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Summary Background The quadrivalent human papillomavirus (HPV) vaccine was shown to prevent infections and lesions related to HPV6, 11, 16, and 18 in a randomised, placebo-controlled study in men aged 16–26 years. We assessed the incidences of external genital warts related to HPV6 or 11, and external genital lesions and anal dysplasia related to HPV6, 11, 16, or 18, over 10 years of follow-up. Methods The 3-year base study was an international, multicentre, double-blind, randomised, placebo-controlled trial done at 71 sites in 18 countries. Eligible participants were heterosexual men (aged 16–23 years) or men who have sex with men (MSM; aged 16–26 years). Men who had clinically detectable anogenital warts or genital lesions at screening that were suggestive of infection with non-HPV sexually transmitted diseases, or who had a history of such findings, were excluded. Eligible participants were randomly assigned (1:1) to receive three doses of either quadrivalent HPV vaccine or placebo on day 1, month 2, and month 6, administered as a 0·5-mL injection into the deltoid muscle. The 7-year, open-label, long-term follow-up extension study was done at 46 centres in 16 countries. Participants who received one or more doses of the quadrivalent HPV vaccine in the base study were eligible for enrolment into the long-term follow-up study (early vaccination group). Placebo recipients were offered the three-dose quadrivalent HPV vaccine at the end of the base study; those who received one or more quadrivalent HPV vaccine doses were eligible for enrolment into the long-term follow-up study (catch-up vaccination group). The primary efficacy endpoints were the incidence of external genital warts related to HPV6 or 11 and the incidence of external genital lesions related to HPV6, 11, 16, or 18 in all participants and the incidence of anal intraepithelial neoplasia (including anal warts and flat lesions) or anal cancer related to HPV6, 11, 16, or 18 in MSM only. The primary efficacy analysis was done in the per-protocol population for the early vaccination group, which included participants who received all three vaccine doses, were seronegative at day 1 and PCR-negative from day 1 through month 7 of the base study for the HPV type being analysed, had no protocol violations that could affect evaluation of vaccine efficacy, and had attended at least one visit during the long-term follow-up study. For the catch-up vaccination group, efficacy was assessed in the modified intention-to-treat population, which included participants who had received at least one vaccine dose, were seronegative and PCR-negative for HPV types analysed from day 1 of the base study to the final follow-up visit before receiving the quadrivalent HPV vaccine, and had at least one long-term follow-up visit. Safety was assessed in all randomised participants who received at least one vaccine dose. This study is registered with ClinicalTrials.gov , NCT00090285 . Findings Between Aug 10, 2010, and April 3, 2017, 1803 participants were enrolled in the long-term follow-up study, of whom 936 (827 heterosexual men and 109 MSM) were included in the early vaccination group and 867 (739 heterosexual men and 128 MSM) were included in the catch-up vaccination group. Participants in the early vaccination group were followed up for a median of 9·5 years (range 0·1–11·5) after receiving the third dose of the quadrivalent HPV vaccine, and participants in the catch-up vaccination group were followed up for a median of 4·7 years (0·0–6·6) after receiving the third dose. In early vaccine group participants during long-term follow-up compared with the placebo group in the base study, the incidence per 10 000 person-years of external genital warts related to HPV6 or 11 was 0·0 (95% CI 0·0–8·7) versus 137·3 (83·9–212·1), of external genital lesions related to HPV6, 11, 16, or 18 was 0·0 (0·0–7·7) versus 140·4 (89·0–210·7), and of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 in MSM only was 20·5 (0·5–114·4) versus 906·2 (553·5–1399·5). Compared with during the base study (ie, before quadrivalent HPV vaccine administration), during the long-term follow-up period, participants in the catch-up vaccination group had no new reported cases of external genital warts related to HPV6 or 11 (149·6 cases per 10 000 person-years [95% CI 101·6–212·3] vs 0 cases per 10 000 person-years [0·0–13·5]) or external genital lesions related to HPV6, 11, 16, or 18 (155·1 cases per 10 000 person-years [108·0–215·7] vs 0 cases per 10 000 person-years [0·0–10·2]), and a lower incidence of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 (886·0 cases per 10 000 person-years [583·9–1289·1] vs 101·3 cases per 10 000 person-years [32·9–236·3]). No vaccine-related serious adverse events were reported. Interpretation The quadrivalent HPV vaccine provides durable protection against anogenital disease related to HPV6, 11, 16, and 18. The results support quadrivalent HPV vaccination in men, including catch-up vaccination. Funding Merck Sharp & Dohme.

Background In men, the incidence of human papillomavirus (HPV)–related cancer is rising, but data regarding male HPV infection and seroprevalence are available from only a few countries. Methods This analysis of a global HPV vaccine trial evaluated baseline data from 1399 human immunodeficiency virus–negative heterosexual men (HM) and men who have sex with men (MSM). Key objectives included assessment of HPV prevalence and risk factors for seropositivity to 9-valent HPV (9vHPV) vaccine types (6, 11, 16, 18, 31, 33, 45, 52, and 58), and concordance between seropositivity and prevalent HPV type. Results Overall, 455 of 3463 HM (13.1%) and 228 of 602 MSM (37.9%) were HPV DNA positive for any 9vHPV vaccine type at baseline. Infection prevalence and seroprevalence (≥1 9vHPV vaccine type) were 13.2% and 8.1%, respectively, among 333 HM from Europe, and 37.9% and 29.9%, respectively, among 335 MSM from Europe or North America. Among men with baseline infection, MSM had higher seroprevalence for concordant HPV types (39.5% vs 10.8% in HM). The seropositivity risk (irrespective of baseline infection status) was higher among MSM versus HM (age-adjusted odds ratio, 3.0 [95% confidence interval, 2.4–6.4]). Among MSM, statistically significant seropositivity risk factors included younger age at sexual debut, higher number of receptive anal sex partners, and less frequent condom use. No factors assessed were associated with seropositivity in HM. Conclusions Higher proportions of MSM than HM were HPV DNA positive and seropositive, and concordance between HPV DNA positivity and seropositivity, a potential marker of true infection versus carriage, was higher in MSM. Most MSM and HM were seronegative for all 9vHPV vaccine types, suggesting the potential benefit of catch-up vaccination after sexual debut. Clinical Trials Registration. NCT00090285.

Targeted ablation of anal canal high-grade dysplasia results in high recurrence over time. Circumferential radiofrequency ablation might decrease recurrence.To determine the safety and efficacy of circumferential radiofrequency ablation for anal high-grade dysplasia.A dual-center prospective trial of circumferential radiofrequency ablation with 1 year follow-up with longer follow-up data abstracted from medical records of study patients returning post trial for surveillance. Ten participants from the identically conducted pilot circumferential radiofrequency ablation trial were combined to improve sample size for longer-term analysis.The study included 51 patients undergoing circumferential radiofrequency ablation for anal canal high-grade dysplasia.Three surgeons at 2 sites.Circumferential radiofrequency ablation of anal canal high-grade dysplasia and targeted radiofrequency ablation of recurrence.The primary measures were circumferential radiofrequency ablation efficacy and associated morbidity.Fifty-one participants underwent circumferential radiofrequency ablation but 48 returned for ≥1 post-procedure high-resolution anoscopy and were evaluable. Participants mean age was 43 years, mostly male (94%), 33% living with HIV and 58% had ≥3 high-grade dysplasias treated. Sixty percent had no recurrence while 19%, 15%, and 6% had 1, 2 or 3 recurrences. Most recurrence (66%) developed within the first 6 months. Kaplan-Meier probability of recurrence combining both series was 19% at 3 months, 30% at 6 months, and approximately 40% after 6 months out to 30 months. Most common morbidities were pain (85.4%) lasting a median of 21 (range, 4-91) days and bleeding (91%) lasting a median of 21 (range 5-87) days. Of those with pain and bleeding 65% and 85%, respectively, described it as mild. No patients developed fistulae, stricture or incontinence. No serious adverse events related to circumferential radiofrequency ablation occurred. Having a prior recurrence was the only significant predictor of a subsequent recurrence (HR 28.53) for recurrence at 9 months or prior.Enrollment ended prematurely and 10 participants from the pilot study were combined to increase sample size. Longer-term follow-up was collected retrospectively.Circumferential radiofrequency ablation has improved efficacy over targeted ablation but with increased pain and bleeding. See Video Abstract at http://links.lww.com/DCR/B973.

