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HIV-positive adults are at risk for various kidney diseases, and apolipoprotein 1 (APOL1) high-risk genotypes increase this risk. This study aimed to determine the prevalence and ethnic distribution of APOL1 risk genotypes among a cohort of HIV-positive Nigerian adults and explore the relationship between APOL1 risk variant status with albuminuria and estimated glomerular filtration rate (eGFR). We conducted a cross-sectional study among 2 458 persons living with HIV who attended an HIV clinic in northern Nigeria and had received antiretroviral therapy for a minimum of six months. We collected two urine samples four-eight weeks apart to measure albumin excretion, and blood samples to measure eGFR and determine APOL1 genotype. The frequency of APOL1 high-risk genotype was 6.2%, which varied by ethnic group: Hausa/Fulani (2.1%), Igbo (49.1%), and Yoruba (14.5%). The prevalence of microalbuminuria (urine/albumin creatinine ratio 30 – 300 mg/g) was 37%, and prevalence of macroalbuminuria (urine/albumin creatinine ratio over 300 mg/g) was 3%. The odds of microalbuminuria and macroalbuminuria were higher for participants with the APOL1 high-risk genotype compared to those carrying the low-risk genotype ((adjusted odds ratio 1.97, 95% confidence interval 1.37-2.82) and (3.96, 1.95-8.02) respectively)). APOL1 high-risk genotype participants were at higher risk of having both an eGFR under 60 ml/min/1.73m(2) and urine/albumin creatinine ratio over 300 mg/g (5.56, 1.57-19.69). Thus, we found a high proportion of HIV-positive, antiretroviral therapy-experienced, and largely virologically suppressed adults had microalbuminuria. Hence, although the high-risk APOL1 genotype was less prevalent than expected, it was strongly associated with some level of albuminuria.

Background HIV-positive persons of African descent are disproportionately affected by chronic kidney disease (CKD). Deterioration to end-stage kidney disease (ESKD) also occurs in this population at a higher frequency. There remains a lot to learn about the genetic susceptibility to CKD in HIV positive patients, and the pathophysiology of progression to ESKD. Objectives We will conduct an exploratory genotype-phenotype study in HIV-positive persons with CKD in Aminu Kano Teaching Hospital, Nigeria, to determine blood-based differential gene expression biomarkers in different kidney risk groups according to the KDIGO 2012 criteria. Methods We will consecutively screen 150 HIV-positive adults (≥18 years of age) attending the HIV clinic of Aminu Kano Teaching Hospital, Kano, Nigeria, for CKD based on proteinuria and elevation of estimated glomerular filtration rate. Among these, two separate groups of 16 eligible participants each (n = 32) will be selected in the four (4) KDIGO 2012 kidney risk categories. The groups will be matched for age, sex, viral suppression level and antiretroviral (ARV) regimen. In the first group (n = 16), we will determine differential gene expression markers in peripheral blood mononuclear cells using mRNA-sequencing (RNA-Seq). We will validate the differential expression markers in the second group (n = 16) using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Using a systems-based approach, we will construct, visualize and analyze gene-gene interaction networks to determine the potential biological roles of identified differential expression markers based on published literature and publicly available databases. Results Our exploratory study will provide valuable information on the potential roles of differential expression biomarkers in the pathophysiology of HIV-associated kidney disease by identifying novel biomarkers in different risk categories of CKD in a sub-Saharan African population. The results of this study will provide the basis for population-based genome-wide association studies to guide future personalized medicine approaches. Conclusion Validated biomarkers can be potential targets for the development of stage-specific therapeutic interventions, an essential paradigm in precision medicine.

