Objectives: Anal cancer risk is elevated in MSM with HIV (MSMWH). Anal high-risk human papillomavirus (hr-HPV) infection is necessary but insufficient to develop high-grade squamous intraepithelial lesion (HSIL), the anal cancer precursor, suggesting additional factors. We sought to determine whether the microbiome of the anal canal is distinct by comparing it with the microbiome of stool. We also sought to determine whether changes in the anal microbiome are associated with HSIL among MSMWH. Design: Cross-sectional comparison of the microbiome of the anal canal with the microbiome of stool in MSMWH and cross-sectional comparison of the anal microbiome of MSMWH with anal HSIL with the anal microbiome of MSMWH without anal HSIL. Methods: Sterile swabs were used to sample the anus of MSMWH for microbiome and HPV testing, followed by high-resolution anoscopy. Stool samples were mailed from home. 16S sequencing was used for bacterial identification. Measures of alpha diversity, beta diversity, and differential abundance analysis were used to compare samples. Results: One hundred sixty-six anal samples and 103 matching stool samples were sequenced. Beta diversity showed clustering of stool and anal samples. Of hr-HPV-positive MSMWH, 31 had HSIL and 13 had no SIL. Comparison of the microbiome between these revealed 28 different species. The highest-fold enrichment among MSMWH/hr-HPV/HSIL included pro-inflammatory and carcinogenic Prevotella, Parasuterella, Hungatella, Sneathia, and Fusobacterium species. The anti-inflammatory Anaerostipes caccae showed the greatest reduction among MSMWH/hr-HPV/HSIL. Conclusion: The anal microbiome is distinct from stool. A pro-inflammatory and carcinogenic environment may be associated with anal HSIL.

Supplemental Digital Content Is Available in the Text. Background:Anal cancer is caused by human papillomavirus (HPV), particularly HPV-16, and is preceded by anal high-grade squamous intraepithelial lesions (HSILs). The incidence of anal cancer is highest among men who have sex with men (MSM) living with HIV (MSMLWH) and increases with age. However, most previous studies of anal HPV infection and anal HSIL were performed on men under 50 years old, and relatively little is known about HSIL among older MSMLWH or MSM not living with HIV (MSM-Not-LWH).Setting:We enrolled MSM who were aged 50+ during 2018-2022 in San Francisco, CA.Methods:One hundred twenty-nine MSMLWH and 109 MSM-not-LWH participated. All participants had anal HPV DNA testing (Atila Biosystems) and high-resolution anoscopy with a biopsy of visible lesions.Results:Among MSMLWH, 47% had anal HSIL, 19% had HPV-16, and 51% had other oncogenic anal HPV types (excluding HPV-16). Among MSM-not-LWH, 37% had anal HSIL, 22% had HPV-16, and 34% had other oncogenic anal HPV types. Increasing age was not statistically associated with prevalent HSIL, HPV-16, or other oncogenic HPV infections in MSMLWH or MSM-not-LWH. HPV-16 (odds ratio: 45.1, 95% confidence interval: 15.8-129); other oncogenic HPV types (odds ratio: 5.95, 95% confidence interval: 2.74-12.9) were associated with increased odds of anal HSIL, adjusted for age, income, education, and HIV status.Conclusion:The prevalence of oncogenic anal HPV, anal HPV-16, and anal HSIL remains very high in older MSMLWH and MSM-not-LWH. With recent evidence showing that treating anal HSIL prevents anal cancer, MSM aged 50+ should be considered for anal cancer screening.

Background: Anal cancer is caused by human papillomavirus (HPV), particularly HPV-16, and is preceded by anal high-grade squamous intraepithelial lesions (HSIL). The incidence of anal cancer is highest among men who have sex with men (MSM) living with HIV (MSMLWH) and increases with age. However, most previous studies of anal HPV infection and anal HSIL were performed on men under 50 years of age, and relatively little is known about HSIL among older MSMLWH or MSM not living with HIV (MSM-Not-LWH). Setting: We enrolled MSM who were aged 50+ during 2018-2022 in San Francisco, California. Methods: 129 MSMLWH and 109 MSM-not-LWH participated. All participants had anal HPV DNA testing (Atila Biosystems) and high-resolution anoscopy with biopsy of visible lesions. Results: Among MSMLWH, 47% had anal HSIL, 19% had HPV-16, and 51% had other oncogenic anal HPV types (excluding HPV-16). Among MSM-not-LWH, 37% had anal HSIL, 22% had HPV-16, and 34% had other oncogenic anal HPV types. Increasing age was not statistically associated with prevalent HSIL, HPV-16, or other oncogenic HPV infections in MSMLWH or MSM-not-LWH. HPV-16 (OR:45.1, 95% CI:15.8-129), other oncogenic HPV types (OR:5.95, 95% CI:2.74-12.9) were associated with increased odds of anal HSIL, adjusted for age, income, education, and HIV status. Conclusion: The prevalence of oncogenic anal HPV, anal HPV-16, and anal HSIL remain very high in older MSMLWH and MSM-not-LWH. With recent evidence showing that treating anal HSIL prevents anal cancer, MSM aged 50+ should be considered for anal cancer screening.

