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BACKGROUND: Advances in laboratory techniques for HPV diagnosis necessitate a thorough assessment of the efficiency, replicability, sensitivity, and specificity of those methods. This study aims to validate and compare HPV detection/genotyping using the Anyplex™ II HPV28 Detection assay (Seegene) assay and the Linear Array HPV Genotyping test (Roche Diagnostics) on genital samples for use in epidemiological studies. METHODS: From 6,388 penile and cervical DNA samples collected in the POP-Brazil, 1,745 were randomly selected to be included in this study. The samples were submitted to HPV detection and genotyping following the manufacturers' protocols. DNA was genotyped using the Anyplex™ II HPV28 Detection kit (Seegene), and the results were compared to those obtained using the Linear Array HPV Genotyping test (Roche Diagnostics). Concordance of HPV genotyping results was assessed by the percentage agreement and Cohen's kappa score (κ). RESULTS: The agreement between the two methodologies was deemed good for HPV detection (κ = 0.78). Notably, Anyplex™ II HPV28 demonstrated enhanced capability in detecting a broader spectrum of genotypes compared to Linear Array. CONCLUSION: Anyplex™ II HPV28 exhibited comparable results to the Linear Array assay in clinical specimens, showcasing its potential suitability for a diverse array of research applications requiring the detection and genotyping of HPV. The study supports the utility of Anyplex™ II HPV28 as an effective tool for HPV screening in epidemiological studies, emphasizing its robust performance in comparison to established diagnostic tests.

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BACKGROUND: HPV-16 driven oropharynx/oral cavity squamous cell carcinomas prevalence varies globally. We evaluated the presence of HPV-16 ctDNA and HPV-16 E6 antibodies in samples obtained from participants treated at the Instituto do Cancer do Estado de Sao Paulo, ICESP, and from whom tumoral HPV DNA, HPV-16 E6*I mRNA, and p16INK4a status was also accessed. METHODS: HPV was genotyped by PCR-hybridization. All HPV DNA positive and ∼10 % HPV DNA negative cases underwent p16INK4a immunohistochemistry and E6*I RNA testing using a multiplex bead based protocol. HPV-16 ctDNA and anti-E6 antibodies were assessed by ddPCR (digital droplet PCR) and multiplex serology, respectively. RESULTS: The prevalence of HPV-16 in oropharynx carcinoma (OPC) cases was low (8.7 %) when considering solely HPV-16 DNA detection, and even lower (5.2 %) when taken into consideration the concomitant detection of HPV-16 E6*I RNA and/or p16INK4 (HPV-16 attributable fraction - AF). None of the oral cavity cancer (OCC) cases were detected with HPV-16 DNA. HPV-16 ctDNA was more commonly detected than HPV-16 E6 antibodies (29.8 % versus 10.6 %). Both serum biomarkers attained 100 % sensitivity of detecting HPV-16 AF OPC, however the specificity of the HPV-16 anti-E6 biomarker was higher compared to ctDNA (93.2 % versus 75.0 %). Finally, when both HPV-16 ctDNA and anti-E6 biomarkers were considered together, the sensitivity and specificity for HPV-16 OPC detection was 100 % and about 70 %, respectively, independently of analyzing HPV-16 DNA positive or HPV-16 AF tumors. CONCLUSIONS: Our findings corroborate that serum biomarkers are highly sensitive and specific biomarkers for detection of HPV-associated OPC.

