Famciclovir is the diacetyl ester prodrug of 6-deoxypenciclovir, an acyclic guanosine analog. After oral administration, famciclovir is rapidly deacetylated and oxidized by first-pass metabolism to penciclovir. It is active in vitro against HSV-1, HSV-2, VZV, EBV, and HBV. As with acyclovir, activation by phosphorylation is catalyzed by the virus-specified thymidine kinase in infected cells, followed by competitive inhibition of the viral DNA polymerase to block DNA synthesis. Unlike acyclovir, however, penciclovir does not cause chain termination. Penciclovir triphosphate has lower affinity for the viral DNA polymerase than acyclovir triphosphate, but it achieves higher intracellular concentrations. The most commonly encountered clinical mutants of HSV are thymidine kinase-deficient; these are cross-resistant to acyclovir and famciclovir.
The bioavailability of penciclovir from orally administered famciclovir is 70%. The intracellular half-life of penciclovir triphosphate is prolonged, at 7–20 hours. Penciclovir is excreted primarily in the urine.
Oral famciclovir is generally well tolerated, although headache, nausea, or diarrhea may occur. As with acyclovir, testicular toxicity has been demonstrated in animals receiving repeated doses. However, men receiving daily famciclovir (250 mg every 12 hours) for 18 weeks had no changes in sperm morphology or motility. In one study, there was no evidence of increased birth defects in infants exposed to famciclovir during the first trimester. The incidence of mammary adenocarcinoma was increased in female rats receiving famciclovir for 2 years.
The guanosine analog penciclovir, the active metabolite of famciclovir, is available for topical use. Penciclovir cream (1%) shortened the median duration of recurrent herpes labialis by ~17 hours compared to placebo when applied within 1 hour of the onset of prodromal symptoms and continued every 2 hours during waking hours for 4 days. Adverse effects are uncommon, other than application site reactions in ~1%.
Docosanol is a saturated 22-carbon aliphatic alcohol that inhibits fusion between the host cell plasma membrane and the HSV envelope, thereby preventing viral entry into cells and subsequent viral replication. Topical docosanol 10% cream is available without a prescription. When applied within 12 hours of the onset of prodromal symptoms, five times daily, median healing time was shortened by 18 hours compared with placebo in recurrent orolabial herpes. Application site reactions occur in ~2%.
Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis in HSV-1, HSV-2, CMV, vaccinia, and some adenoviruses. It is phosphorylated intra-cellularly by host cell enzymes, and then competes with thymidine triphosphate for incorporation by the viral DNA polymerase (Figure 49–2). Incorporation of trifluridine triphosphate into both viral and host DNA prevents its systemic use. Application of a 1% solution is effective in treating keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 or HSV-2. Cutaneous application of trifluridine solution, alone or in combination with interferon-alfa, has been used successfully in the treatment of acyclovir-resistant HSV infections.