HIV-1 exposure and immune activation enhance sexual transmission of Hepatitis C virus by primary Langerhans cells.

INTRODUCTION: The significant rise in incidence of Hepatitis C virus (HCV) infection among men-who-have-sex-with-men (MSM) living with HIV-1 suggests that HCV under specific circumstances is transmitted via sexual contact. During sexual transmission HCV has to cross the epithelial barrier to either directly enter the blood stream or indirectly via mucosal immune cells. However, the mechanisms of sexual transmission of HCV remain unclear. We investigated the role of Langerhans cells (LCs) in HCV susceptibility during sexual contact as LCs are among the first cells in mucosal tissues to encounter invading viruses. METHODS: We investigated the phenotype of primary LCs in anal biopsies from MSM living with HIV-1. To investigate the role of primary LCs in HCV infection and transmission, we have used both isolated primary skin LCs and the ex vivo tissue transmission model. RESULTS: Our data identified an important role for mucosal LCs in facilitating HCV transmission after HIV-1 exposure or immune activation. LCs were detected within mucosal anal tissues obtained from HIV-1 positive MSM biopsies. In order to perform functional studies, we used primary LCs from skin, which have a similar phenotype as mucosal LCs. Immature LCs were neither infected nor transmitted HCV to hepatocytes. Notably, exposure to HIV-1 significantly increased HCV transmission by LCs in the ex vivo transmission model. HIV-1 replication was crucial for the increased HCV transmission as HIV-1 inhibitors significantly reduced HIV-1-induced HCV transmission. Moreover, tissue immune activation of LCs also increased HCV transmission to target cells. CONCLUSIONS: Thus, our data strongly indicate that HIV-1 or immune activation in MSM leads to capture of HCV by mucosal LCs, which might facilitate transmission to other cells or allow entry of HCV into the blood. This novel transmission mechanism by LCs also implicates that the activation state of LCs is an important cellular determinant for HCV susceptibility after sexual contact.

Virological and Serological Predictors of Anal High-grade Squamous Intraepithelial Lesions Among Human Immunodeficiency Virus-positive Men Who Have Sex With Men.

BACKGROUND: Our objective was to identify virological and serological predictors of anal high-grade squamous intraepithelial lesions (HSIL) in human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). METHODS: HIV-positive MSM were recruited from a longitudinal study during which anal self-swabs and serum were collected at up to 5 bi-annual visits. Swabs were human papillomavirus (HPV) genotyped, and the type-specific HPV viral load in the anal swabs was determined. Serum antibodies to the E6, E7, E1, E2, and L1 proteins of 7 high-risk HPV (hrHPV) types and HPV6 and 11 were analyzed. The participants who had a high-resolution anoscopy after the last study visit were included in the current analysis. Anal HSIL was diagnosed by histopathological examinations of anal biopsies. The causative HPV type of anal HSIL was determined in whole tissue sections (WTS) and by laser capture micro-dissection if more than one HPV-type was found in WTS. Multivariable logistic regression was used to study whether persistent anal HPV infections, HPV viral loads, and seropositivity for HPV were predictors of anal HSIL, either in general or caused by the concordant HPV type. RESULTS: Of 193 HIV-positive MSM, 50 (26%) were diagnosed with anal HSIL. HrHPV persistence in anal swabs was common, varying by hrHPV type between 3-21%. Anal HPV persistence was the only determinant independently associated with anal HSIL, both in general and by concordant, causative HPV type. CONCLUSIONS: Persistent HPV infections were strongly associated with anal HSIL, in general as well as for the concordant HPV type.

Detection Rate of High-Grade Squamous Intraepithelial Lesions as a Quality Assurance Metric for High-Resolution Anoscopy in HIV-Positive Men.

