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In women vaccinated against human papillomavirus (HPV), reductions in cervical disease and related procedures results in more women having intact transformation zones, potentially increasing the risk of cervical lesions caused by non-vaccine-preventable HPV types, a phenomenon termed clinical unmasking. We aimed to evaluate HPV vaccine efficacy against cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) attributed to non-preventable HPV types in the long-term follow-up phase of the Costa Rica HPV Vaccine Trial (CVT).CVT was a randomised, double-blind, community-based trial done in Costa Rica. Eligible participants were women aged 18-25 years who were in general good health. Participants were randomly assigned (1:1) to receive an HPV 16 and 18 AS04-adjuvanted vaccine or control hepatitis A vaccine, using a blocked randomisation method (permuted block sizes of 14, 16, and 18). Vaccines in both groups were administered intramuscularly with 0·5 mL doses at 0, 1, and 6 months. Masking of vaccine allocation was maintained throughout the 4-year randomised trial phase, after which participants in the hepatitis A virus vaccine control group were provided the HPV vaccine and exited the study; a screening-only, unvaccinated control group was enrolled. The unvaccinated control group and HPV vaccine group were followed up for 7 years, during which treatment allocation was not masked. One of the prespecified primary endpoints for the long-term follow-up phase was precancers associated with HPV types not prevented by the vaccine, defined as histologically confirmed incident CIN2+ events or CIN3+ events attributed to any HPV type except HPV 16, 18, 31, 33, and 45. Our primary analytical period was years 7-11. Primary analyses were in all participants with at least one follow-up visit and excluded participants with a previous endpoint (ie, modified intention-to-treat cohort). Safety endpoints have been reported elsewhere. This trial is registered with ClinicalTrials.gov, NCT00128661 and NCT00867464. The randomised, masked trial phase is completed; an unmasked subset of women in the HPV-vaccinated group is under active investigation.Between June 28, 2004, and Dec 21, 2005, 7466 participants were enrolled (HPV vaccine group n=3727 and hepatitis A virus vaccine control group n=3739). Between March 30, 2009, and July 5, 2012, 2836 women enrolled in the new unvaccinated control group. The primary analytical cohort (years 7 to 11) included 2767 participants in the HPV vaccine group and 2563 in the unvaccinated group for the CIN2+ events endpoint assessment and 2826 participants in the HPV vaccine group and 2592 in the unvaccinated control group for the CIN3+ events endpoint assessment. Median follow-up during years 7 to 11 for women included for the CIN2+ events analysis was 52·8 months (IQR 44·0 to 60·7) for the HPV vaccine group and 49·8 months (42·0 to 56·9) for the unvaccinated control group. During years 7 to 11, clinical unmasking was observed with a negative vaccine efficacy against CIN2+ events attributed to non-preventable HPV types (-71·2% [95% CI -164·0 to -12·5]), with 9·2 (95% CI 2·1 to 15·6) additional CIN2+ events attributed to non-preventable HPV types per 1000 HPV-vaccinated participants versus HPV-unvaccinated participants. 27·0 (95% CI 14·2 to 39·9) fewer CIN2+ events irrespective of HPV type per 1000 vaccinated participants were observed during 11 years of follow-up. Vaccine efficacy against CIN3+ events attributed to non-preventable HPV types during years 7 to 11 was -135·0% (95% CI -329·8 to -33·5), with 8·3 (3·0 to 12·8) additional CIN3+ events attributed to non-preventable HPV types per 1000 vaccinated participants versus unvaccinated participants.Higher rates of CIN2+ events and CIN3+ events due to non-preventable HPV types in vaccinated versus unvaccinated participants suggests clinical unmasking could attenuate long-term reductions in high-grade disease following successful implementation of HPV vaccination programmes in screened populations. Importantly, the net benefit of vaccination remains considerable; therefore, HPV vaccination should still be prioritised as primary prevention for cervical cancer.National Cancer Institute and National Institutes of Health Office of Research on Women's Health.For the Spanish translation of the abstract see Supplementary Materials section.

Author(s): Massad, Leslie S; Xie, Xianhong; Minkoff, Howard; Kassaye, Seble; Karim, Roksana; Darragh, Teresa M; Golub, Elizabeth T; Adimora, Adaora; Wingood, Gina; Fischl, Margaret; Konkle-Parker, Deborah; Strickler, Howard D | Abstract: ObjectiveTo describe longitudinal changes in the prevalence of abnormal Papanicolau testing among women living with HIV.DesignProspective cohort study with sequential enrollment subcohorts.MethodsFour waves of enrollment occurred in the Women's Interagency HIV Study, the US women's HIV cohort (1994-1995, 2001-2002, 2011-2012, 2013-2015). Pap testing was done at intake, with colposcopy prescribed for any abnormality. Rates of abnormal Pap test results (atypical squamous cells of uncertain significance or worse) and cervical intraepithelial neoplasia grade 2 (CIN2) or worse were calculated. Logistic regression models assessed changes in prevalence across cohorts after controlling for severity of HIV disease and other risk factors for abnormal Pap tests.ResultsThe unadjusted prevalence of any Pap abnormality was 679/1769 (38%) in the original cohort, 195/684 (29%) in the 2001-2002 cohort, 46/231 (20%) in the 2011-2012 cohort, and 71/449 (16%) in the 2013-2015 cohort. In multivariable analysis, compared with risk in the 1994-1995 cohort, the adjusted risk in the 2001-2002 cohort was 0.79 (95% CI 0.59-1.05), in the 2011-2012 cohort was 0.67 (95% CI 0.43-1.04), and in the 2013-2015 cohort was 0.41 (95% CI 0.27-0.62) with P for trend less than 0.0001.ConclusionRates of abnormal cytology among women with HIV have fallen during the past two decades.

Context.—Lower Anogenital Squamous Terminology (LAST) standardization recommended p16INK4a immunohistochemistry (p16 IHC) for biopsies diagnosed morphologically as cervical intraepithelial neoplasia (CIN) grade 2 (CIN2) to classify them as low-grade or high-grade squamous intraepithelial lesions (HSILs).Objective.—To describe the relationships of p16 IHC and other biomarkers associated with cervical cancer risk with biopsy diagnoses.Design.—A statewide, stratified sample of cervical biopsies diagnosed by community pathologists (CPs), including 1512 CIN2, underwent a consensus, expert pathologist panel (EP) review (without p16 IHC results), p16 IHC interpretation by a third pathology group, and human papillomavirus (HPV) genotyping, results of which were grouped hierarchically according to cancer risk. Antecedent cytologic interpretations were also available.Results.—Biopsies were more likely to test p16 IHC positive with increasing severity of CP diagnoses, overall (Ptrend ≤ .001) and within each HPV risk group (Ptrend ≤ .001 except for low-risk HPV [Ptrend < .010]). All abnormal grades of CP-diagnosed biopsies were more likely to test p16 IHC positive with a higher HPV risk group (Ptrend < .001), and testing p16 IHC positive was associated with higher HPV risk group than testing p16 IHC negative for each grade of CP-diagnosed biopsies (P < .001). p16 IHC–positive, CP-diagnosed CIN2 biopsies were less likely than CP-diagnosed CIN3 biopsies to test HPV16 positive, have an antecedent HSIL+ cytology, or to be diagnosed as CIN3+ by the EP (P < .001 for all). p16 IHC–positive, CP-diagnosed CIN1 biopsies had lower HPV risk groups than p16 IHC–negative, CP-diagnosed CIN2 biopsies (P < .001).Conclusions.—p16 IHC–positive, CP-diagnosed CIN2 appears to be lower cancer risk than CP-diagnosed CIN3. LAST classification of “HSIL” diagnosis, which includes p16 IHC–positive CIN2, should annotate the morphologic diagnosis (CIN2 or CIN3) to inform all management decisions, which is especially important for young (

ObjectiveThe objective of this study was to determine the performance characteristics of the Tush brush (TB) compared with a saline moistened Dacron swab (DS) as anal cytology sampling devices.Materials and methodsTB and DS anal cytology tests were randomly collected from 146 patients presenting for anal cytology. High-resolution anoscopy and biopsies were obtained as indicated. Sensitivity and specificity as well as rates of satisfactory specimens were determined for each method using the areas under the receiver operating characteristic curve (AUCROC) and McNemar's test, respectively. Perceived discomfort of each device was determined using a visual analog scale and compared using a paired t test.ResultsThe adjudicated AUCROC, sensitivity, and specificity were greater, but not significantly different, for the brush (0.63, 85.5, and 40.0, respectively) compared with the swab (0.50, 79.6, and 33.3, respectively) when the anal biopsy results were considered the criterion standard. In the 1 subject diagnosed with anal cancer, the swab cytology result was normal, but the brush result was abnormal. Specimen adequacy was 95.2% for the brush and 93.2% for the swab. Mean discomfort (visual analog scale) scores were swab 28.5 mm versus brush 35.6 mm (p = .0003) with both scores within the minimal to moderate discomfort range.ConclusionsAnal cytology AUCROC, sensitivity, and specificity in detecting anal neoplasia were greater using the TB when compared with the DS. A novel anal cytology sampling device designed specifically to increase the detection of anal neoplasia would be clinically beneficial.

