What is the evidence for effective treatments for acquired epidermodysplasia verruciformis in human immunodeficiency virus (HIV) infected patients?
A 13-year-old Dominican boy with a history of congenital HIV infection receiving highly active antiretroviral therapy (HAART), with a CD4 lymphocyte count higher than 1000/μL and undetectable viral load, presented for treatment of asymptomatic but cosmetically distressing skin lesions that had been present for 10 years. (To convert the lymphocyte count to ×109/L, multiply by 0.001.) At presentation, the patient appeared to be healthy and had numerous hypopigmented, round, discrete, and coalescing macules, 2 to 4 mm in diameter, and very thin papules distributed across his forehead, frontal and parietal scalp, and dorsal hands (Figure). Epidermodysplasia verruciformis (EV) was suspected and confirmed by biopsy findings.
A 13-year-old boy with human immunodeficiency virus and epidermodysplasia verruciformis. A, Numerous hypopigmented thin, coalescing papules present on the left dorsal hand. B, After treatment, discrete hypopigmented macules on the left dorsal hand can be seen. Note the decreased density of macules.
Epidermodysplasia verruciformis is a rare genodermatosis first described in 1922 by Lewandowsky and Lutz.1The disease presents with diffuse pityriasis versicolor-like macules and verruca plana–like papules on the body, beginning early in life and persisting through adulthood. Mutations of the EVER1/TMC6(GenBank 11322) and EVER2/TMC8(GenBank 147138) genes on chromosome 17q25 have been identified in patients with autosomal recessive EV, although X-linked transmission has also been suggested based on clinical examination of affected family members.2,3Lesions are important to monitor and treat because those positive for human papillomavirus (HPV) 5 and HPV-8 on polymerase chain reaction are at increased risk of developing squamous cell carcinoma (SCC) presenting by the fourth or fifth decades of life.4,5
In recent years, a number of reports have emerged of EV arising in the setting of immunodeficiency, most commonly in conjunction with HIV.6- 8The disease course of EV and the risk of progression to SCC in immunocompromised patients are unknown, largely owing to the small number of patients and a lack of long-term follow-up. The nature of the disease, however, seems to be similar to inherited EV, and patients with acquired EV are likely at increased risk for development of SCC. In histologic studies, immunocompromised individuals with EV lesions show a higher rate of HPV-related dysplasia than those with congenital EV.9We evaluated available evidence for the treatment options of acquired EV in the pediatric age group.
We searched PubMed using the MeSH descriptor “epidermodysplasia verruciformis” in combination with the terms “immunocompromised,” “HIV,” “therapeutics,” and “treatment.” We reviewed all English-language articles published from January 1950 to June 2009, inclusive of all study types (case reports, case series, and prospective and retrospective studies). We also reviewed relevant textbooks and cross-referenced relevant bibliographies.
We reviewed literature on EV in both immunocompetent and immunocompromised individuals. We found no randomized controlled trials of treatments for this condition in either population. We reviewed 88 articles (case reports and series) that documented approximately 137 cases of EV, 23 of which were secondary to immunosuppression (HIV, renal transplant, graft vs host disease, chemotherapy, and lupus). In addition, of the cases reporting acquired EV secondary to HIV, less than 10 documented treatment courses. Owing to the scarcity of reviews on treatment of acquired EV, we examined treatment of congenital EV with the assumption that efficacy would likely be comparable in acquired EV or EV in the pediatric age group.
Imiquimod has been used in 4 patients, with varying success.
A 22-year-old man presented with SCC in situ in association with EV and was treated with imiquimod applied 5 times weekly for 3 months. This regimen resulted in significant improvement in the multiple facial SCC in situ, but the EV lesions of the extremities were not treated.10
A 52-year-old man was prescribed systemic interferon (6 million U, 2 times weekly for 8 months) and imiquimod (5 times weekly for 17 weeks) for treatment of Bowen disease and EV, with resulting resolution of both at follow-up of 17 weeks.11
In contrast, lesions of 2 HIV-positive brothers (11- and 12-years old) did not improve after treatment with imiquimod 3 times weekly for 2 months.12
Combination therapy with interferon alfa and imiquimod or systemic retinoids has been used.
