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BACKGROUND: Little is known about penile high-risk human papillomavirus (hrHPV) among men who have sex with men (MSM) in low- and middle-income countries. We aimed to determine the incidence, clearance, and persistence of penile hrHPV among Rwandan MSM. METHODS: We enrolled 350 MSM (345 with valid human papillomavirus [HPV] results) aged ≥18 years. At each visit (6-12 months apart), we collected penile PreservCyt specimens and blood for HPV and HIV testing, as well as sociodemographic and behavioral variables. HPV testing was performed with the Ampfire assay. Penile hrHPV incidence and clearance per 1000 person-months of follow-up, as well as prevalent and incident persistence, were computed and compared by HIV status. RESULTS: The mean (SD) age was 27.7 (6.7) years and 19.4% were living with HIV. Penile hrHPV incidence was 34.8 (95% CI, 29.1-41.8) per 1000 person-months of follow-up. HPV-16 (11.7; 95% CI, 9.26-14.9) and HPV-59 (6.1; 95% CI, 4.52-8.39) had the highest incidence rates. Prevalent and incident persistence was 47.5% and 46.6%, respectively. HPV-66 (33.3%), HPV-52 (30.8%), and HPV-16 (29.2%) had the highest prevalent persistence and HPV-33 (53.8%), HPV-31 (46.7%), and HPV-16 (42.6%) the highest incident persistence. No differences were found by HIV status except for HPV-45 (higher in MSM with HIV). CONCLUSIONS: We found high incidence and prevalent/incident persistence of penile hrHPV among Rwandan MSM. This highlights the importance of preventive strategies for HPV-associated anogenital cancers.

Introduction: The etiology of esophageal squamous papilloma (ESP) is largely unknown. Previous studies have shown a variable association with human papillomavirus (HPV) with conflicting data. The aim of this study was to further investigate the possible association of HPV in our ESP series using RNA in-situ hybridization (ISH) and compare study groups from the United States of America and China. Methods: Demographic and clinical data of patients with ESP were retrieved from the University of California Los Angeles (UCLA) (1/2016-3/2019) and Peking Union Medical College Hospital (PUMCH) (9/2014-3/2019) pathology databases. Hematoxylin and eosin slides were reexamined. Confirmed cases were examined by high- and low-risk HPV RNA ISH. Results: For the UCLA cohort, 13 429 upper endoscopies were performed and 78 biopsies from 72 patients were identified as ESP (F:M = 45:27, 66.7% > 45 years). Seventy-four (94.9%) biopsies were designated as polyps or nodules and 46.6% were located in the mid-esophagus. Other abnormal findings included gastroesophageal reflux disease (48.6%), hiatal hernia (38.9%), and esophagitis (36.1%). For the PUMCH cohort, 63 754 upper endoscopies were performed and 73 biopsies from 71 patients were identified as ESP (F:M = 48:23, 71.8% > 45 years). Sixty-four (87.7%) biopsies were designated as polyps or nodules and 57.5% were located in the mid-esophagus. Other abnormal findings included esophagitis (19.7%), and hiatal hernia (8.5%). No features of conventional cytologic dysplasia or viral cytopathic change were found. None of the cases was associated with squamous cell carcinoma, and none showed positive HPV RNA ISH results. Conclusions: No association was found between ESP and active HPV infection in our 2 cohorts. Other etiopathogenetic mechanisms, such as aging, might contribute to the development of these innocent lesions.

BACKGROUND: Detection and treatment of anal histologic high-grade squamous intraepithelial lesions (hHSIL) prevents anal cancer. However, anal hHSIL incidence among women with human immunodeficiency virus (HIV, WHIV) remains unknown. Performance of anal high-risk human papillomavirus ([hr]HPV), anal cytology (anal-cyt), and both for hHSIL detection longitudinally over 2 years also remains undetermined. METHODS: We determined 2-year incidence and cumulative risk estimates (2-y-CR) of anal hHSIL among WHIV using prevalence and incidence (per 100 person-years [py]) observations stratified by baseline hrHPV and/or anal-cyt results. RESULTS: In total, 229 WHIV with complete baseline data were included in the analysis; 114 women without prevalent anal hHSIL were followed with 2 annual evaluations. Median age was 51, 63% were Black, and 23% were Hispanic. Anal hrHPV or abnormal anal-cyt was associated with an increased risk of incident anal hHSIL at 2 years (18.9/100py [95% confidence interval {CI} 11.4-31.3] and 13.4/100py [95% CI 8.0-22.7], respectively) compared with no detection of anal HPV or negative cytology (2.8/100py [95% CI 1.1-7.4] and 4.2 [95% CI, 1.8-10.2]) The presence of anal hrHPV with abnormal cytology was associated with 2-y-CR of anal hHSIL of 65.6% (95% CI 55.4%-75%); negative hrHPV with negative cytology was associated with 2-y-CR of anal hHSIL of 9.2% (95% CI 7.0-16.0). CONCLUSIONS: Detection of anal hrHPV or abnormal anal cytology are comparable predictors for 2-y-CR of anal hHSIL. The absence of anal hrHPV combined with negative cytology was predictive of a lower (but measurable) risk of developing anal hHSIL. These findings provide important data to inform anal cancer screening guidelines for WHIV.

BACKGROUND: International data on anogenital HPV infection incidence among men are limited. METHODS: Incidence of incident-persistent (IP) anogenital HPV infections was evaluated among 295 men who have sex with men (MSM) and 1576 heterosexual men (HM) aged 16-27 years in the placebo arm of a global, multicenter 4-valent (4v) HPV vaccine trial. We estimated IP incidence (penile/scrotal, perineal/perianal, anal) for 4vHPV and 9-valent (9v) HPV vaccine types and cumulative IP incidence over 36 months. RESULTS: IP infection incidence per 100 person-years (95% CI) among HM for 4vHPV and 9vHPV types was 4.1 (3.5-4.9) and 6.8 (5.9-7.6) at penile/scrotal, and 1.2 (.8-1.6) and 1.9 (1.5-2.4) at perineal/perianal sites, respectively; and among MSM, IP infection incidence was 2.3 (1.3-3.8) and 3.2 (2.0-4.9) at penile/scrotal, 6.8 (4.9-9.2) and 9.0 (6.9-11.6) at perineal/perianal, and 12.0 (9.4-15.1) and 16.8 (13.7-20.2) at anal sites, respectively. Cumulative IP incidence over 36 months (excluding anal canal; any 9vHPV type) was higher among MSM versus HM (24.1% vs 18.4%). CONCLUSIONS: A substantial proportion of unvaccinated men of catch-up vaccination age developed IP 9vHPV-related infections. Gender-neutral vaccination could decrease male HPV infection, contribute to herd protection, and reduce disease burden. Clinical Trials Registration. NCT00090285.

BackgroundCervical cancer oncogenesis starts with human papillomavirus (HPV) cell entry after binding to host cell surface receptors; however, the mechanism is not fully known. We examined polymorphisms in receptor genes hypothesized to be necessary for HPV cell entry and assessed their associations with clinical progression to precancer.MethodsAfrican American women (N = 1,728) from the MACS/WIHS Combined Cohort Study were included. Two case-control study designs were used-cases with histology-based precancer (CIN3+) and controls without; and cases with cytology-based precancer [high-grade squamous intraepithelial lesions (HSIL)] and controls without. SNPs in candidate genes (SDC1, SDC2, SDC3, SDC4, GPC1, GPC2, GPC3, GPC4, GPC5, GPC6, and ITGA6) were genotyped using an Illumina Omni2.5-quad beadchip. Logistic regression was used to assess the associations in all participants and by HPV genotypes, after adjusting for age, human immunodeficiency virus serostatus, CD4 T cells, and three principal components for ancestry.ResultsMinor alleles in SNPs rs77122854 (SDC3), rs73971695, rs79336862 (ITGA6), rs57528020, rs201337456, rs11987725 (SDC2), rs115880588, rs115738853, and rs9301825 (GPC5) were associated with increased odds of both CIN3+ and HSIL, whereas, rs35927186 (GPC5) was found to decrease the odds for both outcomes (P value ≤ 0.01). Among those infected with Alpha-9 HPV types, rs722377 (SDC3), rs16860468, rs2356798 (ITGA6), rs11987725 (SDC2), and rs3848051 (GPC5) were associated with increased odds of both precancer outcomes.ConclusionsPolymorphisms in genes that encode binding receptors for HPV cell entry may play a role in cervical precancer progression.ImpactOur findings are hypothesis generating and support further exploration of mechanisms of HPV entry genes that may help prevent progression to cervical precancer.

