Valacyclovir in the Treatment of Herpes Simplex, Herpes Zoster, and Other Viral Infections

Transcription

1 372 Valacyclovir in the Treatment of Herpes Simplex, Herpes Zoster, and Other Viral Infections DOI: /s J Cutan Med Surg 2003; Jashin J. Wu, 1 Mathijs H. Brentjens, 2 Gisela Torres, 2 Kimberly Yeung Yue, 2 Patricia Lee, 2 and Stephen K. Tyring 2 Abstract Background: Genital herpes and herpes labialis are prevalent, physically and pychologically painful, and often disabling. Herpes zoster is often very painful and may result in months or years of postherpetic neuralgia (PHN). Over the past two decades, the treatment of these conditions has been transformed by guanosine nucleoside antivirals such as valacyclovir (Valtrex Ò ), a highly bioavailable prodrug of acyclovir (Zovirax Ò ), and famciclovir (Famvir Ò ), a highly bioavailable prodrug of penciclovir (Denavir Ò ). Objective: We describe the pharmacology, pharmacokinetics, and clinical efficacy of valacyclovir for the treatment of herpes simplex, herpes zoster, and other viral infections. Valacyclovir is also compared with acyclovir and famciclovir. Methods: All published literature containing the word valacyclovir was reviewed and summarized. Results: Valacyclovir is the only oral antiviral agent approved for therapy of herpes labialis, the only antiviral drug approved for a 3-day course in the episodic treatment of recurrent genital herpes, as well as the only antiviral drug approved for once daily dosing for suppressive therapy. In herpes zoster, valacyclovir is more effective than acyclovir and equally effective as famciclovir at hastening the healing of zoster-associated pain and PHN. Conclusion: Valacyclovir is safe and effective in the therapy of patients with herpes simplex and herpes zoster and may be useful in other viral infections. Sommaire Ante ce dents: L herpès génital et l herpès labial sont des affections courantes, physiquement et psychologiquement douloureuses et souvent invalidantes. Le zona est souvent très douloureux et peut causer des mois, voir des années, de névralgie postherpétique. Au cours des deux dernières décennies, le traitement de ces affections a été transformé grâce aux antiviraux nucléosides guansonines, tels que le valaciclovir (Valtrex), un prodrogue hautement biodisponible de l aciclovir (Zovirax), et le famciclovir (Famvir), un prodrogue hautement biodisponible du penciclovir (Denavir). Objectifs: Description de la pharmacologie, de la pharmacocinétique et de l efficacité clinique du valaciclovir dans le traitement de l herpès simplex, du zona et d autres infections virales. Également, le valaciclovir est comparé à l aciclovir et au famciclovir. Me thodes: Revue et résumé de toutes les publications contenant le terme «valaciclovir». Re sultats: Le valaciclovir est le seul agent antiviral oral approuvé dans le traitement de l herpès labial. Il est aussi le seul médicament antiviral approuvé pour un traitement sur trois jours dans le cas de l herpès génital récidivant et pour une dose quotidienne dans le cas d un traitement suppressif. Dans les cas de zona, le valaciclovir est plus efficace que 1 Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA 2 Departments of Dermatology, Microbiology/Immunology and Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA Online publication: 24 September 2003 Correspondence to: Stephen K. Tyring, University of Texas Medical Branch, UTMB Center of Clinical Studies, 2060 Space Park Dr., Suite 200, Houston, TX 77058, USA. styring@utmb.edu

2 J. J. Wu et al. Valacyclovir for Herpes Simplex and Zoster 373 l aciclovir et aussi efficace que le famciclovir dans le traitement rapide de la douleur et de la névralgie postherpétique. Conclusion: L efficacité et l innocuité du valaciclovir ont été établies dans le traitement des patients atteints d herpès simplex et de zona. Il peut également servir au traitement d autres infections virales. Herpes simplex infections and herpes zoster, or shingles, are painful and disabling conditions caused by the viruses in the herpes family. Over the last two decades, the treatment of these diseases has improved by the introduction of guanosine nucleoside antivirals, which act directly, after phosphorylation, on viral DNA to inhibit replication of herpesviruses. The first guanosine nucleoside to be introduced was acyclovir, which became a mainstay of therapy for genital herpes and herpes zoster because of its efficacy for cutaneous healing and relieving acute pain. The need for a medication with improved pharmacokinetic and clinical attributes led to the development of valacyclovir (Valtrex Ò, GlaxoSmithKline, Research Triangle.Park, NC), a highly bioavailable prodrug of acyclovir (Zovirax Ò, GlaxoSmithKline). Pharmacology: Mechanism of Action During initial infection, herpes simplex virus-1 (HSV-1) (the usual cause of herpes labialis) and herpes simplex virus-2 (HSV-2) (both of which cause genital herpes) or varicella zoster (which causes chickenpox and herpes zoster) enter host cells and program host cell DNA to create additional virus copies. 