Clinical Effects of Oral Bacteriotherapy on Anal HPV Infection and Related Dysplasia in HIV-Positive MSM: Results from the “HPVinHIV” Trial

Background. Anal HPV infection, anal dysplasia and, ultimately, anal cancer are particularly common in HIV-infected men who have sex with men. Treatment of anal dysplasia, aiming to prevent evolution to squamous cell carcinoma of the anus, is currently limited to direct ablation and/or application of topical therapy. The aim of the present study is to investigate the effect of oral bacteriotherapy (Vivomixx® in EU, Visbiome® in USA) on anal HPV infection and HPV-related dysplasia of the anal canal in HIV-infected men who have sex with men. Methods. In this randomized, placebo-controlled, quadruple-blinded trial (NCT04099433), HIV-positive men who have sex with men with anal HPV infection and HPV-related dysplasia were randomized to receive oral bacteriotherapy or placebo for 6 months. Anal HPV test, anal cytology and high resolution anoscopy with biopsies of anal lesions were performed at baseline and at the end of the study. Safety and tolerability of oral bacteriotherapy were also evaluated. Interim analysis results were presented. Results. 20 participants concluded the study procedures to date. No serious adverse events were reported. In respect to participants randomized to placebo, individuals in the experimental arm showed higher rate of anal dysplasia regression (p = 0.002), lower rate of onset of new anal dysplasia (p = 0.023) and lower rates of worsening of persistent lesions (p = 0.004). Clearance of anal HPV infection was more frequently observed in the bacteriotherapy group (p = 0.067). Conclusion. Being an interim analysis, we limit ourselves to report the preliminary results of the current study. We refer the conclusions relating to the possible effectiveness of the intervention to the analysis of the definitive data.

HPV-mediated anal squamous cell carcinoma and precancerous lesions in HIV positive patients.

3520 Background: Anal cancer affects over 8,000 patients per year in the United States and the incidence is increasing. A significant risk factor for anal cancer and precancerous lesions is human papilloma virus (HPV), with up to 90% of cases being associated with HPV infection. Another emerging risk factor is HIV co-infection. In the present study, we further address if CD4 count is a significant factor for driving higher-grade HPV-mediated anal squamous lesions in HIV/HPV co-infection patients with a single institution large cohort. Methods: A retrospective cohort of HPV-positive patients with anal biopsies was obtained from 2002-2020. Information on the grade of their anal lesion, HIV status, and CD4 count (cells/mm3) were collected. In patients with HIV, the most recent CD4 count up to one year prior to or one month after their biopsy was utilized in our analysis. Lesions were grouped into low grade squamous intraepithelial lesions (LSIL) and higher grade squamous intraepithelial lesions (HSIL), carcinoma in situ (CIS), or squamous cell carcinoma (SCC). The Center for Disease Control CD4 count levels to define HIV status were utilized in our sub-analyses. The distribution of lesion grades was compared between HIV-negative and -positive patients, and between HIV-negative and three subgroups of HIV-positive patients using the Fisher’s exact test. Results: Our cohort comprised of 3,354 total HPV-positive patients. 2,036 of these patients were HIV-negative and 1318 were HIV-positive. The proportion of higher grade lesions was significantly higher in HIV/HPV co-infected patients regardless of CD4 count (Table). The full cohort of HIV-positive patients had lower rates of LSIL (60.8% vs. 74.0%) and higher rates of higher-grade lesions (39.2% vs. 26.0%) (p<0.001) compared to HIV-negative patients. The distribution of lesion grades was also significantly different between HIV-negative patients and all HIV-positive patient subgroups, with all subgroups having higher rates of higher-grade lesions than HIV-negative patients (all p<0.001). Conclusions: Our data show that HIV-HPV co-infection is a risk factor for higher grade anal lesions, regardless of CD4 status. This suggests that CD4 count is not the only factor responsible for the increased risk of higher-grade anal lesions, as the groups of HIV-positive patients with CD4 counts between 200-499 and above 499 still had a higher rate of higher-grade lesions than HIV-negative patients. Further research into other HIV-related immunologic changes that increase risk for higher-grade HPV-driven anal lesions is warranted.[Table: see text]

Exploiting the Microbiota for the Diagnosis of Anal Precancerous Lesions in Men Who Have Sex With Men