The aetiology of oral squamous cell carcinoma (SCC) in horses is unknown, but papillomavirus infection as well as chronic periodontal disease are suspected to play a pathogenic role. In humans, some oropharyngeal cancers develop in association with human papillomaviruses. Equus caballus papillomavirus 2 (EcPV2) is suspected to play a causal role in the development of equine genital SCC. Given that association, we hypothesized that EcPV2 is associated with the development of oral SCC in horses. We performed standard polymerase chain reaction (PCR) and in-situ hybridization (ISH) for EcPV2 on 31 formalin-fixed paraffin-embedded equine oral SCCs (lingual, gingival, palate) and 10 equine non-SCC oral samples. PCR for EcPV2 was positive in 10/31 (32%) oral SCCs while all non-SCC oral samples were negative. Intense hybridization signals for EcPV2 nucleic acid were detected by ISH within neoplastic epithelial cells in 8/31 (26%) oral SCCs but not in the adjacent normal oral mucosa. No hybridization signals were detected within control samples. This study provides additional support for a pathogenic association of EcPV2 in oral SCC in horses.

Persistent human papillomavirus (HPV) infection is responsible for the majority of oropharyngeal and cervical cancers in the USA. Currently, HPV curricula within medical and dental schools are not standardized. As such, we implemented a brief online educational intervention to increase medical and dental trainees' knowledge of the HPV vaccine and the association between HPV and cancer. The objectives of this study were to (1) assess medical and dental trainees' baseline knowledge regarding HPV and HPV vaccine, (2) determine the willingness to recommend the HPV vaccine to patients, and (3) evaluate the impact of an online intervention on HPV-related knowledge. Medical and dental trainees from two large academic centers in the USA were asked to fill out an online pre-intervention questionnaire, followed by a 10-min HPV educational intervention based on the Center of Disease Control and Prevention (CDC) resources, and then a post-intervention questionnaire. There were 75 participants (67.4% females; median age 18-30 years). When asked about HPV-related cancer types, the correct response increased from 28.4% (pre-intervention) to 51.9% (post-intervention; p

Parent reminders have produced modest improvements in human papillomavirus (HPV) vaccination among adolescents. However, little prior research has compared the effectiveness and feasibility of different HPV reminder types in resource-limited settings. We conducted a quasi-experimental study (2016-2017) to evaluate the effectiveness of three parent reminder types (mailed letters, robocalls, text messages) on next-dose HPV vaccine receipt among 12-year-olds in a large Federally Qualified Health Center in Los Angeles County. Six clinics were matched into three pairs: randomly assigning one clinic within each pair to intervention and control. Intervention clinics were randomly assigned to deliver one of the three parent reminder types. We calculated rates of next-dose vaccine receipt and assessed intervention effects using logistic regression models. We calculated the proportion of each type of reminder successfully delivered as a feasibility measure. The study sample comprised 877 12-year-olds due for an HPV vaccine dose (47% female, >85% Latino). At 4-month follow-up, 23% of intervention patients received an HPV vaccine dose compared to only 12% of control patients. Overall, receipt of any reminder increased rates of the next-needed HPV vaccine compared to usual care (p = 0.046). Significant improvements were observed for text reminders (p = 0.036) and boys (p = 0.006). Robocalls were the least feasible reminder type. Text message reminders are feasible and effective for promoting HPV vaccination. Future research is needed to assess the effectiveness and feasibility of reminders compared to other vaccine promotion strategies.

Literature suggests that deficiencies among dental professional students in both knowledge and awareness of human papillomavirus (HPV) and its association with oropharyngeal cancers (OPC), as well as its risk factors implicating the prevalence of HPV, may be due to the lack of HPV-related education during professional schooling. The aim of this study was to assess the effectiveness of an online learning tool to educate dental and dental hygiene students about HPV and its association with OPC, rapidly evolving disease patterns, and dental professionals' role in HPV-associated OPC prevention efforts. A three-section online learning module was developed to improve dental professionals' comfort levels with, and knowledge of, HPV. The participants were recruited to participate in surveys before and after the intervention. Descriptive statistics and chi-square analysis were computed to study the effectiveness of the modules in improving the knowledge of students about this topic. Pre-intervention survey participants totaled 142, and 107 participants answered the post-intervention survey. The majority of the study participants had some baseline understanding of HPV prior to accessing the modules. After reviewing the modules, there was a statistically significant increase in the proportion of respondents who identified OPC (p = 0.01), vaginal cancer (0.02), vulvar cancer (0.04), and penile cancer (0.01) as associated with HPV. A gap in the understanding of HPV vaccine-eligible groups was noted in almost half of the participants; while most participants could correctly identify that boys and girls aged 9-12 years were eligible to get the vaccine, the gap in knowledge in this regard was related to "25-year-old with an abnormal pap result." Due to the evolving nature of this topic, there is a need to find new and effective methods of disseminating HPV-related information among the existing and future dental workforce.

BackgroundUnderstanding the natural history of anal high-risk human papillomavirus (hrHPV) infection is key for designing anal cancer prevention programs but has not been systematically characterized.MethodsWe reanalyzed data from 34 studies including 16 164 individuals in 6 risk groups defined by human immunodeficiency virus (HIV) status, sex, and male sexuality: men who have sex with men (MSM) and people with HIV (MSMWH), HIV-negative MSM, women with HIV (WWH), HIV-negative women, men who have sex with women (MSW) with HIV (MSWWH), and HIV-negative MSW. We used Markov models to estimate incidence and clearance of 13 hrHPV types and their determinants.ResultsHuman papillomavirus (HPV) 16 had the highest incidence-clearance ratio of the hrHPV types. MSMWH had the highest hrHPV incidence (eg, 15.5% newly HPV-16 infected within 2 years), followed by HIV-negative MSM (7.5%), WWH (6.6%), HIV-negative women (2.9%), MSWWH (1.7%), and HIV-negative MSW (0.7%). Determinants of HPV-16 incidence included HIV status and number of sexual partners for MSM, women, and MSW, and anal sex behavior for MSM only. HPV-16 clearance was lower for people with HIV (PWH) and lower for prevalent than incident infection. Among MSM, increasing age was associated with lower clearance of prevalent, but not incident, HPV-16 infection.ConclusionsThis robust and unifying analysis of anal hrHPV natural history is essential to designing and predicting the impact of HPV vaccination and HPV-based screening programs on anal cancer prevention, particularly in MSM and PWH. Importantly, it demonstrates the higher carcinogenic potential of longstanding anal prevalent hrHPV infection than more recent incident infection.

We advise that only clinically validated HPV assays which have fulfilled internationally accepted performance criteria be used for primary cervical screening. Further, assays should be demonstrated to be fit for purpose in the laboratory in which they will ultimately be performed, and quality materials manuals and frameworks will be helpful in this endeavor. Importantly, there is a fundamental shortage of well validated, low-cost, low complexity HPV tests that have demonstrated utility in a near-patient setting; representing a significant challenge and focus for future development in order to reach the WHOs goal of eliminating cervical cancer.

