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1.  Suitability of self-collected vaginal samples for cervical cancer screening in peri-urban villages in Andhra Pradesh, India 
Objectives:
Our aim was to determine if (1) Hybrid Capture 2 and a PCR-based method were comparable for detection of high-risk HPVs, (2) clinician-collected and self-collected samples were equally efficient to detect HPV and cervical cancer precursor lesions and (3) if participation rates improved with home-based vs. clinic-based self collection.
Methods:
Samples were selected from women participating in a cervical cancer screening study according to human papillomavirus (HPV), visual inspection with acetic acid (VIA), or Pap smear screening results. From 432 of 892 selected women, split sample aliquots were tested for HPV DNA using both the Hybrid Capture 2 assay and the Roche prototype line blot assay. Women from a subset of villages were recruited at two separate time points for clinic-based self-collection and home-based self-collection, and participation rates were compared.
Results:
Pairwise agreement between self- and clinician-collected samples was high by both hc2 (90.8% agreement, kappa=0.7) and PCR (92.6% agreement, kappa=0.8), with significantly increased high-risk HPV detection in clinician-collected specimens (McNemar's p<0.01). Ability to detect precursor lesions was highest by PCR testing of clinician-collected samples and lowest by Hybrid Capture 2 testing of self-collected samples (11/11 and 9/11 cases of cervical intraepithelial neoplasia grade 2/3 and cancer detected, respectively). Participation in home-based screening was significantly higher than clinic-based screening (71.5% and 53.8%, respectively; p<0.001) among women 30-45 years old.
Conclusion:
The combination of improved screening coverage and a high single test sensitivity afforded by HPV DNA testing of home-based self-collected swabs may have a greater programmatic impact on cervical cancer mortality reduction compared to programs requiring a pelvic exam.
doi:10.1158/1055-9965.EPI-08-1171
PMCID: PMC2762740  PMID: 19423518
2.  A Cohort Effect of the Sexual Revolution May Be Masking an Increase in Human Papillomavirus Detection at Menopause in the United States 
The Journal of Infectious Diseases  2013;207(2):272-280.
Background. Cohort effects, new sex partnerships, and human papillomavirus (HPV) reactivation have been posited as explanations for the bimodal age-specific HPV prevalence observed in some populations; no studies have systematically evaluated the reasons for the lack of a second peak in the United States.
Methods. A cohort of 843 women aged 35–60 years were enrolled into a 2-year, semiannual follow-up study. Age-specific HPV prevalence was estimated in strata defined by a lower risk of prior infection (<5 self-reported lifetime sex partners) and a higher risk of prior infection (≥5 lifetime sex partners). The interaction between age and lifetime sex partners was tested using likelihood ratio statistics. Population attributable risk (PAR) was estimated using Levin's formula.
Results. The age-specific prevalence of 14 high-risk HPV genotypes (HR-HPV) declined with age among women with <5 lifetime sex partners but not among women with ≥5 lifetime sex partners (P = .01 for interaction). The PAR for HR-HPV due to ≥5 lifetime sex partners was higher among older women (87.2%), compared with younger women (28.0%). In contrast, the PAR associated with a new sex partner was 28% among women aged 35–49 years and 7.7% among women aged 50–60 years.
Conclusions. A lower cumulative probability of HPV infection among women with a sexual debut before the sexual revolution may be masking an age-related increase in HPV reactivation in the United States.
doi:10.1093/infdis/jis660
PMCID: PMC3532829  PMID: 23242540
Human Papillomavirus; menopause; perimenopause; sexual revolution; cervical cancer; reactivation; cohort effect; age
3.  Nitric Oxide Induces Early Viral Transcription Coincident with Increased DNA Damage and Mutation Rates in Human Papillomavirus–Infected Cells 
Cancer research  2009;69(11):10.1158/0008-5472.CAN-08-4695.
High-risk human papillomavirus (HPV) infections are necessary but insufficient causes of cervical cancers. Other risk factors for cervical cancer (e.g., pregnancy, smoking, infections causing inflammation) can lead to high and sustained nitric oxide (NO) concentrations in the cervix, and high NO levels are related to carcinogenesis through DNA damage and mutation. However, the effects of NO exposure in HPV-infected cells have not been investigated. In this study, we used the NO donor DETA-NO to model NO exposure to cervical epithelium. In cell culture media, 24-hour exposure to 0.25 to 0.5 mmol/L DETA-NO yielded a pathologically relevant NO concentration. Exposure of cells maintaining episomal high-risk HPV genomes to NO increased HPV early transcript levels 2- to 4-fold but did not increase viral DNA replication. Accompanying increased E6 and E7 mRNA levels were significant decreases in p53 and pRb protein levels, lower apoptotic indices, increased DNA double-strand breaks, and higher mutation frequencies when compared with HPV-negative cells. We propose that NO is a molecular cofactor with HPV infection in cervical carcinogenesis, and that modifying local NO cervical concentrations may constitute a strategy whereby HPV-related cancer can be reduced.
