Topical cidofovir for benign human papillomavirus–associated skin lesions

Abstract

Cidofovir is a broad-spectrum antiviral agent that has shown efficacy against skin lesions caused by human papillomavirus (HPV). We present a case of extensive verruca vulgaris lesions refractory to imiquimod that was responsive to topical cidofovir therapy, and analyze other case series in the literature of successful treatment of benign HPV-associated skin lesions with topical cidofovir. Topical cidofovir’s favorable response rate and tolerability make it a useful treatment option for patients of differing ages and immune status who have nonmalignant HPV-associated skin lesions and desire topical therapy.

Introduction

Cidofovir is a broad-spectrum antiviral agent that possesses activity against several DNA viruses. It is a potent nucleoside analog of deoxycytidine monophosphate, and its mechanism of action involves induction of apoptosis in infected cells via accumulation of pro-apoptotic proteins such as p53. ¹ It has been used to treat infections with herpes simplex virus (HSV), molluscum contagiosum, and human papillomavirus (HPV). ² Whereas systemic cidofovir has numerous side effects, topical cidofovir is generally well-tolerated, except for two cases of acute kidney injury reported in association with its use to treat resistant HSV infections. ³ However, both of these cases involved potential confounding factors, including concomitant use of medications known to induce kidney injury. As a result of its overall favorable tolerability and response rate, use of topical cidofovir for HPV-associated skin lesions refractory to other treatment modalities has gained acceptance. Herein, we present a case of large surface area plaque verruca vulgaris refractory to topical imiquimod therapy that was successfully treated with topical cidofovir, and we consider other case series in the literature employing topical cidofovir for benign HPV-associated skin lesions refractory to other treatment modalities. Taken together, this case and those reported in the literature support use of topical cidofovir for HPV-associated lesions for both immunocompetent and immunocompromised patients across a broad range of ages and lesion locations.

Case Report

A 43-year-old woman of African descent presented with multiple large verrucous plaques located on both palms and the right foot, present for 6 months. The lesions had previously been treated with multiple modalities, including cryotherapy, surgical excision, and grafting by plastic surgery. The patient presented to dermatology seeking a second opinion for non-surgical treatment options. Her past medical history was notable for chronic back pain and atopic dermatitis, and she used clobetasol propionate 0.05% ointment twice daily for dermatitis flares.

Physical examination revealed well-demarcated, hyperkeratotic, exophytic, hypopigmented verrucous plaques located on both palms and the medial arch of the right foot (Figure 1). This presentation was unusual in that the lesions were plaque-like and ranged in diameter from 3 to 9 cm, instead of the more typical nodular or papular lesions measuring millimeters in diameter. Serologic tests for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) were negative. Complete blood count, comprehensive metabolic panel, and immunoglobulin profiles were within normal limits.

Figure 1.

Verrucous plaques located on both palms (left) and the medial arch of the right foot (right) before treatment with topical cidofovir.

Three punch biopsy specimens were taken, from lesions on each palm and from the arch of the right foot. Prominent papillomatosis, compact hyperkeratosis with focal hemorrhage, hypergranulosis, and acanthosis were present, yielding findings diagnostic of verruca vulgaris. Topical imiquimod was attempted twice daily with nightly occlusion, 5 days per week for 4 months, but the lesions remained unresponsive. During a return visit, the risks, benefits, and potential side effects of systemic cidofovir, topical cidofovir, intralesional bleomycin, and topical 5-fluorouracil were discussed. The patient elected to attempt topical cidofovir 3% cream, which was prescribed for use twice daily. The 3% topical cidofovir was compounded using 0.75 g cidofovir 75 mg/mL (Vistide injection, Gilead Sciences, Inc., Foster City, CA) in 22.5 g of Eucerin cream (Beiersdorf AG, Hamburg, Germany).

After 8 weeks of treatment, the verrucous lesions had been reduced to pink granulated plaques. Cidofovir was discontinued at this point, and the patient was instructed to apply Vaseline. 15 weeks after initiation of treatment, the patient showed gross re-epithelialization of affected areas and focal repigmentation (Figure 2).

Figure 2.

15 weeks after initiating topical cidofovir therapy, the patient demonstrates re-epithelialization and focal repigmentation.

Discussion

Verruca vulgaris is an HPV-associated lesion that often persists despite a battery of treatment modalities, such as cryotherapy, surgical excision, and laser therapy. Consequently, it is crucial to seek alternative treatments in order to relieve the pain, impairment, or cosmetic distress that patients may experience due to these lesions; topical cidofovir has emerged as one of these second-line therapies. Review of the literature identified a number of case series of verruca vulgaris and other HPV-associated lesions treated with topical cidofovir in cream, gel, ointment, or flexible collodion form. For simplicity, only case reports, series, and randomized controlled trials reporting data on complete resolution of lesions were included, and data from use of intralesional or intraurethral cidofovir were not included. Cohorts were composed of immunocompetent and immunocompromised adult and pediatric patients ranging in size from 2 to 126 patients. Duration of application varied from 1 week to 6 months. Response rates, defined as percentage of patients achieving complete resolution of lesions, ranged from 32% to 100%, with a weighted response rate of approximately 56.6% (Table 1). The majority of outcomes were maintained over time, even in cases of periungual and plantar warts.^2,4-30

Table 1.

