Genome, HLA and polygenic risk score analyses for prevalent and persistent cervical human papillomavirus (HPV) infections.

Genetic variants that underlie susceptibility to cervical high-risk human papillomavirus (hrHPV) infections are largely unknown. We conducted discovery genome-wide association studies (GWAS), replication, meta-analysis and colocalization, generated polygenic risk scores (PRS) and examined the association of classical HLA alleles and cervical hrHPV infections in a cohort of over 10,000 women. We identified genome-wide significant variants for prevalent hrHPV around LDB2 and for persistent hrHPV near TPTE2, SMAD2, and CDH12, which code for proteins that are significantly expressed in the human endocervix. Genetic variants associated with persistent hrHPV are in genes enriched for the antigen processing and presentation gene set. HLA-DRB1*13:02, HLA-DQB1*05:02 and HLA-DRB1*03:01 were associated with increased risk, and HLA-DRB1*15:03 was associated with decreased risk of persistent hrHPV. The analyses of peptide binding predictions showed that HLA-DRB1 alleles that were positively associated with persistent hrHPV showed weaker binding with peptides derived from hrHPV proteins and vice versa. The PRS for persistent hrHPV with the best model fit, had a P-value threshold (PT) of 0.001 and a p-value of 0.06 (-log10(0.06) = 1.22). The findings of this study expand our understanding of genetic risk factors for hrHPV infection and persistence and highlight the roles of MHC class II molecules in hrHPV infection.

Dataset for Vaginal Human Papillomavirus infection among adolescent and early adult girls in Jos, Nigeria.

Objectives: To assess risk factors for HPV infection, determine knowledge about HPV vaccines, assess willingness to receive the HPV vaccine among adolescent and early adult girls in Nigeria, we administered a structured questionnaire. We also collected samples to determine the prevalence and patterns of HPV infections. Data description: The dataset contains the responses of 205 participants from 10 randomly selected public and private secondary schools in Jos, Nigeria. The data includes information on risk factors for HPV infections such as sexual behaviours, knowledge about HPV vaccine and willingness to receive the vaccine. This is valuable information that can be compared to data from studies in other environments or to determine changes in the pattern of risk factors and HPV prevalence in this population over time.

Vaginal microbiota diversity and paucity of Lactobacillus species are associated with persistent hrHPV infection in HIV negative but not in HIV positive women.

The vaginal microbiota is thought to play a role in modulating risk of high-risk human papillomavirus (hrHPV) infection. We examined the relationship between the vaginal microbiota and persistent hrHPV infection in HIV-negative and HIV-positive women. We used 16S-rRNA sequencing to characterize the vaginal microbiota of two serial samples taken six months apart from 211 Nigerian women (67%, 142/211 HIV-positive and 33%, 69/211 HIV-negative) and evaluated the association between the vaginal microbiota and persistent hrHPV infection using generalized estimating equation logistic regression models and linear discriminant analysis effect size (LEfSe) algorithm to identify phylotypic biomarkers of persistent hrHPV infection. The high diversity microbiota, Community State Type IV-B, was the most prevalent in both HIV-negative (38% at baseline, 30% at the follow-up visit) and HIV-positive (27% at baseline, 35% at the follow-up visit) women. The relationship between the vaginal microbiota and persistent hrHPV was modified by HIV status. In HIV-negative women, women with Lactobacillus dominant microbiota had lower odds (OR: 0.35, 95% CI 0.14-0.89, p = 0.03) of persistent hrHPV compared to women with Lactobacillus deficient microbiota. While among HIV-positive women, the odds of being persistently infected with hrHPV was higher in women with Lactobacillus dominant microbiota (OR: 1.25, 95% CI 0.73-2.14 p = 0.41). This difference in effect estimates by HIV was statistically significant (p = 0.02). A high diversity vaginal microbial community with paucity of Lactobacillus species was associated with persistent hrHPV infection in HIV-negative women but not in HIV-positive women.

Prevalence and incidence of genital warts and cervical Human Papillomavirus infections in Nigerian women.

