Effect of zanamivir on duration and resolution of influenza symptoms

doi:10.1016/S0149-2918(00)83026-X

Clinical Therapeutics

Volume 22, Issue 11, November 2000, Pages 1294-1305

https://doi.org/10.1016/S0149-2918(00)83026-X Get rights and content

Abstract

Background: Zanamivir is a neuraminidase inhibitor, the first of a new class of drugs with potent, specific antiviral activity against influenza A and B. Administration by inhalation results in direct delivery to the respiratory tract, the principal site of viral replication.

Objective: This study was undertaken to determine the effectiveness of zanamivir on duration and resolution of influenza symptoms.

Methods: Using a method similar to that employed in amantadine treatment studies to obtain supporting evidence of efficacy for US Food and Drug Administration consideration, pooled data from 6 zanamivir phase II and III clinical trials involving primarily previously healthy adults were analyzed to categorize patients as accelerated resolvers (temperature <37.8°C ≤24 hours after dosing, plus a ≥50% reduction in symptom score by 36 hours), early resolvers (temperature <37.8°C ≤36 hours after dosing), and nonaccelerated resolvers (febrile >36 hours after dosing). Patients in the accelerated and early categories were termed rapid resolvers; the others were slow resolvers. Patients recorded their symptom severity, temperature, ability to perform normal daily activities, and use of relief medication on a diary card. The primary end point of median time to alleviation of symptoms was also reexamined, with the additional requirement that patients were not taking relief medication when their symptoms were alleviated. This analysis was intended to control for the possible effect of relief medication on the primary end point.

Results: In the influenza-positive population (n = 1572), significantly more zanamivir-treated patients were rapid resolvers compared with those receiving placebo (807 [72%] vs 765 [64%], P < 0.001). Significant benefits of zanamivir treatment were observed in patients with a baseline temperature of ≥37.8°C (630 [68%] vs 595 [57%], P < 0.001) or ≥38.3°C (382 [67%] vs 365 [52%], P < 0.001) and in patients considered by their physician to have severe symptoms at the start of therapy (252 [70%] vs 222 [63%], P = 0.02). Differences were even more apparent in patients with high-risk conditions (74% vs 53%, P = 0.014) and in those aged ≥50 years (70% vs 54%, P = 0.005). Zanamivir treatment was also associated with a significant reduction in time to alleviation of symptoms with no use of relief medication. This was particularly noticeable in those aged ≥50 years; time to alleviation was 13 days in patients receiving placebo and 6 days in patients receiving zanamivir (P < 0.001). In these trials, adverse events were reported at a similar frequency in patients receiving zanamivir and those receiving placebo.

Conclusions: Zanamivir is more effective than placebo in patients with influenza at providing early symptom relief and a reduced duration of illness at a time when use of relief medication has ended. These benefits are seen across different patient groups but appear to be particularly marked in patients who are aged ≥50 years, who have underlying illnesses, who are considered high risk, or who are more severely ill at the beginning of therapy.

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In order to compare the baseline characteristics of the group, a severity of symptom score was calculated for each patient as the presented to the ED. This previously validated severity of symptom (SOS) score was calculated by asking participants to record the severity of 7 symptoms: cough, nasal obstruction, sore throat, fatigue, headache, myalgia, and feverishness [15,16]. The patients rated the severity of each symptom on a scale from 0 being none to 3 being severe.
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We enrolled a convenience sample of adults with ILI presenting to an urban academic emergency department from October to March during the 2008 to 2011 influenza seasons. Subjects had nasal aspirates for viral testing, and serum CRP. Bacterial infection was determined by positive blood cultures, radiographic evidence of pneumonia, or a discharge diagnosis of bacterial infection. Receiver operating characteristic curve, analysis of variance, and Student t test were used to analyze results.
Over 3 influenza seasons there were 131 total patients analyzed (48 influenza infection, 42 other viral infection and 41 bacterial infection). CRP values were 25.65 mg/L (95% CI, 18.88-32.41) for influenza, 18.73 mg/L (95% CI, 12.97-24.49) for viral and 135.96 mg/L (95% CI, 99.38-172.54) for bacterial. There was a significant difference between the bacterial group, and both the influenza and other viral infection groups (P < .001). The receiver operating characteristic curve for CRP as a determinant of bacterial infection had an area under the curve of 0.978, whereby a CRP value of <20 had a sensitivity of 100% and >80 had a specificity of 100%.
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Effect of zanamivir on duration and resolution of influenza symptoms

Abstract

Am J Med.

J. Infect.

Efficacy of influenza vaccine in nursing homes: Reduction in illnesses and complications during an influenza A (H3N2) epidemic

JAMA

Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP)

MMWR

Implication of viral resistance to amantadine in control of influenza A

Clin Infect Dis.

Emergence and apparent transmission of rimantadine-resistant influenza A virus in families

N Engl J Med.

Monitoring of viral susceptibility: New challenges with the development of influenza NA inhibitors

Rev Med Virol.

A novel approach to antiviral therapy for influenza

J Antimicrob Chemother.

Zanamivir susceptibility monitoring and characterization of influenza virus clinical isolates obtained during phase II clinical efficacy studies

Antimicrob Agents Chemother.