Valacyclovir for Episodic Treatment of Genital Herpes: A Shorter 3-Day Treatment Course Compared with 5-Day Treatment

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1 MAJOR ARTICLE Valacyclovir for Episodic Treatment of Genital Herpes: A Shorter 3-Day Treatment Course Compared with 5-Day Treatment Peter A. Leone, 1 Sylvie Trottier, 3 and J. Mitchell Miller 2 1 Department of Infectious Diseases University of North Carolina, Chapel Hill, and 2 GlaxoSmithKline, Research Triangle Park, North Carolina; and 3 Centre de Recherche Infectiologie Universite Laval, Sainte Foy, Quebec, Canada Valacyclovir given in a 5-day regimen of 500 mg twice per day is effective as short-term treatment of episodes of recurrent genital herpes. This study compared the efficacy of a shorter, 3-day course (for 402 patients) with that of a 5-day course (for 398 patients) of valacyclovir for persons with frequent recurrence of symptoms. No significant differences were detected between the 2 dosing schedules for any of the end points measured. Median times to lesion healing, of pain duration, and of episode length for the 5-day versus 3-day treatment were 4.7 versus 4.4 days, 2.5 days versus 2.9 days, and 4.4 days versus 4.3 days, respectively. The proportions of patients with aborted lesions were 26.6% and 25.4% in the 5-day and 3-day groups, respectively. A 3-day course of 500 mg of valacyclovir administered twice daily as episodic treatment of recurrent genital herpes is equivalent to a 5-day course with regard to key markers of efficacy. Genital herpes is one of the most prevalent sexually transmitted diseases in the world today: 1 in 5 adults in the United States is seropositive for herpesvirus type 2 (HSV- 2) [1]. Although the disease itself is generally not lifethreatening, it has significant morbidity and impact on patients lives [2 4]. Presently, no cure is available for the condition, but treatment strategies are available to alleviate the acute symptoms of a herpes outbreak or to suppress recurrences. Orally administered antiviral therapy for genital herpes is prescribed either to alleviate the acute symptoms and signs of an outbreak (i.e., episodic treatment) or Received 16 July 2001; revised 16 November 2001; electronically published 20 February Presented in part: Eighth International Congress on Infectious Diseases, Boston, May 1998 (abstract ). Financial support: Glaxo Wellcome (protocol HS2A4004). Members of the study group are listed at the end of the text. Reprints or correspondence: Dr. Peter A. Leone, Div. of Infectious Diseases, University of North Carolina, CB #7030, Chapel Hill, NC (pal007@ med.unc.edu). Clinical Infectious Diseases 2002; 34: by the Infectious Diseases Society of America. All rights reserved /2002/ $03.00 to prevent the herpesvirus (HSV) reactivation and recurrent outbreaks (i.e., suppressive therapy). The specific aims of episodic treatment are to shorten the duration of the outbreak, reduce the severity of pain, and hasten lesion healing. Prompt treatment, starting within a few hours after the patient first detects symptoms of an outbreak, can halt the process of vesicular lesion development (i.e, aborted lesions) [5, 6]. Valacyclovir, the l-valine ester of acyclovir, is widely used to treat genital herpes, both as episodic therapy administered twice daily and as suppressive therapy administered once daily. In controlled, randomized trials using lesion healing, pain, and HSV shedding as measures of clinical efficacy for 5 days, valacyclovir has been shown to be as effective as orally administered acyclovir (200 mg 5 times daily) as episodic treatment for genital herpes recurrences [7]. This double-blind, controlled study compared the efficacy and safety of a 5-day regimen of valacyclovir (500 mg b.i.d.) with a 3-day regimen of valacyclovir (500 mg b.i.d.) for the treatment of a single recurrent genital herpes episode. If a 3-day course of treatment is equivalent in efficacy to the 5-day course, then the reduced therapy duration could increase convenience to patients who pre- 958 CID 2002:34 (1 April) Leone et al.