BACKGROUND:The risk of anal cancer is increased in patients with human immunodeficiency virus (HIV), inflammatory bowel disease (IBD), and among men who have sex with men (MSM). High grade squamous intraepithelial lesions (HSILs) are precursor lesions to anal squamous cell carcinoma (SCC), and treatment of these lesions can decrease progression to anal SCC. This study aims to determine the prevalence of HSIL and anal cancer among MSM patients with and without IBD referred for anal cancer screening. METHODS:This is a retrospective study of all MSM patients seen at an anal squamous intraepithelial lesions (aSILs) and anal cancer screening specialty clinic. Data were manually and electronically collected from clinical documentation and pathology results for the primary outcomes of HSIL and anal cancer. Demographics, HIV status, IBD disease status, disease phenotype, and immunosuppressive medication use were collected through the electronic health record. Descriptive statistics were used. RESULTS:In all, 4623 patients were included for analysis. Among 57 MSM patients with IBD, 25 (43.9%) had a history of HSIL, and 2 (3.5%) had a history of anal cancer. Among 4618 MSM patients without IBD, 2417 (52.3%) had a history of HSIL, and 139 (3.0%) had a history of anal cancer (P = .744). Rates of HIV were 49.1% among MSM patients with IBD and 69.8% among MSM patients without IBD (P = .001). There remained no difference in prevalence of HSIL and anal cancer between groups when adjusting for HIV status. Among IBD patients, only 21.6% were referred for screening by their gastroenterologist. CONCLUSIONS:Among MSM with and without IBD, both groups had an equally high prevalence of HSIL and anal SCC. Awareness of appropriate surveillance to identify aSIL in MSM patients with IBD is needed among gastroenterologists.

BACKGROUND:The incidence of anal cancer is substantially higher among persons living with the human immunodeficiency virus (HIV) than in the general population. Similar to cervical cancer, anal cancer is preceded by high-grade squamous intraepithelial lesions (HSILs). Treatment for cervical HSIL reduces progression to cervical cancer; however, data from prospective studies of treatment for anal HSIL to prevent anal cancer are lacking. METHODS:We conducted a phase 3 trial at 25 U.S. sites. Persons living with HIV who were 35 years of age or older and who had biopsy-proven anal HSIL were randomly assigned, in a 1:1 ratio, to receive either HSIL treatment or active monitoring without treatment. Treatment included office-based ablative procedures, ablation or excision under anesthesia, or the administration of topical fluorouracil or imiquimod. The primary outcome was progression to anal cancer in a time-to-event analysis. Participants in the treatment group were treated until HSIL was completely resolved. All the participants underwent high-resolution anoscopy at least every 6 months; biopsy was also performed for suspected ongoing HSIL in the treatment group, annually in the active-monitoring group, or any time there was concern for cancer. RESULTS:Of 4459 participants who underwent randomization, 4446 (99.7%) were included in the analysis of the time to progression to cancer. With a median follow-up of 25.8 months, 9 cases were diagnosed in the treatment group (173 per 100,000 person-years; 95% confidence interval [CI], 90 to 332) and 21 cases in the active-monitoring group (402 per 100,000 person-years; 95% CI, 262 to 616). The rate of progression to anal cancer was lower in the treatment group than in the active-monitoring group by 57% (95% CI, 6 to 80; P = 0.03 by log-rank test). CONCLUSIONS:Among participants with biopsy-proven anal HSIL, the risk of anal cancer was significantly lower with treatment for anal HSIL than with active monitoring. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT02135419.).

There are few treatment options for patients with extensively drug-resistant gram-negative infections. Cefiderocol is a novel β-lactam with excellent in vitro activity against multidrug-resistant gram-negative isolates, including carbapenem-resistant strains. However, this drug performed poorly versus best available therapy in an open-label randomized study of carbapenem-resistant gram-negative infections. Here, we present a case of a 32-year-old man with necrotizing ventilator-associated pneumonia caused by Pseudomonas aeruginosawho developed resistance to meropenem and ceftolozane/tazobactam while on therapy. Addition of expanded-access cefiderocol to his antimicrobial regimen contributed to successful microbiological cure while limiting exposure to nephrotoxic therapeutic agents.

