Department of Dermatology, Northwestern University, Chicago, IL, USA

ABSTRACT

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.

Key Words:
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

Acyclovir

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

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

Famciclovir

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

Combination Therapies

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

Other Agents

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

Summary

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.

References

1. 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).
2. 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).
3. Bose SK. Herpes simplex virus in association with lip leucoderma. J Dermatol 34(4):280-1 (2007Apr).
4. 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).
5. 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).
6. 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).
7. 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).
8. 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).
9. 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).
10. 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).
11. 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).
12. 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).
13. 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).
14. 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).
15. 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).
16. 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).
17. 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).
18. 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).
19. 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).
20. Baker D, Eisen D. Valacyclovir for prevention of recurrent herpes labialis: 2 double-blind, placebo-controlled studies. Cutis 71(3):239-42 (2003 Mar).
21. 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).
22. 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).

ABSTRACT

Imiquimod 5% cream (Aldara™, Graceway Pharmaceuticals) is an immune response modifier used for the topical treatment of anogenital warts in non-HIV-infected patients. Several randomized controlled trials have demonstrated that imiquimod 5% cream is a safe and efficacious treatment. Current data regarding efficacy shows that complete clearance of warts occurred in up to 50% of patients treated with imiquimod 5% cream applied once-daily, 3 times per week for up to 16 weeks. Recurrence rates ranged from up to 19% at 3 months to 23% at 6 months. Imiquimod 5% cream showed an acceptable safety profile; local inflammatory reactions were the most frequent adverse effects, with local erythema being the most common.

Key Words:
anogenital warts, HPV, human papillomavirus, imiquimod

Imiquimod is an immune response modifier that was approved by the US FDA in 1997 for the topical treatment of anogenital warts in individuals 12 years old and older. An estimated 30%-50% of sexually active adults in the US are infected with human papillomavirus (HPV), and approximately 1%-2% of this same population have clinically evident genital warts.¹ This review will focus on studies that evaluate the safety, efficacy, and recurrence rates of imiquimod 5% cream in the treatment of anogenital warts in non-HIV-infected men and women. Local inflammatory reactions were the most frequent adverse effects, with local erythema being the most common. Overall, imiquimod 5% cream is a safe and efficacious treatment for anogenital warts.

Using Imiquimod

Imiquimod cream is supplied in individual packets. Each gram of the 5% cream contains 50mg of imiquimod in an off-white oil-in-water vanishing cream base.² The US Center for Disease Control recommends that imiquimod 5% cream be applied once daily at bedtime, 3 times per week for up to 16 weeks. The product should be washed off with mild soap and water 6-10 hours following application.^2-4 Many considerations exist when using imiquimod. Some of these are listed in Box 1. The US FDA provides a full list of considerations.³

Mechanism of Action

Imiquimod is a Toll-like receptor agonist that induces the production of local cytokines from predominantly T helper (Th) 1-type cells, thus stimulating both acquired and cellular immunity, which is important for fighting virus-infected and tumor cells.^5-7 Cytokines such as interferon (INF)-á, tumor necrosis factor (TNF)-á, interleukin (IL)-1, -6, -8, -10, and -12 stimulate tissue-specific apoptosis of virus-infected keratinocytes, thus leading to a viral load reduction of HPV types 6 and 11 with subsequent wart regression and normalization of keratinocyte proliferation.^5,6,8 Regression of warts after treatment with imiquimod is strongly associated with evidence of tissue production of INF-á, -â, and -ã and TNF-á as well as a decrease in the presence of HPV DNA and in the expression of mRNA for both early and late viral proteins.⁹

Safety

In all the randomized controlled trials (RCTs) examined, topical imiquimod 5% cream showed an acceptable safety profile. Local skin reactions are associated with a local inflammatory reaction including itching, erythema, burning, irritation, tenderness, ulceration, erosion, and pain.¹⁰ In several studies, local erythema was the most common reaction.^11-13 There were no differences in adverse systemic reactions or flu-like symptoms among treatment groups.^10,12,13 The optimal dosing regimen is 3 times per week. With more frequent applications (up to 3 times daily), wart clearance does not improve significantly and is associated with an increase in local adverse events, such as erythema, vesicle formation, ulceration, and excoriation.¹⁴ Imiquimod 5% cream is effective for up to 16 weeks of treatment for external anogenital warts and is well-tolerated for up to 32 weeks.¹¹ Imiquimod is contraindicated in individuals with a history of sensitivity reactions to any of its components and should be discontinued if hypersensitivity to any of its ingredients is noted. Overall, patient-applied imiquimod 5% cream is an effective treatment for external genital warts and has a favorable safety profile.