BackgroundAge-specific data on anal, and corresponding cervical, human papillomavirus (HPV) infection are needed to inform female anal cancer prevention.MethodsWe centrally reanalyzed individual-level data from 26 studies reporting HPV prevalence in paired anal and cervical samples by human immunodeficiency virus (HIV) status and age. For women with HIV (WWH) with anal high-grade squamous intraepithelial lesions or worse (HSIL+), we also investigated concurrent cervical cytopathology.ResultsIn HIV-negative women, HPV16 prevalence decreased significantly with age, both at anus (4.3% at 15-24 years to 1.0% at ≥55 years; ptrend = 0.0026) and cervix (7.4% to 1.7%; ptrend < 0.0001). In WWH, HPV16 prevalence decreased with age at cervix (18.3% to 7.2%; ptrend = 0.0035) but not anus (11.5% to 13.9%; ptrend = 0.5412). Given anal HPV16 positivity, concurrent cervical HPV16 positivity also decreased with age, both in HIV-negative women (ptrend = 0.0005) and WWH (ptrend = 0.0166). Among 48 WWH with HPV16-positive anal HSIL+, 27 (56%) were cervical high-risk HPV-positive, including 8 with cervical HPV16, and 5 were cervical HSIL+.ConclusionsAge-specific shifts in HPV16 prevalence from cervix to anus suggest that HPV infections in the anus persist longer, or occur later in life, than in the cervix, particularly in WWH. This is an important consideration when assessing the utility of cervical screening results to stratify anal cancer risk.

PurposeThe proportion of head and neck cancers (HNCs) with human papillomavirus (HPV) positivity in sub-Saharan Africa (SSA) is poorly characterized. Characterizing this has implications in staging, prognosis, resource allocation, and vaccination policies. This study aims to determine the proportion of HPV-associated HNC in SSA.Materials and methodsThis systematic review included searches from PubMed, EMBASE, Web of Science, African Index Medicus, Google Scholar, and African Journals Online. All English publications reporting the proportion of HNC specimens from SSA patients who tested positive for HPV and/or p16 were included. Study quality was assessed using the National Institutes of Health Quality Assessment Tool for Case Series Studies.ResultsIn this systematic review of 31 studies and 3,850 patients, the overall p16 positivity was 13.6% (41 of 1,037 patients tested) with the highest proportion among oropharyngeal cancers (20.3%, 78 of 384 patients) and the overall HPV polymerase chain reaction positivity was 15.3% (542 of 3,548 samples tested) with the highest proportion among nasopharyngeal cancers (16.5%, 23 of 139 patients). Among the 369 HPV strains detected, the most common genotypes were HPV 16 (226 patients, 59.2%) and HPV 18 (78, 20.4%).ConclusionHPV was found to be associated with a significant proportion of HNC in SSA. The genotypes reported suggest that the nine-valent vaccine and gender-neutral vaccination policies should be considered. Given that these studies may not accurately capture prevalence nor causation of HPV in HNC subsites, additional research is needed to provide a more thorough epidemiologic understanding of HPV-associated HNC in SSA, including risk factors and clinical outcomes.

High rates of new cervical cancer cases and deaths occur in low- and middle-income countries yearly, and one reason was found related to limitation of regular cervical cancer screening in local and low-resource settings. HPV has over 150 types, yet certain 14-20 high-risk and 13-14 low-risk types are common, and, thus, most conventional HPV nucleic acid assays, for examples, Cobas 4800 HPV test (Roche Diagnostics, New Jersey, USA) and REBA HPV-ID (Molecules and Diagnostics, Wonju, Republic of Korea) were developed to cover these types. We thereby utilized bioinformatics combined with recent isothermal amplification technique at 35-42 °C to firstly describe multiplex recombinase polymerase amplification assay that is specific to these common 20 high-risk and 14 low-risk types, and also L1 and E6/E7 genes that target different stages of cervical cancer development. Multiplex primer concentrations and reaction incubation conditions were optimized to allow simultaneous two gene detections at limit of detection of 1000 copies (equivalent to 2.01 fg) for L1 and 100 copies (0.0125 fg) for E6/E7, respectively. The assay was validated against urogenital and other pathogens, normal flora, and human control. In 130 real clinical sample tests, the assay demonstrated 100% specificity, 78% diagnostic accuracy, and 75% sensitivity compared with REBA HPV-ID test, and is much more rapid (15-40 min), less expensive (~ 3-4 USD/reaction) and does not require instrumentation (35-42 °C reaction condition so hand holding or tropical temperature is possible). Hence, the developed novel assay provides alternative screening tool for potential local screening. Furthermore, as this assay uses safe chemical reagents, it is safe for users.

BackgroundThere is significant interest in treatment de-escalation for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) patients given the generally favourable prognosis. However, 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to risk stratify HPV+ OPSCC patients.MethodsWe created an immune score (UWO3) associated with survival outcomes in six independent cohorts comprising 906 patients, including blinded retrospective and prospective external validations. Two aggressive radiation de-escalation cohorts were used to assess the ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 immune class and outcomes.FindingsA three-gene immune score classified patients into three immune classes (immune rich, mixed, or immune desert) and was strongly associated with disease-free survival in six datasets, including large retrospective and prospective datasets. Pooled analysis demonstrated that the immune rich group had superior disease-free survival compared to the immune desert (HR = 9.0, 95% CI: 3.2-25.5, P = 3.6 × 10-5) and mixed (HR = 6.4, 95% CI: 2.2-18.7, P = 0.006) groups after adjusting for age, sex, smoking status, and AJCC8 clinical stage. Finally, UWO3 was able to identify patients from two small treatment de-escalation cohorts who remain disease-free after aggressive de-escalation to 30 Gy radiation.InterpretationWith additional prospective validation, the UWO3 score could enable biomarker-driven clinical decision-making for patients with HPV+ OPSCC based on robust outcome prediction across six independent cohorts. Prospective de-escalation and intensification clinical trials are currently being planned.FundingCIHR, European Union, and the NIH.

IntroductionDespite the increased risk of cervical cancer among HIV-positive women, many HIV-care programs do not offer integrated cervical cancer screening. Incorporating self-collected Human Papillomavirus (HPV) testing into HIV programs is a potential strategy to identify women at higher risk for cervical cancer while leveraging the staffing, infrastructure and referral systems for existing services. Community-based HIV and HPV testing has been effective and efficient when offered in single-disease settings.MethodsThis cross-sectional study was conducted within a community outreach and multi-disease screening campaigns organized by the Family AIDS Care and Education Services in Kisumu County, Kenya. In addition to HIV testing, the campaigns provided screening for TB, malaria, hypertension, diabetes, and referrals for voluntary medical male circumcision. After these services, women aged 25-65 were offered self-collected HPV testing. Rates and predictors of cervical cancer screening uptake and of HPV positivity were analyzed using tabular analysis and Fisher's Exact Test. Logistic regression was performed to explore multivariate associations with screening uptake.ResultsAmong the 2016 women of screening age who attended the outreach campaigns, 749 women (35.6%) were screened, and 134 women (18.7%) were HPV-positive. In bivariate analysis, women who had no children (p

Head and neck squamous cell carcinoma (HNSCC) tumor phenotypes and clinical outcomes are significantly influenced by etiological agents, such as HPV infection, smoking, and alcohol consumption. Accordingly, the intratumor microbiome has been increasingly implicated in cancer progression and metastasis. However, few studies characterize the intratumor microbial landscape of HNSCC with respect to these etiological agents. In this study, we aimed to investigate the bacterial and fungal landscape of HNSCC in association with HPV infection, smoking, and alcohol consumption. RNA-sequencing data were extracted from The Cancer Genome Atlas (TCGA) regarding 449 tissue samples and 44 normal samples. Pathoscope 2.0 was used to extract the microbial reads. Microbe abundance was compared to clinical variables, oncogenic signatures, and immune-associated pathways. Our results demonstrated that a similar number of dysregulated microbes was overabundant in smokers and nonsmokers, while heavy drinkers were characterized by an underabundance of dysregulated microbes. Conversely, the majority of dysregulated microbes were overabundant in HPV+ tumor samples when compared to HPV- tumor samples. Moreover, we observed that many dysregulated microbes were associated with oncogenic and metastatic pathways, suggesting their roles in influencing carcinogenesis. These microbes provide insights regarding potential mechanisms for tumor pathogenesis and progression with respect to the three etiological agents.