Background While the microbiota has been associated with human papillomavirus malignant transformation, it is unclear whether anal bacteria could improve the low specificity of anal cytology for the screening of high-grade intraepithelial squamous neoplasia (HSIL) Methods We recruited men who have sex with men undergoing anal cytology and high-resolution anoscopy. We assessed the microbiota composition from fecal samples and cytobrush anal samples using 16S ribosomal DNA sequencing in participants with or without biopsy-proven HSIL (bHSIL). We selected bacterial biomarkers based on their linear discriminant analysis. We assessed their predictive performance using logistic regression and bootstrap resampling. Results We included 128 individuals, 47 (36.7%) with bHSIL and 99 (77.3%) with human immunodeficiency virus. We detected 40 potential predictors of bHSIL. Ruminococcaceae NK4A214 group, Alloprevotella genus, Prevotella melanonigenica, and Ruminococcaceae UCG-014 were the most predictive of bHSIL. From 35 false-positive cytologic results, the combination of these 4 biomarkers with the anal cytology reclassified to true-negative 33 individuals (94%) and showed good diagnostic performance (area under the receiver operating characteristic curve, 0.805; 95% confidence interval, .728–.882). Conclusions We found anal-associated bacteria indicative of a higher risk of precancerous anal lesions, which combination was highly specific. The microbiota could be developed as a complementary diagnostic tool to overcome the limitations of the current screening strategy for anal cancer.

Classifying Anal Intraepithelial Neoplasia 2 Based on LAST Recommendations

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.

Highly Bioavailable Curcumin Derivative Ameliorates Crohn’s Disease Symptoms: A Randomized, Double-Blind, Multicenter Study

Background & Aims The new curcumin derivative Theracurmin® has a 27–fold higher absorption rate than natural curcumin powder. Theracurmin® is an inhibitor of nuclear factor-κB, which mediates the expression of inflammatory cytokines. The effect of Theracurmin® on inflammatory bowel disease in humans has not been explored; therefore, we investigated the efficacy and safety of Theracurmin® in patients with Crohn’s disease. Methods In this randomized, double-blinded study performed at 5 independent medical centers in Japan, Theracurmin® (360 mg/day, n = 20) or placebo (n = 10) was administered to patients with active mild-to-moderate Crohn’s disease for 12 weeks. The agent’s efficacy was assessed by evaluating clinical and endoscopic remission, healing of anal lesions, and blood levels of inflammatory markers. Results In the Theracurmin® group, a significant reduction in clinical disease activity was observed in week 12 relative to that in week 0 (p = 0.005). On intention-to-treat analysis, clinical remission rates were 35%, 40%, and 40% at weeks 4, 8, and 12, respectively, which were significantly higher than those in the placebo group (all 0%; p = 0.033, p = 0.020, and p = 0.020, respectively). Furthermore, reduction in endoscopic Crohn’s disease severity (p = 0.032) was observed at week 12 in the Theracurmin® group. The endoscopic remission rates were 15% and 0% in the Theracurmin® and placebo groups, respectively. Significant healing of anal lesions (p = 0.017) was observed at week 8 in the Theracurmin® group. No serious adverse events were observed in either group throughout the study. Conclusions Theracurmin® shows significant clinical and endoscopic efficacy together with a favorable safety profile in patients with active mild-to-moderate Crohn’s disease. Clinical trial UMIN registration ID UMIN000015770.

Establishing an Anal Cancer Screening Program in an Outpatient HIV Clinic: Referral Patterns and Patient Perceptions Survey

People living with HIV are at high risk for anal cancer (AC); however, the impact of screening for and treatment of precancerous anal lesions on AC incidence remains uncertain. In 2013, we conducted a survey of HIV providers evaluating the perceived need for an institutional AC screening program. Based on an overwhelmingly positive response, we established a dedicated AC screening clinic (including provision of high-resolution anoscopies) embedded within the institutional HIV clinic. Here, we describe that referral of high-risk patients in the first 3 years was lower than expected. Referral patterns suggest that screening practices vary widely among HIV providers within the institution. Anal cancer clinic patients who completed a perception survey rated the value of AC screening as high, with perceived positive health impact, and identified their providers as the main source of information on AC and AC screening. Our findings imply remaining provider-related barriers to AC screening.

Comparison between anal cytology, high-resolution anoscopy and HPV DNA genotyping by polymerase chain reaction in the post-treatment follow-up of condylomata acuminata

ABSTRACT Aim: to evaluate the presence of subclinical HPV-induced anal lesions with anal cytology, High-Resolution Anoscopy (HRA) and HPV genotyping by polymerase chain reaction (PCR) in the follow-up of treated condylomata acuminata (CA). Methods: seventy-nine male patients were included. One month after anal CA eradication, the patients underwent brush samples collection for anal cytology and PCR, and HRA with biopsy of acetowhite lesions. These methods were compared within all patients and between groups, according to Human Immunodeficiency Virus (HIV) infection status: HIV-negative; HIV-positive with TCD4 count above and below 350 cells/mm3. Results: the most frequent HPV types were 6 and 16. HPV DNA was isolated in 92%. HIV infection was associated with a higher number of oncogenic HPV types (p=0.038). All patients with negative PCR had negative HRA and cytology. There were no differences in cytological, HRA or histopathological findings between groups. Conclusion: the association of the findings of cytopathology, HRA and genotyping of HPV refined the diagnosis of HPV-induced lesions. The degree of immunodeficiency was not associated with increase in remnant HPV-induced anal lesions.