Department of Dermatology, Northwestern University, Chicago, IL, USA
Recurrent herpes labialis (RHL) is a common condition associated with the formation of vesicles around the mouth, often preceded by prodromal symptoms including tingling and burning. Treatment is targeted toward individual episodes, but in severe cases, suppressive therapy may be indicated. At present, no cure exists for this troublesome condition. The purpose of this article is to serve as a practical guide in the management of RHL by summarizing current treatments and discussing potential new therapies.
recurrent herpes labialis
Recurrent herpes labialis (RHL) occurs in a subset of patients infected with the herpes simplex virus (HSV). HSV type 1 is most commonly associated with oral blisters, and its seroprevalence in the US is 57.7% in those aged 14-49.1 Most patients with RHL experience less than 2 episodes per year, but 5%-10% experience ≥6 occurrences per year.2 After the virus ascends the dorsal root ganglion during primary infection, it lies dormant until reactivated, often by triggers such as sunlight, stress, menses, or trauma to the area. This reactivation leads to what are commonly known as “cold sores” or “fever blisters.” In those with RHL, the pain, discomfort, and temporary disfigurement of these lesions can be reduced by using one of several therapies shown to hasten healing and decrease progression of disease. In episodic therapy, it is essential that patients recognize prodromal symptoms for immediate self-medication.Treatment for RHL can be episodic or suppressive, depending upon the frequency and severity of episodes. There are no specific recommendations regarding when to start suppressive therapy, however, consideration may be given when a patient has ≥6 episodes of RHL in 1 year. Therapy may lead to decreased potential for the rare complication of perioral scarring, although this phenomenon has not been described in the literature. Depigmentation after healing of lesional areas is extremely rare.3
Intermittent Episodic Therapy
When utilizing episodic therapy, patient-initiated administration of therapy at the first sign of prodromal symptoms is key to reducing healing time and lesion pain. Prodromal symptoms include burning, tingling, and itching.
Topical Antiviral Agents
Acyclovir 5% Cream or Ointment
An FDA-approved antiviral treatment for RHL, acyclovir cream has been shown to reduce lesion healing time by 0.5-0.6 days and the duration of pain by 0.3-0.4 days.4 An ointment-based formulation is approved for use in immunocompromised patients.
Docosanol 10% Cream
N-docosanol, a 22-carbon alcohol that has been FDA-approved for over the counter (OTC) use against RHL, has shown efficacy in reducing healing time based on 1 study.
This report described 2 identical randomized placebo-controlled multicenter studies that looked at docosanol 10%, applied 5 times daily until resolution of lesions, vs. polyethylene glycol placebo. Treatment was initiated in the prodrome or erythema stage of an episode. The authors noted an 18 hour decrease in healing time of lesions in the treatment vs. the control group (p=0.008).5
Penciclovir 1% Cream
Penciclovir is an FDA-approved topical antiviral used to treat RHL. It has been shown to decrease healing time and duration of pain when compared with placebo. Two placebo-controlled, randomized trials demonstrated a reduction in median healing time by 0.7 days and by 2 days, respectively, when compared with placebo controls.6,7 When compared with topical acyclovir in a randomized controlled trial with 124 subjects in each treatment group, topical penciclovir showed no significant difference in the clinical cure rate, side-effects, or time to resolution.8
Oral Systemic Antiviral Agents
Several studies have demonstrated the efficacy of oral
acyclovir for the treatment of RHL. Dosages between 200mg-
400mg 5 times daily decreased healing time by 1 to 1.5 days
when compared with placebo.9,10 Although this regimen is
not US FDA-approved for RHL, it is widely used off-label
in clinical practice.
