Barts and The London, Retroscreen Virology Ltd, Queen Marys School of Medicine and Dentistry, 327 Mile End Road, London E1 4NS, UK
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Abstract |
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Keywords: antivirals, pandemics, epidemics, respiratory viruses
Until recently the only truly global respiratory virus was influenza A, causing huge medical and economic problems involving tens of millions of persons in the pandemic years of 1918, 1957 and 19681 as well as in the intervening seasons. But a completely new human pathogen, SARS coronavirus,2 has now joined influenza as a global respiratory virus and the recent outbreaks in South East Asia and Hong Kong although minute by comparison with influenza will at the very least teach us how a modern society reacts to a brand new viral infection.
In comparative terms, the SARS outbreak has been very restricted both in numbers of patients infected and mortality. On the other hand, influenza in 1918 spread very slowly at first from an origin in army camps in the winter of 19173 and therefore we should reserve judgement about the future spread of SARS. Not unexpectedly air travel has transported SARS-infected persons to at least 20 other countries where small outbreaks have been described. In an unprecedented decision, WHO recommended a restriction on travellers entry into Hong Kong, China and Canada in an attempt to contain the outbreak. The virus is new and like pandemic influenza A may have emerged from an avian or animal source possibly civet cats. Since there are no antiviral drugs or vaccines against coronavirus, communities have had to resort to using face masks. Other relatively small interventions such as reduced living density and careful washing of cups and saucers in the family environment could reduce transmission, with a virus like SARS, but not with a highly contagious virus like influenza.
The main lesson from the SARS outbreak is that when the next influenza global or pandemic virus arises there will be virtually unlimited demand for antiviral drugs and vaccines. Every community in the world will place entire reliance on two classes of anti-influenza drugs, the M2 blockers (amantadine and rimantadine) and the anti-neuraminidase drugs (neuraminidase inhibitors; NAIs). With the comparison of SARS in mind and where whole communities in SE Asia were on the edge of panic, would our medical communities be able to cope with a truly global pandemic of influenza? Are we prepared or could the situation descend into chaos and even anarchy? To some extent these are social and political questions but scientific discovery and its practical application, in this case involving anti-influenza drugs, is the key to preventing these problems in the first place.
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Discovery of a new class of anti-influenza drugs: the NAIs |
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Use of anti-NA drugs to prevent influenza in the community and particularly in the family |
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The randomized, double-blind, placebo-controlled post-infection prophylactic study conducted at 76 centres in North America and Europe during the winter of 19981999 is worthy of more detailed analysis.8 The study included three hundred and seventy-seven index cases (ICs) of influenza, 163 (43%) of whom had laboratory-confirmed influenza infection, and 955 household contacts (aged >12 years) of ICs including 415 contacts of influenza-positive ICs. Household contacts were randomly assigned by household cluster to take 75 mg of oseltamivir (n = 493) or placebo (n = 462) once daily for 7 days within 48 h of symptom onset in the IC. The IC of influenza did not receive antiviral treatment. Clinical influenza in contacts of influenza-positive ICs was confirmed by detection of virus shedding in nose and throat swabs or by a four-fold or greater increase in influenza-specific serum antibody titre between baseline and convalescent serum samples. In contacts of an influenza-positive IC, the overall protective efficacy of oseltamivir against clinical influenza was 89% for individuals, and 84% for households. In contacts of all ICs, oseltamivir also significantly reduced the incidence of clinical influenza, with 89% protective efficacy. Viral shedding was inhibited in contacts taking oseltamivir, with 84% protective efficacy. All virus isolates from oseltamivir recipients retained sensitivity to the active metabolite. Oseltamivir was well tolerated; gastrointestinal tract effects were reported with similar frequency in oseltamivir (9.3%) and placebo (7.2%) recipients. Very similar data were reported using zanamivir in prophylactic studies on campus or in the community.7
As regards therapy or use of the drug to abrogate symptoms, clinical studies in the community showed that administration of inhaled zanamivir within 48 h of natural influenza A or B infection significantly reduced the duration of symptomatic illness by 1 day (4 versus 5 days) compared with placebo. Importantly, data also indicated that zanamivir treatment reduced the impact of influenza virus infection on a patients productivity and health status and the number of contacts made with healthcare professionals.9,13
In comparable studies of oseltamivir in the community, a total of 629 healthy, unimmunized adults aged 1865 years were enrolled after presenting within 36 h of onset and with a temperature of 38°C or more plus at least one respiratory symptom and one constitutional symptom.14 Individuals were randomized to one of three treatment groups: oseltamivir 75 mg twice daily, oseltamivir 150 mg twice daily for 5 days or placebo. A total of 374 participants were confirmed to have influenza (60%). Duration of illness from the initiation of therapy was reduced by approximately 30% in the oseltamivir groups. In the 75 mg twice daily group, the median duration of illness was reduced to 3 days compared with 4.3 days in the placebo group (P = 0.001) and in the 150 mg twice daily group the duration was reduced to 2.9 days (P = 0.001). There was also a significant decrease in the symptoms of illness. Volunteers treated with oseltamivir reported a more rapid return to normal health and usual activities. Additionally, the incidence of secondary complication, predefined as pneumonia, bronchitis, sinusitis and otitis media, in subjects with influenza was reduced from 15% in placebo recipients to 59% in the two oseltamivir-treated groups. Antibiotic prescriptions for these complications were reduced.