Background: HIV-positive adults are at risk for various kidney diseases, and apolipoprotein 1 (APOL1) high-risk genotypes increase this risk. This study aimed to determine the prevalence and ethnic distribution of APOL1 risk genotypes among a cohort of HIV-positive Nigerian adults and to explore the relationship between APOL1 risk variant status and albuminuria and estimated glomerular filtration rate (eGFR). Methods: We conducted a cross-sectional study among 2458 persons living with HIV who attended an HIV clinic in northern Nigeria and had received antiretroviral therapy (ART) for a minimum of six months. We collected two urine samples 4-8 weeks apart to measure albumin excretion, and blood samples to measure eGFR and determine APOL1 genotype. Findings: The frequency of the APOL1 high-risk (HR) genotype was 6·2%, which varied by ethnic group: Hausa/Fulani (2%), Igbo (49·1%), and Yoruba (14·5%). The prevalence of microalbuminuria (urine/albumin creatinine ratio [uACR] 30 – 300 mg/g) was 37%, and the prevalence of macroalbuminuria (uACR > 300 mg/g) was 3%. The odds of microalbuminuria and macroalbuminuria were higher for participants with the APOL1 HR genotype compared to those carrying the low-risk (LR) genotype (aOR = 1·97, 95% confidence interval [CI] 1·38-2·82; aOR = 4·01, 95% CI 1·98-8·12; respectively). APOL1 HR genotype participants were also at higher risk of having both eGFR 300 mg/g (aOR = 5·85, 95% CI 1·66-20·62). Interpretation: We found a high proportion of HIV-positive, ART-experienced, and largely virologically suppressed adults had microalbuminuria. Although the high-risk APOL1 genotype was less prevalent than expected, it was strongly associated with albuminuria. Future investigations are needed to determine the etiology of the high rate of microalbuminuria in this population within the context of controlled HIV infection and to determine long-term kidney outcomes. Trial Registration: The study was registered with clinicaltrials.gov (NCT03201939) and the Pan African Clinical Trials Registry (PACTR201711002808414). Funding Statement: This work is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH), U01 DK112271. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The study was approved by the Institutional Review Board of Vanderbilt University Medical Center (FWA00005756) and the Ethics Committee of AKTH (FWA00026225).

Background The purpose of this study was to assess genital recurrence of human papillomavirus (HPV) genotypes included in the 9-valent vaccine and to investigate factors associated with recurrence among men in the HPV Infection in Men (HIM) Study. Methods Men were followed every 6 months for a median of 3.7 years. HPV genotypes were detected using Roche linear array. Factors associated with type-specific HPV recurrence (infections occurring after a ≥12-month infection-free period) were assessed. Results In type-specific analyses, 31% of prior prevalent and 20% of prior incident infections recurred. Among prevalent infections, HPV types 52, 45, 16, 58, and 6 and among incident infections, HPV types 58, 52, 18, 16, and 11 had the highest rates of recurrence. New sexual partners (male or female) and frequency of sexual intercourse with female partners were associated with HPV-6, -16, -31, and -58 infection recurrence. In grouped analyses, lifetime and new male sexual partners were associated with recurrence of prior incident infection with any of the 9 HPV types. Conclusions Recurrence of genital HPV infections is relatively common among men and associated with high-risk sexual behavior. Further studies are needed to understand the role of HPV recurrence in the etiology of HPV-associated diseases.

The purpose of this study was to assess whether the incidence of histopathologically confirmed condyloma and penile intraepithelial neoplasia (PeIN) and rates of genital HPV infection progression to these lesions differs by country (Brazil, Mexico, and the U.S.). At each visit, lesions were biopsied and were categorized by pathologic diagnoses. The Linear Array genotyping method was used to identify HPV genotypes from genital swabs, while the INNO-LiPA HPV Genotyping Extra method was used for tissue specimens. Age-specific analyses were conducted for lesion incidence by country, with Kaplan–Meier estimation of cumulative incidence. The proportion of HPV infections that progressed to condyloma and PeIN, the median time to lesion development, and the incidence rates were estimated by country. When comparing demographic and sexual characteristics across the three countries, sexual orientation (p=0.008) and lifetime number of female sexual partners (p

