Medical Information

• What is Influenza?
• What is Pandemic Influenza?
• Prevention Strategies
• Vaccines
• Antiviral Drugs

Antiviral Drugs

Overview

Influenza antiviral drugs will play an important role during a pandemic, particularly during the first wave of infection when pandemic vaccines may not be available. In the absence of vaccines, antivirals are the only medical intervention for providing protection against disease and some therapeutic benefit in those who are ill. Unlike pandemic vaccines, antivirals are expected to be immediately effective. Two drugs (in the neuraminidase inhibitors class), oseltamivir (commercially known as Tamiflu) and zanamivir (commercially known as Relenza) can reduce the severity and duration of illness caused by seasonal influenza. The efficacy of the neuraminidase inhibitors depends on their administration within 48 hours after symptom onset. For cases of human infection with H5N1, the drugs may improve prospects of survival, if administered early, but clinical data are limited. The H5N1 virus is expected to be susceptible to the neuraminidase inhibitors.

An older class of antiviral drugs, the M2 inhibitors amantadine and rimantadine, could potentially be used against pandemic influenza, but resistance to these drugs can develop rapidly and this could significantly limit their effectiveness against pandemic influenza. Some currently circulating H5N1 strains are fully resistant to these the M2 inhibitors. However, should a new virus emerge through reassortment, the M2 inhibitors might be effective.

Our current knowledge of the use of the drugs and their application in a potential pandemic is based around what we do know about their actions. Currently this includes:

• antivirals- both neuraminidase inhibitors and ion blockers (M2) - are effective in preventing influenza. The effectiveness in studies ranges from 70-80%
• There appears to be resistance by avian influenza strains to the M2 class of drugs.
• if given within 48 hours, antivirals are effective in reducing the severity of thesymptoms of influenza and shortening of the course of illness
• it is unproven that the use of antivirals for treatment also reduces transmission of the virus
• it is unproven that antivirals used for treatment of influenza reduce mortality in humans, although in some animal studies mortality is reduced.

During a pandemic, urgent research will be undertaken to determine transmission dynamics and efficacy of treatment. The efficacy of the antivirals and the development of clinical resistance in the pandemic virus needs to be monitored for both treatment and prophylaxis. The H5N1 strain of influenza A currently (2005) circulating in some parts of the world is resistant to amantadine.

Current Supplies

Currently, the world’s supply of the anti-viral drugs is limited, and production does not meet current demand. For the neuraminidase inhibitors, the main constraints - which are substantial - involve limited production capacity and a price that is prohibitively high for many countries. At present manufacturing capacity, which has recently quadrupled, it will take a decade to produce enough oseltamivir to treat 20% of the world’s population. The manufacturing process for oseltamivir is complex and time-consuming, and is not easily transferred to other facilities.

While some Governments have stockpiled some supplies, and WHO is seeking to stockpile the drugs, this is for the emergency public health response of an emergent pandemic, and these stockpiles are not intended for general public release. They will be used to initially try to contain an outbreak, and provide front-line health and emergency service workers with protection during the pandemic phase. Current stockpiles would not be enough to handle a major global pandemic.

Countries are also being encouraged to stockpile antibiotics.

Ethical Issues

It is important from a public health perspective that these drugs are not used inappropriately, and careful consideration is required to evaluate the need for obtaining and using the drugs. It is important that these medications are not taken without medical guidance, and they remain prescription only medications. It is not appropriate for individuals to be stockpiling these drugs for self-administration.

Use of the Government Stockpile

In the event of a pandemic, there will be a clear public health strategy for the use of antivirals, particularly that already stockpiled by government for this purpose.

In the early phases of a pandemic, a proportion of the antiviral stock will be set aside for treatment of identified cases and their close contacts.

For preventive use, it is recommended that the antivirals are used in this initial containment phase for those individuals:

• who are exposed to a person or animal likely to be infected with pandemic influenza
• who work in areas where there is a high likelihood of exposure, such as:
• poultry workers and animal disease control officers exposed to HPAI
• border workers who are at higher risk of exposure
• health care workers caring for influenza patients or patients with undiagnosed respiratory disease in which pandemic influenza is a differential diagnosis
• staff at quarantine facilities
• public health staff exposed to potential cases
• laboratory staff at high risk of exposure

During the later phases, containment may not be possible and the optimal strategy for reducing morbidity and mortality will be to maintain essential services. This will ensure minimal disruption to the provision of health and emergency services to the community. It will be vital, therefore, to provide antivirals as longer-term prophylaxis to essential service workers.

Teams providing essential services will need to be designated by all governments and may include:

• health care workers at designated-influenza treatment facilities
• laboratory personnel
• power supply
• water supply
• telecommunications personnel
• sewerage workers
• funeral workers
• emergency service workers
• those involved in the production of the pandemic vaccine
• key decision makers

General use of antivirals

If the drug is available in the community, medical practitioners will be able to prescribe the medications based on the clinical situation. These drugs are indicated for both treatment of influenza, if started within 48 hours of onset, and for prevention in people with likely exposures.

For people travelling in countries where exposure to avian or novel influenza is likely, specialist travel medicine advice is recommended (see section for travellers).

Zanamivir and oseltamivir can also be used for prevention of influenza in a setting where exposure is likely, before illness develops. The drugs add protection even in vaccinated persons. Safety and effectiveness have been shown in people taking oseltamivir for up to 6 weeks. If a pandemic is spreading within the community, preventive medication should be started no more than 2 days after exposure, under direct supervision of medical authorities.