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Human papillomaviruses (HPV) of the genus Betapapillomavirus can infect both cutaneous and mucosal sites, but research on their natural history at mucosal sites remains scarce. We examined the risk factors and co-detection patterns of HPVs of the Betapapillomavirus and Alphapapillomavirus genera in cervical samples of the Ludwig-McGill cohort study. We assessed a subset of 505 women from the Ludwig-McGill cohort study from São Paulo, Brazil. Cervical samples over the first year of follow-up were tested for DNA of over 40 alphapapillomavirus types and 43 betapapillomavirus types using a type-specific multiplex genotyping polymerase chain reaction assay. We assessed the risk factors for prevalent and incident betapapillomavirus type detection, and whether types were detected more frequently together than expected assuming independence using permutation tests, logistic regression, and Cox regression. We observed significant within-genus clustering but not cross-genus clustering. Multiple betapapillomavirus types were co-detected in the same sample 2.24 (95% confidence interval [CI]: 1.65-3.29) times more frequently than expected. Conversely, co-detections of alphapapillomavirus and betapapillomavirus types in the same sample occurred only 0.64 (95% CI: 0.51-0.83) times as often as expected under independence. In prospective analyses, positivity to one HPV genus was associated with a nonsignificant lower incidence of detection of types in the other genus. Lifetime number of sex partners and new sex partner acquisition were associated with lower risks of prevalent and incident betapapillomavirus detection. Betapapillomaviruses are commonly found in the cervicovaginal tract. Results suggest potentially different mechanisms of transmission for betapapillomavirus genital infections other than vaginal sex.

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BACKGROUND: Human papillomavirus (HPV) 16 non-A lineage variants have higher carcinogenic potential for cervical cancer. HPV-16 variants natural history among males is not established. We evaluated HPV-16 variants prevalence and persistence in the external genitalia of men enrolled in the prospective HPV Infection in Men (HIM) Study. METHODS: The HIM Study included men from the United States, Brazil, and Mexico. HPV-16 variants were distinguished using polymerase chain reaction sequencing. The prevalence of HPV-16 variants was assessed, and associations with infection persistence were estimated. RESULTS: We characterized the HPV-16 variants for 1700 genital swab samples from 753 men and 22 external genital lesions in 17 men. The prevalence of HPV-16 lineages differed by country and marital status (P < .001). Overall, 90.9% of participants harbored lineage A variants. The prevalence of non-A lineages was heterogenous among countries. HPV-16 lineage A variants were associated with a 2.69-fold increased risk of long-term persistent infections compared with non-A lineages. All high-grade penile intraepithelial neoplasia harbored lineage A variants and occurred in the context of long-term persistent infections with the same variants. CONCLUSIONS: The prevalence and persistence of HPV-16 variants observed at the male external genitalia suggest differences in the natural history of these variants between men and women, which may be associated with intrinsic differences in the infected genital epithelia.

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BACKGROUND: Transgender women (TGW) are susceptible to the acquisition of sexually transmitted infections (STIs), including human papillomavirus (HPV). Nonetheless, the exact data for this population are scarce. We estimated HPV positivity at the anal, genital, and oral sites among TGW and also identified the related characteristics and behaviors that could be risk factors for HPV infection in a sample of TGW in Brazil. Furthermore, we characterized the site-specific HPV genotypes among those who were positive for HPV at these 3 sites. METHODS: A cross-sectional study was conducted on TGW in Goiânia City (Central-Midwest region), Brazil, between April 2018 and August 2019. Respondent-driven sampling was applied for recruitment. Next, self-collected anal, genital, and oral samples were examined for HPV DNA using polymerase chain reaction (SPF-10 primer). Human papillomavirus genotypes were identified in 12 TGW. RESULTS: In the TGW included in the study, the anal, genital, and oral HPV positivity values were 77.2% (95% confidence interval [CI], 67.3%-84.6%), 33.5% (95% CI, 26.1%-48.9%), and 10.9% (95% CI, 5.8%-17.0%), respectively. In addition, the majority of 12 participants who tested for HPV had multiple genotypes. HPV-52 was the most prevalent genotype identified at the anal (66.6%) and genital (40.0%) sites, whereas HPV-62 and HPV-66 were the most common at the oral site (25.0%). CONCLUSIONS: A high HPV positivity was observed among TGW. Therefore, additional epidemiological studies on HPV genotypes should generate health intervention information, including the prevention, diagnosis, and treatment of sexually transmitted infections.