Author(s): Budak, Jehan Z; Brickman, Cristina E; Abdoler, Emily A; Wallender, Erika K; Mulliken, Jennifer S; Kerkhoff, Andrew D; Lampiris, Harry; Babik, Jennifer M; Koss, Catherine A; Schwartz, Brian S

Abstract Background Burnout in graduate medical education is common and reported in ~70% of Internal Medicine (IM) residents. Most studies have described interventions focused on residency training, but fellowship training suffers from similar challenges and likely similar levels of burnout. After conducting a needs assessment amongst fellows within our Infectious Diseases (ID) fellowship program, we developed a wellness program to address these issues. Methods In Spring 2018, we reviewed the existing literature and consulted with local experts on trainee well-being. Based on our findings, we designed a multi-tiered approach to enhance wellness amongst fellows. An ID Fellowship Well-Being Committee (WBC) was created in September 2018 to lead the intervention. The WBC includes an even mix of fellows and faculty at multiple levels at all three main teaching hospitals associated with the program. Meetings occur every other month, and co-chairs (one faculty and one fellow) report back to the program director quarterly. Topic areas and interventions are described in Table 1. Fellows were sent a qualitative survey to evaluate the impact of the well-being interventions to date. Results Four of 5 first year fellows responded to the survey, and all felt the retreat should be repeated yearly. Themes identified from the survey included benefits of having protected time together, convening in a low pressure and informal setting to provide feedback, and spending quality time in a non-clinical setting with co-fellows. Fellows cited the wellness retreat as a strength at our annual fellowship external program review. Conclusion Burnout is likely high among IM sub-specialty fellows, and interventions are needed to support the well-being of those trainees. We describe a roadmap for the development of a well-being program at a relatively large, academic ID fellowship program led by a mixed fellow and faculty committee. We will continue to monitor data on fellow burnout and make programmatic changes based on feedback. We are hopeful that our work will empower other programs to engage in developing their own well-being programs. Disclosures All authors: No reported disclosures.

HIV-positive people are at increased risk for malignancies associated with human papillomavirus (HPV) infection, including oropharyngeal squamous cell carcinoma (OPSCC). The purpose of this study was to determine whether cancer treatment disparities exist between HIV-positive and HIV-negative people with OPSCC. We conducted a retrospective cohort study comparing OPSCC treatment adequacy and treatment outcomes in HIV-positive and HIV-negative people in the post-antiretroviral therapy era. Treatment adequacy was determined by measuring two primary endpoints associated with OPSCC survival: time to therapy and total radiation dose. Treatment outcomes were assessed by measuring disease-free and overall survival. We identified a total of 37 HIV-positive and 149 HIV-negative people with OPSCC. HIV-positive people experienced a median delay of 10 days from time of OPSCC diagnosis to start of therapy compared with HIV-negative people [hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.38-0.98]. Total post-radiation dose in HIV-positive people was lower than that in HIV-negative people [58.5 Gray (Gy) versus 64.4 Gy, p = .04]. HIV-positive people also experienced greater hazards for disease recurrence (HR 3.43, 95% CI 1.39-8.46) and death (HR 4.21, 95% CI 1.29-13.80) compared with HIV-negative people. In conclusion, we detected a clinically important delay in time to therapy as well as worse disease-free and overall survival in HIV-positive people with OPSCC compared with their HIV-negative counterparts. These findings are relevant to understanding how HIV-positive people are diagnosed and undergo therapy for HPV-associated malignancies and highlight the need to address cancer treatment disparities in this group.

Following definitive chemoradiation for anal squamous cell carcinoma (ASCC), patients face a variety of chronic issues including: bowel dysfunction, accelerated bone loss, sexual dysfunction, and psychosocial distress. The increasing incidence of this disease, high cure rates, and significant long-term sequelae warrant increased focus on optimal survivorship care following definitive chemoradiation. In order to establish our survivorship care model for ASCC patients, a multi-disciplinary team of experts performed a comprehensive literature review and summarized best practices for the multi-disciplinary management of this unique patient population. We reviewed principle domains of our survivorship approach: (1) management of chronic toxicities; (2) sexual health; (3) HIV management in affected patients; (4) psychosocial wellbeing; and (5) surveillance for disease recurrence and survivorship care delivery. We provide recommendations for the optimization of survivorship care for ASCC patients can through a multi-disciplinary approach that supports physical and psychological wellness.