doi:10.1158/0008-5472.CAN-08-4695
PMCID: PMC3820841  PMID: 19487298
4.  Looking ahead: a case for HPV testing of self-sampled vaginal specimens as a cervical cancer screening strategy 
Even in the era of highly effective HPV prophylactic vaccines, substantial reduction in worldwide cervical cancer mortality will only be realized if effective early detection and treatment of the millions of women already infection and the millions who may not receive vaccination in the next decade can be broadly implemented through sustainable cervical cancer screening programs. Effective programs must meet three targets: 1) at least 70% of the targeted population should be screened at least once in a lifetime, 2) screening assays and diagnostic tests must be reproducible and sufficiently sensitive and specific for the detection of high-grade precursor lesions (i.e., CIN2+), and 3) effective treatment must be provided. We review the evidence that HPV DNA screening from swabs collected by the women in their home or village is sufficiently sound for consideration as a primary screening strategy in the developing world, with sensitivity and specificity for detection of CIN2+ as good or better than Pap smear cytology and VIA. A key feature of a self-collected HPV testing strategy (SC-HPV) is the move of the primary screening activities from the clinic to the community. Efforts to increase the affordability and availability of HPV DNA tests, community education and awareness, development of strong partnerships between community advocacy groups, health care centers and regional or local laboratories, and resource appropriate strategies to identify and treat screen-positive women should now be prioritized to ensure successful public health translation of the technologic advancements in cervical cancer prevention.
doi:10.1002/ijc.25974
PMCID: PMC3782104  PMID: 21384341
5.  Characterizing the Temporal Dynamics of Human Papillomavirus DNA Detectability Using Short-Interval Sampling 
Background
Variable detection of human papillomavirus (HPV) DNA can result in misclassification of infection status, but the extent of misclassification has not been quantitatively evaluated.
Methods
In 2005–2007, 33 women aged 22–53 self-collected vaginal swabs twice per week for 16 consecutive weeks. Each of the 955 swabs collected was tested for 37 HPV types/subtypes. Assuming that a woman’s underlying infection status did not change over the short study period, biases in prevalence estimates obtained from single versus multiple swabs were calculated. Using event history analysis methods, time to recurrent gain and loss of at least one HPV type was determined, separately. Baseline any- and high risk-HPV prevalence was 60.6% and 24.2%, respectively. Cumulative any- and high risk-HPV prevalence over the 16-week period was 84.8% and 60.6%, separately.
Results
Overall, there were 319 events of detection and 313 events of loss of detection. Median times to a recurrent detection and loss of detection was 11 and 7 days, respectively. Neither vaginal sex nor condom use during follow-up was associated with recurrent viral detection or loss of detection. Assuming the cumulative 16-week prevalence reflects the true prevalence of infection, the baseline any-HPV prevalence under-estimated infection status by 24.2%, with a bootstrapped mean of 20.2% (95% confidence interval [CI]: 8.9%, 29.6%).
Conclusions
These findings suggest that a substantial proportion of HPV-infected women are misclassified as being un-infected when using a single-time DNA measurement.
Impact
Short-term variation in detectable HPV DNA needs to be considered while interpreting the natural history of infections using single samples collected at long intervals.
doi:10.1158/1055-9965.EPI-13-0666
PMCID: PMC3947138  PMID: 24130223
Epidemiology; Human papillomavirus; Interval sampling; Misclassification bias; Prevalence
6.  Combined Oral Contraceptive Use Increases HPV Persistence but Not New HPV Detection in a Cohort of Women From Thailand 
The Journal of Infectious Diseases  2011;204(10):1505-1513.
Background. Women diagnosed with cervical cancer report longer duration and more recent use of combined oral contraceptives (COCs). It is unclear how COC use impacts risk of cervical carcinogenesis.
Methods. We estimated the risk of new human papillomavirus (HPV) DNA detection and persistence among 1135 human immunodeficiency virus (HIV)–negative women aged 20–37 years from Thailand who were followed for 18 months at 6-month intervals. Type-specific HPV DNA, demographic information, hormonal contraceptive use, sexual behavior, genital tract coinfection, and Papanicolaou test results were assessed at baseline and each follow-up.
Results. Women who reported current COC use during follow-up were less likely to clear HPV infection compared with nonusers, independent of sexual behavior, and Papanicolaou test diagnosis (AHR: 0.67 [95% CI: .49–.93]). Similar associations were not observed among women reporting current use of depomedroxyprogesterone acetate (DMPA). Neither COC nor DMPA use was significantly associated with new HPV DNA detection.
Conclusions. These data do not support the hypothesis that contraceptive use is associated with cervical cancer risk via increased risk of HPV acquisition. The increased risk of HPV persistence observed among current COC users suggests a possible influence of female sex hormones on host response to HPV infection.
doi:10.1093/infdis/jir560
PMCID: PMC3222104  PMID: 21964399
7.  Natural immune responses against eight oncogenic human papillomaviruses in the ASCUS-LSIL triage study 
Only a subset of women with human papillomavirus (HPV) infections will become seropositive, and the factors influencing seroconversion are not well-understood. We used a multiplex serology assay in women with mildly abnormal cytology results to examine seroreactivity to oncogenic HPV genotypes. An unbiased subset of women in the atypical squamous cell of undetermined significance /low-grade squamous intraepithelial lesion Triage Study (ALTS) provided blood samples at trial enrollment for serological testing. A Luminex assay based on GST-L1 fusion proteins as antigens was used to test seroreactivity against eight carcinogenic HPV genotypes (16, 18, 31, 33, 35, 45, 52, 58). We analyzed the relationship between seroprevalence in women free of precancer (N=2464) and HPV DNA status, age, sexual behavior, and other HPV-related risk factors. The overall seroprevalence was 24.5% for HPV16 L1 and ~ 20% for 18L1 and 31L1. Among women free of precancer, seroprevalence peaked in women less than 29 years and decreased with age. Type-specific seroprevalence was associated with baseline DNA detection for HPV16 (OR= 1.36, 95%CI: 1.04–1.79) and HPV18 (OR= 2.31, 95%CI: 1.61–3.32), as well as for HPV52 and HPV58. Correlates of sexual exposure were associated with increased seroprevalence across most genotypes. Women who were current or former smokers were less likely to be seropositive for all eight of the tested oncogenic genotypes. The multiplex assay showed associations between seroprevalence and known risk factors for HPV infection across nearly all tested HPV genotypes but associations between DNA- and serostatus were weak, suggesting possible misclassification of the participants’ HPV serostatus.
