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Safety and Efficacy of Topical Cidofovir to Treat High-Grade Perianal And

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Safety and Efficacy of Topical Cidofovir to Treat High-Grade Perianal And Safety and efficacy of topical cidofovir to treat high-grade perianal and vulvar intraepithelial neoplasia in HIV-positive men and women Elizabeth A. Stiera, Stephen E. Goldstoneb, Mark H. Einsteinc, Naomi Jayd, John M. Berryd, Timothy Wilkine, Jeannette Y. Leef, Teresa M. Darraghg, Maria Da Costad, Lori Pantherh, David Aboulafiai and Joel M. Palefskyd 09/15/2020 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD35y8U/jUqeEzZu3CM2R+euzaQ04PJ10v9LxBxxWvdNy4= by https://journals.lww.com/aidsonline from Downloaded Downloaded Objective: To evaluate the safety and efficacy of topical cidofovir for treatment of high- from grade squamous perianal intraepithelial neoplasia (PAIN) and vulvar intraepithelial https://journals.lww.com/aidsonline neoplasia (VIN) lesions in HIV-positive individuals. Design: Phase IIa prospective multicenter trial conducted at eight clinical sites through the AIDS Malignancy Consortium. Methods: HIV-positive patients with biopsy-proven high-grade PAIN that was at least 3cm2 were enrolled. PAIN biopsy specimens were assessed for human papillomavirus by (HPV) using PCR and type-specific HPV probing. Participants applied 1% topical BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD35y8U/jUqeEzZu3CM2R+euzaQ04PJ10v9LxBxxWvdNy4= cidofovir to PAIN and VIN (if present) for six 2-week cycles. Results were designated as complete response (CR), partial response (PR) (>50% reduction in size), stable disease, or progressive disease (PD). Results: Twenty-four men and nine women (eight with high-grade VIN as well) were enrolled. Mean age was 44 years and mean CD4þ cell count was 412 cells/ml. HPV DNA (most commonly HPV16) was detected in all pretreatment study specimens. Twenty six (79%) participants completed treatment per protocol: CR, five (15%); PR, 12 (36%), stable disease, seven (21%); PD, two (6%) (one with a superficially invasive cancer and one with new area of high-grade PAIN). Treatment was well tolerated with most common adverse events being mild to moderate affecting lesional skin: pain/ burning/irritation (25 patients) and ulceration (13 patients). Conclusion: Topical cidofovir had 51% efficacy in the short-term treatment of high- grade PAIN and VIN with acceptable toxicity in HIV-positive individuals. Randomized control studies with more prolonged treatment courses and longer follow-up to assess the durability of the response are needed. ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2013, 27:545–551 Keywords: Bowen’s disease, cidofovir, HIV, human papillomavirus, perianal intraepithelial neoplasia, vulvar intraepithelial neoplasia on 09/15/2020 aDepartment of Obstetrics and Gynecology, Boston University Medical Center, Boston, Massachusetts, bMount Sinai School of Medicine, New York, cAlbert Einstein College of Medicine, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, dUniversity of California at San Francisco, San Francisco, California, eDivision of Infectious Diseases, Weill Cornell Medical College, New York, New York, fUniversity of Arkansas for Medical Sciences, Little Rock, Arkansas, gDepartment of Pathology, University of California at San Francisco, San Francisco, California, hBeth Israel Deaconess Medical Center, Boston, Massachusetts, and iVirginia Mason Medical Center and University of Washington, Seattle, Washington, USA. Correspondence to Elizabeth A. Stier, Department of Obstetrics and Gynecology, Boston University Medical Center, 85 E. Concord Street, 6th floor, Boston, MA 02118, USA. E-mail: [email protected] Received: 3 August 2012; revised: 14 September 2012; accepted: 20 September 2012. DOI:10.1097/QAD.0b013e32835a9b16 ISSN 0269-9370 Q 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins 545 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 546 AIDS 2013, Vol 27 No 4 Introduction Surgery Care, New York, New York, USA; Montefiore Medical Center, Bronx, New York, USA; University of HPV-associated cancers of the perianus and vulva in HIV- California, San Francisco, California, USA; Virginia infected individuals continue to be a significant cause Mason Medical Center, Seattle, Washington, USA; of morbidity in the era of HAART [1]. High-grade Weill-Cornell Medical College, New York, New York, squamous perianal intraepithelial neoplasia (PAIN) and USA; Beth Israel Deaconess Medical Center, Boston, vulvar intraepithelial neoplasia (VIN), the precursors to Massachusetts, USA; University of California, Los invasive squamous cell cancer, are particularly difficult to Angeles, California, USA). Institutional review boards treat due to their multifocal presentation and tendency for of the participating