Background The progression rate and predictors of anal dysplastic lesions to squamous cell carcinoma of the anus remain unclear. Characterizing these parameters may help refine anal cancer screening guidelines. Objective This study aimed to determine the rate of progression of high-grade anal dysplasia to invasive carcinoma in HIV-infected persons. Design Using the Surveillance, Epidemiology, and End Results database linked to Medicare claims from 2000 to 2011, we identified HIV-infected subjects with incident anal intraepithelial neoplasia III. To estimate the rate of progression of anal intraepithelial neoplasia III to invasive cancer, we calculated the cumulative incidence of anal cancer in this cohort. We then fitted Poisson models to evaluate the potential risk factors for incident anal cancer. Settings This is a population-based study. Patients Included were 592 HIV-infected subjects with incident anal intraepithelial neoplasia III. Main outcome measures The primary outcome measured was incident squamous cell carcinoma of the anus. Results Study subjects were largely male (95%) with a median age of 45.7 years. Within the median follow-up period of 69 months, 33 subjects progressed to anal cancer. The incidence of anal cancer was 1.2% (95% CI, 0.7%-2.5%) and 5.7% (95% CI, 4.0%-8.1%) at 1 and 5 years, following a diagnosis of anal intraepithelial neoplasia III. Risk of progression did not differ by anal intraepithelial neoplasia III treatment status. On unadjusted analysis, black race (p = 0.02) and a history of anogenital condylomata (p = 0.03) were associated with an increased risk of anal cancer incidence, whereas prior anal cytology screening was associated with a decreased risk (p = 0.04). Limitations The identification of some incident cancer episodes used surrogate measures. Conclusions In our population-based cohort of HIV-infected subjects with long-term follow-up, the risk of progression from anal intraepithelial neoplasia III to anal squamous cell carcinoma was higher than reported in other studies and was not associated with the receipt of anal intraepithelial neoplasia III treatment. See Video Abstract at http://links.lww.com/DCR/A933.

[Background] Robust age-specific estimates of anal human papillomavirus (HPV) and high-grade squamous intraepithelial lesions (HSIL) in men can inform anal cancer prevention efforts. We aimed to evaluate the age-specific prevalence of anal HPV, HSIL, and their combination, in men, stratified by HIV status and sexuality., [Methods] We did a systematic review for studies on anal HPV infection in men and a pooled analysis of individual-level data from eligible studies across four groups: HIV-positive men who have sex with men (MSM), HIV-negative MSM, HIV-positive men who have sex with women (MSW), and HIV-negative MSW. Studies were required to inform on type-specific HPV infection (at least HPV16), detected by use of a PCR-based test from anal swabs, HIV status, sexuality (MSM, including those who have sex with men only or also with women, or MSW), and age. Authors of eligible studies with a sample size of 200 participants or more were invited to share deidentified individual-level data on the above four variables. Authors of studies including 40 or more HIV-positive MSW or 40 or more men from Africa (irrespective of HIV status and sexuality) were also invited to share these data. Pooled estimates of anal high-risk HPV (HR-HPV, including HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68), and HSIL or worse (HSIL+), were compared by use of adjusted prevalence ratios (aPRs) from generalised linear models., [Findings] The systematic review identified 93 eligible studies, of which 64 contributed data on 29 900 men to the pooled analysis. Among HIV-negative MSW anal HPV16 prevalence was 1·8% (91 of 5190) and HR-HPV prevalence was 6·9% (345 of 5003); among HIV-positive MSW the prevalences were 8·7% (59 of 682) and 26·9% (179 of 666); among HIV-negative MSM they were 13·7% (1455 of 10 617) and 41·2% (3798 of 9215), and among HIV-positive MSM 28·5% (3819 of 13 411) and 74·3% (8765 of 11 803). In HIV-positive MSM, HPV16 prevalence was 5·6% (two of 36) among those age 15–18 years and 28·8% (141 of 490) among those age 23–24 years (ptrend=0·0091); prevalence was 31·7% (1057 of 3337) among those age 25–34 years and 22·8% (451 of 1979) among those age 55 and older (ptrend, [Interpretation] High anal HPV prevalence among young HIV-positive and HIV-negative MSM highlights the benefits of gender-neutral HPV vaccination before sexual activity over catch-up vaccination. HIV-positive MSM are a priority for anal cancer screening research and initiatives targeting HPV16-positive HSIL+., International Agency for Research on Cancer.

Author(s): Chiao, Elizabeth Y; Lensing, Shelly Y; Wiley, Dorothy J; Deshmukh, Ashish A; Lee, Jeannette; Darragh, Teresa M; Einstein, Mark H; Jay, Naomi; Berry-Lawhorn, John Michael; Palefsky, Joel M; Wilkin, Timothy; Barroso, Luis F; Cranston, Ross D; Levine, Rebecca; Guiot, Humberto M; French, Audrey L; Citron, Deborah; Rezaei, Masoumeh Katayoon; Goldstone, Stephen E; Stier, Elizabeth A | Abstract: ObjectiveHIV-infected women (WLHIV) have more than 10-fold higher risk for squamous cell cancer of the anus. Experts suggest cytology-based strategies developed for cervical cancer screening may prevent anal cancer by detecting anal cytologic or histological high-grade squamous intraepithelial lesion (hHSIL) for treatment. Currently, there is no consensus on anal-hHSIL screening strategies for WLHIV.DesignBetween 2014 and 2016, 276 WLHIV were recruited at 12 US AIDS Malignancy Consortium clinical trials sites to evaluate hHSIL prevalence and (test) screening strategies.MethodsParticipants completed detailed questionnaire, underwent anal assessments including high-risk human papillomavirus (hrHPV) testing using hrHPV-Hybrid Capture 2 (HC2) and hrHPV-APTIMA, anal cytology, and concurrent high-resolution anoscopy. Screening test characteristics for predicting hHSIL validated by central review of histologic diagnosis were estimated sensitivity, specificity, positive predictive value, and false-omission rate. Paired analyses compared sensitivity and specificity for hrHPV single tests to anal cytology alone.Results83% (229/276) of enrolled WLHIV had complete anal assessment data and were included in this analysis. Mean age was 50, 62% black and 60 (26%) had hHSIL. Anal cyotology (gatypical squamous cells of undetermined significance), hrHPV-HC2, and hrHPV-APTIMA sensitivity estimates were similarly high (83, 77, and 75%, respectively, P values g 0.2). Specificity was higher for both hrHPV-APTIMA and hrHPV-HC2 compared with anal cytology (67 vs. 50%, P l 0.001) and (61 vs. 50%, P = 0.020), respectively.ConclusionAnal hrHPV testing demonstrated similar sensitivity for anal cytology (gatypical squamous cells of undetermined significance) to predict anal hHSIL. Among tests with similar sensitivity, the specificity was significantly higher for hrHPV-APTIMA and hrHPV-HC2. Thus, anal hrHPV testing may be an important alternative strategy to anal cytology for anal hHSIL screening among WLHIV.

Background Women living with HIV (WLWH) experience high rates of anal cancer. Screening using anal cytology, high-resolution anoscopy (HRA) with biopsies, can histologically diagnose anal cancer precursors called high-grade squamous intraepithelial lesions (HSIL). The low specificity of screening using anal cytology results in HRA referral for many WLWH without HSIL. Screening using high-risk human papillomavirus (HR-HPV) may improve specificity. Methods Two hundred seven WLWH (63% non-Hispanic black) were screened for anal histologic HSIL (hHSIL) using cytology, HRA-guided biopsies, and Xpert HPV. Xpert performance for predicting anal hHSIL was compared with that of cytology. Usng Xpert 5 HPV genotypic results and accompanying cycle thresholds, receiver operator characteristic curve and recursive partitioning analyses were used to create predictive models for hHSIL. Results The performance of Xpert to predict hHSIL was not different from that of cytology with a sensitivity (Sn) of 89% and specificity (Sp) of 49%. Interpretation of Xpert was modified using genotypic results and receiver operator characteristic curve analysis, which produced a screen with an Sn and Sp of 75% and 84% for hHSIL, respectively. Another reinterpretation of Xpert was created using recursive partitioning and cycle thresholds, which predicted hHSIL with an Sn and Sp of 75% and 86%, respectively. The detection of HPV-16 was highly predictive of hHSIL in all analyses. These modified screening tests would reduce HRA referral in this population by almost half compared with anal cytology. Conclusions Xpert HPV is an alternative to anal cytology to screen for anal HSIL and can be optimized to reduce the number of unnecessary HRAs performed in WLWH.

