Training the next generation of Biostatisticians in West Africa: The Vanderbilt Nigeria Biostatistics Training Program (VN-BioStat).

Biomedical HIV research is growing in West Africa, but biostatistical expertise is lagging. The Vanderbilt-Nigeria Biostatistics Training Program (VN-BioStat) seeks to establish a research and training platform for biostatisticians doing HIV-related research in Nigeria. The objectives of the program are: 1) Host two Nigerian data scientists per year (a total of 10 over 5 years) at Vanderbilt University Medical Center to gain hands-on biostatistics training and experience via one-year fellowships. Eligible trainees will be junior investigators with PhDs or nearing completion of their PhDs in statistics or related fields, including mathematics and computer science. 2) Conduct annual workshops in Nigeria to provide biostatistics training. Trainees will undertake biostatistics coursework and hands-on training and participate in mentorship as biostatisticians involved in HIV research. Trainees will be at Vanderbilt for a full year and be part of an active biostatistics department. They will be immersed in a dry-lab HIV biostatistics project in collaboration with a Nigerian HIV research project and lead a methodologically focused research project. They will also participate in a one-month research training/grant writing program in Nashville. The VN-BioStat program will build on the existing momentum of ongoing initiatives to enhance research capacity in Nigeria by developing biostatistics leadership. VN-BioStat trainees will interact with investigators from Nigeria to provide collaborative biostatistical assistance with study design and data analysis, thus gaining real-world experience that will benefit the trainees and the broader research community in Nigeria.

LMIC Research Centers' Experiences Hosting U.S. and LMIC Trainees: Evaluation of the Fogarty Global Health Fellows and Scholars Program, 2012 to 2020.

In this mixed-methods study, we explore themes that emerged from a survey assessing the programmatic experiences of mentors and administrators at institutions in low- and middle-income countries (LMICs) hosting trainees supported by the Fogarty International Center's Global Health Program for Fellows and Scholars. A total of 89 of 170 potential respondents representing 31 countries completed the survey (response rate, 52.4%). There was agreement among respondents that their institutions received sufficient funds to support trainees and had the capacity to manage operational and financial aspects of the program. A majority also agreed that both LMIC and U.S. trainees were beneficial to the host institutions, and that trainee projects were relevant to the needs of the host country. Respondents felt that program benefits to LMIC trainees could be improved by increasing the research consumables budget, increasing the flexibility of program timelines, and increasing engagement between LMIC and U.S. trainees and institutions. Respondents indicated that both U.S. and LMIC trainees behaved professionally (including demonstrating respectful and ethical behavior) and took appropriate initiative to conduct their research projects. Findings from this study will help inform innovations to similar training initiatives that will enhance sustainability and improve program performance, and will be responsive to local needs.

The Vanderbilt Nigeria Biostatistics Training Program (VN-BioStat): Results from a Skills Workshop.

