BACKGROUND:We assessed temporal trends in prevalent anal human papillomavirus (HPV) infection among men who have sex with men (MSM) without HIV who attended sexual health clinics in three U.S. cities during 2018-2024. METHODS:Residual anal specimens from MSM without HIV, aged 18-45 years, were tested for 28 HPV genotypes. Demographic information was obtained from clinic records. Trends in quadrivalent vaccine (4vHPV)-type prevalence and non-vaccine-type HPV prevalence were evaluated using Joinpoint regression, stratified by age group (18-26 and 27-45 years). Non-vaccine-type HPV prevalence was used as a measure of sexual exposure; these HPV types are not targeted by any available vaccine. Joinpoint regression fits a series of joined straight lines on a logarithmic scale to the trends in prevalence; trends were reported as annual percent change (APC). RESULTS:Among persons aged 18-26 years, 4vHPV-type prevalence declined from 23.7% in 2018-2019 to 13.4% in 2023-2024 (APC = -13.4%), while non-vaccine-type HPV prevalence had a slight but non-significant decline. Among persons aged 27-45 years, 4vHPV-type prevalence declined from 37.2% in 2018-2019 to 28.2% in 2023-2024 (APC = -5.6%), while non-vaccine-type HPV prevalence remained stable. CONCLUSIONS:Among MSM aged 18-26 and 27-45 years, there was a decline in 4vHPV-type prevalent anal infections during 2018-2024. There was little to no decline in non-vaccine-type HPV prevalence during the same time period, suggestive of unchanging sexual exposure to HPV. These data demonstrate the impact of HPV vaccine on anal HPV infections in MSM.Summary: During 2018-2024, vaccine-type anal HPV infection declined by 13.4% and 5.6% annually among 18-26-year-old and 27-45-year-old men who have sex with men, respectively.

Supplementary Figure S1 is a flowchart Flowchart showing participant enrollment, sample inclusion, and clinical outcomes.

BACKGROUND:We evaluated human papillomavirus (HPV) vaccine effectiveness (VE) against prevalent anal HPV among men who have sex with men (MSM) by age, age at vaccination, and age at vaccination relative to age at first sex. METHODS:Residual anal specimens from 1092 MSM aged 18 to 45 years attending a Seattle, Washington, sexual health clinic in 2018 to 2020 were tested for 28 HPV types. Demographic, clinical, sexual behavioral, and HPV vaccination data were extracted from clinic and electronic medical records. We calculated adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) for associations between vaccination (≥1 dose of any HPV vaccine) and quadrivalent HPV vaccine (4vHPV)-type infection, by age group (18-26, 27-35, 36-45 years), vaccination age (among age groups 18-26, 27-35 years), and vaccination age relative to first sex (among those 18-26 years). Analyses were adjusted for race and ethnicity, preexposure prophylaxis use for HIV prevention, and lifetime number of sex partners. Vaccine effectiveness was calculated as (1 - aPR) × 100. RESULTS:Among persons aged 18 to 26 years, 4vHPV-type HPV prevalence was lower among those vaccinated before first sex (aPR, 0.12 [95% CI, 0.02-0.87]; VE, 88%) or at <18 years of age (aPR, 0.22 [95% CI, 0.07-0.68]; VE, 78%) versus unvaccinated, but no VE was observed in those vaccinated at 18 to 26 years of age. Among persons aged 27 to 35 years, 4vHPV-type HPV prevalence was lower among those vaccinated at 18 to 26 years of age versus unvaccinated (aPR, 0.56 [95% CI, 0.36-0.87]; VE, 44%). No VE was observed in persons aged 27 to 35 or 36 to 45 years who were vaccinated at >26 years of age. CONCLUSIONS:Results highlight the importance of routine HPV vaccination in adolescence and support efforts to increase catch-up vaccination among MSM.

