Giuseppe
Emeritus
[From European Centre of Diseases Prevention and Control - http://www.ecdc.europa.eu/ ]
SCIENTIFIC ADVANCES- PANDEMIC INFLUENZA – ANTIVIRAL RESISTANCE - Population-wide emergence of antiviral resistance during pandemic influenza.
Moghadas SM, Bowman CS, Röst G, Wu J. PLoS ONE 2008; 3:e1839.
§ Description:
this article describes the application of a mathematical model to estimate how the optimal usage of antivirals at the start of a pandemic could mitigate its impact whilst reducing the emergence and spread of antiviral resistance.(1)
The study was based on a dynamic model where the population was divided into several compartments (susceptible, exposed, asymptomatic and symptomatic individuals).
The clinical course of infection was divided into three stages:
1) pre-symptomatic;
2) primary stage of symptomatic infection (which was considered a two-days window opportunity to start treatment); and
3) a secondary stage of symptomatic infection.
The model assumed different rates of emergence of drug resistance at different stages of infection and according to the time when the treatment was started, being maximal (4.8%) if treatment started at the peak of virus titres and lower (1%) if treatment started in the early stages of symptomatic infection.
Two levels of virus fitness, i.e. the virus ability to replicate and transmit, were also assumed.
Fitness of resistant viruses is usually impaired but can increase if additional compensatory mutations emerges.
Therefore the model also took into account a certain rate of emergence of compensatory mutations, i.e. mutations that would increase the virus ability to replicate and transmit despite the presence of resistance mutations.
This was assumed to occur in a proportion of resistant cases during the secondary stages of symptomatic infection.
Treatment was assumed to reduce the infectiousness by 60% in those infected with a susceptible virus and to have no effect in those infected with a resistant virus.
The authors first assumed a constant proportion of cases being treated with antivirals during the pandemic.
If only 50% of cases were treated, the wild-type virus would spread having a clinical attack rate of 22% and there would be a limited number of resistant cases generated.
Increasing the proportion of the population treated would reduce the clinical attack rate of wild type viruses and would lead resistant cases to emerge at a higher rate.
For example bringing the treatment level up to 90% of cases would enhance the emergence of fit resistant cases to a level where there would be co-existence of outbreaks involving resistant and susceptible viruses, and if 95% of individuals is treated, outbreaks of resistant viruses might become dominant.
The model also explored the effect of changing treatment strategies during a pandemic (adaptive model).
A strategy of giving treatment to 25% of the population during the first 50 days of the pandemic and then increasing the treatment level to 90% of the population not only would reduce the total number of clinical infections but would also according to this model prevent the spread of fit resistant viruses.
The authors concluded that an adaptive antiviral strategy with conservative initial treatment levels, followed by a timely increase in the scale of drug-use, can minimize the final size of a pandemic while preventing large outbreaks of resistant infections to occur.
§ ECDC comment (27/03/2008):
The emergence and spread of viruses resistant to the few antivirals available might considerably affect not only the outcome of patients who become ill, but also the chances of mitigating the effects of an influenza pandemic in a population.
This article, based on a mathematical model and therefore on a number of theoretical assumptions, proposes an adaptive treatment strategy that would reduce the chances of emergence of antiviral resistance and the overall size of the pandemic.
From the conceptual point of view the main limitation of the study would be to translate the adaptive approach into a simple public health policy.
It might be expected that when the pandemic virus starts circulating in the population there will be a number of efforts made to mitigate it including treating patients with antivirals.
However if we assume that a pandemic cannot be controlled but only its impact mitigated, then having a strategy for prolonging the effectiveness of antivirals and reducing the emergence of resistance would be a good and practical strategy option, especially while waiting for a strain-specific vaccine to become available.
This article alone would not provide enough evidence for making plans or for changing policies for antiviral administration during a pandemic.
However this area of research is promising and as more data become available on the dynamics of emergence of influenza antiviral resistance and on the mechanisms regulating the fitness of resistant viruses, for example from the current emergence of oseltamivir resistant influenza A /H1N1 viruses (2,3) and see http://ecdc.europa.eu/Health_topics/influenza/antivirals.html it is likely that these type of studies will gain in terms of precision and reliability.
In addition planning for a pandemic often can only rely on the use of assumptions and modelling data and therefore more studies in this direction are awaited.
One crucial element of mitigation strategies implied by this work is the ability to control and change treatment approaches at a national level in a pandemic. This will not be easy.
--
1) Moscona A. Oseltamivir resistance--disabling our influenza defences. N Engl J Med. 2005a; 353: 2667-72.
2) Lackenby A, Hungnes O, Dudman SG, Meijer A, Paget WJ, Hay A, Zambon MC Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe. Eurosurveillance 2008; 13 (5) Jan 31st 2008
3) Nicoll A, Ciancio B, Kramarz A. Observed oseltamivir resistance in seasonal influenza viruses in Europe interpretation and potential implications. Eurosurveillance 2008 13 (5) Jan 31st 2008
-
------
SCIENTIFIC ADVANCES- PANDEMIC INFLUENZA – ANTIVIRAL RESISTANCE - Population-wide emergence of antiviral resistance during pandemic influenza.