Identifying a relationship between depression and sexual risk behavior in HIV-infected patients could establish a mechanism to enhance prevention efforts. We conducted a cross-sectional analysis using data from the University of Pennsylvania Center for AIDS Research and used ordinal logistic regression to measure the association between depression and non-condom use. 716 men who have sex with men (MSM), 262 heterosexual men and 277 heterosexual women were included. The association between depression and non-condom use was strongest in heterosexual men with and without HIV-infected regular partners (OR 8.53, 95% CI 1.18–61.89 and OR 2.30, 95% CI 0.99–5.36 respectively), but absent in heterosexual women regardless of partner. Although the OR was low in MSM overall, an association was detected in MSM without HIV-infected regular partners (OR 2.44, 95% CI 1.39–4.31). In conclusion, we demonstrated an association between depression and non-condom use driven by heterosexual men and MSM without HIV-infected regular partners. Sexual risk should be addressed when intervening on depressive symptoms in these subgroups.

People living with HIV (PLWH) engaged in medical care represent an accessible group to focus HIV prevention efforts. In an analysis of 1,883 PLWH from 2007 and 2015, we determined the proportion at risk of HIV transmission and identified factors associated with HIV transmission risk using multivariable mixed effects logistic regression models with random intercepts. HIV transmission risk was defined by an HIV viral load > 1,500 copies/mL and self-reported unprotected sex. We found that 174 (9.2%) individuals were at risk for HIV transmission at least once. Factors associated with HIV transmission risk included younger age (adjusted OR [95% CI] per decade decrease = 2.30 [1.84, 2.89]), illicit drug use (adjusted OR = 5.36 [3.02, 9.56]), depression (adjusted OR = 1.88 [1.10, 3.21]), and education <12th grade (adjusted OR = 2.05 [1.15, 3.67]). Thus, nearly 1 in 10 HIV-infected individuals engaged in care between 2007 and 2015 were potentially at risk of transmitting HIV Behavioral interventions to decrease HIV transmission should focus on younger, less educated patients who are depressed and actively using illicit drugs.

Cancer and HIV are inextricably linked. Although the advent of antiretroviral therapy has led to a marked decline in the incidence of malignancies classically linked to immunosuppression (AIDS-defining malignancies, or ADMs), this decrease has been accompanied by a concomitant rise in the incidence of other malignancies (non-AIDS-defining malignancies, or NADMs). Population-based cancer registries provide key information about cancer epidemiology in people living with HIV (PLWH) within resource-rich countries. The risk for NADMs is elevated in PLWH compared with the general population, particularly for lung and anal cancers. Contributory factors include tobacco use, coinfection with oncogenic viruses such as human papillomavirus, and potentially direct effects of HIV itself. Data from resource-poor countries are limited and highlight the need for more studies in countries where the majority of PLWH reside. Strategies for early cancer detection and/or prevention are necessary in PLWH.

Background. The incidence of oropharyngeal squamous cell carcinoma (OPC) is on the rise. This is now known to be largely due to infection with human papillomavirus (HPV), the most common sexually transmitted disease in the world. Patients with human immunodeficiency virus (HIV) are particularly susceptible to all HPV-associated malignancies including OPC, but very little is known to guide their treatment. Studies of other malignancies suggest that patients with HIV experience significant delays in therapy compared to HIV-negative patients. We wished to determine whether this was the case in OPC. Methods. We obtained treatment data for all HIV-positive subjects diagnosed with OPC at the Hospital of the University of Pennsylvania from January 1, 1996 through April 11, 2013 and compared it to a subset of HIV-negative subjects with OPC diagnosed during the same time period. This information is part of a larger, ongoing multicenter retrospective cohort to evaluate the treatment and survival outcomes of OPC in HIV-positive patients. The primary endpoint was time from diagnosis until start of therapy; a difference of 10 days was deemed clinically important based on studies that showed increased mortality in patients with delays longer than this. Results. 19 HIV-positive subjects and 86 HIV-negative subjects with treatment data were identified. The unadjusted hazards ratio for starting therapy in HIV-negative patients was 2.71 (95% confidence interval 1.54-4.76) compared to HIV-positive patients. This hazards ratio was 2.31 (95% confidence interval 1.22 – 4.37) after adjustment for age, sex, insurance type, race, and comorbidities including psychiatric disease and substance abuse. The median number of days from diagnosis to start to therapy was 27 in HIV-negative patients (interquartile range 14-39) and 51 in HIV-positive patients (interquartile range 31-85). Conclusion. HIV-positive subjects with OPC experience clinically important delays from diagnosis until start of therapy compared to HIV-negative patients. A larger study is underway to explore potential mechanisms for these delays and to determine how this impacts survival. Disclosures. All authors: No reported disclosures.