DOI: 10.1111/j.1468-3083.2008.03047.

JEADV

ORIGINAL ARTICLE
Blackwell Publishing Ltd

Valacyclovir and topical clobetasol gel for the episodic treatment of herpes labialis: a patient-initiated, double-blind, placebo-controlled pilot trial
C Hull,* M McKeough, K Sebastian, J Kriesel, S Spruance

Department of Dermatology, University of Utah, Salt Lake City, UT, USA Department of Internal Medicine, Division of Infectious Diseases, University of Utah, Salt Lake City, UT, USA *Correspondence: C Hull. E-mail: christopher.hull@hsc.utah.edu

Abstract
Background Treatment of herpes simplex labialis (HSL) has been associated with modest benets. This difculty results from the rapid resolution of the disease accomplished by the immune system, which narrows the window of therapeutic opportunity. The immune response is also responsible for important clinical manifestations, including oedema and pain. The dual role of immune responses (protection, pathology) is well recognized in other infectious diseases. The addition of corticosteroids to antimicrobial agents has been associated with improvement in some of these diseases. Objective We evaluated the combination of oral valacyclovir plus topical clobetasol compared to placebo for recurrent HSL. Methods Eighty-one subjects were screened, randomized, and dispensed medication (valacyclovir 2 g orally twice daily 1 day and clobetasol gel 0.05% twice daily for 3 days). Forty-two patients developed a recurrence and initiated treatment. Results There were more aborted lesions in the valacyclovirclobetasol arm compared to placeboplacebo (50% vs.15.8%, P = 0.04). Combination therapy reduced the mean maximum lesion size (9.7 vs. 54 mm2, P = 0.002) and the mean healing time of classical lesions (5.8 vs. 9.3 days, P = 0.002). We created a composite statistic, area-under-the-curve (AUC) of classical lesion size versus time. There was a reduction in the AUC in the combination arm compared with placebo (23 vs. 193 mm2, P < 0.001). Adverse events were minimal. Secondary and post-treatment recurrences were not increased by combination therapy. Conclusions This pilot study supports the addition of topical corticosteroids to an oral antiviral agent for the treatment of HSL. Larger studies need to conrm the safety and efcacy of this approach.
Received: 29 May 2008; Accepted 2 July 2008
DOI: 10.1111/j.1468-3083.2007.0@@@@.x

Keywords
clobetasol gel, herpes simplex labialis, valacyclovir

Conicts of interest
Dr Hull has served as a consultant for GlaxoSmithKline

Introduction
Multiple trials of antiviral medications for the episodic treatment of recurrent herpes simplex labialis (HSL) in immunocompetent patients have been undertaken in the last 30 years, and the treatment benefits to date have been modest. There is a clear need to increase the therapeutic benefit of available medications for this common illness. The dual role of immune responses (protection and pathology) is well recognized in a variety of infectious diseases, including bacterial meningitis, tuberculosis and Pneumocystis carinii pneumonia.1 The addition of steroids to antimicrobial agents has
Clinical Trials registration: NCT00297011

been associated with improvement in the clinical outcome and is now accepted as standard management for these illnesses. Steroids are also coming of age as adjunctive therapy in the management of diseases caused by herpes viruses. Steroids are accepted practice in herpetic stromal keratitis, a condition felt to be primarily related to an immune response to viral antigen24. Corticosteroids may have some benefit in conjunction with antiviral agents in herpes zoster.5 There is growing evidence for the role of the inflammatory response in herpes labialis. An intense mononuclear and polymorphonuclear cellular infiltrate has been identified in advanced herpes labialis lesions. Immunologic studies have provided evidence

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for the role of a Th1, or proinflammatory, cytokine response in the pathogenesis of lesions.6 Other studies have correlated vesicle fluid interferon- titres with the time to the next recurrence.7 Two studies have investigated the effect of topical corticosteroids on the severity of ultraviolet radiationinduced herpes labialis8,9 A pilot trial of the combination of oral famciclovir and topical 0.05% fluocinonide gel vs. famciclovir alone8 showed that the addition of corticosteroids to the antiviral drug treatment caused a marked and statistically significant reduction in lesion size and a trend to more aborted lesions. Similarly, a topical cream containing acyclovir and hydrocortisone increased the number of aborted lesions and reduced lesion area in comparison with placebo.9 The pathogenesis of a herpes labialis lesion involves both the destruction of cells by the virus and the host immune response. There is reason to believe that both antiviral drugs and steroids would benefit the clinical course of HSL, and therefore, that used together, an additive or greater benefit might be realized. The efficacy of high-dose, short-course valacyclovir has been reported.10 The objective of this study was to evaluate the safety and efficacy of patient-initiated therapy combining oral valacyclovir with topical clobetasol gel 0.05% in comparison to oral and topical placebo for a single recurrence of HSL.