BACKGROUND: Genital warts are important causes of morbidity and their prevalence and incidence can be used to evaluate the impact of HPV vaccination in a population. METHODS: We enrolled 1020 women in a prospective cohort study in Nigeria and followed them for a mean (SD) of 9 (4) months. Nurses conducted pelvic examinations and collected ectocervical samples for HPV testing. We used exact logistic regression models to identify risk factors for genital warts. RESULTS: The mean age of study participants was 38 years, 56% (535/962) were HIV-negative and 44% (427/962) were HIV-positive. Prevalence of genital warts at enrolment was 1% (4/535) among HIV-negative women, and 5% (23/427) among HIV-positive women. Of 614 women (307 HIV negative and 307 HIV positive women) for whom we could compute genital wart incidence, it was 515 (95% CI:13-2872) per 100,000 person-years in HIV-negative and 1370 (95% CI:283-4033) per 100,000 person-years in HIV-positive women. HIV was associated with higher risk of prevalent genital warts (OR:7.14, 95% CI:2.41-28.7, p < 0.001) while higher number of sex partners in the past year was associated with increased risk of incident genital warts (OR:2.86, 95% CI:1.04-6.47. p = 0.04). HPV11 was the only HPV associated with prevalent genital warts in this population (OR:8.21, 95% CI:2.47-27.3, p = 0.001). CONCLUSION: Genital warts are common in Nigeria and our results provide important parameters for monitoring the impact of future HPV vaccination programs in the country. HIV infection and number of sexual partners in past year were important risk factors for prevalent and incident genital warts respectively.

Secular trend in interobserver agreement of VIA diagnosis for cervical cancer screening in Nigeria.

OBJECTIVE: In low resource settings, visual inspection with acetic acid (VIA) by allied health workers, has been suggested as an alternative for cervical cancer screening. However, there are concerns about the objectivity and time to diagnostic concordance with specialists. We evaluated the secular trend in interobserver agreement between nurse providers and a gynecologist/colposcopist over a five-year period. METHODS: Nurses provided VIA screening with digital cervivography to 4,961 participants in five screening clinics from October 2010 to May 2014 in Nigeria in this observational study. Cervigraphs were reviewed at meetings where a gynaecologist/colposcopist made an assessment from the cervigraphs. We used weighted kappa statistics to calculate agreement in diagnosis between nurse providers and the gynecologist/colposcopist; linear regression models to examine overall trend and investigate potential clinic characteristics that may influence agreement; and time series models to characterize month to month variations. RESULTS: Mean age of participants was 37±8 years. Overall agreement was 0.89 at Site D, 0.78 and 0.73 at Sites A and C respectively, 0.50 for Site E and 0.34 for Site C. The number of trainings attended by nurse providers(ß = 0.47,95%CI:0.02-0.93, p = 0.04), high level of engagement by site gynecologists(ß = 0.11,95%CI:0.01-0.21,p = 0.04) were associated with increased agreement; while increasing distance from the coordinating site(ß = -0.47,95%CI:-0.92-0.02,p = 0.04) was associated with decreased agreement. There were no associations between number of years screening clinics were operational(ß = 0.01,95%CI: -0.01-0.03,p = 0.29), cumulative experience of nurse providers(ß = 0.04,95%CI:-0.03-0.12,p = 0.19) and agreement. There were no significant increases in weighted kappa statistics over time for all sites considered. Monthly variations were significant for only one of two sites considered in time series models (AR1 term = -0.40, 95%CI:-0.71-0.09,p = 0.01). CONCLUSION: Our results showed a lack of objectivity, persistent variation and lack of convergence of diagnostic capabilities of nurse led VIA cervical cancer screening with the diagnostic capabilities of a specialist in a cervical cancer screening program in Nigeria.

Clearance of Type-Specific, Low-Risk, and High-Risk Cervical Human Papillomavirus Infections in HIV-Negative and HIV-Positive Women.

