Sexually Transmitted Diseases:
Suppressive Therapy With Valacyclovir in Early Genital Herpes: A Pilot Study of Clinical Efficacy and Herpes-Related Quality of Life
Handsfield, H Hunter MD*; Warren, Terri RN, ANP†; Werner, Mica BA, CCRC†; Phillips, James A. DrPH‡
From the *Center for AIDS and STD, University of Washington, and Public Health–Seattle & King County, Seattle, Washington; the †Westover Heights Clinic, Portland, Oregon; and ‡Sage Statistical Solutions, Inc., Elfand, North Carolina
The authors thank Jennifer Almekinder of GlaxoSmithKline for her advice, support, and patience; Robert Deeter, PhD, formerly GlaxoSmithKline; Victory Murphy, RN, ARNP, for clinical support; the clinicians and support staff of the Public Health–Seattle and King County STD Clinic and the Westover Heights Clinic; and the numerous other providers who referred patients to the study.
This research was funded by a grant from GlaxoSmithKline, from which Dr. Handsfield and Ms. Warren have received other research support and consulting and speakers fees. Dr. Phillips has been the recipient of contracts from GlaxoSmithKline, including a contract for the statistical analyses for this study.
Correspondence: H. Hunter Handsfield, MD, Battelle Centers for Public Health Research and Evaluation, 1100 Dexter Avenue North, Suite 400, Seattle, WA 98109. E-mail: firstname.lastname@example.org.
Received for publication June 6, 2006, and accepted August 14, 2006.
Background: Suppressive therapy has not been studied during the first year after acquisition of genital herpes, the time of maximum frequency of reactivation, potential for transmission, and impact on quality of life.
Objective: The objective of this study was to evaluate the effectiveness of suppressive therapy with valacyclovir initiated within 3 months of infection.
Study Design: The authors conducted a double-blind, randomized, controlled trial of 1.0 g valacyclovir daily versus placebo for 6 months in 119 patients.
Results: Herpes simplex virus (HSV) type 2 and HSV-1 were documented in 75 and 22 patients, respectively. In intention-to-treat analysis, annualized rates of symptomatic recurrences for valacyclovir and placebo, respectively, were 1.7 ± 2.7 (mean ± standard deviation) and 3.4 ± 4.0 outbreaks per year (P = 0.012). Time to first recurrence was 80 ± 47 days for valacyclovir and 54 ± 49 days for placebo (P = 0.001). The differences in favor of valacyclovir were greatest in patients with confirmed HSV-2 infection. The Recurrent Genital Herpes Quality of Life score in HSV-2 infected patients rose 11.9 ± 11.1 points for valacyclovir and 5.9 ± 9.1 points for placebo (P = 0.040).
Conclusions: Early suppressive therapy with valacyclovir reduces symptomatic recurrent outbreaks, especially in patients with HSV-2 infection. Valacyclovir therapy was associated with improved herpes-related quality of life.
GENITAL HERPES IS THE MOST prevalent sexually transmitted disease (STD) in the United States and perhaps worldwide and a major factor in the sexual transmission of the human immunodeficiency viruses (HIV).1–4 In persons with recurrent genital herpes caused by herpes simplex virus type 2 (HSV-2), suppressive antiviral therapy with acyclovir, valacyclovir, or famciclovir is effective in reducing the frequency and severity of symptomatic recurrent outbreaks and in suppressing subclinical shedding of the virus,5–11 and valacyclovir has been shown to reduce the risk of sexual transmission of HSV-2.12 Successful suppressive therapy often is accompanied by improved herpes-related quality of life.13 The maximum frequency of symptomatic recurrences, subclinical viral shedding, and sexual transmission occur during the first year after the initial infection,12,14 when impact on quality of life probably also is greatest. However, published studies of the efficacy of suppressive therapy have been limited to subjects with HSV-2 infection at least 1 year in duration,5–11 and no available data have addressed suppression soon after acquisition, when substantial benefit might be anticipated, or in patients with genital HSV-1 infection. We therefore undertook a randomized, controlled trial to assess the efficacy of suppressive therapy with valacyclovir, initiated within 3 months of acquisition of genital herpes, to prevent symptomatic recurrences and ameliorate the negative impact of herpes on quality of life.
Patients and Study Design
The study was performed in 2001 and 2002 at a public health STD clinic in Seattle, Washington, and a private clinic in Portland, Oregon, that specializes in STD care. The patients were heterosexual men and women ≥18 years old with their first recognized occurrence of genital herpes who presented to the investigators' clinics or were referred by local healthcare providers. The study originally was designed to enroll persons within 30 days of onset of symptoms, but the interval was extended to 90 days to enhance recruitment after the shorter interval proved restrictive. Persons who had same-sex partners in the preceding year and those who gave histories that they were infected with HIV were excluded.