Background Men who have sex with men (MSM) are at high risk for human papillomavirus (HPV)–related anal cancer. Little is known about the prevalence of low-grade squamous intraepithelial lesions (LSILs) and the anal cancer precursor, high-grade squamous intraepithelial lesions (HSILs), among young MSM with HIV (MSMLWH). HPV vaccination is recommended in this group, but its safety, immunogenicity, and protection against vaccine-type HPV infection and associated LSILs/HSILs have not been studied. Methods Two hundred and sixty MSMLWH aged 18–26 years were screened at 17 US sites for a clinical trial of the quadrivalent (HPV6,11,16,18) HPV (qHPV) vaccine. Those without HSILs were vaccinated at 0, 2, and 6 months. Cytology, high-resolution anoscopy with biopsies of lesions, serology, and HPV testing of the mouth/penis/scrotum/anus/perianus were performed at screening/month 0 and months 7, 12, and 24. Results Among 260 MSMLWH screened, the most common reason for exclusion was detection of HSILs in 88/260 (34%). 144 MSMLWH were enrolled. 47% of enrollees were previously exposed to HPV16. No incident qHPV type–associated anal LSILs/HSILs were detected among men naive to that type, compared with 11.1, 2.2, 4.5, and 2.8 cases/100 person-years for HPV6,11,16,18–associated LSILs/HSILs, respectively, among those previously exposed to that type. qHPV was immunogenic and safe with no vaccine-associated serious adverse events. Conclusions 18–26-year-old MSMLWH naive to qHPV vaccine types were protected against incident qHPV type–associated LSILs/HSILs. Given their high prevalence of HSILs, there is an urgent need to vaccinate young MSMLWH before exposure to vaccine HPV types, before initiating sexual activity, and to perform catch-up vaccination., A high proportion of 18-26 year-old men-who-have-sex-with-men-living-with-HIV screened for a quadrivalent HPV (qHPV) vaccine trial had anal low-grade/high-grade squamous intraepithelial lesions (LSIL/HSIL). Vaccinees naive to qHPV types were protected against incident qHPV type-associated-LSIL/HSIL. Vaccination before sexual initiation is critically important.

BACKGROUND HIV-positive individuals have high incidence of anal high-grade squamous intraepithelial lesions (HSIL) at the squamocolumnar junction (SCJ), which can progress to cancer. Focal radiofrequency ablation (RFA) treats HSIL, but metachronous recurrence remains high and may be improved with circumferential treatment. SETTING The study was performed at a single center. METHODS This was a prospective trial of circumferential anal RFA using Barrx 60 RFA focal catheters in participants with ≥1 anal SCJ HSIL. The entire SCJ was ablated by RFA. Adverse events (AEs), symptoms, including pain, and quality of life were assessed. High-resolution anoscopy assessed recurrences at 3, 6, 9, and 12 months. Lesion site biopsies occurred at month 12. Recurrences were retreated with focal RFA. RESULTS Ten male participants (9 HIV+), with a median 2 HSILs (range 2-8) each, enrolled. Median T-cell count and viral load were 730 cells/mcL and 38 copies/mL. Median duration of RFA treatment was 6.5 (5-13) minutes. Lesion persistence occurred in 4 participants (3 at 3 months, 1 at 6 months). Recurrence at a new site occurred in 1 participant at 3 months. No lesion persisted after retreatment. All participants were HSIL free and completely healed by 12 months. Two device-related mild AEs occurred in 1 participant each (thrombosed external hemorrhoid and soft anal scar; both resolved). No serious AEs occurred. CONCLUSION Circumferential anal SCJ RFA produced total HSIL eradication with no more than 2 treatments. Circumferential RFA seems to be well tolerated with minimal pain and no serious AEs in HIV+ participants. CLINICALTRIALS.GOV:: NCT02189161.

BACKGROUND Human immunodeficiency virus (HIV)–positive men who have sex with men (MSM) are at disproportionately high risk for anal cancer. There is no definitive approach to the management of high-grade squamous intraepithelial lesions (HSIL), which are precursors of anal cancer, and evidence suggests that posttreatment adjuvant quadrivalent human papillomavirus (qHPV) vaccination improves HSIL treatment effectiveness. The objectives of this study were to evaluate the optimal HSIL management strategy with respect to clinical effectiveness and cost-effectiveness and to identify the optimal age for initiating HSIL management. METHODS A decision analytic model of the natural history of anal carcinoma and HSIL management strategies was constructed for HIV-positive MSM who were 27 years old or older. The model was informed by the Surveillance, Epidemiology, and End Results–Medicare database and published studies. Outcomes included the lifetime cost, life expectancy, quality-adjusted life expectancy, cumulative risk of cancer and cancer-related deaths, and cost-effectiveness from a societal perspective. RESULTS Active monitoring was the most effective approach in patients 29 years or younger; thereafter, HSIL treatment plus adjuvant qHPV vaccination became most effective. When cost-effectiveness was considered (ie, an incremental cost-effectiveness ratio [ICER] < $100,000/quality-adjusted life-year), do nothing was cost-effective until the age of 38 years, and HSIL treatment plus adjuvant qHPV vaccination was cost-effective beyond the age of 38 years (95% confidence interval, 34-43 years). The ICER decreased as the age at HSIL management increased. Outcomes were sensitive to the rate of HSIL regression or progression and the cost of high-resolution anoscopy and biopsy. CONCLUSIONS The management of HSIL in HIV-positive MSM who are 38 years old or older with treatment plus adjuvant qHPV vaccination is likely to be cost-effective. The conservative approach of no treatment is likely to be cost-effective in younger patients. Cancer 2017. © 2017 American Cancer Society.

Importance Outcomes of treating high-grade squamous intraepithelial lesions (HSIL), a precursor to anal cancer, remain uncertain. Emerging evidence shows that post HSIL treatment adjuvant quadrivalent human papillomavirus (qHPV) vaccination improves the effectiveness of treatment. However, no recommendations exist regarding the use of qHPV vaccine as an adjuvant form of therapy. Our objective was to determine whether post-treatment adjuvant vaccination should be adopted in HIV-infected MSM (individuals at highest risk for anal cancer) on the basis of cost-effectiveness determined using existing evidence or whether future research is needed. Methods We developed a Markov (state-transition) cohort model to assess the cost-effectiveness of post-treatment adjuvant HPV vaccination of 27 years or older HIV-infected MSM. We first estimated cost-effectiveness and then performed value-of-information (VOI) analysis to determine whether future research is required by estimating the expected value of perfect information (EVPI). We also estimated expected value of partial perfect information (EVPPI) to determine what new evidences should have highest priority. Results With the incremental cost-effectiveness ratio (ICER) of $71,937/QALY, “treatment plus vaccination” was the most cost-effective HSIL management strategy using the willingness-to-pay threshold of 100,000/QALY. We found that population-level EVPI for conducting future clinical research evaluating HSIL management approaches was US$12 million (range $6–$20 million). The EVPPI associated with adjuvant qHPV vaccination efficacy estimated in terms of hazards of decreasing HSIL recurrence was $0 implying that additional data from a future study evaluating efficacy of adjuvant qHPV vaccination will not change our policy conclusion that “treatment plus vaccination” was cost-effective. Both the ICER and EVPI were sensitive to HSIL treatment compliance. Conclusion Post-treatment adjuvant qHPV vaccination in HIV-infected MSM aged 27 or above is likely to be cost-effective. Use of adjuvant qHPV vaccination could be considered as a potential strategy to reduce rising anal cancer burden among these high-risk individuals.

Anal HSIL is the precursor lesion of anal squamous cell carcinoma. The exact rate of cancer progression from HSIL is not clear, but likely approaches 10% in immunocompromised individuals. Just as excision and destruction of cervical dysplasia has been shown to significantly decrease the risk of cervical cancer, several studies have shown a reduced incidence of anal cancer after targeted ablation of HSIL. Given the morbidity of anal mapping and wide local excision, we cannot justify this treatment method, especially since recurrence is common. Except for the most severe cases, anal and perianal lesions are very amenable to office-based treatments. Topical therapies have a role in treating anal and perianal HSIL, especially in the setting of wide-spread disease. However, ablation has been shown to be more effective and better tolerated compared to topical treatments. Recurrence is to be expected following treatment of HSIL, highlighting the need for close long-term follow-up.