Purpose There is a dearth of data on clearance of cervical human papillomavirus (HPV) infection among women in West Africa. We examined the clearance of low-risk (lr) and high-risk (hr) cervical HPV infections, and the factors associated with these measures in HIV-negative and HIV-positive women. Methods We studied 630 Nigerian women involved in a study of HPV infection using short polymerase chain reaction fragment-10 assay and line probe assay-25. Research nurses used a cervical brush to collect samples of exfoliated cervical cells from all the study participants. Cox proportional hazards models were used to estimate associations between HIV and HPV infections. Results The mean age of the study participants was 38 (standard deviation, ± 8) years; 51% were HIV positive. The rate of clearing any HPV infection was 2.0% per month among all women in the study population, 2.5% per month among HIV-negative women, and 1.6% per month, among HIV-positive women. The clearance rate per 1,000 person-months of observation for any lrHPV infection and any hrHPV infection were 9.21 and 8.83, respectively, for HIV-negative women, and 9.38 and 9.37, respectively, for HIV-positive women. In multivariate models, the hazard ratios for HIV-positive compared with HIV-negative women were 0.85 (95% CI, 0.51 to 1.43; P = .55) and 0.95 (95% CI, 0.54 to 1.65; P = .85) for cleared infections with any lrHPV and any hrHPV, respectively. The hazard ratio for HIV-positive compared with HIV-negative women was 0.39 (95% CI, 0.17 to 0.88; P = .02) for cleared infections with any multiple HPV and 0.13 (95% CI, 0.03 to 0.58; P = .007) for cleared infections with multiple hrHPV. Conclusion In this study population, we observed that HIV-positive women were less likely to clear infections with multiple hrHPV types.

Persistent Low-Risk and High-Risk Human Papillomavirus Infections of the Uterine Cervix in HIV-Negative and HIV-Positive Women.

BACKGROUND: The prevalence, persistence, and multiplicity of human papillomavirus (HPV) infection appears different comparing HIV-positive to HIV-negative women. In this study, we examined prevalent, persistent, and multiple low- and high-risk cervical HPV infections in HIV-negative and HIV-positive women. METHODS: We studied 1,020 women involved in a study of HPV infection using SPF25/LiPA10. Two study visits were scheduled, at enrollment and 6 months afterward. At each study visit, research nurses used a cervical brush to collect samples of exfoliated cervical cells from the cervical os, from all the study participants. Exact logistic regression models were used to estimate associations between HIV and HPV infections. RESULTS: The mean (SD) age of the study participants was 38 (8) years, 56% were HIV-negative and 44% were HIV-positive. Among HIV-negative women at baseline, single low-risk HPV (lrHPV) infections occurred in 12%; multiple lrHPV in 2%; single high-risk human papillomavirus (hrHPV) infections in 9%, and multiple hrHPV infections in 2%. Single lrHPV infections were persistent in 6%, but there was no persistent multiple lrHPV infections. Single hrHPV infections were persistent in 4% while multiple hrHPV infections were persistent in 0.3%. Among HIV-positive women at baseline, single lrHPV infections occurred in 19%, multiple lrHPV in 6%, single hrHPV infections in 17%, and multiple hrHPV infections occurred in 12%. Single lrHPV infections were persistent in 9%, multiple lrHPV infections in 0.6%, single hrHPV infections in 13%, while multiple hrHPV were persistent in 3%. Prevalent, persistent, and multiple infections were more common in HIV-positive women, compared to HIV-negative women. In multivariate models adjusted for age, marital status, socioeconomic status, age at sexual initiation, and douching, the odds ratios comparing HIV-positive to HIV-negative women, were 2.09 (95% CI 1.47-2.97, p < 0.001) for prevalent lrHPV, 1.26 (95% CI 0.66-2.40, p 0.47) for persistent lrHPV infections, 3.38 (95% CI 2.34-4.87, p < 0.001) for prevalent hrHPV, and 4.49 (95% CI 2.26-8.91, p < 0.001) for persistent hrHPV infections. CONCLUSION: HIV infection was associated with higher prevalence of lrHPV, hrHPV, and persistence hrHPV infections, but not persistent lrHPV infections.

Mycoplasma hominis and Mycoplasma genitalium in the Vaginal Microbiota and Persistent High-Risk Human Papillomavirus Infection.

