not changed over the last 60 years, despite the increased use of influenza vaccination [2]. As vaccination does not provide complete protection against influenza infection [1], a substantial proportion of previously vaccinated patients still develop influenza illness. Oral oseltamivir, the prodrug of the potent and specific neuraminidase inhibitor oseltamivir carboxylate, is an effective and safe treatment for influenza infection in unvaccinated otherwise healthy patients [3,4]. We studied the benefits of oseltamivir treatment of influenza in a vaccinated population, using data pooled from three studies that included elderly patients and those with chronic cardiac/pulmonary disease.
2. Methods Patients (>13 years) who had been vaccinated in the study season and who presented within 36 h of the onset of symptoms of influenza were eligible for inclusion into the analysis population. Influenza symptoms were defined as fever ( 38 °C/ 100 °F for patients < 65 years, 37.5 °C/99.5 °F for patients 65 years) plus one respiratory symptom (cough, sore throat or nasal congestion) and one constitutional symptom (feverishness/chills, headache, myalgia or fatigue). Influenza infection was confirmed by either positive virus culture or 4-fold rise in influenza specific antibody titres. Influenza symptoms were self-reported and graded for severity using a four-point categorical scale twice daily on a diary card (0 = absent, 1 = mild, 2 = moderate, 3 = severe) throughout the study period (21 days). The primary endpoint was the duration of illness, defined as the length of time from initiation of study drug until all symptoms were alleviated (i.e. symptom scores remained at 0 or 1 for at least 24 h). Efficacy analyses were performed on vaccinated patients with confirmed influenza (ITTI population: placebo n = 76, oseltamivir n = 64). Safety data was based on all patients who received at least one dose of trial medication (placebo n = 117, oseltamivir n = 109).
3. Results Influenza infection was confirmed in 62% (140/226) of vaccinated patients (ITTI population). Most (131/140, 94%) infected patients had nose/throat swabs taken at baseline and 64 (46%) patients (35 placebo, 29 oseltamivir) at both baseline and day 3 of therapy. In the ITTI population, the median duration of illness was reduced by almost 2 days (42.5 h) in oseltamivir recipients (placebo, P, 196.3 h [8.2 days]; oseltamivir, O, 153.8 h [6.4 days]) (Fig. 1). In addition, the median time to alleviation of each individual
M. Zaug et al. / International Congress Series 1219 (2001) 813–816
815
Fig. 1. Oseltamivir 75 mg bid for 5 days reduces the median time to alleviation of individual symptoms in vaccinated patients compared with placebo.
symptom was shorter in oseltamivir recipients compared with placebo, most notably feverishness, myalgia, fatigue and cough (Fig. 1). The mean baseline titres were similar in both treatment groups (3.5 for placebo and 3.3 log10 TCID50/ml with oseltamivir). By day 3 of treatment, the viral titre was reduced 10fold in the oseltamivir group compared with placebo (placebo: 2.3 log10 TCID50/ml, oseltamivir: 1.2 log10 TCID50/ml) (Fig. 2). In addition to alleviating influenza symptoms and reducing virus titre, oseltamivir reduced the incidence of influenza-related secondary respiratory complications (mainly bronchitis) compared with placebo (Table 1).
Fig. 2. Oseltamivir 75 mg bid for 5 days reduces the quantity of virus shed in vaccinated patients compared with placebo.
816
M. Zaug et al. / International Congress Series 1219 (2001) 813–816
Table 1 Oseltamivir 75 mg bid for 5 days reduces the incidence of secondary respiratory complications (bronchitis, LRTIa, pneumonia) in vaccinated patients compared with placebo
Bronchitis (%) LRTIa (%) Pneumonia (%) All respiratory complications (%) a
Placebo (n = 76)
Oseltamivir (n = 64)
11 (14) 1 (1) 2 (3) 13 (17)
5 1 2 8
(8) (2) (3) (12.5)
LRTI: Lower respiratory tract infection.