Efficacy and Recurrence

Several randomized controlled trials demonstrated that imiquimod 5% cream is an efficacious treatment for external anogenital warts when applied 3 times per week for up to 16 weeks. Complete clearance of warts occurred in up to 50% of patients treated with imiquimod 5% cream applied 3 times daily. At the end of 16 weeks, recurrence rates ranged from up to 19% after 3 months and 23% after 6 months.11 See Table 1 for comparisons. The recurrence rates of external genital warts were found to be similar at both 3- and 6-month follow-up, suggesting that after 3 months, the risk of developing recurrence is low.¹⁵

The studies that follow were chosen to evaluate imiquimod 5% cream for the treatment of anogenital warts because of sufficient data on efficacy, recurrence rates, and safety.^10-13 Studies that did not include this data were excluded. Several other studies focused on the treatment of anogenital or vulvar warts in the female population; however, the efficacy rates are generally higher for this population, ranging from 71%-77%.^12,16-18 To maintain continuity, this review focuses on comparing studies that include treatment of anogenital warts with imiquimod 5% cream in non-HIV-infected men and women.

Beutner, Spruance et al.¹⁰

In a prospective, double-blind, placebo-controlled, clinical trial with 108 patients, imiquimod 5% cream was applied 3 times daily for up to 8 weeks. Complete wart clearance was achieved in 37% of the imiquimod-treated patients and 0% of the placebo group. Many patients experienced a partial response: an 80% or more reduction in baseline wart area was achieved in 62% of imiquimod-treated patients versus a 4% reduction in the placebo group. A 50% reduction in baseline wart area was noted in 76% of imiquimod-treated patients compared with 8% of the placebo group. For patients whose warts cleared completely, 19% experienced recurrences after a 10-week follow-up period. There were no differences in systemic reactions between treatment groups. Local inflammatory reactions were predominantly mild or moderate in severity and included itching (54%), erythema (33%), burning (31%), irritation (17%), tenderness (13%), ulceration (10%), erosion (10%), and pain (8%).

Garland et al.¹¹

In an open-label phase IIIB trial consisting of 943 patients in 20 countries, imiquimod 5% cream applied 3 times per week was found to be 47.8% effective for overall complete clearance after 16 weeks of treatment. Recurrence rates at the end of 3- and 6-month follow-up were 8.8% and 23%, respectively. The sustained clearance rates (patients who cleared during treatment and remained clear at the end of the follow-up period) after 3 and 6 months were 41.6% and 33%, respectively. The study also found that a greater proportion of female patients (75.5%) experienced complete clearance than did male patients (56.9%). At least 1 adverse event was reported in 42% of patients; the majority of reactions were mild to moderate in severity. Local erythema was the most common local skin reaction, occurring in 67% of patients.

Edwards et al.¹²

Another RCT consisting of 311 patients was randomized to 3 arms: imiquimod 5% cream, imiquimod 1% cream, or vehicle 3 times per week for a maximum of 16 weeks. Complete clearance of lesions was achieved in 50% of patients who received the imiquimod 5% cream, 21% of those who received imiquimod 1% cream, and 11% of those treated with the placebo. After a 3-month follow-up, the study found a recurrence rate of at least 1 wart in 13% of patients who receive imiquimod 5% cream. The majority of patients experienced no or mild local inflammatory reactions, with local erythema being the most common. Local adverse reactions, which were moderate or severe in intensity after being treated with imiquimod 5% cream, included erythema (40%), erosion (10%), excoriation (7%), edema (2%), and scabbing (5%).

Beutner, Tyring et al.¹³

In another prospective, multicenter, double-blind, RCT with 279 patients, 94 patients used imiquimod 5% cream once-daily for up to 16 weeks. Complete wart clearance was achieved in 52% of patients treated with imiquimod 5% cream, but 19% of these patients had a recurrence at a 3-month follow-up. These results are similar to those obtained with 3 applications per week. When patients were treated with 5% imiquimod cream vs. vehicle, local adverse reactions included erythema (66% vs. 9%), excoriation (21% vs. 4%), erosion (32% vs. 1%), edema (18% vs. 1%), scabbing (18%), induration (5%), ulceration (10%), and vesicles (3%).

Support for Comparable Efficacy in Clearance Rates After 3 Weeks

Garland et al.¹¹ found that a 1-month treatment course of imiquimod 5% cream applied 3 times weekly for women with external genital warts has comparable efficacy to a 4-month treatment with no statistically significant difference in complete clearance rates (i.e., 40% after 1 month and 51.6% after 4 months). The 1-month treatment had a lower incidence of local skin reactions, such as erythema, and no pain.¹⁸

Monotherapy Compared with Combination Therapy: Imiquimod + Surgery

Carrasco et al.¹⁹ showed that treatment with imiquimod 5% cream followed by excision of remaining warts resulted in a lower recurrence rate compared with surgery alone. This strategy represents a viable option for those with residual lesions and may provide long-term clearance of anogenital warts in patients for whom imiquimod monotherapy is insufficient.¹⁹

Conclusion

Patient-applied imiquimod 5% cream is a first-line topical treatment for anogenital warts that is both safe and efficacious, and yields complete and partial responses in the majority of patients. Various studies demonstrate complete clearance rates of up to 50% and partial responses manifest as a 50%-90% reduction in baseline wart area.^12-14 Recurrence rates range up to 19% at 3 months and 23% at 6 months. More studies are needed to compare the efficacy of combination therapies vs. monotherapy vs. other treatment modalities. Longer follow-up is also needed to evaluate recurrence rates after monotherapy, as well as in combination with other treatments for anogenital warts.