2 fer discreet, episodic medication regimens and could reduce the cost of treatment. PATIENTS AND METHODS Study design. This study was a randomized, double-blind comparison of the efficacy of valacyclovir administered orally for 5 days versus 3 days in the treatment of a single recurrent genital herpes episode in otherwise healthy adults. It was conducted at 48 medical centers, including 34 medical centers in the United States and 14 in Canada. The study protocol was approved by the institutional review board at each study site. A flow chart of the study is shown in figure 1. Written informed consent was obtained from patients, who were then screened for eligibility on the basis of the findings of a medical history, physical examination, and blood testing. Patients enrolled in the study were given a 3-day supply of open-label valacyclovir (500 mg b.i.d.) and instructed to selfinitiate treatment no later than 24 h after the first sign or symptom of a recurrence of their genital herpes. They were asked to return to the clinic within 24 h of initiating treatment. At this initial visit to the clinic for a treated recurrence, patients were stratified by sex and randomized into the 2 blinded treatment groups and provided with 2 additional days worth of either valacyclovir (500 mg) or placebo. Patients were asked to maintain a daily diary to record data regarding lesion stages (prodromal, macule/papule, vesicle/pustule/ulcer, crust, or healed), pain severity (none, mild, moderate, or severe), adverse events, concomitant medications, and compliance with the study drug regimen. Patients were evaluated in the clinic daily for 6 consecutive days and, if necessary, twice per week thereafter, until all lesions were healed and clinical symptoms were absent. Clinical assessments included review of the diary information and an assessment of lesion stages by the investigator. The investigator was permitted to override patient diary data that were inconsistent with clinical findings. Patients. Participants in this study were patients aged 18 years who were otherwise healthy and who had a history of 4 episodes of genital or perianal HSV outbreaks in the previous year or 2 episodes in the previous 6 months. Confirmation of genital HSV infection was required for study entry. Confirmation could be done by means of culture, direct antigen detection tests, Tzanck smears, immunofluorescence assays, or be means of a written confirmation by a primary-care doctor. Patients who received suppressive therapy with acyclovir during the 12 months before the study were eligible if they had experienced 1 recurrence within 3 months after discontinuation of therapy and within 3 months before study entry. Patients were excluded if they were currently receiving probenecid, had received systemic antiviral treatment in the 7 days before the first dose of the study drug, or had received an Figure 1. Flow chart of participants and treatment completed in a comparative study of 3- and 5-day regimens of valacyclovir for the episodic treatment of genital herpes. investigational drug or immunomodulatory treatment in the 30 days before receiving the study drug. Immunocompromised patients, those with known HIV infection, and those with renal impairment (creatinine clearance, 30 ml/min) or hepatic impairment ( 5-fold increase in alanine transaminase level above the normal upper limit) were also excluded from the study, as were persons with a history of hypersensitivity to acyclovir. Other patients excluded from the study were pregnant women, nursing mothers, and sexually active women of childbearing age who were not using an effective and acceptable method of contraception (i.e., oral contraceptives, diaphragm, condoms, or an intrauterine device). Efficacy end points. The primary end point of the study was the time to lesion healing, which was measured as the number of days from initiation of therapy to reepithelialization of all lesions. Patients whose lesions aborted or who had clinical symptoms but who did not develop lesions were excluded from the analysis of the primary end point. The secondary end point of this study was duration of pain, 3-Day Treatment for Genital Herpes CID 2002:34 (1 April) 959

3 Table 1. Demographics and disease characteristics of randomized patients in a comparative study of 3- and 5-day regimens of valacyclovir for the episodic treatment of genital herpes. Characteristic Valacyclovir regimen 5 day (n p 398) 3 day (n p 402) Age, median years (range) 34 (18 74) 35 (18 82) Female patients, % Time from initial episode, median years Recurrence of lesions in past 12 months, % of patients 1 8 recurrences recurrences Time from first sign or symptom to beginning of treatment, median days (range) 3.5 (0 82) 3.0 (0 70) Receipt of suppressive therapy in past year, % of patients 10 8 measured as the number of days from initiation of treatment or start of pain or discomfort (whichever was later) to the complete cessation of pain. Other secondary end points included length of the episode and the occurrence of aborted lesions. The length of episode was measured as the number of days from initiation of treatment to complete resolution of all signs and symptoms. All patients, including those with aborted lesions, were included in this analysis. Patients whose lesions aborted were defined as those whose lesions did not progress beyond the macule/papule stag, or as those who had clinical symptoms, such as pain, but who did not develop lesions. Statistical analysis. The intent-to-treat population was defined as all randomized patients. It was presumed that 30% of treated patients would not develop lesions and, thus, would not be included in the analysis of the primary end point (i.e., time to lesion healing). The distributions of times to lesion healing, cessation of pain, and cessation of all symptoms and signs were estimated by the Kaplan-Meier product-limit method. Equivalence in time to lesion healing, duration of pain, and length of episode was assessed by a 95% CI for the Hodges-Lehman estimate of the treatment difference. A difference of!20% from the median time to event for the 5-day regimen was not considered clinically significant. The 400 treated patients per study group provided 180% power to establish equivalence. Hazard ratios and 95% CIs were calculated for each timeto-event end point by use of Cox s proportional hazard models, controlling for the patients sex and the analysis center. The validity of the proportional hazard model (the hazard ratio did not change with time) was checked by plotting the log of the negative log of the survival distributions against time. The Cochran-Mantel-Haenszel test was used to test for treatment differences in proportions of patients with aborted lesions, adjusting for the patients sex and analysis center. RESULTS A total of 1170 patients were enrolled in the study, of whom 800 were randomized to receive the 5-day regimen of valacyclovir (398 patients) or the 3-day regimen of valacyclovir followed by placebo on days 4 and 5 of treatment (402 patients). The majority of the 370 patients enrolled but not randomized did not experience a genital herpes recurrence during the study period. Of those randomized, 362 (91%) of 398 patients in the 5-day group and 359 (89%) of 402 patients in the 3-day group completed the study (figure 1). In each treatment group, the Table 2. Median time to event efficacy end points, with Hodges-Lehman estimates of treatment differences and 95% CIs for differences, in a comparative study of 3- and 5-day regimens of valacyclovir for the episodic treatment of genital herpes. Efficacy end point Time to event, median days 5-day regimen 3-day regimen Hodges-Lehman estimate of difference 95% CI Lesion healing a to 0.4 Duration of pain to 0.0 Length of episode to 0.2 a Data from patients with aborted lesions were excluded from analysis. 960 CID 2002:34 (1 April) Leone et al.

