Dorothy Wiley

BackgroundIndependent of CD4 cell count, a low CD4/CD8 ratio in people with HIV (PWH) is associated with deleterious immune senescence, activation, and inflammation, which may contribute to carcinogenesis and excess cancer risk. We examined whether low CD4/CD8 ratios predicted cancer among PWH in the United States and Canada.MethodsWe examined all cancer-free PWH with 1 or more CD4/CD8 values from North American AIDS Cohort Collaboration on Research and Design observational cohorts with validated cancer diagnoses between 1998 and 2016. We evaluated the association between time-lagged CD4/CD8 ratio and risk of specific cancers in multivariable, time-updated Cox proportional hazard models using restricted cubic spines. Models were adjusted for age, sex, race and ethnicity, hepatitis C virus, and time-updated CD4 cell count, HIV RNA, and history of AIDS-defining illness.ResultsAmong 83 893 PWH, there were 5628 incident cancers, including lung cancer (n = 755), Kaposi sarcoma (n = 501), non-Hodgkin lymphoma (n = 497), and anal cancer (n = 439). The median age at cohort entry was 43 years. The overall median 6-month lagged CD4/CD8 ratio was 0.52 (interquartile range = 0.30-0.82). Compared with a 6-month lagged CD4/CD8 of 0.80, a CD4/CD8 of 0.30 was associated with increased risk of any incident cancer (adjusted hazard ratio = 1.24 [95% confidence interval = 1.14 to 1.35]). The CD4/CD8 ratio was also inversely associated with non-Hodgkin lymphoma, Kaposi sarcoma, lung cancer, anal cancer, and colorectal cancer in adjusted analyses (all 2-sided P < .05). Results were similar using 12-, 18-, and 24-month lagged CD4/CD8 values.ConclusionsA low CD4/CD8 ratio up to 24 months before cancer diagnosis was independently associated with increased cancer risk in PWH and may serve as a clinical biomarker. 

Data for in situ cervical carcinomas are not routinely collected by U.S. tumor registries. Some experts suggest that comparing preinvasive and invasive cervical cancers (ICC) rates may represent our best population-based appraisal of screening strategies. From 1991-1997, a total of 5,921 women diagnosed with in situ or ICC were reported to the Markey Cancer Registry in Lexington, Kentucky, a population-based registry. Maximum-likelihood Poisson regression analyses were used to estimate the incidence rate of in situ and ICC (per 100,000), summarized over age-and race-specific groups for each of seven years, 1991 to 1997. U.S. Census age and race data for 1990 were used to estimate denominators for two race groups: African American (AA) and all others (white). Incidence rates and rate ratios are reported. A total of 4,290 and 1,631 were diagnosed with in situ and ICC in the study period. While more than 80% of cases among women &amp;lt;30 years of age were diagnosed as in situ lesions, only about half of cases diagnosed among 50-54 year-olds were identified at a preinvasive stage. For women &amp;gt;65 years, only 42% (+4%) of tumors were diagnosed as in situ lesions. Specifically, among 20-39 year olds, AA were less likely than white women to be diagnosed with in situ carcinoma (p&amp;lt;0.05), while after age 60, they were more likely than whites to be similarly diagnosed (p&amp;lt;0.05). White women 20-49 years were 1.4-23.8 times more likely to be diagnosed with in situ carcinoma than ICC; however, AA ages 25-34 were 1.4-1.6 times more likely to show in situ disease. Whites &amp;gt;55 were less likely to be diagnosed with in situ disease than ICC. While year of diagnosis was significant in the analyses, relationships between age and diagnostic stage persisted across each of 7 years examined. These data suggest that Pap test most efficiently identifies treatable, high-grade precancerous lesions among women younger than 50 years. HPV infection prevalence varies by age, but not race, while ICC disproportionately affects women of color, especially as they age. Several factors may explain these findings. Screening may be performed less often overall or more inconsistently among older women and among AA. Also, if screening in the population decreases with advancing age, symptomatic older women with higher likelihood of malignancy will be over-represented in the data. Directly tailoring screening programs to recruit and retain non- and under-screened women and women with medical record evidence of poorly triaged Pap test abnormalities may improve detection of cervical cancers at a preinvasive stage, where there is a very high likelihood of survival. We believe that these findings are consistent with those of others, and together they suggest our best public health strategy may be to actively recruit middle-age and older women into cervical cancer screening programs who have undergone Pap test screening fewer than three times in a ten year period. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2807.

