GENITAL HERPES IS frequently associated with profound psychosocial morbidity. 1 Two antiviral treatment strategies are currently available to manage recurrent genital herpes infections: suppressive therapy, in which medication is taken daily to prevent outbreaks, and episodic treatment, in which individual herpes outbreaks are treated as they arise. The episodic treatment strategy has been shown to be effective in reducing the duration and severity of lesion pain and the time to lesion healing. 2 Suppressive therapy prevents herpes simplex virus reactivation and therefore development of herpes lesions; it has benefits over episodic treatment, including improved quality of life. 3 Recent evidence also suggests that suppressive antiviral therapy decreases the frequency of asymptomatic herpes simplex virus (HSV) shedding from the genital tract and may therefore potentially decrease the risk of sexual transmission of infection. 4,5 However, the latter has yet to be prospectively demonstrated.
Valacyclovir (Valtrex, GlaxoSmithKline, Mississauga, Ontario, Canada) is a prodrug of acyclovir and is effective in the treatment of a range of herpesvirus infections. 6,7 With oral administration, the bioavailability of acyclovir is threefold to fivefold greater after valacyclovir administration than after acyclovir is given alone. 8 Valacyclovir has been shown to be effective for both suppressive and episodic treatment of genital herpes recurrences. 9–12 Double-blind, placebo-controlled studies have demonstrated the efficacy of valacyclovir (500 mg once daily) in suppressing recurrent genital herpes outbreaks in immunocompetent subjects. 9,10 Subjects with frequent recurrences (≥10 per year) may derive additional benefit from 1000 mg daily or 250 mg twice daily. 10 Randomized controlled clinical trials have demonstrated the efficacy of valacyclovir given as episodic therapy (500 mg twice daily for 5 days) for genital herpes outbreaks. 11,12
The safety and efficacy of valacyclovir are well documented. 6,7 However, there are few treatment-preference data for patients with recurrent genital herpes. This study examines patients’ preferences for treatment strategy, satisfaction with treatment, and quality of life with suppressive therapy (500 mg valacyclovir once daily) and episodic therapy (500 mg valacyclovir twice daily).
The patients enrolled in this study were immunocompetent males or females ≥18 years of age with a documented history of genital HSV infection (type 1 or 2). A pattern of genital herpes recurrences was annualized to four to nine outbreaks or two to four in the previous 6 months. Patients undergoing suppressive therapy at the time of assessment for the study were required to stop treatment for a 1-month washout period before the start of the study. Patients previously receiving suppressive oral antiviral therapy had to have at least one recurrence within 16 weeks of stopping treatment before the study.
Patients excluded from the study had a history of frequent recurrences (>10 per year), ocular HSV infection, clinically significant impairment of hepatic function (AST or ALT ≥3 times upper normal limit) or renal function (estimated creatinine ≤15 ml/min), or intolerance of acyclovir or valacyclovir. Also excluded were lactating women, patients with significant gastrointestinal dysfunction, and those receiving medication that may have interfered with drug disposition or absorption. Females had to use effective contraceptive methods or not have childbearing potential.
Study Design, Treatments, and Procedures
The study was multicenter, open-label, randomized, and crossover in design. The study was approved at each site by the local ethics committee. Informed written consent was obtained from each patient before initiation of any evaluations.
Patients were seen as outpatients at a screening/randomization visit and routinely at 4-week intervals for the 48-week duration of the study. They were randomized at enrollment to receive either suppressive therapy followed by episodic treatment, each for a period of 24 weeks, or vice versa. All patients received both treatments. Suppressive therapy was valacyclovir at a dosage of 500 mg once daily, and episodic therapy was valacyclovir at a dosage of 500 mg twice daily for 5 days for the treatment of each recurrence. Valacyclovir was supplied as valacyclovir hydrochloride tablets (Valtrex). Treatment order was randomly allocated by means of the PROC PLAN program within SAS software (SAS Institute, Inc., Cary, NC). The first 24-week treatment period was defined as period 1 and the second 24-week treatment period was defined as period 2.