Preventing infection with HPV is likely the best strategy to decrease the incidence of anal cancer. The qvHPV and 9vHPV vaccines are highly immunogenic with the same serious adverse event rates as placebo. The qvHPV vaccine has been FDA approved since 2006 for the prevention of cervical, vaginal, and vulvar cancer and anogenital warts in girls and women from 9 to 26 years of age related to HPV types 6, 11, 16, and 18. In 2009, it was FDA approved for prevention of anogenital warts in men and anogenital dysplasia in males and females 9–26 years of age related to the same HPV types. Since being approved for use in women under the age of 26 years, several studies have been conducted evaluating the role of vaccinating other populations. Though not FDA approved for this population, the qvHPV vaccine is immunogenic, safe, and effective in the prevention of anogenital HPV disease in immunocompetent women and men up to 45 years of age. Although efficacy studies are underway in the HIV-positive population, the qvHPV vaccine has been shown to be safe and immunogenic is HIV-positive individuals up to 61 years of age. There is also some evidence that vaccination may decrease recurrence post treatment for HPV-related dysplasia. In 2014, the FDA approved a nine-valent (9vHPV) vaccine for use in 9–26-year-old women followed in 2015 by approval for use in men. In addition to the original four HPV types present in qvHPV, 9vHPV contains antigen an additional five oncogenic HPV types 31, 33, 45, 52, and 58. Current guidelines recommend vaccination in girls and women 9–26 years of age and boys and men 9–21 years of age. It is recommended that men at greater risk be offered the vaccine up to age 26.

Mistrangelo et al raise a number of issues in connection with the International Anal Neoplasia Society guidelines for the practice of High Resolution Anoscopy (HRA) in the era of COVID‐19.The authors suggest that the guidelines advocate “mandatory” HRA for “screening”. On the contrary, the guidelines clearly define risk prioritisation, in terms of both potential COVID‐19 exposure and the dangers associated with delayed diagnosis of anal cancers.Centres without access to high quality HRA services may have to rely on digital anal rectal examination to eventually diagnose large anal cancers. HRA has the ability to accurately identify early anal cancers and worrisome pre‐cancerous lesions, and thus to facilitate early intervention. It therefore has the capacity to substantially improve survival and quality of life of patients. This remains true in the era of COVID‐19, and will be of increasing importance as the epidemic continues and services remain disrupted.

BACKGROUND: Electrocautery ablation (EA) is a common treatment modality for anal high-grade squamous intraepithelial lesions (HSIL) but its effectiveness is understudied. This study aimed to determine ablation outcomes and to identify clinicopathological factors associated with post-ablation recurrence. METHODS: 330 people living with HIV (PLWH) with de novo intra-anal HSIL treated with EA from 2009 to 2016 were studied retrospectively. Using long-term surveillance high-resolution anoscopy biopsy data, treatment failures were classified as local recurrence (HSIL at the treated site upon surveillance) or overall recurrence (HSIL at treated or untreated sites). The associations of these outcomes with clinical factors were analyzed using Cox proportional hazards models. RESULTS: 88% of participants were men who have sex with men, median age was 45.5 years (range 35–51) and 49% had multiple index HSILs (range 2–6). At a median of 12.2 months post-ablation (range 6.3–20.9), 45% had local recurrence while 60% had overall recurrence. Current cigarette smoking, HIV viremia (HIV-1 RNA ≥100 copies/mL) and multiple index HSILs were predictive of local recurrence. Overall recurrence was more common in current smokers and those with multiple index lesions. In multivariable models that included HPV genotypes, baseline and persistent infection with HPV16/18 were significantly associated with both local and overall recurrence. CONCLUSIONS: EA is an effective treatment modality for anal HSIL in PLWH but recurrence rates are substantial. Multiple index HSILs, HIV viremia, smoking and both baseline and persistent infection with HPV16/18 negatively impact treatment success. Ongoing surveillance is imperative to capture recurrence early and improve long-term treatment outcomes.

Author(s): Stier, Elizabeth A; Lensing, Shelly Y; Darragh, Teresa M; Deshmukh, Ashish A; Einstein, Mark H; Palefsky, Joel M; Jay, Naomi; Berry-Lawhorn, J Michael; Wilkin, Timothy; Wiley, Dorothy J; Barroso, Luis F; Cranston, Ross D; Levine, Rebecca; Guiot, Humberto M; French, Audrey L; Citron, Deborah; Rezaei, M Katayoon; Goldstone, Stephen E; Chiao, Elizabeth | Abstract: BackgroundWomen living with human immunodeficiency virus (WLHIV) have disproportionately high rates of squamous cell carcinoma of the anus compared with the general population of women. Anal high-grade squamous intraepithelial lesions (HSILs) precede anal cancer, and accurate studies of HSIL prevalence among WLHIV in the United States are lacking.MethodsThe AIDS Malignancy Consortium 084 study was a multicenter national trial to evaluate the prevalence of and risk factors for anal HSIL in a US cohort. Eligible participants were WLHIV aged ≥18 years with no history of anal HSIL. Study participants had an examination including collection of cervical/vaginal and anal specimens, followed by high-resolution anoscopy with biopsy.ResultsWe enrolled 256 women with evaluable anal pathology. The mean age was 49.4 years, 64% women were non-Hispanic black, 67% were former or current smokers, and 56% reported ever having anal sex with a man. The median CD4 T-cell count was 664 cells/μL. The prevalence of anal histologic HSIL (hHSIL) was 27% (95% confidence interval [CI], 22%-33%). There was a strong concordance (240/254) between local and consensus pathologists for hHSIL vs less than hHSIL (κ = 0.86 [95% CI, .79-.93]). Current CD4 count of ≤200 cells/μL was the strongest predictor of consensus anal hHSIL diagnosis (adjusted odds ratio [aOR], 10.34 [95% CI, 3.47-30.87]). History of anoreceptive intercourse was also associated with hHSIL (aOR, 2.44 [95% CI, 1.22-4.76]).ConclusionsThe prevalence of anal hHSIL in WLHIV in the United States was 27% in this study where all participants received high-resolution anoscopy and biopsy.

We examined the prevalence of infection with human papillomavirus (HPV) and HIV in a cohort of young gay, bisexual, and other men who have sex with men [sexual minority men (SMM)]. HPV vaccination uptake was assessed; HIV antibody testing was performed and genetic testing for oral and anal HPV infection was undertaken. We examined both HPV vaccination and infection in relation to key demographic and structural variables. Participants (n = 486) were on average 23 years old; 70% identified as a member of a racial/ethnic minority group, and 7% identified as transgender females. Only 18.1% of the participants indicated having received the full dosage of HPV vaccination and 45.1% were unvaccinated. Slightly over half the participants (58.6%) were infected with HPV, with 58.1% testing positive for anal infection and 8.8% for oral infection. HIV seropositivity was associated with infection to oral HPV [adjusted odds ratio (AOR) = 4.03] and vaccine-preventable HPV, whereas both neighborhood-level poverty (AOR = 1.68) and HIV infection (AOR = 31.13) were associated with anal infection to HPV (AOR = 1.68). Prevalence of HPV infection is high among unvaccinated young SMM, despite the availability and eligibility for vaccination. HPV infection adds further health burden to these populations and is particularly concerning for those who are HIV positive as HIV infection increases the risk of developing HPV-related cancers. These findings underscore a missed prevention opportunity for an at-risk and underserved population and suggest the need for active strategies to increase HPV vaccination uptake in young SMM before the onset of sexual behavior.

Anal canal high-grade squamous intraepithelial lesion (HSIL) is the precursor to anal cancer. Immunocompromised patients are at increased risk and disease is usually within 3 cm from the anal verge. High-resolution anoscopy (HRA) with an 8-cm anoscope is used to identify and guide cautery treatment of HSIL. We report three patients with a long-term history of ulcerative colitis (UC) treated with systemic immunomodulators who developed proximally located rectal HSIL. Two patients were HIV-negative women, 63 and 48 years old, and the third was a 51-year-old HIV-positive man with underlying UC for 10, 16, and 3 years, respectively. They each presented with a HPV-positive HSIL visibly extending above the limits of the anoscope used for HRA. None developed cancer. All had episodes of active UC. It is unclear what causative role systemic immunomodulators play in predisposing UC patients to proximal HSIL. HSIL probably developed on a tongue of HPV-infected squamous epithelium growing proximally over the inflamed rectum. Islands developed when areas of squamous epithelium degenerated, creating skip areas. This study highlights the potential for HSIL to extend into the rectum either as a contiguous patch or isolated islands and the need for heightened surveillance in patients with extensive anal canal HSIL treated with immunodulator therapy. HSIL identified at the limit of the anoscope should be investigated further with colonoscopy, and argon plasma coagulation (APC) ablation can serve as an effective treatment option. Patients are at risk for stricture, but it is unclear what role the UC or the ablation played in stricture formation.