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BACKGROUND & AIMS: Perianal fistulizing Crohn's disease is the main risk factor for anal cancer in patients with inflammatory bowel disease. Whether this occurs due to a higher frequency of human papillomavirus remains unclear. The authors aimed to evaluate the prevalence of HPV and high-risk HPV in patients with perianal Crohn's disease, compared with a control group. METHODS: The authors conducted a two-center cross-sectional study in which perianal fistulizing Crohn's disease patients were matched for age and sex with patients with anorectal fistula without Crohn's disease. Biopsy specimens were obtained from fistulous tracts during examination under anesthesia for both groups. The samples were sent for HPV detection and genotyping using the INNO-LiPA test. RESULTS: A total of 108 subjects (54 in each group) were recruited. The perianal fistulizing Crohn's disease group showed a statistically higher frequency of HPV in the fistulous tract than the control group (33.3% vs. 16.7%; p = 0.046). Separate analyses on high-risk types demonstrated that there was a numerically higher frequency of HPV in the perianal fistulizing Crohn's disease group. In multiple logistic regression, patients with perianal fistulizing Crohn's disease were found to have a chance of HPV 3.29 times higher than patients without Crohn's disease (OR = 3.29; 95% CI 1.20‒9.01), regardless of other variables. The types most frequently identified in the perianal fistulizing Crohn's disease group were HPV 11 (12.96%) and HPV 16 (9.26%). CONCLUSION: Perianal fistulizing Crohn's disease is associated with a higher prevalence of HPV than in patients with anorectal fistula without Crohn's disease.

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Abstract Objectives: Prophylactic HPV vaccines are a fundamental tool to reduce infections and tumors caused by the most prevalent types of these viruses, as this review points out. Several countries have adopted immunization programs that recommend vaccination against HPV for girls and adolescents between 9 and 14 years of age and, in some of them, also for boys. The programs also contemplate the immunization of adults, particularly in the case of individuals with different immunodeficiencies. Sources of data: The available vaccines are recommended for the prevention of tumors of the uterine cervix, vulva, vagina, penis, and anal canal. Moreover, two of the vaccines prevent the occurrence of genital warts, having been recently indicated for the prevention of oropharyngeal cancer. Data synthesis: Based on the evidence that antibody responses in girls were non-inferior after two doses when compared to three doses, several countries have decided to reduce the vaccination schedule for girls and boys up to 14 years of age from three to two doses, with an interval of six months between them. Recently, knowledge has been accumulating about the immunogenicity, duration of protection, and efficacy of a single-dose HPV vaccine regimen in girls and young women. Conclusion: Single-dose HPV vaccination could substantially reduce the incidence of pre-cancer and cervical cancer attributable to HPV, with reduced costs for vaccine delivery and simplified implementation, allowing more countries to introduce HPV vaccination or increase the adherence of the target population.

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BACKGROUND: We assessed the incidence and risk factors for first detection and redetection with the same human papillomavirus (HPV) genotype, and prevalence of cytological lesions during HPV redetections. METHODS: The Ludwig-McGill cohort study followed women aged 18-60 years from São Paulo, Brazil in 1993-1997 for up to 10 years. Women provided cervical samples for cytology testing and HPV DNA testing at each visit. A redetection was defined as a recurring genotype-specific HPV positive result after 1 or more intervening negative visits. Predictors of genotype-specific redetection were assessed using adjusted hazard ratios (aHR) with Cox regression modeling. RESULTS: In total, 2184 women contributed 2368 incident HPV genotype-specific first detections and 308 genotype-specific redetections over a median follow-up of 6.5 years. The cumulative incidence of redetection with the same genotype was 6.6% at 1 year and 14.8% at 5 years after the loss of positivity of the first detection. Neither age (aHR 0.90; 95% confidence interval [CI], .54-1.47 for ≥45 years vs < 25 years) nor new sexual partner acquisition (aHR 0.98; 95% CI, .70-1.35) were statistically associated with genotype-specific redetection. High-grade squamous intraepithelial lesion prevalence was similar during first HPV detections (2.9%) and redetection (3.2%). CONCLUSIONS: Our findings suggest many HPV redetections were likely reactivations of latent recurring infections.

