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The patient was subsequently treated with IVIG, 0.4g/ Intralesional Cidofovir for Treating Extensive Genital kg/d, for 5 consecutive days for her newly diagnosed CVID, Verrucous Infection while local application of paraffin gauze dressing (Jelonet; Verrucous herpes simplex viral infections in immunocom- Smith & Nephew) was maintained. Surprisingly, 3 weeks promised patients can be a therapeutic challenge, and we after this single cycle, all ulcerations had healed (Figure 2), present a case of successful treatment with intralesional and complete resolution of pain was reported. The immu- cidofovir. noglobulin levels remained stable 3 months after IVIG treat- ment, and no further ulcerations were detected during a Report of a Case | A 55-year-old man with human immunodefi- 2-year follow-up, and so the patient did not require addi- ciency virus (HIV) and hepatitis C virus coinfection pre- tional therapy. sented with new lesions on his scrotum and perianal area. He noted mild tingling and slow growth over the prior 2 months. Discussion | In our case, no significant success was observed in His medications included darunavir, ritonavir, emtricitabine/ reduction of NL ulcers after administration of currently ac- tenofovir, and trimethoprim-sulfamethoxazole. His CD4 count cepted treatments, the efficiency of which was known to be was stable at 350 cells/μL, and he had an undetectable HIV vi- limited. Interestingly, treatment of the patient’s CVID with IVIG ral load. Findings of a comprehensive metabolic panel and com- appeared to heal the ulcers within 3 weeks. As the IVIG treat- plete blood cell count were normal, and rapid plasma reagin ment showed a similar dramatic ulcer reduction within 2 weeks was nonreactive. Physical examination was notable for exo- inapreviouscase3 (where no investigation of associated hy- phytic, verrucous, and ulcerated plaques on his right inferior pogammaglobulinemia was performed), the immunologic as- scrotum and perianal area (Figure 1A and B). Biopsy and tis- pect of NL appears of major importance in these patients. Be- sue culture were performed. Histopathologic analysis dem- cause of its strong association with diabetes, NL has been onstrated full-thickness epidermal ulceration with adjacent postulated to arise due to microangiopathic vascular changes. pseudoepitheliomatous hyperplasia (Figure 2A and B). Mul- Therefore, NL might be due to immunologically mediated vas- tinucleated keratinocytes with peripheral rimming of nuclear cular changes.4,5 In this context, measures of serum immu- chromatin were present at the edge of the ulceration (Figure 2B noglobulin levels and direct immunofluorescent histologic and C), and immunostaining for herpes simplex virus (HSV) study might be recommended in NL. was positive, confirming HSV infection (Figure 2D). Gram and Our findings suggest that IVIG can be a successful option periodic acid-Schiff stainings and Treponema pallidum im- in the treatment of NL, particularly in patients with CVID, while munostaining were negative. Tissue culture had no growth, a broader approach in NL without underlying CVID requires and viral resistance testing could not be performed. further investigations. The patient began treatment for HSV, and despite suc- cessive 1-month courses of high-dose oral acyclovir, valacy- Neda Barouti, MD clovir, and , his lesions progressed. A repeated Amy Qian Cao, H BSc tissue culture for viral resistance testing was not successful Donato Ferrara, MD in growing virus. A repeated biopsy confirmed the original Christa Prins, MD diagnosis of verrucous HSV. Given concern for acyclovir- resistant HSV, oral therapy was discontinued, and intrave- nous (IV) cidofovir treatment was initiated, with improve- Author Affiliations: Department of Medical Specialties–Dermatology, ment noted after 3 doses. This treatment was complicated by University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland (Barouti, Qian Cao, Ferrara, Prins); Queen’s University School of Medicine, elevations in serum creatinine levels and discontinued. Kingston, Ontario, Canada (Qian Cao). Intralesional cidofovir was then initiated every other week, 1 Corresponding Author: Neda Barouti, MD, Rue Gabrielle-Perret-Gentil 4, 1205 as previously reported, with resolution of his scrotal lesion Genève, Switzerland ([email protected]). and dramatic improvement in his perianal lesion after 6 Conflict of Interests Disclosures: None reported. treatments (Figure 1C and D). Funding/Support: This study was supported by the University Hospitals of Geneva, Geneva, Switzerland. Discussion | Herpes simplex virus infections cause significant Role of the Sponsors: The sponsors had no role in the design and conduct of morbidity in immunocompromised patients, and active HSV the study; in the collection, analysis, and interpretation of data; or in the infection increases HIV transmission.2 Infection with acyclovir- preparation, review, or approval of the manuscript. resistant HSV strains is about 10-fold higher in patients with 1. Ngo B, Wigington G, Hayes K, et al. Skin blood flow in necrobiosis lipoidica diabeticorum. Int J Dermatol. 2008;47(4):354-358. HIV than in immunocompetent individuals and appears re- 2. Salzer U, Warnatz K, Peter HH. Common variable immunodeficiency: an lated to the degree of immunosuppression and duration of an- update. Arthritis Res Ther. 2012;14(5):223. tiretroviral therapy.2 Treatment options for acyclovir- 3. Batchelor JM, Todd PM. Treatment of ulcerated necrobiosis lipoidica with resistant HSV are limited and include , cidofovir, intravenous immunoglobulin and methylprednisolone. J Drugs Dermatol. , and immunomodulating dipeptides.3,4 Foscar- 2012;11(2):256-259. net and cidofovir are not dependent on phosphorylation of vi- 4. Quimby SR, Muller SA, Schroeter AL. The cutaneous immunopathology of ral thymidine kinase for activation and can therefore be used necrobiosis lipoidica diabeticorum. Arch Dermatol. 1988;124(9):1364-1371. in acyclovir-resistant cases; however, both have limited for- 5. Laukkanen A, Fräki JE, Väätäinen N, Korhonen T, Naukkarinen A. Necrobiosis lipoidica: clinical and immunofluorescent study. Dermatologica. 1986;172(2): mulations, and drug-induced nephrotoxic effects are poten- 89-92. tially serious complications. Topical and intralesional admin-