A 19-year-old woman with a 12-year history of persistent EV lesions was treated with interferon alfa-2a, 3 million U, 3 times weekly, and acitretin, 50 mg/d for 6 months, with complete clinical resolution of disease. Lesions recurred after 3 months off treatment, and the patient was prescribed acitretin for an additional 3 months. Her face remained lesion-free at her 1-year follow-up, although EV lesions recurred on the hands.13
A 43-year-old woman with EV and a history of multiple oral and genital SCC was prescribed peginterferon alfa, 1 μg/kg/wk, and acitretin, 0.2 mg/kg/d, but relapsed clinically after peginterferon alfa-2b was discontinued. Six months after her acitretin dose was increased to 0.5 mg/kg/d, only a few EV lesions were visible.14
Oral retinoids (acitretin and etretinate) as monotherapy are helpful in decreasing overall lesion number, but recurrence is common after discontinuation of medication.15- 17
A 20-year-old immunocompetent man with EV achieved marked decrease in the size and number of lesions after 6 months of isotretinoin, 0.8 mg/kg/d, which was maintained with low-dose isotretinoin, 0.3 mg/kg/d.18
Treatment of 4 patients with congenital EV (ages 31-52 years) with etretinate, 1 mg/kg/d for 4 months, resulted in flattening and lightening of lesions. Complete clearing was never seen, and lesions returned after cessation of treatment.15
A 25-year-old woman with extensive EV lesions for 19 years was treated with oral acitretin, 0.5-1 mg/kg/d, for 6 months, which slightly improved the appearance of her lesions. After discontinuation of treatment, the lesions returned to their baseline state.16
A 14-year-old girl and her 18-year-old brother, who had EV and other medical morbidities, were treated with etretinate, 1 to 1.5 mg/kg/d. The lesions initially showed mild to moderate flattening but recurred after discontinuation of the medication.17
Oral cimetidine, a histamine 2 antagonist, has been used in the treatment of EV lesions and was unsuccessful in a case series of 8 female patients, most of whom had cutaneous anergy (ages 15-40 years).19
In HIV-positive patients, the effect of HAART on EV lesions has been reported in 5 cases.
A 45-year-old man presented with numerous EV lesions. With HAART therapy and increase in CD4 lymphocyte count from 100/μL to 500/μL, the lesions had cleared completely by his 3-year follow-up.6
A 38-year-old man with diffusely distributed lesions showed no benefit after starting HAART therapy, despite an increase in CD4 lymphocyte count and a decrease in viral load. He was also unsuccessfully treated with cyrotherapy, podophyllotoxin, and imiquimod.7
In a case series of 3 patients with untreated HIV and a CD4 lymphocyte count of less than 400/μL, only 1 patient showed decrease in lesion number after initiation of HAART therapy.8
To our knowledge, there are no randomized trials reported in the literature on treatments for EV given the rarity of this disease. Long-term follow-up is not available in most cases. Therapies are often used in combination or in succession, making it difficult to evaluate the efficacy of each medication. Ethnicity is underreported, and cosmetic results may vary depending on skin type. Most reports document off-label uses of drugs for congenital EV, not acquired EV.
No treatment options consistently resulted in clearing of lesions.
The number of reported cases for each treatment modality was too small to draw definitive conclusions.
Imiquimod demonstrated mixed results in 3 patients but resulted in decreased lesion number in combination with interferon in a separate patient.
Combination therapy of interferon and retinoids has decreased the number of EV lesions in select case reports. Lesions tend to recur after cessation of therapy, although low-dose maintenance retinoids may prevent recurrence.
Cimetidine is not helpful in resolution of EV lesions.
Highly active antiretroviral therapy may be beneficial in patients with HIV owing to enhanced cellular immunity.
Although no specific treatment guidelines exist for children and adolescents, all of the treatment modalities use medications that have been safely used in the pediatric population.
Although treatments for congenital EV may be effective for acquired EV, clinical response in immunosuppressed patients is unknown.
A formal systematic review of the evidence could provide additional insight into treatment of acquired EV.
Owing to limitations of health care coverage, the only therapy available for our patient in addition to HAART was topical imiquimod. He used the medication twice daily for 2 months and then once daily for 6 months. At 8 months, the lesions appeared clinically resolved, with only residual hypopigmented macules (Figure). Findings from a subsequent biopsy specimen of the hand demonstrated no histologic evidence of EV. His response suggests that prolonged topical use of imiquimod and concomitant oral HAART therapy is effective in eliminating EV in pediatric patients with HIV infection, but long-term follow-up data are not available, and only limited conclusions can be drawn from a single case.
Correspondence:Lionel Bercovitch, MD, Department of Dermatology, Rhode Island Hospital, 593 Eddy St, Providence, RI 02903 (Lionel_Bercovitch@brown.edu).
Author Contributions:All authors had full access to all the patient data in the study and take responsibility for the integrity of the patient data. Study concept and design: Lee and Risser. Acquisition of data: Lee, Risser, and Bercovitch. Analysis and interpretation of data: Lee, Risser, and Bercovitch. Drafting of the manuscript: Lee. Critical revision of the manuscript for important intellectual content: Lee, Risser, and Bercovitch. Study supervision: Bercovitch.
Financial Disclosure:None reported.
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