Summary Background Oncogenic human papillomavirus (HPV) infections cause most cases of cervical cancer. Here, we report long-term follow-up results for the Costa Rica Vaccine Trial (publicly funded and initiated before licensure of the HPV vaccines), with the aim of assessing the efficacy of the bivalent HPV vaccine for preventing HPV 16/18-associated cervical intraepithelial neoplasia grade 2 or worse (CIN2+). Methods Women aged 18–25 years were enrolled in a randomised, double-blind, controlled trial in Costa Rica, between June 28, 2004, and Dec 21, 2005, designed to assess the efficacy of a bivalent vaccine for the prevention of infection with HPV 16/18 and associated precancerous lesions at the cervix. Participants were randomly assigned (1:1) to receive an HPV 16/18 AS04-adjuvanted vaccine or control hepatitis A vaccine. Vaccines were administered intramuscularly in three 0·5 mL doses at 0, 1, and 6 months and participants were followed up annually for 4 years. After the blinded phase, women in the HPV vaccine group were invited to enrol in the long-term follow-up study, which extended follow-up for 7 additional years. The control group received HPV vaccine and was replaced with a new unvaccinated control group. Women were followed up every 2 years until year 11. Investigators and patients were aware of treatment allocation for the follow-up phase. At each visit, clinicians collected cervical cells from sexually active women for cytology and HPV testing. Women with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. Women with negative results at the last screening visit (year 11) exited the long-term follow-up study. The analytical cohort for vaccine efficacy included women who were HPV 16/18 DNA-negative at vaccination. The primary outcome of this analysis was defined as histopathologically confirmed CIN2+ or cervical intraepithelial neoplasia grade 3 or worse associated with HPV 16/18 cervical infection detected at colposcopy referral. We calculated vaccine efficacy by year and cumulatively. This long-term follow-up study is registered with ClinicalTrials.gov , NCT00867464 . Findings 7466 women were enrolled in the Costa Rica Vaccine Trial; 3727 received the HPV vaccine and 3739 received the control vaccine. Between March 30, 2009, and July 5, 2012, 2635 women in the HPV vaccine group and 2836 women in the new unvaccinated control group were enrolled in the long-term follow-up study. 2635 women in the HPV vaccine group and 2677 women in the control group were included in the analysis cohort for years 0–4, and 2073 women from the HPV vaccine group and 2530 women from the new unvaccinated control group were included in the analysis cohort for years 7–11. Median follow-up time for the HPV group was 11·1 years (IQR 9·1–11·7), 4·6 years (4·3–5·3) for the original control group, and 6·2 years (5·5–6·9) for the new unvaccinated control group. At year 11, vaccine efficacy against incident HPV 16/18-associated CIN2+ was 100% (95% CI 89·2–100·0); 34 (1·5%) of 2233 unvaccinated women had a CIN2+ outcome compared with none of 1913 women in the HPV group. Cumulative vaccine efficacy against HPV 16/18-associated CIN2+ over the 11-year period was 97·4% (95% CI 88·0–99·6). Similar protection was observed against HPV 16/18-associated CIN3—specifically at year 11, vaccine efficacy was 100% (95% CI 78·8–100·0) and cumulative vaccine efficacy was 94·9% (73·7–99·4). During the long-term follow-up, no serious adverse events occurred that were deemed related to the HPV vaccine. The most common grade 3 or worse serious adverse events were pregnancy, puerperium, and perinatal conditions (in 255 [10%] of 2530 women in the unvaccinated control group and 201 [10%] of 2073 women in the HPV vaccine group). Four women in the unvaccinated control group and three in the HPV vaccine group died; no deaths were deemed to be related to the HPV vaccine. Interpretation The bivalent HPV vaccine has high efficacy against HPV 16/18-associated precancer for more than a decade after initial vaccination, supporting the notion that invasive cervical cancer is preventable. Funding US National Cancer Institute.

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.

Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV+) individuals. No comprehensive profiling of cancer genomes, transcriptomes or epigenomes has been performed in this population thus far. We characterized 118 tumors from Ugandan patients, of whom 72 were HIV+, and performed extended mutation analysis on an additional 89 tumors. We detected human papillomavirus (HPV)-clade-specific differences in tumor DNA methylation, promoter- and enhancer-associated histone marks, gene expression and pathway dysregulation. Changes in histone modification at HPV integration events were correlated with upregulation of nearby genes and endogenous retroviruses.

The 2019 ASCCP Risk Based Management Consensus Guidelines for prevention of cervical cancer promote clinical management recommendations aligned with our increased understanding of HPV biology and cervical carcinogenesis. They employ HPV-based testing as the basis for risk estimation, allow for personalized risk-based management by incorporating knowledge of current results with prior results, and streamline incorporation of new test methods as they are validated. They continue to support the principles of "equal management for equal risk" and "balancing harms and benefits" adopted in the 2012 version of the guidelines. These updated guidelines will be able to adjust for decreasing CIN3+ risks as more patients who received HPV vaccination reach screening age. Pathology organizations were closely involved in the development of these guidelines. Herein the pathologists who served as representatives to the 2019 ASCCP guidelines steering committee and workgroups, summarize the changes that are relevant to laboratories, pathologists, and cytotechnologists. Prior relevant screening and reporting recommendations that have not been widely and/or inconsistently adopted by laboratories are also discussed and considerations for modification of laboratory practices offered.

Author(s): Greenland, Nancy Y; Wolsky, Rebecca J; Darragh, Teresa M; Vohra, Poonam | Abstract: IntroductionGastric-type endocervical adenocarcinoma (GAS) is an uncommon type of endocervical adenocarcinoma that is not associated with human papillomavirus infection. This diagnosis is relatively rare and may portend a worse prognosis than usual-type endocervical adenocarcinoma. Subtle morphological features make it an under-recognised diagnostic challenge. Study of the cytological features of individual cases is valuable in order to increase awareness of this entity.MethodsThe pathology database of our institution was searched for the diagnosis of GAS and all cytological and surgical specimens for each patient were reviewed. The original cytological interpretation was compared to a retrospective central review interpretation. Clinical history and follow-up results were obtained from the electronic medical record.ResultsFour cases of GAS were identified. The findings on initial cervical cytology varied, with GAS found in both patients with negative cervical cytology and those with atypical glandular cells. Cytological findings included endocervical cells arranged in three-dimensional clusters and honeycomb sheets with abundant vacuolar cytoplasm, and in two patients, moderate nuclear atypia with irregular nuclear membranes, coarse chromatin, hyperchromatic nuclei, and prominent nucleoli. In one patient, GAS was incidentally discovered via thorough sampling of a cystic lesion in the superior portion of the endocervical canal.ConclusionsGAS is an aggressive human papillomavirus-independent type of endocervical adenocarcinoma with subtle morphological features and, as our study shows, varying clinical presentation. Given the aggressive nature of GAS and the difficulties in initial diagnosis, increased awareness of this entity among pathologists is crucial.

IntroductionHuman papillomavirus (HPV) testing is replacing cytology in primary screening. Its limited specificity demands using a second (triage) test to better identify women at high-risk of cervical disease. Cytology represents the immediate triage but its low sensitivity might hamper HPV testing sensitivity, particularly in low-income and middle-income countries (LMICs), where cytology performance has been suboptimal. The ESTAMPA (EStudio multicéntrico de TAMizaje y triaje de cáncer de cuello uterino con pruebas del virus del PApiloma humano; Spanish acronym) study will: (1) evaluate the performance of different triage techniques to detect cervical precancer and (2) inform on how to implement HPV-based screening programmes in LMIC.Methods and analysisWomen aged 30–64 years are screened with HPV testing and Pap across 12 study centres in Latin America. Screened positives have colposcopy with biopsy and treatment of lesions. Women with no evident disease are recalled 18 months later for another HPV test; those HPV-positive undergo colposcopy with biopsy and treatment as needed. Biological specimens are collected in different visits for triage testing, which is not used for clinical management. The study outcome is histological high-grade squamous intraepithelial or worse lesions (HSIL+) under the lower anogenital squamous terminology. About 50 000 women will be screened and 500 HSIL+ cases detected (at initial and 18 months screening). Performance measures (sensitivity, specificity and predictive values) of triage techniques to detect HSIL+ will be estimated and compared with adjustment by age and study centre.Ethics and disseminationThe study protocol has been approved by the Ethics Committee of the International Agency for Research on Cancer (IARC), of the Pan American Health Organisation (PAHO) and by those in each participating centre. A Data and Safety Monitoring Board (DSMB) has been established to monitor progress of the study, assure participant safety, advice on scientific conduct and analysis and suggest protocol improvements. Study findings will be published in peer-reviewed journals and presented at scientific meetings.Trial registration numberNCT01881659

Author(s): Clarke, Megan A; Massad, L Stewart; Khan, Michelle J; Smith, Katie M; Guido, Richard S; Mayeaux, EJ; Darragh, Teresa M; Huh, Warner K; Johnson, Amanda L; Gold, Michael A; Schiffman, Mark; Wentzensen, Nicolas | Abstract: ObjectivesObese women are at increased risk of cervical cancer, partly due to missed detection of cervical precancers during routine cervical cancer screening. We administered a clinician survey to better understand specific challenges and identify potential solutions to performing cervical cancer screening and management in obese women.Materials and methodsWe administered a web-based survey to 2,319 members of the American Society of Colposcopy and Cervical Pathology including questions related to challenges associated with cervical sampling and visualization in obese compared with normal weight women and potential strategies for improvement. We summarized providers' responses using descriptive statistics and used Fisher exact tests to evaluate associations between provider characteristics and challenges with cervical sampling, visualization, and biopsy.ResultsOf the 240 providers that completed the survey, 89% and 93% reported that cervical sampling and visualization are more challenging in obese women, respectively, whereas 80% reported that taking a biopsy was more challenging. Commonly reported barriers included vaginal prolapse, difficulty visualizing and accessing the cervix, and lack of long enough sampling devices and large enough speculums. Frequently used techniques to improve sampling and visualization included use of a condom or examination glove finger to sheath a speculum and using a tenaculum. Most providers identified training for cervical sampling and colposcopy in obese women as a learning gap, and only 8% reported receiving such training.ConclusionsCervical cancer screening and management are more challenging in obese compared with normal weight women. Major barriers to cervical sampling and visualization included lack of adequately sized equipment and lack of education and training.

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.