Background: Breast cancer trial enrollment, while slightly higher than some other histologies, still remains low, at less than 4%. Research suggests lack of clinical trial participation is due to poor patient and clinician commitment and interest. Increasing incentive for trial participation may enhance engagement of patients and healthcare providers leading to increased patient enrollment. One incentive would be to understand benefits of trial participation with regards to better survival and outcomes. The purpose of this study is to determine differences in survival, overall and breast cancer specific, and surgical management, for women who participate in early breast cancer randomized clinical trials (RCT) compared to the general breast cancer population who received similar standard therapy outside of a RCT. Methods: Patients included in this retrospective analysis were from one of three (3) international, randomize, adjuvant breast cancer trials (RCT-participants) and women with breast cancer from the general U.S. population, from Surveillance Epidemiology and End Results Program (SEER-13), the controls. Women diagnosed between 1997-2004 with invasive breast cancer, tumor (T) size 1-3, lymph node (LN) positive (LN1/2), hormone receptor positive or negative, HER2 positive or negative, treated with surgery, adjuvant radiation, and chemotherapy were included in the analysis. In this study, propensity score analysis (PSA) was done to provide weight to each data point for each variable in order to more closely represent similar populations. PSA, considered superior to a standard Cox multivariate analysis as it attempts to reduce the bias due to confounding or correlated predictive variables. Subsequently, the propensity score was applied to a Cox proportional hazards model to determine hazard ratios (HR), with a Wald 95% confidence interval (CI), of trial participation on survival. Similarly, PSA was done for surgical outcomes. A multivariate logistic regression was performed to calculate the odds ratios, with a Wald 95% CI, to determine if RCT participation compared to the SEER-13 control had an impact on surgical outcomes, mastectomy versus breast conserving surgery (BCS). Results: The total sample size was 9255 patients, 1795 RCT-participants and 7460 SEER-13 controls. After controlling for all other significant predictors of survival, RCT participation significantly reduced risk of breast cancer related death at 5-years by more than 25% and 18% at 10 years [HR: 0.75 (95% CI: 0.64-0.87); p=0.00020; and HR: 0.83 (95% CI: 0.74-0.93); p=0.00165, respectively]. Additionally, we demonstrated a significant reduction in risk of all-cause mortality for RCT-participants, at both 5-years and 10-years [HR: 0.83 (95% CI: 0.72--0.95); p=0.009; and HR: 0.79 (95% CI: 0.71-0.87); p&amp;lt;0.00001, respectively]. Additionally, RCT-participants were significantly less likely to undergo invasive surgical management (mastectomy) compared to SEER-13 controls [OR: 0.78 (95% CI: 0.66-0.92;) p=0.03]. Conclusion: RCT-participants have a reduced risk of death at 5 years and 10 years compared to the general breast cancer population. Additionally, RCT-participants are less likely to undergo mastectomy than the SEER-13 controls. Citation Format: Brennan MB, Wiley D, Wang D, Wang X, Fasching P. The effect of participation in RCT on outcomes in patients with early breast cancer compared to the general breast cancer population [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-15-01.

Background and Purpose: Human papillomavirus Type 16 (HPV16) infection is necessary but not alone a sufficient causal risk factor for cervical and other anogenital cancers and nearly 25% of head and neck malignancies (1, 2). HPV16 E7 is one of the important oncoproteins that promotes carcinogenesis. Most treatments for cervical precancers are ablative and few therapeutic drugs are available. Human α-Lactalbumin Made Lethal to Tumor Cells (HAMLET), a complex of Human α-Lactalbumin and oleic acid shows promise for treating skin papillomas by differentially inducing apoptosis in transformed cells without adverse effects on normal cells. Bovine α-Lactalbumin Made Lethal to Tumor Cells (BAMLET) has been shown to be biologically equivalent to HAMLET (3) and in vitro studies suggest BAMLET and HAMLET show similar cytotoxic effects in tumor cell lines (4). Further, in vitro studies suggest both a dose- and time-dependent response to BAMLET treatment (3–6). To determine the effect of BAMLET on tumor number, size and histological characteristics in vivo, we compared two groups of BAMLET-treated with normal saline (NS)-treated HPV16 E7 transgenic C57/BL6 mice (TG) and syngeneic mice receiving chemical carcinogen DMBA topically to induce skin tumor. Methods: For 56 TG and syngeneic mice, in six treatment groups, 100nmol/200μl DMBA was applied topically on the dorsal thoracic flank for up to 20 weeks. BAMLET, 0.7 mM, was applied daily for 7d before and either 11d (18d BAMLET) or up to 23 weeks (24w BAMLET) following DMBA initiation. As a comparison, NS was similarly applied to 10 TG and syngeneic mice for a total of 24 weeks. A series of bivariate zero-inflated repeated-measures Poisson (ZIP) models predicted the number of papillomas based on TG/syngeneic groupings, and treatment group. The fully adjusted model evaluated the effect of the TG, treatment group and duration, and time on study for predicting the number of tumors. Least-squares linear regression (LSLR) was used to estimate the effect of treatment on average tumor size at censoring or death, controlling for the effect of gender, among the transgenic mice. Results: On average, papillomas developed after 9 weeks of DMBA treatment. Analyses showed TG-mice developed more tumors than did syngeneic mice (p&amp;lt;0.0001), controlling for the effect of time on study (p&amp;lt;0.0001). In the fully adjusted analyses, the number of tumors was most affected by the TG (p&amp;lt;0.0001) and time on study (p&amp;lt;0.0001), but treatment showed no effect: 18d (p=0.9) and 24w (p=0.8) vs. normal saline (NS). Among transgenic mice, time on study was shorter than for syngeneic comparators and was a proxy indicator across treatment groups, confounding the ZIP analyses. Among transgenic mice, BAMLET treatment predicted average tumor size at censoring or death in the LSLR analysis. Specifically, among transgenic mice, the average tumor size was greatest for the 18d (μ=0.24 cm, p=0.003) and 24w BAMLET-treated (μ=0.20 cm, p=0.03) mice when compared to NS-treated controls (μ=0.12 cm). Discussion and Conclusion: These preliminary data suggest the effect of the transgene is strong on the number of tumors the result from DMBA treatment and on survival. This strong effect suggests we lack the power to detect an effect of BAMLET in transgenic mice. However, some data herein suggest BAMLET may increase average tumor size among HPV16-E7 transgenic mice. In light of positive findings in human clinical studies using the human analogue, HAMLET, understanding whether the effects of α-Lactalbumins and oleic acid complexes are modulated by HPV E6, E7, or E6/E7 oncogenes warrants further exploration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C31.

