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High-risk human papillomavirus (hrHPV)-induced anal low-grade squamous intraepithelial lesions (LSILs) have the potential to progress to high-grade squamous intraepithelial lesions (HSILs). We investigated whether anal hrHPV infections, particularly types 16 and 18, predict LSIL-to-HSIL progression. One hundred forty-six human immunodeficiency virus (HIV)-infected and 22 HIV-uninfected patients with anal LSILs underwent cytology, HPV genotyping (16, 18, and pooled 12 hrHPV types), and high-resolution anoscopy-guided biopsy at baseline and surveillance. The associations between the rate of LSIL-to-HSIL progression and HPV types as well as longitudinal HPV-16/18 status were assessed by fitting separate Cox regression models. At baseline, 91% of patients harbored hrHPV: HPV-16/18 (44%) and non-16/18 (86%). Upon follow-up (median, 20 [range, 6-36] months), 41% developed HSIL (84% at the same anatomic location as the initial LSIL and 16% at a different location). Baseline HPV-16/18-positive patients had greater probability of progression than patients with non-16/18 types or negative (67%, 25%, and 7%, respectively; P < .001). Persistent HPV-16/18 conferred the highest probability of progression (70%), followed by intermittent HPV-16/18 positivity (52%). In unadjusted and adjusted analyses, baseline and persistent HPV-16/18 were significantly associated with LSIL-to-HSIL progression. Anal LSIL patients who are positive for hrHPV, especially HPV-16/18, have an increased risk of developing HSIL. Type-specific HPV testing could serve as a risk stratification tool, providing prognostic information.

While cancer is a leading cause of death worldwide, significant disparities exist in care access in low‑ and middle‑income countries (LMICs). In Liberia, screening and treatment for anal cancers remain limited, and are exacerbated among vulnerable groups, including men who have sex with men (MSM). Screen‑triage‑treat models for cancerous lesions have been successful in reducing cervical cancer mortality, but the feasibility of this approach has not been studied for anal cancers in a low‑resource context. The aim of this study is to determine the feasibility of implementing a screen‑triage‑treat model for anal high‑grade squamous intraepithelial lesions (aHSIL) among MSM in Liberia. This descriptive study represented a collaboration between Stop AIDS in Liberia (SAIL) and health institutions in Liberia and the USA. MSM and transgender participants were recruited through convenience sampling with SAIL peer‑educators. A survey validated by SAIL experts assessed demographics and sexual risk factors. Participants underwent anal self‑swabbing for high‑risk human papillomavirus (HPV) and offered human immunodeficiency virus (HIV) testing. Those with positive results were offered a screen‑triage‑treat model through high‑resolution anoscopy (HRA) and infrared coagulation (IRC). Data were cleaned and analyzed in SPSS. Among 110 participants, most were single ( = 94, 88%) and without formal employment ( = 21, 75%). Participants engaged in regular anal ( = 64, 60%), oral ( = 62, 58%), and receptive sex ( = 58, 54%), and sex with women ( = 51, 48%). Nearly 20% of participants reported being HIV positive ( = 21). In all, 50 participants (45%) tested positive for anal high‑risk HPV, 34 (68%) elected to undergo HRA, and 10 (84%) were treated with IRC. Of those who underwent HRA, 75% tested HIV positive. Our findings suggest that a screen‑triage‑treat model presents a feasible option to identify and reduce the incidence of anal cancer among MSM in Liberia. The screen‑triage‑treat model, with proven success in management of cervical dysplasia, may be a viable option to treat aHSIL for anal cancer prevention in LMICs.

Abstract Objectives: The Lower Anogenital Squamous Terminology (LAST) recommendations classify human papillomavirus–associated squamous lesions into low- and high-grade squamous intraepithelial lesions (LSILs/HSILs). Our study aimed to assess interobserver agreement among 6 experienced pathologists in assigning 40 anal lesions previously diagnosed as anal intraepithelial neoplasia 2 (AIN 2) to either HSIL or non-HSIL categories. Methods: Agreement based on photomicrographs of H&E alone or H&E plus p16 immunohistochemistry was calculated using κ coefficients. Results: Agreement was fair based on H&E alone (κ = 0.42; 95% confidence interval [CI], 0.34-0.52). Adding p16 improved agreement to moderate (κ = 0.55; 95% CI, 0.54-0.62). On final diagnosis, 21 cases (53%) had unanimous diagnoses, and 19 (47%) were divided. When designating p16 results as positive or negative, agreement was excellent (κ = 0.92; 95% CI, 0.83-0.95). Among variables (staining location, extent, and intensity), staining of the basal/parabasal layers was a consistent feature in cases with consensus for positive results (20/20). Of the 67 H&E diagnoses with conflicting p16 results, participants modified 32 (48%), downgrading 23 HSILs and upgrading 9 non-HSILs. Conclusions: Although p16 increased interobserver agreement, disagreement remained considerable regarding intermediate lesions. p16 expression, particularly if negative, can reduce unwarranted HSIL diagnoses and unnecessary treatment.