PurposeRadiofrequency ablation (RFA) effectively treats esophageal high-grade dysplasia, but its efficacy in treating anal canal high-grade squamous intraepithelial lesions (HSILs) is unsubstantiated. This prospective study assessed the safety and efficacy of applying hemi-circumferential RFA to anal canal HSIL.MethodsTwenty-one HIV-negative participants with HSIL occupying ≤half the anal canal circumference were treated with hemi-circumferential anal canal RFA. Participants were assessed every 3months for 12months with high-resolution anoscopy; recurrence in the treatment zone was re-treated with focal RFA.ResultsTwenty-one participants with a mean of 1.7 lesions (range 1-4) enrolled and completed the trial. Six (29%) participants had recurrent HSIL within the treated hemi-circumference within 1year. Four participants (19%) had persistence of an index lesion at 3months. One (2.9%) index HSIL persisted again at 12months. No participants had more than two RFA treatments. KM curve-predicted HSIL-free survival within the treatment zone at 1year was 76% (95% CI 52-89%). Comparing the first 7 and last 14 participants, the predicted 1-year HSIL-free survivals are 43% (95% CI 10-73%) and 93% (95% CI 59-99%), respectively (p=0.008), suggesting a learning curve with the treating physician. Multivariable analysis showed decreased recurrence in the last 14 participants (HR 0.02; 95% CI 0.001-0.63) while increasing BMI increased recurrence (HR 1.43, 95% CI 1.01-2.01). No participants had device or procedure-related serious adverse events, anal stricture, or heavy bleeding.ConclusionsHemi-circumferential RFA yielded a high rate of anal HSIL eradication in HIV-negative patients at 1year with minimal adverse events. Lesion persistence was probably related to incomplete initial ablation.

Contains fulltext : 215651.pdf (Publisher’s version ) (Open Access) OBJECTIVE: The aim of the study was to develop recommended techniques and quality assurance metrics for the practice of Digital Anal Rectal Examination (DARE). MATERIALS AND METHODS: The International Anal Neoplasia Society undertook a literature review and, using the AGREE II technique, developed guidelines for performing DARE. RESULTS: A consensus was formed regarding the optimum conditions and characteristics of DARE. Several Quality Assurance metrics were developed. CONCLUSIONS: Digital Anal Rectal Examination is a cheap and potentially universally available technique, which has the potential to facilitate the early diagnosis of anal cancers, when they are most amenable to treatment. These guidelines provide a basis for teaching the technique and may be used as for evaluation research.

BACKGROUND More than 90% of anal cancers are caused by human papillomavirus, and human papillomavirus strains 16 and 18 are the most oncogenic. Anal high-grade squamous intraepithelial lesions are cancer precursors. Treating these high-grade intraepithelial lesions likely reduces the risk of cancer, but cytology is an imperfect screening test. OBJECTIVE The purpose of this study was to determine whether human papillomavirus 16 and/or 18 testing better predicts the presence of high-grade squamous intraepithelial lesions. DESIGN In this retrospective study, 894 consecutive patients underwent anal dysplasia screening with digital anorectal examination, anal cytology, high-risk human papillomavirus testing, and high-resolution anoscopy with biopsy. We calculated the sensitivity, specificity, positive predictive value, and negative predictive value of each test and for a novel screening protocol. The absolute and relative risk of high-grade squamous intraepithelial lesions for all of the cytology/human papillomavirus combinations were also calculated. SETTINGS The study was conducted at a single practice specializing in anal dysplasia. PATIENTS Ninety-two percent of participants were men who have sex with men. Forty-four percent were HIV-positive individuals who were well controlled on antiretroviral therapy. The median age was 50 years. MAIN OUTCOME MEASURES The presence of high-grade squamous intraepithelial lesions as a function of human papillomavirus and the cytology results were measured. RESULTS High-risk human papillomavirus testing alone demonstrated better sensitivity (96% vs 89%; p = 0.03) and negative predictive value (99% vs 96%; p = 0.008) over cytology. Human papillomavirus 16/18 testing increased specificity (48% to 71%; p < 0.0001) and positive predictive value (24% to 37%; p = 0.003) over testing for all of the high-risk strains. For each cytology category, high-grade squamous intraepithelial lesions were more prevalent when human papillomavirus 16/18 was detected. Benign cytology with 16/18 had a 31-fold increased risk of high-grade squamous intraepithelial lesions. LIMITATIONS This study was conducted in a single private practice specializing in anal dysplasia screening with a mostly male population, and results might not be generalizable. CONCLUSIONS Testing of high-risk human papillomavirus strains 16/18 improves specificity and positive predictive value over cytology for anal dysplasia screening. Patients testing positive for strains 16/18 are at a high risk for high-grade squamous intraepithelial lesions and should undergo high-resolution anoscopy regardless of the cytology result. See Video Abstract at http://links.lww.com/DCR/A654.

Background Squamous cell carcinoma of the anus (SCCA) is increasing in incidence. High-grade squamous intraepithelial lesion (HSIL), its immediate precursor, arises in the mucosa or perianal skin. SCCA without mucosal involvement is rare and diagnostically challenging. This phenomenon has been described in the cervix after HSIL treatment. We describe six cases of submucosal SCCA. Methods All patients with SCCA seen in our practice from February 2014 through February 2018 were included in this study. We described all six who presented without mucosal involvement. Results Six patients developed submucosal SCCA. The first case occurred in 2009 and all subsequent cases occurred within the past three years. The median age at diagnosis was 58 (range 41–83) years, 4 were male, 5 were HIV+, and none had inflammatory bowel disease. Five patients had a prior or concurrent HSIL discrete from the SCCA. Two HIV+ patients (TJ and JG) developed SCCA within fistula tracts three years after initial abscess drainage. Two (JE and YW) developed submucosal SCCA after multiple HSIL ablations. Two HIV+ patients (LR and JP) developed submucosal SCCA remote from prior HSIL. LR was diagnosed with SCCA in a submucosal rectal nodule after hemorrhoid rubber band ligation and JP developed SCCA deep to the mucosa within an anal canal sinus tract diagnosed by PET/CT. Conclusions We described 6 cases of SCCA without apparent mucosal involvement. One must maintain a high index of suspicion in high risk individuals with submucosal nodules or recurrent abscesses/fistulae. Previous anal procedures may increase risk for submucosal variant SCCA.

Author(s): Goldstone, Stephen E; Lensing, Shelly Y; Stier, Elizabeth A; Darragh, Teresa; Lee, Jeannette Y; van Zante, Annemieke; Jay, Naomi; Berry-Lawhorn, J Michael; Cranston, Ross D; Mitsuyasu, Ronald; Aboulafia, David; Palefsky, Joel M; Wilkin, Timothy | Abstract: BackgroundAnal high-grade squamous intraepithelial lesions (HSILs) ablation may reduce the incidence of invasive cancer, but few data exist on treatment efficacy and natural regression without treatment.MethodsAn open-label, randomized, multisite clinical trial of human immunodeficiency virus (HIV)-infected adults aged ≥27 years with 1-3 biopsy-proven anal HSILs (index HSILs) without prior history of HSIL treatment with infrared coagulation (IRC). Participants were randomized 1:1 to HSIL ablation with IRC (treatment) or no treatment (active monitoring [AM]). Participants were followed every 3 months with high-resolution anoscopy. Treatment participants underwent anal biopsies of suspected new or recurrent HSILs. The AM participants underwent biopsies only at month 12. The primary end point was complete clearance of index HSIL at month 12.ResultsWe randomized 120 participants. Complete index HSIL clearance occurred more frequently in the treatment group than in the AM (62% vs 30%; risk difference, 32%; 95% confidence interval [CI], 13%-48%; P l .001). Complete or partial clearance (clearance of ≥1 index HSIL) occurred more commonly in the treatment group (82% vs 47%; risk difference, 35%; 95% CI, 16%-50%; P l .001). Having a single index lesion, compared with having 2-3 lesions, was significantly associated with complete clearance (relative risk, 1.96; 95% CI, 1.22-3.10). The most common adverse events related to treatment were mild or moderate anal pain and bleeding. No serious adverse events were deemed related to treatment or study participation.ConclusionIRC ablation of anal HSILs results in more clearance of HSILs than observation alone.