1,2 After host cells are inoculated with viral genetic material, a period of latency ensues during which the herpesvirus genetic material is present in the host without actively replicating. The clinical course of genital herpes and herpes zoster subsequent to the primary infection is characterized by alternating periods of latency, when the patient is asymptomatic, and reactivation, which is associated with symptomatic recurrences. The guanosine nucleoside antivirals act on replicating virus to interfere selectively with viral DNA synthesis and thereby to inhibit viral replication. By binding to DNA polymerase, an enzyme that mediates the elongation of viral DNA chains, the guanosine nucleosides (after phosphorylation) prevent further DNA chain elongation. Acyclovir triphosphate replaces deoxyguanosine triphosphate to become rapidly incorporated into viral DNA and to halt DNA synthesis because it is missing the region of the deoxyguanosine molecule to which the next base of the viral DNA chain would be added. The process has been called obligate viral DNA chain termination. After oral administration, more than 99% of valacyclovir is converted to its active form, acyclovir, in the intestinal wall and liver. Acyclovir must be phosphorylated three times before it becomes active in inhibiting viral DNA synthesis. 1 8 Viral thymidine kinases, present in herpesvirus-infected but not noninfected cells, are necessary for acyclovir to become monophosphorylated. Cellular kinases are responsible for the next two phosphorylations resulting in acyclovir triphosphate, the active form. Therefore, acyclovir is highly selective for cells containing virus and does not affect cells not containing virus. In vitro studies have shown acyclovir triphosphate to be nearly undetectable in human lung fibroblasts or liver cells not infected with herpesviruses, whereas it was found in high concentrations in infected cells. 9 This selectivity for infected over noninfected cells is realized in favorable tolerability and safety profiles. The metabolite of oral famciclovir is penciclovir, which is phosphorylated in a manner analogous to that of acyclovir. Penciclovir triphosphate contains the region of deoxyguanosine to which the next base of the viral DNA chain would be added (the 3 hydroxyl group) so that additional bases can be added after incorporation of the famciclovir metabolite. However, the structure of penciclovir triphosphate renders this process inefficient; therefore, replication eventually stops. This process has been termed conditional viral DNA chain termination. The clinical significance of obligate compared with conditional viral DNA chain termination is unknown. On the basis of evidence collected to date, the guanosine nucleoside antivirals appear not to be capable of preventing the establishment of or killing of latent virus in humans, 3 although in animal models all of the drugs have been somewhat effective in preventing latency after initial inoculation. 4 7 Antiviral Activity Acyclovir, the metabolite of valacyclovir, has been shown to be highly effective at inhibiting viral growth in in vitro studies. The IC 50 values (50% inhibitory concentration, i.e., the concentration of drug required to achieve 50% inhibition of viral plaque growth) were similar with acyclovir compared to penciclovir (administered orally as the guanosine nucleoside famciclovir) in separate studies using virally infected MRC-5 cells (Table I). 10 The high affinity for viral DNA polymerase allows acyclovir to inhibit viral replication at lower intracellular concentrations than does famciclovir. 10 While the affinity of penciclovir triphosphate for viral DNA polymerase is approximately 100 times less than that of acyclovir triphosphate, penciclovir triphosphate has a longer intracellular half-life in virus-infected cells than does acyclovir triphosphate (for HSV-1 and HSV-2, h for penciclovir triphosphate compared with approximately 1 h for acyclovir triphosphate). 10 The clinical relevance of these dissimilarities in intracellular pharmacokinetics is unknown; the pharmacokinetic differences have not been