References

1. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med 102(5A):3-8 (1997 May 5).
2. Chang YC, Madkan V, Cook-Norris R, et al. Current and potential uses of imiquimod. South Med J 98(9):914-20 (2005 Sep).
3. US FDA. Aldara (Imiquimod) Cream 5%.
4. Scheinfeld N, Lehman DS. An evidence-based review of medical and surgical treatments of genital warts. Dermatol Online J 12(3):5 (2006 Mar).
5. Tyring SK, Arany II, Stanley MA, et al. Mechanism of action of imiquimod 5% cream in the treatment of anogenital warts. Prim Care Update Ob Gyns 5(4):151-2 (1998 Jul).
6. Berman B, Sullivan T, De Araujo T, et al. Expression of Fas-receptor on basal cell carcinomas after treatment with imiquimod 5% cream or vehicle. Br J Dermatol 149 (Suppl 66):59-61 (2003 Nov).
7. Schiller M, Metze D, Luger TA, et al. Immune response modifiers–mode of action. Exp Dermatol 15(5):331-41 (2006 May).
8. Lacarrubba F, Nasca MR, Micali G. Advances in the use of topical imiquimod to treat dermatologic disorders. Ther Clin Risk Manag 4(1):87-97 (2008 Feb).
9. Tyring SK, Arany I, Stanley MA, et al. A randomized, controlled, molecular study of condylomata acuminata clearance during treatment with imiquimod. J Infect Dis 178(2):551-5 (1998 Aug).
10. Beutner KR, Spruance SL, Hougham AJ, et al. Treatment of genital warts with an immune-response modifier (imiquimod). J Am Acad Dermatol 38(2 Pt 1):230-9 (1998 Feb).
11. Garland SM, Sellors JW, Wikstrom A, et al. Imiquimod 5% cream is a safe and effective self-applied treatment for anogenital warts–results of an open-label, multicentre Phase IIIB trial. Int J STD AIDS 12(11):722-9 (2001 Nov).
12. Edwards L, Ferenczy A, Eron L, et al. Self-administered topical 5% imiquimod cream for external anogenital warts. HPV Study Group. Human PapillomaVirus. Arch Dermatol 134(1):25-30 (1998 Jan).
13. Beutner KR, Tyring SK, Trofatter KF, Jr., et al. Imiquimod, a patient-applied immune-response modifier for treatment of external genital warts. Antimicrob Agents Chemother 42(4):789-94 (1998 Apr).
14. Fife KH, Ferenczy A, Douglas JM, Jr., et al. Treatment of external genital warts in men using 5% imiquimod cream applied three times a week, once daily, twice daily, or three times a day. Sex Transm Dis 28(4):226-31 (2001 Apr).
15. Vexiau D, Decuypère L, Moyse D, et al. [Efficacy and safety of 5% imiquimod cream in external genital warts: a 6 month follow-up evaluation]. Ann Dermatol Venereol 132(11 Pt 1):845-51 (2005 Nov).
16. Haidopoulos D, Diakomanolis E, Rodolakis A, et al. Safety and efficacy of locally applied imiquimod cream 5% for the treatment of condylomata acuminata of the vulva. Arch Gynecol Obstet 270(4):240-3 (2004 Dec).
17. Buck HW, Fortier M, Knudsen J, et al. Imiquimod 5% cream in the treatment of anogenital warts in female patients. Int J Gynaecol Obstet 77(3):231-8 (2002 Jun).
18. Garland SM, Waddell R, Mindel A, et al. An open-label phase II pilot study investigating the optimal duration of imiquimod 5% cream for the treatment of external genital warts in women. Int J STD AIDS 17(7):448-52 (2006 Jul).
19. Carrasco D, vander Straten M, Tyring SK. Treatment of anogenital warts with imiquimod 5% cream followed by surgical excision of residual lesions. J Am Acad Dermatol 47(4 Suppl):S212-6 (2002 Oct).

1. Center for Clinical Studies, Houston, TX, USA
2. The University of Texas Medical School at Houston, Houston, TX, USA
3. Department of Dermatology, University of Texas Health Sciences Center, Houston, TX, USA

ABSTRACT

Psoriasis is a common chronic inflammatory skin disease that is mediated, in part by the body’s T-cell inflammatory response mechanisms. Further insight into the pathogenesis of the disease and the role of various cytokines, particularly interleukin(IL)-12 and IL-23, has led to advances in the treatment of this disease. A relatively new class of drugs that inhibit these interleukins is being developed and studied. Current data regarding the efficacy of these agents show they may have the potential to become the new clinical gold standard for biologic therapy to treat psoriasis.