Lesions occurring near or inside the nostril were not included. Secondary lesions were defined as lesions that developed on the second or third treatment day and that were located at least 1 cm from primary lesions. Post-treatment lesions were lesions that developed 314 days after the start of the episode. Some of these lesions were verified in the clinic, while others were by history from the patients following telephone contact. Classical lesions (non-aborted lesions) were defined as recurrences that progressed beyond the papule stage and included as least one of the following stages: vesicle, ulcer/soft crust, or hard crust. Non-classical lesions (aborted lesions) were defined at recurrences that did not progress beyond the papule stage (no development of vesicle, ulcer/soft crust, or hard crust). Lesion area was determined for classical lesions by measuring length and width Aborted lesions were given a value of 0.
Patient population

Methods
Study design

This randomized, placebo-controlled, double-blind, patient-initiated study was performed at the University of Utah from August 2004 and March 2007. The protocol and consent forms were approved by our Institutional Review Board. All volunteers gave written informed consent before being enrolled in the study. Patients who met entry criteria were randomized in a 1 : 1 ratio by an automated system to receive either valacyclovir 2 g orally twice daily for 1 day and topical clobetasol gel 0.05% twice daily for 3 days applied to the affected area, or matching oral and topical placebo. Patients returned home and were instructed to initiate therapy within 1 h of the onset of prodromal symptoms and before the appearance of the papule stage of the lesion recurrence. After initiation of study medication, subjects were required to return to the clinic within 24 h for a clinical assessment. Subjects were seen daily for 3 days and then every other day until return to normal skin. A final follow-up visit or telephone call was made with the patients 14 days after the start of the episode. Patients were asked to assess their lesions three times daily (lesion stage and pain) at fixed times (on waking, at lunch, and at bedtime) and record their observances in diaries. Pain was reported by the subject in the patient diary using a 010 scale (0 no pain, 10 worst pain imaginable). For data analysis, an investigator assessment of healing time was recorded that considered both the patient diary and findings recorded in the clinic. The lesions that appeared on the first day were designated as primary lesions. Primary lesions had to occur on or within 1 cm of the lip, without mucosal involvement.

Healthy male and female subjects with a history of recurrent HSL were recruited from the general population by advertisements. Subjects were 18 years of age or older with a history of at least three recurrences of HSL in the preceding year. Women of childbearing potential had to agree to use reliable birth control measures during the study. Patients were excluded if they had received an investigational drug in the preceding 4 weeks, had previously received a herpes simplex virus vaccine, or had used topical corticosteroids on or near the face or oral corticosteroids within 30 days of screening. Subjects were also excluded if they had a history of chronic conditions such as heart, pulmonary, renal or hepatic diseases; were immunocompromised; had a significant skin disease of the face such as acne, rosacea, or eczema that the investigator felt would interfere with assessments; had a history of alcohol or substance abuse; known allergy or hypersensitivity to corticosteroids, acyclovir, penciclovir and/or other nucleoside analogues; or impaired renal function as defined as a serum creatinine above the upper limits of normal. Pregnant women or breast-feeding women were excluded. All subjects who initiated therapy with study medication were included in the safety analysis [intent-to-treat population (ITT)]. The per-protocol (PP) population included subjects without major protocol violations and was used for the analysis of efficacy.
Efcacy end points and statistical analysis

The primary null hypothesis was that there was no difference between treatments with respect to the maximum lesion size. The primary efficacy endpoint was the effect of treatment on the maximum size of the primary lesion complex. Mean maximum lesion size was compared between treatments using a Mann Whitney test. Secondary variables included: the frequency of primary lesions that were aborted; the mean time to healing of classical primary lesions; the frequency and mean duration of lesion pain among primary lesions; the frequency of secondary

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lesions; and the frequency of post-treatment lesions. Frequencies were compared between treatments using a Fishers exact test, and values of time were compared by a MannWhitney test. We created a composite statistic, area-under-the-curve (AUC) of lesion size versus time (lesion burden), which captured three clinically important features: (1) type of lesion classical vs. nonclassical; (2) size; and (3) the healing time. For the purposes of the AUC analysis, aborted lesions were assigned a healing time of zero. The AUC values were compared between treatments using a MannWhitney test.