Background Human papillomavirus (HPV)-related biomarkers have shown good cross-sectional performance for anal precancer detection in human immunodeficiency virus–positive (HIV+) men who have sex with men (MSM). However, the long-term performance and risk stratification of these biomarkers are unknown. Here, we prospectively evaluated high-risk (HR) HPV DNA, HPV16/18 genotyping, HPV E6/E7 messenger RNA (mRNA), and p16/Ki-67 dual stain in a population of HIV+ MSM. Methods We enrolled 363 HIV+ MSM between 2009–2010, with passive follow-up through 2015. All had anal cytology and a high-resolution anoscopy at baseline. For each biomarker, we calculated the baseline sensitivity and specificity for a combined endpoint of high-grade squamous intraepithelial lesion (HSIL) and anal intraepithelial neoplasia grade 2 or more severe diagnoses (HSIL/AIN2+), and we estimated the 2- and 5-year cumulative risks of HSIL/AIN2+ using logistic and Cox regression models. Results There were 129 men diagnosed with HSIL/AIN2+ during the study. HR-HPV testing had the highest positivity and sensitivity of all assays, but the lowest specificity. HPV16/18 and HPV E6/E7 mRNA had high specificity, but lower sensitivity. The 2- and 5-year risks of HSIL/AIN2+ were highest for those testing HPV16/18- or HPV E6/E7 mRNA–positive, followed by those testing dual stain–positive. Those testing HR-HPV– or dual stain–negative had the lowest 2- and 5-year risks of HSIL/AIN2+. Conclusions HPV-related biomarkers provide long-term risk stratification for anal precancers. HR-HPV– and dual stain–negativity indicate a low risk of HSIL/AIN2+ for at least 2 years, compared with negative anal cytology; however, the high positivity of HR-HPV in HIV+ MSM may limit its utility for surveillance and management in this population.

PURPOSE Anal cancer risk is substantially higher among HIV-infected men who have sex with men (MSM) as compared with other reproductive-age adults, but screening is rare across sub-Saharan Africa. We report the use of high-resolution anoscopy (HRA) as a first-line screening tool and the resulting early outcomes among MSM in Abuja, Nigeria. METHODS From August 2016 to August 2017, 424 MSM enrolled in an anal cancer screening substudy of TRUST/RV368, a combined HIV prevention and treatment cohort. HRA-directed biopsies were diagnosed by histology, and ablative treatment was offered for high-grade squamous intraepithelial lesions (HSIL). HRA proficiency was assessed by evaluating the detection of squamous intraepithelial lesions (SIL) over time and the proportion biopsied. Prevalence estimates of low-grade squamous intraepithelial lesions and HSIL with 95% CIs were calculated. Multinomial logistic regression was used to identify those at the highest risk of SIL. RESULTS Median age was 25 years (interquartile range [IQR], 22-29), median time since sexual debut was 8 years (IQR, 4-12), and 59% (95% CI, 54.2% to 63.6%) were HIV infected. Rate of detection of any SIL stabilized after 200 screenings, and less than 20% had two or more biopsies. Preliminary prevalence estimates of low-grade squamous intraepithelial lesions and HSIL were 50.0% (95% CI, 44.7% to 55.3%) and 6.3% (95% CI, 4.0% to 9.3%). HIV infection, at least 8 years since anal coital debut, concurrency, and external warts were independently statistically associated with SIL. CONCLUSION Proficiency with HRA increased with experience over time. However, HSIL detection rates were low, potentially affected by obstructed views from internal warts and low biopsy rates, highlighting the need for ongoing evaluation and mentoring to validate this finding. HRA is a feasible first-line screening tool at an MSM-friendly health care facility. Years since anal coital debut and external warts could prioritize screening.

Background Anal precancers and cancers can be detected during screening with high-resolution anoscopy (HRA). The sensitivity of HRA depends on the burden and duration of human papillomavirus (HPV) among those screened as well as anoscopist proficiency, which is highly correlated with prior screening experience. Our objective was to compare the identification and type of HPV and the likelihood of HRA-detected precancer for men who have sex with men (MSM) undergoing their first HRA-screening in Nigeria. Methods MSM were recruited from an HIV test-and-treat cohort, TRUST/RV368, into a new anal cancer screening program. Anal swabs obtained during screening underwent Ion Torrent next-generation sequencing using barcoded HPV PCR broad-spectrum primers 5+/6+ to detect up to 161 HPVs. All high-risk (HR) HPVs and the most abundant low-risk (LR)-HPVs were evaluated as type-specific infections with some categorized as belonging to a multiple infection. HRA screening results included benign, low-grade squamous intraepithelial lesions (LSIL), or HSIL as detected by cytology or histology. Multivariable logistic regression was used to assess the association of HPV and other cofactors with any SIL. Results Among 342 MSM, 60% were HIV-infected, 89% were under 35 years of age, and 51% had 8 or more years since anal coital debut. Of those with SIL, 89% had LSIL and only 11% had HSIL. Prevalence of any HPV and high-risk (HR)-HPV was 92% and 74%, respectively. The most prevalent genotypes in rank order were HPV6 (31%), HPV16 (23%), HPV42 (20%), HPV11 (18%), HPV45 (18%), and HPV51 (17%). For multiple HR-HPVs, 31% had a single HR-HPV, 32% had 2-3, and 10% had 4 or more. Low-risk HPVs, type 6 and/or 11, were common (42%) and were significantly associated with SIL (adjusted odds ratio [aOR]:1.8, 95% confidence interval [CI]: 1.1–3.1) together with perianal warts (aOR:6.7, 95% CI: 3.3–13.5). In contrast, HR-HPV and multiple HR-HPVs were not significantly associated with SIL (all p > 0.05). Conclusions Detection of HSIL was low. Although HR-HPV was abundant, HSIL development also depends on the duration of HR-HPV infections and the anoscopist's level of experience. As our cohort ages and the anoscopist becomes more skilled, detection of HSIL will likely improve.

HPV testing is a better alternative for cervical cancer screening, but additional procedures are required for triage of HPV positive women. HPV encoded oncoproteins E6 and E7, as the main effectors of HPV carcinogenicity represent promising triage alternatives. To evaluate performance of the test, we included 155 women from a screening study and 59 from the same referral population attending colposcopy and with precancerous lesions. All were HPV-tested with HC2 and genotyped with LiPA, and cervical swabs were tested for HPV16/18 E6 oncoproteins. Histologic specimens were reviewed and adjudicated using p16 immunohistochemistry and 55 women had confirmed histologic HSIL, 31 (56.3%) associated with HPV 16/18, 23 with other HPV types and one HPV negative. Sensitivity and specificity were estimated with histologic HSIL/cancer as gold standard. E6 oncoprotein was detectable in all but one HSIL and in all cancers where HPV16/18 DNA was detected, but in none of the cases associated with other HPV types or HPV negatives. Among the few HPV16/18 DNA positive subjects initially without HSIL (n = 4) who were E6 oncoprotein positive, precancer was detected during follow-up in 2 out of 3 with available information. Estimated sensitivity for HPV16/18-related HSIL+ was 96.8% (95%CI = 83.8-99.8) and for all HSIL+ regardless of HPV type it was 56.4% (95%CI = 43.3-68.6). Specificity was 97.5% (95%CI = 93.7-99.0). E6 oncoprotein proved as a highly sensitive and specific marker for detection of HPV16/18-related HSIL lesions in this Honduran population with limited previous screening and may be useful as a triage method in screening programs, particularly in low income countries.

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.

Background A pilot screening campaign in Rwanda, based on careHPV-testing followed by visual inspection with acetic acid triage (careHPV+VIA triage), was evaluated against other WHO-recommended screening options, namely HPV screen-and-treat and VIA screen-and-treat. Methods 764 women aged 30-69 underwent at visit 1: i) VIA, and cervical cell collection for ii) careHPV in Rwanda, and iii) liquid-based cytology and GP5+/6+ HR-HPV PCR in The Netherlands. All 177 women positive by VIA, careHPV and/or PCR were recalled, of whom 84% attended. At visit 2, VIA was again used to triage screen-positive women for treatment and to obtain biopsies from all women either from visible lesions or at 12 o’clock of the squamocolumnar junction. Cross-sectional screening indices were estimated primarily against histological high-grade squamous intraepithelial lesions or worse (hHSIL+), after imputation of missing histology data, based on 1-visit or 2-visit approaches. Results In a 1-visit screen-and-treat approach, VIA had sensitivity and specificity of 41% and 96%, respectively, versus 71% and 88% for careHPV, and 88% and 86% for PCR. In a 2-visit approach (in which hHSIL+ imputed among women without visit 2 were considered untreated) careHPV sensitivity dropped to 59% due to loss of 13% of hHSIL+. For careHPV+VIA triage, sensitivity dropped further to 35%, as another 24% of hHSIL+ were triaged to no treatment. Conclusions CareHPV was not as sensitive as gold-standard PCR, but detected considerably more hHSIL+ than VIA. However, due to careHPV-positive hHSIL+ women being lost to follow-up and/or triaged to no treatment, 2-visit careHPV+VIA triage did not perform better than VIA screen-and-treat. Electronic supplementary material The online version of this article (10.1186/s12905-018-0549-5) contains supplementary material, which is available to authorized users.

Toll-like receptors (TLRs) are innate immune defenders thought to be critical for the clearance of human papillomavirus (HPV) infections hence preventing the development of HPV-associated high-grade cervical intra-epithelial neoplasia (CIN2 or 3), a potential cervical cancer precursor. However, the role of TLRs in the regression of established cervical lesions, such as CIN2, is hindered by a lack of prospective design studies. Using SYBR green real-time PCR assays, we have examined the gene expression of TLR2, TLR3, TLR7, TLR8 and TLR9, in cytobrush collected endocervical cells of 63 women diagnosed with CIN2 at study entry (baseline) and followed over a 3-year period. Wilcoxon rank-sum test was used to examine the association between TLR expression levels, measured at baseline, and CIN2 outcome (regression vs. persistence/progression) over time. HPV genotyping was performed using Roche Linear Array Assay detecting 37 HPV types. Women with CIN2 regression showed significantly higher baseline levels of TLR2 (p = 0.006) and TLR7 (p = 0.007), as well as a non-significant trend for a higher TLR8 expression (p = 0.053) compared to women with CIN2 persistence/progression. Six women with CIN2 regression, who presented with an HR-HPV DNA-negative CIN2 lesion at study entry, had significantly higher baseline levels of TLR2 (p = 0.005), TLR7 (p = 0.013) and TLR8 (p = 0.012), compared to women with CIN2 persistence/progression, suggesting their role in clearance of HPV prior to clearance of the lesion. Our results confirm a key role of TLRs in regression of CIN2 and support the potential use of TLR-agonists for treatment of these lesions.

