Once, twice, or three times daily famciclovir compared with aciclovir for the oral treatment of herpes zoster in immunocompetent adults: a randomized, multicenter, double-blind clinical trial

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Abstract

Background: Famciclovir, the well absorbed oral pro-drug of penciclovir, is effective in the treatment of herpes zoster when given three times daily. Because the intracellular half-life of penciclovir triphosphate in varicella-zoster virus (VZV)-infected cells (7 h) is considerably longer than that of aciclovir triphosphate (1 h), it may be possible to administer famciclovir less frequently than three times daily for herpes zoster: aciclovir is administered five times daily. Methods: 559 immunocompetent adults presenting with herpes zoster whose skin lesions were present for less than 72 h were randomized to receive famciclovir 750 mg once daily (od), 500 mg twice daily (bid), or 250 mg three times daily (tid), or aciclovir 800 mg five times daily. All treatments were given for 7 days. Participants were evaluated until complete healing or for 4 weeks, whichever occurred first. Results: There were no significant differences between the four treatment groups with respect to times to full crusting; loss of vesicles, ulcers and crusts; cessation of new lesion formation; a 50% reduction in the area of affected skin; and the loss of acute pain. Conclusions: Famciclovir 750 mg once daily, 500 mg twice daily and 250 mg daily, and aciclovir 800 mg five times daily are three times comparable in efficacy with respect to the cutaneous healing of herpes zoster. The current study was not designed to assess the effects of the treatments on postherpetic neuralgia (PHN).

Introduction

Herpes zoster is a relatively common condition. A population-based investigation using data from a US health maintenance organization from 1990 to 1992 showed the overall incidence to be 215 per 100,000 person years (Donahue et al., 1995). More recently published data show that between 1979 and 1997, the average physician consultation rates (which are a reasonable indication of incidence) for herpes zoster in Canada and the UK were approximately 1700 per 100,000-population year (Brisson et al., 2001). The incidence of the condition increases sharply with age due to the reduced competency of the immune system in older individuals (Donahue et al., 1995).

Aciclovir demonstrates good efficacy and tolerability in the treatment of herpes zoster in immunocompetent adults when administered at a dose of 800 mg five times a day (McKendrick et al., 1986, Morton and Thomson, 1989, Wood et al., 1996). However, the five times daily dosing regimen, necessary because of the low bioavailability of oral aciclovir (approximately 10% at 800 mg) (de Miranda and Blum, 1983), is clearly inconvenient for patients. Less frequent dosing of antiviral treatments for herpes zoster became possible with the development of famciclovir (Degreef, 1994, Tyring et al., 1995) and valaciclovir (Lin et al., 2001). Valaciclovir, a pro-drug of aciclovir increases bioavailability to about 50%. Famciclovir is the oral pro-drug of penciclovir, a different acyclic guanosine analogue, with high oral bioavailability averaging 77% (Vere Hodge, 1993). In common with aciclovir, penciclovir must first be monophosphorylated by virally encoded thymidine kinase and then further phosphorylated by cellular enzymes to the active nucleotide penciclovir triphosphate. However, penciclovir triphosphate persists in varicella-zoster virus (VZV)-infected cells considerably longer than does aciclovir triphosphate (intracellular half-life of 7 h versus <1 h (Earnshaw et al., 1992). Thus, it may be possible to administer famciclovir in herpes zoster less frequently than aciclovir or valaciclovir.

The current trial was conducted to test the hypothesis that famciclovir is effective in the treatment of herpes zoster when given less frequently than three times daily. This randomized, double-blind trial compared the efficacy (time to full crusting) and safety of famciclovir administered once daily (od), twice daily (bid), and three times daily (tid) with that of aciclovir administered five times daily in the treatment of herpes zoster in immunocompetent adults.

Section snippets

Patients

This was a multicenter, multinational trial. The trial was approved by the Institutional Review Board or Ethics Review Committee responsible at each participating site. The study was funded by SmthKline Beecham Pharma Inc., which was the manufacturer of famciclovir. Consenting, immunocompetent patients, aged 18 years and older, were enrolled if they had herpes zoster and the rash had been present for no more than 72 h. Reasons for exclusion from the trial included: evidence of dissemination of

Demographic characteristics

The demographic characteristics of the 559 patients enrolled in the trial (ITT population) are presented in Table 1. There were no significant differences between the groups at the time of enrolment with respect to age and gender of patients; the duration, severity and area of rash; and the severity of pain. Eighteen patients withdrew while on therapy and 12 withdrew within 30 days of completing study therapy. There was no significant difference between the treatment arms in the proportion of

Discussion

Data from this randomized, double-blind trial show that famciclovir administered once or twice daily was as effective as famciclovir administered three times daily, and as effective as aciclovir administered five times daily, in the cutaneous healing and the reduction of acute pain associated with herpes zoster.

The efficacy and tolerability of aciclovir in the treatment of herpes zoster is well established (Morton and Thomson, 1989, Wood et al., 1996). However, the need to take therapy five

Acknowledgements

This study was funded by SmithKline Beecham Pharma.

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