MAJOR ARTICLE

Two-Day Regimen of Acyclovir for Treatment of Recurrent Genital Herpes Simplex Virus Type 2 Infection
Anna Wald,1,2,3 David Carrell,3 Michael Remington,3 Elizabeth Kexel,3 Judy Zeh,3,4 and Lawrence Corey1,3,5
Departments of 1Medicine, 2Epidemiology, 3Laboratory Medicine, and 4Statistics, University of Washington, and 5Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington

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The standard course of antiviral therapy for recurrent genital herpes requires administration of multiple doses of medication for 5 days. To assess the efcacy of a shorter course of antiviral therapy, patients with recurrent genital herpes simplex virus type 2 (HSV-2) infection were enrolled in a randomized, double-blind, placebocontrolled study of acyclovir (800 mg given by mouth 3 times per day [t.i.d.]) for 2 days. Of 131 people enrolled in the study, 84 (51 women and 33 men) were observed for 1 recurrence and 65 were observed for 2 recurrences, for which the patient was administered the same study drug (acyclovir or placebo). Acyclovir therapy (800 mg given by mouth t.i.d. for 2 days) signicantly reduced the duration of lesions (median for acyclovir versus placebo, 4 days versus 6 days; P p .001 ), episode (4 days versus 6 days; P ! .001), and viral shedding (25 hours versus 58.5 hours; P p .04 ), and it increased the proportion of aborted episodes (P p .029). A 2-day course of acyclovir is a convenient alternative for treatment of recurrent genital herpes.

Antiviral therapy for recurrent genital herpes decreases the duration of lesions, discomfort, and viral shedding [1]. To date, such regimens require multiple daily doses administered for 5 days. This dosing pattern was based on the administration of therapy until clinical healing of lesions was noted. However, the duration of viral replication in most lesions caused by recurrent infection in immunocompetent people is short. Therefore, we undertook a study to evaluate whether a shorter regimen of antiviral medication would also decrease the duration of a recurrent genital herpes episode.

PATIENTS AND METHODS Participants and study protocols. Healthy adult men and women with recurrent genital herpes simplex virus type 2 (HSV-2) infection were recruited at the University of Washington Virology Research Clinic (Seattle). Entry criteria included a history of 3 recurrences in the 12 months before study entry. Potential subjects who had been receiving suppressive antiviral therapy were required to have had a history of 6 recurrences in the year before initiating suppressive therapy, and 2 recurrences within 3 months of discontinuing suppressive therapy. The trial was randomized, double blind, and placebo controlled. Patients who met the entry criteria were randomized in a 1:1 ratio to receive either acyclovir (800 mg given by mouth [po] t.i.d.; the acyclovir group) or matching placebo (the placebo group) for 2 days. The same medication was dispensed for the rst and second recurrence during the study. This study design was chosen so that the mean of the results from both

Received 10 August 2001; revised 14 November 2001; electronically published 20 February 2002. Financial support: National Institutes of Health (grant AI-30731). The investigational drug was in part provided by Burroughs Wellcome. Reprints or correspondence: Dr. Anna Wald, University of Washington Virology Research Clinic, 1001 Broadway, Ste. 320, Seattle, WA 98122 (annawald@ u.washington.edu). Clinical Infectious Diseases 2002; 34:9448 2002 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2002/3407-0009$03.00

944 CID 2002:34 (1 April) Wald et al.

recurrences could be used as a unit of analysis. This allowed us to recruit fewer patients than would have been required had each person been observed through only 1 recurrence. For each episode, each participant was given 3 doses of study medication and a diary card. Subjects were asked to start use of the study medication as soon as possible, but not more than 12 h after the rst signs or symptoms of a genital herpes recurrence, and to return to the clinic within 24 h. At that time, herpes recurrence was conrmed by means of a clinical examination and viral culture, and the remaining 3 doses of medication were dispensed. Patients returned to the clinic for subsequent evaluations on days 2, 3, 5, and 7 after starting treatment, and then every other day thereafter until the lesions healed. Patients were instructed on how to obtain samples for viral culture twice per day, at home, any morning or evening they were not seen in the clinic, and at the initiation of therapy. The times at which samples were obtained for viral cultures, medications were taken, and that lesions healed and symptoms resolved were noted on the diary card. Each patient was observed for up to 2 sequential recurrences. The study protocol was approved by the University of Washington Human Subjects Review Committee, and all participants provided written consent before any study procedures were begun. The Western blot test was used to detect antibodies to HSV type 1 (HSV-1) and HSV-2 in serum samples [2]. Viral isolation was performed as described elsewhere [3], and all isolates were typed with use of monoclonal antibodies. Statistical analysis. In an intent-to-treat analysis, we included all subjects who initiated use of the study medication for 1 genital herpes recurrence. The following efcacy parameters were examined: aborted episode (dened as symptoms that did not progress beyond macular stage), lesion duration (dened as days with papules, blisters, ulcers, or crusts), episode duration (dened as days from beginning of prodrome or appearance of lesions to cessation of all symptoms), episodes with viral shedding (dened as isolation of HSV at least once during the episode), and duration of viral shedding (dened as time from initiation of therapy to the rst negative culture result after the last positive culture result). For aborted episodes and episodes with viral shedding, person-level counts were used as the unit of measurement (i.e., 0, 1 of 2, or all episodes with any shedding). For patients observed for 1 recurrence, the observed value was used for duration measurements, and for patients observed for 2 recurrences, the mean of the 2 values was used. The x2, Fishers exact, and Mann-Whitney tests were used to compare the outcomes of treated and untreated groups. All statistical tests were 2-tailed, and signicance was set at P ! .05. Time to next recurrence was calculated from the time the rst recurrence healed to the rst sign or symptom of the next