Background: We reported higher serum free testosterone (FT) and anal-HPV16/18 infection prevalence in MSM. Associations between serum-FT and -estradiol, anal-HPV16/18 infections, and Estrogen Receptor 1α (ESR1) and histological HSIL (hHSIL) are unclear. Methods: Three serial cross-sectional analyses were performed using data for 489 HIV-infected/HIV-uninfected adult males enrolled in the Multicenter AIDS Cohort Study. For 340, anal cytology residuals were evaluated for 37 HPVs (PCR). For 214 men, 336 HRA/biopsies were evaluated for hHSIL; among them, &amp;lt;3 biopsy specimens for 47% (102) were assessed for ESR1 using immunohistochemistry. Serum specimen collection preceded HPV and HRA/biopsy visits by 24(+9) months. Each specimen was tested for Sex Hormone Binding Globulin (radioimmunoassay), and total testosterone and estradiol (TE2) (Liquid chromatography/mass spectrometry); serum-FT (pg/mL) was estimated. HPVs were classified: HPV16/18+, other Group-1 and -2 high-risk HPVs+ (hrHPVs); low-risk HPVs+ (lrHPVs), and none. Biopsies were evaluated as hHSIL vs. &amp;lt;hHSIL. Formalin-fixed paraffin-embedded anal biopsy (~4μm) were prepared and stained using a standard ESR1 immunohistochemistry protocol and were scored for immunofluorescence (0-3+) and percent affected (0-100%) by two pathologists. Multivariable-adjusted GEE logistic regression models assessed relationships between loge-transformed FT, TE2 and ESR1 (%), and HPV16/18+ and hHSIL separately. Self-reported sociodemographic/behavioral covariates were included. Results: Adjusted estimates showed higher FT increased odds of HPV16/18-infection (OR=1.87 (1.2-2.92)), but odds were inversely associated with TE2 (OR=0.68(0.49-0.94)). White race and other Group-1-hrHPVs+ increased odds for HPV16/18 infection (OR=2.61(1.16-5.87) and (OR=1.65(1.11-2.46)), but neither HIV-infection/CD4+count, receptive anal intercourse partnerships; exogenous-testosterone use, nor smoking increased HPV16/18-infection odds. Serum-TE2 and hHSIL were inversely associated (OR=0.51(0.3-0.89)) Serum-FT was not associated with odds of hHSIL (OR=1.09(0.78-1.74)), but. men testing HPV16/18+ showed higher odds of hHSIL than hrHPV-negative men (OR=4.27(1.71-10.66)). Median IHC ER1α-expression intensity was lower among hHSIL affected men: 10% (hHSIL) vs. 40% (&amp;lt;hHSIL). The percent of immunofluorescence intensity (%) was inversely associated with odds of hHSIL (OR=0.96(0.93-0.99). Conclusions: Higher serum-FT increased odds of anal HPV16/18-infection but not hHSIL. Higher serum-TE2 was inversely associated with the odds of both HPV16/18+ and hHSIL, and ESR1 expression in tissue is lower in hHSIL- than &amp;lt;hHSIL-affected epithelium. More research evaluating sex hormones and ERα expression in stroma and epithelial cells of HPV-associated HSIL/&amp;lt;HSIL-affected tissue is needed. Citation Format: Dorothy J. Wiley. Serum testosterone and estradiol modify risk of anal HPV16/18 infections but only estradiol and Estrogen Receptor 1-alpha influences risk for histological high-grade squamous intraepithelial lesions (HSIL) [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr IA-15.

