Bavaro, Joseph B. MS*; Drolette, Linda BS†; Koelle, David M. MD‡; Almekinder, Jennifer BA§; Warren, Terri ANP¶; Tyring, Stephen MD, PhD∥**††; Wald, Anna MD, MPH*†‡
GENITAL HERPES IS ONE of the most prevalent sexually transmitted diseases, affecting approximately 1 in 5 adults in the United States.1 Almost all patients who experience an initial outbreak of genital herpes simplex virus 2 (HSV-2) will subsequently experience at least 1 recurrence; many patients (∼38%) will experience more than 6 recurrences per year.2 Although recurrences of genital herpes tend to be less severe and of shorter duration than the initial outbreak,3 they are nonetheless inconvenient and can be quite painful and emotionally distressing to the patient.
Episodic treatment with a number of antiviral medications can markedly decrease the severity and duration of genital herpes recurrences. Traditionally, episodic antiviral therapy has consisted of a 5-day course of treatment, corresponding to the typical duration of symptoms of a genital herpes outbreak. Recently, shorter courses of antiviral medication have been investigated, based on the data suggesting that viral replication ceases early during an outbreak in immunocompetent persons.4 Thus, continued administration of antiviral medications may provide little residual benefit after the first few days of a genital herpes recurrence. Recent comparative and/or placebo-controlled studies have demonstrated the efficacy of a 2-day course of acyclovir,5 a 3-day course of valacyclovir,6 and a single-day course of famciclovir,7 in reducing the severity and duration of genital herpes recurrences, when compared with either placebo or traditional, longer therapies. In addition, administration of a 1-day course of valacyclovir has been shown to reduce the duration of an orolabial HSV recurrence by an average of 1 day compared with placebo.8,9
Although a recent study concluded that there was no significant difference in the time to second recurrence among patients treated with a 2-day course of acyclovir versus patients given placebo,5 the effect of episodic therapy on viral shedding immediately after resolution of a genital herpes lesion has not been well characterized. Past studies have demonstrated that viral shedding decreases significantly after the initiation of episodic therapy.10,11 However, it is not known whether viral shedding remains absent for an extended period of time after a recurrence treated with episodic therapy, or whether there is a “rebound” of increased viral shedding after treatment with antiviral medication ends. Such rebound may be hypothesized to occur especially frequently after very short courses of antiviral therapy.
In an open-label pilot study, we sought to determine the efficacy and safety of a patient-initiated 1-day course of valacyclovir (2000 mg twice daily, 4000 mg total) in treating recurrent genital herpes. To evaluate viral shedding patterns subsequent to antiviral treatment, participants collected swabs of genital secretions for viral culture daily while signs and symptoms persisted, and for DNA PCR daily for 14 days after initiation of study treatment.
Participants and Study Protocols
Healthy HSV-2 seropositive men and women, 18 years or older, with a history of recurrent genital herpes, were recruited at 3 research clinics in the United States. Eligibility criteria included a history of at least 4 episodes of genital herpes in the year before study entry. Alternatively, persons who had been taking suppressive therapy for genital herpes were required to have had at least 6 recurrences during the year before starting daily therapy. Such participants were also required to have experienced at least 1 outbreak in the 3 months after discontinuing suppressive therapy and at least 1 outbreak in the 3 months before study entry. Participants must not have taken antiviral medications within 7 days before initiation of treatment with study drug. Pregnant or nursing women, persons with impaired renal or hepatic function, immunocompromised persons, and persons with hypersensitivity to either acyclovir or valacyclovir were excluded from participation in the study. The protocol was approved by the institutional review board at each institution, and the participants signed a written informed consent before initiation of any study procedures.
Participants who met eligibility criteria were given sealed 1-day supplies of open-label valacyclovir (2000 mg twice daily for 1 day) and were instructed to begin treatment within 6 hours of the first indication of either prodromal symptoms or a genital lesion. Participants were asked to complete diary cards of symptoms and signs and to return to the clinic within 12 hours of initiating study medication for clinical evaluation of lesion staging and assessment of the participant’s comfort. Participants were also asked to complete diary cards of signs and symptoms, once per day, for the 14 study days.
Participants were asked to return to the clinic for evaluation each day for 2 additional days and then every other day until symptoms resolved and the lesion was completely healed. Participants were instructed to collect a swab of genital lesions for viral culture once daily until all signs and symptoms resolved, and to collect a swab of lesions (or genital area after the lesion had healed), once daily for all 14 days, for HSV PCR viral quantitation. Blood samples were collected both at the screening visit and day 7 (after taking study medication) of the study for safety analyses, including hematology and clinical chemistry measurements. Adverse events experienced by the participant were also noted at each visit.