3 374 Journal of Cutaneous Medicine and Surgery Volume 7 Number 5 October 2003 TABLE I Comparative antiviral activity of acyclovir and penciclovir (adapted with permission from reference 10) IC 50 (mcg/ml) (mean ± SD) Number of viral isolates Acyclovir Penciclovir HSV ± ± 0.2 HSV ± ± 0.3 Varicella zoster ± ± 1.9 TABLE II Dosing recommendations for valacyclovir, acyclovir, and famciclovir 12,13 Velacyclovir Acyclovir Famciclovir Initial episodes of genital herpes 1 g twice daily for 10 days 200 mg 5 times daily for 10 days (or 400 mg three times daily for 10 days) 250 mg three times daily for 10 days (not FDA approved) Episodic treatment of 500 mg twice daily for 3 days 200 mg 5 times daily for 5 days 125 mg twice daily for 5 days recurrent genital herpes (5 days in Canada) (or 400 mg three times daily for 10 days) Suppressive treatment of 500 mg once daily 400 mg twice daily or 250 mg twice daily recurrent genital herpes (<10 recurrences per year) 200 mg 3 times daily 1 g once daily (10 or more recurrences/year) Herpes zoster 1 g 3 times daily for 7 days 800 mg 5 times daily for 7 10 days 500 mg 3 times daily for 7 days realized in differences in clinical efficacy in either genital herpes or herpes zoster. The differing profiles of acyclovir and penciclovir with respect to DNA polymerase affinity and intracellular half-life possibly offset one another. The relatively greater affinity of acyclovir triphosphate for DNA polymerase may obviate the need for the drug to be available intracellularly for prolonged periods of time. Correspondingly, the long intracellular half-life of penciclovir triphosphate helps to counteract its relative low affinity for viral DNA polymerase. Pharmacokinetics: Absorption After conversion to acyclovir via first-pass metabolism, valacyclovir has the exact pharmacokinetics as does acyclovir. After absorption through the intestines, valacyclovir undergoes extensive first-pass metabolism in the gut and liver to form the essential amino acid, L-valine, and acyclovir. 11 Since valacyclovir is absorbed through the intestines more quickly than acyclovir, the absolute bioavailability of valacyclovir (54%) is much higher compared with acyclovir (10% 20%). Several studies conducted in healthy volunteers, immunocompetent patients, and immunocompromised patients show the greater bioavailability of acyclovir after oral administration of valacyclovir compared with acyclovir. 11 Distribution After absorption, acyclovir is distributed throughout all body tissue and fluids. The volume of distribution after intravenous administration of acyclovir was 49.7 L/1.73 m Plasma protein binding is low at approximately 15%. Metabolism and Elimination The two inactive metabolites 9-[(carboxymethoxy)methyl]guanine and 8-hydroxy-0-[2-(hydroxyethoxy)methyl]guanine and the essential amino acid L-valine, are formed during the first-pass metabolism of valacyclovir. 11 Valacyclovir and its metabolites are not involved in the liver cytochrome P450 system. The primary route of elimination of valacyclovir, acyclovir, and their inactive metabolites is through the kidneys, and the secondary route is through the feces. 12,13 An oral administration of valacyclovir is mostly excreted as acyclovir. Dosage adjustment for valacyclovir and acyclovir is recommended when administering the drugs to renal patients. Drug Interactions There are no reports of clinically significant interactions between valacyclovir and medications known for drug interactions, such as antacids, cimetidine, digoxin, or thiazide diuretics, in individuals with normal renal function. 11,14 Drugs such as probenecid, however, can reduce the clearance of substances eliminated by the kidneys. Thus, dosage reductions of valacyclovir must be considered in patients also taking probenecid. Dosing The more convenient dosing schedule of valacyclovir compared with acyclovir is due to the improved bioavailability (Table II). Valacyclovir is the only oral anti-

4 J. J. Wu et al. Valacyclovir for Herpes Simplex and Zoster 375 viral among the three guanosine nucleosides recommended (i.e., in the United States) for a 3-day course in the episodic treatment of recurrent genital herpes. Furthermore, valacyclovir is the only antiviral among the three that can be used once daily in suppression of recurrent genital herpes. FIGURE 1 Valacyclovir compared with placebo in episodic treatment of recurrent genital herpes (p = valacyclovir versus placebo). 16 Efficacy for Genital Herpes In genital herpes, valacyclovir is indicated for treatment of initial episodes, episodic treatment of recurrent episodes, and suppressive therapy. Clinical trials involving approximately 10,000 patients have used valacyclovir for these indications. Treatment of Initial Episodes of Genital Herpes The use of valacyclovir for initial or primary episodes of genital herpes, defined as the first outbreak of genital lesions caused by HSV-1 or HSV-2, was evaluated in a randomized, double-blind trial conducted in 643 patients treated within 72 hours of symptom onset. 