Epilepsy is the most common serious childhood neurological disorder. In the low- and middle-income countries (LMICs) of Africa, children with epilepsy suffer increased morbidity and mortality compared to their counterparts in high-income countries, and the majority do not receive treatment - the childhood epilepsy treatment gap. Reports of the childhood epilepsy treatment gap in Africa are likely underestimates; most surveys do not include several common childhood seizure types, including most types of non-convulsive epilepsy. Efforts to scale up childhood epilepsy care services in the LMICs of Africa must contend with a shortage of physicians and diagnostic technology [e.g., electroencephalograms (EEGs)]. One pragmatic solution is to integrate epilepsy care into primary care by task-shifting to community health extension workers. The aims of this project (BRIDGE) are to: 1) train, develop, and pilot task-shifted epilepsy care teams; 2) develop and pilot innovative childhood epilepsy screening and diagnostic paradigms adapted to the local Hausa language/culture in Kano, northern Nigeria; and, 3) quantify and map the childhood epilepsy treatment gap, using geographic information systems (GIS), to target limited resources to areas of greatest need. Task-shifted teams will diagnose and manage childhood epilepsy using an innovative epilepsy screening tools and diagnostic and management paradigms in environments with limited EEG access. If validated and demonstrated efficacious in clinical trials, this project can be taken to scale across broader areas of west Africa's LMICs that share language and culture. BRIDGE has the potential to enhance access to basic childhood epilepsy care and establish the foundation for childhood epilepsy clinical trials in west Africa. Keywords: Childhood epilepsy, Epilepsy treatment gap, Task shifting, Nigeria, Hausa

Background Individuals with two copies of the apolipoprotein-1 (APOL1) gene risk variants are at high risk (HR) for non-diabetic kidney disease. The presence of these risk variants is highest in West Africa, specifically in Nigeria. However, there is limited availability of dialysis and kidney transplantation in Nigeria, and most individuals will die soon after developing end-stage renal disease. Blocking the renin angiotensin aldosterone system with angiotensin-converting enzyme inhibitors (ACEi) is a well-recognized strategy to slow renal disease progression in patients with diabetes mellitus with chronic kidney disease (CKD) and in patients with HIV-associated nephropathy. We propose to determine whether presence of the APOL1 HR genotype alters or predicts responsiveness to conventional therapy to treat or prevent CKD and if addition of an ACEi to standard combination antiretroviral therapy (ART) reduces the risk of kidney complications among non-diabetic Nigerian adults. Methods/design We will screen 2600 HIV-positive adults who have received ART to (1) determine the prevalence of APOL1 risk variants and assess whether APOL1 HR status correlates with prevalent albuminuria, estimated glomerular filtration rate (eGFR), and/or prevalent CKD; (2) assess, via a randomized, placebo-controlled trial (RCT) in a subset of these participants with microalbuminura (n = 280) whether addition of the ACEi, lisinopril, compared to standard of care, significantly reduces the incidence or progression of albuminuria; and (3) determine whether the APOL1 HR genotype is associated with worse kidney outcomes (i.e. eGFR slope or regression of albuminuria) among participants in the RCT. Conclusions This study will examine the increasing prevalence of kidney diseases in HIV-positive adults in a West African population, and the relationship between these diseases and the APOL1 high-risk genotype. By evaluating the addition of an ACEi to the care of individuals with HIV infection who have albuminuria, our trial will provide definitive evidence to guide strategies for management and clinical care in this population, with the goal of reducing HIV-related kidney complications. Trial registration ClinicalTrials.gov, NCT03201939. Registered on 26 August 2016. Electronic supplementary material The online version of this article (10.1186/s13063-019-3436-y) contains supplementary material, which is available to authorized users.

