Any condomless anal intercourse is no longer an accurate measure of HIV sexual risk behaviour in gay and other men who have sex with men

Background: Condomless anal intercourse (CLAI) has long been recognised as the primary mode of sexual transmission of HIV in gay and other men who have sex with men (MSM). A variety of measures of CLAI have been commonly used in behavioural surveillance for HIV risk and to forecast trends in HIV infection. However, gay and other MSM’s sexual practices changed as the understanding of disease and treatment options advance. In the present paper, we argue that summary measures such as any CLAI do not accurately measure HIV sexual risk behaviour. Methods: Participants were 1,427 HIV-negative men from the Health in Men cohort study run from 2001 to 2007 in Sydney, Australia, with six-monthly interviews. At each interview, detailed quantitative data on the number of episodes of insertive and receptive CLAI in the last six months were collected, separated by partner type (regular vs. casual) and partners’ HIV status (negative, positive, and HIV status unknown).Results: A total of 228,064 episodes of CLAI were reported during the study period with a mean of 44 episodes per year per participant (median: 14). The great majority of CLAI episodes were with a regular partner (92.6%), most of them with HIV-negative regular partners (84.8%). Participants were more likely to engage in insertive CLAI with casual than with regular partners (66.7% vs. 55.3% of all acts of CLAI with each partner type, p<0.001). Men were more likely to report CLAI in the receptive position with HIV-negative and HIV status unknown partners than with HIV-positive partners (p<0.001 for both regular and casual partners). Conclusion: Gay and other MSM engaging in CLAI demonstrate clear patterns of HIV risk reduction behaviour. As HIV prevention enters the era of antiretroviral-based biomedical approach, using all forms of CLAI indiscriminately as a measure of HIV behavioural risk is not helpful in understanding the current drivers of HIV transmission in the community

Protocol for an open-label, single-arm trial of HIV pre-exposure prophylaxis (PrEP) among people at high risk of HIV infection:the NSW Demonstration Project PRELUDE

INTRODUCTION: Despite a number of HIV prevention strategies, the number of new HIV infections remains high. In Australia, over three-quarters of new HIV diagnoses are in gay and bisexual men (GBM). Pre-exposure prophylaxis (PrEP) has been shown to be effective at preventing new HIV infections in several randomised trials. The PRELUDE study aims to evaluate the implementation of PrEP in healthcare settings in New South Wales (NSW), Australia, among a sample of high-risk adults. METHODS AND ANALYSIS: PRELUDE is an ongoing open-label, single-arm demonstration project, conducted in public and private clinics across NSW, Australia. Enrolment began in November 2014. The study is designed for 300 high-risk participants—mainly GBM and heterosexual women. Participants receive daily oral PrEP, composed of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), for up to 2.5 years. Quarterly study visits include testing for HIV and sexually transmitted infections (STIs), assessment of ongoing eligibility and side effects, and self-reported adherence. Following each study visit, online behavioural surveys are administered to collect information on medication adherence, risk behaviours and attitudes. Blood samples will be collected in a subset of patients 1, 6 and 12 months after PrEP initiation to measure FTC/TDF concentrations. Analyses using longitudinal regression models will focus on feasibility, adherence, safety, tolerability and effects of PrEP on behaviour. This study will inform PrEP policy and guide the implementation of PrEP in Australia in people at high risk of HIV. ETHICS AND DISSEMINATION: The study will be conducted in accordance with the Declaration of Helsinki. All patients will provide written informed consent prior to participation in the study. Publications relating to each of the primary end points will be gradually released after 12 months of follow-up is complete. TRIAL REGISTRATION NUMBER: NCT02206555; Pre-results

Prevalence and risk factors associated with high-grade anal squamous intraepithelial lesions (HSIL)-AIN2 and HSIL-AIN3 in homosexual men

Background: Anal intraepithelial neoplasia grade 2 (AIN2) and AIN grade 3 (AIN3) are commonly grouped together as high grade squamous intraepithelial lesions (HSIL). We assessed risk factors for HSIL-AIN2 and HSIL-AIN3 in a cohort of homosexual men. Methods: At the baseline visit in the Study for the Prevention of Anal Cancer (SPANC), all men completed a questionnaire and underwent anal swabbing for cytology and HPV genotyping, followed by high resolution anoscopy. Results: Composite-HSIL prevalence was 47% and 32% among 220 HIV-positive and 396 HIV-negative men, respectively. HSIL-AIN3 (37.7% versus 24.7%; p<0.001), but not HSIL-AIN2 (9.5% versus 7.6%; p=0.395) was more common in HIV-positive men. Recent receptive anal partners (p-trend=0.045), and increasing number of high-risk (HR)-HPV types (p-trend<0.001) were associated with HSIL-AIN2. Lifetime receptive partners (p-trend<0.001), HIV status (OR 1.74; 95% CI: 1.05–2.87) and HPV16 (OR 3.00; 95% CI: 1.56–5.75) were associated with HSIL-AIN3. HPV16 was the most common HR-HPV type detected in men with HSIL-AIN3, both HIV-negative (61.1%) and HIV-positive (54.9%). HPV16 was less commonly detected in men with HSIL-AIN2. Conclusions: Grouping HSIL-AIN2 and HSIL-AIN3 as HSIL may mask considerable heterogeneity in anal cancer risk. Given the strong link between HPV16 and anal cancer, men with HSIL-AIN3 and HPV16 are likely to be at greatest risk of cancer. Keywords: Risk factors, Surrogate endpoints, HSIL, Cancer screening, Human papillomaviru