recurrence. Time to symptom resolution, lesion healing, and cessation of viral shedding in the patients in the 2 arms were compared by use of Cox regression models. These models were stratied by the patients sex, because the patients sex did not satisfy the proportional hazard assumption. RESULTS One hundred thirty-one persons (81 women and 50 men) were enrolled into the study. Of these 131 persons, 84 (51 women and 33 men) were observed for 1 recurrence, and 65 (40 women and 25 men) were observed for 2 recurrences. The median age of persons observed through a recurrence was 33.5 years (range, 2073 years), and 78 persons (93%) were white (table 1). None of the patients reported adverse events, including allergic reactions. Acyclovir therapy (800 mg po t.i.d. for 2 days) signicantly reduced the duration of lesions, symptoms, and viral shedding in patients with recurrent genital herpes (tables 2 and 3). The median duration of lesions was 4 days in the acyclovir group and 6 days in the placebo group, with a hazard ratio of 1.98 (95% CI, 1.223.22) for faster clearing of lesions in the acyclovir group (gure 1A). The median duration of all episode symptoms was 4 days in the acyclovir group and 6 days in the placebo group (hazard ratio, 2.11; 95% CI, 1.333.35; gure 1B). Men differed from women with regard to the duration of lesions and the duration of all episode symptoms: both durations were longer for men, and the estimated effect of the antiviral therapy was less pronounced in men (table 3). Ten (27%) of 37 people in the acyclovir group had 1 or 2 episodes with aborted lesions, compared with 5 (10.6%) of 47 people in the placebo group (P p .029 , by the x2 test for linear trend for all, some, or no aborted lesion episodes). HSV-2 was
Table 1. Demographic characteristics and histories of herpes infection for 84 patients who experienced 1 recurrence during the comparative study of acyclovir (800 mg given by mouth t.i.d.) versus placebo.
Acyclovir (n p 37) 35 59.5 91.9 7 70.3 29.7 4 Placebo (n p 47) 32 61.7 93.6 7 55.3 44.7 3

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Characteristic Age, median years Female sex White race History of genital herpes, median years HSV serologic ndings HSV-2 only HSV-1 and -2 Median no. of recurrences in the 6 months before study entry

NOTE. Data are percentage of patients, unless otherwise indicated. HSV1, herpes simplex virus type 1; HSV-2, herpes simplex virus type 2.

Two-Day Acyclovir Therapy for HSV-2 CID 2002:34 (1 April) 945

Table 2. Comparison of clinical and virological outcomes among subjects who received either acyclovir (800 mg given by mouth t.i.d.) or placebo for 2 days.
Acyclovir (n p 37) 10 (27.0) 9 (24.3) 25 (19.2545.5) 4 (36.5) 4 (3.36.5) 48 (1387) Placebo (n p 47) 5 (10.6) 21 (44.7) 58.5 (3389) 6 (4.99.1) 6 (510) 40.5 (27.2576)

Variable 12 Aborted episodes, no. (%) of patients 12 Episodes with a positive viral culture, no. (%) of patients Duration of viral shedding, median h (IQR) Duration of lesions, median days (IQR) Duration of episode, median days (IQR) Time to next recurrence, median days (IQR)
NOTE.
a b

P .029a .10
a

.04b .001 .68

b b b

!.001

IQR, interquartile range.