Background: A validated epilepsy screening and seizure classification instrument, used by community health workers (CHWs), can enhance epilepsy diagnosis and classification to bring care to the 60-90% of children with epilepsy who remain untreated in low- and middle-income countries (LMICs). Methods: An epilepsy screening and seizure type classification tool was translated to the local language (Hausa) and administered by CHWs in clinics in Kano, Nigeria. Children were then evaluated by Kano epileptologists (gold standard). An epileptologist in the U.S., blinded to the clinical evaluations in Kano also interpreted the questionnaire results. Sensitivity, specificity, predictive values, and receiver operating characteristics (ROCs) of the questionnaire were determined. Findings: Of 765 consecutive children screened, the 82 who screened positive and 63 randomly selected from those who screened negative were evaluated by epileptologists. The screening tool demonstrated a sensitivity of 0.95 (95% CI= 0.90, 0.99), specificity of 0.88 (0.80, 0.96), and positive and negative predictive values of 0.90 (0.84, 0.97) and 0.94 (0.88, 0.99), respectively, for epilepsy diagnosis. The ROC for predicting a physician diagnosis of epilepsy was 0.92 (0.87, 0.96) and for predicting classification of focal onset and generalized seizures were 0.89 (0.84, 0.95) and 0.88 (0.81,0.94), respectively. Among children who screened positive for epilepsy, positive and negative predictive values were 1.00 (0.90, 1.00) and 0.73 (0.59, 0.86), respectively, for generalized seizures, and 0.67 (0.51, 0.83) and 1.00 (0.90, 1.00), respectively, for focal onset seizures. Interpretation: This childhood epilepsy screening and classification tool performed well when used by CHWs in northern Nigeria. Funding Statement: Fogarty International Center/NIH (1R21TW010899). Declaration of Interests: This study (ATA, ET, US, HA, ASS, HX, UW, ZI, DJI, HMY, MHA) was supported by Fogarty International Center/National Institutes of Health (FIC/NIH, 1R21TW010899). US was also supported by the VECD Fogarty Global Health Fellows Program (FIC/NIH, D43 TW009337). MHA also reports funding from the US Centers for Disease Control (CDC). DJI also reports funding from the US Agency for International Development (USAID). AAP reports funding from the American Academy of Neurology (Practice Research training scholarship). Ethics Approval Statement: This validation study protocol was approved by the Ethics Committees at AKTH and at the Kano State Ministry of Health, and by the Vanderbilt University Medical Center Internal Review Board.

Objectives: Genital HPV infection in men causes benign and cancerous lesions, the incidence of which differs by age. The goal of this work was to comprehensively evaluate incidence and clearance of individual HPV genotypes among men by age group. Methods: HIV-negative men ages 18–70 with no history of anogenital cancer were recruited for the HPV Infection in Men (HIM) Study. Participants completed clinical exams and questionnaires every six months for up to ~4 years. Genital specimens underwent HPV genotyping, with associations between age and HPV assessed using Cox analyses. Results: 4085 men were followed for a median of 48.6 months (range: 0.3–94.0). Significantly lower HPV incidence rates were observed among the oldest age group (55–70 years) for grouped high-risk (incidence rate ratio [IRR]=0.71), HPV16 (IRR=0.54), grouped low-risk (IRR=0.74), and HPV6 (IRR=0.57) infections compared to men ages 18–24. However, incidence of the grouped 9-valent HPV vaccine types remained constant across the lifespan. Likelihood of HPV6 and HPV16 clearance remained constant until age 54, then increased significantly for men ages 55–70 (adjusted hazard ratio [AHR]=1.92 and 1.65, respectively). Conclusions: Men remain susceptible to HPV infections throughout their lifespan, highlighting the need for prevention efforts with long-lasting duration. Keywords: Human papillomavirus, Natural history, Incidence, Clearance, Age-specific, HIM Study