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Figure 1. Verrucous Herpes Simplex Virus Before (A and B) and After (C and D) Treatment

A B

C D

Exophytic, verrucous, and ulcerated plaques were found on his right inferior scrotum (A) and perianal area (B). After 6 treatments with intralesional cidofovir, there was resolution of the plaques on the scrotum (C) and near complete resolution in the perianal area (D).

istrations of cidofovir have also been used for acyclovir- tum and perianal area. Given its low risk of adverse effects and resistant disease.1,5 ease of use in the outpatient setting, it should be considered In this case, acyclovir resistance was not confirmed with in this patient population. viral resistance testing but inferred from lack of treatment re- sponse. Given the disease extent, treatment with IV cidofovir Karolyn A. Wanat, MD was first attempted than discontinued owing to nephrotoxic Rachel H. Gormley, MD effects. Topical cidofovir was considered but not pursued, to Misha Rosenbach, MD avoid the significant potential for local irritation and burning Carrie L Kovarik, MD in the setting of ulcerated plaques. Intralesional cidofovir was ultimately used because of previously reported success in the Author Affiliations: Department of Dermatology, Hospital of the University of 1 treatment of facial acyclovir-resistant HSV. Since increased Pennsylvania, Philadelphia (Wanat, Gormley, Rosenbach, Kovarik). sensation is known to occur in the genital area, a ring block with Corresponding Author: Carrie L. Kovarik, MD; Department of Dermatology, lidocaine and epinephrine followed by a 1:4 dilution of cido- University of Pennsylvania, 3600 Spruce St, Philadelphia, PA 19104 (carrie fovir (75 mg/mL) was used, with 5 mL infiltrated into the scro- [email protected]). tal lesion and 5 mL into the perianal lesion. The patient toler- Conflict of Interest Disclosure: None reported. ated the injections well, requiring no additional pain 1. Castelo-Soccio L, Bernardin R, Stern J, Goldstein SA, Kovarik C. Successful treatment of acyclovir-resistant herpes simplex virus with intralesional medication, and had remarkable improvement without labo- cidofovir. Arch Dermatol. 2010;146(2):124-126. ratory abnormalities (Figure 1C and D). 2. Lolis MS, González L, Cohen PJ, Schwartz RA. Drug-resistant herpes simplex This report highlights the successful use of intralesional virus in HIV infected patients. Acta Dermatovenerol Croat. 2008;16(4): cidofovir in a patient with verrucous HSV infection of the scro- 204-208.