Valacyclovir, the prodrug of acyclovir, is FDA-approved for use in RHL; it shows 3 to 5 times the bioavailability of acyclovir. In 2 large identical randomized controlled trials, Spruance et al. studied 2 groups taking high-dose, short course valacyclovir: The first group self-initiated treatment with 2000mg 2 times daily for 1 day while the second group took 2000mg 2 times daily the first day in addition to 1000mg 2 times daily for a second day. In both studies, each group saw improved healing time compared with the placebo group (0.5 to 1 day reduction) and decreased duration of pain when compared with the placebo group (0.5 to 0.7 day reduction). There was no difference in duration of episode when treating for 1 day vs. 2 days.11 In contrast, a smaller non-randomized double-blind study of 3 treatment groups – taking either a single dose of 500mg, 1000mg, or 2000mg within 2 hours of initiation of the prodromal period – showed no statistically significant difference in aborting lesion formation when comparing the different doses.12
The oral prodrug of penciclovir, famciclovir is FDA-approved for RHL in immunocompetent patients; it demonstrates efficacy in addition to a more convenient dosing regimen. Famciclovir also has an FDA-approved indication for use in episodic therapy of RHL in immunosuppressed patients. In 1 double-blind study of 102 subjects with a history of suninduced herpes labialis, subjects were administered 1 of 4 treatments within 48 hours of ultraviolet (UV) exposure of the lips: 125mg, 250mg, or 500mg of famciclovir, or placebo 3 times daily for 5 days. There was a statistically significant dose-proportionate decrease in lesion size, as well as a reduction in healing time as assessed by the patient (decreased by 2 days, p=0.01) and investigator (decreased by 2.8 days, p=0.008).13 In a larger randomized controlled trial, subjects were assigned to 1 of 3 groups: famciclovir single dose 150mg, famciclovir 750mg twice a day for 1 day, or placebo. Patients were instructed to initiate treatment within 1 hour of prodromal symptom onset. The study found a median healing time of primary vesicular lesions to be decreased by about 2 days in both treatment groups when compared with placebo. There was no statistically significant difference in healing time between the 2 treatment groups. In addition, the time to resolution of pain was decreased in the single-dose group compared with placebo group (median decrease of 1.2 days, p=0.046).14
Although oral antivirals for the treatment of RHL have not been directly compared with each other in any study, some patients may find single-dose therapy to be more convenient while providing similar efficacy to other oral antivirals.15
An area of developing study is the combination of a topical or systemic antiviral agent with a topical steroid.
Acyclovir 5% + Hydrocortisone 1% Cream
In August 2009, the FDA approved a new antiviral/steroidal combination therapy of acyclovir 5% and hydrocortisone 1% for the treatment of RHL. Regulatory approval was based on a randomized controlled trial in 2002 in which 380 immunocompetent adults with a history of herpes labialis were exposed to experimental UV radiation to induce outbreaks. On day 2, prior to the appearance of the majority of lesions, subjects were randomized at a 1:1 ratio to receive active medication or vehicle control 6 times per day for 5 days. Overall, 120 of 380 subjects developed delayed classical lesions. Of these 120 subjects with lesions, 50 (26% of the treatment group) received the treatment cream and 70 (37% of the placebo group) had received the placebo vehicle. Observed differences in healing time were statistically significant: 9 days for those on the treatment regimen and 10.1 days for control subjects (p=0.04). There
was no statistically significant effect on pain.16
Other Experimental Combination Therapies
Oral valacyclovir used with topical clobetasol gel may be an additional potential combination therapy. A recent pilot study randomized patients to a combination of valacyclovir 2000mg orally twice daily for 1 day and clobetasol gel 0.05% twice daily for 3 days or matching oral and topical placebo. Although the study was small, those treated with combination valacyclovir and clobetasol gel saw a mean healing time of 5.8 days compared with 9.3 days in placebo (p = 0.002). The efficacy of clobetasol gel alone was not studied.17
Systemic famciclovir has been studied in combination with topical fluocinonide gel for use at the onset of prodromal symptoms. Twenty-nine patients were randomized to this combination therapy vs. treatment with famciclovir and topical vehicle control. Famciclovir dosing for both groups was 500mg orally 3 times daily for 5 days after onset of prodromal symptoms. Topical therapy with either fluocinonide or vehicle control was simultaneously initiated 3 times daily for 5 days in the treatment and control groups, respectively. The combination treatment group showed a 70% reduction in lesion size, but measures of ulcer progression and healing time were not statistically significant.18
Lysine is an OTC herpes remedy commonly used by RHL sufferers. One study suggests that topical administration of a mixture of L-lysine, zinc, and herbals may reduce the symptoms of an outbreak.19 Daily lysine intake (300mg) in 1 small randomized placebo-controlled study was shown to reduce the overall number of recurrences in the treatment group by 2.4 (p‹0.05).20
Other agents may provide symptomatic relief. These include ice, emollients, topical anesthetics, and OTC occlusive preparations. Such treatment measures have not been shown to reduce the number of lesions in a given episode of RHL or to accelerate the healing of established RHL lesions.