doi:10.1002/ijc.28215
PMCID: PMC4238230  PMID: 23588935
Human papillomavirus; seroepidemiology; antibodies
8.  The known unknowns of HPV natural history 
The Journal of Clinical Investigation  2011;121(12):4593-4599.
The discovery that certain high-risk strains of human papillomavirus (HR-HPV) cause nearly 100% of invasive cervical cancer has spurred a revolution in cervical cancer prevention by promoting the development of viral vaccines. Although the efficacy of these vaccines has already been demonstrated, a complete understanding of viral latency and natural immunity is lacking, and solving these mysteries could help guide policies of cervical cancer screening and vaccine use. Here, we examine the epidemiological and biological understanding of the natural history of HPV infection, with an eye toward using these studies to guide the implementation of cervical cancer prevention strategies.
doi:10.1172/JCI57149
PMCID: PMC3225991  PMID: 22133884
9.  Menstrual Cycle and Detectable Human Papillomavirus in Reproductive-age Women: A Time Series Study 
The Journal of Infectious Diseases  2013;208(9):1404-1415.
Background. Current evidence on the relationship between human papillomavirus (HPV) DNA detection and menstrual cycle has been inconsistent.
Methods. We included 21 nonoral contraceptive pill (non-OCP) users who self-collected vaginal samples twice per week for 16 weeks. We explored whether variable detection of HPV DNA exhibited cyclic or other structured temporal patterns. We also evaluated relationships between serial HPV prevalence, sexual behavior, and suspected bacterial vaginosis (BV) as defined by Nugent Gram stain score ≥7.
Results. During follow-up, any-type HPV prevalence varied between 61.1% and 85.0%. Although not statistically significant, we observed a maximum autocorrelation in serial HPV prevalence lagging 14 days (correlation coefficient [ρ], −0.24). Any-type HPV detection had a periodic behavior, generally repeating every 28.0 days (bootstrapped interquartile range, 22.4–28.0) and peaking around the ovulation time (adjusted odds ratio, 1.96; 95% confidence interval [CI], 1.06–3.62) as compared to menstruation. We also showed that an increase in any-type HPV prevalence preceded the beginning of a menstrual cycle by 9–12 days. There was no evidence of relationships between HPV prevalence and sexual activity or Nugent score.
Conclusions. Serially detected any-type HPV DNA showed a periodic behavior and was likely to peak in the periovulatory phase among non-OCP users.
doi:10.1093/infdis/jit337
PMCID: PMC3789568  PMID: 23885113
Auto-correlation; Bacterial Vaginosis; Human Papillomavirus; Menstrual Cycle; Nugent Score; Periodicity; Spectral Analysis; Time Series Analysis
10.  Comparison of the immune microenvironment of the oral cavity and cervix in healthy women 
Cytokine  2013;64(2):597-604.
Background
Despite similar frequencies of exposure, the low prevalence of certain sexually transmitted infections such as Chlamydia, HPV and HIV-1 in the oral cavity relative to the cervix is poorly understood. This could be explained in part by differences in host immune microenvironments between these two anatomic sites.
Objective
We compared the concentration and correlation of 27 different immune markers in paired secretion specimens collected from the oral and cervical mucosa of healthy women.
Methods
Paired oral and cervical secretion specimens were collected from thirty-nine women. The concentration of twenty-seven different immune markers was estimated using a Luminex multiplex assay. Marker concentration was normalized to total protein present in the specimen. Median immune marker concentrations were compared across anatomic sites. Unsupervised hierarchical clustering analysis was utilized to identify groups of markers that shared similar patterns of relative concentrations across anatomic sites.
Results
The oral cavity had significantly higher concentrations of eotaxin, IFN-γ, IL-2, IL-4, IL-5, IL-7, IL-9, IL-13, IL-15, PDGF-BB, TNF-α, (p < 0.01 for each) while the cervix had higher concentrations of proinflammatory markers such as FGF-basic, IL-1ra, IL-1β, IL-6, IL-8, IP-10, G-CSF, GM-CSF, MCP-1, MIP-1β, VEGF (p < 0.01 for each). Hierarchical cluster analysis identified two groups of immune markers comprised of T-cell related immune markers with significantly higher concentrations in the oral cavity relative to the cervix, and a third cluster consisting of mostly inflammatory immune markers which were higher concentrations in the cervix. The oral cavity had a larger number of significant inter-marker correlations as compared to the cervix.
