Antiviral Drugs & Influenza

What is influenza?

·           Influenza, commonly called ‘the flu’, is a serious disease caused by the influenza A and B viruses¹.

·           Influenza A subtypes are the most important for humans: influenza A strains have been responsible for previous pandemics and are responsible for more deaths than influenza B viruses ¹. Influenza B viruses generally cause less severe disease in humans².

The role of antiviral drugs and vaccination in seasonal influenza management

·           Influenza vaccines work by stimulating the body to produce antibodies against the virus strain contained within the vaccine, thus helping to prevent infection or diminish the symptoms of should the vaccinated person encounter the influenza virus strain again.   Vaccination is the recommended by the Department of Health (DH) as the first line strategy for preventing influenza, for people aged over 65 years old and/or those people defined as ‘at-risk’³.

·           Antiviral drugs specific to the influenza virus are also available for the prevention and treatment   of influenza, as guided by the National Institute for Health and Clinical Excellence (NICE) ^3,4. Antiviral drugs are not vaccines, but work in a different way to provide protection against and treat influenza. They can be used when the vaccine match to the circulating influenza strain is poor, a person has a reduced immune response to vaccination , or a vaccine has not been administered.³

What kind of antiviral drugs are available for influenza?

·           Two types of antiviral drugs are available in the UK : M2 inhibitors and neuraminidase inhibitors

M2 inhibitors:

·           The M2 inhibitors, amantadine and rimantadine (the latter is not available in the UK ), are the older class of antiviral drug.   

·           M2 inhibitors are only effective against influenza A viruses and work by blocking the M2 ion channels present in the membranes of the body’s cells. This stops a vital step in virus replication, thus limiting the spread of the virus in the body⁵.

·           Amantadine is not recommended by NICE for the prevention or treatment of influenza and rimantadine is unlicensed^3,4.

Neuraminidase inhibitors (NAIs):

The NAIs - oseltamivir (Tamiflu^{® ▼} ) and zanamivir (Relenza^{® ▼} ) - are a newer class of antivirals that can be used to prevent and treat in fluenza:^6,7

·           NAIs are effective against influenza A and B viruses, designed to specifically target the influenza virus by binding to a surface protein that is only present on an influenza virus – the neuraminidase protein. Normally, the neuraminidase protein enables the influenza virus to continue to infect host cells. When it is inhibited by an NAI, the virus is unable to break free from the host cell and dies, and therefore cannot spread to and infect other cells in the body.

·           Tamiflu is an oral antiviral treatment, whereas Relenza is inhaled.   Tamiflu acts throughout the body and is available as capsules, and an oral suspension formulation for easy administration to children and/or patients that may have difficulty swallowing capsules.

·           Relenza acts primarily in the lungs and is administered as a dry powder using an inhaler device. It is to be used with caution in individuals with asthma or chronic pulmonary disease because of the risk of bronchospasm⁶.

The efficacy of antiviral treatments

·           In contrast to the older antivirals, Tamiflu and Relenza are effective against both influenza A and B viruses, and their mechanism of action suggests that these treatments should be effective against a wide range of influenza viruses – the key to influenza pandemic management ⁶ .

·           When administered at the correct dose and within 48 hours of symptom onset, Tamiflu delivers:

- 38 per cent reduction in the severity of symptoms⁸

- 59 per cent reduction in hospitalisation⁹

- 30 per cent reduction in the duration of influenza illness¹⁰

·           Treatment with Tamiflu and Relenza should always be initiated within 48 hours of the onset of symptoms^5,6. The sooner Tamiflu is administered following the onset of symptoms, the more efficacious it has been shown to be^10,11.