Patients were instructed to return to the clinic within 24 hours or as soon as possible at the first sign of a recurrence. After a clinical examination to verify lesions, the investigator dispensed a 5-day supply of valacyclovir for episodic treatment (500 mg twice daily). For patients in the suppressive arm, suppressive therapy was resumed after the 5 days. Only the first recurrence required a clinic visit for initiation of episodic therapy. Thereafter, patients self-initiated episodic therapy on the basis of prodromal symptoms or signs, although they were still required to attend for confirmation of a lesional recurrence.
Measurements and Evaluations
The primary endpoint, subject treatment preference, was evaluated once, at the end of the study, with a standardized question. Secondary evaluations were patient satisfaction with treatment and quality of life during suppressive and episodic therapy. Safety was monitored throughout the study. An estimate of the efficacy of suppressive valacyclovir was made from reported dates of herpes recurrences.
Treatment satisfaction and quality of life were assessed with disease-specific questionnaires: the Genital Herpes Treatment Satisfaction Questionnaire (GHERPTSQ) 13 and the Recurrent Genital Herpes Quality Of Life Questionnaire (RGHQoL), respectively. 3,14 The GHERPTSQ was designed with use of the Diabetes Treatment Satisfaction Questionnaire (DTSQ) as a model. It has two versions, the first assessing status and the second assessing change. Efficacy was estimated from the time to first herpes recurrence and the proportion of patients who had a recurrence with each treatment strategy. The safety assessment consisted of adverse-event reporting.
At the screening/randomization visit, subject eligibility was assessed and the subject's genital herpes history was recorded to determine recurrence frequency. A pregnancy test was done for subjects of childbearing potential. A genital examination was conducted to rule out a current genital herpes outbreak. Patients received a diary to record study medication taken, date and time of recurrence onset, date on which recurrence ended, side effects, and changes in nonstudy medication.
At each 4-weekly scheduled visit, patients were assessed for genital herpes recurrences, adverse events were discussed, and the diary was reviewed. A pregnancy test was performed at the end of each treatment period, on the first day before the start of episodic treatment, and at any time that pregnancy was suspected.
At the end of the study (48 weeks), patients were required to answer the following treatment preference question: “Overall, which treatment did you prefer while you were in this study? Treatment A, suppressive therapy (one pill per day plus treatment of outbreaks), or Treatment B, episodic therapy (treatment of outbreaks only)?”
At the end of weeks 12 and 24, patients completed the GHERPTSQ (status version) and the RGHQoL questionnaires. At the end of weeks 36 and 48, patients completed the GHERPTSQ (status and change versions) and RGHQoL questionnaires.
The status version of the GHERPTSQ asks questions to determine the patient's experience over the previous 4 weeks. The change version of the GHERPTSQ asks questions to determine the patient's experience with the present treatment in comparison with the first treatment used in the study. The GHERPTSQ has two subscales. The control/effectiveness subscale consists of six items related to how satisfied the patient was with the control and effectiveness of the treatment. This subscale ranges from 0 (very poorly controlled/very dissatisfied) to 36 (very well controlled/very satisfied). The convenience/lifestyle subscale consists of five items related to the patient's satisfaction with the current treatment during the study and the impact that treatment had on lifestyle. This subscale ranges from 0 (very inconvenient/very dissatisfied) to 24 (very convenient/very satisfied).
The RGHQoL questionnaire consists of 20 statements. Patients respond to each statement by indicating the level of their own limitation on a 4-point Likert scale. Scores range from 0 (maximum limitation) to 3 (minimum limitation).
Patients could choose to discontinue participation in the study at any time. The investigator could also withdraw the patient for safety or noncompliance reasons. The subject was required to complete the treatment-preference question if both treatments were received, as well as the GHERPTSQ and RGHQoL questionnaires.