BACKGROUND: Recent studies have suggested that the vaginal microenvironment plays a role in persistence of high-risk human papillomavirus (hrHPV) infection and thus cervical carcinogenesis. Furthermore, it has been shown that some mycoplasmas are efficient methylators and may facilitate carcinogenesis through methylation of hrHPV and cervical somatic cells. We examined associations between prevalence and persistence of Mycoplasma spp. in the vaginal microbiota, and prevalent as well as persistent hrHPV infections. METHODS: We examined 194 Nigerian women who were tested for hrHPV infection using SPF25/LiPA10 and we identified Mycoplasma genitalium and Mycoplasma hominis in their vaginal microbiota established by sequencing the V3-V4 hypervariable regions of the 16S rRNA gene. We defined the prevalence of M. genitalium, M. hominis, and hrHPV based on positive result of baseline tests, while persistence was defined as positive results from two consecutive tests. We used exact logistic regression models to estimate associations between Mycoplasma spp. and hrHPV infections. RESULTS: The mean (SD) age of the study participants was 38 (8) years, 71% were HIV positive, 30% M. genitalium positive, 45% M. hominis positive, and 40% hrHPV positive at baseline. At follow-up, 16% of the women remained positive for M. genitalium, 30% for M. hominis, and 31% for hrHPV. There was a significant association between persistent M. hominis and persistent hrHPV (OR 8.78, 95% CI 1.49-51.6, p 0.01). Women who were positive for HIV and had persistent M. hominis had threefold increase in the odds of having persistent hrHPV infection (OR 3.28, 95% CI 1.31-8.74, p 0.008), compared to women who were negative for both. CONCLUSION: We found significant association between persistent M. hominis in the vaginal microbiota and persistent hrHPV in this study, but we could not rule out reverse causation. Our findings need to be replicated in larger, longitudinal studies and if confirmed, could have important diagnostic and therapeutic implications.

HIV associated high-risk HPV infection among Nigerian women.

BACKGROUND: In developed countries, the incidence of cervical cancer has remained stable in HIV+ women but the prevalence and multiplicity of high-risk HPV (hrHPV) infection, a necessary cause of cervical cancer, appears different comparing HIV+ to HIV- women. Little is known about HIV and HPV co-infection in Africa. METHODS: We enrolled women presenting at our cervical cancer screening program in Abuja, Nigeria between April and August 2012, and collected information on demographic characteristics, risk factors of HPV infection and samples of exfoliated cervical cells. We used Roche Linear Array HPV Genotyping Test® to characterize prevalent HPV and logistic regression models to estimate the association between HIV and the risk of hrHPV infection. RESULTS: There were 278 participants, 54% (151) were HIV+, 40% (111) were HIV-, and 6% (16) had unknown HIV status. Of these, data from 149 HIV+ and 108 HIV- women were available for analysis. The mean ages (± SD) were 37.6 (± 7.7) years for HIV+ and 36.6 (± 7.9) years for HIV- women (p-value = 0.34). Among the HIV+ women, HPV35 (8.7%) and HPV56 (7.4%) were the most prevalent hrHPV, while HPV52 and HPV68 (2.8%, each) were the most prevalent hrHPV types among HIV- women. The multivariate prevalence ratio for any hrHPV and multiple hrHPV infections were 4.18 (95% CI 2.05 - 8.49, p-value <0.0001) and 6.6 (95% CI 1.49 - 29.64, p-value 0.01) respectively, comparing HIV + to HIV- women, adjusted for age, and educational level. CONCLUSIONS: HIV infection was associated with increased risk of any HPV, hrHPV and multiple HPV infections. Oncogenic HPV types 35, 52, 56 and 68 may be more important risk factors for cervical pre-cancer and cancer among women in Africa. Polyvalent hrHPV vaccines meant for African populations should protect against other hrHPV types, in addition to 16 and 18.

Immunohistochemical and molecular subtypes of breast cancer in Nigeria.

OBJECTIVE: Previous studies suggest that the majority of breast cancer in Africans are hormone receptor negative and thus differ from breast cancer in other populations. We decided to evaluate the hormone receptor status of patients seen in our practice to see if they indeed differ from that of other populations. METHODS: We prospectively collected and analyzed tumors from consecutive patients presenting to our clinic over an 18 months period from July 2004. During the period, we saw 192 patients without previous histological diagnosis and conducted routine histological and immunohistochemical analysis of their tumors for hormone receptor status. RESULTS: Most, 65.1% of tumors were ER+, 54.7% were PR+ and 79.7% were HER2 negative. Majority of the tumors, 77.6% were luminal type A, 2.6% were luminal type B, 15.8% were basal type and the remaining 4.0% (6/152) were HER2+/ER- subtype. We found an association between hormone receptor status and tumor grade but not with stage at presentation. CONCLUSION: We conclude that there is no difference in the pattern of hormone receptors in breast cancer patients of African origin compared to other populations and urge more use of hormone manipulation for management of breast cancer in this population.