The Vanderbilt-Nigeria Biostatistics Training Program (VN-BioStat) aims to establish a research and training platform for biostatisticians doing HIV-related research in Nigeria, including enhancing mid-level biostatistics capacity through annual workshops. This paper describes findings from the inaugural workshop in Kano, Nigeria. Participants were surveyed before and after the workshop to assess their self-perceived familiarity with and confidence in their abilities to use statistical software and apply specific statistical techniques, as well as to gather feedback regarding the conduct of the workshop and future topic areas. Of the 23 participants enrolled in the workshop, 22 (96%) completed both pre- and post-workshop assessments. In both pre-workshop and post-workshop surveys, participants ranked their confidence in statistical skills using Likert scales. Scores were transformed to a 0-100 scale, and averages computed. Participants also shared open-ended feedback about the workshop and suggested future topic areas. Before the training, the average participant reported having either a "beginner" (30% of participants) or "moderate" (43%) level of familiarity with R. Many participants (65%) rated themselves as having "moderate" or "expert" familiarity with SPSS. Pre-workshop averages for confidence ranged from 26 to 64, with lowest confidence in "expanding continuous covariates in regression models and interpret results" and highest confidence in "fitting and interpreting results from a linear regression model". Post-workshop averages for confidence were all above 70. The lowest post-workshop score (74) was for "fit and interpret results from a semiparametric linear transformation model". The greatest increase in confidence was observed in "expanding continuous covariates in regression models using splines and interpreting results" and the lowest increase was in "fitting and interpreting results from a linear regression model." Participants offered positive feedback on instructor effectiveness (4.9/5) and overall course quality (4.9/5). While the overall course was rated on a 0-100 scale as "moderately difficult" (mean ± SD: 40.5 ± 17.5), the participants felt the course was highly organized (87.7 ± 17.8), and the information was moderately easy to learn (81.9 ± 15.9). Suggestions for future workshops included providing supplementary resources for out-of-classroom learning and releasing codes in advance to enhance participants' preparation. Among suggestions for future workshop topics, 80% of respondents listed survival analysis. Lessons learned provide insight into how short-term training opportunities can be leveraged to build biostatistics capacity in similar settings.

Building Physician-Scientist Skills in R Programming:A Short Workshop Report.

Introduction: Statistical analysis programs require coding experience and a basic understanding of programming, skills which are not taught as part of medical school or residency curricula. Methods: We conducted a five-day course for early-career Nigerian physician-scientists interested in learning common statistical tests and acquiring R programming skills. The workshop included didactic presentations, small group learning activities, and interactive discussions. A baseline questionnaire captured participant demographics and solicited participants' level of confidence in understanding/performing common statistical tests. REDCap questionnaires were emailed to obtain feedback on educational format and content. A post-workshop assessment covered participants' overall impression of the program. Results: A total of 23 participants attended the program. Most participants were male (n=14, 60.9%) and at an early stage in their career (assistant professor, n=20, 87.0%). Approximately 70% of respondents indicated having received some prior training in statistics. The proportion of participants without experience using R and SAS software (90% and 85%, respectively) was greater than the corresponding proportions for Stata (55%) and SPSS (20%). Prior to the workshop, most respondents expressed being "not at all confident" in performing one-way ANOVA (60%), logistic regression (68%), simple linear regression (60%), and McNemar's test (80%). There was a statistically significant post-workshop improvement in the level of confidence in understanding and performing common statistical tests. The course was rated on a 0-100 scale as "moderately difficult" (mean ± SD: 51.7 ± 19.5). Most participants felt comfortable in putting the knowledge learned into practice (82.2 ± 17.1). Conclusion and Public Health Implications: Introductory R can be taught to junior physician-scientists in resource-limited settings and can inform the development and implementation of similar training initiatives in analogous settings.

Etiology of Persistent Microalbuminuria in Nigeria (P_MICRO study): protocol and study design.

BACKGROUND: Microalbuminuria is an independent risk factor for cardiovascular and kidney disease and a predictor of end organ damage, both in the general population and in persons with HIV (PWH). Microalbuminuria is also an important risk factor for mortality in PWH treated with antiretroviral therapy (ART). In the ongoing Renal Risk Reduction (R3) study in Nigeria, we identified a high prevalence of microalbuminuria confirmed by two measurements 4-8 weeks apart in ART-experienced, virologically suppressed PWH. Although Stage 1 or 2 hypertension and exposure to potentially nephrotoxic antiretroviral medications were common in R3 participants, other traditional risk factors for albuminuria and kidney disease, including diabetes, APOL1 high-risk genotype, and smoking were rare. Co-infection with endemic pathogens may also be significant contributors to albuminuria, but co-infections were not evaluated in the R3 study population. METHODS: In Aim 1, we will cross-sectionally compare the prevalence of albuminuria and established kidney disease risk factors in a cohort of PWH to age- and sex-matched HIV-negative adults presenting for routine care at the Aminu Kano Teaching Hospital in Kano, Nigeria. We will leverage stored specimens from 2500 R3 participants and enroll an additional 500 PLWH recently initiated on ART (≤ 24 months) and 750 age- and sex-matched HIV-negative adults to determine the contribution of HIV, hypertension, and other comorbid medical conditions to prevalent albuminuria. In Aim 2, we will follow a cohort of 1000 HIV-positive, ART-treated and 500 HIV-negative normoalbuminuric adults for 30 months to evaluate the incidence and predictors of albuminuria. DISCUSSION: The findings from this study will support the development of interventions to prevent or address microalbuminuria in PWH to reduce kidney and cardiovascular morbidity and mortality. Such interventions might include more intensive monitoring and treatment of traditional risk factors, the provision of renin-angiotensin aldosterone system or sodium-glucose cotransporter-2 inhibitors, consideration of changes in ART regimen, and screening and treatment for relevant co-infections.

