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1.  Clinical Human Papillomavirus Detection Forecasts Cervical Cancer Risk in Women Over 18 Years of Follow-Up 
Journal of Clinical Oncology  2012;30(25):3044-3050.
To describe the long-term (≥ 10 years) benefits of clinical human papillomavirus (HPV) DNA testing for cervical precancer and cancer risk prediction.
Cervicovaginal lavages collected from 19,512 women attending a health maintenance program were retrospectively tested for HPV using a clinical test. HPV positives were tested for HPV16 and HPV18 individually using a research test. A Papanicolaou (Pap) result classified as atypical squamous cells of undetermined significance (ASC-US) or more severe was considered abnormal. Women underwent follow-up prospectively with routine annual Pap testing up to 18 years. Cumulative incidence rates (CIRs) of ≥ grade 3 cervical intraepithelial neoplasia (CIN3+) or cancer for enrollment test results were calculated.
A baseline negative HPV test provided greater reassurance against CIN3+ over the 18-year follow-up than a normal Pap (CIR, 0.90% v 1.27%). Although both baseline Pap and HPV tests predicted who would develop CIN3+ within the first 2 years of follow-up, only HPV testing predicted who would develop CIN3+ 10 to 18 years later (P = .004). HPV16- and HPV18-positive women with normal Pap were at elevated risk of CIN3+ compared with other HPV-positive women with normal Pap and were at similar risk of CIN3+ compared with women with a low-grade squamous intraepithelial Pap.
HPV testing to rule out cervical disease followed by Pap testing and possibly combined with the detection of HPV16 and HPV18 among HPV positives to identify those at immediate risk of CIN3+ would be an efficient algorithm for cervical cancer screening, especially in women age 30 years or older.
PMCID: PMC3732003  PMID: 22851570
2.  Optimal Positive Cutoff Points for careHPV Testing of Clinician- and Self-Collected Specimens in Primary Cervical Cancer Screening: an Analysis from Rural China 
Journal of Clinical Microbiology  2014;52(6):1954-1961.
careHPV, a lower-cost DNA test for human papillomavirus (HPV), is being considered for cervical cancer screening in low- and middle-income countries. However, not a single large-scaled study exists to investigate the optimal positive cutoff point of careHPV test. We pooled data for 9,785 women participating in two individual studies conducted from 2007 to 2011 in rural China. Woman underwent multiple screening tests, including careHPV on clinician-collected specimens (careHPV-C) and self-collected specimens (careHPV-S), and Hybrid Capture 2 on clinician-collected specimens (HC2-C) as a reference standard. The primary endpoint was cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) (n = 127), and secondary endpoint was CIN2+ (n = 213). The area under the curves (AUCs) for HC2-C and careHPV-C were similar (0.954 versus 0.948, P = 0.166), and better than careHPV-S (0.878; P < 0.001 versus both). The optimal positive cutoff points for HC2-C, careHPV-C, and careHPV-S were 1.40, 1.74, and 0.85, respectively. At the same cutoff point, careHPV-C was not significantly less sensitive and more specific for CIN3+ than HC2-C, and careHPV-S was significantly less sensitive for CIN3+ than careHPV-C and HC2-C. Raising the cutoff point of careHPV-C from 1.0 to 2.0 could result in nonsignificantly lower sensitivity but significantly higher specificity. Similar results were observed using CIN2+ endpoint. careHPV using either clinician- or self-collected specimens performed well in detecting cervical precancer and cancer. We found that the optimal cutoff points of careHPV were 2.0 on clinician-collected specimens and 1.0 on self-collected specimens.
PMCID: PMC4042749  PMID: 24671789
3.  A Comparison of Cervical and Vaginal Human Papillomavirus 
Sexually transmitted diseases  2007;34(11):849-855.
We wanted to compare detection of a broad spectrum of human papillomavirus (HPV) types detected in cellular specimens from the vagina and cervix, which could provide information about the potential of each anatomical site for harboring infection. Previous studies have failed to present data on or detect a broad spectrum of HPV genotypes and/or have not carefully sampled the vagina, instead relying on self-collection that is likely contaminated with cervical cells.