15 Valacyclovir 1 g twice daily for 10 days was as effective as acyclovir 200 mg 5 times daily for 10 days for all variables assessed in the study. The proportion of patients who formed new lesions after 48 hours of drug administration was 22% with valacyclovir and 24% with acyclovir. The mean maximum number of lesions was 10.5 for valacyclovir and 12.1 for acyclovir. For both medications, the median time to healing all lesions was 9 days, the median duration of pain was 5 days, the median duration of viral shedding was 3 days, and the time to loss of pain and clinical symptoms was 9 days. This important study showed that in the initial episode of genital herpes, valacyclovir twice daily is as effective as acyclovir 5 times daily. In Canada, however, valacyclovir has not been approved for the treatment of initial outbreaks of genital herpes. Episodic Treatment of Recurrent Genital Herpes Valacyclovir also has demonstrated efficacy in the episodic treatment of recurrent genital herpes in several placebo- or acyclovir-controlled clinical trials. A randomized, double-blind, placebo-controlled trial conducted with 987 patients who had at least 4 episodes of genital herpes per year demonstrated that valacyclovir 1 g or 500 mg twice daily for 5 days was consistently superior to placebo. The efficacy parameters were median length of recurrence, median lesion healing time, median time to termination of viral shedding, time from treatment initiation through resolution of episode in 75% of patients, and time from treatment initiation through complete healing in 75% of patients (Fig. 1). 16 The second study, a randomized, placebo-controlled, parallel-group comparison with acyclovir, enrolled 1200 patients with a history of at least 4 recurrent genital herpes episodes in the last year. The patients were treated within 24 hours after onset of an episode. Valacyclovir 1 g FIGURE 2 Valacyclovir compared with placebo and acyclovir in episodic treatment of recurrent genital herpes (p < 0.01 valacyclovir and acyclovir versus placebo). 17 twice daily for 5 days was as effective as acyclovir 200 mg 5 times daily, and both medications were significantly more effective than placebo in healing lesions and reducing viral shedding (Fig. 2). 17 By the seventh day of treatment, significantly (p < 0.05) more patients receiving valacyclovir or acyclovir (91%) compared with placebo (83%) reported no pain. Similar results were obtained in a 739-patient trial comparing valacyclovir 500 mg twice daily to acyclovir 200 mg 5 times daily. 18 Valacyclovir also appears effective in the episodic treatment of recurrent genital herpes with once daily dosing, but it is not approved for this schedule. In a randomized study enrolling 1199 patients with a history of at least 4 recurrences in the past year, valacyclovir 1 g once daily for 5 days was statistically and clinically equivalent to valacyclovir 500 mg twice daily for 5 days in the episodic treatment of recurrences. 19 Furthermore, valacyclovir is also the only antiviral approved (in the United States) for the episodic treat-

5 376 Journal of Cutaneous Medicine and Surgery Volume 7 Number 5 October 2003 FIGURE 3 Valacyclovir 500 mg twice daily for 3 days versus 5 days in episodic treatment of recurrent genital herpes. 20 ment of recurrent genital herpes with a 3-day course of therapy. The recommended duration of therapy for acyclovir and famciclovir is 5 days. In a randomized, double-blind study of 1170 patients with a history of at least 4 recurrences in the past year, valacyclovir in a 3-day course was as efficacious as a 5-day course in the episodic treatment of recurrent genital herpes. 20 Valacyclovir 500 mg twice daily for 3 days and valacyclovir 500 mg twice daily for 5 days were equivalent in the parameters of median length of genital herpes episode, median duration of pain, and median time to lesion healing. The incidence of halting progression of lesions was 25.4% of subjects for 3-day therapy versus 26.6% of subjects for 5-day therapy (Fig. 3). In Canada, however, the recommended course of therapy for recurrent genital herpes remains at 5 days. Not only is the 3-day course of valacyclovir more convenient than the 5-day course, it is also more cost effective. The duration of viral shedding is short during recurrent episodes, as shown by natural history studies. 21 When the patient self-administers the antiviral medication at the first evidence of reactivation, the efficacy of the therapy is the greatest. 22 This implies that earlier treatment may be more beneficial and that later use of antiviral medication may be less efficacious. Suppression of Recurrent Genital Herpes Recurrent genital herpes can be controlled either through episodic treatment, as described above, or through suppressive therapy, in which daily treatment is used to prevent outbreaks. For patients with frequent recurrences, suppressive therapy is the best approach because it reduces the severity and frequency of episodes, reduces the occurrence of asymptomatic shedding of virus (and possibly reduces transmission of genital herpes), and reduces the psychological morbidity by enhancing the patients perception of control over the outbreaks. With suppressive therapy, health care providers and patients adopt a proactive approach to the management of recurrent genital herpes. Of the three guanosine nucleoside antivirals, valacyclovir is the only one shown to be effective for the suppression of genital herpes with a once-daily dosing regimen. In a 1-year study of 1479 patients with a history of at least 6 episodes of genital herpes in the past year, valacyclovir given in regimens of 1 g once daily, 500 mg once daily, 250 mg once daily, or 250 mg twice daily was significantly more effective than placebo and as effective as acyclovir 400 mg twice daily in suppressing recurrences (Table III). 