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Reducing the Recurrence of Herpes Labialis

Reducing the Recurrence of Herpes Labialis

The herpes simplex virus-1 (HSV-1) remains a highly prevalent disease. More than 88% of the population is HSV-1 seropositive by the age of 40.1 HSV-1 is spread primarily through direct contact with contaminated saliva or other infected secretions (Figure). Transmission of the disease can occur during both asymptomatic and symptomatic periods of viral shedding. The primary disease is characterized by gingivostomatitis, sometimes with associated pharyngitis. After inoculation, the virus enters the trigeminal nerve and remains latent in the trigeminal ganglion for the rest of the individual’s life.     

The virus may remain in the latent phase indefinitely, though 20% to 40% of those with latent HSV-1 infection will experience reactivation of the virus as recurrent herpes labialis (RHL) during periods of fever, trauma, sunlight, menstruation or emotional stress.2 Dental extractions can also trigger recurrences. During reactivation, HSV-1 replicates in the basal layer of the mucosa before the onset of mucocutaneous manifestations. Maximal replication occurs within the first to sixth hour following onset of prodromal symptoms, such as burning, stinging, itching, pain and pruritus. Reactivation may lead to cutaneous, and more commonly, mucocutaneous disease, which occurs along the vermillion border of the lip. 

The onset of disease is usually sudden, with characteristic vesicular lesions superimposed on an inflammatory erythematous base. The lesions are painful and often cause psychological stress to the individual. Recurrences typically occur at the site of primary infection or adjacent areas.3 The frequency and severity of recurrence is dependent on many factors, such as the immunocompetency and stress of the host.4 Patients may have specific triggers and lesions tend to recur at the same site. Recurrences may occur as frequently as once a month or infrequently as once or twice a year.

Current Gold Standard Treatments

The treatment of RHL remains a challenge in the 21st century. The currently available antiviral drugs have not been successful in eliminating the virus, and they are only moderately effective in preventing its recurrence. A 2012 systematic review and meta-analysis conducted by Rahimi et al found that systemic antiviral therapy had only modest results in preventing RHL with only about half of the studies showing a significant difference compared with placebo.5 

Most topical agents are based on acyclovir or related compounds as the active ingredient. FDA approved drugs including penciclovir cream (Denavir, Prestium Pharma Inc.), acyclovir and hydrocortisone cream (Xerese, Valeant Pharmaceuticals North America Inc.) and acyclovir (Zovirax, Valeant Pharmaceuticals North America Inc.) are the currently used therapies. Docosanol cream (Abreva, GlaxoSmithKline) is the only FDA-approved non-prescription ointment for RHL. Randomized trials of patients showed that these therapies are of modest benefit.6-9 

Oral antiviral therapies available include acyclovir, famciclovir and valacyclovir. Oral acyclovir is typically dosed at 400 mg 3 times daily for 5 days due to its low bioavailability and short plasma half-life. Famciclovir and valacyclovir are preferred as they have 1 to 2 time dosing, though are generally more expensive. 

Oral antiviral therapy remains the reference treatments for recurrent herpes infection. After cellular intake and conversion to acyclovir triphosphate by cellular enzymes, acyclovir selectively inhibits HSV-1 viral DNA replication. Its half-life inside the infected cell is short, about 1 hour. Systemic acyclovir concentrations are over the 50% inhibitory concentration (IC50: 22.5 ng/mL). However, low, delayed and transient in the deep layers of mucosa and skin and thus poorly target the mucosal reservoir of HSV-1. 

New Treatment Option

Acyclovir Lauriad (Sitavig, BioAlliance Pharma) is a new topical treatment FDA approved for RHL in immunocompetent patients with frequent herpes episodes. The acyclovir mucoadhesive buccal tablet (ABT) is a nucleoside analog that has the same active ingredient found in oral acyclovir. Using the proprietary Lauriad technology, this therapy allows the biologically active compound to traverse the mucous membrane to deliver a high concentration of acyclovir directly to the site of the HSV-1 infection. A 50 mg mucoadhesive buccal tablet is applied to the upper gum just above the incisor tooth and held in place with slight pressure over the upper lip for 30 seconds to ensure adhesion. Patients with dry mouth should drink water prior to applying the tablet to moisten the oral mucous membranes and encourage adhesion of the tablet. Once the tablet is applied, it will stay in position and gradually dissolve. 

Patients should avoid chewing gum or brushing their teeth as it could interfere with adhesion of the tablet. Food and drink can be taken as normal. The tablet is only 8 mm in diameter and 2.2 mm to 2.6 mm in thickness, and is tasteless and odorless. It dissolves to provide a sustained release of medicine.10

Clinical trials have confirmed the safety and efficacy of acyclovir Lauriad. Bieber et al included 775 patients each having at least 4 herpes episodes in the previous year in a randomized (ABT 50 mg vs placebo), double-blind, Phase III trial. Patients were instructed to apply their treatment as soon as the first prodromal symptoms occurred.11 See Table for study results.    