Suppressive Antiviral Therapy
For immunocompetent patients with frequent RHL, daily suppressive therapy may be indicated. Currently, valacyclovir is the only drug approved by the FDA for this indication in immunocompetent patients. Two identical randomized double-blind parallel group studies evaluated the efficacy of oral valacyclovir 500mg daily compared with placebo for the suppression of herpes labialis in subjects with a history of 4 or more recurrences in the previous year. Suppressive treatment was administered daily for 16 weeks. Sixty percent of the subjects in the valacyclovir treatment group remained recurrence free throughout the 4 months compared to 38% of the placebo group.21 In a study by Gilbert, daily suppressive valacyclovir (1000mg daily) therapy was compared with episodic valacyclovir (2 doses of 2000mg administered 12 hours apart) therapy for RHL. The investigators of this study found fewer recurrences and longer median time to recurrence in those subjects on suppressive valacyclovir.22 For immunosuppressed patients, the FDA has approved famciclovir for use as a daily suppressive therapy. Although not FDA-approved, daily suppressive therapy with valacyclovir 500mg once daily may be utilized in clinical practice in select immunosuppressed patients.23
There are numerous treatments for RHL that provide modest improvement to the severity of disease. Suppressive therapy may actually reduce the number of occurrences for those with severe RHL. For those with less frequent occurrences, intermittent episodic therapy is indicated. All of the aforementioned oral antiviral agents have demonstrated the ability to reduce healing time and to decrease the pain of RHL lesions. Valacyclovir and famciclovir offer convenient dosing regimens (1 or 2 doses), which may translate into greater patient adherence to therapy.
- Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA 296(8):964-73 (2006 Aug).
- Rooney JF, Straus SE, Mannix ML, et al. Oral acyclovir to suppress frequently recurrent herpes labialis. A double-blind, placebocontrolled trial. Ann Intern Med 118(4):268-72 (1993 Feb).
- Bose SK. Herpes simplex virus in association with lip leucoderma. J Dermatol 34(4):280-1 (2007Apr).
- Spruance SL, Nett R, Marbury T, et al. Acyclovir cream for treatment of herpes simplex labialis: results of two randomized, double-blind, vehicle-controlled, multicenter clinical trials. Antimicrob Agents Chemother 46(7):2238-43 (2002 Jul).
- Sacks SL, Thisted RA, Jones TM, et al. Clinical efficacy of topical docosanol 10% cream for herpes simplex labialis: A multicenter, randomized, placebo-controlled trial. J Am Acad Dermatol 45(2):222-30 (2001 Aug).
- Spruance SL, Rea TL, Thoming C, et al. Penciclovir cream for the treatment of herpes simplex labialis. A randomized, multicenter, double-blind, placebo-controlled trial. Topical Penciclovir Collaborative Study Group. JAMA 277(17):1374-9 (1997 May).