Study Design
We conducted follow-up study of 353 women who had participated in study of HPV and cervical neoplasia in Costa Rica. We collected paired cervical and vaginal specimens; vaginal specimens were collected from the fornix to minimize cervical contamination. Specimens were tested in a masked fashion for >40 HPV types using a MY09/MY11 PCR method and type-specific dot blot hybridization.
The prevalence for any carcinogenic HPV type in vaginal and cervical specimens was similar (P = 0.3). However, the prevalence for any HPV type in vaginal specimens was greater than in cervical specimens (P = 0.0002), primarily due to a twofold increased vaginal prevalence of HPV types of the α3/α15 phylogenetic species (e.g., HPV61) (P <0.00005).
Carcinogenic HPV types appeared to have a similar affinity for vaginal and cervical epithelium, but noncarcinogenic HPV types of the α3/α15 phylogenetic species may have a tropism for vaginal epithelium.
PMCID: PMC3962831  PMID: 17621246
4.  Human Papillomavirus Genotyping After Denaturation of Specimens for Hybrid Capture 2 Testing: Feasibility Study for the HPV Persistence and Progression Cohort† 
Journal of virological methods  2007;146(1-2):80-85.
Human papillomavirus (HPV) genotyping could be clinically useful, depending on the results of large, prospective studies like the HPV Persistence and Progression cohort. The cohort is based on genotyping and follow-up of Hybrid Capture-positive women at Kaiser Permanente, Northern California. HPV DNA testing by Hybrid Capture 2 requires denaturation with alkali, possibly damaging the DNA for optimal PCR-based genotyping. A feasibility study was conducted on paired aliquots of anonymized specimens from 100 women with low-grade intraepithelial lesion cytology. Test aliquots were left in denaturant for 10 or 18 hours at 4°C and then neutralized; comparison aliquots were not denatured but diluted to match the timing, temperature, concentration and salt conditions of the treated specimens. The masked aliquots were tested using a commercialized PCR-based assay that detects of 37 HPV genotypes. There was no overall effect of treatment on test positivity or number of types. HPV16 was marginally more likely to be detected in untreated versus treated aliquots (P = 0.09) but HPV45 was marginally more likely to be detected in treated than untreated aliquots (P = 0.07), suggesting that these differences represented chance (intra-test variability). It can be concluded that residual Hybrid Capture-positive specimens can be accurately genotyped by PCR after Hybrid Capture 2 processing.
PMCID: PMC2683347  PMID: 17673302
Cervical Cancer; Human Papillomavirus (HPV); HPV genotypes; Cervical Precancer; Cervical Intraepithelial Neoplasia Grade 3 [CIN3]; screening; PCR
5.  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.
PMCID: PMC3911475  PMID: 24197879
6.  Analytic and Clinical Performance of cobas HPV Testing in Anal Specimens from HIV-Positive Men Who Have Sex with Men 
Journal of Clinical Microbiology  2014;52(8):2892-2897.
Anal human papillomavirus (HPV) infections are common, and the incidence of anal cancer is high in HIV-infected men who have sex with men (MSM). To evaluate the performance of HPV assays in anal samples, we compared the cobas HPV test (cobas) to the Roche Linear Array HPV genotyping assay (LA) and cytology in HIV-infected MSM. Cytology and cobas and LA HPV testing were conducted for 342 subjects. We calculated agreement between the HPV assays and the clinical performance of HPV testing and HPV genotyping alone and in combination with anal cytology. We observed high agreement between cobas and LA, with cobas more likely than LA to show positive results for HPV16, HPV18, and other carcinogenic types. Specimens testing positive in cobas but not in LA were more likely to be positive for other markers of HPV-related disease compared to those testing negative in both assays, suggesting that at least some of these were true positives for HPV. cobas and LA showed high sensitivities but low specificities for the detection of anal intraepithelial neoplasia grade 2/3 (AIN2/3) in this population (100% sensitivity and 26% specificity for cobas versus 98.4% sensitivity and 28.9% specificity for LA). A combination of anal cytology and HPV genotyping provided the highest accuracy for detecting anal precancer. A higher HPV load was associated with a higher risk of AIN2/3 with HPV16 (Ptrend < 0.001), HPV18 (Ptrend = 0.07), and other carcinogenic types (Ptrend < 0.001). We demonstrate that cobas can be used for HPV detection in anal cytology specimens. Additional tests are necessary to identify men at the highest risk of anal cancer among those infected with high-risk HPV.