Persistent infection of the anus with high-risk types of human papillomavirus (HPV) causes squamous cell carcinoma, one of the most common non-AIDS-defining cancers [1], [2]. HIV-infected individuals are at much higher risk for developing anal cancer than HIV-uninfected individuals [3], [4], [5], [6]. Approximately 70% of anal cancers are due to HPV types 16 or 18 and most genital warts are associated with HPV types 6 and 11 [7], [8]. The quadrivalent HPV (qHPV) vaccine, which induces neutralizing antibodies titers in recipients against HPV types 6, 11, 16, and 18, prevented 93% of persistent anal infections and 78% of anal squamous intraepithelial lesions caused by these types in HIV-uninfected men who have sex with men (MSM) [9]. While the qHPV vaccine series is highly immunogenic in HIV-infected adults and children, antibody titers are lower than those reported in HIV-uninfected populations [10], [11], [12]. In studies of both HIV infected and HIV-uninfected vaccine recipients, the titers developed in response to the standard three-dose qHPV series peak soon after the third dose then decline. HIV-uninfected women [13] and HIV-infected children [14] demonstrated an anamnestic response to a fourth dose of the qHPV vaccine suggesting that the qHPV vaccine induces immune memory. Published studies of HIV-infected adults receiving qHPV vaccine have relatively limited follow-up and the characteristics of the long-term humoral response have not yet been described. It is unclear how much immunity wanes in this population and whether the standard 3 dose series generates immune memory which is necessary for long-term protection against new infections. A delayed fourth vaccination can simulate antigen exposure and a robust increase in antibodies suggestive of an anamnestic response indicative of immune memory [13], [14], [15]. When exposed to specific antigens, long-lived memory immune cells generate an immune response to prevent or stop infection [13]. The AIDS Malignancy Consortium Protocol 052 (AMC052) demonstrated the safety and immunogenicity of the standard three dose qHPV vaccine series in HIV-infected adult males [10]. Here we describe the long-term titers after vaccination in this study population. Since there are no accepted criteria for an anamnestic response, we sought to describe the titers at one and four weeks after a fourth dose, similar to what has been shown in HIV-uninfected women [13]. We hypothesized that titers would be higher four weeks after a fourth dose compared with four weeks after the third dose.

Background Perianal high-grade dysplasia (Bowen disease) is traditionally treated with mapping and wide excision with possible grafting rather than local ablation. Objective The aim of this study is to examine the results of high-grade perianal dysplasia ablation. Data sources Data for this study were derived from a retrospective chart review at a surgical practice screening and treating patients for high-grade dysplasia between July 1998 and June 2013. Study selection The patients included were men who have sex with men and are undergoing perianal dysplasia ablation. Intervention Ablation of perianal dysplasia with electrocautery, laser, or infrared coagulation was performed. Main outcome measures The primary outcomes measured were the recurrence of perianal dysplasia postablation and factors affecting recurrence. Results Seventy HIV-positive and 11 HIV-negative patients enrolled; the median ages were 44.7 and 42.8 years. Median follow-up times for HIV-positive and HIV-negative patients were 4.62 and 3.53 years, and the median numbers of treatments were 4 and 1, p = 0.004. The median number of lesions treated was 1 for both groups. Only 1 HIV-negative patient had a recurrence 8 months after treatment. For HIV-positive patients, the Kaplan-Meier probability of recurrence at 1, 3, and 5 years was 38% (95% CI 26-50), 59% (95% CI 47-72), and 68% (95% CI 55-81) after the first ablation with no difference for subsequent treatments. HIV-positive patients had a relative risk of perianal high-grade squamous intraepithelial lesions of 3.72 (95% CI 2.10-6.60) compared with HIV-negative patients (p ≤ 0.0001). In multivariate analysis, only each increase in intra-anal high-grade squamous intraepithelial lesions significantly increased recurrence (HR 1.13, 95% CI 1.00-1.28, p = 0.002). Only 3 patients with perianal high-grade squamous intraepithelial lesions did not have canal dysplasia. Perianal cancer developed in 3 after being lost to follow-up. Limitations This is a retrospective analysis of 1 experienced surgeon's results. No precise way exists to accurately determine the size of the disease. Conclusions Perianal dysplasia can be successfully ablated, but recurrence remains high. Almost all patients have anal canal dysplasia. HIV-positive patients are at the greatest risk for disease and recurrence. An increased number of high-grade canal lesions increases recurrence.

Men who have sex with men have increased prevalence of both human papillomavirus and anogenital condyloma.Risk factors for multiple treatment and recurrence of anal condyloma were examined.This is a retrospective study of HIV-negative men who have sex with men who were treated for anal condyloma.This study was conducted in a private surgical practice.The patients were HIV-negative men who have sex with men, aged 18 years or older.Ablation with electrocautery or CO2 laser was performed, as well as excision and topical imiquimod condyloma treatment adjuvant.Primary clearance, defined as 4 months of condyloma-free survival posttreatment, and recurrence, defined as any anal condyloma diagnosis after primary clearance.Of 231 participants, 207 achieved primary clearance (median age, 32.0 years) and were followed (median, 18.2 months) after primary treatment. Most had intra-anal and perianal condyloma (56%), were treated with electrocautery ablation (79.2%), and required 1 treatment (range, 1-6) for clearance. There were 57 recurrences (median, 12 months). One-third each had minimal, moderate, or extensive disease. Forty-six percent of patients received imiquimod posttreatment adjuvant. High-grade dysplasia was found in 31% at presentation and 43% during follow-up. Factors associated with requiring multiple treatments for clearance were participants having moderate disease (adjusted odds ratio, 6.0 (1.7-21.4)) and receiving imiquimod adjuvant (adjusted odds ratio, 4.7 (2.0-10.6)). No single factor predicted recurrence, but those with moderate disease experienced recurrences significantly sooner (median, 25 months of follow-up).This was a retrospective chart review, it was limited to a single practice, and it excluded those who did not achieve primary clearance.Most men who have sex with men have intra-anal and perianal condyloma and concomitant high-grade dysplasia is common. Most achieved clearance with 1 treatment. Having both intra-anal and perianal condyloma, increased severity of disease, and imiquimod adjuvant were significant predictors of requiring multiple treatments for clearance. No identified risk factors proved a significant predictor of recurrence.

Background Precancerous anal high-grade squamous intraepithelial lesions (HSIL) and its associated treatments have the potential to reduce health-related quality of life (HRQoL) in impacted individuals. The ANCHOR (ANal Cancer HSIL Outcomes Research) trial aims to determine whether treating anal HSIL, versus active monitoring, is effective in reducing incidence of anal cancer in HIV-infected individuals. The present study sought to establish preliminary psychometric evidence of the 25-item ANCHOR Health-Related Symptom Inventory (A-HRSI). Methods Eligible ANCHOR participants recruited within two-weeks post-treatment or randomization to active surveillance completed the A-HRSI and well-established legacy HRQoL measures (i.e., Functional Assessment of Cancer Therapy – General [FACT-G] and MD Anderson Symptom Inventory [MDASI]) via telephone. Construct validity was assessed using an exploratory factor analysis (EFA). Pearson correlations were then calculated between summed items within the resulting A-HRSI latent factors and legacy measure outcome subscales to establish convergent and divergent validity. Results 200 participants were enrolled. EFA provided initial confirmation that the A-HRSI items are best represented by the proposed broad three-factor structure (e.g., physical symptoms, physical impacts, psychological symptoms). These three factors had fair to moderate Pearson correlations with FACT-G Total and MDASI Symptom Severity and Interference subscales. Conclusions Preliminary psychometric evidence exists to support the construct validity of the A-HRSI, indicating this measure can capture disease- and treatment-related physical and psychological symptoms and physical impacts. Clinical responsiveness and Spanish-translation of this measure will be completed prior to ultimately deploying this measure in the ANCHOR trial to facilitate participant reporting of their HRQoL to inform clinical decision-making.

BACKGROUND: In this analysis, we examine the incidence and clearance of external genital human papillomavirus (HPV) infection among heterosexual males aged 16-24 years. METHODS: A total of 1732 males aged 16-24 years old in the placebo arm of a quadrivalent HPV vaccine trial were included in this analysis. Participants were enrolled from 18 countries in Africa, the Asia-Pacific region, Europe, Latin America, and North America. Subjects underwent anogenital examinations and sampling of the penis, scrotum, and perineal/perianal regions. RESULTS: The incidence rate of any HPV DNA genotype 6, 11, 16, and/or 18 detection was 9.0 cases per 100 person-years. Rates of HPV DNA detection were highest in men from Africa. Median time to clearance of HPV genotypes 6, 11, 16, and 18 DNA was 6.1, 6.1, 7.7, and 6.2 months, respectively. Median time to clearance of persistently detected HPV 6, 11, 16, and 18 DNA was 6.7, 3.2, 9.2, and 4.7 months, respectively. CONCLUSION: The study results suggest that the acquisition of HPV 6, 11, 16, and/or 18 in males is common and that many of these so-called infections are subsequently cleared, similar to findings for women. Nevertheless, given the high rate of HPV detection among young men, HPV vaccination of males may reduce infection in men and reduce the overall burden of HPV-associated disease in the community.