The sample size was based on the preference for suppressive or episodic treatment with use of a two-sided test with 80% power and a significance level of 0.05. The null hypothesis of no preference between the treatments was rejected if the true preference rate was <39% or >61% for 160 subjects. On the basis of an assumed 25% dropout rate, inclusion of 216 subjects was planned.
The Mainland–Gart test 15,16 was used to investigate whether there was a significant treatment effect on patients’ treatment preference and to test for a significant period effect. The suppressive therapy preference rate of those randomized to receive suppressive therapy first was compared with the episodic therapy preference rate of those randomized to receive episodic therapy first. A 95% confidence interval was also constructed for the suppressive therapy preference rate.
The subscales and total scores from the last visit in each period (24 and 48 weeks) of the status version of the GHERPTSQ were analyzed with analysis of variance (ANOVA) models 17 with variables for sequence, patient within sequence, period, and treatment. Least-squares means adjusted for the other variables in the model are reported for suppressive and episodic therapy. In addition, treatment strategies were compared with a Student's t test at the 12-, 24-, 36-, and 48-week visits. The total scores of the RGHQoL questionnaire were analyzed similarly to the total scores of the GHERPTSQ (status version).
Time to first genital herpes recurrence during period 1 was estimated with the Kaplan–Meier product limit method. 18 Differences between treatment groups were estimated and tested with Cox's proportional hazards model adjusted for center. 19 The effect of treatment strategy, assessed by the presence or absence of a recurrence during each period, was analyzed with the Mainland–Gart test. The prognostic variables of prior genital herpes recurrence frequency, gender, age, prior use of suppressive therapy, and treatment strategy were explored for their potential impact on the time to first recurrence.
All efficacy analyses were conducted on the intent-to-treat population with SAS version 6.12 for Windows NT (Microsoft Corp., Redmond, WA).
A total of 225 patients were enrolled in 16 centers across Canada, with 202 included in the intent-to-treat population. Of the 225 patients enrolled, 185 completed the study as protocoled. The 40 patients who prematurely discontinued the study did so for the following reasons: adverse event (n = 6), consent withdrawn (n = 16), lost to follow-up (n = 7), protocol violation (n = 2), and other reasons (n = 9). None of the adverse events that led to discontinuation were considered serious, and all resolved. Of the patients who withdrew consent, four cited personal reasons, and the reasons for withdrawal were not further identified by the remainder.
Of the 40 patients who prematurely discontinued the study, all were included in the safety analyses. Seventeen of the 40 received the initial treatment and were therefore included in the intent-to-treat analyses; the remaining 23 patients dropped out in the first period and were excluded from the intent-to-treat population.
The mean age of the patients was 38.0 years (range, 20–83). Almost two-thirds of the patients were female (61%). Almost all patients were white (99%). Demographic information for each treatment group is summarized in Table 1.
Preference for Suppressive Versus Episodic Therapy
The majority of patients preferred suppressive therapy to episodic therapy (71.8%; 95% CI, 66% to 78%;Table 2). Even in the presence of a significant period effect, this difference in treatment preference was statistically significant (P < 0.001). In other words, despite patients’ preference for the therapy they received in period 2 to that in period 1 (61.9%;P < 0.001), the preference for suppressive therapy was still statistically significant.
Treatment Satisfaction and Quality of Life
Patients receiving suppressive therapy were found to have significantly better control of genital herpes outbreaks than those receiving episodic therapy (mean scores: 33.6 and 28.0 for suppressive and episodic, respectively;P < 0.001). This treatment effect was in the presence of a nonsignificant sequence effect (P = 0.148) and a statistically significant period effect (higher scores in period 1;P < 0.001). Figure 1 A illustrates the mean GHERPTSQ control/effectiveness scores during suppressive and episodic therapy. Each of the Student's t tests was statistically significant in favor of suppressive therapy (all four time points;P < 0.001). A similar result was seen in the convenience/lifestyle scores: suppressive therapy was considered more convenient and had less negative impact on lifestyle than episodic therapy (mean scores: 21.2 and 19.5, respectively;P < 0.001). Both sequence and period effects were not statistically significant at the 5% level.