Key Words:
IL-12; IL-23; ustekinumab; psoriasis

The Role of IL-12 & IL-23 in the Pathogenesis of Psoriasis

Psoriasis is a chronic skin disease affecting approximately 2%-3% of the general population and is mediated, at least partially, by the body’s T-cell inflammatory response mechanisms. Two interleukins (IL) in particular, IL-12 and IL-23, have been specifically implicated as key players in the pathogenesis of psoriasis secondary to their role in linking the innate and adaptive immune responses.¹ IL-12 and IL-23 are composed of the p40 subunit, which is common to both, as well as the unique subunits, p35 and p19, respectively. The individual subunits facilitate the distinctive biological actions of each molecule. IL-12 functions to induce and sustain TH1 immune responses leading to the secretion of interferon (IFN)-ã and the homing of T cells to the skin via the induction of cutaneous lymphocyte antigen (CLA), whereas, IL-23 functions to maintain chronic autoimmune inflammation via the induction of IL-17, regulation of T memory cells, and direct activation of macrophages.^1-4

Support for IL-12 and IL-23 Involvement in Psoriasis

Through various approaches, a plethora of studies involving transgenic mice, the human genome, and samples from human psoriatic lesions support the hypothesis that IL-12 and IL-23 have a significant role in the disease process. According to the genome-wide association study (GWAS) conducted by Cargill et al., an association exists between psoriasis and the genes for IL-12 and IL-23. This finding was reproduced by Smith et al. in a study of approximately 600 patients with psoriasis. Additionally, scrapings from psoriatic lesions have exhibited not only increased levels of IL-12 and IL-23, but also higher levels of their downstream effectors, including CLA+ T-cells, IFN-ã, and IL-17.^1,4 Recent findings indicate that people with genetic over-expression of this common p40 subunit have a greater risk for the development of psoriasis, and that psoriatic lesions contain high levels of IL-12, IL-23 and their downstream effectors. In light of these findings, further investigation has been directed towards illustrating not only their specific role in its pathogenesis, but also whether direct inhibition may play an integral role in its treatment.^1-3

Mechanism of Action

Both IL-12 and IL-23 bind to the b1 receptor of T cells and natural killer cells via their shared p40 subunit.^1,7 This new class of drugs has been designed to function by binding with high affinity to the p40 subunit, thus preventing its binding at the receptor and the subsequent downstream signaling. Currently, at least 2 drugs exist in this class: the first is CNTO-1275 (ustekinumab), which is being developed by Centocor and ABT-874, which is being developed by Abbott.^1,2 Both drugs, given as subcutaneous injections, are fully human monoclonal antibodies targeting the shared p40 subunit of IL-12 and IL-23. An oral version of these drugs was introduced by Synta Pharmaceuticals as STA-5326, but this version failed in Phase II clinical trials for the treatment of psoriasis; it is still being tested for the treatment of rheumatoid arthritis and common variable immunodeficiency.⁸

Advantages of IL-12/IL-23 Inhibitors

Four double-blinded, placebo controlled trials, 3 evaluating CNTO-1275 and 1 evaluating ABT-874, have shown that both drugs are very effective in the treatment of psoriasis. These studies all used 3 universal criteria to delineate an adequate response:

1. Psoriasis Area and Severity Index (PASI), which combines assessments of the extent of body surface involvement and the severity of desquamation, erythema, and plaque induration
2. Physician’s Global Assessment (PGA), which rates the patient’s psoriasis relative to baseline
3. Dermatology Quality of Life Index (DQLI), which is a 10 item questionnaire to assess the patient’s perspective on how psoriasis is affecting his or her own quality of life.

The Four Studies

Krueger et al.³ evaluated the efficacy of 4 dosing regimens of CNTO-1275:

• one 45mg dose
• one 90mg dose
• 4 weekly 45mg doses
• 4 weekly 90mg doses.

At least 75% improvement from the baseline PASI was seen in more than 50% (54%-81%) of subjects at 12 weeks in all 4 treatment arms. A higher dose of drug correlated with a higher percentage of subjects with a PASI-75 or better. This degree of improvement was seen in only 2% of those who received placebo. With regards to the PGA and DQLI, all active-treatment groups significantly improved when compared with the placebo group.

The PHOENIX 1 and 2 trials^9,10 also evaluated the efficacy of CNTO-1275 by considering 2 treatment arms:

• one 45mg dose at week 0 and week 4, followed by one 45mg dose every 12 weeks
• one 90mg dose in the same dosing schedule.

Both trials illustrated improvement of at least 75% from baseline in more than 50% of both CNTO-1275 arms (66.4% and 63.1% in the 45mg arms, and 66.4% and 72% in the 90mg arms). In the PHOENIX 1 trial, patients who had achieved a satisfactory PASI-75 by weeks 28 or 40 were then rerandomized to a withdrawal vs. maintenance phase. Those who received the maintenance dose did much better than those who were withdrawn.⁹ Furthermore, in both PHOENIX trials, after the primary efficacy data was collected at week 12, patients originally allocated to the placebo arm were again randomized into either 45mg or 90mg dosing every 12 weeks. The results of these crossover randomizations paralleled those of the original treatment groups.

Kimball et al.² conducted a similar study evaluating the efficacy of 5 dosing regimens of ABT-874:

• one 200mg dose at week 0
• 100mg every other week for 12 weeks
• 200mg weekly for 4 weeks
• 200mg every other week for 12 weeks
• 200mg every week for 12 weeks.

Ninety percent of the patients in the ABT-874 multiple-dose arms exhibited improvement of at least 75% from baseline vs. only 3% in the placebo group.

