Acyclovir Cream for Treatment of Herpes Simplex Labialis: Results of Two Randomized, Double-Blind, Vehicle-Controlled, Multicenter Clinical Trials

Abstract

Acyclovir cream has been available for the treatment of herpes labialis in numerous countries outside the United States for over a decade. Evidence for its efficacy comes from a few small clinical trials conducted in the 1980s. To examine more comprehensively the efficacy and safety of this formulation, we conducted two independent, identical, parallel, randomized, double-blind, vehicle-controlled, large-scale multicenter clinical trials. Healthy adults with a history of frequent herpes labialis were recruited from the general population, screened for eligibility, randomized equally to 5% acyclovir cream or vehicle control, given study medication, and told to self-initiate treatment five times daily for 4 days beginning within 1 h of the onset of a recurrent episode. The number of patients who treated a lesion was 686 in study 1 and 699 in study 2. In study 1, the mean duration of episodes was 4.3 days for patients treated with acyclovir cream and 4.8 days for those treated with the vehicle control (hazards ratio [HR] ‫؍‬ 1.23; 95% confidence interval [CI], 1.06 to 1.44; P ‫؍‬ 0.007). In study 2, the mean duration of episodes was 4.6 days for patients treated with acyclovir cream and 5.2 days for those treated with the vehicle control (HR ‫؍‬ 1.24; 95% CI, 1.06 to 1.44; P ‫؍‬ 0.006). Efficacy was apparent whether therapy was initiated "early" (prodrome or erythema lesion stage) or "late" (papule or vesicle stage). There was a statistically significant reduction in the duration of lesion pain in both studies. Acyclovir cream did not prevent the development of classical lesions (progression to vesicles, ulcers, and/or crusts). Adverse events were mild and infrequent.Acyclovir (ACV) has been found to be efficacious in the management of herpes labialis in a variety of formulations and routes of administration. ACV (5%) ointment (Zovirax ointment) accelerated healing of herpes labialis in immunocompromised patients (22). Peroral administration of 400 mg of ACV five times/day for 5 days significantly reduced virus shedding and reduced lesion healing time and the duration of lesion pain among the subgroup of patients who started treatment "early" (in the prodrome or erythema lesion stage) (19). Peroral ACV administered as prophylaxis at 400 mg two times/day significantly reduces the frequency of recurrent episodes and prevents herpes-associated erythema multiforme (4,8,11).Demonstration of the clinical efficacy of topical formulations of antiviral drugs among immunocompetent patients has been difficult because of the marked variance in lesion severity that occurs, necessitating large numbers of subjects; the rapid natural healing of lesions; and the difficulty in finding a topical drug formulation that facilitates skin penetration without causing undue skin irritation (15,16,20). Several studies with ACV ointment in immunocompetent subjects provided sparse evidence of efficacy in this population (1,6,13,17). ACV was shown to penetrate human skin more effectively in a cream than in an ointment formulation (3). According...

High-Dose, Short-Duration, Early Valacyclovir Therapy for Episodic Treatment of Cold Sores: Results of Two Randomized, Placebo-Controlled, Multicenter Studies

“…It is presumed, but not proven, that a strong antiviral effect hastens wound resolution by decreasing the extent of keratinocyte destruction, the viral antigen load, and the attendant inflammatory response, which impair reepithelization at the site of infection (1,9,11,22). One-day, two-dose oral valacyclovir constitutes a convenient treatment for herpes labialis in comparison to topical therapies, which typically require frequent applications for multiple days (13,15,19,20,23). While direct comparisons between oral and topical therapy have not been conducted, the available data suggest that oral therapy is more effective.…”

“…The clinical studies leading to approval demonstrated that the cream was efficacious in shortening the median healing time of classical cold sore episodes by 0.7 to 1.0 days (13 to 17%) compared to the vehicle controls (13,20). Acyclovir 5% cream (Zovirax cream) is also indicated for cold sores and has been shown in two large, well-controlled clinical trials to shorten the duration of classical cold sore episodes by a similar magnitude to that of penciclovir 1% cream (19). The clinical results reported in the two valacyclovir studies indicate a difference between valacyclovir and placebo-treated patients in mean classical lesion healing time of 1.1 to 1.3 days (18 to 21%) ( Table 5).…”

“…For subjects whose duration of episode was unknown, a duration of 15.0 days was assigned. This imputation was based on the results from a previous acyclovir study (19). An estimate and confidence interval of the difference between medians was calculated by using the percentile bootstrap method (4).…”

“…The infection is most often acquired in childhood, but the incidence increases with age (2, 5, 12, 18). Up to 90% of persons over the age of 50, depending on race, sex, and country, would test seropositive for HSV-1, and an estimated 20 to 40% of adults experience cold sore outbreaks (5,12,18,25).Until now, most treatments have consisted of creams that must be applied to affected areas multiple times a day for several days (6,13,15,19,20,23). There have been two previous clinical trials of oral antiviral therapy for episodic treatment of herpes labialis.…”

“…Until now, most treatments have consisted of creams that must be applied to affected areas multiple times a day for several days (6,13,15,19,20,23). There have been two previous clinical trials of oral antiviral therapy for episodic treatment of herpes labialis.…”