Vaccine-preventable anal human papillomavirus in Australian gay and bisexual men

Objective: HPV causes ~90% of anal cancer and HPV16 is the type most commonly associated with anal cancer. Gay and bisexual men (GBM) are at greatly increased risk. We investigated patterns of vaccine-preventable anal HPV in older GBM. Methods: The Study of the Prevention of Anal Cancer (SPANC) is an ongoing, prospective cohort study of HIV-positive and HIV-negative Australian GBM. Participants completed questionnaires and underwent an anal swab for HPV genotyping using Roche Linear Array. We analysed baseline data from SPANC by HPV type, mean number of types, stratified by age and HIV status. Results: Anal HPV results from 606 (98.2%) of 617 participants (median age 49 years, 35.7% HIV-positive) showed 525 (86.7%) had â¥1 HPV type and 178 (29.4%) had HPV16. Over one third of participants (214, 35.3%) had no nonavalent vaccine-preventable types detected. Two (0.3%) participants had all quadrivalent types and none had all nonavalent vaccine types. HIV-positive participants (p<0.001) and younger participants (p=0.059) were more likely to have more vaccine-preventable HPV types detected. Conclusion: Anal HPV was highly prevalent in this largely community-based GBM cohort. Vaccine-preventable HPV16 was detected in approximately one third of participants. These findings suggest that the potential efficacy of HPV vaccination of older GBM should be explored. Keywords: Human papillomavirus, HPV, Anal, Vaccine, Prevalence, Gay and bisexual men, MSM, HI

Laser capture microdissection-identified HPV genotypes associated with intra-anal high and low-grade intraepithelial lesions

Background: Intra-anal lesions caused by human papillomavirus (HPV) can be classified as low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesion (HSIL). The latter can be further subclassified histomorphologically as anal intraepithelial neoplasia (AIN)2 or AIN3. It is not known whether morphological differences within and between these categories are associated with different high-risk HPV (HR-HPV) genotypes. Methods: In a natural history study of anal HPV-related lesions in gay and bisexual men, we identified the presumed causal genotype of all HSIL present at baseline, utilizing laser capture microdissection. For comparison, we also analyzed randomly selected flat LSIL (fLSIL) and negative biopsies. Results: 244 distinct lesions from 175 men were analyzed: 149 AIN3, 64 AIN2 and 31 flat LSIL (fLSIL). HR-HPV genotypes were found in 139 (93.3%) AIN3, 55 (85.9%) AIN2 and 8 (25.8%) fLSIL. HPV16 was found in 59 (39.6%) AIN3, 11 (17.2%) AIN2 and 1 (3.2%) fLSIL. HR-HPV types were not significantly more common in AIN3 than AIN2 (p=0.08) but HPV16 was (p=0.001). HR-HPV genotypes were significantly more common in HSIL than in LSIL (p<0.001) as was HPV16 (p<0.001). None of 24 negative biopsies contained HR-HPV. Conclusions: There were differences observed between the two subdivisions of HSIL, namely AIN3 and AIN2, in proportions of causal HPV16 but not in proportions of HR-HPV overall. As HPV16 is the most carcinogenic HPV subtype, histomorphologic differences within the category of HSIL could have prognostic significance

Correlation between HPV16 positivity on anal swab and biopsy-confirmed HSIL caused by HPV16 in the study of the prevention of anal cancer (SPANC)