Pacific Islander (PI) women experience disproportionately high rates of cervical cancer and mortality and have lower rates of Pap testing. Since up to 70% of cervical cancers could be prevented by being vaccinated for human papilloma virus (HPV), this cross-sectional study explored the predictors of HPV and vaccine awareness, receipt of the vaccine, and attitudes toward vaccinating children among adult PI women in southern California, who historically have low rates of HPV vaccination and high rates of cervical cancer that could be prevented with HPV vaccination. Participants (n=148) consist a subsample of Chamorro, Samoan, and Tongan women, ages 21 to 65 years, who were in a larger randomized community study to promote Pap testing. Overall, younger age and higher American acculturation were significantly associated with ever hearing about HPV and the vaccine. However, American acculturation was also associated with negative attitudes toward vaccinating their children for HPV. This paper provides preliminary insights into barriers and facilitators to HPV vaccination among PIs in the USA and also informs the development of educational programs to reduce cervical cancer incidence and mortality in this underserved population.

BACKGROUND: We investigated the impact of human papillomavirus (HPV) vaccination on the performance of cytology-based and HPV-based screening for detection of cervical precancer among women vaccinated as young adults and reaching screening age. METHODS: A total of 4632 women aged 25-36 years from the Costa Rica HPV Vaccine Trial were included (2418 HPV-vaccinated as young adults and 2214 unvaccinated). We assessed the performance of cytology- and HPV-based cervical screening modalities in vaccinated and unvaccinated women to detect high-grade cervical precancers diagnosed over 4 years and the absolute risk of cumulative cervical precancers by screening results at entry. RESULTS: We detected 95 cervical intraepithelial neoplasia grade 3 or worse (52 in unvaccinated and 43 in vaccinated women). HPV16/18/31/33/45 was predominant (69%) among unvaccinated participants, and HPV35/52/58/39/51/56/59/66/68 predominated (65%) among vaccinated participants. Sensitivity and specificity of cervical screening approaches were comparable between women vaccinated as young adults and unvaccinated women. Colposcopy referral rates were lower in the vaccinated group for HPV-based screening modalities, but the positive predictive value was comparable between the 2 groups. CONCLUSIONS: Among women approaching screening ages, vaccinated as young adults, and with a history of intensive screening, the expected reduction in the positive predictive value of HPV testing, associated with dropping prevalence of HPV-associated lesions, was not observed. This is likely due to the presence of high-grade lesions associated with nonvaccine HPV types, which may be less likely to progress to cancer.

ObjectiveTo assess concordance and acceptability of a modified menstrual pad compared with a clinician-collected high-risk human papillomavirus (HPV) sample.MethodsThis was a prospective observational study. Women presenting for either cervical cancer screening or with a history of high-risk HPV positivity were eligible. Three samples were requested from participants: 1) clinician-collected cervical specimens; 2) self-collected vaginal swabs; and 3) a modified menstrual pad, which was taken home for use during the next menstruation. All samples were processed using the Cobas HPV test. Menstrual pad dried blood spots were eluted, then similarly processed.ResultsOf 153 women enrolled in the study, 106 provided menstrual pad samples and clinician-collected cervical specimens for high-risk HPV analysis. For samples in which the interval between the clinician-collected specimen and the menstrual pad sample was less than 2 months, the concordance was 94% (95% CI 83-98). For women who tested positive for high-risk HPV who presented for general screening and those with more than cervical intraepithelial neoplasia 2, menstrual pad and clinician-collected specimen agreement was 100% (95% CI 32.5-100). Among participants, 22.9% expressed discomfort with the self-collected vaginal swabs and opted out of collection. Overall, 94.0% of participants preferred the menstrual pad over clinician-collected sampling. Twelve patients were found to be positive for HPV on the menstrual pad sample but negative on the clinician-collected specimen.ConclusionAmong women who tested positive for HPV, the menstrual pad showed highly concordant results compared with clinician-collected sampling. This collection approach shows promise for integration into cervical cancer prevention programs.

BACKGROUND: 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). METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: National Cancer Institute and National Institutes of Health Office of Research on Womens Health. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

BackgroundThe aim of this study was to determine individual-level, partner-level, and sexual networking factors associated with vaccine- and non-vaccine-type human papillomavirus (HPV) in young women, by vaccination status.MethodsSexually experienced women 13 to 26 years old (n = 784) completed a survey and were tested for 36 HPV genotypes. We determined factors associated with 4-valent vaccine-type HPV (HPV-6, HPV-11, HPV-16, HPV-18) and non-vaccine-type HPV among vaccinated and unvaccinated women, using univariable and multivariable logistic regression models.ResultsParticipants' mean age was 19.2 years, 77.7% had received ≥1 vaccine dose, and 7.7% were positive for vaccine-type HPV (HPV-6, HPV-11, HPV-16, and/or HPV-18). Factors associated with vaccine-type HPV in vaccinated women included gonorrhea history (adjusted odds ratio [AOR], 2.71), new female sex partner(s) (AOR, 4.79), age at vaccination (≥15 vs.

The incidence of oropharyngeal cancer (OPC) has been rising, especially among middle-aged men. While Human Papillomavirus (HPV) has been irrevocably implicated in the pathogenesis of oropharyngeal cancer (OPC), the current HPV vaccination uptake rate remains low in the US. The aim of our study was to evaluate the impact of increased HPV vaccination coverage on HPV-associated OPC incidence and costs. A decision analytic model was constructed for hypothetical cohorts of 9-year-old boys and girls. Two strategies were compared: 1) Maintaining the current vaccination uptake rates; 2) Increasing HPV vaccination uptake rates to the Healthy People 2030 target (80%) for both sexes. Increasing HPV vaccination coverage rates to 80% would be expected to prevent 5,339 OPC cases at a cost of $0.57 billion USD. Increased HPV vaccination coverage would result in 7,430 quality-adjusted life year (QALY) gains in the overall population, and it is estimated to be cost-effective for males with an incremental cost-effectiveness ratio of $86,940 per QALY gained under certain conditions. Expanding HPV vaccination rates would likely provide a cost-effective way to reduce the OPC incidence, particularly among males.

PurposeCurrent cervical cancer screening guidelines recommend 3-year screening intervals, in contrast to the previous recommendation of annual screening, to prevent over screening and overtreatment. We evaluated the impact of viewing a tablet-based educational tool prior to seeing a clinician on young women's knowledge and understanding of cervical cancer screening, HPV vaccination follow-up of abnormal pap smears, and comfort in communicating with their providers.MethodsThis cross-sectional study was part of a cluster-randomized study of fourteen primary care clinics from January 2015 to December 2016. We developed the cervical cancer education tool in English and Spanish using a community-based approach that included formative work and cognitive interviewing. Clinics were randomized to use the intervention (tablet-based patient education tool) or to participate as a control group. We administered surveys to a convenience sample of 229 English- or Spanish-speaking women aged 19 to 35 years in these clinics. We used descriptive analyses and logistic regression models with cluster-robust standard errors to compare differences among the two groups.ResultsCompared to women seen in control clinics, women seen in intervention clinics demonstrated greater knowledge regarding human papilloma virus (HPV (p = 0.004) and understanding (p

PurposeWe aimed to identify human papillomavirus (HPV) and HPV vaccine-related knowledge, attitudes, and beliefs among women aged 27-45 years, who became eligible for HPV vaccination in 2018.MethodsEight virtual focus groups were conducted with 52 unvaccinated cisgender women aged 27-45 years living in Southern California's Inland Empire. Themes related to women's knowledge, attitudes, and beliefs were systematically identified using the rigorous and accelerated data reduction technique.ResultsThe sample was diverse: 62% of participants were Hispanic, Black, or Asian; 17% identified as lesbian or bisexual; and annual household incomes ranged from $0 to $260,000 (median, $60,500). Key qualitative themes centered on 1) questions about HPV and HPV vaccination, 2) knowledge and beliefs about HPV and HPV vaccination, 3) concerns about vaccine side effects and safety, 4) low perceived benefits of vaccination, and 5) social factors influencing vaccine acceptance. Few participants were aware adults aged 27-45 years are eligible for HPV vaccination or that vaccination can still be beneficial after sexual debut. Many believed HPV vaccination caused serious side effects among adolescents and questioned whether safety had been adequately studied for newly eligible adults. Although many participants associated HPV vaccination with social stigma, some emphasized that vaccination was a way to exercise control over their health and prevent illness, given they could not always control the actions of their sexual contacts.ConclusionsFindings provide insight into knowledge, attitudes, and beliefs about HPV and HPV vaccination among women aged 27-45 years, which may be useful for informing interventions to promote shared clinical decision-making between patients and health providers.