All HSV-2 antibody tests, viral culture, and PCR analyses were performed at the University of Washington. HSV-2 antibody status was assessed by Western blot.12 Real-time quantitative HSV-2 DNA PCR and viral isolation and typing were performed as previously described.13,14
The intent-to-treat (ITT) population was defined as all eligible participants who initiated the use of the study medication during a genital herpes recurrence, including those who experienced prodrome only, whereas the modified ITT population comprised the subset that developed lesions. The primary end point was episode duration, defined as the number of days between the earlier of prodrome or initiation of therapy and complete resolution of all symptoms and signs. Secondary end points were lesion duration, duration of pain, duration of viral shedding, and percentage of aborted lesions, defined as prodromal symptoms only.
Time-to-event variables including episode, lesion, viral shedding, and pain durations were analyzed using the Kaplan-Meier product limit. Episode and lesion durations were computed for both the ITT and modified ITT populations. All other time-to-event variables were computed for the modified ITT population. Lesion duration was defined as the number of days between the initiation of therapy and complete reepithelialization of lesion. Prodrome-only subjects were assigned a lesion duration of zero for the ITT population. Lesions that occurred after a 24-hour lesion-free interval were considered a new recurrence; however, if a participant had a lesion recurrence during the study period of 14 days, only the initial recurrence for which study medication was taken was considered for the computation of median episode and lesion durations. Participants whose initial lesions had not healed by the fourteenth study day (n = 1) and participants who were lost to follow-up before clinician assessment of healing occurred (n = 4) were censored at the last known date of lesion, as were participants who had missing clinician or patient diary lesion data (n = 2).
Pain duration was defined as the number of days beginning with treatment initiation or onset of pain and ending with the last day of reported pain. If pain data were missing for a given day but that day was both preceded and followed by a day with pain, the missing day was presumed to be positive. One participant reported pain for 3 days and was then lost to follow-up; therefore, the duration of pain was unknown for that participant.
Viral shedding duration was calculated separately for viral culture results and for HSV PCR results. For viral shedding duration as calculated by viral culture, 2 days of negative samples indicated the end of a shedding episode, and a single negative sample followed by a positive sample indicated continued viral shedding. A missing culture sample on study day 1 was presumed to be positive if it was followed by a positive culture. If a missing sample was both preceded and followed by a positive culture, the missing day was also assumed to be positive. If a missing sample was preceded by a positive culture and followed by a negative culture, the data were censored at the last known positive culture result. Six participants had shedding episodes of indeterminate length due to missing culture data.
For viral shedding duration as calculated by HSV DNA PCR, 2 days of negative samples indicated the end of a shedding episode, and a single negative sample followed by a positive sample indicated continued viral shedding. A missing PCR sample on the first study day was presumed to be positive if it was followed by a positive PCR sample. If a missing sample was both preceded and followed by a positive PCR, the missing day was also assumed to be positive. If a missing sample was preceded by a positive PCR and followed by a negative PCR, the data were censored at the last known positive PCR result. Ten participants had shedding episodes of indeterminate length because of either missing PCR data or a positive PCR result on the last day that the participant was followed. These cases were censored at the last known positive PCR result.
Data were collected by the participating sites and entered into a database by the study sponsor (GlaxoSmithKline, Research Triangle Park, NC). All analyses were directed by study authors and conducted at the University of Washington.
One hundred fifteen persons were enrolled into the study, of whom 91 (79%) experienced prodrome and/or recurrence and commenced treatment. One participant received acyclovir for episodic treatment 5 days before initiating study drug; this participant was deemed to be ineligible and excluded from analysis, leaving 90 subjects for analysis.
Fifty-four percent of participants were women, the median age was 46 years, and 80% were white (Table 1). Six participants (7%) had taken suppressive antiviral therapy within 12 months before study entry; the median number of recurrences in the year before study entry was 7. All participants took both doses of valacyclovir. Overall, the median interval between the onset of symptoms and taking the first dose was 2 hours (range, 0–61 hours); the median interval between taking the first and second doses was 11 hours (range, 7–25 hours); and the median interval between taking the first dose and the first clinic visit was 5 hours (range, 0–27 hours). Thirteen (14%) participants experienced prodromal symptoms only and 77 (86%) participants developed lesions.