Author(s): Patel, Pragna; Bush, Tim; Kojic, Erna Milunka; Conley, Lois; Unger, Elizabeth R; Darragh, Teresa M; Henry, Keith; Hammer, John; Escota, Gerome; Palefsky, Joel M; Brooks, John T | Abstract: Background:The natural history of anal human papilloma virus (HPV) infection among human immunodeficiency virus (HIV)-infected men is unknown. Methods:Annually, from 2004 to 2012, we examined baseline prevalence, incidence, and clearance of anal HPV infection at 48 months, and associated factors among HIV-infected men. Results:We examined 403 men who have sex with men (MSM) and 96 men who have sex with women (MSW) (median age 42 years for both, 78% versus 81% prescribed cART, median CD4+ T-lymphocyte cell count 454 versus 379 cells/mm3, and 74% versus 75% had undetectable viral load, respectively). Type 16 prevalence among MSM and MSW was 38% versus 14% (P l .001), and incidence 24% versus 7% (P = .001). Type 18 prevalence was 24% versus 8% (P l .001), and incidence 13% versus 4% (P = .027). Among MSM and MSW, clearance of prevalent HPV 16 and HPV 18 was 31% and 60% (P = .392), and 47% and 25% (P = .297), respectively. Among MSM, receptive anal sex (with or without a condom) was associated with persistent HPV 16 (OR 2.24, P l .001). Conclusions:MSM had higher prevalence and incidence of HPV than MSW, but similar clearance. Receptive anal sex may predict cancer risk among HIV-infected MSM.

Author(s): Kojic, Erna Milunka; Conley, Lois; Bush, Tim; Cu-Uvin, Susan; Unger, Elizabeth R; Henry, Keith; Hammer, John; Escota, Gerome; Darragh, Teresa M; Palefsky, Joel M; Brooks, John T; Patel, Pragna | Abstract: Background:Nonavalent (9v) human papilloma virus vaccine targets high-risk human papillomavirus (HR-HPV) types 16, 18, 31, 33, 45, 52, 58, and low-risk 6, 11. We examined prevalence, incidence, and clearance of anal and cervical HR-HPV in HIV-infected women. Methods:The SUN Study enrolled 167 US women in 2004-2006. Anal and cervical specimens were collected annually for cytology and identification of 37 HPV types: 14 HR included: 9v 16, 18, 31, 33, 45, 52, 58; non-9v 35, 39, 51, 56, 59, 66, 68. Results:Baseline characteristics of 126 women included: median age 38 years; 57% non-Hispanic black; 67% HIV RNA l 400 copies/mL; 90% CD4 counts ≥200 cells/mm3. HPV prevalence at anus and cervix was 90% and 83%; for 9v HR-HPV types, 67% and 51%; non-9v HR-HPV, 54% and 29%, respectively. The 9v and non-9v HR-HPV incidence rates/100 person-years were similar (10.4 vs 9.5; 8.5 vs 8.3, respectively); 9v clearance rates were 42% and 61%; non-9v 46% and 59%, in anus and cervix, respectively. Conclusions:Anal HR-HPV prevalence was higher than cervical, with lower clearance; incidence was similar. Although prevalence of non-9v HR-HPV was substantial, 9v HR-HPV types were generally more prevalent. These findings support use of nonavalent vaccine in HIV-infected women.

Author(s): Conley, Lois J; Bush, Timothy J; Darragh, Teresa M; Palefsky, Joel M; Unger, Elizabeth R; Patel, Pragna; Steinau, Martin; Kojic, E Milu; Martin, Harold; Overton, E Turner; Cu-Uvin, Susan; Hammer, John; Henry, Keith; Wood, Kathleen; Brooks, John T; SUN Study Group | Abstract: BackgroundAnal cancer rates are higher for human immunodeficiency virus (HIV)-infected adults than for uninfected adults. Limited published data exist characterizing the incidence of precursor lesions detected by anal cytology.MethodsThe Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy was a prospective cohort of 700 HIV-infected participants in 4 US cities. At baseline and annually thereafter, each participant completed a behavioral questionnaire, and healthcare professionals collected anorectal swabs for cytologic examination and human papillomavirus (HPV) detection and genotyping.ResultsAmong 243 participants with negative baseline results of anal cytology, 37% developed abnormal cytology findings (incidence rate, 13.9 cases/100 person-years of follow-up; 95% confidence interval [CI], 11.3-16.9) over a median follow-up duration of 2.1 years. Rates among men having sex with men, among women, and among men having sex with women were 17.9 cases/person-years of follow-up (95% CI, 13.9-22.7), 9.4 cases/person-years of follow-up (95% CI, 5.6-14.9), and 8.9 cases/person-years of follow-up (95% CI, 4.8-15.6), respectively. In multivariable analysis, the number of persistent high-risk HPV types (adjusted hazard ratio [aHR], 1.17; 95% CI, 1.01-1.36), persistent high-risk HPV types except 16 or 18 (aHR, 2.46; 95% CI, 1.31-4.60), and persistent types 16 or 18 (aHR, 3.90; 95% CI, 1.78-8.54) remained associated with incident abnormalities.ConclusionsThe incidence of abnormal anal cytology findings was high and more likely to develop among persons with persistent high-risk HPV.

The Costa Rica Vaccine Trial (CVT) was a randomized clinical trial conducted between 2004 and 2010, which randomized 7466 women aged 18 to 25 to receive the bivalent HPV-16/18 vaccine or control Hepatitis-A vaccine. Participants were followed for 4 years with cross-over vaccination at the study end. In 2010 the long term follow-up (LTFU) study was initiated to evaluate the 10-year impact of HPV-16/18 vaccination, determinants of the immune response, and HPV natural history in a vaccinated population. Herein, the rationale, design and methods of the LTFU study are described, which actively follows CVT participants in the HPV-arm 6 additional years at biennial intervals (3 additional study visits for 10 years of total follow-up), or more often if clinically indicated. According to the initial commitment, women in the Hepatitis-A arm were offered HPV vaccination at cross-over; they were followed 2 additional years and exited from the study. 92% of eligible CVT women accepted participation in LTFU. To provide underlying rates of HPV acquisition and cervical disease among unvaccinated women to compare with the HPV-arm during LTFU, a new unvaccinated control group (UCG) of women who are beyond the age generally recommended for routine vaccination was enrolled, and will be followed by cervical cancer screening over 6 years. To form the UCG, 5000 women were selected from a local census, of whom 2836 women (61% of eligible women) agreed to participate. Over 90% of participants complied with an interview, blood and cervical specimen collection. Evaluation of comparability between the original (Hepatitis-A arm of CVT) and new (UCG) control groups showed that women's characteristics, as well as their predicted future risk for cervical HPV acquisition, were similar, thus validating use of the UCG. LTFU is poised to comprehensively address many important questions related to long-term effects of prophylactic HPV vaccines.

ObjectiveWe suggested cervical cancer screening strategies for women living with HIV (WLHIV) by comparing their precancer risks to general population women, and then compared our suggestions with current Centers for Disease Control and Prevention (CDC) guidelines.DesignWe compared risks of biopsy-confirmed cervical high-grade squamous intraepithelial neoplasia or worse (bHSIL+), calculated among WLHIV in the Women's Interagency HIV Study, to 'risk benchmarks' for specific management strategies in the general population.MethodsWe applied parametric survival models among 2423 WLHIV with negative or atypical squamous cell of undetermined significance (ASC-US) cytology during 2000-2015. Separately, we synthesized published general population bHSIL+ risks to generate 3-year risk benchmarks for a 3-year return (after negative cytology, i.e. 'rescreening threshold'), a 6-12-month return (after ASC-US), and immediate colposcopy [after low-grade squamous intraepithelial lesion (LSIL)].ResultsAverage 3-year bHSIL+ risks among general population women ('risk benchmarks') were 0.69% for a 3-year return (after negative cytology), 8.8% for a 6-12-month return (after ASC-US), and 14.4% for colposcopy (after LSIL). Most CDC guidelines for WLHIV were supported by comparing risks in WLHIV to these benchmarks, including a 3-year return with CD4 greater than 500 cells/μl and after either three negative cytology tests or a negative cytology/oncogenic human papillomavirus cotest (all 3-year risks≤1.3%); a 1-year return after negative cytology with either positive oncogenic human papillomavirus cotest (1-year risk = 1.0%) or CD4 cell count less than 500 cells/μl (1-year risk = 1.1%); and a 6-12-month return after ASC-US (3-year risk = 8.2% if CD4 cell count at least 500 cells/μl; 10.4% if CD4 cell count = 350-499 cells/μl). Other suggestions differed modestly from current guidelines, including colposcopy (vs. 6-12 month return) for WLHIV with ASC-US and CD4 cell count less than 350 cells/μl (3-year risk = 16.4%) and a lengthened 2-year (vs. 1-year) interval after negative cytology with CD4 cell count at least 500 cells/μl (2-year risk = 0.98%).ConclusionsCurrent cervical cancer screening guidelines for WLHIV are largely appropriate. CD4 cell count may inform risk-tailored strategies.

In order to estimate the incidence of invasive cervical cancer (ICC) across up to 21 years of follow-up among women with human immunodeficiency virus (HIV) and to compare it to that among HIV-uninfected women, we reviewed ICC diagnoses from a 20-year multi-site U.S. cohort study of HIV infected and uninfected women who had Pap testing every six months. Incidence rates were calculated and compared to those in HIV-negative women. Incidence ratios standardized to age-, sex-, race-, and calendar-year specific population rates were calculated. After a median follow-up of 12.3 years, four ICCs were confirmed in HIV seropositive women, only one in the last 10 years of observation, and none in seronegative women. The ICC incidence rate did not differ significantly by HIV status (HIV seronegative: 0/100,000 person-years vs. HIV seropositive: 19.5/100,000 person-years; p=0.53). The standardized incidence ratio for the HIV-infected WIHS participants was 3.31 (95% CI: 0.90, 8.47; p=0.07). Although marginally more common in women without HIV, for those with HIV in a prevention program, ICC does not emerge as a major threat as women age.