Anal cancer incidence is significantly higher in people living with HIV as HIV increases the oncogenic potential of human papillomavirus. The incidence of anal cancer in the United States has recently increased, with diagnosis and treatment hampered by high loss-to-follow-up rates. Novel methods for the automated, real-time diagnosis of AIN 2+ could enable \"see and treat\" strategies, reducing loss-to-follow-up rates. A previous retrospective study demonstrated that the accuracy of a high-resolution microendoscope (HRME) coupled with a deep learning model was comparable to expert clinical impression for diagnosis of AIN 2+ (sensitivity 0.92 [P = 0.68] and specificity 0.60 [P = 0.48]). However, motion artifacts and noise led to many images failing quality control (17%). Here, we present a high frame rate HRME (HF-HRME) with improved image quality, deployed in the clinic alongside a deep learning model and evaluated prospectively for detection of AIN 2+ in real-time. The HF-HRME reduced the fraction of images failing quality control to 4.6% by employing a high frame rate camera that enhances contrast and limits motion artifacts. The HF-HRME outperformed the previous HRME (P < 0.001) and clinical impression (P < 0.0001) in the detection of histopathologically confirmed AIN 2+ with a sensitivity of 0.91 and specificity of 0.87.

Human papilloma virus–associated anal dysplastic lesions are prevalent in human immunodeficiency virus (HIV)–infected persons. In this study we compare patterns of lymphocytic infiltration in high-grade anal dysplastic lesions by HIV status and in association with treatment outcomes. Abstract Background Anal high-grade squamous intraepithelial lesions (HSILs) are the precursors to anal cancer and frequently persist or recur following electrocautery ablation (EA). Impaired mucosal immunity may facilitate anal carcinogenesis. We characterized the immune microenvironment of anal HSILs in correlation with human immunodeficiency virus (HIV) serostatus and ablation outcomes. Methods Using immunohistochemistry, mucosa-infiltrating CD4+ and CD8+ lymphocytes were quantified in HSILs and benign mucosa from 70 HIV+ and 45 HIV− patients. Clinicopathological parameters were compared. Results Anal HSILs harbored more T lymphocytes than benign mucosa regardless of HIV status (P ≤ .03). Total T lymphocyte count and CD8+ subset were significantly higher in HIV+ HSILs versus HIV− HSILs (median cell count, 71 vs 47; 47 vs 22/high power field [HPF]; P < .001), whereas the CD4+ subset was comparable between groups (median, 24 vs. 25; P = .40). Post EA, HSILs persisted in 41% of HIV+ and 19% of HIV− patients (P = .04). Unadjusted analysis showed trends toward EA failures associated with HIV seropositivity (incidence rate ratio [IRR], 2.0; 95% CI, .8–4.9) and increased CD8+ cells (IRR, 2.3; 95% CI, .9–5.3). Conclusions . Human immunodeficiency virus is associated with alterations of the immune microenvironment of anal HSILs manifested by increased local lymphocytic infiltrates, predominately CD8+. Human immunodeficiency virus seropositivity and excess mucosa-infiltrating CD8+ cells may be associated with ablation resistance.

Objectives: The Lower Anogenital Squamous Terminology (LAST) recommendations classify human papillomavirus-associated squamous lesions into low- and high-grade squamous intraepithelial lesions (LSILs/HSILs). Our study aimed to assess interobserver agreement among 6 experienced pathologists in assigning 40 anal lesions previously diagnosed as anal intraepithelial neoplasia 2 (AIN 2) to either HSIL or non-HSIL categories. Methods: Agreement based on photomicrographs of H&E alone or H&Eplus p16 immunohistochemistry was calculated using k coefficients. Results: Agreement was fair based on H&E alone ([kappa] = 0.42; 95% confidence interval [CI], 0.34-0.52). Adding p16 improved agreement to moderate (k = 0.55; 95% CI, 0.54-0.62). On final diagnosis, 21 cases (53%) had unanimous diagnoses, and 19 (47%) were divided. When designating p16 results as positive or negative, agreement was excellent ([kappa] = 0.92; 95% CI, 0.83-0.95). Among variables (staining location, extent, and intensity), staining of the basal/parabasal layers was a consistent feature in cases with consensus for positive results (20/20). Of the 67 H&E diagnoses with conflicting p16 results, participants modified 32 (48%), downgrading 23 HSILs and upgrading 9 non-HSILs. Conclusions: Although p16 increased interobserver agreement, disagreement remained considerable regarding intermediate lesions. p16 expression, particularly if negative, can reduce unwarranted HSIL diagnoses and unnecessary treatment. Key Words: Interobserver agreement; Human papillomavirus; Anal intraepithelial neoplasia 2; p16 Immunohistochemistry