Objective: To determine rates of anal dysplasia in a cohort of HIV-infected men who have sex with men (MSM), women, and heterosexual men with abnormal anal cytology. Design/methods: We evaluated histologic findings in 728 HIV-infected MSM, women, and heterosexual men referred for high-resolution anoscopy (HRA) after abnormal anal cytology in a single-center cohort study. Using multivariable logistic regression, we evaluated predictors of high-grade squamous intraepithelial lesion (HSIL) histology or invasive carcinoma including age, sexual behavior, receptive anal intercourse (RAI), anogenital warts, smoking status, antiretroviral therapy, CD4+ T-cell count, and HIV-1 plasma viral load. Results: A total of 2075 HIV-positive patients were screened with anal cytology and 62% of MSM, 42% of women, and 29% of heterosexual men had abnormal findings (P

Objective: Random biopsy (RB) of normal appearing cervix during colposcopy increases high-grade dysplasia (HSIL) diagnosis but has not been studied in high-resolution anoscopy (HRA), that is, colposcopy transferred to the anal canal. We investigated the utility of RB during HRA. Design: At HRA, the anal canal was divided into 4 quadrants. Areas suspicious for HSIL had standard biopsy (SB); random biopsies were taken from quadrants without apparent HSIL. Inclusion required $1 RB. Two providers performed all procedures (S.E.G., .10 years experience; M.M.G. 3 years experience) Results: Overall, 391 participants enrolled (mean age, 44.7 years); most were male (87.2%), non-Hispanic (69.8%), white (62.7%), and HIV positive (72.9%). Of 1761 biopsies, 883 were RBs (mean, 2.26/ participant). HSIL was identified in 252 lesions, and in 132 participants (33.8%). Thirty-two HSILs (12.7%) and 13 participants (9.8%) were diagnosed by RB. RB increased total HSILs identified per participant (mean, 0.65 vs. 0.56; P , 0.001) and participants with HSIL (P , 0.001). Histologically, HSIL diagnoses via SB were no more dysplastic than random biopsies (relative risk, 0.82; range, 0.37– 1.8). In multivariable analysis, factors affecting adjusted relative risk (ARR) of HSIL with any biopsy were provider [S.E.G vs. M.M.G.; ARR, 5.9; 95% confidence interval (CI), 1.3 to 25.8] and oncogenic human papillomaviral infection (ARR, 24.3; 95% CI, 2.8 to 213.3). Risk of HSIL on RB alone in multivariate analysis was associated with HSIL via SB (ARR, 3.4; 95% CI, 1.6 to 7.1 or ARR, 1.4; 95% CI, 1.1 to 1.9 per standard HSIL). Provider, HIV status, detectable viral load, age, or prior screening for or treatment of HSIL did not affect the utility of RB. Conclusions: Addition of RB to HRA significantly increased both the number of HSILs and participants with HSIL identified.

Purpose: High-grade anal intraepithelial neoplasia (HGAIN) is the precursor lesion to invasive anal cancer. Human papillomavirus (HPV) vaccination holds great promise for preventing anal cancer. Methods: We examined 235 HIV-1-infected men screening for participation in a multisite clinical trial of a quadrivalent HPV vaccine. All participants had anal swabs obtained for HPV testing and cytology and high-resolution anoscopy with biopsies of visible lesions to assess for HGAIN. Results: HPV types 16 and 18 were detected in 23% and 10%, respectively; abnormal anal cytology was found in 56% and HGAIN in 30%. HGAIN prevalence was significantly higher in those with HPV16 detection compared to those without (38% vs 17%; P = .01). Use of antiretroviral therapy and nadir and current CD4+ cell count were not associated with abnormal anal cytology or HGAIN. Conclusion: HGAIN is highly prevalent in HIV-infected men. Further studies are needed on treatment and prevention of HGAIN.

Human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) are at disproportionately high risk for anal cancer. There is no definitive approach to the management of high-grade squamous intraepithelial lesions (HSIL), which are precursors of anal cancer, and evidence suggests that posttreatment adjuvant quadrivalent human papillomavirus (qHPV) vaccination improves HSIL treatment effectiveness. The objectives of this study were to evaluate the optimal HSIL management strategy with respect to clinical effectiveness and cost-effectiveness and to identify the optimal age for initiating HSIL management.A decision analytic model of the natural history of anal carcinoma and HSIL management strategies was constructed for HIV-positive MSM who were 27 years old or older. The model was informed by the Surveillance, Epidemiology, and End Results-Medicare database and published studies. Outcomes included the lifetime cost, life expectancy, quality-adjusted life expectancy, cumulative risk of cancer and cancer-related deaths, and cost-effectiveness from a societal perspective.Active monitoring was the most effective approach in patients 29 years or younger; thereafter, HSIL treatment plus adjuvant qHPV vaccination became most effective. When cost-effectiveness was considered (ie, an incremental cost-effectiveness ratio [ICER]$100,000/quality-adjusted life-year), do nothing was cost-effective until the age of 38 years, and HSIL treatment plus adjuvant qHPV vaccination was cost-effective beyond the age of 38 years (95% confidence interval, 34-43 years). The ICER decreased as the age at HSIL management increased. Outcomes were sensitive to the rate of HSIL regression or progression and the cost of high-resolution anoscopy and biopsy.The management of HSIL in HIV-positive MSM who are 38 years old or older with treatment plus adjuvant qHPV vaccination is likely to be cost-effective. The conservative approach of no treatment is likely to be cost-effective in younger patients. Cancer 2017;123:4709-4719. © 2017 American Cancer Society.

ObjectivesTo define minimum standards for provision of services and clinical practice in the investigation of anal cancer precursors.MethodsAfter initial face to face meetings of experts at the International Papillomavirus meeting in Lisbon, September 17 to 21, 2015, a first version was drafted and sent to key stakeholders. A complete draft was reviewed by the Board of the International Anal Neoplasia Society (IANS) and uploaded to the IANS Web site for all members to provide comments. The final draft was ratified by the IANS Board on June 22, 2016.ResultsThe essential components of a satisfactory high-resolution anoscopy (HRA) were defined. Minimum standards of service provision, basic competencies for clinicians, and standardized descriptors were established. Quality assurance metrics proposed for practitioners included a minimum of 50 HRAs per year and identifying 20 cases or more of anal high-grade squamous intraepithelial lesions (HSILs). Technically unsatisfactory anal cytological samples at first attempt in high-risk populations should occur in less than 5% of cases. Where cytological HSIL has been found, histological HSIL should be identified in ≥ 90% of cases. Duration of HRA should be less than 15 minutes in greater than 90% of cases. Problematic pain or bleeding should be systematically collected and reported by 10% or lesser of patients.ConclusionsThese guidelines propose initial minimum competencies for the clinical practice of HRA, against which professionals can judge themselves and providers can evaluate the effectiveness of training. Once standards have been agreed upon and validated, it may be possible to develop certification methods for individual practitioners and accreditation of sites.

The hc2 human papillomavirus DNA test (HC2) is effective when screening women for cervical dysplasia, and it might be effective in the screening for anal dysplasia. Differences between the anal and the cervical canals could affect the test performance. This prospective study (n = 292) measured the HC2 signal and in agreement with a histologic endpoint of high- grade dysplasia for anal specimens collected in various ways. Sensitivities were 91%, 85%, and 62% for specimens collected in a sample transport medium and a liquid-based cytology medium processed by Gyn or Non-Gyn protocol, respectively. HC2 sensitivity and specificity to predict high-grade anal dysplasia were similar for brush or swab specimen collections, but HC2 signal was 6 times higher with the brush. Specificity and sensi- tivity were similar whether the sample was collected first or after a cytology sample for brush or swab, but swab specimens at the second collection had an HC2 signal (mean) 48% lower than that of the first collection, and the swab cellularity was lower. The presence of maximum stool decreased the HC2 signal in anal swab specimens. Consensus polymerase chain reaction (PCR) confirmed that the 13 human papillomavirus probe types in HC2 were optimal for performance. HC2 could potentially be further investigated for use in screening anal dysplasia. A larger prospective study is indicated.

