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Emerging Infections: Microbial Threats to Health in the United States
Antiviral drugs can interfere with viral invasion and replication at several specific points. For example, the drug can prevent the attachment of the virus to the host cell, or it may interfere with the assembly of new viruses within the host cell. Although many compounds that have antiviral activity exist or can be synthesized, most cannot be used because of toxicity, because they adversely affect a host cell function, or because they fail to reach concentrations required for antiviral activity in humans (Hayden and Douglas, 1990).
The emergence of antiviral resistance is not well understood. Primary resistance, which exists even before first exposure to a drug, is uncommon, although virus populations appear to consist of heterogenous mixtures of mutants with varying drug sensitivities. Emergence of resistant subpopulations, or de novo mutations creating drug resistance, occur because of selective drug pressure. The frequency and speed at which this occurs varies among virus-drug combinations and is heavily influenced by the type of infection and nature of the host. The usefulness of drug sensitivity assays in such situations is limited. The clinical significance of in vitro resistance is often unclear, a factor that complicates therapeutic decisions.
Antiviral resistance is linked to critical amino acid changes in viral proteins that are targets of drug action or responsible for drug metabolism. Individuals who are immunocompromised, with chronic or recurrent viral infections (particularly herpesvirus infections), often develop drug-resistant viruses. Because resistance to antiviral drugs appears to occur quite rapidly in such individuals, appropriate use and availability of drugs with alternative mechanisms of action are important. Sufficient data are not yet available, however, to recommend limitations on the use of antiviral drugs.
Acyclovir and Herpes Simplex Virus
Acyclovir, an antiviral that inhibits viral DNA synthesis, is the agent of choice for managing infections with herpes simplex virus (HSV). Resistance to acyclovir was a relatively uncommon event prior to the onset of the HIV disease pandemic. Previously, occasional resistance to acyclovir was seen in cancer patients or transplant recipients who were receiving treatment for HSV infection. Acyclovir-resistant HSV in HIV-infected individuals with advanced disease can cause extensive ulcerative lesions that may lead to progressively more serious HSV disease (Laughlin et al., 1991).
The occurrence of resistance does not appear to be linked to dosage or to treatment schedule. Even initial exposure to acyclovir can induce resistance. Most commonly, resistance is caused by a mutation in the virus that results in an inability to produce thymidine kinase, the enzyme toward which acyclovir is targeted. Foscarnet, an antiviral drug that inhibits viral DNA polymerase, is used in the treatment of acyclovir-resistant HSV (Laughlin et