Conclusions
The oral cavity and cervix have significantly different immune marker profiles, which may in part explain the significantly lower burden of sexually transmitted infections such as Chlamydia, HPV, and HIV-1 in the oral cavity vs. the cervix.
doi:10.1016/j.cyto.2013.08.009
PMCID: PMC4075766  PMID: 24021705
Oral; Cervical; Pro-inflammatory; T-cell; Immunoregulatory
11.  Determinants of VIA (Visual Inspection of the Cervix After Acetic Acid Application) Positivity in Cervical Cancer Screening of Women in a Peri-Urban Area in Andhra Pradesh, India 
Objectives
Visual inspection of the cervix after acetic acid application (VIA) is widely recommended as the method of choice in cervical cancer screening programs in resource-limited settings because of its simplicity and ability to link with immediate treatment. In testing the effectiveness of VIA, human papillomavirus DNA testing, and Pap cytology in a population-based study in a peri-urban area in Andhra Pradesh, India, we found the sensitivity of VIA for detection of cervical intraepithelial neoplasia grade 2 and worse (CIN2+) to be 26.3%, much lower than the 60% to 90% reported in the literature. We therefore investigated the determinants of VIA positivity in our study population.
Methods
We evaluated VIA positivity by demographics and reproductive history, results of clinical examination, and results from the other screening methods.
Results
Of the 19 women diagnosed with CIN2+, only 5 were positive by VIA (positive predictive value, 3.1%). In multivariate analysis, VIA positivity (12.74%) was associated with older age, positive Pap smear, visually apparent cervical inflammation, and interobserver variation. Cervical inflammation of unknown cause was present in 21.62% of women. In disease-negative women, cervical inflammation was associated with an increase in VIA positivity from 6.1% to 15.5% (P < 0.001). Among the six gynecologists who performed VIA, the positivity rate varied from 4% to 31%.
Conclusions
The interpretation of VIA is subjective and its performance cannot be readily evaluated against objective standards.
Impact
VIA is not a robust screening test and we caution against its use as the primary screening test in resource-limited regions.
doi:10.1158/1055-9965.EPI-09-1282
PMCID: PMC2913449  PMID: 20447927
12.  Obesity and Human Papillomavirus Infection in Perimenopausal Women 
The Journal of Infectious Diseases  2013;208(7):1071-1080.
Introduction. Obesity is known to increase susceptibility to certain infections in men. It is unclear whether obesity increases women's risk for human papillomavirus (HPV) infection.
Methods. In a prospective cohort of 696 perimenopausal women enrolled in 2008–2012, we sought to determine whether obesity predicted incident HPV detection or nondetection. Obesity was defined as body mass index (BMI) ≥ 30 kg/m2.
Results. Baseline any type HPV prevalence was comparable between obese and nonobese women (18.7% vs 19.1%; P > .05). Over a median follow-up period of 17.9 months (interquartile range: 12.1–24.5), 187 new HPV detections occurred among 123 women, 60 of whom subsequently lost 76 detectable infections. When compared with nonobese participants, obese women had a similar rate of new HPV detection (7.1 vs 7.8 infections per 1000 infection-years; P > .05) or loss of detection (100.3 vs 85.8 infections per 100 infection-years; P > .05). Similar results were found after adjusting for age, menopausal status, smoking habit, and sexual exposure history.
Conclusions. Results from the current analysis suggest little effect of obesity on HPV detection and loss of detection in mid-adult women. More research is needed to determine whether adipokines or cytokines better capture the potential immune modulating effects of obesity on HPV infection.
doi:10.1093/infdis/jit297
PMCID: PMC3762384  PMID: 23840046
adipokine; body mass index; discrete-time survival analysis; frailty model; human papillomavirus; obesity; waist circumference
13.  Correlates of Cervicovaginal Human Papillomavirus Detection in Perimenopausal Women 
Journal of Women's Health  2009;18(9):1341-1346.
Abstract
Objective
The aim of this research was to determine correlates of prevalent cervicovaginal human papillomavirus (HPV) infection in perimenopausal women.
Methods
A total of 178 women, ages 40–60, were recruited from four clinics in the metropolitan area of Baltimore, Maryland. A self-collected cervicovaginal specimen and questionnaire were completed following enrollment and consent. HPV was detected by L1 consensus polymerase chain reaction (PCR) and genotyped using a prototype line blot assay. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CIs) from Poisson regression models with robust variance identified correlates of prevalent HPV infection.
Results
Prevalence of any HPV genotype at baseline among 172 women with complete data was 20% (6% for high-risk HPV). HPV prevalence was higher among single compared to married women (aPR = 4.3 [95% CI: 2.0, 9.5]), and among women with ≥2 sex partners in the last six months compared to women who reported none (aPR = 4.9 [1.7, 13.9]) after adjustment for confounders. Menopausal stage was also associated with HPV detection, with increased prevalence among perimenopausal compared to premenopausal women (aPR 2.3 [1.1, 5.1]), after adjustment for confounders. Age was moderately correlated with menopausal staging (r = 0.57).
Conclusions
Our observations suggest the independent associations of sexual behavior and hormones on prevalent HPV in perimenopausal women. Age was not a good surrogate for menopausal stage, as it was only moderately correlated with menopausal stage.
doi:10.1089/jwh.2008.1223
PMCID: PMC2825723  PMID: 19702476
14.  Human Papillomavirus-Type Distribution in Women With and Without Cervical Neoplasia in North India 
Our objective was to determine the human papillomavirus (HPV)-type prevalence in cervical samples in women with and without cervical neoplasia in an opportunistic hospital-based cancer-screening program.