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OBJECTIVES: Prophylactic HPV vaccines are a fundamental tool to reduce infections and tumors caused by the most prevalent types of these viruses, as this review points out. Several countries have adopted immunization programs that recommend vaccination against HPV for girls and adolescents between 9 and 14 years of age and, in some of them, also for boys. The programs also contemplate the immunization of adults, particularly in the case of individuals with different immunodeficiencies. SOURCES OF DATA: The available vaccines are recommended for the prevention of tumors of the uterine cervix, vulva, vagina, penis, and anal canal. Moreover, two of the vaccines prevent the occurrence of genital warts, having been recently indicated for the prevention of oropharyngeal cancer. DATA SYNTHESIS: Based on the evidence that antibody responses in girls were non-inferior after two doses when compared to three doses, several countries have decided to reduce the vaccination schedule for girls and boys up to 14 years of age from three to two doses, with an interval of six months between them. Recently, knowledge has been accumulating about the immunogenicity, duration of protection, and efficacy of a single-dose HPV vaccine regimen in girls and young women. CONCLUSION: Single-dose HPV vaccination could substantially reduce the incidence of pre-cancer and cervical cancer attributable to HPV, with reduced costs for vaccine delivery and simplified implementation, allowing more countries to introduce HPV vaccination or increase the adherence of the target population.

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Abstract Background & Aims Perianal fistulizing Crohn's disease is the main risk factor for anal cancer in patients with inflammatory bowel disease. Whether this occurs due to a higher frequency of human papillomavirus remains unclear. The authors aimed to evaluate the prevalence of HPV and high-risk HPV in patients with perianal Crohn's disease, compared with a control group. Methods The authors conducted a two-center cross-sectional study in which perianal fistulizing Crohn's disease patients were matched for age and sex with patients with anorectal fistula without Crohn's disease. Biopsy specimens were obtained from fistulous tracts during examination under anesthesia for both groups. The samples were sent for HPV detection and genotyping using the INNO-LiPA test. Results A total of 108 subjects (54 in each group) were recruited. The perianal fistulizing Crohn's disease group showed a statistically higher frequency of HPV in the fistulous tract than the control group (33.3% vs. 16.7%; p = 0.046). Separate analyses on high-risk types demonstrated that there was a numerically higher frequency of HPV in the perianal fistulizing Crohn's disease group. In multiple logistic regression, patients with perianal fistulizing Crohn's disease were found to have a chance of HPV 3.29 times higher than patients without Crohn's disease (OR = 3.29; 95% CI 1.20‒9.01), regardless of other variables. The types most frequently identified in the perianal fistulizing Crohn's disease group were HPV 11 (12.96%) and HPV 16 (9.26%). Conclusion Perianal fistulizing Crohn's disease is associated with a higher prevalence of HPV than in patients with anorectal fistula without Crohn's disease.

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The poor prognosis of head and neck cancer (HNC) is associated with metastasis within the lymph nodes (LNs). Herein, the proteome of 140 multisite samples from a 59-HNC patient cohort, including primary and matched LN-negative or -positive tissues, saliva, and blood cells, reveals insights into the biology and potential metastasis biomarkers that may assist in clinical decision-making. Protein profiles are strictly associated with immune modulation across datasets, and this provides the basis for investigating immune markers associated with metastasis. The proteome of LN metastatic cells recapitulates the proteome of the primary tumor sites. Conversely, the LN microenvironment proteome highlights the candidate prognostic markers. By integrating prioritized peptide, protein, and transcript levels with machine learning models, we identify nodal metastasis signatures in blood and saliva. We present a proteomic characterization wiring multiple sites in HNC, thus providing a promising basis for understanding tumoral biology and identifying metastasis-associated signatures.

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Penile cancer (PeC) is a rare disease, and no prognostic biomarkers have been adopted in clinical practice yet. The objective of the present study was to identify differentially expressed miRNAs (DEmiRs) and genes (DEGs) as potential biomarkers for lymph node metastasis and other prognostic factors in PeC. Tumor samples were prospectively obtained from 24 patients with squamous cell carcinoma of the penis. miRNA microarray analysis was performed comparing tumors from patients with inguinal lymph node metastatic and localized disease, and the results were validated by qRT-PCR. Eighty-three gene expression levels were also compared between groups through qRT-PCR. Moreover, DEmiRs and DEGs expression levels were correlated with clinicopathological variables, cancer-specific (CSS), and overall survival (OS). TAC software, TM4 MeV 4.9 software, SPSS v.25.0, and R software v.4.0.2 were used for statistical analyses. We identified 21 DEmiRs in microarray analysis, and seven were selected for validation. miR-744-5p and miR-421 were overexpressed in tissue samples of metastatic patients, and high expression of miR-421 was also associated with lower OS. We found seven DEGs (CCND1, EGFR, ENTPD5, HOXA10, IGF1R, MYC, and SNAI2) related to metastatic disease. A significant association was found between increased MMP1 expression and tumor size, grade, pathological T stage, and perineural invasion. Other genes were also associated with clinicopathological variables, CSS and OS. Finally, we found changes in mRNA-miRNA regulation that contribute to understanding the mechanisms involved in tumor progression. Therefore, we identified miRNA and mRNA expression profiles as potential biomarkers associated with lymph node metastasis and prognosis in PeC, in addition to disruption in mRNA-miRNA regulation during disease progression.