BackgroundMultiple anal human papillomavirus (HPVs) may increase the risk of anal cancer among men who have sex with men (MSM) living with human immunodeficiency virus (HIV). The Jaccard Similarity Index (JSI) was explored as a measure of multiple HPV persistence.MethodsThe TRUST/RV368 cohort enrolled MSM living with and without HIV in Abuja and Lagos, Nigeria. Participants with anal swabs at baseline, 3- and 12-month visits were tested for high- and low-risk HPVs using a next-generation sequencing assay. Persistence of the same HPV genotypes over time was calculated using the JSI and categorized into high, medium, and low similarity tertiles. Factors associated with higher versus lower similarity were estimated with multivariable ordinal logistic regression and reported as adjusted odds ratios (aORs) and 95% confidence intervals (CIs).ResultsOf the 225 participants, median age was 25 years (interquartile range, 22-29 years), 62% were living with HIV, median HPVs was 3 (interquartile range, 2-5), and HPV6 (28%), HPV16 (26%), HPV11 (23%), and HPV45 (20%) were most prevalent. Fifty-three percent of participants had highly similar HPVs at 3 months, and the similarity was associated with HIV (aOR, 3.11; 95% CI, 1.6-5.9) and recent receptive sex (aOR, 1.9; 95% CI, 1.0-3.5). By 12 months, 20% had highly similar HPVs, and it was associated with 12 years or longer since anal coital debut (aOR, 6.8; 95% CI, 3.1-5.2), self-reported genital warts (aOR, 3.1; 95% CI, 1.5-6.6), and 200 or less CD4 cells/mm3 (aOR, 13.3; 95% CI, 2.7-65.2) for those living with HIV.ConclusionsStudies evaluating the JSI as a predictor of high-grade intraepithelial lesions would further confirm its applicability as a quantitative measure of multiple HPV persistence.

ObjectiveTo review overall survival (OS), recurrence patterns, and prognostic factors of de novo sinonasal squamous cell carcinoma (DN-SCC).Data sourcesPubMed, Scopus, OVID Medline, and Cochrane databases from 2006 to December 23, 2020.Review methodsThe study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Articles were required to report either recurrence patterns or survival outcomes of adults with DN-SCC. Case reports, books, reviews, meta-analyses, and database studies were all excluded.ResultsForty-one studies reported on survival or recurrence outcomes. The aggregate 5-year OS was 54.5% (range, 18%-75%) from 35 studies (n = 1903). Patients undergoing open surgery were more likely to receive radiation therapy and present at an advanced stage compared to those receiving endoscopic surgery (all P < .001). Advanced T stage, presence of cervical nodal metastases, maxillary sinus primary site, and negative human papillomavirus (HPV) status were all correlated with significantly worse 5-year OS. Direct meta-analysis of 8 studies demonstrated patients with surgery were more likely to be alive at 5 years compared to those who did not receive surgery (odds ratio, 2.26; 95% CI, 1.48-3.47; P < .001). Recurrence was reported in 628 of 1471 patients from 26 studies (42.7%) with an aggregate 5-year locoregional control rate of 67.1% (range, 50.4%-93.3%).ConclusionThis systematic review and meta-analysis suggests that the 5-year OS rate for DN-SCC may approach 54.5% and recurrence rate approaches 42.7%. In addition, various tumor characteristics including advanced T stage, positive nodal status, maxillary sinus origin, and negative HPV status are all associated with decreased survival.

ObjectiveVaccine-preventable human papillomavirus (HPV) infection is common, especially in sub-Saharan Africa where HIV risk is also high. However, unlike other sexually transmitted infections (STIs), HPV's role in HIV acquisition is unclear. We evaluated this relationship using data from MTN-003, a clinical trial of HIV chemoprophylaxis among cisgender women in sub-Saharan Africa.DesignA case-control study.MethodsWe matched 138 women who acquired HIV (cases) to 412 HIV-negative controls. Cervicovaginal swabs collected within 6 months before HIV seroconversion were tested for HPV DNA. We estimated the associations between carcinogenic (high-risk) and low-risk HPV types and types targeted by HPV vaccines and HIV acquisition, using conditional logistic regression models adjusted for time-varying sexual behaviors and other STIs.ResultsMean age was 23 (±4) years. Any, high-risk and low-risk HPV was detected in 84, 74 and 66% of cases, and 65, 55 and 48% of controls. Infection with at least two HPV types was common in cases (67%) and controls (49%), as was infection with nonavalent vaccine-targeted types (60 and 42%). HIV acquisition increased with any [adjusted odds ratio (aOR) 2.5, 95% confidence interval (95% CI) 1.3-4.7], high-risk (aOR 2.6, 95% CI 1.5-4.6) and low-risk (aOR 1.8, 95% CI 1.1-2.9) HPV. Each additional type detected increased HIV risk by 20% (aOR 1.2, 95% CI 1.1-1.4). HIV acquisition was associated with HPV types targeted by the nonavalent (aOR 2.1, 95% CI 1.3-3.6) and quadrivalent vaccines (aOR 1.9, 95% CI 1.1-3.2).ConclusionHPV infection is associated with HIV acquisition in sub-Saharan African women. In addition to preventing HPV-associated cancers, increasing HPV vaccination coverage could potentially reduce HIV incidence.

Anal human papillomavirus (HPV) disproportionately affects men who have sex with men (MSM), particularly those who are older and those living with HIV. After experiencing difficulty recruiting older MSM into a study on aging and anal HPV, we conducted a sub-study to gain feedback on our recruitment methods and explore barriers and facilitators to participating in anal HPV research. We conducted focus groups with 30 men who have sex with men (MSM), both HIV-negative and MSM living with HIV, ages 50-75. We identified multiple themes that were barriers to participation including: (1) lack of knowledge about human papillomavirus and anal cancer; (2) research focused on anal cancer or discomfort with topics or procedures concerning the anus; (3) stigma including stigma associated with being men who have sex with men, being out, being a receptive partner, and being considered "older" in the gay community; and (4) confidentiality concerns including a fear of breach of confidentiality. Facilitators to participation were also identified; these motivational factors include altruism, wanting recommendations from a doctor, and desire to receive the best available care. Researchers seeking to enroll older men who have sex with men should be aware of these barriers and facilitators to participation in order to maximize recruitment.

BackgroundHuman Papillomavirus associated oropharyngeal cancers have been on the rise in the past three decades. Dentists are uniquely positioned to discuss vaccination programs with their patients. The goal of this project was to assess the readiness of dentists in the state of Indiana in being able to administer vaccines.MethodsAn 18-question online survey was sent to licensed dentists in the state of Indiana. Mantel-Haenszel chi-square tests, followed by multivariable analyses using ordinal logistic regression were conducted to assess providers' comfort levels and willingness to administer vaccines in both children and adults, by provider characteristics (practice type, location, and years in practice).ResultsA total of 569 completed surveys were included for data analyses. Most dentists (58%) responded positively when asked if they would consider offering vaccinations in their office, if allowed by state legislation. In general, dentists working in academic settings and federally qualified health centers were more agreeable to offering vaccination in their practice. The level of agreement with "Dentists should be allowed to administer HPV, Influenza, Hep A and COVID 19 vaccines" for both children and adults decreased with increased years of practice. More than half of the respondents (55%) agreed that dental providers were competent to administer vaccines and needed no further training.ConclusionThe study results suggest the willingness of dentists in the state of Indiana to offer vaccinations in their practices, if allowed by legislation.Practical implicationsDental providers can be a unique resource to add to workforce for improving vaccination efforts.