Building Research Capacity in HIV and Noncommunicable Diseases in Africa: A Mentorship and Leadership Workshop Report.

INTRODUCTION: Few structured mentoring programs target early-stage investigators in Africa, creating a gap in mentorship skills where HIV burden is greatest. We describe findings from a Nigeria-based workshop for early-career physician scientists to build mentoring and leadership capacity in HIV and noncommunicable disease research. METHODS: Baseline surveys captured participant demographics, confidence in implementing mentoring competencies, and perceived importance of workshop training domains. The workshop included didactic presentations, small group activities, and interactive discussions. Daily surveys evaluated sessions, and postworkshop surveys solicited overall course impressions. RESULTS: Of the 33 participants, most were male (n = 21, 63.6%) and from medicine, laboratory sciences, and surgical specialties. "Building mentees' confidence" and "setting mentees' research goals" were ranked as areas where participants most believed they needed training. Sessions were rated favorably across five areas. Greatest improvements in mean scores were for confidence in identifying personal temperament styles, describing mentoring and leadership theories/frameworks, and developing mentoring plans. Additional identified workshop strengths were content relevance, leadership case series, interactive nature, and collegial atmosphere. All respondents indicated learning something new/useful/helpful in each session. At 6-month postworkshop, most respondents (25 of 26, 96%) had replicated or plan to replicate parts of the workshop in their departments/institutions. DISCUSSION: Effective mentoring training initiatives targeting future academic leaders have the potential to create skilled academicians who can impart mentoring skills and competencies to their mentees.

Expanding Global Health Engagement through Fogarty Fellowship Programs.

Training the next generation of global health researchers is vital for sustainable research partnerships and global health equity. The Fogarty International Center (National Institutes of Health) supports postdoctoral fellows and professional/graduate students in long-term, hands-on mentored research in low- and middle-income countries (LMICs). We surveyed 627 alumni (58% from the United States, 42% from LMICs) from three sequential Fogarty-sponsored global health research training programs (response rate: N = 257, 41%). Publications in the Index Medicus were used to ascertain scholarly output. Most alumni (63%) reported remaining engaged in LMICs and/or worked in academic/research careers (70%). Since completing their Fogarty fellowship, 144 alumni (56%) had received 438 new grants as principal investigator (PI), co-/multi-PI, or site PI. The 257 responding alumni had 5,318 publications during and since their Fogarty fellowships; 2,083 (39%) listed the Fogarty trainee as the first or senior author. These global health training programs highlight the value of LMIC research experience in nurturing the global health research workforce.

The V-RAMP Program: Building Research Administration and Management Capacity in Nigeria.

