R. Gary Sibbald, BSc, MD, M.Ed., FRCPC, ABIM DABD, FAPWCA

Faculty of Medicine and Faculty of Public Health, University of Toronto, Toronto, ON


Herpes simplex virus (HSV) is responsible for an infection around the lips (herpes labialis) that often occurs with a longer primary infection and then may result in shorter recurrences (cold sores, fever blisters).1 Herpes simplex infection is ubiquitous in the adult population with various studies documenting between 60-90% of tested individuals having previous infections.2 Currently available treatments include prescription and non-prescription drugs in topical and oral formulations, with antiviral medications representing a mainstay of treatment. They are reviewed below, as are data from a clinical trial of a new formulation of topical 5% acyclovir with 1% hydrocortisone cream (Xerese®).


  • Most herpes labialis lesions are caused by herpes simplex type 1 (HSV-1). Genital herpes simplex is predominantly herpes simplex type 2 virus (HSV-2).2
  • With an increase in oral sex, there are more cases (although still a minority) of herpes labialis associated with type 2 infections.2
  • Primary HSV infection in children or young adults may cause severe stomatitis and pharyngitis with an erosive, painful infection of the buccal mucosa and gums.2
  • Primary infections may be associated with pain on swallowing and lymphadenopathy.
  • In adults, the primary infection may be limited to a pharyngitis without involvement of the mouth (gingival- stomatitis).2
  • Some primary infections are completely asymptomatic.
  • Viral shedding and potential spread of infection is most common with an open lesion.
  • After the primary infection, the virus remains latent in the sensory nerve (Trigeminal) ganglion of the facial nerve for life.3 It may re-activate at a later date, in a non-primary episode, with a clinical course that is often less severe than a primary episode but more severe than a typical recurrence.4
  • Asymptomatic viral shedding can occur sporadically between acute episodes and result in spread of the infection.
  • Recurrent infections follow a shorter time period and have a number of identifiable stages, specifically:3
    1. Prodrome: tingling, itching, burning or local pain may occur for a few hours up to a couple of days prior to the development of local erythema.
    2. Day 1 of the eruption is often associated with virus replication at the end of the nerve and in the epithelial cells resulting in local erythema and swelling.
    3. Days 2-3 (or sooner) results in the appearance of tender papules and subsequent vesicles usually around the lips but the lesions may appear on the nose, chin or cheeks.
    4. Day 4 or sooner, a painful ulcer may develop from ruptured vesicles that may coalesce into a larger single ulcer with the characteristic herpetiform edges that have a semi-circular peripheral appearance similar to the outline of a cluster of grapes. The serous or serosanginous discharge is loaded with viral particles and represents the most contagious stage of the cold sore. Submental lymphadenopathy may be present but is less severe than signs associated with a primary infection. Secondary bacterial infection with staphylococcus or streptococcus may result in a pustular element to the discharging fluid.
    5. Days 5-8 is the crusting stage (serosanginous, occasionally pustular) which forms from the dried exudate.
    6. The healing stage can take from day 9 to day 14 but is variable. It may be shorter with aborted recurrent episodes or with early treatment at the prodrome or early lesion stage.


  • The diagnosis of herpes labialis is often recognized by the clinical appearance alone.
  • If a lesion is atypical, laboratory investigations can be ordered that will identify HSV-1, HSV-2, or return a negative result (more common from late lesion samples).5

Patient Impact

A recent survey of 231 patients (age >18 years) with recurrent herpes labialis (outbreaks at least once a year) revealed that cold sores had a severe negative influence on social life/self-image in 55.5% of survey respondents.6 Additional findings include:

  • The most troublesome aspects of the cold sores are the blister/ulcer and the subsequent crust formation.
  • The duration of the cold sores can be prolonged and more significant than acknowledged by many clinicians.
  • The majority of infected individuals (65.9%) preferred topical treatment, either over-the-counter or prescription treatment for cold sore recurrences.
  • 77.2% preferred a topical preparation for the first sign of an outbreak (46.2% prescription, 31% non-prescription) and 9.6% would prefer not to prevent or treat outbreaks. Oral prophylaxis was preferred by 19.8% with a topical agent for a breakthrough.