4 Table 3. Median duration of pain for persons enrolled in a comparative study of 3- and 5-day regimens of valacyclovir for the episodic treatment of genital herpes. Variable Valacyclovir regimen 5 day 3 day Male sex Female sex Overall majority of patients who did not complete the study (31 patients in the 5-day group and 35 patients in the 3-day group) discontinued the study as a result of a protocol violation. The other persons who did not complete the study did not return for follow-up visits or voluntarily withdrew from participation. Demographic and disease characteristics of randomized patients are presented in table 1. Compliance with dosing was high: 99% of patients were reported to have continued use of the study medication until the end of the dosing period. Efficacy. In the intent-to-treat analysis, the median time to lesion healing (table 2) was 4.7 days in the valacyclovir 5- day group (292 developed lesions) and 4.4 days in the 3-day group (299 developed lesions). The Kaplan-Meier plot for lesion healing is illustrated in figure 2. No significant differences in time to lesion healing were noted between treatment groups by either method of analysis. The duration of pain and length of episodes were similar in both treatment groups, with no significant differences between persons who received the 5-day and 3-day dosing regimens for either end point (table 2). To satisfy the proportional hazard RR P assumption, the patients sex was included in the Cox model as a stratification variable for duration of pain and as a covariate for length of episode. In men, the median duration of pain was 2.0 days for the valacyclovir 5-day group and 2.4 days for the valacyclovir 3-day group. The difference in duration of pain was not statistically significant ( P p.2563). Because the 95% CI is 20% of the 5-day group s median duration of pain, the 2 regimens are considered to be equivalent. Women experienced a longer duration of pain, with a median duration of 2.9 days for the valacyclovir 5-day group and 3.0 days for the valacyclovir 3-day group. ( P p.0773; table 3). For length of episode, the effect of the patients sex in the Cox proportional hazard model was statistically significant (hazard ratio, 0.81; 95% confidence limits, 0.70, 0.95). Prevention of lesion progression beyond the macule/papule stage (i.e., progression to aborted lesions) was reported by 26% of patients. No differences were detected between the valacyclovir 5-day and valacyclovir 3-day treatment groups (26.6% vs. 25.4%, respectively), as shown by an RR of 1.04 and 95% confidence limits of 0.83 and Safety. Adverse events that occurred during the study period were similar between treatment groups. The most common adverse events reported in the 5- and 3-day treatment groups were headache (in 10% of patients), nausea (in 4%), diarrhea (in 4% and 2%, respectively), and fatigue (in 1% and 2%, respectively). DISCUSSION The results of this study indicate that a shorter 3-day course of valacyclovir is as effective as a 5-day course for the episodic Figure 2. Time to lesion healing in a comparative study of 3- and 5-day regimens of valacyclovir for the episodic treatment of genital herpes. Hazard ratio, 0.95; 95% CI, ; P p Day Treatment for Genital Herpes CID 2002:34 (1 April) 961

5 treatment of recurrent genital herpes, with median durations to event end points similar to those for trials described elsewhere [5 7]. The previously recommended 5-day valacyclovir treatment regimen is based on the results of 2 controlled trials in immunocompetent patients with recurrent genital herpes [5, 6]. The clinical basis of testing a 3-day valacyclovir regimen for episodic treatment of recurrent genital herpes was the previous viral shedding data from a study of 5-day courses of valacyclovir (500 mg b.i.d.) [5]. For HSV culture positive patients who received a 5-day regimen of valacyclovir, the median time to cessation of viral shedding was 2 days. Thus, it was theorized that maximum effect of valacyclovir on HSV is achievable within the first 3 days of treatment, which is consistent with the mode of action of acyclovir in inhibiting virus replication. Virologic evidence of 3- and 5-day equivalence can be inferred on the basis of a similar trial in Europe [8], in which 531 patients with recurrent genital herpes were randomized to receive valacyclovir (500 mg b.i.d.) for