Resistance to antiviral drugs This is often a big problem-especially with RNA viruses Resistant mutants arise spontaneously(even in the absence of drug) and are selected eg acyclovir-resistant mutants are unable to phosphorylate the drug(TK mutants)or do not incorporate the phosphorylated drug into dNA(pol mutants amantadine resistant mutant influenza a viruses emerge rapidly in treated patients To overcome resistance it is crucial to use drugs at sufficient concentration to completely block replication The use of more than one drug, with more than one target, reduces significantly the emergence of resistant mutants