A cross-sectional study of 524 women presenting from January 2003 through June 2005 with symptoms of persistent vaginal discharge, intermenstrual bleeding, and postcoital bleeding or detected to have an unhealthy cervix underwent HPV genotyping by consensus polymerase chain reaction and reverse line-blot hybridization assay, conventional Pap smear, and colposcopy, with directed biopsy from all lesions detected.
The prevalence rates of HPV infection among women with normal, low-grade cervical neoplasia (CIN 1) and high-grade CIN (>CIN2) were found to be 7.6%, 42.3%, and 87.5%, respectively. Seventeen high-risk and 6 low-risk HPV types were identified by the reverse line-blot assay. Multiple infections were seen in 20% of women. In normal women, the 6 commonest types were HPV-16, HPV-89, HPV-39, HPV-52, HPV-62, and HPV-18, whereas in high-grade disease, these were all high-risk types HPV-16, HPV-18, HPV-33, HPV-39, HPV-35, and HPV-56. HPV-16 was the commonest type in all groups, seen in 49.4% cases overall and in 74.3% of high-grade squamous intraepithelial lesion. It was followed by HPV-18 (7.4%) and HPV-33 and HPV-39 (4.9% each). HPV-89 was the commonest low-risk type (9.9%). HPV-16/18 were associated with 34.3% of normal, 45.4% of low-grade and 65.7% of high-grade lesions. A wide spectrum of HPV types is seen in north Indian women, with the majority being HPV-16 in all grades of histology. A vaccine against HPV-16 and HPV-18 could prevent two thirds of cases of high-grade cervical neoplasia.
doi:10.1097/PGP.0b013e31816085ba
PMCID: PMC4156035  PMID: 18580322
15.  Male circumcision decreases high-risk human papillomavirus viral load in female partners: a randomized trial in Rakai, Uganda 
Male circumcision (MC) reduces high-risk human papillomavirus (HR-HPV) infection in female partners. We evaluated the intensity of HR-HPV viral DNA load in HIV-negative, HR-HPV-positive female partners of circumcised and uncircumcised men. HIV-negative men and their female partners were enrolled in randomized trials of MC in Rakai, Uganda. Vaginal swabs were tested for HR-HPV genotypes by Roche HPV Linear Array which provides a semi-quantitative measure of HPV DNA by the intensity of genotype-specific bands (graded:1-4). We assessed the effects of MC on female HR-HPV DNA load by comparing high intensity linear array bands (3-4) to low intensity bands (1-2) using an intention-to-treat analysis. Prevalence risk ratios (PPR) of high intensity bands in partners of intervention versus control arm men were estimated using log-binomial regression with robust variance. The trial included 335 women with male partners in the intervention arm and 340 in the control arm. At enrollment, the frequency of HR-HPV high intensity linear array bands was similar in both study arms. At 24 months follow-up, the prevalence of high intensity bands among women with detectable HRHPV was significantly lower in partners of intervention arm (42.7%) than control arm men (55.1%, PRR= 0.78, 95%CI 0.65-0.94, p=0.02), primarily among incident HR-HPV infections (PRR=0.66, 95% CI 0.50-0.87, p=0.003), but not persistent infections (PRR=1.02, 95% CI 0.83-1.24). Genotypes with high HR-HPV band intensity were more likely to persist (adjHR=1.27 95% CI 1.07-1.50), irrespective of male partner circumcision status. MC reduces HR-HPV DNA load in newly infected female partners.
doi:10.1002/ijc.28100
PMCID: PMC3732529  PMID: 23400966
Human papillomavirus (HPV); male circumcision; Uganda; cervical cancer; sexually transmitted infections; viral shedding; viral load; linear array band intensity; HIV
16.  Comparison of Human Papillomavirus Detections in Urine, Vulvar, and Cervical Samples from Women Attending a Colposcopy Clinic 
Journal of Clinical Microbiology  2014;52(1):187-192.
While urine-based sampling for human papillomavirus (HPV) is being explored as a simple and noninvasive approach for cervical cancer screening, data comparing HPV genotyping in urine and those in cellular sampling of the cervix and vulva, and their correlation with rigorously confirmed cervical disease status, are sparse. We performed HPV genotyping on voided-urine and clinician-collected vulvar and cervical samples from 72 women undergoing colposcopy. Although urine-based HPV carcinogenic HPV detection was lower (58.3%) than cervical (73.6%) and vulvar (72.1%) detection (P = 0.05 and 0.07, respectively), the agreement of urine HPV with cervical and vulvar HPV was moderate (kappa = 0.55) and substantial (kappa = 0.62), respectively. Urine-based carcinogenic HPV detection had a clinical sensitivity of 80.8% (95% confidence interval [CI] = 60.7 to 93.5) and a specificity of 53.3% (95% CI = 37.9 to 68.3) for diagnosing cervical intraepithelial neoplasia grades 2/3 (CIN2/3) on histology; 90.0% of CIN3 was positive for urine HPV. The corresponding sensitivity and specificity values for vulvar sampling were 92% (95% CI = 74 to 99) and 40.5% (95% CI = 25.6 to 56.7), and those for cervical sampling were 96.2% (95% CI = 80.4 to 99.9) and 40% (95% CI = 25.7 to 55.7), respectively. HPV16 was the most common carcinogenic genotype detectable in 25% of urine, 33.8% of vulvar, and 31.9% of cervical samples overall, with prevalence increasing with cervical disease grade, regardless of the sampling method. Stronger cervical HPV PCR signal strengths were associated with increased frequency of urine HPV detection. In summary, the relatively lower detection rates but comparable clinical performance of urine-based HPV sampling underscore the need for larger studies to evaluate urine-based sampling for cervical cancer screening, epidemiologic studies, and postvaccination HPV disease surveillance.