·           Tamiflu delivers a reduction in the following:

o          severity of symptoms¹⁰

o          duration of influenza illness (initiation of treatment within the first 12 hours after fever onset reduces total media illness duration by 3.1 days more than intervention at 48 hours) ¹¹

o          secondary lower respiratory tract complications, bronchitis, pneumonia and hospitalisations⁹

·           Tamiflu and Relenza are highly effective at reducing the spread of influenza in households exposed to the influenza virus, an important aspect of intervention in pandemic influenza¹². Analysing four household-based studies, the authors demonstrated that Tamiflu reduced the chance of an exposed person becoming ill with influenza by 81% compared with 75% for Relenza¹². These data also show that antiviral drugs reduce the infectiousness (ability to transmit) and pathogenicity (ability to cause disease) of the influenza virus. Efficacy in reducing pathogenicity was 79% and 56% in the two Tamiflu studies; for Relenza, it was 52% and 56% ¹² . Only Tamiflu significantly reduced the infectiousness of the virus, with an 80% reduction seen¹².    The effect was not significant with Relenza, demonstrating only a 19% reduction¹². Considering reasons for the greater impact of Tamiflu on infectiousness, the authors speculated that the oral formulation of Tamiflu could ensure it works successfully throughout the respiratory tract, versus the inhaled formulation of Relenza, which could make it less effective at targeting the influenza virus in the nose.¹²

Resistance to NAIs

·           The potential exists for any influenza virus to mutate and become resistant to the action of   NAIs. In practice, however, the observed incidence of resistant   influenzavirus is low (0.32% in adults and 4.1% in children),⁶ despite the high usage of Tamiflu across the world. Importantly, mutations to the neuraminidase protein has actually been shown to reduce the ability of the virus to replicate and transmit. This means that the majority of NAI-resistant influenza viruses that have emerged had a reduced ability to be transmitted, infect cells and therefore cause disease.¹³

Treating and preventing influenza with antiviral drugs

·           The NICE guidance provides recommendations for the management of influenza during a standard seasonal outbreak, placing vaccination as first line for the prevention of influenza. The scope of the guidance does not cover antiviral drug use in a widespread epidemic or pandemic situation^3,4. Tamiflu is licensed for treatment and prophylaxis of influenza in adults and children > 1 year.⁶ Relenza is licensed for treatment and prophyalxis in adults and children 5 years and over.⁷

NAIs and the H5N1 avian influenza virus

·          NAIs are designed to be active against all clinically relevant influenza viruses, including the H5N1 virus. Tamiflu has been shown to be effective against the H5N1 virus in the laboratory . There has also been some early data from people infected with H5N1 that shows Tamiflu is active against the H5N1 virus,   particularly when given early.¹⁴ The currently circulating H5N1 virus has been shown to be extremely virulent, inducing a severe infection, which results in deaths in an extremely high proportion (52%) of those infected.  

• The World Health Organisation (WHO) advocates that doses of Tamiflu used for seasonal human influenza continue to be recommended for the treatment of people infected with the currently circulating avian influenza strains.¹⁵ However, when a pandemic strain emerges, it will be vital to test the susceptibility of the pandemic strain to Tamiflu to determine the optimal dose and duration for treatment.
• While Tamiflu is being used for the prophylaxis of people involved in the culling of animals infected with H5N1 and for healthcare workers involved in the management of people infected with the virus, there are no clinical data currently available for the use of Tamiflu to prevent H5N1 infections.

WHO recommendations for pharmacological management of patients with H5N1 infection in a non-pandemic situation¹⁶

• According to the WHO, cases of people becoming infected with H5N1 have remained rare and sporadic, but the disease is very severe and the case fatality is high. With the H5N1 virus now confirmed in birds in more than 50 countries, additional cases can be anticipated.
• A strong recommendation was made by WHO for H5N1 infected patients to be treated with Tamiflu   as early as possible, with Relenza receiving a weak recommendation.   The WHO also strongly recommend that high-risk exposure groups (household or close family contacts of a H5N1 infected patient) should be given Tamiflu or Relenza as a prophylactic measure, within 7 – 10 days of the last known exposure.

