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Antivirals for Pandemic Influenza: Guidance on Developing a Distribution and Dispensing Program
may spread more readily than previously thought. It is important to note, however, that in Europe use of oseltamivir for treatment of seasonal influenza is limited, thus the emergence of resistance may not be related to use. Japan, with its higher rates of seasonal oseltamivir use has not yet reported an increase in resistant strains. The implications of increasing antiviral resistance for pandemic planning are unclear, but troubling.
The factors influencing the rate of antiviral resistance are complex. Based on what is known about the emergence of antiviral resistance in HIV, potential factors driving the emergence of neuraminidase inhibitor–resistant influenza include the structure of the circulating neuraminidase, the relationship of the susceptibility of the pandemic strain and the drug levels among the patients, and the degree of inappropriate use or partial prophylaxis in the presence of circulating resistant virus. Perhaps the most important drivers will be the number of courses of drug that are used and adherence to the drug regimen. Widespread use for post-exposure and seasonal prophylaxis as well as treatment may create selective pressure for the emergence of resistance (Lipsitch et al., 2007). However, the rate of emergence and spread of resistant viruses must be measured against the time it takes to produce an effective vaccine. If neuraminidase inhibitors remain largely effective until a well-matched vaccine can be deployed, there will be a large net benefit despite the emergence of resistance. Conversely, delays in vaccine availability could coincide with rapid development of neuraminidase inhibitor resistance, presenting a grave challenge to effective pandemic response.
Mathematical modeling of resistance in the context of treatment and prophylaxis provides some insight, albeit with a high degree of uncertainty. Lipsitch and colleagues (2007) modeled the predicted impact of four strategies for antiviral use on the number of cases and the emergence of resistance: no antivirals; antivirals for treatment only; antivirals for household prophylaxis without treatment; and antivirals for treatment and household prophylaxis. They predicted that use of antivirals exclusively for treatment led to the least emergence of resistance. Exclusive use for household and seasonal prophylaxis eventually led to significant emergence of resistant virus in the model, but only after some lag time. However, Lipsitch and colleagues predicted that combined use for both treatment and prophylaxis led to the most widespread and rapid emergence of resistant virus.
The committee believes that after resistance-modified effectiveness, the second core issue in identifying the most appropriate strategies for dispensing the medication is the quantity of available antiviral drugs.