Background:Mailed human papillomavirus (HPV) self-sampling kits improve cervical cancer screening adherence. The HOME trial found information needs and anxiety among HPV-positive patients. We designed a STEP trial to test optimized intervention strategies with bolstered educational materials and a centralized nurse communicating positive results. Here, we evaluate the effect of the strategies by comparing interviews of HOME and STEP participants receiving HPV-positive results. Materials and Methods:STEP participants were interviewed during December 2021-March 2022, and asked about their kit reaction and nurse communication, and surveyed on attitudes toward the kit. Transcripts were analyzed in two phases: (1) Coders used iterative content analysis to organize codes into node reports and identify themes and (2) coders compared node reports between the HOME and STEP trials. Results:Sociodemographic of 46 HOME and 28 STEP participants were similar (White, older, had prior Pap). Participants from both trials appreciated the kit's convenience, although some questioned its accuracy compared to clinician-performed screening. While many STEP participants were surprised by the positive result, most felt reassured by the nurse and understood the recommended follow-up. STEP participants expressed fewer negative emotions. More STEP than HOME participants believed the HPV result was correct (86% vs. 59%) and trusted it (90% vs. 65%). Willingness to recommend the HPV kit to a friend and use it in the future was high in both the trials. Discussion:Qualitative comparison of HOME and STEP participants' reactions suggests STEP patients received the information needed to understand HPV-positive results and complete follow-up. Findings support a centralized nurse communicating results and building trust in this new screening technology.

BACKGROUND:Molecular biomarkers could enhance anal cancer screening accuracy in people living with human immunodeficiency virus. We assessed the performance of human papillomavirus (HPV) 16/18 E6 oncoprotein in detecting anal high-grade squamous intraepithelial lesions (HSIL) in men living with human immunodeficiency virus. METHODS:We analyzed clinical data from 125 clinic visits of 82 men living with human immunodeficiency virus who underwent high-resolution anoscopy in Seattle, Washington (2015-2016), including the presence and extent of HSIL. Anal brush specimens were tested for high-risk HPV DNA, with HPV-16/18-positive samples further tested for E6 oncoprotein. Sensitivity, specificity, positive predictive value, and negative predictive value of HPV-16/18 E6 oncoprotein for HSIL were calculated, along with prevalence ratios with 95% confidence intervals. RESULTS:Forty-eight (38.4%) samples were HPV-16/18 positive, including three E6 positive. Forty-nine (39.2%) samples had corresponding HSIL. Specificity and positive predictive value of HPV-16/18 E6 for HSIL was 100%, and the prevalence ratio was 7.33 (95% confidence interval, 2.44-22.07) for HPV-16/18 E6-positive versus high-risk HPV-negative samples. Sensitivity for HSIL, however, was only 6.1%, with a moderate negative predictive value (62.3%). Two of four persons with HSILs with >75% disease extent had corresponding HPV-16/18 E6-positive samples, whereas none of 30 persons with <25% extent did. CONCLUSIONS:The HPV-16/18 E6 oncoprotein has potential utility as a triage biomarker for identifying and prioritizing lesions at the highest risk for progression. IMPACT:People living with human immunodeficiency virus are at an increased risk of anal cancer and would benefit from improved screening methods. Further research may elucidate the role of HPV-16/18 E6 oncoprotein in anal cancer prevention, alone or combined with other biomarkers.

BACKGROUND:Men who have sex with men (MSM) with HIV are disproportionately affected by human papillomavirus (HPV) and related diseases. We assessed HPV vaccine effectiveness (VE) against anal HPV among MSM with HIV. METHODS:During 2018-2023, residual anal specimens from MSM with HIV, aged 18-45 years, attending sexual health clinics in three U.S. cities were collected and tested for HPV. Demographic and vaccination information were obtained from clinic records or immunization registries. Timing of vaccination relative to HIV acquisition was unknown. Log-binomial regression was used to calculate adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) for associations between vaccination (≥1 dose) and quadrivalent vaccine (4vHPV)-type infection, adjusting for city. Models were stratified by age group (18-26, 27-45 years). VE was calculated as (1-aPR) x 100. RESULTS:Among 224 persons aged 18-26 years, 54% were vaccinated. Compared with unvaccinated persons, 4vHPV-type prevalence was lower in those vaccinated at age <18 (aPR=0.31, 95% CI:0.14-0.72, VE=69%) and ≥2 years before specimen collection (aPR=0.54, 95% CI:0.31-0.92, VE=46%). Among 700 persons aged 27-45 years, 17% were vaccinated. Compared with unvaccinated persons, 4vHPV-type prevalence was lower in those vaccinated at ages 18-26 (aPR=0.63, 95% CI:0.45-0.89, VE=37%) and ≥2 years before specimen collection (aPR=0.63, 95% CI:0.46-0.86, VE=37%). CONCLUSIONS:While timing of vaccination relative to HIV acquisition was unknown, we found significant VE against prevalent HPV infection in adult MSM with HIV. Within each age group, VE was higher with younger age at vaccination.