PurposeHuman papillomavirus (HPV) plays a major role in oncogenesis and circular extrachromosomal DNA (ecDNA) is found in many cancers. However, the relationship between HPV and circular ecDNA in human cancer is not understood.Experimental designForty-four primary tumor tissue samples were obtained from a cohort of patients with HPV-positive oropharynx squamous cell carcinoma (OPSCC). Twenty-eight additional HPV oropharyngeal cancer (HPVOPC) tumors from The Cancer Genome Atlas (TCGA) project were analyzed as a separate validation cohort. Genomic, transcriptomic, proteomic, computational, and functional analyses of HPVOPC were applied to these datasets.ResultsOur analysis revealed circular, oncogenic DNA in nearly all HPVOPC, with circular human and human-viral hybrid ecDNA present in over a third of HPVOPC and viral circular DNA in remaining tumors. Hybrid ecDNA highly express fusion transcripts from HPV promoters and HPV oncogenes linked to downstream human transcripts that drive oncogenic transformation and immune evasion, and splice multiple, diverse human acceptors to a canonical SA880 viral donor site. HPVOPC have high E6*I expression with specific viral oncogene expression pattern related to viral or hybrid ecDNA composition.ConclusionsNonchromosomal circular oncogenic DNA is a dominant feature of HPVOPC, revealing an unanticipated link between HPV and ecDNA that leverages the power of extrachromosomal inheritance to drive HPV and somatic oncogene expression.

Human papillomavirus (HPV) infections cause more than 35,900 cancers annually in the United States. Although cervical cancer is the most prevalent HPV-related malignancy in women, the virus is also responsible for a significant percentage of anal, vaginal, and vulvar cancers. A comprehensive approach to mitigating cervical cancer includes HPV vaccination (primary prevention), screening and treatment of precancerous lesions (secondary prevention), and diagnosis and treatment of invasive cancer (tertiary prevention). Although a successful strategy, there are opportunities to innovate and increase access that can also be adapted to address the unique clinical care gaps that exist with the other anogenital cancers. The Society for Womens Health Research held a series of interdisciplinary meetings and events, during which expert researchers, clinicians, patient advocates, and health care policy leaders evaluated the current landscape of HPV-related cancers and their effects on womens health. This report summarizes the discussions of this working group and areas it identified in which to address gaps in primary and secondary prevention approaches to improve access and health outcomes for women with HPV-related anogenital cancers.

Based on epidemiology studies, Chlamydia trachomatis has been proposed as a co-factor for human papillomavirus (HPV) in the development of cervical cancer. These two intracellular pathogens have been independently reported to induce the production of extra centrosomes, or centrosome amplification, which is a hallmark of cancer cells. We developed a cell culture model to systematically measure the individual and combined effects of Chlamydia and HPV on the centrosome in the same host cell. We found that C. trachomatis caused centrosome amplification in a greater proportion of cells than HPV and that the effects of the two pathogens on the centrosome were additive. Furthermore, centrosome amplification induced by Chlamydia, but not by HPV, strongly correlated with multinucleation and required progression through mitosis. Our results suggest that C. trachomatis and HPV induce centrosome amplification through different mechanisms, with the chlamydial effect being largely due to a failure in cytokinesis that also results in multinucleation. Our findings provide support for C. trachomatis as a co-factor for HPV in carcinogenesis and offer mechanistic insights into how two infectious agents may cooperate to promote cancer. TAKE AWAYS: • Chlamydia and HPV induce centrosome amplification in an additive manner. • Chlamydia-induced centrosome amplification is linked to host cell multinucleation. • Chlamydia-induced centrosome amplification requires cell cycle progression. • Chlamydia and HPV cause centrosome amplification through different mechanisms. • This study supports Chlamydia as a co-factor for HPV in carcinogenesis.

BackgroundMen who have sex with men (MSM) living with human immunodeficiency virus (HIV) are at increased risk of anal cancer. Anal cytology can be used to screen for dysplasia, with high-resolution anoscopy (HRA) required for diagnostic confirmation. We describe the impact lack of HRA had on management of abnormal screening results in Bogotá, Colombia.Material and methodsThis retrospective cohort study includes MSM with HIV who underwent anal cytology screening between January 2019February 2020, with colorectal surgery (CRS) follow-up through July 2020. Cytology results included atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), and high-grade squamous intraepithelial lesion (HSIL). Categorical and continuous variables were compared via Fisher's exact test and Wilcoxon rank-sum, respectively.ResultsOf 211 MSM screened, 68 had abnormal cytology: ASC-US (n = 23), LSIL (n = 41), HSIL (n = 4). Sixty (88.2%) were referred to CRS, and 51 (75.0%) attended ≥ 1 appointment. At initial assessment, 17 were referred for anal exam under anesthesia (EUA) for tissue resection, and 21 for rectosigmoidoscopy. Having perianal condyloma was associated with recommendation for EUA (P < 0.001), while cytology grade of dysplasia was not (P = 0.308). Eleven (16.2%) underwent EUA for condyloma resection.ConclusionsFew studies have described anal cancer screening in settings without HRA. We found lack of HRA limited management of abnormal cytology in Colombia. Those with condyloma underwent resection, but HRA remains necessary to localize and treat microscopic disease. Next steps include implementation of HRA in order to further develop the anal cancer screening program for MSM with HIV in Bogotá.

BackgroundMen 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.MethodsTwo 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.ResultsAmong 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.Conclusions18-26-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.

ObjectivesTumor HPV status is an established independent prognostic marker for oropharynx cancer (OPC). Recent studies have reported that tumor estrogen receptor alpha (ERα) positivity is also associated with prognosis independent of HPV. Little is known about the biologic and behavioral predictors of ERα positivity in head and neck squamous cell cancer (HNSCC). We therefore explored this in a multicenter prospective cohort study.Materials and methodsParticipants with HNSCC completed a survey and provided a blood sample. Tumor samples were tested for ERα using immunohistochemistry. ERα positivity was defined as ≥1%, standardized by the American Society of Clinical Oncology/College of American Pathologists in breast cancer. Characteristics were compared with χ2 and Fisher's exact test. Odds ratios (OR) were calculated using logistic regression.ResultsOf 318 patients with HNSCC, one third had ERα positive tumors (36.2%, n = 115). Odds of ERα expression were significantly increased in those with HPV-positive tumors (OR = 27.5, 95% confidence interval[CI] 12.1-62), smaller tumors (≤T2, OR = 3.6, 95% CI 1.9-7.1), male sex (OR = 2.0, 95% CI 1.1-3.6), overweight/obesity (BMI ≥ 25, OR = 1.9, 95% CI 1.1-3.3), and those married/living with a partner (OR = 1.7, 95% CI 1.0-3.0). In a multivariate model, HPV-positivity (aOR = 27.5, 95% CI 11.4-66) and small tumor size (≤T2, aOR = 2.2, 95% CI 1.0-4.8) remained independently associated with ERα status. When restricted to OPC (n = 180), tumor HPV status (aOR = 17.1, 95% CI 2.1-137) and small tumor size (≤T2, aOR = 4.0 95% CI 1.4-11.3) remained independently associated with ERα expression.ConclusionTumor HPV status and small tumor size are independently associated with ERα expression in HNSCC.

Overexpression of p16 is closely related to human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (SCC) and pertains a prognostic relevance. Programmed cell death 1-ligand 1 (PD-L1) is another important marker, as anti-PD-L1 immunotherapy is available. Retrospective analysis of 57 cases of the SCC involving oropharynx (27 cases), hypopharynx (5 cases), larynx (11 cases), and oral cavity (14 cases) was performed. Each case was scrutinized for the basaloid morphology, p16, and PD-L1 expression. Basaloid morphology was identified in 47% of total cases. The majority of basaloid SCC variants were located in the oropharynx (89%). High expression of p16 was mostly observed in the oropharynx. High PD-L1 expression was seen predominantly in oropharyngeal and hypopharyngeal locations. Further studies in a larger cohort are necessary to correlate PD-L1 and p16 expression with survival.