OBJECTIVE To estimate the frequency of abnormal Pap and human papillomavirus (HPV) positivity among human immunodeficiency virus (HIV)-seropositive and -seronegative women who have sex with women (WSW). METHODS Pap and HPV DNA polymerase chain reaction tests were obtained every 6 months from women in a US cohort of HIV-seropositive and -seronegative women. Women who have sex with women were women reporting no male and at least 1 female sex partner for 5 years. They were frequency matched 1:5 to women reporting sex only with men (WSM) and assessed using multivariable generalized estimating equation logistic regression models. RESULTS Paps at study entry were abnormal in 12 (21%) of 49 HIV-seropositive WSW, 151 (64%) of 245 HIV-seropositive WSM, 3 (9%) of 24 HIV-seronegative WSW, and 16 (11%) of 120 HIV-seronegative WSM. Human papillomavirus was found at entry in 18 (42%) HIV-seropositive WSW, 109 (52%) HIV-seropositive WSM, 6 (27%) HIV-seronegative WSW, and 13 (13%) HIV-seronegative WSM. After controlling for HIV serostatus and CD4 count, WSW had marginally lower odds than WSM of Pap abnormality (odds ratio = 0.59, 95% confidence interval = 0.33-1.03) and of HPV (odds ratio = 0.53, 95% confidence interval = 0.32-0.89). After controlling for partner's gender, HIV seropositivity and lower CD4 count were associated with any HPV, oncogenic HPV, any abnormal Pap result, and high-grade squamous intraepithelial lesion or worse (p < .0001 for all). CONCLUSIONS Although risks for abnormal Pap and HPV are modestly lower in WSW than in WSM, both are common in HIV-seropositive women regardless of sexual preference. Both WSW and WSM should be screened similarly.

Background HIV-seropositive women face high risk for infection with oncogenic human papillomavirus (oncHPV) types, abnormal Pap test results, and precancer, but cervical cancer risk is only modestly increased. Human papillomavirus (HPV)16 is highly oncogenic but only weakly associated with HIV status and immunosuppression, suggesting HPV16 may have a greater innate ability to evade host immune surveillance than other oncHPV types, which in turn should result in a greater relative increase in the prevalence of other oncHPV types among women with cervical precancer. Objective We sought to assess whether the underrepresentation of HPV16 among HIV-seropositive relative to HIV-seronegative women remains among those with cervical precancers. Study Design HIV-seropositive and HIV-seronegative women in the Women's Interagency HIV Study were screened for cervical intraepithelial neoplasia (CIN) grade ≥3 (CIN3 + ). DNA from >40 HPV types was detected by polymerase chain reaction in cervicovaginal lavage specimens obtained at the visit at which CIN3 + was diagnosed. Results HPV16 was detected in 13 (62%) of 21 HIV-seronegative women with CIN3 + but only 44 (29%) of 154 HIV-seropositive women with CIN3 + ( P = .01). The lower prevalence of HPV16 in CIN3 + among HIV-seropositive women persisted after controlling for covariates (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.08–0.78). The prevalence of other members of the HPV16-related alpha-9 oncHPV clade as a group was similar in HIV-infected and uninfected women with CIN3 + (OR, 1.02; 95% CI, 0.53–1.94). The prevalence of non-alpha-9 oncHPV types was increased in HIV-seropositive vs HIV-seronegative women with CIN3 + (OR, 3.9; 95% CI, 1.3–11.8). Conclusion The previously demonstrated increase in CIN3 + incidence among HIV-seropositive women is associated with lower HPV16 and higher non-alpha-9 oncHPV prevalence. This is consistent with prior reports that HIV has a weak effect on infection by HPV16 relative to other oncHPV and supports use of nonavalent HPV vaccine in HIV-seropositive women.

Author(s): DʼSouza, Gypsyamber; Wentz, Alicia; Wiley, Dorothy; Shah, Nisha; Barrington, Francine; Darragh, Teresa M; Joste, Nancy; Plankey, Michael; Reddy, Susheel; Breen, Elizabeth C; Young, Stephen; Cranston, Ross D | Abstract: ObjectiveTo evaluate the prevalence of anal cytology (ACyt) abnormalities among HIV-infected and HIV-uninfected men who have sex with men (MSM).DesignMulticenter cohort study of 723 HIV-infected and 788 HIV-uninfected MSM with ACyt, with a second ACyt collected 2 years later. A referral for high-resolution anoscopy was suggested for abnormal ACyt.MethodsACyt samples were collected using a polyester swab and liquid cytology media and read in a central laboratory.ResultsPrevalence of any abnormal ACyt was 25% in HIV-uninfected MSM and increased to 38%, 41%, and 47% among HIV-infected MSM with current CD4 T-cell counts ≥500, 350-499, and l350 cells/mm (P l 0.001), respectively. Anal HPV16 DNA was also more common in HIV-infected than HIV-uninfected MSM (25% versus 16%, P l 0.001). Abnormal baseline ACyt together with prevalent HPV16 DNA detection was present in only 7% of HIV-uninfected MSM compared to 18% of HIV-infected MSM with current CD4 l 350, P l 0.001. Among HIV-infected men, 56% of the men with atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesions ASCs-US/LSILs and 81% of men with atypical squamous cells cannot exclude high-grade (ASC-H/)/high-grade squamous intraepithelial lesions (HSIL) had lower grade ACyt findings 18-30 months later ("regressed"). However, 19% of untreated HIV-infected men with ASC-H/HSIL cytology maintained that same grade of cytology in their second test approximately 2 years later, and 15% with ASC-US/LSIL "progressed" to ASC-H/HSIL. Abnormal ACyt had high sensitivity (96%) but low specificity (17%) for biopsy-proven HSIL.ConclusionsPrevalence of abnormal ACyt remains elevated in HIV-infected men during the current antiretroviral therapy era.

Background Human papillomavirus vaccines prevent human papillomavirus infection and cervical precancers. The impact of vaccinating women with a current infection or after treatment for an human papillomavirus-associated lesion is not fully understood. Objectives To determine whether human papillomavirus-16/18 vaccination influences the outcome of infections present at vaccination and the rate of infection and disease after treatment of lesions. Study Design We included 1711 women (18−25 years) with carcinogenic human papillomavirus infection and 311 women of similar age who underwent treatment for cervical precancer and who participated in a community-based trial of the AS04-adjuvanted human papillomavirus-16/18 virus-like particle vaccine. Participants were randomized (human papillomavirus or hepatitis A vaccine) and offered 3 vaccinations over 6 months. Follow-up included annual visits (more frequently if clinically indicated), referral to colposcopy of high-grade and persistent low-grade lesions, treatment by loop electrosurgical excisional procedure when clinically indicated, and cytologic and virologic follow-up after treatment. Among women with human papillomavirus infection at the time of vaccination, we considered type-specific viral clearance, and development of cytologic (squamous intraepithelial lesions) and histologic (cervical intraepithelial neoplasia) lesions. Among treated women, we considered single-time and persistent human papillomavirus infection, squamous intraepithelial lesions, and cervical intraepithelial neoplasia 2 or greater. Outcomes associated with infections absent before treatment also were evaluated. Infection-level analyses were performed and vaccine efficacy estimated. Results Median follow-up was 56.7 months (women with human papillomavirus infection) and 27.3 months (treated women). There was no evidence of vaccine efficacy to increase clearance of human papillomavirus infections or decrease incidence of cytologic/histologic abnormalities associated with human papillomavirus types present at enrollment. Vaccine efficacy for human papillomavirus 16/18 clearance and against human papillomavirus 16/18 progression from infection to cervical intraepithelial neoplasia 2 or greater were −5.4% (95% confidence interval −19,10) and 0.3% (95% confidence interval −69,41), respectively. Among treated women, 34.1% had oncogenic infection and 1.6% had cervical intraepithelial neoplasia 2 or greater detected after treatment, respectively, and of these 69.8% and 20.0% were the result of new infections. We observed no significant effect of vaccination on rates of infection/lesions after treatment. Vaccine efficacy estimates for human papillomavirus 16/18 associated persistent infection and cervical intraepithelial neoplasia 2 or greater after treatment were 34.7% (95% confidence interval −131, 82) and −211% (95% confidence interval −2901, 68), respectively. We observed evidence for a partial and nonsignificant protective effect of vaccination against new infections absent before treatment. For incident human papillomavirus 16/18, human papillomavirus 31/33/45, and oncogenic human papillomavirus infections post-treatment, vaccine efficacy estimates were 57.9% (95% confidence interval −43, 88), 72.9% (95% confidence interval 29, 90), and 36.7% (95% confidence interval 1.5, 59), respectively. Conclusion We find no evidence for a vaccine effect on the fate of detectable human papillomavirus infections. We show that vaccination does not protect against infections/lesions after treatment. Evaluation of vaccine protection against new infections after treatment and resultant lesions warrants further consideration in future studies.

Background: Although anal squamous cell carcinoma (SCC) and adenocarcinoma (ADC) are generally combined in cancer surveillance, their etiologies likely differ. Here, we describe demographic characteristics and trends in incidence rates (IR) of anal cancer by histology (SCC, ADC) and behavior (invasive, in situ) in the United States. Methods: With data from the Surveillance, Epidemiology, and End Results (SEER) Program, we estimated age-adjusted anal cancer IRs across behavior/histology by demographic and tumor characteristics for 2000–2011. Trends in IRs and annual percent changes during 1977–2011 were also estimated and compared with rectal cancer. Results: Women had higher rates of SCC [rate ratio (RR), 1.45; 95% confidence interval (CI), 1.40–1.50] and lower rates of ADC (RR, 0.68; 95% CI, 0.62–0.74) and squamous carcinoma in situ (CIS; RR, 0.36; 95% CI, 0.34–0.38) than men. Blacks had lower rates of SCC (RR, 0.82; 95% CI, 0.77–0.87) and CIS (RR, 0.90; 95% CI, 0.83–0.98) than non-Hispanic whites, but higher rates of ADC (RR, 1.48; 95% CI, 1.29–1.70). Anal cancer IRs were higher in men and blacks aged Conclusions: Rates of anal SCC and CIS have increased strongly over time, in contrast to rates of anal ADC, similar to trends observed for rectal SCC and ADC. Impact: Anal SCC and ADC likely have different etiologies, but may have similar etiologies to rectal SCC and ADC, respectively. Strong increases in CIS IRs over time may reflect anal cancer screening patterns. Cancer Epidemiol Biomarkers Prev; 24(10); 1548–56. ©2015 AACR.