Figure 1 B illustrates the mean scores for convenience/lifestyle from the GHERPTSQ during suppressive and episodic therapy. The individual Student's t test values were statistically significant in favor of suppressive therapy at weeks 12, 36, and 48 (P ≤ 0.004). The analysis of total GHERPTSQ scores indicated that patients receiving suppressive therapy had significantly higher overall satisfaction than with episodic therapy (mean scores: 54.8 and 47.4 for suppressive and episodic, respectively;P < 0.001). This treatment effect was in the presence of a nonsignificant sequence effect (P = 0.102) and a significant period effect (higher scores in period 1;P = 0.004).
The RGHQoL questionnaire comparisons indicated a significant difference in favor of suppressive therapy over episodic therapy (mean scores: 61.1 and 59.1 overall for suppressive and episodic, respectively;P = 0.002). The effect of treatment sequence was not statistically significant (P = 0.233). The effect of period was significant (higher scores in period 2;P < 0.001). Table 3 presents the means at each of the four time points measured.
Efficacy of Suppressive Therapy
The median time to first recurrence for patients receiving episodic therapy during period 1 was approximately 34 days. The median time to first recurrence for patients on suppressive therapy during period 1 could not be calculated, because fewer than 50% had a recurrence (Fig. 2). The risk ratio for the probability of patients suffering a recurrence during suppressive versus episodic treatment was 0.22 (95% CI, 0.15–0.34;P < 0.001), i.e., the probability of recurrence was reduced by 78% for patients receiving suppressive therapy.
Significantly fewer patients experienced recurrences during suppressive therapy than with episodic treatment (43.1% versus 83.7%;P < 0.001). Again, this statistically significant effect in favor of suppressive therapy was present despite a significant period effect (P = 0.001). At 12 and 24 weeks, the percentages of recurrence-free patients undergoing suppressive therapy were 69% and 57%, respectively, compared with 30% and 17% undergoing episodic therapy, respectively.
Other variables, in addition to treatment, found to significantly affect time to first genital herpes recurrence were gender and prior recurrence frequency (Table 4). Male patients were 38% less likely to have a recurrence, and as expected, patients with a history of relatively more frequent recurrences were 15% more likely to have recurrences during the first 24 weeks of the study.
A similar percentage of patients were affected by adverse events during each treatment strategy (75% in episodic, 80% in suppressive). Drug-related events were experienced by 9% and 19% of the patients during episodic and suppressive therapy, respectively. The most common events considered drug-related were headache and nausea, which occurred in 6% and 2%, respectively, of patients during episodic treatment and in 13% and 5%, respectively, during suppressive therapy.
A total of eight adverse events were considered serious—five during episodic treatment and three during suppressive therapy—but none were considered to be drug-related.
The increasing prevalence and psychosocial morbidity associated with recurrent genital herpes highlight the importance of understanding the merits of different treatment options for this disease. Valacyclovir has been demonstrated to be effective and safe in suppressive or episodic therapy for patients with recurrent genital herpes. This study demonstrates that, of the two antiviral therapeutic strategies, suppressive therapy is preferred by significantly more patients than is episodic treatment.
