Resistance to Anti-viral Agents: Mutations Side-step Inhibition Processes

Viruses, although genetically simple, have the ability to replicate to high titers in host cells and can mutate very rapidly. Therefore, most viral resistance results from genetic mutation: Very few resistant viruses have been isolated from immunocompetent patients receiving antiviral treatment. Resistant herpes viruses are isolated from immuno-compromised patients receiving prolonged courses of antiviral treatment: severely immuno-compromised patients may provide an environment for mutant viruses to prosper, and a larger viral load creates a larger gene pool from

which mutations can emerge. Further selective pressure from antiviral agents could result in the propagation and transmission of resistant viruses.

Another very important issue is cross-resistance among antiviral drugs. Resistance to one compound is usually accompanied by decreased susceptibility to other drugs of the same class, but predictable cross-resistance among different classes of drugs has also been found and is thought to indicate overlap of drug-binding sites.

Combination therapy may slow or even prevent drug resistance. Other measures to prevent drug resistance include administration of therapeutic levels of anti-viral medications: prolonged courses of subinhibitory levels has the potential for increased resistance resulting from viral mutation.

Treatment with antiviral agents does not prevent future recurrence of eventual progression suggesting that antiviral agents do not eliminate viruses in their latent or nonactive states (e.g. acyclovir does not prevent recurrence of HSV; zidovudine does prevent progression of AIDS). Treatment during latent viral infection may actually encourage drug resistance due to prolonged contact between virus and drug.

Successful treatment of latent infection is dependent on identification and characterization of metabolic processes during latent infection that can then be targeted by antiviral agents.

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