Treatment of Recurrent Herpes Simplex Labialis

Topical Prescription Drugs

  • A recent, multicenter, randomized, double-blind study identified the combination of 5% acyclovir with 1% hydrocortisone cream (Xerese®) as effective and well tolerated in the control of herpes simplex labialis recurrences in adults.2
  • Topical acyclovir (Zovirax®) is a nucleoside antiviral agent that targets the viral replication stage.2 The 1% hydrocortisone component is anti-inflammatory, designed to decrease the host response time post viral replication.2
  • The study compared a new base of 5% acyclovir with 1% hydrocortisone cream to 5% acyclovir base and the Xerese® vehicle base cream. The study included 1,443 treated subjects with 601 receiving combination 5% acyclovir / 1% hydrocortisone cream, 610 receiving topical acyclovir cream, and 232 placebo cream for a randomization ratio of 2.7/ 2.7 to 1.
  • The number of patients not progressing to the ulcerative stage compared to non-ulcerative recurrences was 42% for the acyclovir combined with 1% hydrocortisone (Fig. 1) compared to 35% for acyclovir cream alone (p=0.14) and 20% for Xerese® vehicle alone (p=0.001). This is the first study to demonstrate effectiveness of topical acyclovir cream compared to the vehicle alone.
  • The enhanced effect was likely due to the reformulation with the partial replacement of propylene glycol with isopropyl myristate that enhances stratum corneum penetration of the topical acyclovir.
  • The addition of the anti-inflammatory effect of topical 1% hydrocortisone further enhanced the effectiveness of the topical acyclovir in the new cream formulation.
  • The cumulative lesion area in the study was calculated from the area of the ulcerative lesions that were added from daily measurements. The combination of 5% acyclovir with 1% hydrocortisone had a cumulative lesion area that was 50% smaller than the placebo cream cumulative area (p<0.0001), and the 5% acyclovir area was 25% smaller than the placebo cream cumulative area.
  • Healing of lesions with the combination cream occurred in 3 vs. 4 days for acyclovir cream and 5 days for the placebo cream.
  • The average lesion tenderness duration with the combination cream was 5 days, similar to acyclovir cream but less than the 6 day average for placebo cream (p=0.019). Positive cultures for herpes simplex were no higher with the combination cream (22%) compared to acyclovir cream alone (24%) and less than the placebo cream (40%).
  • Overall adverse event rates were similar in all 3 groups.
  • The combination cream is applied 5 times per day for 5 days.
  • These results can be compared favourably to a previous study by Shaw et al, using an original vehicle formulation of topical acyclovir.7 This older formulation of topical acyclovir in the relatively small number of subjects failed to demonstrate benefit in 45 patients with 72 recurrences.
  • Spruance et al, combined the results of two randomized clinical trials (RCTs) comparing the original topical 5% acyclovir cream with placebo cream in 1,385 subjects, and found a reduced time to healing with the 5% acyclovir preparation, from 5 to 4.4 days.8

Clinical Management of Recurrent Herpes Labialis - image

Significantly reduced cold sore ulceration and duration of ulcerative lesions£,Δ

ΔHull CM, Brunion S. The Role of topical 5% Acyclovir and 1% hydrocortisone Cream (Xerese) in the Treatment of Recurrent Herpes Simplex Labilias: Postgraduate Medicine. Vol 122. June 5, Sept 2010. ISSN = 0032-5481.

£ Adapted from Spruance et al. High-Dose, Short Duration Early Valacyclovir Therapy for Episodic Treatment of Cold Sores: Results from Two Randomized, Placebocontrolled, multicenter studies.

Figure 1: Similar efficacy between Xerese® and Valtrex® in preventing ulcerative lesions

Topical Non-Prescription Formulations

  • Topical docosanol (Abreva®) is a saturated fatty alcohol proposed to be effective in preventing the HSV envelope from attaching to the host cell.
  • Sacks et al, published results of an RCT with 737 patients comparing the 10% docosanol cream to a placebo (polyethylene glycol) in the prodromal stage.9
  • Treatment with docosanol cream significantly (p=0.002) shortened the duration of pain, itching, tingling or burning and reduced the time to complete healing (p=0.002).9
  • Docosanol cream has a low risk of drug resistance.
  • Symptomatic relief may be obtained by preparations with local anesthetic effects including Blistex® with menthol, phenol and camphor and zilactin with benzoyl alcohol.10
  • Propolis extract from honey is the active component in ColdSore-FX® with in vitro anti-inflammatory and antimicrobial properties.10