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The present study aimed to evaluate the association of genital and oral HPV infection among different sexual practices in both sexes. In total, 6388 unvaccinated men and women aged 16-25 years from all state capitals of Brazil were enrolled in through primary care services between September 2016 and November 2017. Genital and oral HPV genotyping was performed using the Roche Linear Array. Poisson regression analysis with robust variance was conducted to examine factors associated with overall HPV infection. A higher prevalence of genital HPV was found in women who practiced oral sex (57.85%) and in men who practiced all types of sex (65.87%). However, having more sexual partners and being younger were more important than the type of sex practiced. HPV 6 (7.1%) and 16 (10.5%) were significantly more prevalent in women who practiced oral sex, while HPV 6 (23.96%) and 11 (21.49%) were more prevalent in men who practiced anal sex. The type of sex was not associated with oral HPV prevalence. Genital and oral HPV infection were not associated by different sexual practices in the studied population.

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Human Papillomavirus is responsible for a wide range of mucosal lesions and tumors. The immune system participate in tumorigenesis in different ways. For example, signaling pathways triggered by Toll-like receptors (TLR) play a role in chemotherapy resistance in several tumor types and are candidates for contributing to the development of HPV-induced tumors. Here, we studied the receptor TLR4 and the adaptor molecule SARM1 in HeLa cells, an HPV-positive cervical cancer cell line. Knocking out of these genes individually proved to be important for maintaining cell viability and proliferation. TLR4 knock out cells were more sensitive to cisplatin treatment, which was illustrated by an increased frequency of apoptotic cells. Furthermore, TLR4 and SARM1 modulated ROS production, which was induced by cell death in response to cisplatin. In conclusion, TLR4 and SARM1 are important for therapy resistance and cervical cancer cell viability and may be relevant clinical targets.

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BACKGROUND: HPV-16 causes approximately 90% of anal canal (AC) cancers worldwide. This study aimed to evaluate the prevalence and persistence of HPV-16 genetic variants in the AC of men from three different countries (Brazil, Mexico and United States) and to further identify sociodemographic and behavioral factors associated with these infections. METHODS: Participants from the multinational prospective HPV Infection in Men (HIM) Study who had at least one HPV-16 positive AC swab were included. Characterization into HPV-16 genetic variants was successfully performed by PCR-sequencing in 95.6% (217/227) samples and these were classified into HPV-16 lineages and sublineages. RESULTS: We observed higher prevalence of lineage A variants, mainly from A1 sublineage, in all countries. Non-A lineage variants were mostly detected in men from Brazil, where higher diversity of sublineage variants was detected during follow-up. Compare to men detected with Non-A HPV-16 lineage variants, men infected with lineage A reported a higher lifetime number of female sexual partners. Finally, a significantly higher prevalence of Non-A lineage variants was observed among men who have sex with men (MSM) with a transient HPV-16 AC infection (p = 0.033), but no significant differences regarding variants lineages and persistence status were observed when stratified by country, self-reported ethnicity or age. CONCLUSIONS: Our data extend previous reports which indicate that globally HPV-16 variants are unevenly distributed, and contribute further to studies of the natural history of AC HPV infections in men.