These studies exhibited a dose-response phenomenon, and response rates declined across all dosages after treatment was discontinued for more than 12 weeks.³ Additional support for this drug class as a treatment option for psoriasis includes a short response latency and sustainable efficacy. Response time for both drugs was very rapid, measured by PASI-50 at week 2 and PASI-75 by week 4.^2,9,10 The PHOENIX 1 trial continued for a total follow-up time of 76 weeks, and the PHOENIX 2 trial for 52 weeks, illustrating that maintenance dosing every 8-12 weeks ensures a sustained response.
This further indicates that IL-12 and IL-23 inhibitors have the potential to provide a treatment regimen that is not only successful but also convenient.¹²
Data further showed that maximum effects were reached by week 20, and that response rates had stabilized by week 28. They were successfully maintained throughout the remainder of the study at the dosage frequency of 1 dose (either the 45mg or 90mg originally assigned) every 8-12 weeks.^9,10

Disadvantages of IL-12/IL-23 Inhibitors

For studies using CNTO-1275, there were no significant differences in adverse events (AEs) between the treatment groups and placebo groups.^3,9,10 However, for ABT-874, Kimball et al.² reported a higher percentage of AEs in the treatment group vs. the placebo group.²
Patients receiving any dose of ABT-874 were significantly more likely to experience an AE than those in the placebo group, 36.1% vs. 10%, respectively. The AEs in the ABT-874 treated group were most commonly related to reactions at the injection site (erythema, pruritus, and irritation), but also included nasopharyngitis (12.0%) and upper respiratory tract infections (10.7%), followed by bronchitis and viral infection (both 2.7%). The incidences of other AEs were not statistically significantly different in the ABT-874 treatment group compared with placebo-treated patients.

The most commonly encountered AE was infection, which, surprisingly, did not show a significant dose-related trend. One major difference noted between CNTO-1275 and ABT-874 was the rate of AEs at the injection site. Such events occurred at a much higher frequency with ABT-874. Injection site reactions occurred in 16.7% of patients in the study arms treated with ABT-8742 vs. only 1.2%-2% in the CNTO-1275 studies.^3,9,10 In all 4 studies the occurrence of adverse injection reactions among the placebo groups was 0%-2%. The development of antibodies to the drugs also remains a concern with these treatments.


Krueger et al.3 reported AEs in 51 of 64 patients (79%) in the treatment group vs. 46 of 64 patients (72%) in the placebo group (p=0.19). Three of these patients (4%) developed antibodies to CNTO-1275. AEs leading to hospitalizations and discontinuation of treatment occurred in 3 patients in the treatment group vs. 1 in the placebo group (p=0.69). Among the patients in the groups receiving treatment who experienced a serious AE, 2 of them were hospitalized for infections (1 for cellulitis and 1 for pneumonia).

The PHOENIX 1 trial9 reported AEs in 54% of patients in either treatment arm and in 48% of patients in the placebo arm. Of the patients who were getting CNTO-1275, 5.1% developed antibodies to this formulation. Serious AEs occurred in 1.2% of treatment groups vs. 0.8% in the placebo group.

The PHOENIX 2 trial10 reported AEs at an equal frequency among the treatment and placebo arms, both measuring in at approximately 50%. Twelve percent of patients developed antibodies to CNTO-1275. For the most part, these antibodies were found to be neutralizing. Serious AEs occurred in 2% of treatment groups vs. 0% in the placebo group.

Prior to the use of IL-12 and IL-23 inhibitors for the treatment of psoriasis, concern arose because of unrelated studies involving people and transgenic mice with IL-12 deficiencies. Populations of people with a congenital deficiency of the IL-12 p40 subunit or the IL-12 receptor were found to have an increased susceptibility to intracellular pathogens, including tuberculosis, Toxoplasma gondii and Leishmania major, as well as defective delayed type hypersensitivity reactions. Furthermore, IL-12 plays an integral role in immunity against multiple viruses, including herpes simplex virus, vesicular stomatitis virus, and murine aquired immunodeficiency syndrome (MAIDS).⁷ These specific concerns have not yet been proven to be an issue in the trials, but due to the tuberculosis concern, an exclusion criterion common to all 4 studies outlined that no person with active disease would be allowed to participate. Ultimately, long-term consequences of IL-12 and IL-23 inhibitor usage beyond 76 weeks have yet to be determined as the clinical trials are very recent.

Various studies involving autoimmune diseases in non-human models have shown that targeting IL-23 alone instead of targeting both may be a better strategy.1 Specifically, a study by Chan et al. showed that direct intradermal administration into mice of IL-23 alone, but not IL-12 alone, initiates a psoriatic type reaction. This TNF-mediated spectrum of events culminates in erythema, and acanthosis with parakeratosis that is accompanied by a mixed dermal infiltrate.

Another important consideration is the cost of these drugs. Although the exact market cost has not yet been established, biologic agents tend to be very expensive, and IL-12 and IL-23 inhibitors will likely not be an exception to this trend.

Conclusions

IL-12 and IL-23 inhibitors remain on the forefront of treatment options for inflammatory diseases such as psoriasis, Crohn’s disease, multiple sclerosis, and rheumatoid arthritis. Although the current data does not provide insight into the long-term effects of these drugs, results have been extremely encouraging. In light of the current research and results, IL-12 and IL-23 inhibitors are a very promising option in the treatment of psoriasis.