Determined by means of the x2 test. Determined by means of the 2-tailed Mann-Whitney U test.

isolated from 9 participants (24.3%) randomized to receive acyclovir and from 21 participants (44.7%) randomized to receive placebo (P p .10, by the x2 test for linear trend for all, some, or no viral shedding). For the 30 patients with 1 positive culture result, the median duration of viral shedding was 25 h among patients receiving acyclovir and 58.5 h among patients receiving placebo (P p .04; table 2; gure 1C). To ascertain whether acyclovir administration for 2 days does not result in rapid reactivation of HSV infection and a shorter time to a subsequent recurrence when the therapy is discontinued, we compared the time to the second recurrence in 22 men and 37 women who were treated with the study drug for 2 consecutive recurrences. As shown in gure 1D, there was no discernible difference between the 2 groups, with a median time of 48 days in the acyclovir group and of 40.5 days in the placebo group (P p .68). In addition, the proportion of patients who experienced a second recurrence within 3 weeks of the rst recurrence was 30% (8 of 27 patients) in the acyclovir group and 22% (7 of 32) in the placebo group (P p .56).
Table 3. by sex.

DISCUSSION
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In a randomized, double-blind, controlled trial, we showed that acyclovir (800 mg po t.i.d. for 2 days) reduces the duration of viral shedding, lesions, and symptoms in patients with recurrent genital HSV-2 infection. In addition, acyclovir signicantly increased the proportion of episodes that involved aborted lesions. The magnitude of the reductionfrom a median duration of lesions of 6 days to 4 daysis similar to that reported in the recent studies of acyclovir, valacyclovir, and famciclovir [46]. Our study showed that high-dose episodic therapy with acyclovir for recurrent genital herpes is effective even if it is administered for only 2 days. This therapy is more convenient, and probably more acceptable to patients, than is the standard dosage (200 mg po 5 times a day or 400 mg po t.i.d.) administered for 5 days. The costs of these regimens are likely to remain similar, because the total dose of acyclovir is 4800 mg for the shorter regimen, compared with 5000 mg for the standard 5-times-a-day regimen.

Hazard ratios for duration of episode and lesion healing time, stratied

Patient group, treatment Men Acyclovir Placebo Women Acyclovir Placebo Alla Acyclovir Placebo
NOTE.
a

Episode duration Median days HR (95% CI)

Lesion duration Median days HR (95% CI)

6.5 8.3 4.0 5.5 4.0 6.0

1.67 (0.823.40) NA 2.50 (1.364.57) NA 2.11 (1.333.35) NA

6.5 8.0 3.5 5.0 4.0 6.0

1.36 (0.662.82) NA 2.67 (1.415.06) NA 1.98 (1.223.22) NA

HR, hazard ratio; NA, not applicable.

The analysis for the total population was stratied by sex.

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Figure 1.

Time to resolution of (A) lesions, (B) episode, (C) viral shedding, and (D) time to next recurrence, by study arm

Several observations support the use of short-course therapy for recurrent genital herpes. First, natural history studies have shown that the duration of viral shedding is short during recurrent episodes of genital herpes [7]. Second, the efcacy of episodic antiviral therapy is clearly greatest when the patient self-administers the medication at the rst sign or symptom of reactivation; the therapy is much less effective when initiated in a clinic after recognition of lesions [8]. This suggests that intervention must occur early and that later administration of antiviral therapy is less relevant to lesion clearing. In our study design, we observed each patient for up to 2 subsequent recurrences, which allowed us to enroll fewer patients and to perform the study at a single center. Accordingly, it provided an efcient trial design for evaluation of new antiviral agents in phase 2 studies. In addition, this study design allowed us to evaluate not only the effect of therapy on the duration of episode, but also the effect on the time to subsequent recurrence. Although studies published elsewhere have not detected a rapid recurrence of symptoms in patients treated with acyclovir compared with untreated patients [9, 10], in this study, we were concerned about a potentially detrimental effect of such short therapy. The antiviral effect found in our study was similar to the effect reported in placebo-controlled studies of other agents. In a study of genital herpes recurrences in patients who received valacyclovir, the median duration of lesions decreased from 6

days to 4 days, and viral shedding decreased from 4 days to 2 days [11]. Similarly, a study of famciclovir showed a decrease of 1 day in lesion duration and 2 days in viral shedding [6]. A recent study of valacyclovir for treatment of recurrent genital herpes compared 5-day and 3-day regimens of valacyclovir (500 mg b.i.d.) administered to 800 patients with recurrent genital herpes [12]. The results showed that the regimens used in the 2 treatment arms were equally effective: the median time to lesion healing was 4.7 days for the 5-day therapy course and 4.4 days for the 3-day course. The total dose of acyclovir given in the shorter regimen (4800 mg) was lower than that given in the standard dosing regimens (5000 mg total for 200 mg of acyclovir given 5 times per day for 5 days, and 6000 mg total for 400 mg of acyclovir given t.i.d. for 5 days), so the cost of this regimen may also be somewhat lower. We used a higher-than-standard dose of acyclovir to maximize the effect of short-dose therapy. It is not clear whether the standard dosage given for 2 days would have been as effective. Previous studies have shown that higher dosages of acyclovir (800 mg po 5 times a day) do not result in shorter durations of the primary episode than does a standard dosage of acyclovir [13]. Similarly, treatment with valacyclovir has not demonstrated improvement in any efcacy measurements for episodic or suppressive therapy of genital herpes compared with acyclovir [4, 5, 14]. A higher blood level of acyclovir, which can be achieved with higher doses of acyclovir or by adminTwo-Day Acyclovir Therapy for HSV-2 CID 2002:34 (1 April) 947