The increasing volume and complexity of research activities in Nigeria necessitates urgent measures to improve research infrastructure in grants administration and management. The Vanderbilt-Nigeria Research Administration and Management Training Program (V-RAMP) seeks to build infrastructure capacity in research administration and management and research ethics at a major teaching hospital in Nigeria. We will perform a mixed methods needs assessment of the administrative and management environment and develop an action plan to address infrastructure needs, prioritize processes, and guide program implementation. We will capacitate a newly established Office of Research Administration and improve the knowledge and skills of research administrators and grant managers via short term in-person trainings in Nashville, Tennessee and in Kano, Nigeria and through remote learning opportunities. We will enhance local administrative efficiency and performance of research ethics operations through training and mentoring of members and staff of the ethics review committee. Systematic processes to streamline protocols, including a REDCap protocol tracking database and standard operating procedures in the responsible conduct of research and rigor and reproducibility will also be developed. V-RAMP will enable the creation of a high-quality research administration environment that is knowledgeable, efficient, and compliant regarding the fiscal, management and ethical standards of sponsored research.

Strategies for Successful Clinical Trial Recruitment of People Living with HIV in Low- and Middle-Income Countries: Lessons Learned and Implementation Implications from the Nigeria Renal Risk Reduction (R3) Trial.

PURPOSE OF REVIEW: Clinical trials represent a bedrock for measuring efficacy of interventions in biomedical research, but recruitment into clinical trials remains a challenge. Few data have focused on recruitment strategies from the perspective of clinical trial teams, especially in low- and middle-income countries (LMIC), where HIV is most prevalent. RECENT FINDINGS: We summarized data from the literature and our experience with recruitment for the Renal Risk Reduction trial, aimed at reducing risk of kidney complications among people living with HIV in Nigeria. Using an implementation science framework, we identified strategies that contributed to successful clinical trial recruitment. For strategies that could not be categorized by this framework, we summarized key features according to selected action, actor, target, context, and time. We identified how these identified strategies could map to subsequent implementation outcomes at the patient and provider/health system level, as well as capacity-building efforts to meet needs identified by LMIC partners, which is a priority for success. Our experience highlights the importance of considering implementation outcomes, and the strategies necessary to achieve those outcomes early, in the planning and execution of clinical trials. Clinical trial recruitment can be optimized via methodologies grounded in implementation science.

Apolipoprotein-1 risk variants and associated kidney phenotypes in an adult HIV cohort in Nigeria.

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/1.73m2 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.

HIV-associated nephropathy: Protocol and rationale for an exploratory genotype-phenotype study in a sub-Saharan African population.

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.

The V-BRCH Project: building clinical trial research capacity for HIV and noncommunicable diseases in Nigeria.

Antiretroviral therapy has turned HIV into a chronic condition, with morbidity from HIV-associated noncommunicable diseases (NCDs) becoming more common as HIV-infected individuals live longer. In Nigeria, the additional challenge of an under-capacitated health system highlights the need for skilled clinical investigators who can generate evidence to tackle the double burden of HIV and NCDs. The Vanderbilt-Nigeria Building Research Capacity in HIV and Non-communicable Diseases (V-BRCH) programme is a training platform to create a cohort of skilled Nigerian investigators with the capacity to lead independent clinical trial research focused on the intersection of HIV and NCDs. V-BRCH will solidify an atmosphere of continuous mentoring and skills acquisition for physician faculty at the Aminu Kano Teaching Hospital via short- and medium-term learning opportunities, paired mentoring arrangements, and mentored research projects. Trainees will attend an annual faculty enrichment programme in Nashville, in addition to on-site workshops in Nigeria on HIV-associated NCD epidemiology, clinical trials methodology, evidence synthesis, qualitative research methods, stakeholder engagement, knowledge translation, and grant writing. Research-oriented junior faculty will undergo focused training in clinical trials administration and regulatory oversight. Scholars will share best practices through mentoring panels, regular 'Works in Progress' meetings, and monthly career development seminars. Competitive seed grants will be provided to mentor-mentee teams to promote targeted in-country pilot studies focused on HIV-associated NCDs. For long-term training, physician scientists will be supported to undergo enhanced Master of Public Health (MPH) training at Bayero University in Nigeria and Master of Science in Clinical Investigation (MSCI) training at Vanderbilt. Short-term regional courses, staff development workshops, and MPH curriculum refinement will help to strengthen institutional capacity in HIV-associated NCD clinical trial research. V-BRCH will create a cohort of skilled Nigerian scientists who will be able to compete for independent funding and design and implement high quality research that will generate evidence to inform policy and practice and lead to improved outcomes for Nigerians impacted by HIV-associated NCDs.