23 Valacyclovir 1 g once daily reduced the yearly recurrence rate by 78% relative to placebo compared with 79% in the acyclovir 400 mg twice daily group. The efficacy of valacyclovir was not enhanced by increasing the dosing frequency. In a second study, a valacyclovir 500 mg once daily regimen was evaluated in a 16-week, randomized, double-blind trial of 382 patients with a past-year history of 8 recurrences. 24 At the end of the treatment period, 69% of patients in the valacyclovir group compared with 10% of placebo patients were free of recurrences. The median time to first recurrences was more than 112 days with valacyclovir compared with 20 days with placebo. In a noncomparative study of 127 patients with recurrent genital herpes, valacyclovir showed efficacy in reducing the likelihood of recurrence. 25 These patients were previously enrolled in a 10-year study of suppressive therapy using acyclovir 400 mg twice daily. 26,27 All subjects received valacyclovir 500 mg twice daily for 1 year. Overall, 67% were free of HSV recurrence and 80% had 0 1 recurrences. This efficacy is higher compared with the earlier 10-year acyclovir study where 44% of patients had no recurrences after 1 year of treatment. 28 In summary, these studies demonstrate the efficacy of valacyclovir once daily for suppressive therapy of genital herpes. Once-daily dosing is important in improving patient convenience and compliance, which will help the success of therapy. Suppression of Recurrent Genital Herpes in Immunocompromised Patients Immunocompromised patients, such as those infected with the human immunodeficiency virus (HIV), are frequently burdened with recurrent genital herpes. The seroprevalence for HSV in patients with HIV is high, with approximately 80% of homosexual men having infections with HSV Similar to other infections, the frequency and severity of HSV are highly increased in immunocompromised patients compared with immunocompetent patients. 32,33 Current suppressive regimens with acyclovir are 200 mg 3 or 4 times daily or 400 mg twice daily. 34,35 However, such frequent dosing schedules may not be popular

6 J. J. Wu et al. Valacyclovir for Herpes Simplex and Zoster 377 TABLE III Valacyclovir compared with placebo and acyclovir in the suppressive treatment of recurrent genital herpes 21 Regimen % Recurrence-free at 12 months % Reduction in yearly recurrence rate Valacyclovir 250 mg once daily 15 a 22 b 54 Valacyclovir 250 mg twice daily 34 a 50 b 79 Valacyclovir 500 mg once daily 28 a 40 b 71 Valacyclovir 1 g once daily 34 a 48 b 78 Acyclovir 400 mg twice daily 35 a 49 b 79 Placebo 5 a 5 b NA a Based on analysis ot crude proportions; all valacyclovir doses p < versus placebo. b Based on Kaplan Meier estimates of proportions based on the time-to-event analysis. with HIV patients since they may already be taking several other medications. A randomized, double-blind trial conducted using HIV patients compared the efficacy of valacyclovir 500 mg twice daily or 1 g once daily with that of acyclovir 400 mg twice daily in the suppression of recurrent genital herpes. 36 Both treatments were equally effective in the time to first and second recurrence or in the percentage of patients free of recurrences at the end of the 48- week treatment period. However, it is difficult to draw conclusions from these findings because of a low recurrence rate (18%) and a high patient discontinuation rate (43%). A second study assessed the efficacy of valacyclovir in HIV-infected patients before highly active antiretroviral therapy was used. 37 In the first part of this study, 1062 patients were randomized into schedules of valacyclovir 500 mg twice daily, 1 g once daily, or acyclovir 400 mg twice daily. The hazard ratio (confidence interval) for time to recurrence for valacyclovir 500 mg twice daily versus acyclovir was 0.73 [0.50, 1.06], p = This shows the efficacy of valacyclovir over acyclovir. For valacyclovir 1 g once daily versus acyclovir, the hazard ratio was 1.31 [0.94, 1.82], p = 0.11, suggesting that the acyclovir regimen is superior. For valacyclovir twice daily, valacyclovir once daily, and acyclovir, the Kaplan Meier estimates of recurrence-free patients were 82%, 71%, and 78%, respectively. Side effects were rare, mild, and no different between acyclovir and valacyclovir. This evidence shows that valacyclovir is very safe and effective for the suppression of recurrent genital herpes in HIVinfected patients. Episodic Treatment of Recurrent Genital Herpes in Immunocompromised Patients In the second part of the above-mentioned trial, the efficacy of valacyclovir was studied for the episodic treatment of recurrent genital herpes in HIV-infected patients. 