BACKGROUND: High-resolution anoscopy-guided biopsies are the gold standard for identifying anal intraepithelial neoplasia, but diagnosing high-grade squamous intraepithelial lesions depends on the skills of the anoscopist. OBJECTIVE: This study aims to validate the high-grade squamous intraepithelial lesion detection rate as a quality assurance metric for high-resolution anoscopy in HIV-positive men. DESIGN: This is a retrospective study. SETTING: This study was conducted at 3 HIV outpatient clinics in Amsterdam, The Netherlands. PATIENTS: HIV-positive men who have sex with men were selected for this study. MAIN OUTCOME MEASURES: We analyzed the high-grade squamous intraepithelial lesion detection rate per high-resolution anoscopy, the mean number of biopsies taken, and the mean high-grade squamous intraepithelial lesion rate per biopsy in time-subsequent groups for 7 anoscopists performing high-resolution anoscopy. RESULTS: Seven anoscopists performed high-resolution anoscopy in 1340 HIV-positive men who have sex with men. The overall high-grade squamous intraepithelial lesion detection rate for all 7 anoscopists combined increased significantly over time, from 27% to 40% (p < 0.001; OR, 1.15; 95% CI, 1.08-1.23 per 50 high-resolution anoscopies). The mean number of biopsies increased significantly from 1.4 (22% high-grade squamous intraepithelial lesions per biopsy) to 2.0 biopsies per patient (29% high-grade squamous intraepithelial lesions per biopsy) (p < 0.001). Three anoscopists showed a significant increase in proportion of high-grade squamous intraepithelial lesions per biopsy with increasing experience. LIMITATIONS: There were statistically significant differences, with limited clinical significance, in the characteristics of patient populations between anoscopists and clinics. CONCLUSIONS: We found significant variations in the high-grade squamous intraepithelial lesion detection rate among anoscopists performing high-resolution anoscopy in HIV-positive men who have sex with men. The high-grade squamous intraepithelial lesion detection rate and mean high-grade squamous intraepithelial lesion rate per biopsy can be used as a quality assurance metric to follow up the learning curve of high-resolution anoscopists. See Video Abstract at http://links.lww.com/DCR/A555.

Cryotherapy for Intra- and Perianal High-Grade Squamous Intraepithelial Lesions in HIV-Positive Men who have Sex with Men.

BACKGROUND: Available treatment options for anal high-grade squamous intraepithelial lesions (HSIL) in HIV-positive men who have sex with men (MSM) are limited by low response rates and frequent recurrences. Cryotherapy is an established therapeutic option for several pre-malignant skin disorders. METHODS: This retrospective, non-randomized study included HIV-positive MSM who received intra- and/or perianal HSIL cryotherapy treatment between 30 December 2008 and 23 April 2015. Cryotherapy was applied in sessions 4-6 weeks apart for a maximum of five sessions. Patients received a follow-up high-resolution anoscopy (HRA) to assess treatment response. Complete and partial treatment responders were followed-up after 6 months and then every 6-12 months to investigate recurrent HSILs. RESULTS: Of 64 patients [median age 48 years; interquartile range (IQR) 42-56] included in the study, six were lost to follow-up. In total, 35 (60%) of 58 patients responded to treatment. Of 64 patients, 31 (48%) reported one or more side effects, of which anal pain or tenderness and mild blood loss were reported most frequently. A total of 19 patients who responded to cryotherapy were adequately followed-up for over 18 months, of whom 13 (68%) had recurrent HSILs. CONCLUSION: Cryotherapy is capable of clearing HSIL in HIV-positive MSM, and treatment success rates are comparable with those reported for current treatment modalities. The treatment is well tolerated, and side effects are relatively mild. Future studies should therefore compare the efficacy and tolerability of cryotherapy with those of current treatment modalities in randomized controlled trials.

Risk factors for anal high-grade squamous intraepithelial lesions in HIV-positive MSM: is targeted screening possible?