istering the prodrug, may be an important contributor to the antiviral effect early during the treatment. Therefore, another option may be to administer a loading dose followed by lower doses, a model that has been successfully used for dosing of other antimicrobials. In summary, we have shown that a 2-day course of acyclovir therapy (800 mg po t.i.d.) shortens the duration of genital herpes episodes, lesions, and viral shedding. The proportion of aborted episodes was also signicantly increased among patients who received acyclovir. The large differences in the treatment arms observed in this study, the low cost of generic acyclovir, and the ease of a 2-day, 6-pill treatment course should encourage clinicians to recommend this regimen. Our study was performed with many fewer patients than most studies of recurrent genital herpes have used. However, the statistical power was sufcient to demonstrate clinically useful differences, because we observed each patient for up to 2 recurrences. This may be an efcient alternative design for studies that assess the antiviral efcacy of candidate agents for the treatment of genital herpes.

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References
1. Centers for Disease Control and Prevention. 1998 guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep 1998; 47(RR-1):1111. 2. Ashley RL, Militoni J, Lee F, Nahmias A, Corey L. Comparison of Western blot (Immunoblot) and G-specic immunodot enzyme assay for detecting antibodies to herpes simplex virus types 1 and 2 in human sera. J Clin Microbiol 1988; 26:6627. 3. Lafferty WE, Krofft S, Remington M, et al. Diagnosis of herpes simplex virus by direct immunouorescence and viral isolation from samples of external genital lesions in a high prevalence population. J Clin Microbiol 1987; 25:3236. 4. Bodsworth NJ, Crooks RJ, Borelli S, et al. Valaciclovir versus acyclovir

12.

13.

14.

in patient-initiated treatment of recurrent genital herpes: a randomized, double-blind clinical trial. International Valaciclovir HSV Study Group. Genitourin Med 1997; 73:1106. Tyring SK, Douglas JM, Corey L, Spruance SL, Esmann J. A randomized, placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. International Valaciclovir HSV Study Group. Arch Dermatol 1998; 134: 18591. Sacks SL, Aoki FY, Diaz-Mitoma F, Sellors J, Shafran SD. Patientinitiated, twice-daily oral famciclovir for early recurrent genital herpes: a randomized, double-blind multicenter trial. Canadian Famciclovir Study Group. JAMA 1996; 276:449. Wald A, Zeh J, Selke S, Ashley RL, Corey L. Virologic characteristics of subclinical and symptomatic genital herpes infections. N Engl J Med 1995; 333:7705. Reichman RC, Badger GJ, Mertz GJ, et al. Treatment of recurrent genital herpes simplex infections with oral acyclovir: a controlled trial. JAMA 1984; 251:21037. Corey L, Mindel A, Fife KH, Sutherland S, Benedetti J, Adler MW. Risk of recurrence after treatment of rst episode genital herpes with intravenous acyclovir. Sex Transm Dis 1985; 12:2158. Benedetti JK, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic rst-episode infection. Ann Intern Med 1994; 121: 84754. Spruance S, Trying S, Degregorio B, Miller C, Beutner K. A large-scale, placebo-controlled, dose-ranging trial of peroral valacyclovir for episodic treatment of recurrent herpes genitalis. Valaciclovir HSV Study Group. Arch Intern Med 1996; 156:172935. Leone P, Trottier S, Miller J, and International Valaciclovir Study Group. A comparison of oral valaciclovir 500 mg twice daily for three or ve days in the treatment of recurrent genital herpes [abstract 22.012]. In: Program and abstracts of the 8th International Congress of Infectious Diseases (Boston). Boston: International Society for Infectious Diseases, 1998:90. Wald A, Benedetti J, Davis G, Remington M, Winter C, Corey L. A randomized, double-blind, comparative trial comparing high and standard dose oral acyclovir for rst-episode genital herpes infections. Antimicrob Agents Chemother 1994; 38:1746. Reitano M, Tyring S, Lang W, et al. Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose range-nding study. J Infect Dis 1998; 178:60310.

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948 CID 2002:34 (1 April) Wald et al.