37 Four hundred sixty-seven patients were treated episodically for 5 or more days with valacyclovir 1 g twice daily or acyclovir 200 mg 5 times daily. The median episode duration was 5 days, and the median healing time was 5 days. The hazard ratio for valacyclovir versus acyclovir on episodic duration was 0.93 [0.75, 1.14], p = The hazard ratio for valacyclovir versus acyclovir on lesion healing was 0.98 [0.79, 1.22], p = This shows valacyclovir is as effective as acyclovir for episodic treatment of genital herpes in this population. With its less frequent dosing schedule, valacyclovir is the drug of choice. Reduction of Asymptomatic Shedding Asymptomatic viral shedding is thought to cause transmission of most cases of genital herpes, 38 and transmission of genital herpes may be reduced by prevention of asymptomatic viral shedding. In a double-blind crossover study conducted with 69 patients with recurrent genital herpes, valacyclovir was shown to markedly reduce asymptomatic shedding of HSV Participants received valacyclovir 500 mg twice daily for 7 weeks, acyclovir 400 mg twice daily for 7 weeks, or placebo for 7 weeks. The percentage of days with viral shedding (7.5% valacyclovir vs. 40% placebo) or asymptomatic viral shedding (6.2% valacyclovir vs. 26.8% placebo) was reduced as measured by polymerase chain reaction (PCR). 39 Acyclovir 400 mg twice daily was similarly effective in reducing asymptomatic viral shedding. It was recently demonstrated that reducing asymptomatic viral shedding with valacyclovir significantly reduces transmission of genital herpes. 40 Treatment of Herpes Labialis Twice-daily dosing of valacyclovir for one day has been approved in the United States for therapy of cold sore (herpes labialis) lesions. 41 In this double-blind trial, 3151 patients were randomized into groups treated with placebo, valacyclovir 2 g twice daily, and valacyclovir 2 g twice daily and then 1 g twice daily. Valacyclovir reduced episodic duration by 1.3 days in the single-day dosing group and by 1.2 days in the two-day dosing group compared with the placebo group. Furthermore, valacyclovir prevented the lesions from advancing to the macular/papular stage in almost half the subjects. Single-day dosing was as effective as two-day dosing.

7 378 Journal of Cutaneous Medicine and Surgery Volume 7 Number 5 October 2003 Treatment of Other Herpes Simplex Infections Cutaneous resurfacing by CO 2 laser has been associated with the reactivation of HSV-1, which causes delayed reepithelialization and scarring. In 204 patients in two clinical studies, there was no evidence of recurrence of HSV-1 when valacyclovir 500 mg twice daily was used as prophylaxis. 42,43 It is recommended that patients start a 10-day or 14-day course of valacyclovir 500 mg twice daily starting the day before the procedure. One study sought to determine whether antiviral nucleoside analogs could suppress recurrent HSV-1 in wrestlers, commonly known as herpes gladiatorum. For patients with a history of herpes gladiatorum of more than 2 years, valacyclovir 500 mg daily suppressed recurrent outbreaks. 44 The prevalence of viral infections in oncology patients has prompted the use of valacyclovir in these patients, with favorable results. Chemotherapy-related mucositis is further exacerbated by the oral lesions of HSV-1. Oral valacyclovir was as effective as intravenous acyclovir for the prophylaxis of HSV reactivation in HSV-seropositive autologous progenitor cell transplantation patients. 45 Efficacy for Herpes Zoster Herpes zoster is a physically debilitating condition caused by the reactivation of the varicella virus. Several factors are associated with persistent pain of herpes zoster. 46,47 Age was the most important factor, and patients older than 50 years were significantly more likely to have prolonged zoster-associated pain than younger patients. Prodromal pain and moderate to severe pain at presentation were also strong factors. A multicenter, double-blind, randomized, placebocontrolled study of valacyclovir 1 g 3 times daily for 7 days showed efficacy for herpes zoster. 48,49 There were 400 immunocompetent patients enrolled in this study. Valacyclovir was more effective than placebo in several parameters. Large clinical trials have compared the efficacy of valacyclovir, acyclovir, or famciclovir for herpes zoster. In a randomized, double-blind, comparative trial in which 1141 patients were administered valacyclovir 1 g 3 times daily for 7 or 14 days or acyclovir 800 mg 5 times daily for 7 days, valacyclovir was shown to be more efficacious than acyclovir. 