While the therapeutic effects were shown to have a dose-response relationship, the AEs illustrated no such trend. Furthermore, although the rate of AEs was higher in the ABT-874 treatment groups, these events were reported to be generally tolerable, easily managed, and did not cause a significant percentage of subjects to be discontinued from the study.² The current standard of care for psoriasis includes the use of broad spectrum anti-T-cell agents with accompanying immunosuppression,¹² and often necessitates early discontinuation and subsequent psoriatic flares. With the introduction of the IL-12 and IL-23 inhibitors, there is new hope for patients battling psoriasis, as these formulations offer a favorable balance between disease treatment, resolution, tolerable side-effects, and an overall improved quality of life.

References

1. Reddy M, Davis C, Wong J, et al. Modulation of CLA, IL-12R, CD40L, and IL-2Rá expression and inhibition of IL-12 and IL-23-induced cytokine secretion by CNTO 1275. Cell Immunol 247(1):1-11 (2007 May).
2. Kimball AB, Gordon KB, Langley RG, et al. Safety and efficacy of ABT-874, a fully human interleukin 12/23 monoclonal antibody, in the treatment of moderate to severe chronic plaque psoriasis. Arch Dermatol 144(2):200-7 (2008 Feb).
3. Krueger GG, Langely RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 356(6):580-92 (2007 Feb).
4. Piskin G, Sylva-Steenland RMR, Bos J, et al. In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol 176(3):1908-15 (2006 Feb).
5. Cargill M, Schrodi SJ, Chang M, et al. A Large-scale genetic association study confirms IL-12B and leads to IL-23R as psoriasis-risk genes. Am J Hum Genet 80(2):273-90 (2007 Feb).
6. Smith RL, Warren RB, Eyre S, et al. Polymorphisms in the IL-12â and IL-23R genes are associated with psoriasis of early onset in a UK cohort. J Invest Dermatol 128(5):1325-7 (2008 May).
7. Torti DC, Feldman SR. Interleukin-12, Interleukin-23, and psoriasis: current prospects. J Am Acad Dermatol 57(6):1059-68 (2007 Dec).
8. Stetsko D, Sauder DN. IL-12 and IL-23 in health and disease. Expert Rev Clin Immunol 4(3):301-3 (2008 May).
9. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and Safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371(9627):1665-74 (2008 May).
10. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 371(9625):1675-84 (2008 May).
11. Chan RC, Blumenschein W, Murphy E, et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med 203(12):2577-87 (2006 Nov).
12. Bartlett BL, Tyring SK. Ustekinumab for chronic plaque psoriasis. Lancet 371(9625):1639-40 (2008 May).

¹Center for Clinical Studies, Houston, TX, USA
²The Institute of Human Virology, University of Maryland, Baltimore, MD, USA
³Department of Dermatology, University of Texas Health Sciences Center,
Houston, TX, USA

ABSTRACT

Atypical presentations of typical dermatological conditions are common in human immunodeficiency virus (HIV). This article will focus on three specific topics: eosinophilic folliculitis, psoriasis, and cutaneous mycoses. Their unique presentations in HIV and treatments are discussed.

Key Words:
HIV, eosinophilic folliculitis, psoriasis, cutaneous mycoses

Despite attempts at increasing awareness of HIV and its transmission, this infection continues to spread and remains a significant cause of morbidity and mortality worldwide. As of 2003, there were an estimated 1 million people living in the US with HIV infection, and nearly 40,000 cases were diagnosed in 2005.¹ HIV infection affects nearly every organ system in the body, including the skin. HIV-infected patients can pose diagnostic challenges, as their altered immune status may lead to atypical presentations of common cutaneous diseases, as well as the occurrence of uncommon or opportunistic skin disorders. Management of cutaneous disease in sero-positive patients can also be challenging, as the dermatological manifestations may be more severe, may recur with greater frequency, and may be refractory to standard treatment. The addition of highly active antiretroviral therapy (HAART) further complicates the picture as other dermatologic manifestations may arise as part of the immune reconstitution phenomenon. The scope of issues encountered in HIV positive patients is too broad to discuss in its entirety. This article will focus on three diseases and their management: eosinophilic folliculitis, psoriasis, and cutaneous mycoses.

