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Recent Approval of Xerese in Canada: 5% Acyclovir and 1% Hydrocortisone Topical Cream in the Treatment of Herpes Labialis

Harrison P. Nguyen, BA1,2; Kelly R. Stiegel, BS1;
Christopher Downing, MD3; Stephen K. Tyring, MD, PhD, MBA2,3
1Department of Dermatology, Baylor College of Medicine, Houston, TX, USA
2Department of Dermatology, University of Texas Medical School at Houston, Houston, TX, USA
3Center for Clinical Studies, Houston, TX, USA

Conflict of Interest: None reported

ABSTRACT

Herpes labialis is a frequently occurring viral infection of the lips and oral mucosa. Recurring lesions are induced by viral reactivation and replication, but the symptoms leading to morbidity, such as pain and inflammation, are immune-mediated. The introduction of 5% acyclovir/1% hydrocortisone in a topical cream (Xerese™) represents a therapeutic strategy directed at both of these pathogenic processes. Applied at the onset of prodromal symptoms, this combination treatment has a good safety profile and is more effective in reducing healing time than antiviral or anti-inflammatory agents alone. Although it was US FDA-approved for herpes labialis in 2009, Xerese™ has only recently been approved for use in Canada in October 2013. Herein, we review the basic science and clinical studies that support the efficacy of this topical combination acyclovir-hydrocortisone product in treating herpes labialis and examine its safety profile, as well as touch upon other therapies that have been shown to be effective in treating this common viral condition.

Key Words: cold sores, herpes labialis, Xerese, viral infection, Canada, drug approval

Introduction

Herpes labialis (colloquially known as “cold sores”) is a common viral infection characterized by vesicular lesions of the lips and oral mucosa. It is estimated to affect 1 in 5 Canadians annually and is associated with a negative stigma that can lead to depression, fear of rejection, and isolation for infected individuals during an outbreak.1 Herpes labialis is mostly caused by the herpes simplex virus-1 (HSV-1), which enters the nerve during primary infection and remains latent in the ganglionic neuron for the rest of the individual’s life. Periodically, the virus travels back down the nerve to the skin and replicates, producing a clinical episode of reactivated HSV-1 infection. Intralesional viral replication is halted by the host immune response approximately 7 days after primary infection and 3 days after recurrent infection;2 however, inflammation secondary to immune defense is also the cause of redness, swelling, and tenderness that is characteristic of herpes labialis lesions. As a result, although viral clearance happens rapidly following reactivation, the lesion often takes 7-10 days to heal completely.

Since the pathogenesis of herpes labialis is both viral- and immune-mediated, it is not surprising that administration of exclusively antiviral drugs has limited effects on the clinical parameters of the disease.3 Therefore, medications demonstrating dual mechanisms via inhibition of viral replication and modulation of the inflammatory response to facilitate healing, indicate a more successful therapeutic approach.4 Such an agent was introduced by Valeant Pharmaceuticals, consisting of 5% antiviral acyclovir plus 1% anti-inflammatory hydrocortisone (ACHC) in a topical cream formulation (Xerese™). Although it has been FDA-approved in the US for the treatment of recurrent herpes labials since 2009, authorization for Xerese™ in Canada was not officially granted until October 2013. In light of this recent Canadian approval, we review the data supporting the efficacy of this topical combination therapy and discuss the details regarding its clinical use, specifically incorporating our experience in prescribing ACHC for the past half-decade.