Optimal management of HIV- positive adults at risk for kidney disease in Nigeria (Renal Risk Reduction "R3" Trial): protocol and study design.

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.

Bridging the childhood epilepsy treatment gap in northern Nigeria (BRIDGE): Rationale and design of pre-clinical trial studies.

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.

Recurrence of Genital Infections With 9 Human Papillomavirus (HPV) Vaccine Types (6, 11, 16, 18, 31, 33, 45, 52, and 58) Among Men in the HPV Infection in Men (HIM) Study.

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.

Country-specific HPV-related genital disease among men residing in Brazil, Mexico and The United States: The HIM study.

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 < 0.0001) were differentially associated with lesion incidence in the three countries. Condyloma incidence in Brazil and the U.S. decreased with age, while incidence remained constant across the lifespan in Mexico. There were no differences by country and age for PeIN incidence. HPV types 6 and 11 were the most common types to progress to condyloma and HPV types 16, 6 and 11 were the most common types to progress to PeIN in all three countries. The continuous risk of condyloma and PeIN across all age groups and countries in this study emphasizes the need to ensure that strong HPV immunity, such as that obtained through vaccination, is maintained across the lifespan of men.

Seroprevalence of cutaneous human papillomaviruses (HPVs) among men in the multinational HPV Infection in Men study.

Data on cutaneous human papillomavirus (HPV) seroprevalence are primarily derived from skin cancer case-control studies. Few studies have reported the seroprevalence of cutaneous HPV among healthy men. This study investigated the seroprevalence of cutaneous HPV types and associated risk factors among men residing in Brazil, Mexico and the USA. Six hundred men were randomly selected from the HPV Infection in Men study. Archived serum specimens were tested for antibodies against 14 cutaneous HPV genotypes, ß-HPV types (5/8/12/14/17/22/23/24/38/48), α-HPV 27, γ-HPV 4, µ-HPV1 and ν-HPV 41 using a glutathione S-transferase L1-based multiplex serology assay. Risk factor data were collected by a questionnaire. Binomial proportions were used to estimate seroprevalence, and logistic regression to examine factors associated with seropositivity. Overall, 65.4 % of men were seropositive to ≥1 of the 14 cutaneous HPV types, and 39.0 % were positive for ≥1 ß-HPV types. Seroprevalence was 8.9, 30.9, 28.6 and 9.4 % for α-HPV 27, γ-HPV 4, µ-HPV 1 and ν-HPV 41, respectively. In multivariate analyses, seropositivity for any cutaneous HPV type was associated with higher education [adjusted odds ratio (AOR) 1.75; 95 % confidence interval (CI) 1.08-2.83], and seropositivity of any ß-HPV type was significantly associated with increasing age (AOR 1.72; 95 % CI 1.12-2.63, for men aged 31-44 years vs men aged 18-30 years). Other factors associated with various type-specific cutaneous HPV seropositivity included country, circumcision and lifetime number of male sexual partners. These data indicate that exposure to cutaneous HPV is common. Future studies are needed to assess the role of cutaneous HPV in diseases.

Impact of Serum Antibodies to HPV Serotypes 6, 11, 16, and 18 to Risks of Subsequent Genital HPV Infections in Men: The HIM Study.

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.

Incidence, Duration, Persistence, and Factors Associated With High-risk Anal Human Papillomavirus Persistence Among HIV-negative Men Who Have Sex With Men: A Multinational Study.

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.

Salivary secretory leukocyte protease inhibitor (SLPI) and head and neck cancer: The Cancer Prevention Study II Nutrition Cohort.

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.