Introduction: Human papillomavirus (HPV) is an important risk factor for oropharyngeal cancer. Individuals with human immunodeficiency virus (HIV) have higher oral HPV prevalence but the risk factors for oral HPV infection are not well understood for either HIV-positive or HIV-negative individuals.Methods: This study was nested within the Multicenter AIDS Cohort Study (MACS; men) and Women Interagency HIV Study (WIHS; women) cohorts. Exfoliated oral epithelial cells were collected from 379 HIV-positive and 266 at-risk HIV-negative individuals using a rinse and gargle with Scope mouthwash. Samples were tested for 36 types of HPV DNA using PGMY09/11 consensus primers and reverse line blot hybridization. Risk factors for oral HPV infection were explored using logistic regression with generalized estimating equations in this cross-sectional analysis.Results: Prevalent oral HPV infection was common (34%), including HPV16 infection in 5.7% of participants. HIV-positive individuals had increased odds of prevalent oral HPV infection compared with HIV-negative individuals [adjusted OR = 2.1; 95% confidence interval (CI), 1.6–2.8]. Risk factors for prevalent oral HPV differed in HIV-positive and HIV-negative participants. Among HIV-negative individuals, higher number of recent oral sex or rimming partners were strong risk factors for prevalent oral HPV infection (each Ptrend &amp;lt; 0.01). In contrast, among HIV-positive individuals, lower CD4 T-cell count (Ptrend &amp;lt; 0.001) and higher number of lifetime sexual partners (Ptrend = 0.03) were strong risk factors.Conclusions: Oral HPV prevalence was elevated in HIV-positive individuals after controlling for differences in cigarette smoking and sexual behavior, supporting the possibility that HIV may affect the natural history of oral HPV.Impact: Immunosuppression may contribute to increased persistence or progression of oral HPV infection. Cancer Epidemiol Biomarkers Prev; 21(1); 122–33. ©2011 AACR.

Purpose: To describe sociodemographic, HIV and HPV infection characteristics in MACS men. Background: HPV-associated invasive anal cancer (IAC) is a health crisis for gay, bisexual, transgender and other MSM. MSM show 20-40 fold higher risk for IAC, especially within the context of HIV and since the introduction of combined antiretroviral therapy (CART) (1-4). Experts classify high-risk HPVs as having sufficient (Group 1) or limited (Group 2) evidence of causality for cervical cancer. The prevalence of these HPVs in MSM may inform risk for cancer. Methods: For 1262 MACS men evaluated at visits 56-58, Dacron swab specimens were tested for HPV using the Linear Array assay (Roche Diagnostic Laboratories, Pleasanton, CA). HPVs were classified as high-risk Groups 1 (HPV16/18/31/33/35/39/45/51/52/56/58/59) and 2 (HPV26/30/34/53/66/67/68/69/70/73/82), and low-risk HPVs (HPV6/11/40/42/54/56/61/62/64/70/71/72/82/83/84/IS39/CP6108). Descriptive and tabular analyses were used to explore the data. Poisson regression with robust error variance analyses were used to estimate prevalence ratios (PR, (95% confidence intervals)) comparing HPV groupings in both univariate and multivariate models using the SAS 9.2 GENMOD procedure (SAS Institute, Cary, North Carolina, USA). Final models included age and race, period-specific self-reported number of sexual partnerships, HIV-infection status, and CD4+ count (cell/mm3) among HIV-infected participants. Results: Participants are best described as older (µ=55 (9.4), M=55.6), and although Whites comprised &amp;gt;50% of both groups, HIV-infected men were &amp;gt;2 times as likely as uninfected men to report being Black, 25% vs. 10%. On average, the prevalence of all HPVs was 1.35-1.91 fold higher among HIV-infected than -uninfected men. Trend analyses showed CD4+ cell count was inversely associated with HPV Group 2 prevalence alone (p&amp;lt;0.0001). Only the number of receptive anal sex partners reported in the 24 months preceding the HPV test visit consistently predicted higher prevalence of Group 1 and 2 HPVs. However, for low-risk HPVs, the lifetime number of male sex partners reported at MACS visit 1, partners reported between visit 1 and the visit 24 months before HPV testing, and those recorded during the last 24 months were all significantly and positively associated with higher prevalence of low-risk HPVs (p=&amp;lt;0.05), e.g., 30+ vs. &amp;lt;30 lifetime male partners at visit 1, PR=1.20 (1.06, 1.37); receptive anal intercourse partners during the last 24 mo prior to HPV testing, 1-3 and &amp;gt;4 vs. 0: PR=1.13 (1.01, 1.26) and 1.16 (1.05, 1.30), respectively. Conclusions: HIV-infected MSM demonstrated a higher prevalence of all HPV groups evaluated and while number of sex partners were important for predicting the prevalence of low-risk HPVs, only the most recent receptive anal intercourse partnerships predicted prevalence of Group 1 and 2 HPVs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 551. doi:1538-7445.AM2012-551