either 3 or 5 days. The median times to cessation of viral shedding for patients with a positive HSV culture result immediately before starting treatment for 3 or 5 days were similar (1.7 vs. 1.8 days, respectively), which replicates earlier findings [5]. The results of our study demonstrate that a shorter 3-day treatment course with valacyclovir is clinically equivalent to a 5-day course for the episodic treatment of recurrent genital herpes. In this study, a trend toward longer duration of pain was seen in men who received the shorter course of therapy. Although almost statistically significant, the magnitude of the difference is small and almost certainly not clinically relevant. In clinical situations in which patients exhibit pain as well as other clinical evidence of delayed healing after receiving 3 days of therapy, an additional 2 days of therapy may prove to be beneficial. In addition to the convenience of a shorter course of treatment, a 3-day regimen has the benefit of a 40% decrease in the amount of drug and may result in a 40% reduction in the drug price of a prescription. Whether the patient or insurance company sees a full 40% reduction in prescription price would involve tablet quantity, prescription fees, and other aspects of filling a prescription. STUDY GROUP MEMBERS Participating investigators included the following persons: Fred Aoki, Winnipeg, Manitoba; Karl Beutner, Vallejo, CA; Ronald Castellanos, Fort Myers, FL; Robert Cesarec, Wauwatosa, WI; Scott Clark, Longmont, CO; Loretta Davis, Augusta, GA; Francisco Diaz-Mitoma, Ottawa, Ontario; Frank Dunlap, Tucson, AZ; Kenneth Fife, Indianapolis, IN; Gumaro Garza, McAllen, TX; Harold Guy, San Diego, CA; David Haase, Halifax, Nova Scotia; H. Hunter Handsfield, Seattle, WA; John Imig, Boulder, CO; Terry Jones, Bryan, TX; Terrance Kurtz, Des Moines, IA; William Lang, San Francisco, CA; Mark Lebwohl, New York, NY; Peter Leone, Raleigh, NC; Lisa Marr, Portland, OR; Kim Papp, Waterloo, Ontario; John Pickens, Memphis, TN; Gerald Pierone, Vero Beach, FL; Michel Poisson, Montreal, Quebec; Donald Poretz, Annandale, VA; Jerold Powers, Scottsdale, AZ; Kuljeet Rai, San Jose, CA; Howard Reisman, Roswell, GA; Michael Reitano, New York, NY; Dennis Riff, Anaheim, CA; Jason Rivers, Vancouver, British Columbia; Barbara Romanowski, Edmonton, Alberta; Jeff Rosen, Coral Gables, FL; Bob Roth, Chico, CA; Stephen Sacks, Vancouver, British Columbia; John Sellors, Hamilton, Ontario; Steve Sharp, Nashville, TN; Neil Shear, Toronto, Ontario; Gary Sibbald, Mississauga, Ontario; Susan Skalsky, East Brunswick, NJ; Malcolm Sperling, Fountain Valley, CA; Claude Saint Pierre, Sherbrooke, Quebec; Dale Terrell, Saint Louis, MO; Sylvie Trottier, Sainte Foy, Quebec; Stephen Tyring, Nassau Bay, TX; Anna Wald, Seattle, WA; David Whiting, Dallas, TX; and Kurt Williams, Saskatoon, Saskatchewan. Acknowledgment We thank Mike Colopy for performing statistical analysis. References 1. Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the United States, 1976 to N Engl J Med 1997; 337: Patel R, Tyring S, Strand A, et al. Impact of suppressive antiviral therapy on the health related quality of life of patients with recurrent genital herpes infection. Sex Transm Infect 1999; 75: Benedetti J, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first-episode infection. Ann Intern Med 1994; 121: Marques AR, Straus SE. Herpes simplex type 2 infections an update. Adv Intern Med 2000; 45: Spruance SL, Tyring SK, DeGregorio B, et al. A large-scale, placebocontrolled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Arch Intern Med 1996; 156: Tyring SK, Douglas JM, Corey L, et al. A randomized placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. Arch Dermatol 1998; 134: Bodsworth NJ, Crooks RJ, Borelli S, et al. Valaciclovir versus aciclovir in patient initiated treatment of recurrent genital herpes: a randomised, double-blind clinical trial. Genitourin Med 1997; 73: Patel R, Strand A, Crooks RJ. Virological evidence that valaciclovir aborts genital herpes simplex virus lesions [abstract 106]. In: Program and abstracts of STIs at the Millennium: Past, Present, and Future (Baltimore). Medical Society for the Study of Venereal Diseases/American Sexually Transmitted Diseases Association (MSSVD/ASTDA), 2000: CID 2002:34 (1 April) Leone et al.

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