doi:10.1128/JCM.01623-13
PMCID: PMC3911475  PMID: 24197879
17.  Risk of precancer determined by HPV genotype combinations in women with minor cytologic abnormalities 
Background
Studies suggest that testing for individual HPV genotypes can improve risk stratification in women with minor cytological abnormalities. We evaluated genotyping for HPV16, HPV16/18, and HPV16/18/45 in carcinogenic HPV-positive women with atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) cytology.
Methods
For women enrolled in the ASCUS-LSIL Triage Study (ALTS), we calculated the age-stratified (<30 and 30+ years) positivity, and cumulative risk over two years of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) when testing positive or negative for three genotype combinations: HPV16, HPV16/18, and HPV16/18/45.
Results
Among women with ASCUS cytology, HPV16 positivity was 17.1% and increased to 22.0% (P<.001) for HPV16/18 and 25.6% (P<.001) for HPV16/18/45. Among women with LSIL cytology, HPV16 positivity was 21.1% and increased to 30.0% (P<.001) for HPV16/18 and 34.0% (P=.017) for HPV16/18/45. Regardless of cytology and age group, the greatest risk difference between test-positives and test-negatives was observed for HPV16 with decreasing risk stratification for HPV16/18 and HPV16/18/45. However, testing negative for any of the three combinations while being positive for another carcinogenic type still implied a 2-year risk of CIN3+ of 7.8% or greater.
Conclusions
Although genotyping for HPV16, 18, and 45 provided additional risk stratification in carcinogenic HPV-positive women with minor cytological abnormalities, the risk among genotype-negative women was still high enough to warrant immediate colposcopy referral.
Impact
HPV genotyping in HPV-positive women with minor cytological abnormalities will likely not alter clinical management. Adding HPV45 to genotyping assays is not warranted.
doi:10.1158/1055-9965.EPI-12-1455
PMCID: PMC3687215  PMID: 23603204
HPV testing; cervical intraepithelial neoplasia; cervical cytology; risk stratification
18.  High risk human papillomavirus viral load and persistence among heterosexual HIV-negative and HIV-positive men 
Sexually transmitted infections  2014;90(4):337-343.
Objectives
High-risk human papillomavirus (HR-HPV) viral load is associated with HR-HPV transmission and HR-HPV persistence in women. It is unknown whether HR-HPV viral load is associated with persistence in HIV-negative or HIV-positive men.
Methods
HR-HPV viral load and persistence were evaluated among 703 HIV-negative and 233 HIV-positive heterosexual men who participated in a male circumcision trial in Rakai, Uganda. Penile swabs were tested at baseline and 6, 12 and 24 months for HR-HPV using the Roche HPV Linear Array, which provides a semi-quantitative measure of HPV shedding by hybridization band intensity (graded:1–4). Prevalence risk ratios (PRR) were used to estimate the association between HR-HPV viral load and persistent detection of HR-HPV.
Results
HR-HPV genotypes with high viral load (grade:3–4) at baseline were more likely to persist than HR-HPV genotypes with low viral load (grade:1–2) among HIV-negative men (month 6: adjPRR=1.83, 95%CI:1.32–2.52; month 12: adjPRR=2.01, 95%CI:1.42–3.11), and HIV-positive men (month 6: adjPRR=1.33, 95%CI:1.06–1.67; month 12: adjPRR=1.73, 95%CI:1.18–2.54). Long-term persistence of HR-HPV was more frequent among HIV-positive men compared to HIV-negative men (month 24: adjPRR=2.27, 95%CI: 1.47–3.51). Persistence of newly detected HR-HPV at the 6 and 12 month visits with high viral load were also more likely to persist to 24 months than HR-HPV with low viral load among HIV-negative men (adjPRR=1.67, 95%CI 0.88–3.16).
Conclusions
HR-HPV genotypes with high viral load are more likely to persist among HIV-negative and HIV-positive men, though persistence was more common among HIV-positive men overall. The results may explain the association between high HR-HPV viral load and HR-HPV transmission.