Background Human papillomavirus (HPV) infection of the cervix and related abnormal cervical cytology in HIV-infected women has been well described. Little is known about anal HPV infection in HIV-infected women. Methods The SUN Study is a prospective cohort study of 700 HIV-infected patients including 167 women. At baseline, patients completed a behavioral questionnaire and provided, among other samples, cervical and anal swabs for HPV detection and genotyping and for cytologic examination. Here, we present the available baseline data on the 167 women in the SUN study. Results Baseline results were available for 120 women (median age: 38 years, 57% non-Hispanic black, median CD4 cell count 444.5 cells/mm3), of whom, 77% were taking antiretroviral therapy. The prevalences in the anus and cervix of any HPV were 90% and 83%, respectively (P = 0.039), and of high-risk (HR) types 85% and 70%, respectively, (P = 0.001). There was no significant difference in the prevalences of abnormal cytology between the anus and cervix: 38% and 33%, respectively (P = 0.217). Although the presence of abnormal cervical cytology was associated with the presence of abnormal anal cytology (relative risk: 1.7, P = 0.024), its sensitivity (52.5%) and positive predictive value positive (45.6%) for identifying women with abnormal anal cytology were poor. A history of anal sex was not associated with anal HPV infection or abnormal anal cytology. Conclusions In this cohort of HIV-infected women, anal HPV infection was more prevalent and diverse than cervical HPV infection. Anal cytologic abnormalities were as prevalent as cervical cytologic abnormalities, and although abnormal cervical cytology was predictive of abnormal anal cytology, results were not highly concordant. These data support the need for studies of anal cytologic screening of HIV-infected women.

Objective. To explore the previously reported associations between cervical squamous lesions and psychologic measures of stress and depression. Methods. In a multicenter cohort study, women with HIV and HIV-seronegative women had Pap tests and completed self-report questionnaires including the Perceived Stress Scale-10 (PSS), which measures perceived stress, the Posttraumatic Stress Disorder (PTSD) Checklist-Civilian Version (PCL-C), which measures symptoms of PTSD, and the Center for Epidemiologic Studies Depression (CES-D) scale, which measures depressive symptoms. Results. Median scores were 13 (range = 0-38) for the PSS, 24 (range = 17-85) for the PCL-C, and 8 (range = 0-57) for the CES-D, indicating moderate stress and minimal depression. For PSS, compared with women in the lowest tertile of reported stress, the odds ratios (ORs) for squamous intraepithelial lesions (SIL) were 0.88 (95% confidence interval [CI] = 0.50-1.54) for women in the middle tertile and 0.96 (95% CI = 0.54-1.68) for women in the highest tertile. For PCL-C, compared with women in the lowest tertile of PTSD symptoms, ORs for SIL were 0.79 (95% CI = 0.43-1.41) for women in the middle tertile and 1.17 (95% CI = 0.68-2.01) for women in the highest tertile. Rates of SIL were similar for CES-D scores 16 or higher (compared with women with lower scores; OR = 1.41, 95% CI = 0.88-2.26) and 23 or higher (OR = 1.39, 95% CI = 0.81-2.40). In the multivariable analysis including the number of sexual partners, age, income, ethnicity, and serostatus, stress as measured by PSS and PCL-C and depressive symptoms as measured by CES-D remained unassociated with SIL. Conclusions. We found no evidence that stress and depression affect the prevalence of cervical squamous lesions.

Objective: Human papillomavirus (HPV) is a common sexually transmitted agent that causes anogenital cancer and precancer lesions that have an inflammatory infiltrate, may be friable and bleed. Our aim was to determine the association between anal HPV infection and HIV acquisition. Design: A prospective cohort study. Methods: We recruited 1409 HIV-negative men who have sex with men from a community-based setting in Boston, Denver, New York and San Francisco. We used Cox proportional hazards regression modeling and assessed the independent association of HPV infection with the rate of acquisition of HIV infection. Results: Of 1409 participants contributing 4375 person-years of follow-up, 51 HIVseroconverted. The median number of HPV types in HPV-infected HIV-seroconverters was 2 (interquartile range 1‐3) at the time of HIV seroconversion. After adjustment for sexual activity, substance use, occurrence of other sexually transmitted infections and demographic variables, there was evidence (P ¼0.002) for the effect of infection with at least two HPV types (hazard ratio 3.5, 95% confidence interval 1.2‐10.6) in HIV seroconversion. Conclusion: Anal HPV infection is independently associated with HIV acquisition. Studies that incorporate high-resolution anoscopy to more accurately identify HPVassociated disease are needed to determine the relationship between HPV-associated disease and HIV seroconversion. 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2009, 23:000‐000

To study anal intraepithelial neoplasia and its associations with anal and cervical human papillomavirus (HPV), cervical neoplasia, host immune status, and demographic and behavioral risk factors in women with and at risk for HIV infection.Point-prevalence analysis nested within a prospective study of women seen at three clinical centers of the Women's Interagency HIV Study.In 2001-2003 participants were interviewed, received a gynecological examination, anal and cervical cytology testing and, if abnormal, colposcopy-guided or anoscopy-guided biopsy of visible lesions. Exfoliated cervical and anal specimens were assessed for HPV using PCR and type-specific HPV probing. Logistic regression analyses were performed, and odds ratios (ORs) estimated risks for anal intraepithelial neoplasia.Four hundred and seventy HIV-infected and 185 HIV-uninfected women were enrolled. Low-grade anal intraepithelial neoplasia was present in 12% of HIV-infected and 5% of HIV-uninfected women. High-grade anal intraepithelial neoplasia was present in 9% of HIV-infected and 1% of HIV-uninfected women. In adjusted analyses among HIV-infected women, the risk factors for low-grade anal intraepithelial neoplasia were younger age [OR = 0.59, 95% confidence interval (CI) = 0.36-0.97], history of receptive anal intercourse (OR = 3.2, 95% CI = 1.5-6.8), anal HPV (oncogenic types only OR = 11, 95% CI = 1.2-103; oncogenic and nononcogenic types OR = 11, 95% CI = 1.3-96), and cervical HPV (oncogenic and nononcogenic types OR = 3.5, 95% CI = 1.1-11). In multivariable analyses among HIV-infected women, the only significant risk factor for high-grade anal intraepithelial neoplasia was anal HPV infection (oncogenic and nononcogenic types OR = 7.6, 95% CI = 1.5-38).Even in the era of highly active antiviral therapy, the prevalence of anal intraepithelial neoplasia was 16% in HIV-infected women. After controlling for potential confounders, several risk factors for low-grade anal intraepithelial neoplasia differed from risk factors for high-grade anal intraepithelial neoplasia.

To estimate the frequency of and trends in abnormal Pap test results in women with human immunodeficiency virus (HIV) and HIV-uninfected women.In a cohort study of HIV-infected and uninfected women, Pap tests were obtained every 6 months. Results of atypical squamous cells of undetermined significance (ASC-US) or worse were considered abnormal.Over a median of 8.4 years, 23,843 Pap tests were obtained from 1,931 HIV-positive women with 6,828 Pap tests from 533 HIV-negative women (13 women seroconverted during the study). Among women with HIV, Pap test results were ASC-US in 4,462 (19%), low-grade squamous intraepithelial lesion (LSIL) in 3,199 (13%), high-grade squamous intraepithelial lesion (HSIL) in 267 (1%), and cancer in 11 (0.05%). The incidence of abnormal Pap test results was 179 in 1,000 person-years for HIV-positive and 75 in 1,000 person-years for HIV-negative women (incidence rate ratio 2.4, 95% confidence interval 2.0-2.8). The incidence of HSIL or cancer was 4.4 in 1,000 person-years for HIV-positive and 1.3 in 1,000 person-years for HIV-negative women (incidence rate ratio 3.4, 95% confidence interval 1.2-9.5).Among women with HIV in a cervical cancer prevention program, Pap test abnormalities are common, but high-grade abnormalities are infrequent.II.

OBJECTIVES To test a therapeutic vaccine consisting of a fusion of the human papillomavirus (HPV) 16 E7 protein and the Mycobacterium bovis heat shock protein 65 (SGN-00101) to treat high-grade anal intraepithelial neoplasia (HG-AIN) in HIV-positive individuals. DESIGN A phase I/II trial with three cohorts of five participants each, sequentially assigned to receive 100, 500 or 1000 microg SGN-00101, injected three times subcutaneously in alternating thighs at 4-week intervals. Anal disease was assessed at baseline, 8, 12, 24 and 48 weeks and was classified as the more severe of anal cytology and anal biopsy. Anal HPV DNA was detected using L1 consensus primer-based PCR followed by type-specific probing and dot-blot hybridization (DBH). HPV16, 18 and 31 DNA copy numbers were measured using quantitative real-time PCR. SETTING University-based research clinic. PARTICIPANTS Thirteen HIV-positive men and two HIV-positive women with HG-AIN. RESULTS There were no drug-related serious adverse events or significant changes in HIV viral load and CD4/CD8 ratio. At 48 weeks, two of five participants in both the 100 and 500 microg cohorts regressed to AIN 1 and one of five participants in the 1000 microg cohort regressed to atypical squamous cells of undetermined significance (ASC-US). All participants had at least one oncogenic HPV type at baseline. Three of five (60%) participants who regressed to AIN 1 or ASC-US became HPV-negative using DBH and real-time PCR, compared with none of 10 participants with no clinical response (P = 0.02). CONCLUSIONS SGN-00101 was well tolerated in HIV-positive individuals, with preliminary evidence for clinical activity.