Background: The majority of anal carcinomas are caused by human papillomavirus (HPV) 16. Identifying which of the high-grade squamous intraepithelial lesions (HSIL) are caused by HPV16 may enable targeted management of those most likely to progress. Methods: In a natural history study of anal HPV-related lesions in gay and bisexual men, HPV typing of all baseline histologic HSIL was performed utilizing laser capture microdissection (LCM). The results were compared with HPV types detected by Cobas 4800 in matched anal swabs. We calculated the performance of Cobas testing in identifying HSIL caused by HPV16. Results: 158 men had both lesion and swab genotyping. Overall 54 men (34%) had HPV16 identified as the causal genotype of at least one HSIL by LCM. 51 of these had HPV16 detected on their anal swabs (sensitivity of 94%). Of the 104 men with non-HPV16 HSIL biopsies, 73 had swabs negative for HPV16 (specificity of 70%). 51 of 82 men with swabs positive for HPV16 had HPV16 positive biopsies (positive predictive value - 62%). 73 of 76 men without HPV16 detected on their swabs had only non-HPV16 HSIL biopsies (negative predictive value (NPV) - 96%). Conclusions: In men with prevalent histologic HSIL, Cobas testing of a concurrent anal swab has high sensitivity for detecting those with HPV16-associated HSIL and a high NPV. HPV testing with the Cobas platform may have a role in the identification and management of those with HSIL caused by HPV16 and who are at highest risk of development of anal carcinoma

CpG methylation analysis of HPV16 in laser capture microdissected archival tissue and whole tissue sections from high grade anal squamous intraepithelial lesions:A potential disease biomarker

Incidence and mortality rates of anal cancer are increasing globally. More than 90% of anal squamous cell carcinomas (ASCC) are associated with human papillomavirus (HPV). Studies on HPV-related anogenital lesions have shown that patterns of methylation of viral and cellular DNA targets could potentially be developed as disease biomarkers. Lesion-specific DNA isolated from formalin-fixed paraffin-embedded (FFPE) tissues from existing or prospective patient cohorts may constitute a valuable resource for methylation analysis. However, low concentrations of DNA make these samples technically challenging to analyse using existing methods. We therefore set out to develop a sensitive and reproducible nested PCR-pyrosequencing based method to accurately quantify methylation at 10 CpG sites within the E2BS1, E2BS2,3,4 and Sp1 binding sites in the viral upstream regulatory region of HPV16 genome. Methylation analyses using primary and nested PCR-pyrosequencing on 52 FFPE tissue [26 paired whole tissue sections (WTS) and laser capture microdissected (LCM) tissues] from patients with anal squamous intraepithelial lesions was performed. Using nested PCR, methylation results were obtained for the E2BS1, E2BS2,3,4 and Sp1 binding sites in 86.4% of the WTS and 81.8% of the LCM samples. Methylation patterns were strongly correlated within median values of matched pairs of WTS and LCM sections, but overall methylation was higher in LCM samples at different CpG sites. High grade lesions showed low methylation levels in the E2BS1 and E2BS2 regions, with increased methylation detected in the E2BS,3,4/Sp1 regions, showing the highest methylation at CpG site 37. The method developed is highly sensitive in samples with low amounts of DNA and demonstrated to be suitable for archival samples. Our data shows a possible role of specific methylation in the HPV16 URR for detection of HSIL

The Natural History of Anal High-grade Squamous Intraepithelial Lesions in Gay and Bisexual Men (vol 72, pg 853, 2021)

In the original publication of this article [Poynten IM, Jin F, Roberts JM et al. The Natural History of Anal High-grade Squamous Intraepithelial Lesions in Gay and Bisexual Men. Clin Infect Dis. Volume 72 Issue 5; March 1 2021, 853-861. https://doi.org/10.1093/cid/ciaa166], the term HSIL was erroneously used in the Methods and Results section of the abstract and has been replaced where necessary with cHSIL. The authors regret this error

Is there a role for the thinprep imaging system in reporting anal cytology?

Background The ThinPrep Imaging System (TIS) is an accurate time-saving method of reading cervical ThinPrep slides in screening programs. As anal and cervical cytology are morphologically similar, TIS can potentially be used for anal cytology. We assessed the performance of TIS on anal ThinPrep slides from homosexual men in a natural history study of human papillomavirus-related anal abnormalities. Methods Four hundred nineteen anal cytology slides were processed by TIS and classified by a cytologist as either No further review (slide archived) or Manual review (slide requiring full manual screen). The results were compared with the original manual screening report for all slides and specifically for those screening episodes accompanied by a high-grade squamous intraepithelial lesion (HSIL) on concurrent biopsy. Results One hundred seventy six of 419 (42.0%) slides were classified as No further review, with a trend of decreasing proportions as the degree of severity of the cytological abnormality increased. Thirteen (27.7%) slides with an original unsatisfactory report were classified as No further review. Eighty two (92.1%) of those with biopsy HSIL and cytological abnormality were classified for Manual review, including all 45 (100%) with cytological HSIL. Conclusion The cervical algorithm of TIS performed best on anal samples when HSIL was present both cytologically and histologically. The 27.7% unsatisfactory slides classified as No further review may indicate need for use of different criteria from cervical cytology. Because of the high prevalence of abnormalities, and hence the large proportion of slides needing manual review, the cytologist time-saving would compare unfavorably with use of TIS in cervical screening