Drug Information

ACHC is intended for the early treatment of recurrent herpes simplex labialis (HSL) in adults and adolescents (12 years of age and older). It is designed for cutaneous use only and is applied to the lips and skin around the mouth. Usage should be avoided on the eyes, inside the mouth or nose, and on the genitals. The patient should be instructed to apply a thin layer across the affected area, including the outer margins of the cold sore. Treatment should be initiated at the first sign or symptom (prodromal stage), applying 5 times per day for a period of 5 consecutive days. If there is no noticeable improvement and/or the cold sore fails to heal within 2 weeks, patients are encouraged to seek further medical attention. At present, the efficacy of ACHC has not been established in the immunocompromised population.5

From Bench to Bedside: Duration and Efficacy

In order to obtain maximum clinical benefit from a topical antiviral medication, therapy should be initiated within 72 hours of onset of symptoms.6 Patients with recurrent herpes labialis experience a rapid onset of disease and a short viral shedding period, both of which make it difficult to measure responses to therapy.

In an early basic science study conducted in 2003, researchers used mice that had undergone adaptive transfer of immunity and infected the skin on the mice’s ear pinna with HSV-1.7 After the mice developed a zosteriform infection, treatment groups received topical ACHC, 5% acyclovir (Zovirax®), 1% hydrocortisone, or no treatment at all. Medication was applied 3 times daily for 4 days. The treatment groups were analyzed based on ear thickness increase and zoster score. The zoster scores were adapted from a scale previously described in another study, and the scores used were: 0 for unchanged ear, 1 for isolated zosteriform lesions, and 2-4 for describing the ulceration of confluent zosteriform lesions from mild to severe.8 ACHC outperformed both 5% acyclovir and 1% hydrocortisone creams, with an average increase in ear thickness of only 0.15 ± 0.03 mm compared to 0.48 ± 0.08 mm and 0.23 ± 0.03 mm, respectively. The average increase in ear thickness for ACHC was only 34% of that experienced by the mice in the control group, compared to 110% observed with acyclovir and 52% with hydrocortisone. The average zoster score for the ACHC group at day 9 was also the lowest of the four groups at 2.0 ± 0.2 (58% of control), compared to 2.4 ± 0.3 (70% of control) for acyclovir and 2.8 ± 0.2 (80% of control) for hydrocortisone.7

In a 2012 Phase 3 study, Strand et al instructed their human subjects to apply ACHC 5 times daily for 5 days at the onset of prodromal symptoms, preferably before the appearance of actual papules or vesicles. Of the 131 test subjects, 78 (59.5%) had nonulcerative recurrences, and 53 (40.5%) had ulcerative recurrences. At the follow-up visit, all 131 of the test subjects had returned to the stage of normal skin, 3 weeks after the last dose, with no signs or symptoms of herpes labialis recurrence. In the 40% of subjects who experienced ulcerative herpes lesions despite applying the ACHC cream, the mean maximum lesion area was 39 mm2, which was a 48% decrease from the mean lesion area size of 75 mm2 typically reported in immunocompetent adults.9,10

A similar study published in 2011, also using a dosing regimen of applying cream 5 times daily for 5 days, studied a much larger patient population in a randomized, double-blind, placebocontrolled trial.11 The 2,437 volunteers were randomized to receive either ACHC, acyclovir in the ACHC vehicle, or placebo in the form of the ACHC vehicle. Of the 1,443 subjects who experienced a recurrence of herpes labialis during the trial and initiated treatment, 42% used ACHC, 42% acyclovir, and 16% placebo. The authors reported that 58% of the patients on ACHC developed an ulcerative lesion, vs. 65% in the acyclovir group and 74% in the placebo group. In patients who experienced an ulcerative lesion, the healing times were reduced in those who received ACHC or acyclovir, compared with placebo. The patients using ACHC also had a smaller cumulative lesion area (~50% less) than the placebo group (Tables 1 and 2).

Finally, in a simulated 2002 trial, researchers tested the efficacy of ACHC in patients whose latent HSV-1 infection was intentionally reactivated using ultraviolet (UV) light.12 Of the 380 subjects, 120 patients developed classical cold sores 2 days after UV light exposure, which was followed by initiation of treatment with either ACHC or placebo. Treatment with ACHC reduced lesion size, healing time, and lesion tenderness when compared with placebo. Healing time (defined as the time to restoration of normal skin) was reduced from 10.1 days in the placebo group to 9.0 days in the ACHC group (Table 2).