- Boon R, Goodman JJ, Martinez J, et al. Penciclovir cream for the treatment of sunlight-induced herpes simplex labialis: a randomized, double-blind, placebo-controlled trial. Penciclovir Cream Herpes Labialis Study Group. Clin Ther 22(1):76-90 (2000 Sep).
- Lin L, Chen XS, Cui PG, et al. Topical Penciclovir Clinical Study Group. Topical application of penciclovir cream for the treatment of herpes simplex facialis/labialis: a randomized, doubleblind, multicentre, aciclovir-controlled trial. J Dermatolog Treat 13(2):67-72 (2002 Jun).
- Raborn GW, McGaw WT, Grace M, et al. Oral acyclovir and herpes labialis: a randomized, double-blind, placebo-controlled study. J Am Dent Assoc 115(1):38-42 (1987 Jul).
- Spruance SL, Stewart JC, Rowe NH, et al. Treatment of recurrent herpes simplex labialis with oral acyclovir. J Infect Dis 161(2):185-90 (1990 Feb).
- Spruance SL, Jones TM, Blatter MM, et al. High-dose, shortduration, early valacyclovir therapy for episodic treatment of cold sores: results of two randomized, placebo-controlled, multicenter studies. Antimicrob Agents Chemother 47(3):1072-80 (2003 Mar).
- Chosidow O, Drouault Y, Garraffo R, et al. Valaciclovir as a single dose during prodrome of herpes facialis: a pilot randomized doubleblind clinical trial. Br J Dermatol 148(1):142-6 (2003 Jan).
- Spruance SL, Rowe NH, Raborn GW, et al. Peroral famciclovir in the treatment of experimental ultraviolet radiation-induced herpes simplex labialis: A double-blind, dose-ranging, placebo-controlled, multicenter trial. J Infect Dis 179(2):303-10 (1999 Feb).
- Spruance SL, Bodsworth N, Resnick H, et al. Single-dose, patientinitiated famciclovir: a randomized, double-blind, placebo-controlled trial for episodic treatment of herpes labialis. J Am Acad Dermatol 55(1):47-53 (2006 Jul).
- Hull C, Spruance S, Tyring S, et al. Single-dose famciclovir for the treatment of herpes labialis. Curr Med Res Opin 22(9):1699-702 (2006 Sep).
- Evans TG, Bernstein DI, Raborn GW, et al. Double-blind, randomized, placebo-controlled study of topical 5% acyclovir-1% hydrocortisone cream (ME-609) for treatment of UV radiation-induced herpes labialis. Antimicrob Agents Chemother 46(6):1870-4 (2002 Jun).
- Hull C, McKeough M, Sebastian K, et al. Valacyclovir and topical clobetasol gel for the episodic treatment of herpes labialis: a patientinitiated, double-blind, placebo-controlled pilot trial. J Eur Acad Dermatol Venereol 23(3):263-7 (2009 Mar).
- Singh BB, Udani J, Vinjamury SP, et al. Safety and effectiveness of an L-lysine, zinc, and herbal-based product on the treatment of facial and circumoral herpes. Altern Med Rev 10(2):123-7 (2005 Jun).
- Griffith RS, Walsh DE, Myrmel KH, et al. Success of L-lysine therapy in frequently recurrent herpes simplex infection. Treatment and prophylaxis. Dermatologica 175(4):183-90 (1987).
- Baker D, Eisen D. Valacyclovir for prevention of recurrent herpes labialis: 2 double-blind, placebo-controlled studies. Cutis 71(3):239-42 (2003 Mar).
- Gilbert SC. Suppressive therapy versus episodic therapy with oral valacyclovir for recurrent herpes labialis: efficacy and tolerability in an open-label, crossover study. J Drugs Dermatol 6(4):400-5 (2007 Apr).
- Centers for Disease Control and Prevention; Infectious Disease Society of America; American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep 49(RR-10):1-125, CE1-7 (2000 Oct).