Geffen School of Medicine, Fielding School of Public Health, University of California, Los Angeles, CA, USA 2 Center for Public Health and Disasters, Fielding School of Public Health, University of California, Los Angeles, CA, USA 3 School of Nursing, UCLA Clinical Translational Science Institute, University of California, Los Angeles, CA, USA 4 Department of Public Health Sciences, School of Medicine, University of California, Davis, CA, USA 5 Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, CA, USA 6 Department of Epidemiology, Center for Global and Immigrant Health, Fielding School of Public Health, University of California, Los Angeles, CA, USA 7 Department of Family Medicine &amp; Public Health, and Department of Neurosciences, University of California, San Diego, CA, USA 8 Department of Public Health, University of California, Merced, Merced, CA, USA 9 Department of Community Health Systems, School of Nursing, University of California, San Francisco, CA, USA

Performance of commercially available human papillomavirus (HPV) assays (approved for cervical HPV detection) is unknown for detecting HPV-related oropharyngeal cancer (HPV-OPC). Assays for detection of HPV DNA [ELISA (DEIA) and Cobas], and RNA (Aptima) in oral rinse samples, and serum HPV oncogene antibodies were evaluated. Sensitivity and specificity of each test was explored among HPV-OPC cases and controls. Biomarker prevalence was evaluated among 294 “at-risk” people (screening) and 133 “high-risk” people [known to previously have oral oncogenic HPV (oncHPV) DNA and/or HPV16 E6/E7 antibodies detected]. HPV16 E6 antibodies had the best overall test performance with sensitivity of 88%, compared with oral HPV16 DNA sensitivity of 51% by DEIA and 43% by Cobas (each P &lt; 0.001). Specificity was comparable in each of these tests (≥98%). When positivity for any oncHPV type was compared with HPV16 for the same test, sensitivity was comparable (60% vs. 51%, 40% vs. 43%, and 92% vs. 88...

Purpose Comparison of anal pre-cancer screening strategies in men who have sex with men (MSM). Methods MSM in the Multicenter AIDS Cohort Study underwent repeated anal cytology (aCyt), oncogenic human papillomavirus (oncHPV) testing. A subset received High-Resolution Anoscopy (HRA). We evaluated three screening strategies for their ability to predict anal histological High-Grade Squamous Intraepithelial lesion (HSIL): single aCyt, sequential aCyt, and oncHPV co-testing. Multivariable logistic regression models evaluated risk of HSIL among participants undergoing HRA within 5 years of screening. Sensitivity and specificity were estimated among participants with HRA, and results corrected for verification bias using weighted generalized estimating equations. Results There were 1426 MSM with aCyt screening (48% people with HIV [PWH]) and 428 that underwent HRA. Median age was 57 years, 14% of PWH had CD4&lt; 350 cells/mm3. HSIL probability was higher in MSM with one (39%, p &lt; 0.01) ...

Background Understanding 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. Methods We 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. Results Human 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 in...

&lt;p&gt;&lt;sup&gt;a&lt;/sup&gt; Statistically significant associations appear in bold type-face, &lt;i&gt;p&lt;/i&gt;&lt;0.05&lt;/p&gt;&lt;p&gt;&lt;sup&gt;b&lt;/sup&gt; Additionally controlled for Hepatitis C virus (HCV), smoking and alcohol use prior to baseline and testosterone testing visit, cumulative pack years prior to baseline, testosterone visit, and HPV testing visit, study site, and time cohort, QIC = 508.5534.&lt;/p&gt;&lt;p&gt;&lt;sup&gt;c&lt;/sup&gt; Additionally controlled for Hepatitis C virus (HCV), alcohol use prior to HPV testing visit, study site, and time cohort, QIC = 501.2063.&lt;/p&gt;&lt;p&gt;&lt;sup&gt;d&lt;/sup&gt; Additionally controlled for study site, and time cohort, QIC = 506.7745.&lt;/p&gt;&lt;p&gt;&lt;sup&gt;e&lt;/sup&gt; QIC = 491.2723&lt;/p&gt;&lt;p&gt;Univariate and Four Iterations of Multivariate Evaluation of Risk Factors for Anal HPV16/18 DNA Positivity for 340 Men Who Have Sex with Men.&lt;a href=&quot;http://www.plosone.org/article/info:doi/10.1371/journal.pone.0119447#t003fn001&quot; target=&quot;_blank&quot;&gt;&lt;sup&gt;a&lt;/sup&gt;&lt;/a&gt;&lt;/p