OBJECTIVE To estimate the risk of and risk factors for progression among human immunodeficiency virus (HIV)-seropositive women with abnormal cervical cytology but negative colposcopy. METHODS In a prospective cohort study, 391 HIV-seropositive and 103 seronegative women with cervical cytology read as atypical squamous cells (ASC) or low-grade squamous intraepithelial lesion (LSIL) but negative colposcopy were followed up for a mean of 4.0 years with cytology at 6-month intervals. Colposcopy was prescribed for any epithelial abnormality. RESULTS Progression to CIN2, CIN3, high-grade SIL/severe dysplasia, or cancer occurred in 47 (12%) HIV-seropositive women and 4 (4%) HIV-seronegative women (P = .02). Progression to CIN1 was seen in an additional 12 HIV-seropositive women and 1 seronegative woman. In multivariate analysis, high-risk but not low-risk HPV detection (hazard ratio [HR] 2.46-95% confidence interval [CI] 1.18-5.12, P = .02 for high risk, HR 1.41, 95% CI 0.62-3.21, P = .42 for low risk), satisfactory colposcopy (HR 2.01, 95% CI 1.11-3.65, P = .02), and non-Hispanic African-American ethnicity (HR 5.08, 95% CI 1.72-14.98, P = .003) were the only factors associated with progression, while HIV serostatus was marginally significant (HR 2.53, 95% CI 0.85-7.50, P = .09). CONCLUSION Human immunodeficiency virus-seropositive women with negative colposcopy after borderline cytology face a higher risk of progression than seronegative women, but the absolute risk is low and becomes nonsignificant after controlling for HPV risk type, ethnicity, and colposcopic findings. Observation is appropriate. LEVEL OF EVIDENCE II-2.

Background. In the United States, anal cancer in men who have sex with men (MSM) is more common than cervical cancer in women. Human papillomavirus (HPV) is causally linked to the development of anal and cervical cancer. In women, cervical HPV infection peaks early and decreases after the age of 30. Little is known about the age-specific prevalence of anal HPV infection in human immunodeficiency virus (HIV)-negative MSM. Methods. We studied the prevalence and determinants of anal HPV infection in 1218 HIV-negative MSM, 18-89 years old, who were recruited from 4 US cities. We assessed anal HPV infection status by polymerase chain reaction. Results. HPV DNA was found in the anal canal of 57% of study participants. The prevalence of anal HPV infection did not change with age or geographic location. Anal HPV infection was independently associated with receptive anal intercourse (odds ratio [OR], 2.0; P 5 sex partners during the preceding 6 months (OR, 1.5; P

Summary Background The aim of this study was to assess the probability of low-grade squamous intra-epithelial lesion (LSIL) regression in young women, and to examine the factors associated with this regression. Methods In a longitudinal study of human papilloma virus (HPV) infection, female adolescents aged 13–22 years were examined every 4 months by cytology, colposcopy, and HPV DNA status. Both prevalent and incident LSIL cases were included in the analysis, with regression defined as at least three consecutive normal Pap smears. Findings Median follow-up time from baseline (defined as the time of first LSIL diagnosis) for the 187 women with LSIL was 61 months (IQR 34–80). Median time they had been sexually active at diagnosis was 3·2 years (2·6–6·5). Probability of regression for the entire cohort was 61% (95% CI 53–70) at 12 months and 91% (84–99) at 36 months of follow-up. No associations were found between LSIL regression and HPV status at baseline, sexual behaviour, contraceptive use, substance or cigarette use, incident sexually transmitted infection, or biopsy. Multivariate analysis showed that only HPV status at the current visit was associated with rate of regression, whether infection was caused by one or more viral types (relative hazard=0·3 [95% CI 0·21–0·42], and 0·14 [0·08–0·25], respectively). Interpretation The high rate of regression recorded in this study lends support to observation by cytology in the management of LSIL in female adolescents. Negative HPV status was associated with regression, suggesting that HPV testing could be helpful in monitoring LSIL.

We sought to estimate rates of progression and regression of grade 1 cervical intraepithelial neoplasia (CIN 1) among women with human immunodeficiency virus (HIV).In a multicenter prospective cohort study, HIV-seropositive and HIV-seronegative women were evaluated colposcopically after receiving an abnormal cytology test result between November 1994 and September 2002. Women with CIN 1 were included, except those who had undergone hysterectomy, cervical therapy, or had CIN 2-3 or cervical cancer. Those women who were included were followed cytologically twice yearly, with colposcopy repeated for atypia or worse.We followed 223 women with CIN 1 (202 HIV seropositive and 21 HIV seronegative) for a mean of 3.3 person-years. Progression occurred in 8 HIV-seropositive women (incidence density, 1.2/100 person-years; 95% confidence interval [CI] 0.5-2.4/100 person-years) and in no HIV seronegative women. Regression occurred in 66 (33%) HIV-seropositive women (13/100 person-years, 95% CI 10-16/100 person-years) versus 14 (67%) seronegative women (32/100 person-years, relative risk 0.40, 95% CI 0.25-0.66; P.001). In multivariate analysis, regression was associated with human papillomavirus (HPV) detection (hazard ratio [HR] for low risk 0.28, 95% CI 0.13-0.61, P = .001; and for high-risk 0.34, 95% CI 0.20-0.55, P.001 versus no HPV detected) and Hispanic ethnicity (HR 0.48, 95% CI 0.230.98; P = .04); HIV serostatus was only marginally linked to regression (HR 0.52, 95% CI 0.27-1.03; P = .06), but seropositive women were less likely to regress when analysis was limited to 146 women with HPV detected at CIN 1 diagnosis (HR 0.18, 95% CI 0.05-0.62; P = .006).Grade 1 cervical intraepithelial neoplasia infrequently progresses in women with HIV. Thus, observation appears safe absent other indications for treatment.II-1.

Background: The impact of highly active antiretroviral therapy (HAART) on the natural history of HPV infection and anal squamous intraepithelial lesions (SIL) in HIV-infected men who have sex with men (MSM) is poorly documented. Goal: The goal of this study was to evaluate the prevalence of anal HPV infection and SIL inpatients under HAART. Study Design: Forty-five HIV-infected protease inhibitor-experienced MSM were enrolled in a cross-sectional study. Each patient provided anal samples for anal cytology, histology, and human papillomavirus (HPV) DNA testing. Results: The patients had previously received HAART for a median of 32 months. Anal cytology was abnormal in 32 of 45 (71%) patients, including high-grade SIL in 10 patients (22%), low-grade SIL in 19 patients (42%), and atypical squamous cells of undetermined significance in 3 patients (7%). HPV DNA was detected 36/45 men (80%). The prevalence of anal SIL and HPV infection were similar in patients exhibiting a significant increase in CD4+ cell count after HAART initiation compared with those who did not. Conclusion: Our results demonstrate a high prevalence of anal SIL, including high-grade SIL, and anal HPV infection in HIV-infected MSM despite immune restoration under HAART.

To compare cytology with cervicography in HIV-infected and uninfected adolescent females.At the time of analysis, 334 girls aged 13-19 years from 13 U.S. cities were participating in a prospective study of HIV infection. All subjects had cytology and a Cervigram (cervicography) performed at two consecutive visits 6 months apart, referred to as visit (V) 1 and 2. Cervigrams were sent to the parent company for diagnosis and were categorized as: "negative" or "positive" (compatible with low-grade or high-grade squamous intraepithelial lesions [SIL]). Cytology was considered abnormal if the subject had SIL at either V1 or V2. Sensitivity, specificity, and positive predictive value (PPV) of the Cervigram were calculated compared with repeat Papanicolaou (Pap) smears.Two consecutive adequate Pap smears were available for analysis in 200 adolescents; 51% (95% CI, 43-59) of the 142 HIV-positive youth and 19% (95% CI, 9-29) of the 58 HIV-negative youth had SIL on at least one Pap smear (p.001). A positive Cervigram was observed in 44% (95% CI, 36-53) of the HIV-infected group and 29% (95% CI, 17-41) of the HIV-uninfected group (p =.06). For the HIV-infected group, the sensitivity, specificity, and PPV of the Cervigram to detect SIL were 58% (95% CI, 45-71), 69% (95%CI, 57-80), and 64% (95%CI, 52-77), respectively. For the HIV-uninfected group, the sensitivity, specificity, and PPV were 64% (95% CI, 31-89), 80% (95% CI, 65-90), and 44% (95% CI, 19-68), respectively. The combined sensitivity, using both the Pap smear and Cervigram result from V1 to detect SIL, was 82% (95% CI, 71-91 for HIV+ and 48-98 for HIV-) in both groups. However, the PPV based the performance of the Cervigram in Pap smear-negative women as 33% (95% CI, 17-53) and 15% (95% CI, 2-45) for the HIV-infected and uninfected group, respectively (p = not significant [ns]).Although the sensitivity of a single Pap smear increased significantly when the Cervigram was used as an adjunct, the low PPV in both HIV-infected and uninfected groups, suggests that cervicography has a limited utility for precancer and cervical cancer screening in high-risk adolescent populations.