BackgroundFactors that lead human papillomavirus (HPV) infections to persist and progress to cancer are not fully understood. We evaluated co-factors for acquisition, persistence, and progression of non-HPV-16/18 infections among HPV-vaccinated women.MethodsWe analyzed 2153 women aged 18-25 years randomized to the HPV-vaccine arm of the Costa Rica HPV Vaccine Trial. Women were HPV DNA negative for all types at baseline and followed for approximately 11 years. Generalized estimating equation methods were used to account for correlated observations. Time-dependent factors evaluated were age, sexual behavior, marital status, hormonally related factors, number of full-term pregnancies (FTPs), smoking behavior, and baseline body mass index.ResultsA total of 1777 incident oncogenic non-HPV-16/18 infections were detected in 12 292 visits (average, 0.14 infections/visit). Age and sexual behavior-related variables were associated with oncogenic non-HPV-16/18 acquisition. Twenty-six percent of incident infections persisted for ≥1 year. None of the factors evaluated were statistically associated with persistence of oncogenic non-HPV-16/18 infections. Risk of progression to Cervical Intraepithelial Neoplasia grade 2 or worst (CIN2+) increased with increasing age (P for trend = .001), injectable contraceptive use (relative risk, 2.61 [95% confidence interval, 1.19-5.73] ever vs never), and increasing FTPs (P for trend = .034).ConclusionsIn a cohort of HPV-16/18-vaccinated women, age and sexual behavior variables are associated with acquisition of oncogenic non-HPV-16/18 infections; no notable factors are associated with persistence of acquired infections; and age, parity, and hormonally related exposures are associated with progression to CIN2+.

BackgroundWomen 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.MethodsTwo 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.ResultsThe 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.ConclusionsXpert 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.

BackgroundOutcomes of oropharyngeal squamous cell carcinoma (OPSCC) after development of distant metastases (DM) in the context of human papillomavirus (HPV) tumor status remain controversial in the literature.MethodsOPSCC patients with DM treated between June 2015 and March 2019 were included from a prospectively enrolled database. Characteristics of DM including sites, episodes, and timing of disease were analyzed in addition to survival after DM.ResultsSixty-nine HPV-positive and 18 HPV-negative OPSCC patients with DM were included. The 2-year survival after DM was higher for HPV-positive patients (54.0% vs. 11.3%, p

BackgroundOutcomes of oropharyngeal squamous cell carcinoma (OPSCC) after development of distant metastases (DM) in the context of human papillomavirus (HPV) tumor status remain controversial in the literature.MethodsOPSCC patients with DM treated between June 2015 and March 2019 were included from a prospectively enrolled database. Characteristics of DM including sites, episodes, and timing of disease were analyzed in addition to survival after DM.ResultsSixty-nine HPV-positive and 18 HPV-negative OPSCC patients with DM were included. The 2-year survival after DM was higher for HPV-positive patients (54.0% vs. 11.3%, p

ObjectivesThe Lower Anogenital Squamous Terminology (LAST) recommendations classify human papillomavirus-associated squamous lesions into low- and high-grade squamous intraepithelial lesions (LSILs/HSILs). Our study aimed to assess interobserver agreement among 6 experienced pathologists in assigning 40 anal lesions previously diagnosed as anal intraepithelial neoplasia 2 (AIN 2) to either HSIL or non-HSIL categories.MethodsAgreement based on photomicrographs of H&E alone or H&E plus p16 immunohistochemistry was calculated using κ coefficients.ResultsAgreement was fair based on H&E alone (κ = 0.42; 95% confidence interval [CI], 0.34-0.52). Adding p16 improved agreement to moderate (κ = 0.55; 95% CI, 0.54-0.62). On final diagnosis, 21 cases (53%) had unanimous diagnoses, and 19 (47%) were divided. When designating p16 results as positive or negative, agreement was excellent (κ = 0.92; 95% CI, 0.83-0.95). Among variables (staining location, extent, and intensity), staining of the basal/parabasal layers was a consistent feature in cases with consensus for positive results (20/20). Of the 67 H&E diagnoses with conflicting p16 results, participants modified 32 (48%), downgrading 23 HSILs and upgrading 9 non-HSILs.ConclusionsAlthough p16 increased interobserver agreement, disagreement remained considerable regarding intermediate lesions. p16 expression, particularly if negative, can reduce unwarranted HSIL diagnoses and unnecessary treatment.

BackgroundMen who have sex with men (MSM) are at high risk for HPV-related anal cancer. Little is known about the prevalence of low-grade squamous intraepithelial lesions (LSIL) and the anal cancer precursor, high-grade squamous intraepithelial lesions (HSIL), among young MSM living with HIV (MSMLWH). HPV vaccination is recommended in this group but its safety, immunogenicity and protection against vaccine-type HPV infection and associated LSIL/HSIL have not been studied.Methods260 MSMLWH 18-26 years-old were screened at 17 U.S. sites for a clinical trial of the quadrivalent (HPV6/11/16/18) HPV (qHPV) vaccine. Those without HSIL 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.ResultsAmong 260 MSMLWH screened, the most common reason for exclusion was detection of HSIL, in 88/260 (34%). 144 MSMLWH were enrolled. 47% of enrollees were previously exposed to HPV 16. No incident qHPV type-associated anal LSIL/HSIL was detected among men naïve to that type, compared with 11.1, 2.2, 4.5, and 2.8 cases/100 person-years for HPV 6/11/16/18-associated LSIL/HSIL, respectively, among those previously exposed to that type. qHPV was immunogenic and safe with no vaccine-associated serious adverse events.Conclusions18-26 year-old MSMLWH naïve to qHPV vaccine types were protected against incident qHPV type-associated LSIL/HSIL. Given their high prevalence of HSIL there is an urgent need to vaccinate young MSMLWH prior to exposure to vaccine HPV types, before initiating sexual activity, and to perform catch-up vaccination.

BackgroundPrimary human papillomavirus (HPV) screening (PHS) utilizes oncogenic human papillomavirus (oncHPV) testing as the initial cervical cancer screening method and typically, if positive, additional reflex-triage (eg, HPV16/18-genotyping, Pap testing). While US guidelines support PHS usage in the general population, PHS has been little studied in women living with HIV (WLWH).MethodsWe enrolled n = 865 WLWH (323 from the Women's Interagency HIV Study [WIHS] and 542 from WIHS-affiliated colposcopy clinics). All participants underwent Pap and oncHPV testing, including HPV16/18-genotyping. WIHS WLWH who tested oncHPV[+] or had cytologic atypical squamous cells of undetermined significance or worse (ASC-US+) underwent colposcopy, as did a random 21% of WLWH who were oncHPV[-]/Pap[-] (controls). Most participants additionally underwent p16/Ki-67 immunocytochemistry.ResultsMean age was 46 years, median CD4 was 592 cells/µL, 95% used antiretroviral therapy. Seventy WLWH had histologically-determined cervical intraepithelial neoplasia grade 2 or greater (CIN-2+), of which 33 were defined as precancer (ie, [i] CIN-3+ or [ii] CIN-2 if concurrent with cytologic high grade squamous intraepithelial lesions [HSILs]). PHS had 87% sensitivity (Se) for precancer, 9% positive predictive value (PPV), and a 35% colposcopy referral rate (Colpo). "PHS with reflex HPV16/18-genotyping and Pap testing" had 84% Se, 16% PPV, 30% Colpo. PHS with only HPV16/18-genotyping had 24% Colpo. "Concurrent oncHPV and Pap Testing" (Co-Testing) had 91% Se, 12% PPV, 40% Colpo. p16/Ki-67 immunochemistry had the highest PPV, 20%, but 13% specimen inadequacy.ConclusionsPHS with reflex HPV16/18-genotyping had fewer unnecessary colposcopies and (if confirmed) could be a potential alternative to Co-Testing in WLWH.

