Huchko, Megan J.

Objective The purpose of this review was to examine new evidence since the authors' 2019 guidelines for cervical cancer (CC) screening in non-HIV immunocompromised persons and to provide updated recommendations based on literature review and expert opinion. In addition, human papillomavirus (HPV) vaccine efficacy in these populations was reviewed. Methods A literature search was performed similar to the authors' previous publication but was conducted through March 2023. Risk of CC, squamous intraepithelial lesions, and HPV infection in those living with solid organ transplant (SOT), end-stage renal disease (ESRD), hematopoietic stem cell transplant (HSCT), and autoimmune diseases (AID), specifically systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD) with addition of multiple sclerosis (MS) were researched. This update also summarizes data available on newer disease-modifying therapies (DMTs) including monoclonal antibodies (MABs). The authors then made recommendations for HPV vaccine administration, and screening using either general population guidelines or increased surveillance, the latter based on following current recommendations for women living with HIV. Additionally, the literature search included antibody response to HPV vaccines and recommendations for their administration for these same conditions. Results Based on the reviewed risks, evidence continued to support those persons living with SOT, ESRD, HSCT, and SLE, whether on immunosuppressant therapy or not, had an increased risk of HPV, squamous intraepithelial lesions, and CC whereas there was weak evidence that those persons with IBD, RA, and MS not on immunosuppressants were at risk. Data on persons using DMT/MAB were conflicting. Data showed that patients on certain immunosuppressants had lower antibody titers following HPV vaccination. There were no studies on HPV vaccine efficacy. Conclusions Following US Center for Disease Control and Prevention HIV Cervical cancer screening (CCS) guidelines is recommended for the following: SOT, ESRD, HSCT, and SLE whether on immunosuppressants or not, and IBD, RA, and MS on immunosuppressants. Shared decision-making about increased surveillance for IBD and RA not on immunosuppressants and persons on any DMT or MAB is reasonable based on conflicting data. Human papillomavirus vaccination should not change the recommendations for increased CC surveillance. A 3-dose series of the HPV vaccine is recommended for all age-eligible patients starting at 9 years of age, with catch-up to 26 years of age. Vaccination from age 27 up to age 45 years per Advisory Committee on Immunization Practices guidelines should be considered in shared decision-making. When possible, HPV vaccine series should be initiated and completed before SOT or initiation of DMT/MAB. For HSCT, the vaccine series should be readministered along with other childhood vaccines.

Executive Summary The risk of cervical cancer (CC) among women immunosuppressed for a variety of reasons is well documented in the literature. Although there is improved organ function, quality of life and life expectancy gained through use of immunosuppressant therapy, there may be increased long-term risk of cervical neoplasia and cancer and the need for more intense screening, surveillance, and management. Although guidance for CC screening among HIV-infected women (see Table 1) has been supported by evidence from retrospective and prospective studies, recommendations for CC screening among non-HIV immunosuppressed women remains limited because quality evidence is lacking. Moreover, CC screening guidelines for HIV-infected women have changed because better treatments evolved and resulted in longer life expectancy. The objective of this report was to summarize current knowledge of CC, squamous intraepithelial lesions, and human papillomavirus (HPV) infection in non-HIV immunocompromised women to determine best practices for CC surveillance in this population and provide recommendations for screening. We evaluated those with solid organ transplant, hematopoietic stem cell transplant, and a number of autoimmune diseases. A panel of health care professionals involved in CC research and care was assembled to review and discuss existing literature on the subject and come to conclusions about screening based on available evidence and expert opinion. Literature searches were performed using key words such as CC, cervical dysplasia/squamous intraepithelial lesion, HPV, and type of immunosuppression resulting in an initial group of 346 articles. Additional publications were identified from review of citations in these articles. All generated abstracts were reviewed to identify relevant articles. Articles published within 10 years were considered priority for review. Reviews of the literature were summarized with relevant statistical comparisons. Recommendations for screening generated from each group were largely based on expert opinion. Adherence to screening, health benefits and risks, and available clinical expertise were all considered in formulating the recommendations to the degree that information was available. Results Solid Organ Transplant: Evidence specific for renal, heart/lung, liver, and pancreas transplants show a consistent increase in risk of cervical neoplasia and invasive CC, demonstrating the importance of long-term surveillance and treatment. Reports demonstrate continued risk long after transplantation, emphasizing the need for screening throughout a woman's lifetime. Hematopoietic Stem Cell Transplant: Although there is some evidence for an increase in CC in large cohort studies of these patients, conflicting results may reflect that many patients did not survive long enough to evaluate the incidence of slow-growing or delayed-onset cancers. Furthermore, history of cervical screening or previous hysterectomy was not included in registry study analysis, possibly leading to underestimation of CC incidence rates. Genital or chronic graft versus host disease is associated with an increase in high-grade cervical neoplasia and posttransplant HPV positivity. Inflammatory Bowel Disease: There is no strong evidence to support that inflammatory bowel disease alone increases cervical neoplasia or cancer risk. In contrast, immunosuppressant therapy does seem to increase the risk, although results of observational studies are conflicting regarding which type of immunosuppressant medication increases risk. Moreover, misclassification of cases may underestimate CC risk in this population. Recently published preventive care guidelines for women with inflammatory bowel disease taking immunosuppressive therapy recommend a need for continued long-term CC screening. Systemic Lupus Erythematosus and Rheumatoid Arthritis: The risk of cervical high-grade neoplasia and cancer was higher among women with systemic lupus erythematosus than those with rheumatoid arthritis (RA), although studies were limited by size, inclusion of women with low-grade neoplasia in main outcomes, and variability of disease severity or exposure to immunosuppressants. In studies designed to look specifically at immunosuppressant use, however, there did seem to be an increase in risk, identified mostly in women with RA. Although the strength of the evidence is limited, the increase in risk is consistent across studies. Type 1 DM: There is a paucity of evidence-based reports associating type 1 DM with an increased risk of cervical neoplasia and cancer. Recommendations The panel proposed that CC screening guidelines for non-HIV immunocompromised women follow either the (1) guidelines for the general population or (2) current center for disease control guidelines for HIV-infected women. The following are the summaries for each group reviewed, and more details are noted in accompanying table: Solid Organ Transplant: The transplant population reflects a greater risk of CC than the general population and guidelines for HIV-infected women are a reasonable approach for screening and surveillance. Hematopoietic Stem Cell Transplant: These women have a greater risk of CC than the general population and guidelines for HIV-infected women are a reasonable approach for screening. A new diagnosis of genital or chronic graft versus host disease in a woman post–stem cell transplant results in a greater risk of CC than in the general population and should result in more intensive screening and surveillance. Inflammatory Bowel Disease: Women with inflammatory bowel disease being treated with immunosuppressive drugs are at greater risk of cervical neoplasia and cancer than the general population and guidelines for HIV-infected women are a reasonable approach for screening and surveillance. Those women with inflammatory bowel disease not on immunosuppressive therapy are not at an increased risk and should follow screening guidelines for the general population. Systemic Lupus Erythematosus and Rheumatoid Arthritis: All women with systemic lupus erythematosus, whether on immunosuppressant therapy or not and those women with RA on immunosuppressant therapy have a greater risk of cervical neoplasia and cancer than the general population and should follow CC screening guidelines for HIV-infected women. Women with RA not on immunosuppressant therapy should follow CC screening guidelines for the general population. Type 1 Diabetes Mellitus: Because of a lack of evidence of increased risk of cervical neoplasia and cancer among women with type 1 DM, these women should follow the screening guidelines for the general population.