doi:10.1136/sextrans-2013-051230
PMCID: PMC4030299  PMID: 24482488
Human papillomavirus (HPV); human immunodeficiency virus (HIV); male circumcision; Uganda; penile cancer; sexually transmitted infections; viral shedding; viral load; linear array band intensity
19.  High load for most high risk human papillomavirus genotypes is associated with prevalent cervical cancer precursors but only HPV16 load predicts the development of incident disease 
Cervicovaginal human papillomavirus (HPV) viral load has been purported as a potential marker for the detection of high-grade cervical intraepithelial neoplasia or cancer (≥CIN2). To examine disease association with type-specific viral load for the full-range of anogenital HPV infections, we conducted cross-sectional and prospective analyses of ∼2,000 HPV-infected women from a 10,000-woman population-based study in Guanacaste, Costa Rica with 7 years of follow-up. Cervical specimens were tested for >40 HPV types using a MY09/MY11 L1 consensus primer PCR method with type-specific dot blot hybridization and PCR signal intensity as a measure of viral load. A positive association was observed between prevalent ≥CIN2 and high viral load compared to low viral load for women with baseline single HPV16 infections (OR = 19.2, 95% CI = 4.4–83.2) and single non-16 carcinogenic infections (OR = 9.2, 95% CI = 2.1–39.9). Inclusion of women with multiple HPV types did not substantially change these associations. In prospective follow-up, only women infected with HPV16 alone (OR = 27.2, 95% = 3.5-213.5) had a strong association between high viral load and incident ≥CIN2; non-16 carcinogenic high viral load was not associated with incident ≥CIN2 (OR = 0.7, 95% CI = 0.2–1.9). Single noncarcinogenic type viral load was not associated with increased risk of prevalent or incident ≥CIN2 (OR = 1.2 and 1.1, respectively). In conclusion, carcinogenic high viral load was associated with prevalent ≥CIN2; however HPV16 was uniquely associated with incident ≥CIN2. The extent to which these observations can be translated into clinical practice must be rigorously examined in the context of the method of viral load measurement and the type-specific differences observed for incident ≥CIN2.
doi:10.1002/ijc.23012
PMCID: PMC3962984  PMID: 17722112
human papillomavirus; viral load; genotype; screening
20.  High-risk human papillomavirus prevalence is associated with HIV infection among heterosexual men in Rakai, Uganda 
Sexually transmitted infections  2012;89(2):122-127.
Objectives
Human papillomavirus (HPV) infection causes genital warts, penile cancer and cervical cancer. Africa has one of the highest rates of penile and cervical cancers, but there are little data on high-risk human papillomavirus (HR-HPV) prevalence in heterosexual men. Knowledge of HR-HPV prevalence, risk factors and genotype distribution among heterosexual men is important to establish risk-reduction prevention strategies.
Methods
1578 uncircumcised men aged 15–49 years who enrolled in male circumcision trials in Rakai, Uganda, were evaluated for HR-HPV from swabs of the coronal sulcus/glans using Roche HPV Linear Array. Adjusted prevalence risk ratios (adjPRRs) were estimated using modified Poisson multivariable regression.
Results
HPV prevalence (either high risk or low risk) was 90.7% (382/421) among HIV-positive men and 60.9% (596/978) among HIV-negative men (PRR 1.49, 95% CI 1.40 to 1.58). HIV-positive men had a significantly higher risk of infection with three or more HR-HPV genotypes (PRR = 5.76, 95% CI 4.27 to 7.79). Among HIV-positive men, high-risk sexual behaviours were not associated with increased HR-HPV prevalence. Among HIV-negative men, HR-HPV prevalence was associated with self-reported genital warts (adjPRR 1.57, 95% CI 1.07 to 2.31). Among all men (both HIV negative and HIV positive), HR-HPV prevalence was associated with more than 10 lifetime sexual partners (adjPRR 1.30, 95% CI 1.01 to 1.66), consistent condom use (adjPRR 1.31, 95% CI 1.08 to 1.60) and HIV infection (adjPRR 1.80, 95% CI 1.60 to 2.02). HR-HPV prevalence was lower among men who reported no sexual partners during the past year (adjPRR 0.47, 95% CI 0.23 to 0.94).
Conclusion
The burden of HR-HPV infection is high among heterosexual men in sub-Saharan Africa and most pronounced among the HIV-infected individuals.
doi:10.1136/sextrans-2012-050524
PMCID: PMC3640492  PMID: 22628661
21.  Cervical Cancer Screening in Older Women: New Evidence and Knowledge Gaps 
PLoS Medicine  2014;11(1):e1001586.
Anne Rositch and colleagues discuss the study by Peter Sasieni and colleagues on cervical cancer screening in older women and describe the further information needed to help inform decisions about whether to extend screening programs beyond 65 years for women with adequate negative screening.
Please see later in the article for the Editors' Summary
doi:10.1371/journal.pmed.1001586
PMCID: PMC3891623  PMID: 24453947
22.  THE CORRELATION BETWEEN HPV POSITIVITY AND ABNORMAL CERVICAL CYTOLOGY DIFFERS BY AGE AMONG PERIMENOPAUSAL WOMEN 
Objectives
We explored the age-stratified correlates and correlations between HR-HPV infection and cervical abnormalities in perimenopausal women.
Materials and methods
HPV testing and Pap smear screening were performed at baseline on 841 routinely screened women age 35–60 years in the HPV in Perimenopause (HIP) cohort. Demographic, behavioral and medical information was collected through telephone administered questionnaires. Descriptive analyses were used to examine the correlation between HR-HPV infection and cervical abnormalities by age. Logistic regression was used to determine correlates of HPV and abnormalities in women under and over 45 years of age.
Results
The prevalence of HPV, HR-HPV and cervical abnormalities decreased significantly with increasing age, as did the correlation between HR-HPV and cervical abnormalities. The prevalence of HR-HPV was 50% among younger women with abnormalities but this decreased steadily to 20% HR-HPV detection among 50–54 year old, and no abnormalities were detected in 55–60 year old women. Different correlates of HR-HPV infection and abnormalities were observed in women ≥45 years, a pattern not seen in the younger women.