PurposeThis study aimed to determine individual- and partner-level factors associated with human papillomavirus (HPV) infection in vaccinated and unvaccinated men.MethodsA total of 747 men, aged 13-26 years, completed a survey of sexual behaviors and were tested for genital and perianal/anal HPV (36 types). Sexual network variables included recent and lifetime concurrency (being in more than one sexual relationship at the same time) and recent sex partner discordance (by race, ethnicity, age, and number of sexual partners). We determined individual-level and sexual network variables associated with ≥1 HPV type and HPV16/18, stratified by vaccination status, using separate multivariable logistic regression models.ResultsParticipants' mean age was 21.2 years; 64% were positive for ≥1 HPV type and 21% for HPV16/18. Factors associated with ≥1 HPV type in unvaccinated men included recruitment site and lifetime concurrency. Factors associated with ≥1 HPV type among vaccinated men included recruitment site, Chlamydia history, main male partner, number of lifetime female partners, and no condom use with female partner. Factors associated with HPV16/18 in unvaccinated men included race and partner concurrency. Factors associated with HPV16/18 in vaccinated men included ethnicity, main male partner, and recent concurrency.ConclusionsSexual network variables associated with HPV infection were different based on vaccination status and HPV type, suggesting risk factors for HPV infection may change as the proportion of vaccinated men increases. In addition, participant report of concurrency and not knowing whether one had practiced concurrency were consistent risk factors; clinicians should consider including concurrency in the sexual history to determine the risk of HPV.

PurposeReducing radiation treatment dose could improve the quality of life (QOL) of patients with good-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). Whether reduced-dose radiation produces disease control and QOL equivalent to standard chemoradiation is not proven.Patients and methodsIn this randomized, phase II trial, patients with p16-positive, T1-T2 N1-N2b M0, or T3 N0-N2b M0 OPSCC (7th edition staging) with ≤ 10 pack-years of smoking received 60 Gy of intensity-modulated radiation therapy (IMRT) over 6 weeks with concurrent weekly cisplatin (C) or 60 Gy IMRT over 5 weeks. To be considered for a phase III study, an arm had to achieve a 2-year progression-free survival (PFS) rate superior to a historical control rate of 85% and a 1-year mean composite score ≥ 60 on the MD Anderson Dysphagia Inventory (MDADI).ResultsThree hundred six patients were randomly assigned and eligible. Two-year PFS for IMRT + C was 90.5% rejecting the null hypothesis of 2-year PFS ≤ 85% (P = .04). For IMRT, 2-year PFS was 87.6% (P = .23). One-year MDADI mean scores were 85.30 and 81.76 for IMRT + C and IMRT, respectively. Two-year overall survival rates were 96.7% for IMRT + C and 97.3% for IMRT. Acute adverse events (AEs) were defined as those occurring within 180 days from the end of treatment. There were more grade 3-4 acute AEs for IMRT + C (79.6% v 52.4%; P < .001). Rates of grade 3-4 late AEs were 21.3% and 18.1% (P = .56).ConclusionThe IMRT + C arm met both prespecified end points justifying advancement to a phase III study. Higher rates of grade ≥ 3 acute AEs were reported in the IMRT + C arm.

ObjectiveTo evaluate access to treatment after community-based HPV testing as testing within screen-and-treat programs has the potential to lower mortality from cervical cancer in low-resource settings.MethodsA prospective cohort study was conducted in western Kenya in 2018. Women aged 25-65 years underwent HPV self-testing. HPV-positive women were referred for cryotherapy. Participant data were obtained from questionnaires during screening and treatment. The proportion successfully accessing treatment and variables associated with successful treatment was determined.ResultsOf the 750 women included, 140 (18.6%) tested positive for HPV. Of them, 135 were notified of their results, of whom 77 (59.2%) sought treatment and 73 (52.1%) received cryotherapy. Women who received treatment had a shorter time from screening to result notification (median 92 days, interquartile range [IQR] 84-104) compared to those who did not (97 days, IQR 89-106; P=0.061). In adjusted analyses, women with a history of cervical cancer screening (odds ratio [OR] 11, 95% confidence interval [CI] 1.42-85.20) and those electing result notification through a home visit (OR 4, 95% CI 1.23-14.17) were significantly more likely to acquire treatment at follow-up.ConclusionLinkage to treatment after community-based HPV screening in this population was low, highlighting the need for strategies aimed at strengthening treatment linkage in similar settings.

Genetic alterations of CYLD lysine 63 deubiquitinase (CYLD), a tumor-suppressor gene encoding a deubiquitinase (DUB) enzyme, are associated with the formation of tumors in CYLD cutaneous syndrome. Genome sequencing efforts have revealed somatic CYLD alterations in multiple human cancers. Moreover, in cancers commonly associated with human papillomavirus (HPV) infection (e.g., head and neck squamous cell carcinoma), CYLD alterations are preferentially observed in the HPV-positive versus HPV-negative form of the disease. The CYLD enzyme cleaves K63-linked polyubiquitin from substrate proteins, resulting in the disassembly of key protein complexes and the inactivation of growth-promoting signaling pathways, including pathways mediated by NF-κB, Wnt/β-catenin, and c-Jun N-terminal kinases. Loss-of-function CYLD alterations lead to aberrant activation of these signaling pathways, promoting tumorigenesis and malignant transformation. This review summarizes the association and potential role of CYLD somatic mutations in HPV-positive cancers, with particular emphasis on the role of these alterations in tumorigenesis, invasion, and metastasis. Potential therapeutic strategies for patients whose tumors harbor CYLD alterations are also discussed. IMPLICATIONS: Alterations in CYLD gene are associated with HPV-associated cancers, contribute to NF-κB activation, and are implicated in invasion and metastasis.

Gay, bisexual, and other men who have sex with men (MSM) experience disproportionately high burdens of Human Papilloma Virus (HPV)-associated anal cancers. Recent focus has shifted to anorectal cancer prevention through high-resolution anoscopy (HRA); however, little is known about sexual minority men's perceptions, attitudes, or beliefs regarding HRA. We conducted 4 qualitative Focus Group Discussions (FGDs) (n = 15) with sexual minority men, focusing on their beliefs, attitudes, and perceptions of undergoing HRA. Participants discussed their experiences of HPV/HRA as influenced by both their gender and sexuality, including unawareness of HPV disease as a male health issue, challenges relating to female-oriented HPV/HRA language, conception of HPV/HRA as related to prostate health, and connecting their sexual behavior identification as "bottoms" to their need for HRA. As efforts to improve HRA knowledge, access, and uptake among sexual and gender minority communities increase, special attention should be paid to language and messaging choices around HRA.

Background & aimWomen with HIV/HPV coinfection and cervical lesions are at increased risk of developing HPV related anal cancer. Self-collection of anal swabs may facilitate HPV molecular testing in anal cancer screening, especially in high-risk groups, and yet it is not adequately studied. We evaluated level of agreement between self-collected anal swabs (SCAS) and clinician-collected anal swabs (CCAS) when used for HPV genotyping. We also described the anal HPV genotype distribution and HIV/HPV coinfection.MethodsWe performed a cross sectional study with participants from a visual-inspection-with-acetic-acid and cervicography (VIAC) clinic, in Harare, Zimbabwe. In a clinic setting, the women aged ≥18 years provided anal swabs in duplicate; first CCAS and then SCAS immediately after. HPV detection and genotyping were performed using next generation amplicon sequencing of a 450bp region of the HPV L1 gene. Level of agreement of HPV genotypes between CCAS and SCAS was calculated using the kappa statistic. McNemar tests were used to evaluate agreement in the proportion of genotypes detected by either method.ResultsThree-hundred women provided 600 samples for HPV genotyping. HPV genotypes were detected in 25% of SCAS and in 22% of CCAS. The most common genotypes with CCAS were HPV52, HPV62 and HPV70 and with SCAS were HPV62, HPV44, HPV52, HPV53 and HPV68. Total HPV genotypes detected in CCAS were more than those detected in SCAS, 32 versus 27. The agreement of HPV genotypes between the two methods was 0.55 in kappa value (k). The test of proportions using McNemar gave a Chi-square value of 0.75 (p = 0.39). Multiple HPV infections were detected in 28/75 and 29/67 women for CCAS and SCAS respectively.ConclusionsSCAS and CCAS anal swabs showed moderate agreement, with no statistically significant difference in the proportion of genotypes detected by either methods. Although the differences between the two methods were not statistically significant, CCAS detected more HPV genotypes than SCAS and more HPV infections were detected in SCAS than in CCAS. Our data suggest that self-collected anal swabs can be used as an alternative to clinician-collected anal swabs for HPV genotyping.