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ORIGINAL RESEARCH |
From the State University of New York, Stony Brook, New York; St. John’s Mercy Medical Center, St. Louis, Missouri; and Glaxo Wellcome Inc., Research Triangle Park, North Carolina.
Address reprint requests to: David A. Baker, Stony Brook Health Sciences Center, State University of New York, Stony Brook, NY 11794, E-mail: david.baker{at}sunysb.edu
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Abstract |
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Methods: In an open-label clinical trial conducted at 11 centers, 127 subjects (46 women and 81 men) with histories of recurrent genital herpes (at least 6 recurrences per year) were treated with valacyclovir HCl (500 mg once daily), and their clinical status was followed up for 1 year. Genital herpes recurrences were documented in diaries, and quarterly clinic visits were made for evaluating lesion recurrences and drug safety. In cases of recurrence, subjects self-treated with valacyclovir HCl 500 mg twice daily for 5 days, then resumed once-daily treatment.
Results: After the first 3 months of suppressive therapy, 81% of subjects were free of recurrence. Recurrence-free rates remained undiminished during the second, third, and fourth quarters (84%, 84%, and 91%, respectively) and were similar for men and women. Thirty of 46 women (65%) and 56 of 81 men (69%) remained recurrence free during the study and therapy was well tolerated. Adverse events were mild, infrequent, and not considered related to the study drug.
Conclusion: Valacyclovir HCl was highly effective and well tolerated as continuous suppressive therapy in men and women with recurrent genital herpes. Potential benefits of the once-daily regimen of valacyclovir HCl include improved patient compliance
In the United States, the prevalence of herpes simplex virus (HSV) type 2 infections has increased by 30% over the past 20 years and incidence currently exceeds 45 million cases.1 Genital herpes caused by HSV type 2 is recurrent in 90% or more of those infected,2 and 88% have at least one recurrence during the 12 months after the initial episode.3 Recurrences can be triggered by emotional stress, sunlight, concurrent infections, and menstruation, and can be accompanied by painful urethral lesions and sacral radiculoneuropathy, which can cause urinary retention.4 Valacyclovir hydrochloride (HCl), the L-valine ester of the antiherpetic agent acyclovir (Valtrex; Glaxo Wellcome, Research Triangle Park, NC), is rapidly and almost completely converted to acyclovir after oral administration,5,6 which increases the bioavailability of acyclovir to three to five times that usually observed after acyclovir itself (54% versus 12–20%) is taken.5,7 Peak plasma acyclovir concentrations achieved after a 500-mg once-daily dose of valacyclovir HCl are above the concentration needed to inhibit most HSV isolates by 50% (IC50 values).5,7 Thus, valacyclovir HCl should be an effective suppressant of recurrent genital herpes, with a once-a-day dosing regimen that might be convenient for long-term treatment of HSV infection. The objective of the present study was to document the frequency of recurrences in subjects with histories of recurrent genital herpes and acyclovir suppressive therapy during a 1-year period of continuous suppressive therapy with valacyclovir HCl.
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Methods |
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This was an open-label study conducted at 11 centers. At screening visits, study candidates had physical examinations, gave general medical histories, and were assessed for concomitant medications. Eligible subjects received 3-month supplies of valacyclovir HCl (500 mg) as single tablets to be taken once daily for 12 months, and diary cards to chart prodromes, recurrences, adverse experiences, concurrent medications, and interruption of study medication. At the first signs or symptoms of recurrence, subjects self-treated by increasing the dose to 500 mg twice daily for 5 days, then resumed the once-daily regimen. All subjects provided written informed consent, and the institutional review boards of each study center approved the protocol.
After subjects began once-daily suppressive therapy, they returned to the clinic at the end of 3, 6, 9, and 12 months. At each clinic visit, investigators reviewed diary cards, documented the number of genital herpes recurrences during the previous 3 months, noted usage of concomitant medications (including over-the-counter medications), and recorded adverse experiences. Remaining study tablets were collected from subjects and compliance was reviewed. After those assessments, investigators gave subjects a 3-month supply of valacyclovir HCl and new diary cards.