OBJECTIVE: HIV-positive MSM are at increased risk for developing anal squamous cell carcinoma. Detection of precursor lesions of anal cancer [anal high-grade squamous intraepithelial lesions (HSIL)] is cumbersome and expensive. Our objective was to identify potential risk factors for anal HSIL in HIV-positive MSM to develop more stringent screening criteria. DESIGN: We studied a cohort of MSM screened by high-resolution anoscopy at three HIV clinics in Amsterdam, the Netherlands. METHODS: For every first high-resolution anoscopy performed in a patient, we analyzed five demographic and seven HIV-related potential risk factors for four different outcome measures: histologically proven anal HSIL vs. no squamous intraepithelial lesions (SIL), HSIL-anal intraepithelial neoplasia 2 vs. no SIL, HSIL-anal intraepithelial neoplasia 3 vs. no SIL, and HSIL vs. no HSIL. We used univariable and multilevel, multivariable logistic regression. RESULTS: From 2008 through 2015, 497 out of 1678 (30%) screened HIV-positive MSM had anal HSIL. The mean age was 49 years (SD 9.6), 96% used combination antiretroviral therapy, and median duration of combination antiretroviral therapy use was 7.8 years (interquartile range 4.0-12.4). Increasing age [adjusted odds ratio (aOR) 0.82, 95% confidence interval (CI) 0.70-0.94, P = 0.006] and years living with suppressed viral load [1-5 years suppressed aOR 0.52 (95% CI 0.34-0.80), 5.01-10 years aOR 0.47 (95% CI 0.29-0.74), >10 years aOR 0.54 [0.34-0.87], all compared to less than 1 year suppressed, P = 0.009] were found to be protective for HSIL vs. no SIL. CONCLUSION: Young HIV-positive MSM without viral suppression are statistically at highest risk for anal HSIL, but given the high prevalence among all virally suppressed men, we advise that all HIV-positive MSM should be screened for HSIL.

Health-Related Quality of Life and Sexual Functioning of HIV-Positive Men Who Have Sex With Men Who Are Treated for Anal Intraepithelial Neoplasia.

BACKGROUND: The impact of the treatment of precursor lesions of anal cancer (anal intraepithelial neoplasia) on health-related quality of life has not been investigated. OBJECTIVE: This study aimed to evaluate the impact of 3 treatment options for anal intraepithelial neoplasia on health-related quality of life and sexual functioning in HIV-positive men who have sex with men. DESIGN: The prospective cohort was embedded in a randomized clinical trial evaluating the optimal treatment of anal intraepithelial neoplasia. SETTING: This study was performed at the HIV outpatient clinic of the Academic Medical Center, Amsterdam, the Netherlands. PATIENTS: Included in the study were HIV-positive men who have sex with men with anal intraepithelial neoplasia. INTERVENTION: Treatment with imiquimod (n = 54), topical fluorouracil (n = 48), or electrocautery (n = 46) was given for 16 weeks. MAIN OUTCOME MEASURES: Health-related quality of life and sexual functioning were assessed before, during, and 4 weeks after treatment. Health-related quality of life was assessed using the EQ5D, sexual functioning was assessed using items derived from the International Index of Erectile Function, and the female sexual function index adapted for anal intercourse. RESULTS: One hundred forty-five patients (98%) completed at least 1 questionnaire. There was a significant different pattern of change over time in health-related quality of life among the 3 treatment groups. Patients in the imiquimod group were more likely to report pain/discomfort at week 8 than patients in the electrocautery group. Patients in the electrocautery group were more likely to report anxiety/depression and were less satisfied with their overall sex life at week 16 than patients in the imiquimod and fluorouracil groups, and patients in the electrocautery group were also more likely to report pain/discomfort and problems with usual activities at week 20 than patients in the fluorouracil group. LIMITATIONS: The follow-up method differed slightly among treatment groups. There is no standardized, validated sexual functioning questionnaire for HIV-positive men who have sex with men. CONCLUSIONS: All treatment options have a negative impact on aspects of health-related quality of life. Electrocautery has significantly more negative effects on health-related quality of life than imiquimod and fluorouracil and also has a negative effect on sexual functioning.