Importance:Mailing human papillomavirus (HPV) self-sampling kits to underscreened individuals increases cervical cancer screening and can be cost-effective. However, cost-effectiveness has not been evaluated across other screening histories. Objective:To conduct an economic evaluation of mailed HPV self-sampling among members of a US health care system with adherent, overdue, or unknown screening histories. Design, Setting, and Participants:This economic evaluation was a cost-effectiveness analysis (CEA) and budget impact analysis (BIA) based on results of a randomized clinical trial (RCT) conducted between November 20, 2020, to July 29, 2022, in an integrated health care system in Washington State. Intervention delivery costs were calculated from Kaiser Permanente Washington and Medicare perspectives and used wellness-based or screening-only visit costs. Participants included female members aged 30 to 64 years identified through electronic medical records. Data were analyzed from August 1, 2022, to July 29, 2025. Intervention:Members were randomized by screening history. Adherent participants were assigned to 4 groups: usual care (UC), patient reminders, clinician electronic health record [HER] alerts), education (UC and mailed educational materials), direct mail (UC, education, and mailed self-sampling kit), or opt-in (UC, education, and mailed invitation to request kit). Overdue participants were assigned to 3 groups: UC, education, or direct mail. Participants with unknown adherence were assigned to UC, education, or opt-in. Main Outcome and Measures:Primary RCT outcome was screening completion 6 months postrandomization. CEA outcome was incremental cost-effectiveness ratio for screening completion. BIA outcome was annual program implementation cost over 4 years. Results:Analyses included 31 355 individuals (mean [SD] age, 45.9 [10.4] years). Among screening adherent members, direct mail dominated all other strategies (more effective and cost-saving). Among overdue members, direct mail was also more effective than UC and generated an additional completed screen at a cost ranging from -$19 (95% CI, -$21 to -$16) (cost saving) to $63 (95% CI, $39 to $87) depending on cost basis and visit type. Among unknown members, opt-in generally dominated UC (more effective and cost-saving). The BIA indicated that although the screening adherent subgroup had the largest year 1 program budget, its budget declined fastest and, by year 4, was lowest among the 3 subgroups. Conversely, the smallest annual budget decreases were among eligible individuals with unknown history. Conclusions and Relevance:In this economic analysis of a randomized clinical trial, directly mailing HPV kits to individuals who were screening adherent and overdue for screening was economically dominant over other strategies. Program costs declined rapidly over 4 years. Results support directly mailing HPV kits to eligible individuals as an effective, efficient, and affordable outreach strategy.