Results
Patient population
Figure 1 Time to healing. A KaplanMeier curve demonstrates the healing time for classical lesions. There was improvement in the healing time for subjects with classical lesions. The mean time to healing for the 10 subjects in the valacyclovirclobetasol arm who had classical lesions was 5.8 2.18 days. In contrast, the time to healing for the 16 subjects in the placeboplacebo arm who had classical lesions was 9.3 2.95 days. VACV, valacyclovirclobetasol arm; PLCB, placeboplacebo arm.

A total of 81 subjects were screened, enrolled, and randomized. Each subject was dispensed study medication and given written instructions to start medication within 1 h of the start of their next HSL recurrence. In total, 42 subjects developed signs/symptoms of a recurrence, self-initiated study medication, and were analysed in the ITT population. Thirty-nine of these 42 subjects completed study medication and had no major protocol violations and were included in the efficacy analysis. This included 20 subjects in the valacyclovir-clobetasol arm and 19 subjects in the placebo-placebo arm. The three subjects with major protocol violations failed to complete all study-related visits and were lost to follow-up. Patient demographics were similar across patient groups with respect to age, sex, race, and characteristics of HSV disease. These data are summarized in Table 1.
Lesion size

(50%) lesions in the valacyclovirclobetasol group were aborted compared with 3 of 19 (15.8%) in the placeboplacebo arm (P = 0.04).
Time to healing

Mean maximum lesion size was markedly reduced in the patients treated with valacyclovirclobetasol (n = 10), compared with the patients treated with placeboplacebo (n = 16) (9.7 13.5 mm2 vs. 54 60 mm2, P = 0.002).
Lesion prevention

There was improvement in the healing time for subjects with classical lesions. The mean time to healing for the 10 subjects in the valacyclovirclobetasol arm who had classical lesions was 5.8 2.18 days. In contrast, the time to healing for the 16 subjects in the placeboplacebo arm who had classical lesions was 9.3 2.95 days. The results were statistically significant (P = 0.002). Time to healing is shown as a KaplanMeier plot in Fig. 1.
AUC lesion size versus time

There was a statistically significant increase in the number of aborted lesions in the valacyclovirclobetasol arm. Ten of 20

Table 1 Demographic and disease characteristics

Demographic/characteristic Valacyclovir clobetasol N = 20 29.5 73% 91% 4.0 0 22 Placebo placebo N = 19 31.0 60% 90% 5.0 0 24

There was a major reduction in the mean maximum AUC in the combination arm compared with placeboplacebo (23 22 vs. 193 219 mm2, P = 0.001). The differences in AUC values for classical lesions and for all lesions for the valacyclovirclobetasol and placeboplacebo arms are illustrated in Fig. 2.
Lesion pain

Median age, years % Female % Caucasian Median no. of episodes that produced classical lesions in past year Median no. of episodes that produced non-classical lesions in past year Median time in years since rst HSL episode

The differences in pain between the two groups were not statistically different. In the combination valacyclovirclobetasol arm, the mean maximum lesion pain was 1.6 1.0 compared with 1.7 1.3 in the placeboplacebo arm. Additionally, the number of subjects reporting pain at any time was not statistically different with 17/20 (85%) patients in the valacyclovirclobetasol arm reporting pain at least once compared with 16/19 (80%) patients in the placeboplacebo arm.

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Figure 2 AUC of lesion size versus time. We created a composite statistic, AUC of lesion size versus time, which captures three clinically important features: (1) type of lesion classical vs. non-classical; (2) size; and (3) the healing time). There was a major reduction in the AUC in the combination arm compared with placebo for classical lesions and all lesions.

Safety

Adverse events (AEs) were similar in the valacyclovirclobetasol arm compared with the placeboplacebo arm. Overall, AEs were infrequent and mild. There were no serious AEs, and no subjects withdrew from the study because of AEs. Headache occurred most commonly and was seen in 4 (18%) of the subjects in the valacyclovirclobetasol arm compared with 2 (10%) subjects in the placeboplacebo arm. One (4.5%) subject in the valacyclovir clobetasol arm reported exacerbation of acne and 1 (4.5%) subject in this same group reported a transient, mild, warm sensation at the site of clobetasol application.