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BACKGROUND: Interplay between vaginal microbiome and human papillomavirus (HPV) remains unclear, partly due to heterogeneity of microbiota. METHODS: We used data from 546 women enrolled in a cross-sectional study in 5 Brazil. We genotyped vaginal samples for HPV and sequenced V3-V4 region of 16S rRNA gene for vaginal microbiome analysis. We used stepwise logistic regression to construct 2 linear scores to predict high-risk HPV (hrHPV) positivity: one based exclusively on presence of individual bacterial taxa (microbiome-based [MB] score) and the other exclusively on participants' sociodemographic, behavioral, and clinical (SBC) characteristics. MB score combined coefficients of 30 (of 116) species. SBC score retained 6 of 25 candidate variables. We constructed receiver operating characteristic curves for scores as hrHPV correlates and compared areas under the curve (AUC) and 95% confidence intervals (CI). RESULTS: Overall, prevalence of hrHPV was 15.8%, and 26.2% had a Lactobacillus-depleted microbiome. AUCs were 0.8022 (95% CI, .7517-.8527) for MB score and 0.7027 (95% CI, .6419-.7636) for SBC score (P = .0163). CONCLUSIONS: The proposed MB score is strongly correlated with hrHPV positivity-exceeding the predictive value of behavioral variables-suggesting its potential as an indicator of infection and possible value for clinical risk stratification.

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BACKGROUND: Chagasic megaesophagus (CM) as well as the presence of human papillomavirus (HPV) has been reported as etiological factors for esophageal squamous cell carcinoma (ESCC). OBJECTIVE: We assessed the prevalence of HPV DNA in a series of ESCCs associated or not with CM. Data obtained were further correlated to the pathological and clinical data of affected individuals. METHODS: A retrospective study was performed on 92 formalin-fixed and paraffin-embedded tissues collected from patients referred to 3 different hospitals in São Paulo, Brazil: Barretos Cancer Hospital, Barretos, São Paulo; Federal University of Triângulo Mineiro, Uberaba, Minas Gerais; and São Paulo State University, Botucatu, São Paulo. Cases were divided into 3 groups: (i) 24 patients with CM associated with ESCC (CM/ESCC); (ii) 37 patients with ESCC without CM (ESCC); and (iii) 31 patients with CM without ESCC (CM). Detection of HPV DNA was assessed in all samples by a genotyping assay combining multiplex polymerase chain reaction and bead-based Luminex technology. RESULTS: We identified a high prevalence of high-risk HPV in patients in the CM group (12/31, 38.8%) and CM/ESCC (8/24, 33.3%), compared to individuals in the ESCC group (6/37, 16.3%). The individuals in the groups with cancer (ESCC and CM/ESCC) had a higher frequency of HPV-16 (4/9, 44.5% and 2/8, 25.0%). The other types of high-risk HPVs detected were HPV-31, 45, 51, 53, 56, 66, and 73. We also observed in some samples HPV coinfection by more than one viral type. Despite the high incidence of HPV, it did not show any association with the patient's clinical-pathological and molecular (TP53 mutation status) characteristics. CONCLUSION: This is the first report of the presence of HPV DNA in CM associated with ESCC. HPV infection was more presence in megaesophagus lesions. Further studies are needed to confirm and better understand the role of persistent HPV infection in patients with CM.

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BACKGROUND: Human papillomavirus (HPV)-driven head/neck squamous cell carcinomas (HNSCC) prevalence varies globally. We evaluated HPV DNA and p16INK4a in formalin fixed paraffin embedded (FFPE) HNSCC from Argentina, Brazil, Colombia, and Peru. METHODS: HPV was genotyped by PCR-hybridization. All HPV DNA positive and some HPV DNA negative cases underwent p16INK4a immunohistochemistry. RESULTS: HPV DNA was detected in 32.8%, 11.1%, and 17.8% of oropharyngeal (OPC), oral cavity (OCC) and laryngeal (LC) cancers, respectively. OPC HPV prevalence was higher in Colombia (94.7%), and Argentina (42.6%) compared to Brazil (10.6%) and Peru (0.0%). HPV-16 was the most detected. Other HPVs were found in LC. Higher rates of p16INK4a positivity were observed among HPV positive OPC/OCC cases compared to LC cases. CONCLUSIONS: Our results support a role for HPV-16 in a subset of HNSCC, corroborate the heterogeneity observed in samples from different countries, and contribute additional etiological and biomarkers information in tumors of significant impact worldwide.

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