BackgroundIndependent of CD4 cell count, low CD4/CD8 ratio in people with HIV (PWH) is associated with deleterious immune senescence, activation, and inflammation, which may contribute to carcinogenesis and excess cancer risk. We examined whether low CD4/CD8 ratios predicted cancer among PWH in the USA and Canada.MethodsWe examined all cancer-free PWH with one or more CD4/CD8 values from NA-ACCORD observational cohorts with validated cancer diagnoses between 1998-2016. We evaluated the association between time-lagged CD4/CD8 ratio and risk of specific cancers in multivariable, time-updated Cox proportional hazard models using restricted cubic spines.Models were adjusted for age, sex, race/ethnicity, hepatitis C virus, and time-updated CD4 cell count, HIV RNA, and history of AIDS-defining illness.ResultsAmong 83,893 PWH, there were 5,628 incident cancers, including lung cancer (n=755), Kaposi sarcoma (KS, n=501), non-Hodgkin lymphoma (NHL, n=497), and anal cancer (n=439). Median age ...

Intra-anal malignancies disproportionately affect individuals who engage in anal intercourse because of infection with human papillomaviruses (HPVs), with an increased risk attributed to infection with HIV because of a declining immunity against HPVs. Long-term persistence of HPVs suggests yet other mechanisms that determine the clinical outcome, however. Because methylation of HPV DNA represses oncogene expression in cervical samples, we investigated whether this mechanism also occurs in HIV-positive men and studied the methylation of CpG dinucleotides overlapping with the HPV-16 enhancer and promoter in 16 anal samples. Similar to cervical infections, the average methylation frequency was 12.3%, with heterogeneities between clones from different and the same samples. In low-grade anal intraepithelial neoplasia (AIN), methylation was high in CpGs overlapping the viral enhancer but rare in promoter positions, whereas methylation was high in promoter regions in high-grade AIN, especi...

Soccer participation in the United States (U.S.) has increased over time, and injuries as well as interest to prevent injuries has become more common. This study described Emergency Department (ED) visits related to concussions, intracranial injuries (ICI), and all-other injuries attributed to soccer play; described healthcare cost and length of hospital stay of soccer-related injuries; and determined independent predictors of concussions, ICI, and all-other soccer injuries leading to ED visits. The study examined soccer-related weighted discharge data from the Nationwide Emergency Department Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. Weighted tabular analysis of univariate and bivariate analyses and weighted and adjusted logistic regression models were conducted. A total of 480,580 of U.S. ED visits related to soccer injuries were available for analysis between 2010 to 2013. Generally, 98% of soccer-related ED visits resulted in rou...

Chronic inflammation, including among persons with HIV (PWH), elevates immune cell expression of lymphocyte activation gene 3 (LAG3); however, low plasma LAG3 predicts cardiovascular disease events in the general population. The associations among LAG3 plasma levels, subclinical atherosclerosis, inflammation, and HIV infection have not been well described. We measured plasma LAG3 in 704 men with and without HIV from the Multicenter AIDS Cohort Study who underwent coronary CT angiography. HIV serostatus was not independently associated with LAG3 after adjustment for sociodemographic and cardiovascular disease (CVD) risk factors. Current smoking status and African-American race were associated with lower LAG3, and age and sTNFαRI concentration were associated with greater LAG3. LAG3 was not associated with coronary artery stenosis. Thus, no difference was found in plasma LAG3 concentration by HIV serostatus, and no association between LAG3 and subclinical coronary atherosclerosis in men with and without HIV was observed.

OBJECTIVE HIV-infected women (WLHIV) have &gt;10-fold higher risk for squamous cell cancer of the anus (SCCA). Experts suggest cytology-based strategies developed for cervical cancer screening may prevent anal cancer by detecting anal histological High-Grade Squamous Intraepithelial Lesion (hHSIL) for treatment. Currently, there is no consensus on anal-hHSIL screening strategies for WLHIV. DESIGN Between 2014 and 2016, 276 WLHIV were recruited at 12 U.S. AIDS Malignancy Consortium (AMC) clinical-trials sites to evaluate hHSIL prevalence and (test) screening strategies. METHODS Participants completed detailed questionnaire, underwent anal assessments including high-risk human papillomavirus (hrHPV) testing using hrHPV-HC2™ and hrHPV-APTIMA™, anal cytology, and concurrent high-resolution anoscopy. Screening test characteristics for predicting hHSIL validated by central pathology, were estimated: sensitivity (SN), specificity (SP), positive predictive value (PPV) and false-omission rate. Paired analyses compared SN and SP for hrHPV single tests to anal cytology alone. RESULTS 83% (229/276) of enrolled WLHIV had complete anal assessment data and were included in this analysis. Mean age was 50, 62% black and 60 (26%) had hHSIL. Anal cyotology (&gt;ASC-US), hrHPV-HC2, and -APTIMA SN estimates were similarly high, (83%, 77%, and 75%, respectively, p-values&gt;0·2). SP was higher for both hrHPV-APTIMA, and -HC2 compared with anal cytology (67% vs. 50%, p &lt; 0.001), and (61% vs. 50%, p = 0·020), respectively. CONCLUSION Anal hrHPV testing demonstrated similar SN for anal cytology (&gt;ASC-US) to predict anal hHSIL. Among tests with similar SN, the SP was significantly higher for hrHPV-APTIMA and -HC2. Thus, anal hrHPV testing may be an important alternative strategy to anal cytology for anal hHSIL screening among WLHIV.

