M2 and Neuraminidase Inhibitors: Anti-Influenza Activity, Mechanisms of Resistance, and Clinical Effectiveness
Larisa Gubareva, and Frederick G. Hayden
from: Influenza Virology: Current Topics (Edited by: Yoshihiro Kawaoka). Caister Academic Press, U.K. (2006)
Antivirals have an important role in the treatment and prevention of influenza infections. This chapter describes the antiviral activity, mechanisms of action and resistance, clinical efficacy, and consequences of antiviral resistance for two available classes of anti-influenza drugs. Amantadine and rimantadine target the M2 protein of influenza A viruses; single mutations in the trans-membrane domain of M2 confer high-level resistance to this drug class. Therapeutic use is frequently associated with emergence of drug-resistant variants; such variants are transmissible from person-to-person and pathogenic. The approved neuraminidase inhibitors (zanamivir and oseltamivir) and investigative drugs are potent, specific inhibitors of influenza A and B viruses. Resistance emerges in vitro due to point mutations in hemagglutinin that alter cellular receptor binding or in viral neuraminidase that alter drug binding. Zanamivir and oseltamivir are highly effective for prophylaxis of influenza A and B infections; early therapeutic use reduces illness duration, lower respiratory complications, and in the case of oseltamivir, hospitalizations. Resistant variants with neuraminidase mutations have be infrequently isolated from adults and more commonly from pediatric patients treated with oseltamivir. Available evidence indicates that the relative efficiency of resistance emergence, the biologic fitness of resistant variants, and their transmissibility varies for two drug classes and for specific drugs within the neuraminidase inhibitor class. These differences have important implications for their clinical use read more ...