Local and overall tolerance of acyclovir Lauriad 50 mg was acceptable. Application site irritation was slight and infrequent with this mucoadhesive buccal tablet (<1%). Acyclovir cream is known to induce local adverse effects and particularly burning, peeling and tingling. This has not been reported in the acyclovir Lauriad 50 mg trial. Likewise, the incidence of headache was much lower than the 10% incidence reported with systemic agents.

In a 9-month follow-up study, incidence of RHL and time to recurrence during this period was assessed. Of the original 775 patients in the Phase III trial, 537 agreed to participate. In patients who applied acyclovir Lauriad within the first hour in the original study, the mean time to first recurrence was 312 days (± 20.6) compared to 203 days (± 10.0) in the placebo group. Overall risk of recurrence was also decreased by 22.7% in this study. These exploratory data need to be confirmed with further study. If confirmed, this “delayed effect” could also reduce interindividual transmission of HSV-1 through a decrease in the oral shedding of patients with frequent RHL episodes.12 

Conclusion

Acyclovir Lauriad affords patients greater convenience with 1 time dosing, and will likely increase patient compliance when compared to topical and some oral therapies. We believe that for patients requiring episodic treatment, acyclovir Lauriad will meet patients’ needs for a highly effective, local-acting product that does not require frequent dosing. 

In clinical trials, acyclovir Lauriad provided clinical benefit to patients independently of the lesion stage. It reduced the occurrence of vesicular lesions, which is the most important burden of the disease. It also prevented and delayed the recurrence of the next herpes episode. Therefore, the acyclovir Lauriad buccal tablet is an attractive alternative option to systemic or topical antiviral treatment for patients with RHL when applied within 1 hour after the occurrence of prodromal symptoms. 

Dr. Downing, MD, is a clinical investigator at the Center for Clinical Studies in Houston, Texas

 

Dr. Tyring, is a clinical professor in the Departments of Dermatology, Microbiology/Molecular Genetics and Internal Medicine at the University of Texas Health Science Center at Houston. 

 

Disclosure: Dr. Downing is a speaker for Innocutis. 

 

Dr. Tyring is a consultant for Innocutis.

 

References

1. Pica F, Volpi A. Public awareness and knowledge of herpes labialis. J Med Virol. 2012;84(1):132-137.

2. Spruance SL, Overall JC Jr, Kern ER, Kruegger GG, Pliam V, Miller W. The natural history of recurrent herpes simplex labialis: implications for antiviral therapy. N Engl J Med. 1977;297(2):69-75.

3. Steiner I, Kennedy PG. Herpes simplex virus latent infection in the nervous system. J Neurovirol. 1995;1(1):19-25.

4. Freeman ML, Sheridan BS, Bonneau RH, Hendricks RL. Psychological stress compromises CD8+ T cell control of latent herpes simplex virus type 1 infections. J Immunol. 2007;179(1):322-328.

5. Rahimi, H, Mara T, Costella J, Speechley M, Bohay R. Effectiveness of antiviral agents for the prevention of recurrent herpes labialis: a systematic review and meta-analysis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113(5):618-627.

6. Spruance SL, Rea TL, Thoming C, Tucker R, Saltzman R, Boon R. Penciclovir cream for the treatment of herpes simplex labialis. A randomized, multicenter, double-blind, placebo-controlled trial. Topical Penciclovir Collaborative Study Group. JAMA. 1997;277(17):1374-1379.

7. Spruance SL, Nett R, Marbury T, Wolff R, Johnson J, Spaulding T. Acyclovir cream for treatment of herpes simplex labialis: results of two randomized, double-blind, vehicle-controlled, multicenter clinical trials. Antimicrob Agents Chemother. 2002;46(7):2238-2243.

8. 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. 2001;45(2):222-230.

9. McCarthy JP, Browning WD, Teerlink C, Veit G. Treatment of herpes labialis: comparison of two OTC drugs and untreated controls. J Esthet Restor Dent. 2012;24(2):103-109.

10. Downing C, Moayyad J, Tamirisa A, Tyring S. Acyclovir Lauriad®: a mucoadhesive buccal tablet for the treatment of recurrent herpes labialis. Expert Rev Anti Infect Ther. 2014;12(3):283-287. 

11. Bieber T, Chosidow O, Bodsworth N, et al. Efficacy and safety of acyclovir Lauriad mucoadhesive buccal tablet in immunocompetent patients with labial herpes (LIP trial): a double-blind placebo-controlled self-initiated trial. J Drugs Dermatol. 2014;13(7):791-798.

12. Tyring SK, Bieber TO, Chosidow O, et al. A single application of acyclovir mucoadhesive buccal tablet reduces recurrence of herpes labialis in a randomized double-blind phase 3 study: Exploratory results. J Invest Dermatol. 2014;134(suppl 1):S91.

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