Outwitting mutating flu during a pandemic

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Secondary drug could delay resistance to stockpiled medication

In a global influenza pandemic, small stockpiles of a secondary flu medication – if used early in local outbreaks – could extend the effectiveness of primary drug stockpiles, according to research made available April 30 ahead of publication in PLoS Medicine.

Many countries are investing in large stockpiles of a single drug, oseltamivir (Tamiflu). But influenza viruses can become resistant to antiviral drugs, and the widespread use of a single drug is likely to increase the risk that a resistant strain will emerge. If such a strain were to spread widely, the effectiveness of antiviral drugs in treating infected patients, as well as their ability to slow the spread of a pandemic, would be greatly reduced.

Using a mathematical model to represent the global spread of pandemic influenza, an international team of researchers led by Joseph Wu of the University of Hong Kong, and including collaborators in the U.K. and the United States, found that treating as few as only the first 1 percent of the population in a local epidemic with a secondary drug rather than with oseltamivir could substantially delay the development of resistance to oseltamivir.

This reduction in resistance was predicted to benefit not only local populations, but also those in distant parts of the world where the pandemic would subsequently spread through air travel. Marc Lipsitch, professor of epidemiology in the Department of Epidemiology at Harvard School of Public Health, is one of the five co-authors of the study.

In the context of the currently emerging swine flu, the secondary drug could be zanamivir (Relenza), the only other approved drug to which the new H1N1 strain has been found to be susceptible.

This strategy is predicted to be effective because it delays use of the primary stockpiled drug until a certain proportion of the local population (about 1.5 percent according to the model) has been infected with a virus that remains susceptible to the primary drug. With a drug-sensitive virus in the majority as people recover from infection and develop immunity, only a minority of further infections are likely to be resistant to the primary drug.

Technically, such a delay could be achieved by postponing the launch of any antiviral intervention. However, because even a short delay would mean denying antiviral drugs to people who would benefit from them, the researchers instead propose the deployment of a small stockpile of a secondary antiviral during the early phase of the local epidemic.

The model, prepared before the current swine flu crisis, considered two possible strategies, “early combination chemotherapy” (treatment with two drugs together while both are available, assuming that clinical trials show such a combination to be safe for patients) and “sequential multi-drug chemotherapy” (treatment with the secondary drug until its stockpile is exhausted, then treatment with the primary drug). While either strategy could be effective in principle, only the sequential strategy would be practical in responding to the currently emerging H1N1 swine flu, because the safety of combining zanamivir with oseltamivir (for combination therapy) is not established.

After simulating the impact of these strategies in a single population, the researchers then introduced international travel data into their model to investigate whether these two strategies could limit the development of antiviral resistance at a global scale. This analysis predicted that, provided the population that was the main source of resistant strains used one of the strategies, both strategies in distant, subsequently affected populations would be able to reduce the consequences of resistance, even if some intermediate populations failed to control resistance.

As of Thursday (April 30), the U.S. Centers for Disease Control and
Prevention reported 109 cases of H1N1 or “swine flu” in this country
and one death. The U.S. government has declared a public health
emergency because of the flu. Internationally, the World Health
Organization (WHO) reported 257 cases in 11 countries with eight deaths.

On April 29, the World Health Organization (WHO) raised the
influenza pandemic alert status to phase 5 out of 6, and said that all
countries should activate pandemic preparedness plans. 

Authors are Joseph T. Wu, Gabriel M. Leung, and Steven Riley, all of Department of Community Medicine and School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Marc Lipsitch, Department of Epidemiology and Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Mass.; Ben S. Cooper, Statistics, Modelling, and Bioinformatics Department, Centre for Infections, Health Protection Agency, London, United Kingdom.

Funding of this study: The Research Fund for the Control of Infectious Diseases of the Health, Welfare and Food Bureau of the Hong Kong SAR Government; The University of Hong Kong SARS Research Fund; the EU Sixth Framework Programme for research for policy support; the Area of Excellence Scheme of the Hong Kong University Grants Committee; and U.S. National Institutes of Health MIDAS cooperative agreement. Riley also received funding support from the Fogarty International Center RAPIDD Program. Lipsitch received consulting fees from the Pandemic Flu Registry, which is sponsored in part by Roche.