Backgroud. For over a decade we have known of an epidemic of sexually transmitted hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM), but there still remains significant controversy over which bodily fluid(s) are responsible for HCV transmission in these men. Methods. We enrolled HIV-infected MSM with recent and chronic HCV infection and quantified HCV from rectal fluid obtained by blind swab. We compared the rectal HCV viral load (VL) with paired blood HCV VL. Results. We found rectal HCV shedding in 20 (47%) of 43 men, only one (2%) of whom had visible bleeding. Detection of rectal HCV shedding was associated with blood VL > 5 log IU/mL (p = .01), and 85% with blood VL > 5 log IU/mL had rectal shedding. The HCV VL of the rectal fluid ranged from 2.6 to 5.5 log IU/mL. Based on the median rectal fluid VL, the surface of an average human penis would be exposed to at least 2,300 IU of HCV for the duration of anal intercourse. Conclusion. This study provides the first direct evidence to our knowledge that a sufficient quantity of HCV is shed into the rectum in HIV-infected men with HCV infection to directly infect an inserted penis or be passed indirectly through fomite-like transmission to the rectum of sex partner. We must develop an appropriate public health campaign to educate MSM about these routes of HCV infection to reverse the HCV epidemic among HIV-infected MSM.

Women living with HIV (WLHIV) are at increased risk for human papillomavirus (HPV)-associated anal cancer. Given the “field effect” of HPV pathogenesis, some recommend that anal cancer screening should be limited to WLHIV with prior genital disease. This study aimed to characterize the relationship between anal and genital disease in WLHIV in order to better inform anal cancer screening guidelines. We retrospectively studied 153 WLHIV with biopsy-proven anal high-grade squamous intraepithelial lesions (AHSIL) and long-term evaluable cervical/vaginal/vulvar histopathology. Based on the absence or presence of genital HSIL, subjects were categorized as having isolated AHSIL or multicentric HSIL . Demographics, HIV parameters and cervical/anal HPV status were recorded. Chi-square test was used for bivariate analyses. Of 153 WLHIV with AHSIL, 110 (72%) had isolated AHSIL, while 43 (28%) had multicentric HSIL (28 cervical, 16 vulvar, and 8 vaginal HSIL). The median genital surveillance was 8 years (range 1–27). Cervical HPV16/18 infection was associated with multicentric disease ( P  = 0.001). Overall, 53% of multicentric cases presented genital HSIL preceding AHSIL with median interval 13 years (range 2–23). Paired anal and cervical high-risk HPV results were available for 60 women within 12 months of AHSIL diagnosis: 30 (50%) had anal infection alone, while 30 (50%) had anal/cervical coinfection by 16/18 (15%), non-16/18 (13%), or different types (22%). In conclusion, WLHIV frequently develop AHSILs without pre-existing genital disease or after long latency following a genital HSIL diagnosis. Our findings support anal cancer screening for WLHIV irrespective of prior genital disease.

Objectives. People living with HIV/AIDS (PLWHA) have an increased incidence of anal squamous cell carcinoma. Since high-risk human papillomavirus (hrHPV) is the primary cause, hrHPV DNA testing may play an important role in anal cancer screening. This study aims to determine the negative predictive value (NPV) of hrHPV testing in PLWHA as well as factors that may lead to false-negative results. Methods. Anal swabs were collected for cytology and Cobas® 4800 HPV test for 14 hrHPV types. Patients underwent concomitant high-resolution anoscopy (HRA) examination and biopsy. High-grade squamous intraepithelial lesions (HSIL, synonymous with anal intraepithelial neoplasia AIN2 and 3) detected in Cobas-negative patients were genotyped for 22 HPV types using BioPerfectus Multiplex Real-time PCR. Results. 156 PLWHA tested negative for hrHPV on anal swab samples (i.e., Cobas-negative). HRA-guided biopsy detected HSIL/AIN3 in 13 patients (8%, NPV 92%), HSIL/AIN2 in 5 patients (3%), low-grade squamous intraepithelial lesions in 82 (LSIL, 53%), or benign findings in 56 (36%). No cancer was found. The HSIL group was similar to the LSIL/benign group regarding age, gender, race/ethnicity, clinical HIV parameters, cytological diagnoses, history of receptive anal sex, and smoking (p≥0.02). Genotyping HSIL tissue derived from Cobas-negative patients revealed hrHPV (n=7), possibly carcinogenic HPV53, 67, 73, 82 (n=12), or absence of hrHPV (n=4). Conclusions. In this series, anal hrHPV DNA testing offered 92% NPV for PLWHA; in other words, a 8% risk of occult precancer remains for those who test hrHPV negative on anal swab samples.

Anorectal cytology (ARC) is a widely used screening tool for anal cancer in human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). Its diagnostic accuracy needs to be improved, especially for high-grade squamous intraepithelial lesions (HSILs). Using 100 HIV+ MSM with biopsy-proven anal HSILs, we correlated histologic/cytologic findings. Upon review, HSIL cells were present in 58 cytology samples and absent in 42. Positive samples were higher in cellularity and contained transformation zones ( P  < .05). Cytology was able to predict HSILs in 36%, 48%, 68%, and 78% of patients with one, two, three, and four or more high-grade lesions. HSIL cells were identified in all cytology samples initially reported as HSILs or atypical squamous cells, cannot exclude HSIL and in 34 samples reported as low-grade squamous intraepithelial lesions or less. Notably, among this last category, 15 (44%) were keratinized-type HSILs. Our findings should improve the ARC detection rate for anal HSILs, helping to implement ARC as the primary screening tool for anal cancer.