There are likely multiple reasons for this preference. Patients’ treatment satisfaction, measured by the GHERPTSQ, was greater for suppressive therapy than for episodic treatment. This satisfaction occurred on several levels: control/effectiveness, convenience/lifestyle, and overall. In this study, suppressive therapy resulted in improved quality of life and decreased recurrence risk in comparison with episodic therapy. The RGHQoL questionnaire scores in our study were significantly improved at the 24-week time point, a change that was unlikely to be clinically significant, and demonstrated a nonsignificant increase at 12 weeks. These results are similar to those reported in a recent large, double-blind, parallel-design, placebo-controlled study of suppressive valacyclovir in which therapy was found to have a significant positive impact on the RGHQoL at 3, 6, and 12 months in comparison with placebo. 3
In the first 6 months of our study, the results reflected those reported previously. In the second 6 months of our study, a lack of difference between treatment strategies in RGHQoL scores was observed. A number of factors may have influenced this result. During the second 6-month period of our study, recurrences were markedly fewer during episodic treatment than in the first period. There was also a reduction in statistical power as patients withdrew prematurely and possibly as a result of less diligent reporting of herpes recurrences by patients during the second half of a year-long study. Furthermore, the earlier study 3 was larger and enrolled patients with higher recurrence rates overall. For these patients, a reduced RGHQoL score may have been easier to demonstrate. Finally, unlike the Patel study, 3 our smaller study was powered for the primary endpoint of patients’ satisfaction with treatment, and it should not be assumed that the sample size calculation would be the same for the secondary quality-of-life endpoint.
The nature of the period effect in the GHERPTSQ control/total scores and in the RGHQoL total score was different. The GHERPTSQ had higher scores in period 1, and the RGHQoL questionnaire yielded higher scores in period 2. Not all subscales of the GHERPTSQ were affected: the convenience/lifestyle subscale had no significant period effect. In the GHERPTSQ, the control and total scores had the largest treatment differences and may have emphasized a period effect. The decrease in GHERPTSQ scores between periods 1 and 2 was greater for episodic treatment versus suppressive therapy. A positive experience in period 1 with suppressive therapy may have raised patients’ expectations, resulting in lower scores in period 2 with episodic treatment. The relevance of these period effects is unclear, as significantly higher questionnaire scores and treatment preference during suppressive therapy versus episodic treatment were consistent even in the presence of a period effect.
The proportions of recurrence-free patients during suppressive valacyclovir therapy were similar to those estimated from Kaplan–Meier plots in publications of other controlled studies. The recurrence-free rates for suppressive therapy in our trial were 69% at 12 weeks and 57% at 24 weeks of treatment. Patel et al. reported recurrence-free rates of approximately 71% at 12 weeks of treatment. 9 Recurrence-free rates reported by Reitano et al 10 were approximately 68% at 12 weeks and 55% at 24 weeks of treatment. An open-label study of valacyclovir for 1 year reported higher recurrence-free rates, of 81% and 84%, for the same time points. 20 Because genital herpes recurrences may be triggered by a variety of poorly defined physical, biochemical, and emotional factors, 21 the recurrence rates among studies would be expected to vary.
These comparisons with other studies should be viewed cautiously, because the controlled trials of Reitano et al 10 and Patel et al 9 were of parallel design and our study had a crossover design; patient-enrollment criteria in terms of prior recurrence frequency were also different among trials. Furthermore, the study by Baker et al 20 was of patients with 10 years’ prior experience with suppressive acyclovir therapy for genital herpes.
Prognostic variables found to influence time to first recurrence were as expected from previous reports. 9,10,22 The effect of frequency of recurrence supports the long-standing evidence that suppressive antiviral therapy does not change the underlying disease pathology or influence recurrence rates in the short term, such as the 24-week period in which our study evaluated this therapeutic strategy.
The long-term safety of valacyclovir has been consistently reported as highly acceptable, and the findings in this trial are in keeping with those of previous studies. 6,7 Headache has been described in other valacyclovir study reports as the most frequent adverse event, and it occurred at a rate similar to that with placebo in a study of immunocompetent patients. 10
In conclusion, valacyclovir as suppressive therapy (500 mg once daily) was preferred by 72% of patients over episodic treatment (500 mg twice daily) to manage recurrent genital herpes outbreaks. Treatment satisfaction and quality-of-life measures were significantly better among patients undergoing suppressive therapy than during episodic treatment. The risk of recurrence was 78% lower for patients undergoing suppressive therapy than with episodic treatment. Suppressive valacyclovir demonstrated a highly acceptable safety profile. The overall preference for suppressive therapy, lower risk of recurrence, and higher treatment satisfaction and quality of life demonstrated with once-daily valacyclovir should encourage good compliance.
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