Background The quadrivalent (types 6/11/16/18) human papillomavirus (HPV) vaccine, Gardasil, has demonstrated efficacy against persistent HPV infection and associated anogenital disease in males. The goal of this Phase II trial was to establish the immunogenicity and safety of Gardasil among mid-adult men ages 27–45 years. Methods One hundred and fifty men from Tampa, FL, US, and Cuernavaca, Mexico who met eligibility criteria (male, 27–45 years old, completed four years of follow-up in the HPV Infection in Men (HIM) natural history study) were enrolled. Subjects completed four visits over seven months, with Gardasil administered at Day 1 and Months 2 and 6. Sera were collected at Day 1 (pre-vaccination) and Month 7 (one month post-dose three). Anti-HPV6, 11, 16, and 18 IgG levels were determined by competitive Luminex immunoassay. Findings 100% of men seroconverted to each of the four HPV vaccine components, and the vaccine was generally well-tolerated. Antibody responses to vaccine did not differ by age group or sexual orientation, regardless of HPV type, and were significantly higher at Month 7 among men who entered the trial seropositive for HPV 6 or 11. Interpretation The immune response to HPV vaccination in men ages 27–45 was comparable to that observed in younger men, in whom clinical efficacy was demonstrated. Further trials to assess the efficacy of HPV vaccines to prevent persistent HPV infections in mid-adult men are needed. Funding Merck & Co. Inc. was the main sponsor of this trial (IISP39256) and provided the study product.

Early HPV infection in males is difficult to detect clinically and pathologically. This study assessed histopathology in diagnosing male genital HPV. External genital lesions (n = 352) were biopsied, diagnosed by a dermatopathologist, and HPV genotyped. A subset (n = 167) was diagnosed independently by a second dermatopathologist and also re-evaluated in detail, tabulating the presence of a set of histopathologic characteristics related to HPV infection. Cases that received discrepant diagnoses or HPV-related diagnoses were evaluated by a third dermatopathologist (n = 163). Across dermatopathologists, three-way concordance was fair (k = 0.30). Pairwise concordance for condyloma was fair to good (k = 0.30-0.67) and poor to moderate for penile intraepithelial neoplasia (k = -0.05 to 0.42). Diagnoses were 44-47% sensitive and 65-72% specific for HPV 6/11-containing lesions, and 20-37% sensitive and 98-99% specific for HPV 16/18. Presence of HPV 6/11 was 75-79% sensitive and 35% specific for predicting pathologic diagnosis of condyloma. For diagnosis of penile intraepithelial neoplasia, HPV 16/18 was 95-96% specific but only 40-64% sensitive. Rounded papillomatosis, hypergranulosis, and dilated vessels were significantly (P

Objectives This cross-sectional study examined the distribution and correlates of salivary secretory leukocyte protease inhibitor (SLPI) concentrations within a multinational cohort of men. Methods Extracellular SLPI was measured in oral gargle cell supernatants of 378 men from three countries using an ELISA-based assay. Risk factor data were collected by a questionnaire. Factors associated with SLPI were assessed using linear and logistic regression for continuous and categorical SLPI, respectively. Results Among men ages 18-73 years, the median SLPI concentration was 492.0 ng/mL (range: 2.3–1919.9). In multivariable modeling, men in Brazil and younger men (18–30 years) were more likely to have higher levels of SLPI, (adjusted odds ratio (aOR) 3.84; 95% confidence interval (CI): 1.94-7.59, and aOR 3.84; 95% CI: 1.98-7.43, respectively). Men with a self-reported STD diagnosis in the past six months were more likely to have higher SLPI levels (aOR 2.98; 95%CI: 1.1-7.83) and men reporting bleeding/swollen gums were less likely to have higher SLPI, (aOR 0.34; 95%CI: 0.15-0.79). Similar results were observed for linear regression models. Conclusions SLPI concentrations varied significantly by country and decreased with increasing age. The interaction between SLPI, modifiable factors, and oral infections that influence cancer risk warrants further investigation. This article is protected by copyright. All rights reserved.