Subjects were randomized to double-blind treatment with 1.0 g valacyclovir orally once daily, or placebo, for 6 months. Clinic follow-up visits were scheduled 1 month, 3 months, and 6 months after enrollment, interspersed with telephone follow up at 2 weeks and 2, 4, and 5 months after enrollment. Subjects also were instructed to return on occurrence of the first suspected recurrent outbreak of genital herpes, and subsequent suspected recurrences were evaluated by telephone. Recurrent herpes outbreaks, whether diagnosed at a return visit or by telephone evaluation, were treated with 500 mg valacyclovir twice daily for 5 days, during which time the study drug was withheld. The primary outcome measures were the frequency of symptomatic outbreaks of genital herpes during the treatment period, time to the first symptomatic recurrence, and herpes-related quality of life. The study was approved by the Institutional Review Boards representing both clinics, and the subjects gave written informed consent.
A clinical diagnosis of a first recognized episode of genital herpes, made either by the investigators or the referring clinician, was required for enrollment. Subsequently, a confirmed first episode of genital herpes was defined by laboratory documentation of HSV infection in a person with a clinical syndrome consistent with genital herpes in the absence of both a prior diagnosis of genital herpes and past symptoms suggestive of the disease. Most cases were confirmed virologically, either by isolation of HSV or identification of HSV DNA by polymerase chain reaction (PCR) from a genital lesion specimen. In subjects in whom HSV was not identified by culture or PCR, a first episode of HSV-2 infection was defined by a positive serologic test for HSV-2 antibody within 3 months after onset of symptoms. A diagnosis of first-episode herpes resulting from HSV-1 without virologic confirmation from a genital lesion required documented seroconversion, i.e., a negative assay for antibody to HSV-1 at enrollment followed by a positive assay within 90 days.
HSV isolation was done by standard methods using the shell vial technique,14 and PCR was done as reported previously.15 Viral cultures were performed in most Seattle subjects, whereas both culture and PCR were performed in most patients enrolled in Portland. Antibody to HSV-1 and HSV-2 was measured in Portland subjects by Western blot16 and in Seattle subjects primarily by enzyme-linked immunosorbent assay for antibody to HSV glycoprotein G (HerpeSelect; Focus Diagnostics, Inc., Herndon, VA), with Western blot confirmation of selected specimens.16
Herpes-Related Quality of Life
The impact of genital herpes on quality of life was measured with the Recurrent Genital Herpes Quality of Life (RGHQoL) instrument,17 a validated self-administered questionnaire previously used in the evaluation of the response of genital herpes to antiviral therapy.13,18,19 The RGHQoL measure addresses 5 psychosocial domains: self-esteem, social functioning, sexual functioning, personal relationships, and mental health. Sample items include “Herpes affects my self confidence,” “Herpes is affecting my sex life,” “I get depressed about having herpes,” and “Herpes makes it difficult to plan ahead.” Each of 20 items was scored on a 4-point Likert scale from 0 (“very much”) to 3 (“not at all”) with a range of possible total scores from 0 to 60. Thus, higher scores indicate improved quality of life.17
Outcomes were assessed in an intention-to-treat (ITT) analysis of all subjects, regardless of diagnostic confirmation of first-episode genital herpes, and in separate analyses of subjects with confirmed first-episode infection. All analyses were ITT in regard to compliance with treatment and follow up. SAS Version 9.1 (SAS Institute, Inc., Cary, NC) was used for all statistical analyses. Dichotomous categorical variables were compared using the Fisher exact test. Ordered categorical variables measuring treatment efficacy were compared using the Cochran-Mantel-Haenszel test. Continuous variables were compared using analysis of variance (ANOVA) with a term for study site, and the effects of gender were analyzed using ANOVA with terms for study site, treatment, gender, and gender by treatment interaction. Time to first recurrence was analyzed by Kaplan-Meier time-to-event curves and treatment groups compared with the log-rank test.
Table 1 displays the study population according to treatment arm. The 119 subjects had a mean age of 28.7 years and 78 (66%) were women. The initial clinical diagnosis of first-episode genital herpes was confirmed in 97 patients (82%), including 75 cases (63%) resulting from HSV-2 and 22 cases (18%) of genital HSV-1 infection. The diagnosis was confirmed virologically in 87 patients and by serologic criteria in 10 persons. Thirty-two (43%) of the patients classified as having their first recognized episodes of HSV-2 infection, and 13 (59%) of those with apparent first episodes of genital HSV-1 infection, were seropositive to the corresponding virus type when first tested. The clinical manifestations of initial herpes included fever in 31 patients (26%) and inguinal lymphadenopathy in 50 subjects (42%). The randomization was balanced, with no significant differences between valacyclovir and placebo recipients in virus type, demographic characteristics, clinical manifestations, baseline RGHQoL score, or the proportion of patients followed for ≥3 months (Table 1). There were no differences in the proportions enrolled in Portland or Seattle or in the basis for the laboratory diagnosis of initial genital herpes (data not shown).