People living with HIV (PLWH) are at highest risk of anal cancer and will benefit from optimized screening for early disease detection. We compared host DNA methylation markers in high-grade squamous intraepithelial lesions (HSIL) versus samples negative for intraepithelial lesions (NILM) or low-grade intraepithelial lesions (LSIL) in PLWH. We recruited PLWH identifying as male aged ≥18 years undergoing high-resolution anoscopy (HRA) in Seattle, Washington, 2015-2016. Anal brush samples were collected for HPV detection, genotyping, and pyrosequencing methylation (host genes ASCL1, PAX1, FMN2, and ATP10A); clinical data were abstracted from medical records. We assessed associations between methylation and presence and extent of HSIL using generalized estimating equation logistic regression, adjusting for age, CD4 count and HIV viral load. Marker panels using HPV DNA and methylation were also evaluated to predict prevalent HSIL. We analyzed 125 samples from 85 participants (mean age 50.1; standard deviation 11.0 years). ASCL1 (adjusted odds ratio [aOR] per 1 unit increase mean percent methylation: 1.07, 95% CI: 1.01-1.13) and FMN2 (aOR per 1 unit increase mean percent methylation: 1.14, 95% CI: 1.08-1.20) methylation were significantly associated with HSIL versus NILM/LSIL. ASCL1 (aOR: 1.06, 95% CI: 1.01-1.11) and FMN2 (aOR: 1.13, 95% CI: 1.08-1.17) methylation were positively associated with increasing HSIL extent. A panel combining methylation (ASCL1 and FMN2) and HPV DNA (HPV16, HPV18, and HPV31) demonstrated best balance of sensitivity (78.2%) and specificity (73.9%) for HSIL detection compared with methylation or HPV alone. Increasing levels of DNA methylation of ASCL1 and FMN2 were positively associated with HSIL detection in PLWH. Host gene methylation testing shows promise for HSIL screening and triage.

Less than two-thirds of US adolescents are up-to-date with HPV vaccination. While mothers engaged in preventive care are more likely to seek preventive care for their children, current studies on associations between maternal cervical cancer screening (CCS) and adolescent HPV vaccination are needed. We assessed associations between maternal preventive service utilization and adolescent HPV vaccination using electronic health record data from a healthcare system in Washington State. We included adolescents (11–17 years) and their mothers with ≥ 1 primary care visit between 2018 and 2020. Outcomes were HPV vaccine initiation and completion. The primary exposure was maternal adherence to guideline-recommended CCS. Secondary exposures were maternal breast cancer screening adherence (for mothers ≥ 52 years) and ≥ 1 wellness visit ≤ 2 years. We used Generalized Estimating Equations to estimate prevalence ratios, and explore effect modification by adolescent sex, adolescent provider characteristics, and maternal language interpreter use. Of 4121 adolescents, 66

Background Reemergence of human herpesvirus 8 (HHV-8)-induced Kaposi sarcoma (KS) in people living with HIV (PLWH) despite antiretroviral therapy (ART) poses a clinical challenge because they already have favorable CD4 T-cell numbers and undetectable viral loads. We observed that clinical presentation in PLWH on ART resembled classic KS found in older HIV-uninfected patients and hypothesized that immunosenescence may thus play a role in occurrence of KS on ART. We compared viral and immune factors implicated in the development of KS in ART-treated PLWH (HIV KS) and HIV-uninfected classic KS patients (cKS), compared to controls without KS (HIV Control, cControls respectively).Methods Plasma, peripheral blood mononuclear cell, and skin tissues were obtained from 11 HIV KS and 11 cKS patients and 2 groups of age-matched controls.Results HIV KS participants were younger than cKS (aged 53 vs 75 years). HHV-8 genotypes did not differ between groups. Despite the younger age and a lower CD4/CD8 ratio, activated, exhausted, and senescent T-cell frequencies were similar between HIV KS and cKS. Anti-HHV-8 immunoglobulin G levels were higher and circulating HHV-8 DNA lower in HIV KS compared with cKS. Circulating platelet-derived growth factors AA-BB and granulocyte colony-stimulating factors were higher in HIV KS We observed similar levels of HHV-8 DNA and PD-1 expression in skin lesions from HIV KS and cKS patients.Conclusions Altogether, early immune senescence could be involved in the development of KS in ART-treated PLWH. Higher anti-HHV-8 immunoglobulin G levels could be linked with lower circulating viral load. Such insights should help developing therapeutical strategies to prevent development and treat KS in PLWH on ART.

