The potential for therapeutic intervention is limited owing to the pathogenesis and rapid evolution of the disease. The mean duration of classical lesions in placebo-controlled clinical trials is seven to eight days, but individual recurrences are highly variable, and untreated episodes may persist longer.^1–3 In large, well-controlled studies of other antiviral drugs used in the treatment of HSL, multiple therapeutic benefits with a topical agent in immunocompetent patients have not been consistently and unequivocally demonstrated.^4,5

Penciclovir is a unique nucleoside analogue that has a potency, selectivity and antiviral spectrum of activity similar to that of acyclovir.⁶ Penciclovir has demonstrated good activity in cell culture against herpes simplex virus, or HSV, types 1 and 2. In HSV-infected cells, penciclovir is selectively phosphorylated to penciclovir monophosphate by the viral thymidine kinase and then converted into active triphosphate by cellular enzymes.⁷ In contrast to acyclovir, penciclovir-triphosphate has a prolonged half-life in HSV-infected cells (at least 10 to 20 times longer) and persists in the absence of extracellular compound, suggesting potential pharmacological advantages for penciclovir.

This article describes analysis of data from two multicenter investigations of the efficacy and safety of penciclovir 1 percent cream for the topical treatment of recurrent HSL in otherwise healthy patients. The results of the individual trials were remarkably similar, indicating multiple therapeutic benefits with penciclovir cream and have been published previously.^8,9 We combined the clinical data from these two trials to better comprehend the relative effects of early and late treatment as defined by lesion stage, as well as the importance of compliance with the study medication. This created the largest data set currently available in HSL trials with any antiviral drug.

The study medication was either 1 percent penciclovir in a cetomacrogol cream base that contained 40 percent propylene glycol or a matching placebo.

	METHODS

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Both trials were performed in accordance with the Declaration of Helsinki. Ethical committee or institutional review board approval was granted by appropriate local authorities in the participating centers before patients were recruited and before they gave written informed consent to participate.

Patients. There were 2,364 patients enrolled in the first trial from 43 centers in Europe, Canada and Singapore. Another 2,209 patients from 31 centers in the United States were enrolled in the second trial. The trials included men and women 18 years of age or older who were in good general health. Eligible patients had histories of clinically diagnosed HSL that recurred at least three times a year; more than 50 percent of the cases were preceded by prodromal symptoms and resulted in classical lesions. Those patients who frequently (more than 25 percent of the time) experienced "false" prodromes or lesions that failed to develop beyond the papule stage (also known as "aborted lesions") were excluded. Women with childbearing potential agreed to use adequate contraception during the study and were excluded if they were found to be pregnant. Use of antiviral therapy during the 30-day period before use of the study medication was prohibited, as was the use of systemic corticosteroids. Topical application of any other product to the lesion area was not permitted.

Study medication. The study medication was either 1 percent penciclovir in a cetomacrogol cream base that contained 40 percent propylene glycol or a matching placebo—a vehicle control cream with the same ingredients as the test medication, except for the penciclovir.

At enrollment, patients were randomly assigned to double-blind treatment and instructed to apply study medication to the affected area within one hour of noticing the first sign or symptom of a recurrence of HSL. They were required to apply the cream at least six times during the first day and to continue applying cream every two hours while awake for a total of four consecutive days.

Blinding and assignment. The double-blind study medications were packaged in identical appearing 10-gram tubes. Patients were assigned sequentially to study medication that was numbered according to a computer-generated randomized code allocated to each investigator in blocks of either four or eight. The assigned study medication was dispensed prospectively at enrollment to enable self-initiation of therapy. The treatment blind was kept intact and was not broken for any patient during the trials.

Study design and procedures. Both trials were prospective, randomized, double-blind, placebo-controlled, parallel group (two-arm) studies. After being recruited and receiving randomized study medication, patients were asked to report to the clinic within 24 hours of initiating treatment and to return daily until all crusts from the lesions were gone. Thereafter, patients were to visit the clinic every other day until their skin had healed completely.

An investigator recorded lesion stages, development of new lesions and lesion area at each visit. Lesions were swabbed daily during the vesicle and ulcer stages for virus isolation. The presence or absence of HSV was determined by viral culture. In addition, patients completed a diary card four times a day to self-assess lesion stage and pain level. Adverse events were elicited from the patients at each clinic visit.

Data were collected for one treated recurrence per patient. Patients who had not returned to the clinic for assessment were followed up by telephone at monthly intervals. Patients who reported having had a recurrence since enrollment but who had not initiated study medication during that episode were permitted to remain in the study.

Evaluation of efficacy. Clinical measures of efficacy included healing of classical lesions (vesicles, ulcers and hard crusts), resolution of lesion pain and duration of viral shedding. Healing of a classical lesion was the primary efficacy variable. Treatment effects on healing were evaluated in two ways: time to loss of a classical lesion and the percentage of patients who had lost a classical lesion by days 6 and 8. We analyzed loss of lesion pain and cessation of viral shedding as time-to-event variables.