The median episode duration was 5 days (range, 1–15) for both the ITT and modified ITT populations, and the median lesion duration was 5 days (range, 1–15) for the modified ITT population and 4 days for the ITT population (range, 0–15). Pain persisted for a median of 3 days (range, 1–10) (Table 2). Four (5%) participants who developed lesions had a clinically assessed second recurrence of genital herpes after the initial lesions had healed. The median time from the end of the first episode to the beginning of the second episode was 6.5 days (range, 2–11). HSV DNA was detected in 3 of the 4 recurrences.
Participants obtained a median of 5 (range, 0–15) samples for viral culture and 14 (range 3–15) samples for HSV DNA PCR during the study. Overall, the virologic analysis included 478 swabs for HSV cultures and 1164 swabs for HSV DNA PCR. Among the 13 participants who experienced prodrome only, HSV was detected by both culture and PCR in 1 participant and by PCR only in 1 participant. Among the 77 participants who developed a lesion, HSV was detected by culture in 31 (42%) participants and by PCR in 60 (78%) participants. Three participants did not collect any culture samples. All 31 participants whose lesional episodes were positive by HSV culture were also positive by HSV PCR. Twenty-seven (36%) participants were positive by HSV PCR only. The median duration of shedding was 2 days (range, 1–4) by culture and 3 days (range, 1–13) by PCR (Fig. 1).
Among 60 participants for whom HSV was detected by PCR during their initial lesional episode, 14 (23%) participants had a second shedding episode, and 2 (3%) participants had a third shedding episode, during the 14-day study period. The additional shedding episodes lasted a median of 2 days (range 1–5). Three of the additional shedding episodes were concurrent with a second lesional recurrence, but most were asymptomatic.
Forty-three participants (48%) reported at least 1 adverse event during the study. One serious adverse event (worsening of depression) was reported during the study and considered to be not related to the study medication. The most common nonserious adverse events were headache (18% of participants), nausea (7%), and fatigue (3%).
In our study, we found that a 1-day course of valacyclovir led to a reduction in the days with lesions and viral shedding compared with natural history studies of genital HSV-2.3,15 In addition, following episodic treatment, only a minority of participants subsequently experienced a second lesional recurrence within 14 days of the initial recurrence. The short, high dose of valacyclovir was safe and well tolerated.
Almost a quarter of participants had subsequent viral reactivation after healing of the lesions. Further studies are needed to evaluate if 1-day therapy is associated with higher rates of subsequent asymptomatic HSV reactivation than longer courses, or whether such reactivation reflected the natural course of the underlying disease. Such a phenomenon could be attributable to the persistence of relatively metabolically inactive virus within or outside of cells during a short course of therapy. Once the suppressive pressure of a short burst of acyclovir declined below an inhibitory threshold, persistent virus could resume productive replication. Alternatively, delivery of infectious virus down the ganglia may occur continuously over a short period of time, creating a situation in which cells in the periphery were exposed to new virus coming out of the neural ending for some period of time. Acyclovir probably does not affect delivery of preformed virions exiting the neuron, although it likely inhibits creation of new infectious virions in the neuron.
Although we did not include a control or placebo group in this study, the results of this study can be interpreted in the context of previous studies that have considered outcomes of genital herpes recurrences both with and without clinical intervention. Indeed, several recent studies have focused on reducing the length of treatment in the hopes of improving patient compliance. One such study investigated the efficacy of a shorter, 3-day course of valacyclovir instead of the previously recommended 5-day course,6 and found that the median episode length was comparable for the 2 treatment regimens (4.4 days for the 5-day regimen vs. 4.3 days for the 3-day regimen). Another study considered a 2-day course of acyclovir versus placebo.5 This study found that among recipients of a 2-day course of acyclovir, the median episode duration was 4.0 days, compared with 6.0 days for placebo recipients. Lesions persisted for 4.0 days with acyclovir, versus 6.0 days with placebo, and viral shedding lasted for 25 hours with acyclovir versus 58.6 hours with placebo. Finally, in a trial using a 1-day regimen of famciclovir,7 the lesion duration was reduced to 4.3 days, compared with 6.1 with a matching placebo. An important caveat when evaluating these data are that each study employed different methodologies for assessing lesion and episode duration, precluding the possibility of direct comparisons between these studies and the current study. However, our results suggest that a 1-day course of valacyclovir would yield similar results to other short regimens in direct comparisons. Such comparative studies should be performed.
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