Zanamivir for influenza: a public health perspective

Its use will require careful management by GPs

Influenza epidemics cause much disruption, including time off school and work, and increased demands on health services. Though the incidence of infection is highest in children and young adults, serious complications, including death, are commonest in elderly people and those suffering from “high risk” chronic illnesses.1 In Britain annual influenza vaccination is therefore recommended for high risk patients and those aged 75 years and over. Despite offering worthwhile reductions in both mortality and hospital admissions, influenza vaccine is underused.2 3

Zanamivir has recently been licensed in Australia, Sweden, and the United Kingdom for treating influenza. Another similar compound, ostelamivir, is waiting in the wings. Created by computer assisted design, the drug works by inhibiting the neuraminidase activity of both influenza type A and B viruses.4 5 Although its bioavailability through oral administration is poor, zanamivir is successfully delivered as a nasal spray or dry powder inhalation.

Randomised, double blind, placebo controlled trials of zanamivir for preventing and treating experimental human influenza have established that the drug is safe, well tolerated, and reduces viral shedding by a median of three days.6 In a large randomised, double blind, placebo controlled trial among healthy adults, zanamivir was 67% effective in preventing laboratory confirmed clinical influenza (AS Monto et al, 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1998). Other randomised, double blind, placebo controlled trials, have shown it to reduce the duration of major symptoms due to proved natural influenza A and B infections by a median of 1-1.5 days (20-25% of the normal duration of symptoms).7 8 The benefits appeared greatest in patients presenting with fever,7 8 those treated within 30 hours of the onset of symptoms,7 and the small number of high risk patients studied (mainly people with mild asthma).8 Among these high risk patients, significant reductions in complications, mainly bronchitis and pneumonia (from 46% to 14%), and antibiotic use (from 38% to 14%) were also reported.8 Of particular importance to people of working age was a reduction in the time taken to resume normal daily activities of up to two days (median), reported in both studies. In severe epidemics such a reduction in working days lost may represent a considerable societal economic gain but it is unlikely to reduce healthcare costs.

Amantadine is an antiviral drug for treatment and prophylaxis against influenza type A, available in Britain since the early 1970s. Its use has been limited by a lack of activity against influenza type B, low awareness of the drug among British doctors, and concerns over accumulation and dose related central nervous side effects in elderly people, and the rapid emergence of resistant viruses.9 In contrast, zanamivir is effective against both influenza A and B and has fewer major side effects, although it is likely to be more costly. A recent randomised trial of zanamivir versus rimantadine for prophylaxis against influenza A in nursing homes was too small to reach any firm conclusions about the relative effectiveness of the two drugs10; more studies are therefore needed.

However, the biggest issue relating to zanamivir is how it may alter the responses of medical practitioners and their patients to the threat of influenza. In Britain influenza is managed almost exclusively in primary care. During the 1989-90 epidemic, which lasted five to six weeks, an estimated 755 000 people consulted their general practitioner and were recognised to be suffering from influenza.11 To manage the demands on primary care, organisations such as the Doctor Patient Partnership and the National Association of GP Cooperatives encourage patients suffering from uncomplicated influenza to refrain from consulting a general practitioner.

By offering a reduction in the duration of symptoms and earlier return to normal activity, however, zanamivir may encourage patients with influenza, especially adults of working age, to visit their general practitioner when before they would have stayed at home. Moreover, since maximum benefit is obtained by starting treatment within 30 hours of the onset of symptoms, the need for early consultation is likely to further increase pressure on general practice appointments during the busiest winter months.

During trials the predictive value of clinical diagnoses of influenza (as later confirmed by virus culture or serology) exceeds 70% 7 8; however, patients' self diagnoses are much less accurate. In a study of hospital workers in Glasgow only 30% of people who recalled the symptoms of influenza showed evidence of seroconversion 12; this finding suggests that general practitioners may receive requests for zanamivir from patients presenting early with a wide variety of other viral respiratory illnesses. Doctors must exercise caution because the results of an intention to treat analysis by the MIST study group suggest that, in the absence of rapid antigen testing, the population benefits of prescribing zanamivir to influenza positive patients are eroded by prescribing the drug for non-influenza respiratory illnesses.8

Further evaluations, based on the intention to treat, are still needed to establish the effectiveness and cost effectiveness of zanamivir compared with influenza vaccine in reducing hospital admissions and mortality among high risk patients. These studies should also consider the possibility that vaccination and zanamivir may be more effective in combination than either one alone. In the meantime, for reasons of practicality, zanamivir should not replace annual influenza vaccination for high risk patients. Nevertheless, it may prove useful for treating those who have missed routine vaccination and those in whom vaccine is contraindicated. Until more evidence becomes available, doctors should reserve zanamivir for high risk patients and those in whom a reduction in the duration of symptoms is of pressing importance, who present early, and in whom a clinical diagnosis of influenza is reasonably certain.