Background. Most squamous cell anal cancers and precancerous lesions are attributed to human papillomavirus (HPV) infection. By preventing HPV infection, quadrivalent HPV vaccine (qHPV) reduces risk of anal cancer/precancerous lesions in young men who have sex with men (MSM) without history of anal cancer/precancerous lesions. In our practice, many persons with history of precancerous anal lesions or high-grade anal intraepithelial neoplasia (HGAIN) have been vaccinated electively. We determined whether qHPV is effective at preventing recurrence of HGAIN. Methods. This nonconcurrent cohort study evaluated 202 patients with a history of previously treated HGAIN. Eighty-eight patients were vaccinated, and 114 patients were unvaccinated. We determined the recurrence rate of histologic HGAIN in vaccinated versus unvaccinated patients. Results. During 340.4 person-years follow-up, 12 (13.6%) vaccinated patients and 35 (30.7%) unvaccinated patients developed recurrent HGAIN. Multivariable hazards ratio (HR) analysis showed testing positive for oncogenic HPV genotypes within 8 months before study entry was associated with increased risk of recurrent HGAIN at 2 years after study entry (HR 4.06; 95% confidence interval [CI], 1.58‐10.40; P 5 .004), and qHPV was associated with decreased risk of recurrent HGAIN (HR .50; 95% CI, .26‐.98; P 5 .04). Among patients infected with oncogenic HPV, qHPV was associated with decreased risk of recurrent HGAIN at 2 years after study entry (HR .47; 95% CI, .22‐1.00; P 5 .05). Conclusions. qHPV significantly reduces HGAIN recurrence among MSM and may be an effective posttreatment adjuvant form of therapy. A randomized controlled trial is needed to confirm these results.

The rate of anal cancer is increasing among both women and men, particularly men who have sex with men. Caused by infection with human papillomavirus (HPV), primarily HPV type 16 or 18, anal cancer is preceded by high-grade anal intraepithelial neoplasia (grade 2 or 3). We studied the safety and efficacy of quadrivalent HPV vaccine (qHPV) against anal intraepithelial neoplasia associated with HPV-6, 11, 16, or 18 infection in men who have sex with men.In a substudy of a larger double-blind study, we randomly assigned 602 healthy men who have sex with men, 16 to 26 years of age, to receive either qHPV or placebo. The primary efficacy objective was prevention of anal intraepithelial neoplasia or anal cancer related to infection with HPV-6, 11, 16, or 18. Efficacy analyses were performed in intention-to-treat and per-protocol efficacy populations. The rates of adverse events were documented.Efficacy of the qHPV vaccine against anal intraepithelial neoplasia associated with HPV-6, 11, 16, or 18 was 50.3% (95% confidence interval [CI], 25.7 to 67.2) in the intention-to-treat population and 77.5% (95% CI, 39.6 to 93.3) in the per-protocol efficacy population; the corresponding efficacies against anal intraepithelial neoplasia associated with HPV of any type were 25.7% (95% CI, -1.1 to 45.6) and 54.9% (95% CI, 8.4 to 79.1), respectively. Rates of anal intraepithelial neoplasia per 100 person-years were 17.5 in the placebo group and 13.0 in the vaccine group in the intention-to-treat population and 8.9 in the placebo group and 4.0 in the vaccine group in the per-protocol efficacy population. The rate of grade 2 or 3 anal intraepithelial neoplasia related to infection with HPV-6, 11, 16, or 18 was reduced by 54.2% (95% CI, 18.0 to 75.3) in the intention-to-treat population and by 74.9% (95% CI, 8.8 to 95.4) in the per-protocol efficacy population. The corresponding risks of persistent anal infection with HPV-6, 11, 16, or 18 were reduced by 59.4% (95% CI, 43.0 to 71.4) and 94.9% (95% CI, 80.4 to 99.4), respectively. No vaccine-related serious adverse events were reported.Use of the qHPV vaccine reduced the rates of anal intraepithelial neoplasia, including of grade 2 or 3, among men who have sex with men. The vaccine had a favorable safety profile and may help to reduce the risk of anal cancer. (Funded by Merck and the National Institutes of Health; ClinicalTrials.gov number, NCT00090285.).

BACKGROUND: Ten years ago, we published findings from anal dysplasia screening in a metropolitan surgical practice where the majority of men who have sex with men had biopsy-proven high-grade anal intraepithelial neoplasia. OBJECTIVE: This study aimed to determine the effect of 10 years of experience in anal dysplasia screening on the prevalence of high-grade anal intraepithelial neoplasia. DESIGN: A retrospective chart review was performed of all anal cytology results of 1189 men who have sex with men screened in a 1-year period, with subsequent highresolution anoscopy and biopsy as necessary. PATIENTS: The patients studied were men who have sex with men. MAIN OUTCOME MEASURE: The main outcome measure was biopsy-proven high-grade anal intraepithelial neoplasia. RESULTS: There were 315 (37.2%) biopsy-verified instances of high-grade anal intraepithelial neoplasia. Regression analysis determined that age, HIV status, infection by high-risk human papillomavirus, and abnormal cytology results were significant predictors of high-grade anal intraepithelial neoplasia. In a 1-year period, the number of men who have sex with men screened was nearly 7 times greater than in the 2-year period studied 10 years earlier. LIMITATIONS: We did not separately analyze patients who had previously been treated for high-grade anal intraepithelial neoplasia. CONCLUSIONS: Severity of cytology and infection with high-risk human papillomavirus are the most significant predictors of high-grade anal intraepithelial neoplasia, underscoring the importance of anal dysplasia screening. Our ability to identify high-grade anal intraepithelial neoplasia has improved with 10 years of experience performing high-resolution anoscopy.

Anal human papilloma virus (HPV) infection causes significant pathology, including condylomata as well as low- and high-grade anal intraepithelial lesions, the precursors of invasive cancer. Men who have sex with men, women with concomitant high-grade cervical/vulvar disease, and immunocompromised patients are particularly vulnerable. The incidence of anal cancer is increasing in men and women, but human immunodeficiency virus-infected patients regardless of immune reconstitution are at greatest risk. A critical review of the literature and evidence-based, comparative analysis and discussion of treatment modalities for anal HPV related diseases was undertaken. Anal cytology screening for high-grade dysplasia has been shown to be sensitive and cost-effective in men who have sex with men; any abnormal anal cytology result should be followed with high-resolution anoscopy. Condylomata must be considered a marker for intraanal HPV disease, and patients should be screened for concomitant high-grade dysplasia. A variety of topical and ablative treatment modalities are available, including pharmacologic, targeted ablation of lesions and surgery. Treatment modality is directed not only by the extent and location of disease but also by available expertise and resources. Currently, there is no pharmacologic therapy approved by the Food and Drug Administration for intraanal HPV-related disease. Once treated, recurrence over time remains high, and patients should be closely monitored.

Background. We examined the baseline prevalence of penile, scrotal, and perineal/perianal human papillomavirus (HPV) in heterosexual men (HM). We also evaluated baseline characteristics of HM to assess factors associated with prevalent HPV detection. Methods. We tested serum samples from 3463 HM aged 16–24 years with 1–5 lifetime female sexual partners for antibodies to HPV 6, 11, 16, and 18. We collected baseline swab specimens for the detection of DNA of HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 from 3 areas: penile, scrotal, and perineal/perianal. Risk factors for prevalent HPV DNA detection were evaluated. Results. The prevalence of any tested HPV type was 18.7% at the penis, 13.1% at the scrotum, 7.9% at the perineal/perianal region, and 21.0% at any site. Having .3 lifetime female sexual partners had the greatest impact on HPV prevalence: odds ratio (OR) 3.2 (95% confidence interval (CI) 2.1–4.9) for HPV 6, 11, 16, and 18; and OR 4.5 (95% CI 3.3–6.1) for all HPV types tested. HPV DNA detection was highest in Africa. Neither condom usage nor circumcision was associated with HPV DNA prevalence. Conclusion. Genital-HPV DNA detection is common in young, sexually active HM. We found HPV to be most prevalent in African men and least prevalent in men from the Asia-Pacific region. Increased numbers of sexual partners was an important risk factor for HPV DNA prevalence.

Background. We examined the baseline prevalence of penile, scrotal, perineal/perianal, and intra-anal human papillomavirus (HPV) infection in human immunodeficiency virus (HIV)‐seronegative men who have sex with men (MSM). Methods. Data were analyzed from 602 MSM aged 16‐27 years with