Statistical analysis. We conducted an analysis of the combined patient population from the two penciclovir clinical trials. The efficacy analysis was based on the intent-to-treat population, which comprised all patients who had applied at least one dose of study medication. Time-to-event variables were measured from the initiation of the study medication until the resolution of the condition. Differences between treatments were analyzed with the Cox proportional hazards regression model.¹⁰ We expressed the rate at which patients who were treated with penciclovir lost the condition compared with those treated with the placebo by hazard ratio, or HR, and 95 percent confidence interval, or CI. Differences between treatments in the percentage of patients who lost classical lesions by days 6 and 8 of the study were analyzed using the Cochran-Mantel-Haenszel procedure and expressed them as an odds ratio, or OR, and 95 percent CI. All statistical analyses stratified treatment effects by center. For HR and OR, a value greater than one indicated a treatment effect in favor of penciclovir cream.

Ninety-seven percent of patients had a history of herpes simplex labialis that usually was preceded by prodrome and developed mostly as classical lesions.

We analyzed lesion healing using both investigator assessments and patient assessments for the overall population to corroborate these data. Positive correlation was demonstrated between these data sets (Spearman rank correlation coefficient of 0.74 to 0.90). In these studies in which patients initiated treatment, we categorized the patients into subgroups according to their self-assessments of the lesion stage at initiation of therapy, as the first investigator assessment may have taken place up to 24 hours after initiation of therapy. Frequency of patient assessment (four times daily) also offered greater precision for time to healing analyses than did the schedule of the investigator’s assessment (once daily).

	RESULTS

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Demographics of the study population. A total of 4,573 patients were enrolled in the trials and randomized to blinded study medication. Of these, 3,057 (1,516 patients treated with penciclovir and 1,541 patients treated with the placebo) applied study medication for a recurrent episode of HSL. Of these patients, 83 percent (2,537: 1,254 patients treated with penciclovir and 1,283 patients treated with the placebo) developed classical lesions.

For the intent-to-treat population, we found that key demographic and clinical history variables were comparable between the treatment groups (Table 1). The average age of patients who initiated therapy was 39 years, and the population was predominantly female (74 percent) and Caucasian (97 percent). Ninety-seven percent of patients had a history of HSL that usually was preceded by prodrome and developed mostly as classical lesions. On average, patients had experienced the disease for a little more than 20 years and had a frequency of recurrence of six episodes per year (Table 1).

Penciclovir cream is effective at speeding healing and pain relief by approximately one day.

Safety. We found that the frequency and profiles of all adverse events reported by the patients during the study were comparable between the penciclovir and placebo groups. Similarly, the incidence of adverse events related to the application of the study medication (including any that were possibly related or unknown) as attributed by the investigator was comparable between the penciclovir group (3.3 percent of patients) and the placebo group (5.3 percent of patients). The most common related adverse event was application site reaction (localized irritation, paresthesia, hypesthesia), which was reported by 2.1 percent of patients who were treated with penciclovir compared with 2.9 percent of patients who were treated with the placebo.

	DISCUSSION

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Based on this large data set, we found convincing evidence that treatment with penciclovir of recurrent HSL in immunocompetent patients is effective for a range of clinically important outcomes, even after the lesion has developed beyond the early stages.

Analysis of the combined results of these two studies provides compelling evidence that penciclovir cream is effective at speeding healing and pain relief by approximately one day. Significant clinical and virologic benefits were obtained when penciclovir cream was used even when treatment was initiated as late as the vesicle stage. Patients who applied the study medication as instructed derived a significantly greater benefit from penciclovir cream than did less compliant patients. The positive outcome from this combined data set is corroborated by findings in the individual trials, reported previously.^8,9 Penciclovir cream has been licensed for the treatment of HSL in major international markets and was the first topical agent licensed as such in the United States.

We observed no treatment difference in the percentage of patients whose lesions were aborted during the study. This finding is consistent with the current theory that reinfection of the epidermis occurs by a process of multifocal inoculation from a single neuron. This process is unlikely to be altered by administration of nucleoside antiviral agents. Histopathologic evidence supports this view.¹⁰ As a consequence, only two or three cycles of virus replication would lead to coalescence of the foci and clinical lesion formation.¹¹

No agent has consistently and convincingly prevented HSL lesions when based on the results of clinical trials.¹² The case for penciclovir, however, continues to build. In a small trial, penciclovir cream was reported to be effective in the treatment of recurrent HSL, while acyclovir cream was reported to be ineffective.¹³ Another trial reported success in treating sunlight-induced HSL with penciclovir cream.¹⁴

Significant clinical benefits of treatment during the papule and vesicle stages have not been reported previously with any other antiviral therapy. Early initiation of antiviral therapy that is started within a few hours after the first signs or symptoms of a recurrence generally has been considered crucial in treatment of HSL. The results of studies with penciclovir cream have shown that it is possible to reduce viral replication and hasten lesion resolution with treatment beyond the early prodromal and erythema stages. What the precise mechanism is needs to be investigated further.

Another important finding in the present study was the significant difference in drug efficacy between patients who were compliant and those who were noncompliant with the dosing regimen. In the design of the protocol, it was decided to treat patients at frequent intervals (every two waking hours) because of the concern that medication applied to lesions on or near the lips might be consciously or unconsciously removed with the hands or tongue. Whereas this has been documented for sunscreen products, our findings are the first to suggest that formulation "substantivity" and topical product duration may be important issues for the treatment of HSL.

	CONCLUSIONS

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Combining these two data sets created the largest data set currently available for any antiviral drug in the treatment of HSL. Penciclovir cream was the first topical antiviral treatment to significantly affect the course of recurrent HSL and has been licensed in the United States for that indication. Regardless of time of application, early or late in the development of lesions, topical penciclovir was effective in favorably altering the course of recurrent HSL.