Recurrent Outbreaks of Genital Herpes
In the ITT analysis, patients treated with valacyclovir experienced an annualized rate of recurrences (mean ± standard deviation [SD]) of 1.7 ± 2.7 outbreaks per year compared with 3.4 ± 4.0 outbreaks per year among subjects who received placebo (P = 0.012). Figure 1 shows the distribution of recurrent outbreaks during follow up. Among the valacyclovir recipients, 35 (60%) of 60 patients had no symptomatic recurrences during follow-up, compared with 20 (34%) of the 59 subjects randomized to placebo; and ≥3 recurrences were reported by 3 valacyclovir recipients and 13 placebo recipients (P = 0.005). Figure 2 displays the time to first recurrence in the entire patient population (Fig. 2A) and in subjects with confirmed HSV-2 infection (Fig. 2B). In the ITT analysis, the mean times to first recurrence in the valacyclovir and placebo groups were 80 ± 47 days and 54 ± 49 days, respectively (log rank P = 0.0013).
Among patients with confirmed HSV-2 infection, recurrent herpes occurred at an annualized rate of 2.0 ± 2.6 episodes per year in the valacyclovir group and 4.3 ± 4.4 outbreaks per year in those given placebo (P = 0.010). Eighteen (47%) of 38 subjects who received valacyclovir were recurrence-free during follow-up, compared with 10 (27%) of 37 placebo recipients; and ≥3 recurrences were reported by 3 (8%) and 12 (32%) of valacyclovir and placebo recipients, respectively (P = 0.014). The mean times to first recurrence in the valacyclovir and placebo groups were 86 ± 44 days and 45 ± 42 days, respectively (log rank P = 0.0045). Among patients with their first recognized episodes of genital HSV-1 infection, 8 (89%) of 9 given valacyclovir and 6 (46%) of 13 treated with placebo were recurrence-free during follow up (P = 0.074), and the mean rates of recurrent outbreaks were 0.5 ± 1.3 and 1.4 ± 1.4 outbreaks per year for valacyclovir and placebo, respectively (P = 0.194). Stratification by gender and study site did not significantly affect the outcomes in any analytic group (ITT, HSV-2, HSV-1; data not shown).
Herpes-Related Quality of Life
The RGHQoL instrument was completed at enrollment by 110 subjects with a mean ± SD baseline score of 30.4 ± 14.0. In the ITT analysis, the mean score rose among valacyclovir recipients from 29.5 at enrollment (N = 55) to 43.7 at 3 months (N = 45) and 45.5 at 6 months (N = 43). In the placebo group, the mean scores increased from 31.2 at enrollment (N = 55) to 41.1 at 3 months (N = 47) and 40.1 at 6 months (N = 41). These trends were similar among patients with confirmed HSV-2 or HSV-1 infection (data not shown).
Table 2 compares the changes in mean RGHQoL scores in the valacyclovir- versus placebo-treated patients with HSV-2 during the course of the study. From enrollment to the 3-month visit, the mean score rose by 11.9 points in valacyclovir-treated subjects and 7.7 points in those given placebo (P = 0.081). From enrollment through 6 months, the mean scores rose by 11.9 points and 5.9 points in the valacyclovir and placebo groups, respectively (P = 0.040).
In this study, apparently the first to assess the efficacy of suppressive antiviral therapy for patients with recently acquired genital herpes, treatment with 1.0 g valacyclovir daily was substantially superior to placebo in preventing symptomatic outbreaks of recurrent genital herpes resulting from HSV-2 as measured by the frequency of recurrent outbreaks, the proportions of patients who remained recurrence-free during follow up, and time to first recurrence. There were no significant differences in treatment response according to gender, study site, or clinical presentation. As expected,20 we observed a lower frequency of recurrences in patients with HSV-1 than those with HSV-2, but the modest number of subjects with HSV-1 precluded definitive comparison.