Oseltamivir was well tolerated in this at-risk population. Adverse events were reported with similar frequency in the placebo and oseltamivir-treated groups (placebo: 55%, oseltamivir: 46%). Diarrhoea and vomiting were more common in the placebo group than oseltamivir (diarrhoea: placebo 12 [10%], oseltamivir 5 [5%]; vomiting: placebo 6 [5%], oseltamivir 2 [2%]). Nausea was reported more often by oseltamivir recipients (placebo 5 [4%], oseltamivir 8 [7%]). Consistent with the reduced frequency of influenza-related secondary complications, fewer oseltamivir recipients reported respiratory or cardiac events compared with placebo (respiratory: placebo 14 [12%], oseltamivir 10 [9%]; cardiac: placebo 4 [3%], oseltamivir 2 [2%]). 4. Discussion Our analysis showed that treatment with oral oseltamivir provides additional, clinically significant benefits for patients who develop influenza despite having received an annual vaccination. These data confirm previous results from studies in otherwise healthy unvaccinated adults [3,4]. The quantity of virus shed by oseltamivir recipients was reduced by more than 10-fold compared with placebo. This antiviral effect translated into faster resolution of illness (by almost 2 days) and individual symptoms compared with placebo and a reduced incidence of secondary complications. Finally, oseltamivir was well tolerated by this high-risk population: the incidence of adverse events was similar in both groups. Oseltamivir-treated patients with cardiac and/or pulmonary conditions reported fewer exacerbations of underlying disease compared with placebo. References [1] Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR 49 (RR-03) (2000) 1 – 38. [2] K.G. Nicholson, Human influenza, in: K.G. Nicholson, R.G. Webster, A.J. Hay (Eds.), Textbook of Influenza, Blackwell Science, Oxford, 1998, pp. 219 – 264. [3] K.G. Nicholson, F.Y. Aoki, A.D.M.E. Osterhaus, et al., Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial, Lancet 355 (2000) 1845 – 1850. [4] J.J. Treanor, F.G. Hayden, P.S. Vrooman, et al., Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized, controlled trial, JAMA, J. Am. Med. Assoc. 283 (2000) 1016 – 1024.
Effective treatment of inf luenza with oral oseltamivir in a vaccinated population of high-risk patients M. Zauga,*, P. Mahoneyb, P. Wardb a
F. Hoffman-La Roche Ltd., PDC2 Bldg. 52/1115, CH-4070, Basel, Switzerland b Roche Global Development, Welwyn, UK
Abstract Background: Annual vaccination is recommended for patient groups considered at risk from significant morbidity and mortality from influenza, however, vaccination does not provide complete protection against influenza. Oral oseltamivir is effective for the treatment of influenza in healthy unvaccinated patients. We evaluated oseltamivir for the treatment of influenza in vaccinated ‘at-risk’ patients, including the elderly and patients with pre-existing cardiac and/or pulmonary disease. Methods: 226 vaccinated patients (>13 years) from a pooled dataset of 613 at-risk patients with acute febrile influenza ( 36 h duration) were randomized to receive oral oseltamivir 75 mg or placebo twice daily for 5 days. Influenza symptoms were recorded (0 = absent, 1 = mild, 2 = moderate, 3 = severe) in a diary twice daily. The primary endpoint was duration of illness (symptoms score 1 for 24 h). Results: 62% of vaccinated patients had confirmed influenza (placebo: n = 76, oseltamivir: n = 64). The median duration of illness was reduced by 1.8 days by oseltamivir compared with placebo (placebo: 8.2 days, oseltamivir: 6.4 days). Oseltamivir reduced individual influenza symptoms, secondary complications and viral shedding compared with placebo. Oseltamivir was well tolerated. Conclusions: Oral oseltamivir provides additional clinical benefit to vaccination for influenza-infected at-risk patients who develop the disease. D 2001 Elsevier Science B.V. All rights reserved. Keywords: Neuraminidase inhibitor; At-risk patients; Antiviral
*
Corresponding author. Tel. +41-61-688-7117; fax: +41-61-688-2790. E-mail address: [email protected] (M. Zaug).
0531-5131/01/$ – see front matter D 2001 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 3 6 0 - 0
814
M. Zaug et al. / International Congress Series 1219 (2001) 813–816
1. Introduction Vaccination against influenza infection is recommended for the elderly population and those considered at risk from the substantial morbidity and mortality associated with influenza infection (e.g. subjects with chronic cardiac and/or pulmonary disease) [1]. Death rates from influenza have not changed over the last 60 years, despite the increased use of influenza vaccination [2]. As vaccination does not provide complete protection against influenza infection [1], a substantial proportion of previously vaccinated patients still develop influenza illness. Oral oseltamivir, the prodrug of the potent and specific neuraminidase inhibitor oseltamivir carboxylate, is an effective and safe treatment for influenza infection in unvaccinated otherwise healthy patients [3,4]. We studied the benefits of oseltamivir treatment of influenza in a vaccinated population, using data pooled from three studies that included elderly patients and those with chronic cardiac/pulmonary disease.
2. Methods Patients (>13 years) who had been vaccinated in the study season and who presented within 36 h of the onset of symptoms of influenza were eligible for inclusion into the analysis population. Influenza symptoms were defined as fever ( 38 °C/ 100 °F for patients < 65 years, 37.5 °C/99.5 °F for patients 65 years) plus one respiratory symptom (cough, sore throat or nasal congestion) and one constitutional symptom (feverishness/chills, headache, myalgia or fatigue). Influenza infection was confirmed by either positive virus culture or 4-fold rise in influenza specific antibody titres. Influenza symptoms were self-reported and graded for severity using a four-point categorical scale twice daily on a diary card (0 = absent, 1 = mild, 2 = moderate, 3 = severe) throughout the study period (21 days). The primary endpoint was the duration of illness, defined as the length of time from initiation of study drug until all symptoms were alleviated (i.e. symptom scores remained at 0 or 1 for at least 24 h). Efficacy analyses were performed on vaccinated patients with confirmed influenza (ITTI population: placebo n = 76, oseltamivir n = 64). Safety data was based on all patients who received at least one dose of trial medication (placebo n = 117, oseltamivir n = 109).