Adverse Effects

The combination cream of 5% acyclovir and 1% hydrocortisone has been shown to induce only minimal side effects when used to treat herpes labialis infections. In Strand et al’s 2012 Phase 3, open-label, multicenter study, 131 of 134 subjects were categorized with recurrence at the post-treatment visit.10 Of these 131 subjects, only 5 reported any adverse events. The events were classified as mild to moderate in intensity and consisted of secondary herpes labialis recurrences (n=2), infectious rhinitis (n=1), application site inflammation (n=1), and bronchial asthma (n=1). Additional studies have corroborated the safety of ACHC, observing only minor side effects.11,12 The most common adverse reactions reported in clinical trials were drying or flaking of the skin, burning or tingling at the application sight, erythema, and pigmentation changes; these infrequent adverse effects occurred in less than 1% of patients studied.5

Other Therapies for Herpes Labialis

Prior to the authorization of Xerese™ by Health Canada, the mainstays of treatment for recurrent HSL included over-thecounter docosanol cream, and prescription-only members of the acyclovir family (oral and topical). If ACHC is contraindicated for use in a particular patient due to adverse effects, docosanol or acyclovir may provide therapeutic benefit.

Docosanol 10% cream (Abreva®) is an approved treatment for recurrent herpes labialis, with efficacy demonstrated in two identical double-blind, placebo-controlled studies conducted at 21 sites.13 Therapy was initiated at the onset of prodromal symptoms or the erythema stage in subjects who were otherwise healthy adults with documented histories of herpes labialis. Treatment was administered 5 times daily until healing occurred, with twice-daily visits to the investigative clinic for the first 7 days. For the 370 patients who were treated with docosanol, the median time to heal was 4.1 days, which was 18 hours shorter than the healing time for the 367 patients treated with placebo (Table 2). The patients treated with docosanol also reported earlier cessation of pain and exhibited complete healing, as well as experienced reduced lesion progression to the ulcer or soft crust stage.

A well-established mainstay in the treatment of recurrent herpes labialis is valacyclovir. This prodrug of acyclovir has proven to be a safe and effective therapy for long-term HSV suppression.14 It has been studied in children, pregnancy, and immunocompromised patients. The most common adverse events associated with oral valacyclovir are headache, rhinitis, infection, nausea, and pharyngitis, with all of these occurring infrequently. Despite many years of use by clinicians, HSV resistance remains low at approximately 0.1-0.4% in the UK and the US.14

A new form of acyclovir was recently approved by the US FDA in April 2013. This medication consists of acyclovir in the form of a mucoadhesive buccal tablet (ABT) (Sitavig®), which is applied to the upper gum region within the first hour of prodromal symptoms. A Phase 3 double-blind trial found that acyclovir, utilizing the proprietary Lauriad® technology, decreased the median duration time and development of primary vesicular lesions when compared to placebo (Tables 1 and 2).15

Lastly, a non-pharmacologic treatment for recurrent HSL involves low-level light therapy. A paper published in 2013 demonstrated that 1072 nm light-emitting diode therapy applied 3 times a day for 2 days was able to shorten healing time in patients with HSL to a median of 129 hours vs. 177 hours for the control group (Table 2).16

