Inter-Pandemic Period and Pandemic Alert Period 115

avian influenza; healthcare workers and workers in essential services when a pandemic is imminent or established (WHO 2005e).

Antiviral Drugs

Antiviral drugs include M2 inhibitors, which are ion channel blockers (amantadine and rimantadine), and the neuraminidase inhibitors (oseltamivir and zanamivir) (Hoffmann 2006b). The emergence of resistant variants is a concern with the use of any antiviral drugs. Treatment with M2 inhibitors can cause emergence of fully pathogenic and transmissible resistant variants in at least 30 % of individuals (Hayden 1997). Moreover, M2 inhibitors are ineffective against H5N1 in vitro (Lipatov 2004).

After treatment with neuraminidase inhibitors, resistant variants were initially found in approximately 4 % to 8 % of children and < 1 % of adults (McKimm-Breschkin 2003, Stilianakis 2002), and were identified later in 18 % of Japanese children during treatment with oseltamivir (Kiso 2004). The emergence of resistant influenza A (H5N1) variants during oseltamivir treatment was recently reported in two Vietnamese patients (de Jong 2005). Influenza A (H5N1) viruses with a H274Y substitution in the neuraminidase gene, which confers high-level resistance to oseltamivir (Gubareva 2001), were isolated from both patients. Even though oseltamivir was administered at the recommended dose and duration (75 mg twice daily for five days, with a weight-based reduction in the dose for children less than 13 years old) and treatment was started when the greatest clinical benefit could be expected (within 48 hours after the onset of symptoms), both patients died. These observations suggest that the development of drug resistance contributed to the failure of therapy in these patients. The authors conclude that strategies aimed at improving antiviral efficacy (e.g., the use of higher doses, longer durations of therapy, or combination therapy) deserve further evaluation.

New routes of administration of antivirals should also be explored, as altered pharmacokinetics in severely ill influenza patients, who may be affected by diarrhoea, have been reported (Hien 2004).

There are concerns that young children and patients with intellectual or coordination impairments are not able to inhale zanamivir properly (Imuta 2003). However, as resistance against oseltamivir can emerge during the currently recommended regimen, and as zanamivir might be less prone to the development of resistance mutations (Moscona 2005), zanamivir might be included in the treatment arsenal for influenza A (H5N1) virus infections.

Drug Stockpiling

Some governments have recently opted for stockpiling of oseltamivir. The number of courses of oseltamivir to be stockpiled by each country depends on existing resources and population size. The World Health Organisation has been urging countries to stockpile the drug in advance (Abbott 2005). For example, the Dutch government has stockpiled approximately 225,000 courses of oseltamivir (Groeneveld 2005). However, many developing countries may not be able to afford to stockpile antiviral drugs.

The cost benefit of stockpiling and the optimal strategy for antiviral use were recently investigated for the Israeli population by using data (numbers of illness episodes, physician visits, hospitalisations, and deaths) derived from previous influ-

116 Pandemic Preparedness

enza pandemics. Costs to the healthcare system and overall costs to the economy, the latter including the value of lost workdays but not the potential value of lost lives, were calculated (Balicer 2005). Three strategies for the use of oseltamivir during a pandemic were defined: therapeutic use, long-term pre-exposure prophylaxis, and short-term postexposure prophylaxis for close contacts of influenza patients (with index patients under treatment). The first two strategies could target either the entire population or only those at high risk of complications. The economic outcomes of each of the five strategies were compared with nonintervention. Stockpiling costs were estimated and cost-benefit ratios were calculated. The most favourable cost-benefit ratio was found when stockpiled antiviral drugs were administered either solely as a therapeutic measure or as a short-term prophylaxis for exposed contacts, a strategy termed “targeted prophylaxis” (Longini 2004). The objective of targeted strategies is to minimise drug usage while maximising effect. Therefore, in developing countries targeted prophylaxis is particularly important for saving resources.

While in most developing countries the use of antiviral agents is not expected, in developed nations the use of antiviral agents depends on whether the drugs are in short or large supply (see Table 3).

Table 3. Recommended use of antiviral agents by the Dutch Ministry of Health (adapted from Groeneveld 2005)

1. When the pandemic first reaches the Netherlands

Treat	Provide prophylaxis to
Index patientsa	Families, housemates and
	other contacts of index
	patients: post-exposure
	prophylaxis

2. In a manifest pandemic or in the event of large-scale virus introduction from abroad

If neuraminidase inhibitors are in short supply

If neuraminidase inhibitors are not in short supply

Treat

Risk groupsb, professionalsc, and (when relevant) people in pan- demic-specific risk groupa; otherwise healthy people: in the event of hospitalisation due to complications

Treat

Patients displaying symptoms consistent with influenza

Provide prophylaxis to

Individual patientsd and risk groups, professionals, and (where relevant) people in pandemic-specific risk groupe

a.As soon as possible following the appearance of the first symptoms; if treatment is not started within 48 hours, it may not be effective.

b.Patients with serious respiratory, pulmonary or cardiovascular abnormalities or dysfunction, who, if infected with the pandemic influenza virus, would be at serious risk of pulmonary or cardiovascular function decompensation, patients with an insulin-dependent form of diabetes.

c.All persons responsible for the diagnosis, treatment and care of influenza patients, or for logistic management of the necessary resources.

d.Where considered appropriate by the doctor in charge of the individual patient.

e.Following vaccination and while the virus is circulating.