Studies utilizing topical cidofovir for cutaneous HPV-associated lesions.

Reference No	Study population	Location of treatment	Topical cidofovir formulation	Dosing schedule	Response rate, %
2	9 immunocompromised patients with age range 27–45	Face, lips, hands, anal, and genital	1%	BID x 2 weeks for cutaneous lesions, QD x 5 consecutive days for 2 weeks for mucosal lesions	100
4	41 immunocompetent patients with age range 4–60	Periungual	3%	BID (37/41 patients) or QD (4/41 patients) for median duration 10 weeks	56.1
5	35 immunocompetent patients with age range 6–55	Plantar	1% or 3%	BID (31/35 patients) or QD (4/35 patients) for median duration 11 weeks	54.3
6	5 immunocompetent and 2 immunocompromised patients with age range 9–12	Hands and feet	1%	QD for average duration 8 weeks	57.1
7	17 immunocompromised patients with average age 38	Anogenital	1%	QD x5 consecutive days, then 1 week off, repeating this cycle for average duration 12.1 weeks	32
8	4 immunocompetent patients with age range 29–59	Vulvar, periungual, hands, inguinal, and perianal	1%	QD x 5 consecutive days, then 1 week off, repeating this cycle until clear	50
9	2 immunocompetent patients, ages 8 and 13	Legs, fingers	3%	BID x 10–14 days or QD x 10 weeks	100
10	16 immunocompetent patients with age range 6–14	Face, lips, hands, feet, anal, and periungual	3%	BID x 1–24 weeks	75
11	3 immunocompromised patients with age range 31–37	Perianal	1%	QD x 2 weeks	100
12	19 immunocompetent patients with age range 20–51	Genital and perianal	1%	QD x 5 consecutive days, then 1 week off for maximum 12 weeks	47
13	1 immunocompetent patient, age 48	Genital	1.5%	2–3 applications per week x 6 weeks	100
14	1 immunocompromised patient, age 36	Gingival	1%	QD x 8 weeks	100
15	1 immunocompromised patient, age 42	Unspecified	1%	Two weeks	100
16	1 immunocompromised patient, age 36	Right lower extremity	1%	BID x 1 week, then 1 week off for total of 6 weeks	100
17	1 immunocompromised patient, age 37	Right foot	3%	BID x 4 weeks	100
18	1 immunocompromised patient, age 16	Bilateral hands	1%	QD x 6 months	100
19	1 immunocompetent patient, age 10	Hands and nose	1%	QD x 8 weeks	100
20	2 immunocompromised and 10 immunocompetent patients, age range 4–16	Hands, feet, face, and knees	1–3%	Variable, QD or QOD x 3–16 weeks	25
21	9 immunocompetent patients, age range 5–36	Genital and perianal	1–3%	Variable, QD or BID x 1–12 weeks	66
22	126 immunocompetent patients, age range 3–67	Periungual, anogenital, plantar, lips, knees, and elbows	1–3%	QD or BID x 3–40 weeks	53.2
23	1 immunocompromised patient, age 9	Right foot	1%	QD x 6 weeks	100
24	2 immunocompromised patients, ages 7 and 12	Plantar	3%	QD x 5 months	100
25	7 immunocompromised patients	Unspecified	1%	QD x 2–4 weeks	28.6
26	1 immunocompetent patient, age 3	Penile	1%	QD x 5 consecutive days for two weeks, 30-day hiatus, and then repeat for total two cycles	100
27	1 immunocompromised patient, age 5	Genital	1%	BID x 2 weeks on then 2 weeks off for 4 months	100
28	1 immunocompromised patient, age 13	Bilateral hands	1%	QD x 5 days on then 9 days off for total of two cycles	100
29	1 immunocompromised patient, age 8	Bilateral hands, perioral, nose, eye, and toe	3%	2 months	100
30	3 immunocompromised patients, age range 36–51	Oral	1 or 3%	3–10 weeks	100

The diverse array of patients who demonstrated positive response to topical cidofovir according to the literature was notable, corroborating this as a widely applicable treatment option in patients of varying age, immune status, and lesion presentation. In conjunction with the multitude of literature-reported successes in treating HPV-associated lesions with topical cidofovir, our case substantiates use of this treatment in patients with severe refractory disease.