Reference Treatment Initiated Treatment (n) Ulcerative Lesions (%) p-value
Spruance 1997 Penciclovir cream
Placebo
782
791
84.8
84.2
NA
Raborn 2002 Penciclovir cream
Placebo
1516
1541
82.7
83.3
NA
Spruance 2003 Study 1 Valacyclovir, 1 day
Valacyclovir, 2 days
Placebo
311
299
292
55.6
53.5
62.0
0.096
0.061
Spruance 2003 Study 2 Valacyclovir, 1 day
Valacyclovir, 2 days
Placebo
298
339
317
56.7
56.6
64.7
0.054
0.036
Spruance 2006 Famciclovir 1500 mg single dose
Famciclovir 750 mg twice per day
Placebo
227
220
254
67.0
71.4
66.1
NA
NA
Morrel 2006 Iontophoresis of 5% acyclovir
Placebo
99
100
80.8
86.0
NA
Hull 2011 ACHC
Acyclovir
Placebo
601
610
232
57.7
64.6
74.1
<0.0001
Downing 2014 Acyclovir Lauriad®
Placebo
376
395
65.1
71.9
0.042
Table 1. Comparing efficacies of therapy by percent of lesions that ulcerate2,11,15,17,18,19,20
Reference Treatment Initiated Treatment (n) Ulcerative Lesions (%) p-value
Sacks 2001 Docosanol 10% cream
Placebo
370
367
4.1
4.9
0.008
Dougal 2013 1072 nm light
Placebo
41
47
5.4
7.4
0.01
Evans 2002 ACHC
Placebo
50
70
9.0
10.1
0.04
Hull 2011 ACHC, 5 days
Acyclovir, 5 days
Placebo
582
591
225
5.7
5.9
6.5
0.008
0.365
Downing 2014 Acyclovir Lauriad®
Placebo
376
395
5.57
6.38
0.003
Table 2. Comparing efficacies of therapy by median time to heal11,12,13,15,16

Clinical Observations

When taken daily (along with topical sunscreens), oral acyclovir, famciclovir, or valacyclovir are better at preventing herpes labialis than topical therapies are at treating outbreaks; however, it is the authors’ experience over the past 5 years that when used appropriately, ACHC is the superior topical therapy. Because the signs and symptoms of herpes labialis are attributable to both viral and inflammatory mechanisms, prescription topicals exerting only antiviral or anti-inflammatory activities have limited efficacy. Most over-the-counter therapies fail to target underlying pathogenic mechanisms (i.e., viral and inflammatory) and, thus, have little to no efficacy. While the optimal strategy is to prevent herpes labialis outbreaks via reduction of sun exposure, as well as through the use of sunscreen and oral anti-viral agents (especially in individuals experiencing frequent outbreaks), we recommend to our patients that they fill their prescriptions for ACHC as soon as possible and keep the cream at home, at work, and/or carry it with them while on vacation. At the onset of prodromal symptoms, therapy should be initiated immediately and no later than the appearance of the first sign of a recurrence.

Conclusion

Herpes labialis still lacks a cure, but several options are now available to limit inflammation and decrease healing time. The introduction of 5% acyclovir/1% hydrocortisone topical cream represents a forward step in understanding disease pathogenesis and targeting both the viral and immunogenic components of recurrent HSL.