It is recommended that antivirals for ongoing prophylaxis should be provided on a daily basis for a period of up to 6 weeks. There are no studies examining the effect of continuing antivirals for longer periods. Therefore, continued prophylaxis should be considered in clinical grounds and if the antivirals are continued, the person should be monitored for adverse effects.

Influenza antivirals available in Australia

There are currently four antiviral medicines that can shorten the course of infection if given early in the disease (treatment) and provide short-term protection against influenza (prophylaxis). These are: amantadine, rimantadine, oseltamivir and zanamivir. Amantadine, oseltamivir and zanamivir are registered for supply in Australia, but rimantadine is not registered for use in Australia.

Antivirals available in Australia

Drug class	Generic name (Brand name)	Route of administration	Indication *
Neuraminidase inhibitor	Oseltamivir (Tamiflu)	Oral (Tablet or Suspension)	Treatment - Age ≥ 1 year Prophylaxis - Age ≥ 13 years
Neuraminidase inhibitor	Zanamivir (Relenza)	Inhalation (Diskhaler)	Prophylaxis and Treatment - Age ≥ five years **
M2 inhibitor	Amantadine (Symmetrel)	Oral	Prophylaxis - Age ≥ five years

* When used for treatment, neuraminidase inhibitors must be commenced within 48 hours of onset of symptoms. After this time, they are not effective.

** Relenza used for prophylaxis in children is presumptive, further data pending.

M2 inhibitors

Amantadine (Symmetrel)

Amantadine hydrochloride inhibits the replication of influenza A viruses at low concentrations. The exact mechanism of action is unknown. It has been shown that human influenza viruses, including H1N1, H1N2, H2N2 and H3N2 subtypes are inhibited by amantadine.

Amantadine is active only against type A influenza viruses. When used as treatment it does not prevent the host immune response to influenza A infection. Prophylactic administration has no effect on the host immune response to vaccination with the current inactivated influenza virus vaccines.

Although amantadine is approved for the prevention and treatment of influenza, it is not currently listed on the Pharmaceutical Benefits Schedule for subsidy for this indication (it is listed for use in Parkinson’s Disease).

Individuals already on amantadine for other conditions (eg Parkinson’s disease) will need to have their supply maintained during the increased demand in an influenza pandemic.

Amantadine is supplied as 100mg soft gelatin capsules. Shelf-life is up to five years.

Amantadine must be imported, as it is not manufactured in Australia. Inter-pandemic use in Australia for the prevention and treatment of influenza is low.

Neuraminidase inhibitors (Tamiflu/ Relenza)

1. Oseltamivir (Tamilflu)

Oseltamivir is a selective inhibitor of influenza virus neuraminidase enzymes, which are glycoproteins found on the virion surface. Viral neuraminidase is essential for the release of recently formed virus particles from infected cells and the further spread of infectious virus in the body. It is presented as tablets for oral use.

Oseltamivir inhibits neuraminidases of influenza viruses of both types A and B. The active metabolite also inhibits influenza virus growth in vitro and inhibits influenza virus replication and pathogenicity in animal models. Oseltamivir is approved for both treatment of infections due to influenza A and B viruses in adults and children aged one year and older and prevention of influenza in adults and adolescents 13 years and older.

Treatment should commence as soon as possible, but no later than 48 hours after the onset of the initial symptoms of infection. Vaccination is the preferred method of routine prophylaxis against infection with influenza virus.

The incidence of viral resistance in samples derived from clinical isolates is about 2%, depending on viral subtype. The limited resistance data available relates predominantly to H3N2 isolates, with few H1N1 or B virus isolates currently studied.

2. Zanamavir (Relenza)

Zanamivir is a potent and highly selective inhibitor of the influenza virus surface enzyme neuraminidase. It is administered by oral inhalation using its own diskhaler packaging. Viral neuraminidase may facilitate access of virus to cell surfaces and aid the release of newly formed virus particles from infected cells, to allow viral infection of other cells. The inhibition of this enzyme is demonstrated by both in vitro and in vivo activity against influenza A and B virus replication and encompasses all known neuraminidase subtypes of influenza A viruses.

Influenza viral replication is confined to the superficial epithelium of the respiratory tract. The activity of zanamivir is extracellular. It inhibits the release of infective influenza virions from the epithelial cells of the respiratory tract, thereby reducing the propagation of both influenza A and B viruses. The efficacy of zanamivir following oral inhalation to the respiratory tract has been confirmed in clinical studies.

Zanamavir is approved for both treatment and prophylaxis of infections due to influenza A and B viruses in adults and children aged five years and older. Zanamivir can reduce the period of illness caused by current epidemic strains when administered early in the infection. Treatment should commence as soon as possible, but no later than 48 hours after the onset of the initial symptoms of infection.

For prophylaxis, vaccination remains the primary method of preventing and controlling influenza. Zanamavir is indicated for prophylaxis of infection due to influenza A and B viruses in circumstances where prophylaxis of healthy young adults is justified, such as a pandemic with a strain that is not included in the annual vaccine or when vaccine is unavailable. It is not recommended for routine prophylaxis against influenza infection.

Studies indicate that when taken therapeutically to treat an existing influenza infection, it does not interfere with the development of immunity. Based on human challenge studies, in successful prophylaxis most individuals do not develop immunity to influenza and remain fully susceptible to infection when the drug is ceased. It remains to be determined whether the drug is equally effective under pandemic conditions. It would be expected (although untested) that zanamivir would be active against any strain of influenza virus.

There has been no detectable emergence of virus to date with reduced susceptibility to zanamivir during the clinical development program. Data obtained from in vitro studies and from clinical treatment and prophylaxis studies suggest that the potential for the development of reduced clinical susceptibility to zanamivir in the future is low.

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