Safety evaluation included adverse event reporting at each visit and laboratory testing (hematology, blood chemistry, and urinalysis) at screening and at the 12th month. Investigators classified adverse events according to seriousness, intensity, and causal relationship to study drug. All women of childbearing potential were tested at screening and excluded if pregnant. No women became pregnant during the study.
During the study period, recurrences were evaluated quarterly and annually. Incidence of recurrences and proportions of recurrence-free subjects were derived. Confidence intervals (CI) for the proportion (p) of subjects with recurrences were calculated using a reliability coefficient of 1.96 (corresponding to a confidence level of .95) and an estimate of the standard error calculated as the square root of p(1 - p)/n, where n equals the number of subjects.
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Results |
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Once-daily valacyclovir HCl consistently maintained the quarterly recurrence-free rate at 81% or greater. During the first, second, third, and fourth quarters, 81%, 84%, 84%, and 91% of subjects, respectively, remained recurrence free. Eighty-four of 126 (67%) subjects eligible for evaluation were recurrence-free for the entire year, 80% having no or one recurrence (Table 1
). The mean annual recurrence rate was 0.8 per year. Recurrence-free rates per quarter were similar for men and women. In the eligible population, 30 of 46 females (65%) and 56 of 81 males (69%) remained recurrence free during the study. Of the 116 subjects who completed a full year of therapy, 26 of 40 women (65%) and 54 of 76 men (71%) remained recurrence free.
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None of the adverse experiences was considered drug related. The most frequently reported adverse experiences (affecting over 5% of subjects) were headaches (16 subjects [13%]), rhinitis (12 subjects [9%]), sinusitis (10 subjects [8%]), and bronchitis (7 subjects [6%]). Two subjects reported adverse experiences considered serious during the study: moderate chest pains, shortness of breath, and tachycardia in one 54-year-old man, and chest pain in another 48-year-old man. Three subjects, including one of the above, withdrew after the adverse event.
There were no differences in hematology or chemistry median values between screening and end of treatment. No women reported pregnancy during the study.
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Discussion |
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The efficacy of once-daily valacyclovir HCl in preventing genital herpes recurrences was expected because of the high serum concentrations of acyclovir that were achieved.5 Compliance with the once-daily regimen was excellent, with 81% of subjects complying totally and 19% missing one or more doses, which exceeded that reported in abstract form with twice-daily acyclovir during the final year of the acyclovir therapy study (65%), when 35% missed one or more doses (6% missed one or two doses and 29% missed three or more) (Goldberg L, Baker D, Miller J, Shaefer M. Ten-year effectiveness of continuous suppressive therapy with acyclovir in patients with recurrent genital herpes. Washington, DC: 54th Annual Meeting of the American Academy of Dermatology, 1996). The convenient, once-daily regimen might have promoted the high rate of compliance with valacyclovir HCl. Guidelines for improving compliance include single rather than multiple doses of medications.10 The more frequently a medication needs to be taken, the greater the likelihood a dose will be missed or administered at an incorrect time.11 Omission of a dose of acyclovir poses a risk to men and women with histories of recurrent HSV infections because serum acyclovir concentrations, which are much lower than those achieved with valacyclovir HCl, can decrease below the IC50 for HSV isolates, possibly contributing to treatment failure.
The safety findings reported for once-daily valacyclovir HCl in the present study are consistent with previous evaluation of long-term valacyclovir HCl treatment.12 Valacyclovir HCl was well tolerated, adverse events were generally mild and infrequent, and none were considered drug related. The adverse event profile and incidence during 4 months to 1 year of valacyclovir HCl were not different from those of placebo.12 The success rate of valacyclovir HCl (500 mg once-daily) suppressive therapy in the present study was similar to that of other recent studies.12,13
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Footnotes |
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Members of the International Valacyclovir Hydrochloride Herpes Simplex Virus Study Group: Marcus Conant, MD, San Francisco, CA; Clyde Crumpacker, MD, Boston, MA; Kenneth Fife, MD, PhD, Indianapolis, IN; Suzanne Bruce, MD, Houston, TX; Lisa Kaplowitz, MD, Richmond, VA; Raymond Kaufman, MD, Houston, TX; Terrance Kurtz, DO, Des Moines, IA; Donald Poretz, MD, Annandale, VA; Sharon Safrin, MD, San Francisco, CA.
