Chemistry and Mechanisms.

Most of the nucleoside analogues used to treat herpesvirus infections contain a naturally occurring purine or pyrimidine base combined with a synthetic carbohydrate moiety.

The nucleoside analogues are prodrugs that are phosphorylated by viral and host cell kinases to form active triphosphate metabolites (Fig. 43-1). In this process, the nucleoside analogues are initially converted to monophosphate metabolites by a virus-encoded thymidine kinase. The conversion occurs only in infected host cells, thereby contributing to the selective toxicity of the analogues. Host cell kinases subsequently convert the monophosphates to active triphosphate metabolites. The active metabolites then compete with endogenous nucleoside triphosphates and competitively inhibit viral DNA polymerase, which in turn prevents the synthesis of viral DNA. Some nucleoside analogues (e.g., acyclovir) are incorporated into nascent viral DNA and cause DNA chain termination because they lack the 3′-hydroxyl group required for attachment of the next nucleoside (see Fig. 43-1). Other analogues (e.g., ganciclovir and penciclovir) inhibit viral DNA polymerase but do not cause DNA chain termination.

Pharmacokinetics and Indications.

The properties and clinical uses of individual drugs for herpesvirus infections are compared in Tables 43-1 and 43-2.

Viral Resistance.

The incidence of resistance to the nucleoside analogues varies with the drug and viral pathogen. Resistance of HSV and VZV to acyclovir is not common, and resistant strains are usually less infective than are sensitive strains. Furthermore, most acyclovir-resistant HSV and VZV strains are not resistant to other nucleoside analogues or to foscarnet. Most acyclovir-resistant strains have been recovered from immunocompromised patients. Loss of thymidine kinase activity is the major cause of innate and acquired resistance to acyclovir.

Resistance of CMV to ganciclovir is a more serious clinical problem than is HSV resistance, but most ganciclovir-resistant CMV strains are sensitive to cidofovir and foscarnet. Loss of a virus-specific protein kinase is the major cause of resistance to ganciclovir.

Acyclovir, Famciclovir, and Valacyclovir

Acyclovir, famciclovir, and valacyclovir are nucleoside analogues that are effective in the treatment of various HSV and VZV infections (see Table 43-2). These drugs are not sufficiently active against CMV to be effective in treating CMV infections, but acyclovir and valacyclovir can be used for prophylaxis of CMV infections, such as in bone marrow and organ transplant recipients and in persons with HIV infection. All three drugs are available for oral use. In addition, acyclovir is available for intravenous and topical use.

The intravenous form of acyclovir is the most effective treatment for serious herpesvirus infections, including herpetic encephalitis and severe HSV and VZV infections in immunocompromised patients.

The topical form of acyclovir can be used to treat herpes genitalis and mild mucocutaneous infections in immunocompromised patients. In cases of herpes genitalis, however, the topical form is less effective than the oral form of acyclovir.

In its oral form, acyclovir has a relatively low bioavailability (22%). Valacyclovir, which was developed later than acyclovir, is a prodrug that is rapidly converted to acyclovir by intestinal and hepatic enzymes and is more completely absorbed than acyclovir. Because of its greater bioavailability (55%), valacyclovir requires less frequent administration than acyclovir. Famciclovir has the greatest bioavailability (80%) and is rapidly hydrolyzed to penciclovir after its absorption.

When acyclovir, famciclovir, or valacyclovir is given orally for the treatment of herpes genitalis, it prevents the replication of HSV and thereby reduces pain and other symptoms of acute infection. It also shortens the time to healing of lesions and reduces the amount of viral shedding. It does not eliminate the virus, and recurrent episodes of infection are common. Shorter courses of therapy are usually sufficient for these episodes, because recurrent infections are usually milder than the initial infection. Severe herpes genitalis may require intravenous acyclovir therapy.

When acyclovir, famciclovir, or valacyclovir is given orally for the treatment of shingles, it shortens the duration of acute illness, acute pain, and postherpetic pain (neuralgia). In patients with shingles, famciclovir and valacyclovir appear to be more effective than acyclovir. The newer drugs allow for less-frequent administration and provide higher serum drug levels because of their greater oral bioavailability. A new vaccine has been shown to reduce the incidence and severity of herpes zoster infections in older adults.

Acyclovir is available in an oral suspension for the treatment of children with chickenpox. The drug has a good safety record in this setting.

Acyclovir, famciclovir, and valacyclovir are well tolerated when given orally, and they do not have significant interactions with other drugs. Gastrointestinal disturbances, headache, and rash are the most common side effects. Intravenous administration of acyclovir can produce phlebitis and reversible renal dysfunction. Resistance to these drugs is rare in immunocompetent patients, but drug-resistant strains have been recovered from immunocompromised subjects.