PMCID: PMC4136172  PMID: 24899025
7.  Age-specific occurrence of HPV16- and HPV18-related cervical cancer 
The age-specific of occurrence of cervical cancer related to human papillomavirus genotypes HPV16 and HPV18, the two targeted by current HPV vaccines, is not well described. We therefore used data from two large, tissue-based HPV genotyping studies of cervical cancer, one conducted in New Mexico (USA) (n = 744) and an international study restricted to cancers (n = 1,729) from Europe, North America, and Australia to represent those regions with widely available cervical cancer screening facilities. HPV results were categorized as HPV16 or HPV18 positive (HPV16/18) versus other HPV genotype. We observed a decreasing proportion of HPV16/18-positive cancers with increasing age in the international study (ptrend < 0.001) and New Mexico study (ptrend < 0.001). There was no heterogeneity in the relationship between age of diagnosis and the proportion of HPV16/18-positive cancers between studies (p = 0.8). Combining results from the two studies (n = 2,473), the percentages of HPV16/18-positive cases were 77.0% (95%CI: 75.1%-78.9%) for women less than 65 years old and 62.7% (95%CI: 58.4%-66.9%) for women aged 65 and older (p < 0.001). In women who are under the age of 25 and have been vaccinated before becoming sexually active, the cervical cancer incidence is expected to be approximately 3.5 per million by 2020. HPV vaccination against HPV16/18 may have a greater impact on cervical cancers in women under 65 than in women aged 65 and older. These data will inform the age-specific impact of HPV vaccination and its integration with cervical cancer screening activities.
PMCID: PMC4306595  PMID: 23632816
8.  Three-Year Risk of Cervical Precancer and Cancer After the Detection of Low-Risk Human Papillomavirus Genotypes Targeted by a Commercial Test 
Obstetrics and gynecology  2014;123(1):49-56.
To investigate the risk of cervical precancer and cancer associated with detection of human papillomavirus (HPV) 6, 11, and 42.
We used data from the New Mexico HPV Pap Registry. A stratified sample of 59,644 residual cervical cytology specimens from a population of 379,000 underwent HPV genotyping. We measured the 3-year cumulative incidence of cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) and grade 3 or more severe (CIN3+) after detection of single HPV6, 11, or 42 infections or single or multiple infections by of HPV6, 11, or 42 (“HPV6, 11, 42, or combinations”)(n=581).
The overall prevalence of a single infection of HPV6, 11, or 42 was 0.8% (95% confidence interval [95%CI]: 0.7%, 0.9%). The 3-year risks of CIN2+ and CIN3+ after HPV6, 11, 42, or combinations infections (n = 581) were 0.4% (CI: 0.1%, 0.7%) for CIN2+ and 0.0% for CIN3+ (nota bene, no confidence interval was calculable because no events occurred), respectively. By comparison, the 3-year risks of CIN2+ and CIN3+ after a negative HPV result (n = 27,522) were 0.2% (95%CI: 0.1%, 0.2%) and 0.1% (95%CI: 0.0%, 0.1%), respectively.
Detection of HPV6, 11, 42, or combinations in the absence of high risk HPV types does not identify women at increased 3-year risk for cervical precancer. Testing for HPV6, 11, 42, or combinations of those types should be discontinued as it has no proven benefit to patients.
PMCID: PMC3926945  PMID: 24463663
9.  Evaluation of Any or Type-Specific Persistence of High-Risk Human Papillomavirus for Detecting Cervical Precancer 
Journal of Clinical Microbiology  2012;50(2):300-306.