Oral Prescription and Non-Prescription Drugs

  • Effective oral antiviral medications that can speed the healing of labial herpes simplex recurrences include acyclovir and penciclovir.
  • Spruance et al, conducted an RCT of 114 subjects with recurrent herpes labialis treated with oral acyclovir 400 mg 5 times a day for 5 days compared to 60 patients given a similar course of placebo treatment. The lesions treated with acyclovir were less painful and healed faster compared to placebo.11
  • Valacyclovir (Valtrex®) is the prodrug of acyclovir. It increases gastrointestinal absorption of the antiviral agent. Spruance et al, conducted a high-dose, short duration, early valacyclovir treatment RCT for recurrent episodes of labial cold sores vs. placebo. The dose of valacyclovir was either 2 grams twice daily for 1 day or with the addition of 1 gm twice daily on day 2.12 There were more aborted episodes with both of these treatment regimens compared with placebo, but the episode duration was reduced by a half to one day.
  • Famciclovir, (Famvir®) the prodrug of penciclovir, increases the gastrointestinal absorption of this antiviral agent. An RCT conducted with high dose famciclovir (750 mg twice daily or 1500 mg in a single dose) vs. placebo showed that recurrences healed in both active groups in 4 vs. 6 days with placebo. 13
  • The newer, high dose, short treatment duration studies have shown better therapeutic efficacy compared to the traditional treatment of lower doses over 5-7 days.
  • One non-prescription drug, oral lysine, is available in most health food stores. This medication has been popular with patients for the treatment or prevention of herpes labialis based on in vitro studies but the evidence supporting this treatment in humans is inconclusive.


  • A study by Rooney et al, utilizing an experimental system of ultraviolet light to induce reactivation of herpes labialis lesions did not produce any lesions in 35 patients using sunscreen but reactivated a herpes lesion in 27 of 38 patients (71%) utilizing the placebo sunscreen.14
  • Continuous prophylaxis is often considered for individuals with 6 or more herpes lesions per year. Twenty patients completed a randomized, 4-month crossover trial with oral acyclovir 400 mg twice daily or placebo.15 Placebo treatment was associated with 1.8 reactivation episodes per subject while the continuous prophylaxis had 0.85 reactivation episodes.15
  • Similar continuous prophylaxis has also been proposed for valacyclovir at a dose of 500 mg or 100 mg p/day or famciclovir 250 mg or 500 mg daily.12


Because oral antivirals have a narrow therapeutic window, they should be initiated at the prodromal stage. However, if the antiviral medication is taken after the prodromal stage, efficacy is decreased significantly. The oral medication has no effect on the inflammatory component of a cold sore. A way to optimize treatment is to offer patients two options, i.e. oral therapy and the topical treatment that contains acyclovir 5% and hydrocortisone 1% (Xerese®). The combination would address not only the viral replication but the inflammatory response. This strategy could potentially optimize patient outcomes.


  1. Lee C, et al. Cochrane Database of Systematic Reviews. Published Online: 5 OCT 2011. DOI: 10.1002/14651858.CD009375
  2. Hull CM, et al. ME-609 Study Group. J Am Acad Dermatol. 2011;(64):696.
  3. Bruce AJ, et al. Clin. Dermatol. 2004;(22):520–527.
  4. Opstelten W, et al. J Canadian Fam Physician. 2008;(54):1683–1687.
  5. Sterling JC. Herpes labialis. In:Lebwohl MG, Heymann WR, Berth-Jones J, Coulson I. Treatment of skin disease; comprehensive therapeutic strategies. 3rd ed. Saunders Elsevier. 2010;303-305.
  6. Sibbald RG. Evaluation of patient concerns and quality of life aspects of early cold sores treatment in 231 subjects. Poster presentation: Derm Update. 2013. Montreal, Canada.
  7. Shaw M, et al. Br Med J (Clin Res Ed). 1985;(291):7-9.
  8. Spruance SL, et al. Antimicrob Agents Chemother. 2002;(46):2238-2243.
  9. Sacks SL, et al. J Am Acad Dermatol. 2001;(45):222-230.
  10. Harmenberg J, et al. Acta Dermato Venereologica. 2010;(90):122–130.
  11. Spruance SL, et al. J Infect Dis. 1990;(161):185-190.
  12. Spruance SL, et al. Antimicrob Agents Chemother. 2003;(47):1072-1080.
  13. Spruance SL, et al. J Am Acad Dermatol. 2006;(1):47-53.
  14. Rooney JF, et al. Lancet.1991;(338):1419-1422.
  15. Rooney et al. Ann Intern Med. 1993;(118):268-272