institutions approved the study. Each recurrence [2–4]. participant gave written-informed consent (clinical trial.gov unique identifier: NCT00550589). Standard therapies for diffuse high-grade perianal or vulvar disease include laser ablation, cryotherapy, We enrolled adult men and women with documented electrocautery, and surgical excision with possible skin HIV-1 infection and biopsy-proven high-grade PAIN grafting or skin flaps [2–4], all of which carry significant within 12 weeks of study entry covering a surface area of morbidity such as prolonged postprocedure pain, at least 3 cm2. The perianus was defined as the skin within scarring, risk for infection, incomplete healing, incon- a 5 cm radius of the anal verge, and thereby included tinence, and sexual dysfunction [5–8]. Immunocompe- women with high-grade VIN on the posterior perineum. tent patients have recurrence rates after treatment of 25– Patients receiving ART had to be on a regimen for at least 50% [5] and HIV-positive patients have recurrence rates 12 weeks prior to entry. If they were not receiving ART, of 60–80% [9–11]. the CD4þ T-cell level needed to exceed 200 cells/ml. For patients receiving ART, any CD4þ T-cell level was Topical treatments such as imiquimod and 5-fluorouracil acceptable. creams have some efficacy for treatment of high-grade PAIN and anal canal intraepithelial neoplasia (AIN) in Cidofovir was provided by Gilead Sciences, Inc (Foster HIV-infected men [12–15]. However, treatment with City, California, USA) and compounded by the study these agents have substantial skin and mucosal toxicity compound pharmacy (MasterPharm, LLP, Richmond that often leads to discontinuation of treatment. There are Hill, New York, USA) into a 1% topical cream packaged few reports of topical treatments applied to high-grade in 10 g tubes, sufficient for two treatment cycles. The VIN and PAIN in HIV-infected women [7,16]. vanishing cream base was an emulsion of mineral oil, deionized water, cetyl alcohol, ceresin wax, beeswax, and Cidofovir is a cytidine nucleotide analogue with in-vitro sodium borate. Each batch underwent testing by a third and in-vivo activity against a broad spectrum of party (Eagle Analytical Services, Houston, Texas, USA) herpesviruses as well as adenoviruses, human papilloma- to confirm potency and uniformity. Approval of the viruses (HPVs), polyomaviruses, and human poxviruses compounded product by the Food and Drug Adminis- [17]. It is currently licensed for intravenous treatment of tration was obtained prior to initiating the trial cytomegalovirus infections. The mechanisms of action of (Investigational New Drug 74 757). cidofovir on HPV-associated neoplasia are not fully elucidated [18,19]. Study protocol Lesion measurements were taken from the photo- Several small studies have shown near-complete clearance documentation of high-grade PAIN and VIN with the rates of genital warts, with acceptable toxicity, using skin on gentle stretch after application of 3–5% acetic topical cidofovir in HIV-infected patients [9,20–23]. acid. A software program (Second Opinion, Torrance, Because of the clinical efficacy and tolerability for warts California or DermImage, New York, New York, USA) reported in these studies, we conducted a pilot study to was used to calculate the total lesion area from the evaluate the safety and efficacy of topical cidofovir in digital images. HIV-infected patients for treatment of high-grade squamous intraepithelial neoplasia of the perianus and Pretreatment specimens for histology and correlative vulva. studies included two 3-mm biopsies of the lesions. One specimen was placed in formalin. The other biopsy was flash-frozen for HPV DNA typing. All biopsy sites were photo-documented, so that biopsies collected during and Methods after treatment could be taken from the same location(s). AIDS Malignancy Consortium (AMC) Protocol 046 was The participants self-applied the study cream sparingly in a multicenter, single-arm, open-label, pilot trial con- a thin layer over the affected areas with a gloved finger ducted at eight AMC clinical trial sites (Boston University once daily and then washed the cream off 6–8 h later. Medical Center, Boston, Massachusetts, USA; Laser Women with high-grade VIN were instructed to apply Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Topical cidofovir for high-grade PAIN Stier et al. 547 the treatment medication to both the high-grade VIN two pathologists. Each study pathologist was blinded to and PAIN. Treatments occurred for 5 consecutive days the interpretation of the others. followed by no treatment for 9 days (a 14-day treatment cycle). Participants received a treatment diary to record Sample size the timing of treatment and any side effects during each Thirty-three participants were enrolled to detect a 50% week treatment
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