Even with the prolific clinical use of next-generation cancer therapeutics, many tumors remain unresponsive or become refractory to therapy, creating a medical need. In cancer, DCs are indispensable for T cell activation, so there is a restriction on cytotoxic T cell immunity if DCs are not present in sufficient numbers in the tumor and draining lymph nodes to take up and present relevant cancer antigens. To address this bottleneck, we developed a therapeutic based on albumin fused with FMS-related tyrosine kinase 3 ligand (Alb-Flt3L) that demonstrated superior pharmacokinetic properties compared with Flt3L, including significantly longer half-life, accumulation in tumors and lymph nodes, and cross-presenting-DC expansion following a single injection. We demonstrated that Alb-Flt3L, in combination with standard-of-care chemotherapy and radiation therapy, serves as an in situ vaccination strategy capable of engendering polyclonal tumor neoantigen-specific immunity spontaneously. In addition, Alb-Flt3L-mediated tumor control synergized with immune checkpoint blockade delivered as anti-PD-L1. The mechanism of action of Alb-Flt3L treatment revealed a dependency on Batf3, type I IFNs, and plasmacytoid DCs. Finally, the ability of Alb-Flt3L to expand human DCs was explored in humanized mice. We observed significant expansion of human cross-presenting-DC subsets, supporting the notion that Alb-Flt3L could be used clinically to modulate human DC populations in future cancer therapeutic regimens.

Human papillomavirus (HPV) self-collect shows promise to increase cervical cancer screening rates in underscreened populations, such as Somali patients, but little is known about how to integrate such an approach in primary care. In this study, primary care providers and staff who provide primary care services to Somali women were asked for their views on integrating HPV self-collect into routine care to address cervical cancer screening disparities. Thirty primary care providers and staff participated in semi-structured interviews exploring their views on HPV self-collect and their anticipated needs or barriers to implementing this approach into the clinic generally and with specific patient populations, such as Somali women. A thematic analysis using the constructivist version of grounded theory was undertaken. Providers and staff anticipate positive patient reaction to the option of HPV self-collect, and were interested in using this approach both for Somali patients and for all patients in general. HPV self-collect was viewed as straightforward to integrate into existing clinic workflows. Providers largely lacked awareness of the evidence supporting primary HPV testing and HPV self-collect specifically, sharing concerns about effectiveness of self-collect and the lack of a physical exam. Providers felt clinic-wide staff education and patient education, along with strategies to address disparities, such as cultural and linguistic tailoring would be needed for successful implementation. Integrating HPV self-collect as an option in the cervical cancer screening process in a primary care clinical encounter offers considerable opportunity to address health disparities and may benefit all patients.

Background Somali American individuals have lower cervical cancer screening rates than the U.S. general population. Offering HPV self-sampling in primary care clinics could increase screening rates in Somali American individuals by addressing screening barriers. Methods The Isbaar Project is a Hybrid Type 2 effectiveness-implementation study of a patient-centered, culturally tailored HPV self-sampling intervention for Somali American individuals. Guided by the Consolidated Framework for Implementation Research and Social Cognitive Theory, we conducted focus groups with Somali American individuals, and interviews with clinicians and clinic staff to inform refinement and development of implementation strategies. HPV self-sampling was then implemented as a usual care screening option at 3 community-based primary care clinics in Minneapolis, Minnesota in February 2023. The primary objective is to assess the effect of implementing in-clinic HPV self-sampling on screening completion in Somali American individuals. The secondary objective is to assess the effect of implementing HPV self-sampling on screening completion in all patients. Using difference-in-difference methods, we will evaluate changes in screening rates one-year pre and post implementation and compare changes with control clinics followed over the same time period. Using RE-AIM, we will conduct a post-implementation mixed methods analysis of processes and strategies needed to successfully implement HPV self-sampling in primary care. Conclusions The study was designed to evaluate a real-world in-clinic HPV self-sampling intervention for Somali American individuals, generating data on both effectiveness and implementation applicable to other community-based clinics in the U.S. The objective of this report is to describe the rationale and design of the study.