Tamiflu and resistance to H5N1

·          To date, a few cases of Tamiflu resistance to H5N1 have been observed, despite the number of people infected increasing.^17,18   Three of these cases have been fully investigated. One patient only received the prophylactic dose (75 mg once daily) rather than the treatment dose (75 mg twice daily), thus under dosing the patient and increasing the risk of resistance. Once the twice daily treatment dose was provided, the patient recovered from the illness. Again this resistant virus was shown to cause less severe infection and was less capable of transmission. Two patients received the recommended dose and duration of Tamiflu. However, while one patient received treatment on the second day of illness, the other patient did not start treatment on the sixth day of illness. Resistant strains of the virus were detected in both patients who subsequently died.

Preventing and treating pandemic influenza¹⁵

·          The WHO estimates it may take at least 6 - 9 months to develop and manufacture a new vaccine that is effective against the circulating strain. Until a vaccine is developed governments will need to rely on antiviral drugs to help contain the spread of influenza virus.

Pandemic stockpiling¹⁵

·          The WHO advises that stockpiling antiviral drugs in advance is presently the only way to ensure that sufficient supplies are available in the event of a pandemic.

·          It is the responsibility of the governments of individual countries to ensure that a pandemic plan and stockpiles are in place.

·          Roche has been working with many governments over the last few years to discuss their needs for stockpiling of Tamiflu and has received and fulfilled orders from around 60 countries. The UK Government has stockpiled 14.6 million treatment courses, enough to cover 25% of the UK population.

·          In order to meet the needs of governments, Roche has increased manufacturing capacity and is now able to deliver an order of over 14 million courses in 3 months (400 million treatment courses per year).

  References

1.         WHO fact sheet no 211. Revised March 2003. Http://www.who.int/mediacentre/factsheets/fs211/en/index.html

2.         Myxoviruses. Microbiology at Leicester, University of Leicester . Updated April 2006 http://www-micro.msb.le.ac.uk/3035/Orthomyxoviruses.html

3.         NICE Technology appraisal No. 67. Guidance on the use of oseltamivir and amantadine for the prophylaxis of influenza. September 2003. http://www.nice.org.uk/page.aspx?o=TA067guidance

4.         NICE Technology appraisal No. 58. Guidance on the use of zanamivir, oseltamivir and amantadine for the treatment of influenza. February 2003. http://www.nice.org.uk/page.aspx?o=TA058guidance

5.         European Medicines Agency: Summary Report – Review on influenza antiviral medicinal products for potential use during pandemic. http://www/emea.eu.int/pdfs/human/pandemicinfluenza/33997205.pdf

6.         Tamiflu summary of product characteristics. Electronic Medicines Compendium. November 2006 http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=10446

7.         Relenza Summary of product characteristics. Electronic Medicines Compendium. November 2006 http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=2608

8.         Treanor JJ et al, Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza. A randomised controlled trial. JAMA. 2000; 283(8): 1016-1024.

9.         Kaiser et al, Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalisations. Arch Intern Med; 2003: 163: 1667-1672.

10.      Nicholson KG et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Lancet 2000; 355:1845–1850

11.      Aoli FY et al. Early administration of oral oseltamivir increases the benefits of influenza treatment. J Ant Chem 2003;51:123-129.

12.      Halloran EM et al. Antiviral effects on influenza viral transmission and pathogenicity: observations from household-based trials' Am J Epidemiol 2007; 165:212-221.

13.      Roberts N. Treatment of influenza with neuraminidase inhibitors virological implications. Philos. Trans. R. Soc. London. B. Biol. Soc. (2001) 356:1895-1897.

14.      Oner et al, Avian influenza A (H5N1) infection in Eastern Turkey in 2006. NEJM 2006: 2179-2672

15.      WHO global influenza preparedness plan http://www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_GIP_2005_5/en/index.html

16.      World Health Organisation Rapid Advice Guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus. Lancet Infect Dis 2007; Vol 7 January 200 7 : 21–3. http://infection.thelancet.com )

17.      Le QM et al, Isolation of drug-resistant H5N1 virus. Brief Communications. Nature 2005.

18.      de Jong et al. Oseltamivir Resistance During treatment of influenza A (H5N1) infection. NEJM 2005; 353;25: 2667-2672.

(6/2/07)