In a double-blind, randomized, patient-initiated clinical trial, 174 nonimmunocompromised patients with a history of virus-culture-confirmed herpes simplex labialis were treated with acyclovir capsules, 400 mg five times daily for 5 days, or placebo capsules. For 97% of the patients, treatment started within 1 h of the first sign or symptom of a recurrence. The frequency of positive lesion virus cultures was significantly lower among acyclovir-treated subjects (29/114, 25%) than among placebo-treated subjects (29/60, 48%; P = .004). Drug treatment did not affect the development of lesions, measured by the frequency of macular and papular (aborted) lesions and mean maximum lesion size. However, acyclovir hastened lesion resolution among the patients who could start treatment in the prodrome or erythema lesion stage. For this group, the mean duration of pain was reduced by 36% (P = .02) and the mean healing time to loss of crust by 27% (P = .03). Thus, oral acyclovir alleviated some of the clinical manifestations of herpes simplex labialis.

The lips of 196 patients with a history of sun-induced herpes labialis were exposed to experimental ultraviolet radiation (UVR) and treated with acyclovir (ACV) or placebo at different times and by different routes. Of 98 placebo recipients, 39 (40%) developed 43 lesions inside or within 10 mm of the irradiated zone. The temporal distribution of lesions was bimodal. 11 (26%) occurring within 48 h (immediate) and 32 (72%) 2-7 days after UVR exposure (delayed). Prophylactic peroral ACV begun 7 days before or 5 min after UVR prevented the development of the delayed but not the immediate lesions (P less than .001). When peroral ACV was started 48 h after UVR, delayed lesions developed but were less severe (P = .01-.05). Prophylactic topical ACV begun 5 min after UVR did not reduce lesion frequency or severity. ACV therapy can be efficacious, but some rapidly developing lesions are unresponsive to treatment. This suggests that more than one process may contribute to the pathogenesis of herpes labialis.

Inadequate penetration of antiviral agents through the stratum corneum of the skin may be one of the limiting factors in the topical therapy of recurrent cutaneous herpes simplex virus infections in humans. In vitro studies of the penetration of the nucleoside analog acyclovir (ACV) through guinea pig skin demonstrated a marked increase in drug flux when ACV was formulated in dimethyl sulfoxide (DMSO), compared with water or polyethylene glycol (PEG) as the vehicle. To examine whether the increased transcutaneous flux of ACV effected by DMSO was meaningful in vivo, topical 5% ACV in DMSO was evaluated for the treatment of cutaneous herpes simplex virus infection in guinea pigs and compared with topical 5% ACV in PEG. When compared with infection sites treated with the vehicle alone, ACV in DMSO produced a greater percent reduction than did ACV in PEG in median lesion number (8 versus 58%; P < 0.001), median lesion area (35 versus 73%; P = 0.001), and median lesion virus titer (21 versus 84%; P = 0.08). We conclude that DMSO is a highly effective vehicle for topical administration of ACV and is superior to PEG in our model. Careful choice of vehicle and consideration of transcutaneous penetration may be important for realization of the full potential of topical antiviral therapy in humans.Development of an effective topical therapy for recurrent mucocutaneous herpes simplex virus (HSV) infections in immunologically normal humans has been difficult (16). Acyclovir (ACV) is a new anti-herpesvirus compound which is 10-to 150-fold more potent in vitro than older drugs such as vidarabine or iodoxuridine (IDU). In addition, ACV is phosphorylated selectively to an active form in virus-infected cells and is nontoxic to uninfected mammalian cells over a wide range of concentrations (22). The value of ACV applied intravenously, orally, and topically in the treatment of severe HSV infections in immunosuppressed hosts and in primary genital HSV infections has been documented (5,7,15,25,27). However, the results of treatment of recurrent mucocutaneous HSV infections in normal subjects with topical 5% ACV in polyethylene glycol (PEG; Zovirax) were disappointing. Topical treatment of recurrent herpes simplex labialis and recurrent herpes genitalis effected a reduction in the excretion of virus from the lesions, but there was no change in the clinical course of infection (7, 24).Assessment of the reasons for the clinical failure of topical ACV therapy in the treatment of recurrent herpes labialis and genitalis has led to the conclusion that either ACV was applied too late to affect the natural course of recurrent HSV disease or that it did not penetrate the stratum corneum and reach infected cells in the lower layers of the epidermis in adequate concentrations (24). To evaluate the latter possibility, we studied the flux of ACV through guinea pig skin in vitro from different drug vehicles and have compared these findings with the in vivo efficacy of two drug vehicle combinations in the topical treatment of an experimental HSV in...