50 Compared with acyclovir, valacyclovir quickened the resolution of zoster-associated pain and postherpetic pain. The median time to cessation of zoster-associated pain was 38 days for the valacyclovir 7-day regimen and 44 days for the valacyclovir 14-day regimen compared with 51 days for the acyclovir group (p < 0.05). Valacyclovir reduced pain cessation 34% faster compared with acyclovir (p < 0.05 both valacyclovir groups versus acyclovir). Postherpetic neuralgia, which occurred in 85%, 79%, and 80% of patients in the acyclovir, valacyclovir 7-day, and valacyclovir 14-day groups, respectively, was resolved 32% quicker by valacyclovir compared with acyclovir (p < 0.05 for each valacyclovir group versus acyclovir). Six months after complete healing of the lesions, 19% of subjects using valacyclovir had pain compared with 26% of subjects using acyclovir. 51 Valacyclovir given in 7- and 14-day regimens had similar clinical efficacy. Although valacyclovir was more effective than acyclovir in alleviating acute and postherpetic pain, the drugs were similar in respect to cutaneous endpoints. In both treatment groups, the median time to cessation of new lesions was 3 days, and the median time to at least 50% crusting or healed rash was 5 days. In a multicenter, randomized, double-blind study of Japanese patients, valacyclovir 1 g 3 times daily for 7 days was compared with acyclovir 800 mg 5 times daily for 7 days. 52 There were 202 patients enrolled in the study. The mean scores for severity of skin rash were not significantly different between the two treatment groups. There were no significant differences between the two groups for time to 50% lesion crusting or to complete healing. Postherpetic neuralgia was seen in 28% of patients in the valacyclovir group compared with 35% in the acyclovir group. The median time for resolution of postherpetic neuralgia was 58 and 86 days in the valacyclovir and acyclovir groups, respectively. A randomized, prospective study compared the efficacy of valacyclovir with acyclovir in the treatment of herpes zoster in Taiwanese patients. 53 Fifty-seven patients were enrolled. The intent-to-treat analysis showed that valacyclovir significantly accelerated the resolution of pain compared with acyclovir. On day 29, the valacyclovir group was 23% less likely to complain of pain compared with the acyclovir group. Although valacyclovir and acyclovir provide similar cutaneous measures, valacyclovir is better than acyclovir in shortening the length and severity of zoster-associated pain and postherpetic neuralgia. One study in the United States measured the costs and consequences of treating herpes zoster with either valacyclovir or acyclovir in immunocompetent patients over age When comparing baseline direct costs of medication, valacyclovir resulted in a saving of $60.01 (17%) compared with acyclovir. For patients in the workforce, mean work days lost was 1.7 less for patients who used valacyclovir, representing a saving of $46.54 (25%) across all patients. The total savings for treating with valacyclovir was $ (20%) compared with those using acyclovir. Furthermore, those in the valacyclovir group had shorter duration of pain by 13 days in the intent-to-treat analysis or by 19 days in patients with pain after rash healing. A randomized, double-blind study conducted in 597 immunocompetent patients with herpes zoster directly compared valacyclovir 1 g 3 times daily to famciclovir 500 mg 3 times daily. 55 Both drugs were equally safe and

8 J. J. Wu et al. Valacyclovir for Herpes Simplex and Zoster 379 TABLE IV Most commonly reported adverse events of valacyclovir in placebo-controlled trials. Results expressed in percentages of patients 12 Adverse events Valacyclovir 1 g TID (n = 967) Herpes zoster Genital herpes treatment Genital herpes suppression Placebo (n = 195) Valacyclovir 1 g BID (n = 1194) Valacyclovir 500 mg BID (n = 359) Placebo (n = 439) Valacyclovir 1gOD (n = 269) Valacyclovir 500 mg OD (n = 266) Nausea Headache Vomiting < Dizziness Abdominal pain Dysmenorrhea 0 0 < Arthralgia 1 0 <1 1 < Depression < a t.i.d. = three times a day, b.i.d. = twice a day, q.d. = every day. Placebo (n = 134) similarly effective in cutaneous and pain-related endpoints (i.e., zoster-associated pain or PHN). The resolution of zoster-associated pain was 42 days for valacyclovir compared with 49 days for famciclovir (p = 0.84). The resolution of postherpetic neuralgia was 36 days for valacyclovir compared with 37 days for famciclovir (p = 0.89). By day 7 of therapy, the rash was 100% crusted or healed in 32% of valacyclovir patients and 25% of famciclovir patients. Valacyclovir is as effective as acyclovir in preventing ocular complications of herpes zoster ophthalmicus, such as pain, superficial and stromal keratitis, and conjunctivitis. 56,57 There is currently no data regarding the safety and efficacy of valacyclovir for the treatment of herpes zoster in immunocompromised patients. A study comparing valacyclovir 1 g 3 times daily to 2 g 3 times daily for 7 days is currently ongoing in this population. Treatment of Cytomegalovirus Infections Other viral infections have been found to be effectively treated or prevented with valacyclovir. Valacyclovir reduces the incidence or delays the onset of cytomegalovirus (CMV) infection in kidney transplant recipients 58,59 and allogeneic stem cell transplantation recipients. 