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Figure 2. Histopathologic Images

A B

C D A, Acanthotic epidermis at the edge of an ulceration with acute inflammation (hematoxylin-eosin, original magnification ×100) with prominent multinucleated giant cells (B and C, hematoxylin-eosin, original magnification ×200 and ×400, respectively). D, Herpes viral infection was confirmed with positive immunoperoxidase staining of multinucleated giant cells (herpes simplex virus immunohistochemical staining, original magnification ×200).

3. Lascaux AS, Caumes E, Deback C, et al. Successful treatment of and follow-up after controlling for the baseline levels. If baseline foscarnet resistant Herpes simplex virus lesions with topical imiquimod in adjustments yielded nonsignificant results, then interven- patients infected with human immunodeficiency virus type 1. J Med Virol. 2012;84(2):194-197. tion effects would need to be interpreted with more caution. 4. Rose WA II, Tuthill C, Pyles RB. An immunomodulating dipeptide, SCV-07, is a An additional major concern pertains to the handling of potential therapeutic for recurrent genital herpes simplex virus type 2 (HSV-2). missing data. Of 210 individuals who completed the baseline Int J Antimicrob Agents. 2008;32(3):262-266. assessment and were randomized, 78 (37%) did not complete 5. Toro JR, Sanchez S, Turiansky G, Blauvelt A. Topical cidofovir for the the 3-month follow-up assessment (although Figure 11 incor- treatment of dermatologic conditions: verruca, condyloma, intraepithelial rectly indicates that 76 individuals were lost to follow-up). neoplasia, herpes simplex and its potential use in . Dermatol Clin. 2003;21(2):301-309. However, the outcomes in both articles were analyzed using a complete-case approach focusing on the 132 individuals with data available from the baseline and follow-up assessments. COMMENT & RESPONSE This approach commonly produces biased results, which can be mitigated using intent to treat analytic methods (eg, model- Concerns Regarding Results of a Randomized based strategies or imputation).3 Controlled Trial to Promote Skin Self-Examination There are also issues related to the reporting and inter- and Sun Protection Behaviors pretation of the study results. In both articles, the authors To the Editor We write regarding 2 articles by Aneja and misinterpreted odds ratios as relative risks and thus over- colleagues1,2 describing results of a randomized trial to pro- stated the impact of the intervention. For example, an odds mote skin self-examination (SSE) and sun-protection behav- ratio of 2.40 is described as showing that “[t]hose in the iors among individuals attending dermatology clinics. A key intervention group were 2.4 times more likely to wear sun- concern is that imbalance in baseline levels of each behav- protective clothing.”2(p1326) Calculation demonstrates that ioral outcome (ie, performance of SSE, use of sun-protective with a rate of 0.35 among the controls, this odds ratio would clothing, and sunscreen use) may explain or attenuate treat- be equivalent to a relative risk of 1.61. ment arm differences at follow-up. For example, use of sun- Additionally, based on the reported odds ratios, the au- protective clothing at the follow-up was significantly higher thors claim that their intervention produced a greater in- among intervention than control group participants.2 How- crease in SSE than a study by Glazebrook and colleagues.4 How- ever, 40.2% of intervention group participants reported al- ever, the authors did not demonstrate that the odds ratio of ways or frequently using sun-protective clothing at baseline 2.36 obtained in their study is statistically significantly greater compared with 28.6% of control group participants.1 Apru- than the odds ratio of 1.67 reported by Glazebrook et al. More- dent approach should include sensitivity regression analyses over, the fact that the 2 studies used different approaches to (akin to those summarized in Table 31 and the Table2) estimat- measure SSE limits the ability to compare their relative im- ing intervention effects on behavioral outcomes at the 3-month pact on SSE.

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