Moghadas SM, Bowman CS, Röst G, Wu J. PLoS ONE 2008; 3:e1839.
§ Description:
this article describes the application of a mathematical model to estimate how the optimal usage of antivirals at the start of a pandemic could mitigate its impact whilst reducing the emergence and spread of antiviral resistance.(1)
The study was based on a dynamic model where the population was divided into several compartments (susceptible, exposed, asymptomatic and symptomatic individuals).
The clinical course of infection was divided into three stages:
1) pre-symptomatic;
2) primary stage of symptomatic infection (which was considered a two-days window opportunity to start treatment); and
3) a secondary stage of symptomatic infection.
The model assumed different rates of emergence of drug resistance at different stages of infection and according to the time when the treatment was started, being maximal (4.8%) if treatment started at the peak of virus titres and lower (1%) if treatment started in the early stages of symptomatic infection.
Two levels of virus fitness, i.e. the virus ability to replicate and transmit, were also assumed.
Fitness of resistant viruses is usually impaired but can increase if additional compensatory mutations emerges.
Therefore the model also took into account a certain rate of emergence of compensatory mutations, i.e. mutations that would increase the virus ability to replicate and transmit despite the presence of resistance mutations.
This was assumed to occur in a proportion of resistant cases during the secondary stages of symptomatic infection.
Treatment was assumed to reduce the infectiousness by 60% in those infected with a susceptible virus and to have no effect in those infected with a resistant virus.
The authors first assumed a constant proportion of cases being treated with antivirals during the pandemic.
If only 50% of cases were treated, the wild-type virus would spread having a clinical attack rate of 22% and there would be a limited number of resistant cases generated.
Increasing the proportion of the population treated would reduce the clinical attack rate of wild type viruses and would lead resistant cases to emerge at a higher rate.
For example bringing the treatment level up to 90% of cases would enhance the emergence of fit resistant cases to a level where there would be co-existence of outbreaks involving resistant and susceptible viruses, and if 95% of individuals is treated, outbreaks of resistant viruses might become dominant.
The model also explored the effect of changing treatment strategies during a pandemic (adaptive model).
A strategy of giving treatment to 25% of the population during the first 50 days of the pandemic and then increasing the treatment level to 90% of the population not only would reduce the total number of clinical infections but would also according to this model prevent the spread of fit resistant viruses.
The authors concluded that an adaptive antiviral strategy with conservative initial treatment levels, followed by a timely increase in the scale of drug-use, can minimize the final size of a pandemic while preventing large outbreaks of resistant infections to occur.
§ ECDC comment (27/03/2008):
The emergence and spread of viruses resistant to the few antivirals available might considerably affect not only the outcome of patients who become ill, but also the chances of mitigating the effects of an influenza pandemic in a population.
This article, based on a mathematical model and therefore on a number of theoretical assumptions, proposes an adaptive treatment strategy that would reduce the chances of emergence of antiviral resistance and the overall size of the pandemic.
From the conceptual point of view the main limitation of the study would be to translate the adaptive approach into a simple public health policy.
It might be expected that when the pandemic virus starts circulating in the population there will be a number of efforts made to mitigate it including treating patients with antivirals.
However if we assume that a pandemic cannot be controlled but only its impact mitigated, then having a strategy for prolonging the effectiveness of antivirals and reducing the emergence of resistance would be a good and practical strategy option, especially while waiting for a strain-specific vaccine to become available.
This article alone would not provide enough evidence for making plans or for changing policies for antiviral administration during a pandemic.
However this area of research is promising and as more data become available on the dynamics of emergence of influenza antiviral resistance and on the mechanisms regulating the fitness of resistant viruses, for example from the current emergence of oseltamivir resistant influenza A /H1N1 viruses (2,3) and see http://ecdc.europa.eu/Health_topics/influenza/antivirals.html it is likely that these type of studies will gain in terms of precision and reliability.
In addition planning for a pandemic often can only rely on the use of assumptions and modelling data and therefore more studies in this direction are awaited.
One crucial element of mitigation strategies implied by this work is the ability to control and change treatment approaches at a national level in a pandemic. This will not be easy.
--
1) Moscona A. Oseltamivir resistance--disabling our influenza defences. N Engl J Med. 2005a; 353: 2667-72.
2) Lackenby A, Hungnes O, Dudman SG, Meijer A, Paget WJ, Hay A, Zambon MC Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe. Eurosurveillance 2008; 13 (5) Jan 31st 2008
3) Nicoll A, Ciancio B, Kramarz A. Observed oseltamivir resistance in seasonal influenza viruses in Europe interpretation and potential implications. Eurosurveillance 2008 13 (5) Jan 31st 2008
-
------