Eosinophilic Folliculitis

Eosinophilic folliculitis (EF) is seen commonly in HIV with CD4 cell counts of <250-300/mm3.2,³ It presents as recurrent, pruritic, erythematous papules and pustules that are usually distributed on the face, shoulders, upper back, and upper extremities.³ The pruritus associated with EF can be severe and debilitating. Its etiology is not well elucidated, but some theories propose an infectious derivation. EF is an example of a dermatosis that is associated with immune-reconstitution.³ It is described as a phenomenon wherein HAART triggers a generalized immune activation as viral loads decrease and CD4 lymphocytes increase.^{4, 5} Studies have shown that EF typically flares shortly after starting antiretroviral therapy, but will resolve from 3 weeks to several months later.³ Clinicians should warn patients with EF that after starting HAART, their skin will likely worsen initially, then improve.
EF can be difficult to manage, as response to treatment is variable and it tends to recur once treatment is discontinued. Various treatments have been employed, including: isotretinoin, UVB phototherapy, itraconazole, and metronidazole, among others, with contrasting results.² The treatment of EF with potent topical corticosteroids is reportedly effective, but is accompanied by skin atrophy and hypopigmentation. This can be a problem given the distribution of EF on the face, and can be especially challenging in dark-skinned individuals.⁶ A relatively recent case study showed promising results with topical tacrolimus. Subjects who applied daily topical tacrolimus 0.1% to the face had an average lesion clearance time of 2.6 months with an absence of residual scarring. The average remission of 12.3 months was seen in subjects with well controlled viremia on HAART. The associated pruritus subsided within days.² Given these promising results and the relative safety of topical tacrolimus, clinicians may want to consider this as an alternative to corticosteroids, which can cause hypopigmentation and scarring in dark skinned patients, resulting in potential disfigurement.

Psoriasis

The prevalence of psoriasis in HIV-infected individuals is the same or slightly higher than that seen in noninfected individuals, but its clinical presentation can be more severe.^{7, 8} The severity of presentation often correlates with the degree of immunosuppression. HIV-positive patients with pre-existing psoriasis may see a flare of lesions as their CD4 count decreases and their viral load increases. A higher frequency of guttate and inverse psoriasis, as well as cases of generalized erythrodermic type psoriasis, has been reported in HIV-positive patients.⁹ Psoriasis has been the presenting manifestation of HIV in some individuals, thus HIV testing should be considered in patients that present with de novo psoriasis.⁸

Treatment of psoriasis in HIV-positive patients can be challenging, as it is often refractory to standard psoriasis treatments.⁷ When started on HAART, patients’ psoriasis tends to improve as the immune system is reconstituted.¹⁰ Case reports have shown a dramatic and rapid improvement of psoriasis in HIV-positive patients who have been either started or restarted on HAART.^{7, 10} Consequently, these reports emphasize the importance of strict adherence to antiretroviral regimens. This response is paradoxical, as drugs effective at treating psoriasis are targeted at Tlymphocytes, yet a low CD4 cell count causes worsening of the psoriasis. Although still unclear, the development of psoriasis is postulated to be an expression of the disease, which depends on the ratio of CD4 to CD8 cells. This ratio decreases in advanced HIV.11 It is also thought that TNF-á, an inflammatory cytokine associated with both psoriasis
and HIV replication, may play a role.¹⁰ Subjects on HAART should have lower viral replication and therefore, reduced levels of TNF-á. The regulatory T-cell subpopulation may also play a role, as this dedicated population is deficient in psoriasis, but expanded in the peripheral blood of HIV patients on HAART.¹⁰ Additional research will need to be conducted to further elucidate this phenomenon. Regardless, strict adherence to an antiretroviral treatment regimen is an important point to remember and to relay to patients.

Cutaneous Mycoses

Cutaneous dermatophytosis is generally more varied, extensive, and atypical in HIV than in immunocompetent hosts. As with psoriasis, the frequency of cutaneous dermatophytosis in the HIV population is not significantly greater than in noninfected individuals. Involvement of the nails is seen as proximal, subungual onychomycosis. Often the majority of the toenails are involved, which is a classic sign in HIV-infected patients.¹² Extensive lesions refractory to treatment are typical.¹³ Pruritus and pain are not always present in this population despite the potential for extensive involvement.¹²

The most common etiologic organism of cutaneous fungal infection is Trichophyton rubrum, which generally inhabits the cornified layer of the dermis. Deeper penetration into the stratum corneum occurs after the dermatophyte releases enzymes, such as keratinase.¹⁴ The skin has a number of defense mechanisms in place to prevent penetration below the epidermis, including a cell-mediated response.¹⁵ In the immunocompromised population, however, invasive fungal infections can be identified, although they are rare. It is important to recognize and treat cutaneous fungal infections early, as delay of treatment allows for the
infection to become more deeply invasive. Deep or locally invasive dermatophyte infection will typically present as nodular eruptions near the initial site of infection. Abscesses, mycetomas, and atypical lesions may also occur.¹⁴

Treatments used for various mycoses in immunocompetent individuals may not be sufficient to treat the same infections in the immunocompromised. For example, systemic therapy may be necessary even for superficial infections, whereas topicals alone would likely be adequate to treat the same infection in immunocompetent patients.¹² Resistance to oral antifungals, such as fluconazole, is a problem when it is used long-term as prophylaxis or for frequent short-term exposures. These drugs are used to treat candidal infections. In addition, immunosuppressed patients are more likely to be infected with atypical fungi.¹² Oral antifungals such as ketoconazole, fluconazole, and griseofulvin are usually effective in treating superficial and deep dermatophyte infections in this population.¹⁴ However, when systemic therapy fails to be curative, surgery may be required. Failure to eradicate the infection has led to death in patients due to septicemia and systemic dissemination.^{16, 17} In order to make a proper diagnosis and prescribe an appropriate treatment regimen, it is important that, in addition to potassium hydroxide (KOH) mounts, cultures be performed on Sabouraud’s agar to allow for specific species identification.¹⁴