60 In addition, valacyclovir was more effective than acyclovir in preventing CMV in bone marrow transplantation (BMT) recipients 61 and heart transplant recipients. 62 Treatment of Epstein Barr Virus Infections A serious and often fatal complication after solid organ transplantation is postransplant lymphoproliferative disease (PTLD). The major risk factor for PTLD after lung transplantation is primary Epstein Barr virus (EBV) infection; 30% 50% of EBV-seronegative patients who seroconvert are diagnosed with PTLD. High-risk EBVseronegative recipients who receive valacyclovir are significantly less likely to develop PTLD after lung transplantation in the absence of induction therapy. 63 Treatment of Multiple Sclerosis It has been theorized from virologic studies that herpesvirus infection could play a role in the progression of multiple sclerosis. The effect of valacyclovir on MRIevident lesions in patients with relapsing remitting multiple sclerosis was studied in a phase 2, randomized, double-blind, placebo-controlled study. The formation of active lesions in patients with relapsing remitting multiple sclerosis who had two or more relapses during the previous 2-year period was not reduced by valacyclovir. However, in a subgroup of patients with high levels of disease activity, valacyclovir treatment was associated with fewer new active MRI-evident lesions and more scans free of new active lesions. 64 Safety As the prodrug of acyclovir, valacyclovir shares the safety heritage of acyclovir, which has been shown to be extremely well-tolerated when used as either episodic treatment or as continuous daily suppressive therapy for up to 10 years. Besides having a favorable tolerability profile, valacyclovir has been observed not to impair fertility in animal studies or to be carcinogenic. 12 Adverse Events In clinical trials, valacyclovir and its metabolite acyclovir have similar adverse event profiles. In 1-year-long, placebo-controlled genital herpes and herpes zoster trials and employing daily doses of up to 3 g, valacyclovir generally had a placebo-like adverse event profile (Table IV). 12 The two most common adverse events were headache and nausea, which were also reported in the placebo (Table IV).

9 380 Journal of Cutaneous Medicine and Surgery Volume 7 Number 5 October 2003 Viral Resistance Resistance to acyclovir, valacyclovir, and famciclovir is usually due to mutations in the gene coding for thymidine kinase. There is no evidence that valacyclovir therapy causes significant viral resistance. The clinical use of acyclovir over two decades has shown a very low risk of developing viral resistance, which does not increase over time. A study of 239 immunocompetent patients with genital herpes, who stopped suppressive acyclovir therapy after at least 6 years, showed that HSV isolates had similar median acyclovir sensitivity compared with pretherapy isolates or isolates from patients naive to acyclovir. 65 The percentage of resistant isolates in this population (3.5%) was also similar to that of pretherapy isolates or isolates from acyclovir-naïve patients. Finally, there was no evidence of resistance in paired pre- and posttherapy viral isolates obtained from 13 patients. Use in Special Patient Populations Immunocompromised patients enrolled in clinical trials tolerate valacyclovir well. However, severely immunocompromised patients receiving high investigational doses of valacyclovir (8 g daily with appropriate adjustment for renal function) for 8 84 weeks demonstrated evidence of a thrombotic microangiopathy (TMA)-like syndrome, initially reported as thrombotic thrombocytopenic purpura/hemolytic uremic-like syndrome. 66,67 These reports were among patients with advanced HIV disease with a median CD4+ cell count of 32 or among allogeneic bone marrow transplant or renal transplant recipients. It is important to note that thrombotic microangiopathy can occur in these patient groups in the absence of antiviral therapy. There are no reports of this syndrome in healthy patients receiving valacyclovir at doses up to 3 g daily or in HIV-infected patients using valacyclovir for the suppression of genital herpes. 37 The current theory of the occurrence of TMA-like syndrome is that it is restricted to severely immunocompromised patients and may occur in a small percentage of patients regardless of the use of valacyclovir. Conclusions The above data demonstrate that valacyclovir is more efficacious than placebo and more convenient than acyclovir in the episodic and suppressive treatment of recurrent genital herpes. The improved bioavailability of valacyclovir relative to acyclovir allows it to be dosed less frequently and in a shorter course. Valacyclovir is more effective than placebo in the episodic therapy of herpes labialis. 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