Financial Disclosure
This research was supported by a grant from Glaxo-Wellcome, Inc., which markets valacyclovir hydrochloride as Valtrex. In addition, David Baker is a consultant and member of a speaker’s program, and J. Mitchell Miller is an employee who holds stock options, all involving Glaxo-Wellcome, Inc.
Received September 28, 1998. Received in revised form December 14, 1998. Accepted January 7, 1999.
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References |
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2. Pereira FA. Herpes simplex: Evolving concepts. J Am Acad Dermatol 1996;35:503–20.[Medline]
3. Corey L, Adams HG, Brown ZA, Holmes KK. Genital herpes simplex virus infections: Clinical manifestations, course, and complications. Ann Intern Med 1983;98:958–72.
4. Purvis R, Lewis L. Viral diseases of the skin. In: Rakel R, ed. Conn’s current therapy. Philadelphia, Pennsylvania: W. B. Saunders Company, 1995.
5. Perry CM, Faulds D. Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpes virus infections. Drugs 1996;52:754–72.[Medline]
6. Soul-Lawton J, Seaber E, On N, Wootton R, Rolan P, Posner J. Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans. Antimicrob Agents Chemother 1995;39:2759–64.[Abstract]
7. Weller S, Blum MR, Doucette M, Burnette T, Cederberg DM, de Miranda P, et al. Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther 1993;54:595–605.[Medline]
8. Mertz GJ, Jones CC, Mills J, Fife KH, Lemon SM, Stapleton JT, et al. Long-term acyclovir suppression of frequently recurring genital herpes simplex virus infection. A multicenter double-blind trial. JAMA 1988;260:201–6.[Abstract]
9. Fife KH, Crumpacker CS, Mertz GJ, Hill EL, Boone GS. Recurrence and resistance patterns of herpes simplex virus following cessation of > or = 6 years of chronic suppression with acyclovir. Acyclovir Study Group. J Infect Dis 1994;169:1338–41.[Medline]
10. Murphy J, Coster G. Issues in patient compliance. Drugs 1997;54: 797–800.[Medline]
11. Benet L. Principles of prescription order writing and patient compliance instructions. In: Hardman J, ed. Goodman & Gilman’s the pharmacological basis of therapeutics. New York: McGraw-Hill, 1996.
12. Patel R, Bodsworth NJ, Woolley P, Peters B, Vejlsgaard G, Saari S, et al. Valaciclovir for the suppression of recurrent genital HSV infection: A placebo controlled study of once daily therapy. International Valaciclovir HSV Study Group. Genitourin Med 1997;73:105–9.[Medline]
13. Reitano M, Tyring S, Lang W, Thoming C, Worm A, Borelli S, et al. Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: A large scale dose range-finding study. International Valaciclovir HSV Study Group. J Infect Dis 1998;178: 603–10.[Medline]
This article has been cited by other articles:
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  J. S. Sheffield, J. B. Hill, L. M. Hollier, V. R. Laibl, S. W. Roberts, P. J. Sanchez, and G. D. Wendel Jr Valacyclovir prophylaxis to prevent recurrent herpes at delivery: a randomized clinical trial. Obstet. Gynecol., July 1, 2006; 108(1): 141 - 147. [Abstract] [Full Text] [PDF]
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 Prophylactic Valacyclovir HCl Reduces Herpes Simplex Recurrence Journal Watch Women's Health, August 1, 1999; 1999(801): 24 - 24. [Full Text]
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