Discussion
The results of this study demonstrated that the combination of a topical corticosteroid with an oral antiviral agent was both effective and safe in the episodic treatment of recurrent HSL. Combination therapy using valacyclovir and topical clobetasol gel 0.05% significantly increased the number of aborted lesions, decreased the mean maximum lesion size, and decreased the mean healing time of classical lesions. Current antiviral agents limit replication of the virus. The clinical manifestation of this activity, on the course of herpes labialis, has been to reduce the healing time, as evidenced in multiple prior clinical trials1014 and the current trial. There has been scarce evidence for activity on any other aspect of the disease. In contrast, corticosteroids impact the pro-inflammatory response. The type of new clinical activity demonstrated in this trial (more aborted lesions and decreased lesion size) is different than that seen with

antiviral medications alone (more rapid healing), and supports the concept that corticosteroids can be a valuable new therapeutic modality in this disease. In this study, AEs were uncommon and mild, and the number of secondary and post-treatment lesions was not increased by the use of a topical corticosteroid. Topical corticosteroids have well-known local cutaneous side effects including atrophy, telangiectasia, and ulceration.15 The use of topical corticosteroids on the face, especially potent steroids like clobetasol, can exacerbate other conditions such acne, rosacea, and perioral dermatitis. They may predispose to Candida infections when used on the oral mucosa. One purpose of this study was to examine how the combination of an oral antiviral agent and a potent topical corticosteroid was tolerated by patients for episodic self-initiated therapy. Importantly, combination therapy was well tolerated by study subjects, and AEs were similar to placebo. Despite the immunomodulatory effects of topical clobetasol, we were encouraged to see that secondary lesions and post-treatment lesions were not increased compared with placebo. Additional longitudinal studies are needed to further investigate the potential for AEs with the addition of topical corticosteroids. It is unknown if repeated topical application of clobetasol for patients with frequent HSL recurrences would lead to some of these side effects. However, the results from this small study suggest that occasional, short duration therapy of three days with a small amount of gel is safe. It is unknown whether a topical corticosteroid alone would be beneficial in the treatment of HSL, as this was not addressed in this study. The optimal dosing scheme and therapeutic agents for the combination therapy are unknown. We chose to use the approved dose for valacyclovir taking advantage of high-dose, short duration therapy, which optimizes patient compliance and targets the period of maximal viral replication. Clobetasol was used in this study because it is a potent, class I topical steroid, and it was felt that this medication would provide the greatest magnitude of benefit as an anti-inflammatory agent. A gel was used as the vehicle because it allows for more precise application at the site and absorbs quickly. The optimal topical corticosteroid and vehicle for the treatment of HSL are unknown. A less potent topical corticosteroid may provide equal efficacy with the additional benefit of limiting the risk of side effects. Furthermore, a cream or ointment vehicle may provide a better environment for wound healing, and cause less burning and stinging which can be seen with gels. Additional studies should address the question of preferred vehicle for the topical corticosteroid. In this study, we have introduced the concept of the cold sore AUC. Lesion AUC has long been used to study treatments in animal models,16 but has not been applied to clinical trials. This is a composite statistic, the AUC of lesion size versus duration, which we feel more accurately captures the full morbidity of the outbreak than traditional endpoints that measure only a single aspect of the lesional experience. Cold sore AUC incorporates three clinically important features: (1) type of lesion classical vs.

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non-classical; (2) lesion size; and (3) lesion healing time. The overall effect is to quantify large ulcer days. Type of lesion is captured in cold sore AUC by assigning aborted lesions a lesion healing time of zero. The rationale for this is reviewed elsewhere.17 Briefly, aborted lesions can be given a lesion healing time of zero since they are not lesions in the classic sense of cold sores, and by definition have a zero duration of the painful, disfiguring, clinically important vesicle, ulcer and eschar stages. Furthermore, the statistic of time becomes more qualitatively consistent by this procedure, measuring similar troublesome lesion periods among patients rather than giving equal weight to time with ulcers and time with redness, for example. Lastly, AUC can reflect the benefit of an agent that may increase the rate of aborted lesions, reduce lesion size, reduce lesion duration, or all three, as in the present study. Measurement of these effects individually may each alone be statistically insignificant or show only modest benefit, whereas an analysis using a global term may be highly significant and the apparent clinical impact very noteworthy. As new treatments are developed which can impact lesions in multiple ways, new and improved study endpoints can be justified. The results from this small pilot study confirm and extend data from previous studies demonstrating the benefit of adding topical corticosteroids to the treatment of recurrent HSL.8,9 Additional, larger controlled-studies are warranted to further investigate the potential benefit of adding topical corticosteroids to an oral antiviral agent for recurrent HSL.

6 7

10

11 12 13

Acknowledgments
Funding for conduct of the study was provided by an educational grant from GlaxoSmithKline.
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References
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