3. Results Influenza infection was confirmed in 62% (140/226) of vaccinated patients (ITTI population). Most (131/140, 94%) infected patients had nose/throat swabs taken at baseline and 64 (46%) patients (35 placebo, 29 oseltamivir) at both baseline and day 3 of therapy. In the ITTI population, the median duration of illness was reduced by almost 2 days (42.5 h) in oseltamivir recipients (placebo, P, 196.3 h [8.2 days]; oseltamivir, O, 153.8 h [6.4 days]) (Fig. 1). In addition, the median time to alleviation of each individual
M. Zaug et al. / International Congress Series 1219 (2001) 813–816
815
Fig. 1. Oseltamivir 75 mg bid for 5 days reduces the median time to alleviation of individual symptoms in vaccinated patients compared with placebo.
symptom was shorter in oseltamivir recipients compared with placebo, most notably feverishness, myalgia, fatigue and cough (Fig. 1). The mean baseline titres were similar in both treatment groups (3.5 for placebo and 3.3 log10 TCID50/ml with oseltamivir). By day 3 of treatment, the viral titre was reduced 10fold in the oseltamivir group compared with placebo (placebo: 2.3 log10 TCID50/ml, oseltamivir: 1.2 log10 TCID50/ml) (Fig. 2). In addition to alleviating influenza symptoms and reducing virus titre, oseltamivir reduced the incidence of influenza-related secondary respiratory complications (mainly bronchitis) compared with placebo (Table 1).
Fig. 2. Oseltamivir 75 mg bid for 5 days reduces the quantity of virus shed in vaccinated patients compared with placebo.
816
M. Zaug et al. / International Congress Series 1219 (2001) 813–816
Table 1 Oseltamivir 75 mg bid for 5 days reduces the incidence of secondary respiratory complications (bronchitis, LRTIa, pneumonia) in vaccinated patients compared with placebo
Bronchitis (%) LRTIa (%) Pneumonia (%) All respiratory complications (%) a
Placebo (n = 76)
Oseltamivir (n = 64)
11 (14) 1 (1) 2 (3) 13 (17)
5 1 2 8
(8) (2) (3) (12.5)
LRTI: Lower respiratory tract infection.
Oseltamivir was well tolerated in this at-risk population. Adverse events were reported with similar frequency in the placebo and oseltamivir-treated groups (placebo: 55%, oseltamivir: 46%). Diarrhoea and vomiting were more common in the placebo group than oseltamivir (diarrhoea: placebo 12 [10%], oseltamivir 5 [5%]; vomiting: placebo 6 [5%], oseltamivir 2 [2%]). Nausea was reported more often by oseltamivir recipients (placebo 5 [4%], oseltamivir 8 [7%]). Consistent with the reduced frequency of influenza-related secondary complications, fewer oseltamivir recipients reported respiratory or cardiac events compared with placebo (respiratory: placebo 14 [12%], oseltamivir 10 [9%]; cardiac: placebo 4 [3%], oseltamivir 2 [2%]). 4. Discussion Our analysis showed that treatment with oral oseltamivir provides additional, clinically significant benefits for patients who develop influenza despite having received an annual vaccination. These data confirm previous results from studies in otherwise healthy unvaccinated adults [3,4]. The quantity of virus shed by oseltamivir recipients was reduced by more than 10-fold compared with placebo. This antiviral effect translated into faster resolution of illness (by almost 2 days) and individual symptoms compared with placebo and a reduced incidence of secondary complications. Finally, oseltamivir was well tolerated by this high-risk population: the incidence of adverse events was similar in both groups. Oseltamivir-treated patients with cardiac and/or pulmonary conditions reported fewer exacerbations of underlying disease compared with placebo. References [1] Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR 49 (RR-03) (2000) 1 – 38. [2] K.G. Nicholson, Human influenza, in: K.G. Nicholson, R.G. Webster, A.J. Hay (Eds.), Textbook of Influenza, Blackwell Science, Oxford, 1998, pp. 219 – 264. [3] K.G. Nicholson, F.Y. Aoki, A.D.M.E. Osterhaus, et al., Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial, Lancet 355 (2000) 1845 – 1850. [4] J.J. Treanor, F.G. Hayden, P.S. Vrooman, et al., Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized, controlled trial, JAMA, J. Am. Med. Assoc. 283 (2000) 1016 – 1024.