Background Human papillomavirus–related oropharyngeal cancer (HPV-OPC) incidence is increasing, but the natural history of the precursor—oral HPV—has not been well described. Methods This observational cohort study of people living with HIV and at-risk HIV uninfected people evaluated participants semiannually using 30-second oral rinse and gargle specimens over 7 years. Initially, 447 participants were followed for 4 years as part of the Persistent Oral Papillomavirus Study, and a subset of 128 who showed persistent infections at the last Persistent Oral Papillomavirus Study visit had an additional visit, as part of the Men and Women Understanding Throat HPV Study, on average 2.5 years later. Extracted DNA from oral rinse and gargle specimens was amplified using polymerase chain reaction and type specification of 13 oncogenic HPV types. Risk factors for oncogenic oral HPV clearance were evaluated using Cox models. Results The majority of oncogenic oral HPV infections cleared quickly...

Background. Increasing body mass index (BMI) is generally associated with loss of metabolic health, although some obese individuals remain metabolically healthy. Among nonobese men, HIV infection has been associated with a lower prevalence of metabolic health. Methods. We conducted a cross-sectional analysis of 470 HIV-infected and 368 HIV-uninfected men enrolled in the Multicenter AIDS Cohort Study Cardiovascular substudy. Circulating biomarker levels were compared by BMI category and by HIV serostatus. Poisson regression with robust variance determined associations between metabolic health and circulating inflammatory biomarker levels after adjusting for factors previously associated with metabolic health. Results. HIV-infected men were younger and less likely to be obese. Among HIV-infected, normal weight metabolically healthy men (compared to unhealthy) had significantly lower circulating levels of interleukin- (IL-) 6, soluble tumor necrosis factor receptors (sTNFR) I and II, a...

Performance of commercially available human papillomavirus (HPV) assays (approved for cervical HPV detection) is unknown for detecting HPV-related oropharyngeal cancer (HPV-OPC). Assays for detection of HPV DNA [ELISA (DEIA) and Cobas], and RNA (Aptima) in oral rinse samples, and serum HPV oncogene antibodies were evaluated. Sensitivity and specificity of each test was explored among HPV-OPC cases and controls. Biomarker prevalence was evaluated among 294 “at-risk” people (screening) and 133 “high-risk” people [known to previously have oral oncogenic HPV (oncHPV) DNA and/or HPV16 E6/E7 antibodies detected]. HPV16 E6 antibodies had the best overall test performance with sensitivity of 88%, compared with oral HPV16 DNA sensitivity of 51% by DEIA and 43% by Cobas (each P &lt; 0.001). Specificity was comparable in each of these tests (≥98%). When positivity for any oncHPV type was compared with HPV16 for the same test, sensitivity was comparable (60% vs. 51%, 40% vs. 43%, and 92% vs. 88...

BackgroundWomen living with human immunodeficiency virus (WLHIV) have disproportionately high rates of squamous cell carcinoma of the anus compared with the general population of women. Anal high-grade squamous intraepithelial lesions (HSILs) precede anal cancer, and accurate studies of HSIL prevalence among WLHIV in the United States are lacking.MethodsThe AIDS Malignancy Consortium 084 study was a multicenter national trial to evaluate the prevalence of and risk factors for anal HSIL in a US cohort. Eligible participants were WLHIV aged ≥18 years with no history of anal HSIL. Study participants had an examination including collection of cervical/vaginal and anal specimens, followed by high-resolution anoscopy with biopsy.ResultsWe enrolled 256 women with evaluable anal pathology. The mean age was 49.4 years, 64% women were non-Hispanic black, 67% were former or current smokers, and 56% reported ever having anal sex with a man. The median CD4 T-cell count was 664 cells/μL. The prev...