Conclusions
Although the relative proportion of low and high-grade abnormalities did not change with age, we saw a loss of concordance between HR-HPV detection and cytological abnormalities with increasing age. Current guidelines for cervical cancer screening group together all women age 30 and above. Our data raise important questions about the interpretation of HPV and Pap test results in this age group and suggest that ongoing surveillance of HPV and cytology in cervical cancer screening programs consider a third age stratification among older women.
doi:10.1097/LGT.0b013e3182503402
PMCID: PMC3499667  PMID: 22885643
perimenopausal women; menopause; human papillomavirus; HPV; cervical lesions; cytology; cervical cancer; screening; guidelines
23.  Human Leukocyte Antigen Class I and II Alleles and Cervical Adenocarcinoma 
Frontiers in Oncology  2014;4:119.
Background: Associations between human leukocyte antigens (HLA) alleles and cervical cancer are largely representative of squamous cell carcinoma (SCC), the major histologic subtype. We evaluated the association between HLA class I (A, B, and C) and class II (DRB1 and DQB1) loci and risk of cervical adenocarcinoma (ADC), a less common but aggressive histologic subtype.
Methods: We pooled data from the Eastern and Western US Cervical Cancer studies, and evaluated the association between individual alleles and allele combinations and ADC (n = 630 ADC; n = 775 controls). Risk estimates were calculated for 11 a priori (based on known associations with cervical cancer regardless of histologic type) and 38 non a priori common alleles, as odds ratios (OR) and 95% confidence intervals (CI), adjusted for age and study. In exploratory analysis, we compared the risk associations between subgroups with HPV16 or HPV18 DNA in ADC tumor tissues in the Western US study cases and controls.
Results: Three of the a priori alleles were significantly associated with decreased risk of ADC [DRB1*13:01 (OR = 0.61; 95% CI: 0.41–0.93), DRB1*13:02 (OR = 0.49; 95% CI: 0.31–0.77), and DQB1*06:03 (OR = 0.64; 95% CI: 0.42–0.95)]; one was associated with increased risk [B*07:02 (OR = 1.39; 95% CI: 1.07–1.79)]. Among alleles not previously reported, DQB1*06:04 (OR = 0.46; 95% CI: 0.27–0.78) was associated with decreased risk of ADC and remained significant after correction for multiple comparisons, and C*07:02 (OR = 1.41; 95% CI: 1.09–1.81) was associated with increased risk. We did not observe a difference by histologic subtype. ADC was most strongly associated with increased risk with B*07:02/C*07:02 alleles (OR = 1.33; 95% CI: 1.01–1.76) and decreased risk with DRB1*13:02/DQB1*06:04 (OR = 0.41; 95% CI: 0.21–0.80).
Conclusion: Results suggest that HLA allele associations with cervical ADC are similar to those for cervical SCC. An intriguing finding was the difference in risk associated with several alleles restricted to HPV16 or HPV18-related tumors, consistent with the hypothesis that HLA recognition is HPV type-specific.
doi:10.3389/fonc.2014.00119
PMCID: PMC4062965  PMID: 24995157
HLA class I; HLA class II; cervical adenocarcinoma; host genetics; HPV
24.  Contributions of recent and past sexual partnerships on incident human papillomavirus detection: acquisition and reactivation in older women 
Cancer research  2012;72(23):6183-6190.
Understanding the fraction of newly detected human papillomavirus (HPV) infections due to acquisition and reactivation has important implications on screening strategies and prevention of HPV-associated neoplasia. Information on sexual activity and cervical samples for HPV DNA detection using Roche Linear Array were collected semi-annually for two years from 700 women age 35–60 years. Incidence and potential fraction of HPV infections associated with new and lifetime sexual partnerships were estimated using Poisson models. Cox frailty models were used to estimate hazard ratios (HR) for potential risk factors of incident HPV detection. Recent and lifetime numbers of sexual partners were both strongly associated with incident HPV detection. However, only 13% of incident detections were attributed to new sexual partners whereas 72% were attributed to ≥5 lifetime sexual partners. Furthermore, 155 out of 183 (85%) incident HPV detections occurred during periods of sexual abstinence or monogamy, and were strongly associated with cumulative lifetime sexual exposure (HR: 4.1, 95% CI: 2.0, 8.4). This association increased with increasing age. These data challenge the 20 paradigm that incident HPV detection is driven by current sexual behavior and new viral acquisition in older women. Our observation that most incident HPV infection was attributable to past, not current, sexual behavior at older ages supports a natural history model of viral latency and reactivation. As the highly exposed baby-boomer generation of women with sexual debut after the sexual revolution transition to menopause, the implications of HPV reactivation at older ages on cervical cancer risk and screening recommendations should be carefully evaluated.
doi:10.1158/0008-5472.CAN-12-2635
PMCID: PMC3513486  PMID: 23019223
human papillomavirus; HPV; sexual behavior; older women; reactivation; incidence; acquisition; perimenopause; aging
25.  HPV infection and increased risk of HIV acquisition. A systematic review and meta-analysis 
AIDS (London, England)  2012;26(17):10.1097/QAD.0b013e328358d908.
doi:10.1097/QAD.0b013e328358d908
PMCID: PMC3831022  PMID: 22874522
papillomavirus infections; HIV; meta-analysis; human papillomavirus; risk factors

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