Summary Objectives Secretory leukocyte protease inhibitor (SLPI) is an innate-immunity protein displaying antimicrobial and anti-inflammatory properties that is found in high concentrations in saliva. The role of extracellular salivary SLPI in head and neck squamous cell carcinoma (HNSCC) remains unclear. Thus, we aimed to evaluate the association between SLPI and HNSCC risk in the Cancer Prevention Study II Nutrition Cohort. Materials and methods Among 53,180 men and women with no history of cancer who provided an oral rinse between 2001 and 2002, 60 were subsequently diagnosed with incident HNSCC between specimen collection and June 2009. In this nested case-control study, archived oral supernatants were evaluated using the Human SLPI Quantikine ELISA Kit for all 60 cases and 180 controls individually matched on gender, race, date of birth, and date of oral rinse collection. Conditional logistic regression was used to estimate HNSCC risk. Results Overall, pre-diagnostic salivary SLPI was associated with a non-statistically significant higher risk of HNSCC (OR = 1.6, 95% CI = 0.9–3.0). Among never smokers, high SLPI was associated with a non-statistically significant lower risk (OR = 0.5, 95% CI = 0.1–1.9), whereas among ever smokers, high SLPI was associated with a statistically significant higher risk (OR = 2.1, 95% CI = 1.0–4.3) of HNSCC, compared to low SLPI. Conclusion While results from this study suggest that higher concentrations of salivary SLPI might increase the risk of HNSCC among ever smokers, more research is needed to verify these findings and define the mechanisms by which SLPI and smoking influence the etiology of HNSCC.

Naturally induced serum antibodies against human papillomavirus (HPV) may affect risks of subsequent incident genital infections by HPV 6, 11, 16, or 18 in men. In this study, we examined the hypothesis by following 4,123 healthy men every 6 months (median follow-up time, 4.1 years). HPV antibodies were measured at baseline using a virus-like particle-based ELISA assay. Genital HPV genotypes were detected using Roche Linear Array. Incidence proportions and 6-month persistence proportions were calculated at 6-month intervals. Kaplan–Meier curves and Cox models were used to assess genotype-specific cumulative incidence and HRs, respectively. HPV 6, 11, 16, and 18 seroprevalence was 8.1%, 13.9%, 12.7%, and 10.8%, respectively. Significantly higher rates of incident infections were observed for HPV 16 among baseline-seropositive men [adjusted HR, 1.37; 95% confidence interval (CI), 1.01–1.86], with similar but nonsignificant HRs for 6-month persistent infections. Risk of persistent HPV 18 infection was significantly lower among seropositive men in the unadjusted model (HR, 0.22; 95% CI, 0.06–0.91), but not in the adjusted model (HR, 0.19; 95% CI, 0.03–1.37). Incident and 6-month persistent infections for HPV 6 and 11 did not differ by baseline serostatus. Baseline serostatus among men was not associated with a reduction in subsequent incident genital HPV 6, 11, and 16 infections. However, protection against persistent HPV18 infections was observed in unadjusted models. Our research suggests a need of further studies to examine the potentially protective effects of naturally induced HPV18 antibodies in men. Cancer Res; 76(20); 6066–75. ©2016 AACR.

Background Given high rates of anal disease, we investigated the natural history of high-risk anal human papillomavirus (HPV) among a multinational group of men who have sex with men (MSM) aged 18-64 years. Methods Anal specimens from human immunodeficiency virus-negative men from Brazil, Mexico, and the United States were genotyped. Over 2 years, 406 MSM provided evaluable specimens every 6 months for ≥2 visits. These men were stratified into men who have sex only with men (MSOM, n = 70) and men who have sex with women and men (MSWM, n = 336). Persistence was defined as ≥12 months' type-specific duration and could begin with either a prevalent or incident infection. Prevalence ratios and 95% confidence intervals were calculated by Poisson regression. Results Median follow-up time was 2.1 years. Retention was 82%. Annual cumulative incidence of 9-valent vaccine types was 19% and 8% among MSOM and MSWM, respectively (log-rank P = .02). Duration of anal HPV did not differ for MSOM and MSWM and was a median of 6.9 months for HPV-16 after combining men from the 2 groups. Among men with prevalent high-risk infection (n = 106), a total of 36.8%, retained the infection for at least 24 months. For those with prevalent HPV-16 (n = 27), 29.6% were persistent for at least 24 months. Persistence of high-risk HPV was associated with number of male anal sex partners and inversely associated with number of female sex partners. Conclusions MSM with prevalent high-risk HPV infection should be considered at increased risk for nontransient infection.