References

  1. Kuehl B. Cold sores - how to prevent and treat them [Cold Sores Guide website]. Available at: http://www.coldsores.ca/articles/art3.html. Accessed April 6, 2014.
  2. Spruance SL, Rea TL, Thoming C, et al. Penciclovir cream for the treatment of herpes simplex labialis. A randomized, multicenter, double-blind, placebocontrolled trial. Topical Penciclovir Collaborative Study Group. JAMA. 1997 May 7;277(17):1374-9.
  3. Corey L, Nahmias AJ, Guinan ME, et al. A trial of topical acyclovir in genital herpes simplex virus infections. N Engl J Med. 1982 Jun 3;306(22):1313-9.
  4. Hull CM, Levin MJ, Tyring SK, et al. Novel composite efficacy measure to demonstrate the rationale and efficacy of combination antiviral-antiinflammatory treatment for recurrent herpes simplex labialis. Antimicrob Agents Chemother. 2014 Mar;58(3):1273-8.
  5. Xerese® prescribing information. Date of revision: January 2012. Coria Laboratories, a division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ. Available at: http://www.xerese.com/Portals/81/Pdf/pi_ information.pdf. Accessed April 6, 2014.
  6. Vestey JP, Norval M. Mucocutaneous infections with herpes simplex virus and their management. Clin Exp Dermatol. 1992 Jul;17(4):221-37.
  7. Harmenberg JG, Awan AR, Alenius S, et al. ME-609: a treatment for recurrent herpes simplex virus infections. Antivir Chem Chemother. 2003 Jul;14(4): 205-15.
  8. Nagafuchi S, Oda H, Mori R, et al. Mechanism of acquired resistance to herpes simplex virus infection as studied in nude mice. J Gen Virol. 1979 Sep;44(3):715-23.
  9. Spruance SL. Herpes simplex labialis. In: Sacks SL, Straus SE, Whitley RJ, et al. editors. Clinical management of herpes viruses. Amsterdam, Washington DC: IOS Press. 1995;p3-42.
  10. Strand A, Bottiger D, Gever LN, Wheeler W. Safety and tolerability of combination acyclovir 5% and hydrocortisone 1% cream in adolescents with recurrent herpes simplex labialis. Pediatr Dermatol. 2012 Jan-Feb;29(1): 105-10.
  11. Hull CM, Harmenberg J, Arlander E, et al. Early treatment of cold sores with topical ME-609 decreases the frequency of ulcerative lesions: a randomized, double-blind, placebo-controlled, patient-initiated clinical trial. J Am Acad Dermatol. 2011 Apr;64(4):696 e1-11.
  12. Evans TG, Bernstein DI, Raborn GW, et al. Double-blind, randomized, placebocontrolled study of topical 5% acyclovir-1% hydrocortisone cream (ME-609) for treatment of UV radiation-induced herpes labialis. Antimicrob Agents Chemother. 2002 Jun;46(6):1870-4.
  13. Sacks SL, Thisted RA, Jones TM, et al. Clinical efficacy of topical docosanol 10% cream for herpes simplex labialis: A multicenter, randomized, placebocontrolled trial. J Am Acad Dermatol. 2001 Aug;45(2):222-30.
  14. Tyring SK, Baker D, Snowden W. Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years' experience with acyclovir. J Infect Dis. 2002 Oct 15;186 Suppl 1:S40-6.
  15. Downing C, Moayyad J, Tamirisa A, et al. Acyclovir Lauriad((R)): a mucoadhesive buccal tablet for the treatment of recurrent herpes labialis. Expert Rev Anti Infect Ther. 2014 Mar;12(3):283-7.
  16. Dougal G, Lee SY. Evaluation of the efficacy of low-level light therapy using 1072 nm infrared light for the treatment of herpes simplex labialis. Clin Exp Dermatol. 2013 Oct;38(7):713-8.
  17. Raborn GW, Martel AY, Lassonde M, et al. Effective treatment of herpes simplex labialis with penciclovir cream: combined results of two trials. J Am Dent Assoc. 2002 Mar;133(3):303-9.
  18. Spruance SL, Jones TM, Blatter MM, et al. High-dose, short-duration, early valacyclovir therapy for episodic treatment of cold sores: results of two randomized, placebo-controlled, multicenter studies. Antimicrob Agents Chemother. 2003 Mar;47(3):1072-80.
  19. Morrel EM, Spruance SL, Goldberg DI. Topical iontophoretic administration of acyclovir for the episodic treatment of herpes labialis: a randomized, double-blind, placebo-controlled, clinic-initiated trial. Clin Infect Dis. 2006 Aug 15;43(4):460-7.
  20. Spruance SL, Bodsworth N, Resnick H, et al. Single-dose, patient-initiated famciclovir: a randomized, double-blind, placebo-controlled trial for episodic treatment of herpes labialis. J Am Acad Dermatol. 2006 Jul;55(1):47-53.

In this issue:

  1. Rosacea: An Update on Medical Therapies
  2. Recent Approval of Xerese in Canada: 5% Acyclovir and 1% Hydrocortisone Topical Cream in the Treatment of Herpes Labialis
  3. Update on Drugs and Drug News - May-June 2014