Accepted Manuscript. Reply to: Risk of skin cancer in HIV-infected patients: a Danish nationwide cohort study

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1 Accepted Manuscript Reply to: Risk of skin cancer in HIV-infected patients: a Danish nationwide cohort study Matthew D. Mansh, MD, Dustin H. Marks, BS PII: S (18) DOI: /j.jaad Reference: YMJD To appear in: Journal of the American Academy of Dermatology Received Date: 25 July 2018 Accepted Date: 26 July 2018 Please cite this article as: Mansh MD, Marks DH, Reply to: Risk of skin cancer in HIV-infected patients: a Danish nationwide cohort study, Journal of the American Academy of Dermatology (2018), doi: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 1 Article type: Letters Notes & Comments Title: Reply to: Risk of skin cancer in HIV-infected patients: a Danish nationwide cohort study Matthew D. Mansh, MD 1, Dustin H. Marks, BS 2 1 Department of Dermatology, University of Minnesota, Minneapolis, MN. 2 Department of Dermatology, Massachusetts General Hospital, Boston, MA. Corresponding author: Matthew Mansh, MD Department of Dermatology University of Minnesota 516 Delaware Street S.E. Phillips-Wangensteen Bldg., Suite Minneapolis, Minnesota mansh@umn.edu Funding sources: None IRB approval: Not applicable Conflicts of Interest: None declared. Manuscript word count: 499 words [excluding references] References: 5

3 2 To the Editor: We read with interest Omland et al s 1 study investigating skin cancer risk in HIV-infected individuals.in this Danish retrospective cohort study, the authors found a 5.4-fold increased risk of cutaneous squamous cell carcinoma (SCC) in HIV-infected individuals compared to age- and sex-matched HIV-negative controls this was consistent regardless of HIV-infection route and correlated with immunosuppression. 1 Similar findings have been previously reported 2,3 and are supported by biological plausibility given the potential viral-related pathogenesis of SCC. Omland et al 1 also found a 2.0-fold increased risk of basal cell carcinoma (BCC) in HIV-infected individuals. However, this was restricted only to HIV-infected men-who-have-sex-with men (MSM), and there was no relationship with immunosuppression. 1 In a retrospective cohort study of HIV-infected and matched HIV-negative controls from Kaiser Permanente, Asgari et al also found that the relative risk of BCC was greatest among HIV-infected MSM, with a lesser increased relative risk among HIV-infected men with other HIV-infection routes, no increased relative risk among HIV-infected women, and no association between BCC risk and immunosuppression. 2 Sexual minority men (SMM), regardless of HIV-infection status, also report between a 1.5 to 2.0 fold increased odds of melanoma and non-melanoma skin cancer. 4 This is likely due to increased ultraviolet exposure in SMM, who report much higher rates of indoor tanning and decreased use of sun protection methods compared with heterosexual men. 4,5 Given the increased risk of BCC in HIV-infected individuals appears primarily restricted to MSM, similar in magnitude to the increased skin cancer risk among all SMM regardless of HIV-infection status, and unrelated to immunosuppression, we believe that uncontrolled differences in sexual orientation, and thus related behavioral risk factors, are the most likely explanation for the increased rates of BCC among HIV-infected persons observed in these studies. 1,2

4 3 This highlights a major limitation of current study designs for investigating skin cancer risk in HIVinfected individuals. In Omland et al s 1 cohort study, 54.4% of HIV-infected persons were MSM compared to an estimated 3-8% of MSM in the general population. As sexual orientation was not controlled for in matching, this demographic variable likely differed significantly between the HIVinfected and control groups. While behavioral factors related to ultraviolet light exposure are challenging to capture, particularly in retrospective studies, sexual orientation can be more easily identified. We propose that studies investigating HIV-infection and skin cancer risk must consider sexual orientation as a critical demographic variable to better control for behavioral risk factors when such data is unavailable or incomplete. In defense of Omland et al., 1 we acknowledge that sexual orientation has not been traditionally included as a standard demographic variable in epidemiological and clinical studies. However, forthcoming policy changes will likely change this norm. In 2019, all electronic health records in the United States certified under Stage 3 of meaningful use guidelines will be required to allow users to record, change, and access structured data on sexual orientation. Increased routine collection of sexual orientation in clinical settings will provide novel opportunities for better designed studies to determine the true relationship between HIV-infection and skin cancer risk.

5 4 References 1. Omland S, Ahlström M, Gerstoft J et al. Risk of skin cancer in HIV-infected patients: a Danish nationwide cohort study. J Am Acad Dermatol doi: /j.jaad Asgari M, Ray G, Quesenberry C, Katz K, Silverberg M. Association of Multiple Primary Skin Cancers With Human Immunodeficiency Virus Infection, CD4 Count, and Viral Load. JAMA Dermatol. 2017;153(9):892. doi: /jamadermatol Silverberg M, Leyden W, Warton E, Quesenberry C, Engels E, Asgari M. HIV Infection Status, Immunodeficiency, and the Incidence of Non-Melanoma Skin Cancer. JNCI: Journal of the National Cancer Institute. 2013;105(5): doi: /jnci/djs Mansh M, Katz KA, Linos E, Chren MM, Arron S. Association of Skin Cancer and Indoor Tanning in Sexual Minority Men and Women. JAMA Dermatol. 2015;151(12): Gao Y, Arron S, Linos E, Polcari I, Mansh M. Indoor Tanning, Sunless Tanning, and Sun-Protection Behaviors Among Sexual Minority Men. JAMA Dermatol. 2018;154(4):477. doi: /jamadermatol