Persistent infection with oral HPV16 is believed to drive the development of most oropharyngeal cancers. However, patterns of oral HPV16 persistence remain understudied, particularly among HIV-negative individuals. Oral HPV16 persistence was evaluated among 1,626 participants of the HPV Infection in Men (HIM) Study. Twenty-three oral HPV16-positive men who provided an oral gargle sample on ≥2 study visits were included in the analysis. Archived oral samples from all follow-up visits were tested for HPV16 using Linear Array and INNO-LiPA detection methods. Persistence was evaluated using consecutive HPV16-positive visits held approximately 6 months apart and using the Kaplan–Meier method. Oral HPV16-positive men were aged 18 to 64 years [median, 36 years; interquartile range (IQR), 25–42] and were followed for a median of 44.4 months (IQR, 29.9–49.5). Of 13 incident infections, 4 (30.8%) persisted ≥12 months, 1 (10.0%) persisted ≥24 months, and none persisted ≥36 months [median infection duration, 7.3 months; 95% confidence interval (CI), 6.4–NA)]. Of 10 prevalent infections, 9 (90.0%) persisted ≥12 months, 8 (80.0%) persisted ≥24 months, 4 (57.1%) persisted ≥36 months, and 2 (40.0%) persisted ≥48 months (median infection duration, NA). Twelve-month persistence of incident infections increased significantly with age (Ptrend = 0.028). Prevalent oral HPV16 infections in men persisted longer than newly acquired infections, and persistence appeared to increase with age. These findings may explain the high prevalence of oral HPV observed at older ages. Understanding oral HPV16 persistence will aid in the identification of men at high-risk of developing HPV-related oropharyngeal cancer. Cancer Prev Res; 8(3); 190–6. ©2015 AACR.

Human papillomavirus (HPV) is known to cause external genital lesions (EGLs) in men, including condylomata acuminata, commonly referred to as condyloma or genital warts, as well as penile intraepithelial neoplasia (PeIN), which is believed to be a precursor to penile cancer [1]. While HPV-related condyloma is considered a benign lesion, the substantial economic and psychosocial burden of this clinical manifestation of infection cannot be overlooked. The incidence of penile cancer is increasing globally, with incidence rates in Brazil among the highest worldwide [2] and no routine screening tests available for penile cancer or the precursor PeIN lesions. Studies of HPV-related EGLs have primarily been limited to condyloma and low-risk HPV genotypes 6 and 11, owing to the rarity of PeIN and the lack of long-term, prospective cohorts of men. Studies to determine the role of other high- or low-risk types in the etiology of these EGLs are similarly limited. A quadrivalent vaccine, offering protection against HPV genotypes 6 and 11 and high-risk HPV genotypes 16 and 18, has been demonstrated as efficacious in men [3] but has not yet been approved for the prevention of penile cancer. This vaccine is also approved only for use in young men (ages 9–26 years); it is recommended by the Centers for Disease Control and Prevention for males ages 11–22 years and for high-risk males aged up to 26 years, but no HPV vaccine prevention options are currently available for men at older ages. Further studies of the causative HPV genotypes of benign and precancerous lesions and the ages at which these lesions occur are necessary to inform development of prevention and screening strategies. Using the established HPV Infection in Men (HIM) study cohort, a multinational study of men across the life span from the United States, Brazil, and Mexico, we sought to determine the incidence of pathologically confirmed EGLs, by lesion type, among men in different age groups and to evaluate the HPV types that were associated with EGL development.

