Oral brivudin in comparison with acyclovir for improved therapy of herpes zoster in immunocompetent patients: results of a randomized, double-blind, multicentered study
Introduction
Herpes zoster, the acute reactivation of latent varicella-oster virus (VZV) infection, is a common ailment with an annual incidence reported to reach values between 1.3 and 4.8 cases per 1000 person-ears (McGregor, 1957, Hope-Simpson, 1965, Ragozzino et al., 1982, Wilson, 1986, Glynn et al., 1990, Helgason et al., 1996). Particularly in the elderly, herpes zoster is often accompanied by acute zoster-associated pain (ZAP) and chronic pain prevailing after resolution of acute signs and symptoms, the so-called postherpeutic neuralgia (PHN). Growing clinical experience with antiviral compounds in zoster therapy has shown that the rapid initiation of treatment with drugs like acyclovir, penciclovir, and their respective prodrugs reduces the duration of zoster lesion formation, accelerates healing of zoster rash, and reduces the duration of acute zoster-related pain (McKendrick et al., 1986, Huff et al., 1988, Wood et al., 1988, Tyring et al., 1995, Beutner et al., 1995). Oral acyclovir is still widely used for the treatment of herpes zoster, although it requires the inconvenient and high dose regimen of 800 mg given five times daily because of its relatively low anti-ZV activity, its poor oral bioavailability, and its short half-life (de Miranda and Blum, 1983, Brigden and Whiteman, 1985). The newer antiviral compounds valaciclovir (prodrug of acyclovir) and famciclovir (prodrug of penciclovir) offer improved oral bioavailability over acyclovir, but still have to be administered three times daily in relatively high doses of 1000 and 250–500 mg, respectively (Degreef, 1994, Beutner et al., 1995, Dworkin et al., 1998, Tyring et al., 2000).
Thus, there is still need for an effective antiviral therapy providing a more convenient dose regimen at lower drug doses, aiming at enhancing compliance and reducing the risk of suboptimal treatment of herpes zoster.
Brivudin [(E)-5-(2-bromovinyl)-2′-deoxyuridine] is a 5′ halogenated thymidine nucleoside analogue with a high and selective antiviral activity against varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV-1) (De Clercq, 1984, De Clercq, 1993, Snoeck et al., 1994). In cell culture, brivudin proved to be substantially more potent against VZV than acyclovir and penciclovir. In clinical VZV strains, the 50% inhibitory concentration (IC50) was 0.0033 μM for brivudin compared to 0.93 μM for acyclovir and 3.6 μM for penciclovir (Andrei et al., 1995). It was therefore anticipated that a once daily dose regimen with brivudin 125 mg once daily for 7 days, may be sufficient for an effective antiviral treatment of herpes zoster. The present Phase III study was conducted to confirm this hypothesis by comparing safety and efficacy of a 7-day treatment course with oral brivudin 125 mg once daily and standard oral acyclovir in immunocompetent adult patients with herpes zoster.
To date, oral brivudin (1×125 mg for 7 days) is licensed for the treatment of herpes zoster in several countries of the European Union (Austria, Belgium, Germany, Greece, Italy, Luxembourg, Portugal, and Spain).
Section snippets
Materials and methods
The study was conducted from February 1997 to August 1997 in compliance with the European guidelines on Good Clinical Practice (GCP).
Results
After giving written informed consent, a total of 1227 patients underwent randomization and were enrolled in the study. Six hundred and fourteen patients were randomly allocated to treatment with brivudin and 613 to treatment with acyclovir. Eighteen brivudin recipients and 21 acyclovir recipients discontinued the study prematurely. Of these, 7 brivudin recipients and 11 patients treated with acyclovir were withdrawn because of adverse events. Altogether, 592 acyclovir recipients and 596
Discussion
The study described here compares efficacy and safety of brivudin 125 mg once daily and standard acyclovir 800 mg five times daily, both for 7 days, in the treatment of herpes zoster in immunocompetent patients and introduces oral brivudin as a new option in herpes zoster therapy.
The rationale of antiviral treatment in herpes zoster is to stop viral replication as quickly as possible, first to limit the acute disease, and second to prevent neurological damage which can result in troublesome
Acknowledgements
The study was supported by grant from BERLIN-CHEMIE AG/MENARINI Group, Berlin, Germany. We also gratefully acknowledge the major contribution of the Brivudin Herpes Zoster Study Group comprising the following clinical investigators. Belgium: Dr. Beeckmans E.M., Ninove-Meerbeke, Dr. Behets J., Paal-Beringen, Dr. Boelanders J., Leopoldsburg-Heppen, Dr. Cerstelotte E., Beringen, Dr. De Graef E., Humbeek, Dr. De Roover P. Bruges-Dudzele, Dr. De Witte E., Schilde, Dr. Denier W., Genk, Dr. Eeckhout
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