BackgroundAn anal histological high‐grade squamous intraepithelial lesion (hHSIL) is an anal cancer precursor. Experts recommend Dacron swab anal cytology as a primary screen for anal hHSILs, especially among human immunodeficiency virus–infected and –uninfected men who have sex with men (MSM). Studies have shown that Dacron cytology inaccurately predicts anal hHSILs and results in unnecessary diagnostic procedures. Nylon‐flocked (NF) swabs have been shown to trap pathogens and cells well. Thus, this study compared test characteristics of anal cytology using NF and Dacron swab collection protocols to predict anal hHSILs.MethodsA single‐visit, randomized clinical trial compared NF and Dacron swab anal cytology specimens to predict high‐resolution anoscopy and biopsy–diagnosed anal hHSILs. Data for 326 gay men, bisexual men, other MSM, and male‐to‐female transgender women contributed descriptive and tabular statistics with which unadjusted and fully adjusted logistic regression models...

To estimate the proportion of vulvar and vaginal low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) in females 15-26 years of age attributable to 14 human papillomavirus (HPV) genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59). A post hoc analysis of prospectively diagnosed vulvar and vaginal LSILs and HSILs among females 15-26 years of age enrolled in the placebo arms of two phase 3, randomized HPV vaccine trials assessed 14 prespecified HPV genotypes associated with cervical cancers or anogenital warts using a type-specific multiplex polymerase chain reaction assay. The frequency of lesions associated with specific HPV genotypes was estimated by proportional and other attribution methods. During approximately 4 years of follow-up in 8,798 females, 40 vulvar LSILs and 46 vulvar HSILs were diagnosed in 68 females, and 118 vaginal LSILs and 33 vaginal HSILs were diagnosed in 107 females. Females developing vulvar (41.2%) or vaginal (49.5%) lesi...

Men who have sex with men (MSM) are at increased risk for anal cancer. In cervical cancer screening, patterns of repeated cytology results are used to identify low- and high-risk women, but little is known about these patterns for anal cytology among MSM. We analyzed Multicenter AIDS Cohort Study (MACS) data for MSM who were offered anal cytology testing annually (HIV-positive) or every 2 years (HIV-negative) for 4 years. Following an initial negative (normal) cytology, the frequency of a second negative cytology was lower among HIV-positive MSM with CD4 ≥ 500 (74%) or CD4 &lt; 500 (68%) than HIV-negative MSM (83%) (p &lt; 0.001). After an initial abnormal cytology, the frequency of a second abnormal cytology was highest among HIV-positive MSM with CD4 &lt; 500 (70%) compared to CD4 ≥ 500 (53%) or HIV-negative MSM (46%) (p = 0.003). Among HIV-positive MSM with at least three results, 37% had 3 consecutive negative results; 3 consecutive abnormal results were more frequent among CD4 ...

Primary analyses of a study in young women aged 16-26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years. We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16-26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or ...

The association between oral HPV16 DNA viral load and infection clearance was evaluated among 88 individuals with oral HPV16 infection identified within a prospective cohort of 1,470 HIV-infected and uninfected individuals. Oral rinses were collected semi-annually for up to five years. Oral HPV16 viral load at the first positive test was significantly associated with time to clearance of infection (continuous p-trends&lt;0.01). Notably, clearance rates by 24-month were 41% and 94% in the highest and lowest HPV16 viral load tertiles (p=0.03), respectively. High oral HPV16 viral load warrants consideration as a biomarker for infection persistence, the presumed precursor of HPV16-associated oropharyngeal cancer.

Human papillomavirus (HPV) causes the majority of oropharyngeal cancers in the United States, yet the risk factors for and natural history of oral HPV infection are largely unknown. In 2010-2011, a US-based longitudinal cohort study of 761 human immunodeficiency virus (HIV)-infected and 469 at-risk HIV-uninfected participants from the Multicenter AIDS Cohort Study and the Women&#39;s Interagency HIV Study was initiated. Semiannually collected oral rinses were evaluated for 37 HPV genotypes using the Roche LINEAR ARRAY HPV Genotyping Test (Roche Molecular Systems, Pleasanton, California), and factors associated with oral HPV incidence and clearance were explored using adjusted Wei-Lin-Weissfeld modeling. Through 2013, the 2-year cumulative incidence of any type of oral HPV infection was 34% in HIV-infected persons and 19% in HIV-uninfected persons. However, many of these infections cleared. Seven percent of incident infections and 35% of prevalent infections persisted for at least 2 ...

To evaluate the perspectives and preferences of homeless women for traditional provider- and a novel low cost self-collected cytology screening technique, 17 interviews were conducted with women who participated in both phases of a comparative trial. Subjects were recruited from a comprehensive homeless service center and a residential program serving homeless women. Constructivist grounded theory guided data collection and analysis. Results showed self-collection was favored over provider-collected cytology, but that the women perceived that test accuracy trumped comfort. Although many women expressed inaccurate perceptions and beliefs about cervical cancer and screening, the women participated in and valued screening. Misconceptions about cervical malignancy and prevention strategies contributed to their complex appraisal of the two screening methods. Homeless women may partner with providers to develop and test effective interventions with high promise for improving their health ...