High-risk human papillomavirus (HR-HPV) testing is increasingly important. We therefore examined the impact on accuracy of repeated versus one-time testing, type-specific versus pooled detection, and assay analytic sensitivity. By using a nested case-control design from the ASCUS-LSIL Triage Study, we selected women with incident cervical intraepithelial neoplasia grade 2 or grade 3 (CIN2/3; n = 325) and a random sample of women with
PMCID: PMC3264159  PMID: 22162556
The Journal of Infectious Diseases  2013;208(11):1768-1775.
Background. Carcinogenic human papillomaviruses (HPVs) cause a large proportion of anal cancers. Human immunodeficiency virus (HIV)–infected men who have sex with men (MSM) are at increased risk of HPV infection and anal cancer compared with HIV-negative men. We evaluated risk factors for HPV infection and anal precancer in a population of HIV-infected MSM.
Methods. Our study included 305 MSM at an HIV/AIDS clinic in the Kaiser Permanente Northern California Health Maintenance Organization. Logistic regression was used to estimate associations of risk factors comparing men without anal HPV infection; men with anal HPV infection, but no precancer; and men with anal precancer.
Results. Low CD4 count (<350 cells/mm3) and previous chlamydia infection were associated with an increased risk of carcinogenic HPV infection (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.28–10.40 and OR, 4.24; 95% CI, 1.16–15.51, respectively). History of smoking (OR, 2.71 95% CI, 1.43–5.14), duration, recency, and dose of smoking increased the risk of anal precancer among carcinogenic HPV-positive men but had no association with HPV infection.
Conclusions. We found distinct risk factors for anal HPV infection and anal precancer. Risk factors for HPV infection and anal precancer are similar to established risk factors for cervical cancer progression.
PMCID: PMC3814839  PMID: 23908478
anal cancer; human papillomavirus (HPV); human immunodeficiency virus (HIV); men who have sex with men (MSM); anal intraepithelial neoplasia (AIN)
American Journal of Epidemiology  2011;173(12):1388-1390.
Metrics such as relative hazards and relative risks do not account for the prevalence of a marker over time and its relation to whether and when an outcome occurs. Uncommon markers that have good predictive values and common markers that are poorly predictive may not be (clinically) useful in predicting disease and other health outcomes. Recent work by Little et al. (Am J Epidemiol. 2011;173(12):1380–1387) highlights the development of a new method that considers both factors in predicting outcomes. Measures that incorporate both marker prevalence and predictive values and therefore are measures of “effectiveness” may be broadly helpful in deciding which markers or exposures are useful in disease screening or should be targeted by health interventions.
PMCID: PMC3145395  PMID: 21571873
biological markers; censored data; life change events; menopause; premenopause; survival analysis
Vaccine  2013;31(0 8):I1-31.
Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread—optimally universal—implementation of HPV prevention strategies in both developed and developing countries.
This article summarizes information from the chapters presented in a special ICO Monograph ‘Comprehensive Control of HPV Infections and Related Diseases’ Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters.
PMCID: PMC4062073  PMID: 24229716
HPV; Cervical cancer; Anal cancer; Penile cancer; Vaginal cancer; Vulvar cancer; Oropharyngeal cancer; Screening; HPV vaccination; HPV testing; Prevention
There are limited data on the prospective risks of detecting cervical precancer and cancer in United States (US) populations specifically where the delivery of opportunistic cervical screening takes place outside managed care and in the absence of organized national programs. Such data will inform the management of women with positive screening results before and after widespread human papillomavirus (HPV) vaccination and establishes a baseline preceding recent changes in US cervical cancer screening guidelines. Using data reported to the statewide passive surveillance systems of the New Mexico HPV Pap Registry, we measured the 3-year HPV type-specific cumulative incidence of cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) and grade 3 or more severe (CIN3+) detected during real-world health care delivery across a diversity of organizations, payers, clinical settings, providers and patients. A stratified sample of 47,541 cervical cytology specimens from a screening population of 379,000 women underwent HPV genotyping. Three-year risks for different combinations of cytologic interpretation and HPV risk group ranged from <1% (for several combinations) to approximately 70% for CIN2+ and 55% for CIN3+ in women with high-grade (HSIL) cytology and HPV16 infection. A substantial proportion of CIN2+ (35.7%) and CIN3+ (30.9%) were diagnosed following negative cytology, of which 62.3 and 78.2%, respectively, were high-risk HPV positive. HPV16 had the greatest 3-year risks (10.9% for CIN2+,8.0% for CIN3+) followed by HPV33, HPV31, and HPV18. Positive results for high-risk HPV, especially HPV16, the severity of cytologic interpretation, and age contribute independently to the risks of CIN2+ and CIN3+.