The objective of the study was to estimate the impact of human immunodeficiency virus (HIV) infection on the incidence of high-grade cervical intraepithelial neoplasia (CIN).HIV-seropositive and comparison seronegative women enrolled in a prospective US cohort study were followed up with semiannual Papanicolaou testing, with colposcopy for any abnormality. Histology results were retrieved to identify CIN3+ (CIN3, adenocarcinoma in situ, and cancer) and CIN2+ (CIN2 and CIN3+). Annual detection rates were calculated and risks compared using a Cox analysis. Median follow-up (interquartile range) was 11.0 (5.4-17.2) years for HIV-seronegative and 9.9 (2.5-16.0) for HIV-seropositive women.CIN3+ was diagnosed in 139 HIV-seropositive (5%) and 19 HIV-seronegative women (2%) (P.0001), with CIN2+ in 316 (12%) and 34 (4%) (P.0001). The annual CIN3+ detection rate was 0.6 per 100 person-years in HIV-seropositive women and 0.2 per 100 person-years in seronegative women (P.0001). The CIN3+ detection rate fell after the first 2 years of study, from 0.9 per 100 person-years among HIV-seropositive women to 0.4 per 100 person-years during subsequent follow-up (P.0001). CIN2+ incidence among these women fell similarly with time, from 2.5 per 100 person-years during the first 2 years after enrollment to 0.9 per 100 person-years subsequently (P.0001). In Cox analyses controlling for age, the hazard ratio for HIV-seropositive women with CD4 counts less than 200/cmm compared with HIV-seronegative women was 8.1 (95% confidence interval, 4.8-13.8) for CIN3+ and 9.3 (95% confidence interval, 6.3-13.7) for CIN2+ (P.0001).Although HIV-seropositive women have more CIN3+ than HIV-seronegative women, CIN3+ is uncommon and becomes even less frequent after the initiation of regular cervical screening.

Objective The aim of this study is to compare colposcopic findings and the accuracy of colposcopic impression in HIV seropositive and seronegative women with abnormal Pap tests. Methods HIV seropositive and seronegative women in a national cohort study had Pap tests collected every six months, with colposcopy for any abnormal result. Prospectively collected colposcopy and histology findings were analyzed retrospectively using Pearson Chi-square, t -test and Wilcoxon two-sample tests, logistic regression models, and Kappa coefficients. Results After adjusting for age and Pap result, 1618 eligible HIV seropositive women were more likely than 406 seronegative women to have inadequate colposcopic examinations, abnormal colposcopic findings, and large cervical lesions. However, among those with abnormal colposcopy, colposcopic characteristics and lesion size and number did not differ by HIV serostatus. Agreement between colposcopists' impressions and highest grade biopsy diagnoses was fair (kappa coefficient 0.35, 95% C.I. 0.31, 0.38). Agreement did not differ by HIV serostatus and did not improve with multiple biopsies (weighted kappa coefficient 0.35, 95% C.I. 0.32, 0.39) or after including all histology results over two years following colposcopy. Conclusion Although HIV seropositive women with abnormal cytology are more likely to have colposcopic abnormality, the performance of colposcopy appears to be similar to that in HIV seronegative women. Biopsy is required to confirm colposcopic impression.

Anal human papillomavirus (HPV) infections are common, and the incidence of anal cancer is high in HIV-infected men who have sex with men (MSM). To evaluate the performance of HPV assays in anal samples, we compared the cobas HPV test (cobas) to the Roche Linear Array HPV genotyping assay (LA) and cytology in HIV-infected MSM. Cytology and cobas and LA HPV testing were conducted for 342 subjects. We calculated agreement between the HPV assays and the clinical performance of HPV testing and HPV genotyping alone and in combination with anal cytology. We observed high agreement between cobas and LA, with cobas more likely than LA to show positive results for HPV16, HPV18, and other carcinogenic types. Specimens testing positive in cobas but not in LA were more likely to be positive for other markers of HPV-related disease compared to those testing negative in both assays, suggesting that at least some of these were true positives for HPV. cobas and LA showed high sensitivities but low specificities for the detection of anal intraepithelial neoplasia grade 2/3 (AIN2/3) in this population (100% sensitivity and 26% specificity for cobas versus 98.4% sensitivity and 28.9% specificity for LA). A combination of anal cytology and HPV genotyping provided the highest accuracy for detecting anal precancer. A higher HPV load was associated with a higher risk of AIN2/3 with HPV16 ( P trend < 0.001), HPV18 ( P trend = 0.07), and other carcinogenic types ( P trend < 0.001). We demonstrate that cobas can be used for HPV detection in anal cytology specimens. Additional tests are necessary to identify men at the highest risk of anal cancer among those infected with high-risk HPV.

The effect of highly active antiretroviral therapy (HAART) on the natural history of anal squamous intraepithelial lesions (ASIL)-the likely anal cancer precursor-and anal human papillomavirus (HPV) infection is unknown. ASIL severity and level of anal HPV DNA were evaluated among HIV-positive men who have sex with men (MSM) for at least 6 months before initiation of HAART. The results were compared with those from a 6-month period after initiation of HAART. Anal swabs for cytology and HPV studies were obtained, followed by high-resolution anoscopy and biopsy. Among men whose most severe pre-HAART diagnosis was atypical squamous cells of undetermined significance or low-grade ASIL, 18% (confidence interval [CI], 6-31%, 7 of 38) progressed and 21% (CI, 8-34%, 8 of 38) regressed 6 months after starting HAART. Seventeen percent (CI, 0-38%, 2 of 12) of study subjects who began with a normal diagnosis developed ASIL. Only 4% (CI, 0-10%, 1 of 28) of study subjects with high-grade ASIL regressed to normal. There was no reduction in the proportion of study subjects who tested positive for HPV DNA or HPV DNA levels after HAART initiation. The ASIL and HPV data were similar to those of the pre-HAART comparison period. These results indicate that HAART has little effect on either ASIL or HPV in the first 6 months after HAART initiation.

Anal cancer is relatively uncommon in the United States, with an expected 6000 new cases in 2012 and an overall annual incidence rate of 2/100 000 [1, 2]. Most anal cancers are caused by human papillomavirus (HPV) infection [3]. Certain populations, such as human immunodeficiency virus (HIV)–infected and other immunosuppressed individuals, appear to have an increased risk of both HPV infection and anal cancer. A recent worldwide metaanalysis showed that HIV-infected men who have sex with men (MSM) have an estimated 46/100 000 incident anal cancer cases per year compared with HIV-negative MSM who have 5/100 000 incident cases per year [4]. Since the advent of highly active antiretroviral therapy (HAART), the life expectancy for HIV-infected individuals has significantly increased. This may have allowed time for progression of carcinogenic HPV infections to anal cancer and possibly explains an increase in anal cancer incidence in the United States [5–8]. Anal cancer natural history presumably follows the same steps as cervical cancer natural history: HPV acquisition, HPV persistence, progression of persistent HPV infections to high-grade anal intraepithelial neoplasia (AIN), and invasion to anal cancer [5]. Studies have identified risk factors for each stage in the progression from cervical HPV infection to cervical cancer [9–11], and we are beginning to find similar risk factors in anal cancer natural history. Risk factors for anal HPV infection are related to sexual behavior, such as lifetime number of sexual partners, as well as low CD4 count in HIV-infected populations [12–15]. Smoking history has been shown to be associated with anal HPV persistence [16, 17] and anal cancer [18, 19], but it is unclear at what stage smoking influences the natural history. To add to our understanding of risk factors that influence the natural history of HPV and anal cancer, we conducted a study of lifestyle characteristics and clinical parameters for HIV-infected MSM undergoing routine anal cancer screening at Kaiser Permanente Northern California (KPNC) Health Maintenance Organization.

Author(s): Sharma, Rachna; Efird, Jimmy T; Chein, Aung; Holly, Elizabeth A; Krajden, Mel; Berry, J Michael; Darragh, Teresa M; Jay, Naomi; Palefsky, Joel M | Abstract: ObjectiveHuman papillomavirus (HPV) vaccination is routinely recommended in HIV-positive men who have sex with men (MSM) aged ≤ 26 years. Levels of previous HPV exposure in older HIV-positive MSM are assumed to be too high to warrant routine HPV vaccination. However, little is known about the prevalence of and risk factors for neutralizing antibody seropositivity to HPV-16 or HPV-18, a key measure of previous exposure to these types.MethodsCross-sectional analysis of baseline visit for 296 HIV-positive MSM participating in a prospective cohort study of anal squamous intraepithelial lesions at a university-based research clinic. Participants completed a questionnaire detailing behaviors and medical history. Phlebotomy, anal cytology, HPV DNA testing with quantitation, and high-resolution anoscopy with biopsy were performed. A pseudovirion-based neutralizing antibody assay was used to measure HPV-16 and HPV-18 neutralizing antibodies.ResultsOne hundred thirty-two of 296 (45%) men were HPV-16 seropositive and 141 of 296 (48%) were HPV-18 seropositive. One hundred seventy-five of 296 (59%) of the men were positive for HPV-16 antibodies or DNA and 167 of 296 (56%) were positive for HPV-18 antibodies or DNA. In multivariable analysis, HPV-16 seropositivity did not correlate with age, years of HIV positivity, CD4 level, or HIV viral load. Significant risk factors included HPV-16 DNA positivity with higher DNA levels (ptrend l 0.001) and higher number of receptive sexual partners in the last year (ptrend = 0.012).ConclusionsA high proportion of HIV-positive MSM aged g26 years are DNA negative and seronegative to HPV-16 and HPV-18 even when using a sensitive pseudovirion-based neutralizing antibody assay. Prospective studies are needed to determine the clinical- and cost-effectiveness of HPV vaccination in HIV-positive MSM aged g26 years.

BACKGROUND The purpose of this study was to examine, prospectively, the presence and extent of cervical epithelial immaturity as well as the rate of squamous metaplastic activity as a risk for the development of low grade squamous intraepithelial lesions (LSIL). METHODS The study was a nested case-control design that used subjects from an ongoing cohort study of human papillomavirus infection. Fifty-four sexually active young women who developed LSIL were matched for age and number of visits with 54 women who had never developed LSIL. The percent of cervical immaturity was interpreted from colpophotography using a computer-generated pixel count of delineated immature and total cervical areas. Activity of squamous metaplasia was interpreted as the percent change in the area of immaturity over a defined time period. Conditional logistic regression analysis examined risks for the development of LSIL. RESULTS Baseline area of biologic immaturity was not a predictor of LSIL. However, women with the a high degree of metaplastic activity near the SIL event were more likely to develop LSIL (odds ratio = 3.01 [95% confidence interval, 1.3, 6.8] for every 10% unit change in area of immaturity). CONCLUSIONS A rapid rate of metaplastic change within the transformation zone, rather than the initial area of biologic immaturity, is a significant risk factor for the development of LSIL. Cancer 1999;85:1139–44. © 1999 American Cancer Society.