Although valacyclovir clearly was effective compared with placebo, symptomatic recurrences appeared to occur somewhat more frequently in our subjects than in patients receiving suppressive therapy with valacyclovir, acyclovir, or famciclovir for genital herpes ≥1 year in duration.5–11 During 3 to 6 months (mean 4.6 months) of follow up, 18 (47%) of our 38 HSV-2-infected subjects treated with valacyclovir were recurrence-free. By contrast, Patel et al reported that 69% of 288 patients with recurrent HSV-2 infection ≥1 year in duration were recurrence-free during a similar follow-up interval (4 months), despite selection for persons with ≥8 symptomatic outbreaks per year and treatment with only 500 mg valacyclovir daily.8 However, Reitano et al reported results more like ours: 55% of 269 persons with ≥6 outbreaks annually and treated with 1.0 g valacyclovir daily were recurrence-free after 6 months.5 We selected the 1.0-g dose of valacyclovir for study rather than 500 mg because we anticipated that newly infected patients might experience more breakthrough recurrences than patients with longstanding infection14 and because the 1.0-g dose of valacyclovir is more effective as suppressive therapy than 500 mg, especially in persons with frequent outbreaks.5
Therapy with valacyclovir was associated with improved herpes-related quality of life among patients infected with HSV-2 who were followed for 6 months. A lesser effect was observed in the ITT analysis, probably because some patients did not have genital herpes, diluting the apparent benefit of therapy. There was no difference in the change in quality of life between valacyclovir and placebo in our patients with HSV-1, but we had too few patients with HSV-1 infection to determine whether this influenced the overall outcome. Our results confirm other investigators' observations that persons with genital herpes experience improved quality of life over several months, regardless of treatment, undoubtedly as a result of acclimatization to the diagnosis.8,19 The baseline RGHQoL scores, the magnitude of the improvement in placebo recipients, and the rise in scores associated with valacyclovir therapy all were quantitatively similar to those in earlier reports.8,18,19 This consistency provides further validation of the RGHQoL instrument as a measure of quality of life in persons with genital herpes.
The most important limitation of this study is that not all our patients had first-episode genital herpes infections. Some did not have genital herpes at all because we enrolled patients in whom the first recognized episode of genital herpes was diagnosed clinically before laboratory confirmation. We addressed this issue by separately analyzing the entire study population by ITT and those with confirmed HSV infection. In addition, 43% of our patients classified as having first-episode HSV-2 infection and 59% of those with apparent first-episode genital HSV-1 infection were seropositive to the corresponding virus type at enrollment. The initial serologic tests were obtained up to 3 months after onset of symptoms, and a positive result does not exclude first-episode infection. Nevertheless, some of our patients probably were experiencing the first recognized symptoms of preexisting genital HSV infection, as reported previously.23 Although these factors constitute an important analytic limitation, our population may accurately represent persons who present with clinically diagnosed first-episode genital herpes, and the results account for the frequent need for clinicians and patients to make therapeutic decisions prior to diagnostic confirmation. At the same time, these results reinforce the need for virologic or serologic confirmation of all suspected cases of genital herpes,1,3,21,22 including determination of virus type because of its influence on clinical course, treatment, and counseling.20–22
There are other limitations as well. After the first recurrence, subsequent outbreaks were self-diagnosed and monitored by telephone. This approach reduced the precision of the analysis of recurrent herpes and might have inflated the number of outbreaks reported by anxious patients, perhaps partly explaining the possibly lower efficacy of suppression compared with previous studies. Our sample size was modest in this pilot study and lacked the power to address several outcomes of interest, such as potentially significant differences in relation to virus type, gender, or true primary HSV infection compared with nonprimary first-episode genital herpes. Finally, after experiencing an unexpectedly low enrollment rate, we modified the study design by extending the maximum interval from onset of initial herpes to enrollment from 30 days to 90 days. In retrospect, we believe 30 days might have been too short a time for potential subjects and their providers to contemplate the long-term consequences of genital herpes. Perhaps some patients who had not yet experienced recurrent outbreaks had little interest in suppressive therapy in the hope that ongoing therapy might not be necessary. It is not clear whether or how this change might have influenced the outcome.
In summary, valacyclovir in a dose of 1.0 g daily, initiated within 90 days of onset of genital herpes, reduces the frequency of symptomatic recurrent outbreaks over the next 3 to 6 months and increases the interval to the first recurrence, especially in patients infected with HSV-2. There also was a trend toward fewer outbreaks in patients with first recognized episodes of genital HSV-1 infection. Furthermore, valacyclovir treatment was associated with improved herpes-related quality of life in persons with HSV-2. Preliminary analysis of this research informed the design of 2 multicenter trials, currently underway, to determine the efficacy of early suppressive therapy with valacyclovir, including the effect on subclinical viral shedding. Our findings should be viewed as tentative until those results are available. In the meantime, clinicians should consider offering suppressive therapy to their patients with genital herpes in the first months after the first clinically recognized episode, especially when HSV-2 infection is suspected. Nevertheless, early suppressive treatment might be somewhat less effective than in longstanding recurrent herpes, which suggests in turn that subclinical shedding also might continue despite therapy. Until results of the multicenter trials are available, we recommend that patients offered early suppressive therapy be counseled that substantial risk for transmission to uninfected sex partners may persist despite treatment. Regardless of treatment, routine and consistent use of condoms to protect uninfected partners24 should be recommended to all patients for the first several months after the first recognized occurrence of genital herpes.
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