Whitley et al.15 described a randomized double-blind placebo study in children from 1 to 12 years of age with clinically diagnosed influenza (fever > 38°C, history of cough and coryza) of <48 h duration. The children received 2 mg/kg oseltamivir or placebo twice daily for 5 days. Six hundred and ninety-five children were enrolled and 65% had serologically proven influenza. In children treated with oseltamivir, the median duration of illness was reduced by 36 h compared with placebo. New diagnosis of otitis media was reduced by 44% and the incidence of prescribed antibiotics was significantly reduced in the drug group. There was a 5.8% excess of emesis in the drug group. Oseltamivir therefore appeared to be an efficacious and well-tolerated therapy when used in children within 48 h of onset of influenza symptoms.
The IMPACT study reported by Aoki et al.16 was designed to investigate the relationship of time-to-treatment with illness duration and other efficacy parameters and confirmed that greater and incremental benefits can be gained from treating influenza as soon as possible after the appearance of symptoms. A total of 1426 patients (1270 years) presenting within 48 h of the onset of influenza symptoms were treated with oseltamivir 75 mg twice a day for 5 days during the 19992000 influenza season; 958 (67%) had laboratory-confirmed influenza virus infection. Earlier intervention was associated with shorter illness duration (P < 0.0001). Initiation of therapy within the first 12 h after fever onset reduced the total median illness duration by 74.6 h (3.1 days; 41%) more than intervention at 48 h. Intermediate interventions reduced the illness proportionately compared with 48 h. In addition, the earlier administration of oseltamivir further reduced the duration of fever, severity of symptoms and the times to return to baseline activity and health scores. Oseltamivir was well tolerated. The most common adverse events were nausea and vomiting, which were transient and generally occurred only with first dosing. Influenza illness is associated with virus replication in the respiratory tract that peaks 2472 h after illness onset. Thus, drugs like oseltamivir or zanamivir that would ameliorate illness solely by inhibiting virus replication must be administered in the first 4872 h of illness, and preferably as early as possible. Early intervention was shown to be strongly associated with a shorter duration and a reduced severity of illness, a faster resolution of fever and a faster return to normal health and activity. For the primary endpoint, the data demonstrated that the total duration of illness could be halved if influenza patients were treated early compared with intervention at 48 h. These data complement the results from an earlier study with oseltamivir in which subjects who started active treatment within 24 h of symptom onset had a 37% duration compared with 25% in those who initiated therapy within 36 h after onset of illness.
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The conundrum: how to use the new anti-influenza drugs and how not to use them |
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The practical problem is also to make sure that the drugs are not wasted on non-influenza respiratory disease. This is unlikely to be the case in an acute influenza outbreak but could occur in the intervening years when influenza does not reach epidemic levels yet circulates in the community and is even harder to diagnose clinically. The other problem, rather more managerial than medical or scientific, is how to arrange prescription and use of the new drugs within 48 h of onset of clinical symptoms. But in a modern mobile society with text messages, mobile phones and the internet it is surely possible to arrange a nurse or prescriber appointment especially whilst an influenza outbreak is in progress? Most influenza outbreaks last 46 weeks and thereafter the practice can soon return to normal. In reality, use of the drugs in a general practice would be expected to reduce the number of patients or staff with influenza and therefore help the efficient running of the clinic through a winter influenza crisis.
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Drug resistance and the problem of a great pandemic |
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Therefore nothing can replace the careful year-by-year use and monitoring of the new anti-influenza drugs which should simultaneously give confidence to both doctor and patients alike that firstly influenza is not like the common cold virus because it can develop into a serious infection, that it can spread rapidly in the family and workplace, that it can be confidently diagnosed by the family physician and, most importantly that there is a new family of powerful drugs which can actually protect against infection.
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The future is the crystal ball exercise |
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Footnotes |
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References |
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