ABSTRACT In the United States, adherence for cervical cancer screening decreased from 86% to 77% between 2005 and 2019. Over 50% of cervical cancers are diagnosed in individuals overdue for screening, and promoting access and adherence is essential. Unlike traditional Papanicolaou testing, human papillomavirus (HPV) screening can use self-collected samples, which have comparable sensitivity and specificity to clinician-collected samples. Self-collecting has been shown to increase screening adherence, possibly by circumventing important barriers such as scheduling clinic appointments and negativity about pelvic examinations. Despite this, most individuals in prior studies remained unscreened with low follow-up of HPV-positive results, and kit uptake among populations that are screening adherent or have unknown screening history is unknown. The STEP trial (self-testing options in the era for primary HPV screening for cervical cancer) was a parallel, single-blind, randomized clinical trial comparing cervical cancer screening completion across groups of individuals with due (screening-adherent), overdue, or unknown screening history. Participants were randomized to traditional care (patient reminders and clinician electronic health record [HER] alerts), education (usual care plus educational materials about screening), direct mail (traditional care plus educational materials plus a mailed HPV self-collection kit), or to opt in (traditional care plus educational materials plus the option to request a self-collection kit). Patients were identified using the Kaiser Permanente Washington HER and administrative claims. Eligible participants were females aged 30 to 64 years with current Kaiser Permanente Washington insurance and primary care, intact cervix, who were either due or overdue for screening. The primary study outcome was screening completion within 6 months after randomization, which could be done either in clinic or using the self-collection kit. Modified Poisson regression was used to estimate relative risk (RR) of screening completion for the direct-mail and opt-in groups, relative to the education group. A total of 32,771 participants were randomized between November 2020 and January 2022, of which 13,356 were due for screening, 8682 were overdue, and 10,733 had unknown screening history. Of those due for screening, the RR for screening completion was 1.30 (95% confidence interval [CI], 1.23–1.36; absolute difference, 14.1% [95% CI, 11.2%–16.9%]) for direct mail and 1.07 (95% CI, 1.02–1.12; absolute difference, 3.5% [95% CI, 1.2%–5.7%]) for the opt-in group compared with education. Of those overdue for screening, the RR for screening completion was 1.90 (95% CI, 1.68–2.16; absolute difference 16.9% [95% CI, 13.8%–20.0%]) for direct mail compared with education. Of those with unknown screening history, the RR for screening completion was 1.14 (95% CI, 1.03–1.25; absolute difference 2.2% [95% CI, 0.5%–3.9%]) for the opt-in group compared with education. The results of this randomized controlled trial showed that directly mailing HPV self-collection kits increased cervical cancer screening by over 14% compared with education alone. The effect was similar between participants that were due or overdue for screening, and an opt-in approach was found to minimally increase screening.

Background: Among men who have sex with men (MSM) and transgender women (TGW), the dynamics of human papillomavirus (HPV) infections at different anatomical sites are not well understood. Information on HPV concordance between anatomic sites can inform the extent of autoinoculation, and susceptibility of different anatomic areas to HPV infection. We described and assessed correlates of HPV concordance across anal, oral, and genital samples. Methods: We enrolled 1876 MSM and TGW aged 18 to 26 years in 3 US cities. Oral, genital, and anal samples were self-collected for type-specific HPV DNA testing (37 types). Demographics, sexual behaviors, and health history were self-reported. Kappa statistics based on percent positive agreement (kappa+) and generalized estimating equations were used to describe and identify correlates of HPV type-specific concordance between anatomic sample pairs. Results: Any HPV was detected in 69.9%, 48.6%, and 7.4% of anal, genital, and oral samples, respectively. Detection of any HPV (concurrence) was most common in anal-genital pairs (40.9%) and uncommon in oral-genital and oral-anal pairs (3.4% and 6.5% respectively). Type-specific concordance was poor across all sample pairs (kappa+ <0.20). Younger age and older age at first sex were positively associated with type-concordant anal-genital infections. Sexual behaviors were unassociated with concordance. Conclusions: Poor oral/anogenital concordance suggests the oral mucosa has different susceptibility to HPV infection, differential clearance and/or autoinoculation between oral and anogenital sites is unlikely. There was some observed concurrence and concordance between anal and genital sites, unassociated with sexual behavior, suggesting autoinoculation. Longitudinal studies are necessary to further elucidate mechanisms of multisite infections.