PMCID: PMC4020996  PMID: 24226935
cervical intraepithelial neoplasia (CIN); cervical cancer; human papillomavirus (HPV); HPV vaccine effectiveness; cervical screening effectiveness; US opportunistic cervical screening; cytology; Pap test
Using human papillomavirus (HPV) testing for cervical cancer screening in lower-resource settings (LRS) will result in a significant number of screen-positive women. This analysis compares different triage strategies for detecting cervical precancer and cancer among HPV-positive women in LRS. This was a population-based study of women aged 25–65 years living in China (n = 7,541). Each woman provided a self-collected and two clinician-collected specimens. The self-collected and one clinician-collected specimen were tested by two HPV DNA tests—careHPV™ and Hybrid Capture 2; the other clinician-collected specimen was tested for HPV16/18/45 E6 protein. CareHPV™-positive specimens were tested for HPV16/18/45 DNA. HPV DNA-positive women underwent visual inspection with acetic acid (VIA) and then colposcopic evaluation with biopsies. The performance for detection of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) among HPV DNA-positive women was assessed for different triage strategies: HPV16/18/45 E6 or DNA detection, VIA, colposcopic impression, or higher signal strength (≥10 relative light units/positive control [rlu/pc]). The percent triage positive ranges were 14.8–17.4% for VIA, 17.8–20.9% for an abnormal colposcopic impression; 7.9–10.5% for HPV16/18/45 E6; 23.4–28.4% for HPV16/18/45 DNA; and 48.0–62.6% for higher signal strength (≥10 rlu/pc), depending on the HPV test/specimen combination. The positivity for all triage tests increased with severity of diagnosis. HPV16/18/45 DNA detection was approximately 70% sensitive and had positive predictive values (PPV) of approximately 25% for CIN3+. HPV16/18/45 E6 detection was approximately 50% sensitive with a PPV of nearly 50% for CIN3+. Different triage strategies for HPV DNA-positive women provide important tradeoffs in colposcopy or treatment referral percentages and sensitivity for prevalent CIN3+.
What's new?
The careHPV™ test is a novel technology for primary cervical cancer screening of women from lower-resource settings. However, triage strategies are needed to identify which HPV-positive women are at highest risk of cervical precancer and cancer. Here, multiple viable and affordable strategies to manage HPV-positive women depending on local requirements and resources are identified, based on evaluation of the performance of different triage strategies for developing countries. The different strategies for women who test positive for HPV DNA provide important tradeoffs in colposcopy or treatment referral percentages and sensitivity for cervical intraepithelial neoplasia grade 3 or cancer (CIN3+).
PMCID: PMC4232922  PMID: 24248915
HPV; triage; cervical cancer; careHPV; developing countries; E6
The Journal of Infectious Diseases  2011;203(6):814-822.
Background. Detailed descriptions of long-term persistence of human papillomavirus (HPV) in the absence of cervical precancer are lacking.
Methods. In a large, population-based natural study conducted in Guanacaste, Costa Rica, we studied a subset of 810 initially HPV-positive women with ≥3 years of active follow-up with ≥3 screening visits who had no future evidence of cervical precancer. Cervical specimens were tested for >40 HPV genotypes using a MY09/11 L1-targeted polymerase chain reaction method.