In some cases, antiretroviral therapy alone is sufficient to clear dermatophyte infections in immunosuppressed patients. However, it is important to consider possible interactions between antiretrovirals and antifungals, particularly ketoconazole. Although not contraindicated, it is advisable to use the medications concomitantly with close observation, as both ketoconazole and certain antiretrovirals have an effect on cytochrome P-450, leading to increases or decreases in either ketoconazole levels and/or antiretroviral levels.¹⁸ Other antifungals such as griseofulvin and terbinafine have not been shown to interact with HIV medications, and no specific warnings exist.¹⁴ Amphotericin B, a potent broad spectrum antifungal agent is still used in certain cases. However, this drug has substantial toxicity and must be used with caution. The development of an entirely different class of antifungals, echinocandins, has had a significant impact on the therapeutic approach to fungal infections. Drugs in this class, such as caspofungin, have few side-effects and few drug interactions. However, this drug does not have an oral preparation and has a relatively narrow spectrum of activity when compared with amphotericin B.¹² The choice of an antifungal agent will depend on the patient, the organism being treated, and the severity of the infection.

Conclusion

HIV infection can lead to a myriad of dermatoses with complicated clinical presentations. The altered immune status of HIV-infected individuals leads to diagnostic and therapeutic challenges. As dermatologists, it is important to be aware of the varied dermatoses associated with HIV, as well as their management. Knowledge of HIV-associated dermatologic manifestations may be useful in helping to make the diagnosis of HIV. Additionally, recognition of the need for more intensive therapy in these patients can provide improved care, and ultimately, improved patient outcomes.

References

1. Department of Health and Human Services. Center for Disease Control Cases of HIV infection and AIDS in the United States and dependent areas, 2005.
   HIV/AIDS Surveillance Report, Volume 17, Revised Edition, June 2007.
2. Toutous-Trellu L, Abraham S, Pechere M, et al. Topical tacrolimus for effective treatment of eosinophilic folliculitis associated with human immunodeficiency virus infection. Arch Dermatol 141(10):1203-8 (2005 Oct).
3. Rajendran PM, Dolev JC, Heaphy MR, et al. Eosinophilic folliculitis: before and after the introduction of antiretroviral therapy. Arch Dermatol 141(10):1227-31 (2005 Oct).
4. Lawn SD, Wilkinson RJ. Immune reconstitution disease associated with parasitic infections following antiretroviral treatment. Parasite Immunol 28(11):625-33 (2006 Apr).
5. Couppie P, Abel S, Voinchet H, et al. Immune reconstitution inflammatory syndrome associated with HIV and leprosy. Arch Dermatol 140(8):997-1000(2004 Aug).
6. Grange F, Schoenlaub P, Tortel MC, et al. AIDS-related eosinophilic folliculitis: efficacy of high dose topical corticotherapy. Ann Dermatol Venereol 123(8):456-9(1996).
7. Mamkin I, Mamkin A, Ramanan SV. HIV-associated psoriasis. Lancet Infect Dis 7(7):496 (2007 Jul).
8. Rigopoulos D, Paparizos V, Katsambas A. Cutaneous markers of HIV infection. Clin Dermatol 22(6):487-98 (2004 Nov-Dec).
9. Morar N, Dlova N, Gupta AK, et al. Erythroderma: a comparison between HIV positive and negative patients. Int J Dermatol 38(12):895-900 (1999 Dec).
10. De Socio GV, Simonetti S, Stagni G. Clinical improvement of psoriasis in an AIDS patient effectively treated with combination antiretroviral therapy. Scand J Infect Dis 18(1):44-57 (2006 Jan).
11. Fife DJ, Waller JM, Jeffes EW, Koo JYM. Unraveling the paradoxes of HIV-associated psoriasis: a review of T-cell subsets and cytokine profiles. Dermatol Online J 13(2):4 (2007).
12. Venkatesan P, Perfect JR, Myers SA. Evaluation and management of fungal infections in immunocompromised patients. Dermatol Ther 18(1):44-57 (2005 Jan-Feb).
13. Trope BM, Lenzi ME. AIDS and HIV infections: uncommon presentations. Clin Dermatol 23(6):572-80 (2005 Nov-Dec).
14. Burkhart CN, Chang H, Gottwald L. Tinea corporis in human immunodeficiency virus-positive patients: case report and assessment of oral therapy. Int J Dermatol 42(10):839-43 (2003 Oct).
15. Chastain MA, Reed RJ, Pankey GA. Deep dermatophytosis: report of two cases and review of the literature. Cutis 67(6):457-62 (2001 Jun).
16. Hironaga M, Okazaki N, Saito K, et al. Trichophyton mentagrophytes granulomas: unique systemic dissemination to lymph nodes, testes, vertebrae, and bone. Arch Dermatol 119(6):482-90 (1983 Jun).
17. Rinaldi MG. Dermatophytosis: epidemiological and microbiological update. J Am Acad Dermatol 43(5 suppl1):S120-4 (2000 Nov).
18. Bartlett JG, Gallant JE. Medical Management of HIV Infection. 2007 ed. Baltimore (MD): Johns Hopkins University, Division of Infectious Diseases (2007).