Background Human papillomavirus (HPV) causes two types of external genital lesions (EGLs) in men: genital warts (condyloma) and penile intraepithelial neoplasia (PeIN). Objective The purpose of this study was to describe genital HPV progression to a histopathologically confirmed HPV-related EGL. Design, setting, and participants A prospective analysis nested within the HPV Infection in Men (HIM) study was conducted among 3033 men. At each visit, visually distinct EGLs were biopsied; the biopsy specimens were subjected to pathologic evaluation and categorized by pathologic diagnoses. Genital swabs and biopsies were used to identify HPV types using the Linear Array genotyping method for swabs and INNO-LiPA for biopsy specimens. Outcome measurements and statistical analysis EGL incidence was determined among 1788 HPV-positive men, and cumulative incidence rates at 6, 12, and 24 mo were estimated. The proportion of HPV infections that progressed to EGL was also calculated, along with median time to EGL development. Results and limitations Among 1788 HPV-positive men, 92 developed an incident EGL during follow-up (9 PeIN and 86 condyloma). During the first 12 mo of follow-up, 16% of men with a genital HPV 6 infection developed an HPV 6-positive condyloma, and 22% of genital HPV 11 infections progressed to an HPV 11-positive condyloma. During the first 12 mo of follow-up, 0.5% of men with a genital HPV 16 infection developed an HPV 16-positive PeIN. Although we expected PeIN to be a rare event, the sample size for PeIN ( n =10) limited the types of analyses that could be performed. Conclusions Most EGLs develop following infection with HPV 6, 11, or 16, all of which could be prevented with the 4-valent HPV vaccine. Patient summary In this study, we looked at genital human papillomavirus (HPV) infections that can cause lesions in men. The HPV that we detected within the lesions could be prevented by a vaccine.

Background Cutaneous human papillomaviruses (HPVs) may be associated with cutaneous epithelial lesions and non-melanoma skin cancers. No study has systematically evaluated the presence of genus beta [β]-HPV in male genital skin or external genital lesions (EGLs) Objectives To examine cutaneous β-HPV types detected on the surface of EGLs in men and describe their presence prior to EGL development. Study design A retrospective case series was conducted among 69 men with pathologically confirmed EGLs (n = 72) who participated in the HPV Infection in Men Study. Archived exfoliated cells collected from the surface of each EGL and normal genital skin specimens 6–12 months preceding EGL development were tested for β-HPV DNA using a type-specific multiplex genotyping assay. Results β-HPV DNA was detected on 61.1% of all EGLs, with types 38 (16.7%), 5 (15.3%), and 12 (12.5%) most commonly identified. HPV prevalence differed across pathological diagnoses, with the largest number of β-HPV types detected on condylomas. Most β-HPV types were detected on normal genital skin prior to EGL development, though the prevalence was lower on EGLs compared to preceding normal genital skin. Conclusions EGLs and the normal genital skin of men harbor a large number of β-HPV types; however, it appears that β-HPVs are unrelated to EGL development in men. Despite evidence to support a causal role in skin carcinogenesis at UVR-exposed sites, cutaneous HPV appears unlikely to cause disease at the UVR-unexposed genitals.

Antibodies against the Human papillomavirus 16 (HPV16) E6 oncoprotein appear years prior to clinical diagnosis of anal and oropharyngeal cancer, but whether they develop around the time of HPV infection is unclear. Serum samples from 173 cancer-free men from the Human Papillomavirus Infection in Men (HIM) Study were tested for HPV antibodies and DNA. HPV16 E6 seropositivity was low among men with oral HPV16-infection (1/28; 3.6%, 95%CI=0.0–18.4%), anal HPV16-infection (1/61; 1.6%, 95%CI=0.0–8.8%), and 24-month persistent genital HPV16-infection (1/84; 1.2%, 0.0–6.5%). This suggests E6 seroconversion may not occur around the time of oral, anal, or genital HPV16 acquisition. Keywords: HPV, HPV16 E6 seropositivity, Oropharyngeal cancer, Anal cancer, Penile cancer