Results. Seventy-two prevalently-detected HPV infections (5%) in 58 women (7%) persisted until the end of the follow-up period (median duration of follow-up, 7 years) without evidence of cervical precancer. At enrollment, women with long-term persistence were more likely to have multiple prevalently-detected HPV infections (P <.001) than were women who cleared their baseline HPV infections during follow-up. In a logistic regression model, women with long-term persistence were more likely than women who cleared infections to have another newly-detected HPV infection detectable at ≥3 visits (odds ratio, 2.6; 95% confidence interval, 1.2–5.6).
Conclusions. Women with long-term persistence of HPV infection appear to be generally more susceptible to other HPV infections, especially longer-lasting infections, than are women who cleared their HPV infections.
PMCID: PMC3071125  PMID: 21343148
Gynecologic oncology  2013;130(3):10.1016/j.ygyno.2013.06.005.
Chromosomal gains at 3q26, 5p15 and 20q13 have been described in cervical precancer and cancer. We evaluated a novel fluorescence in situ hybridization (FISH) assay that detects gains at these three loci simultaneously as a possible biomarker for detecting cervical precancer.
Chromosomal copy numbers at 3q26 (3q), 5p15 (5p), 20q13 (20q) and the centromere of chromosome7 (cen7) in liquid-based cytology specimens from 168 women enrolled in the Biopsy Study were determined by FISH. The number of cells with ≥3 or ≥4 signals for a genomic locus was enumerated and diagnostic test performance measures were calculated using receiver operating characteristic (ROC) analyses. Sensitivity and specificity values were determined for the detection of CIN2+ and/or HSIL.
The median number of cells with ≥3 signals increased with the severity of cervical lesion for each genomic locus (p-trend<0.02 for each locus). ROC analysis for the number of cells with ≥3 signals resulted in area under the curve values of 0.70 (95% CI: 0.54-0.86), 0.67 (0.52-0.83), 0.67 (0.51-0.83) and 0.78 (0.64-0.92) for 3q, 5p, 20q and cen7, respectively, for the detection of CIN2+ and/or HSIL. Positivity for gains at multiple loci resulted in only slightly better test performance measures than those for the individual probes for four distinct combinations of probes.
Chromosomal gains at 3q, 5p, 20q and cen7 are associated with severity of cervical lesions. Further studies are required to quantify risk stratification of FISH assays for cervical cancer screening.
PMCID: PMC3833871  PMID: 23769811
cervical cancer; genomic gains; 3q; FISH; HPV
AIDS (London, England)  2012;26(17):2185-2192.
Anal cancer incidence is high in HIV-infected MSM. Screening for anal intraepithelial lesions and cancers is performed at specialized clinics and relies on high-resolution anoscopy (HRA) and anal cytology. Both approaches have limited reproducibility and sensitivity for detecting anal cancer precursors. We evaluated biomarkers for human papillomavirus (HPV)-related disease in a population of HIV-infected MSM.
A cross-sectional screening study with passive follow-up included 363 MSM followed at a HIV/AIDS clinic. All men had anal cytology samples taken and were evaluated using HRA and anal biopsies. Using a composite endpoint of biopsy results and cytology, we compared the performance of HPV16/18 genotyping, HPVE6/E7 mRNA expression, and p16/Ki-67 cytology to detect high-grade anal intraepithelial neoplasias (AINs).
For all biomarkers analyzed, there was a significant trend of increasing percentage of men testing positive with increasing severity of disease (P< 0.001). HPV DNA testing had the highest sensitivity for anal intraepithelial neoplasia grade 2 and anal intraepithelial neoplasia grade 3 (AIN3), followed by p16/Ki-67, HPVE6/E7 mRNA testing, and HPV16/18 genotyping. The highest Youden's index was observed for HPVE6/E7 mRNA testing, followed by HPV16/18 genotyping, p16/Ki-67 cytology, and HPV DNA testing. Increasing the threshold for positivity of p16/Ki-67 to five or more positive cells led to significantly higher specificity, but unchanged sensitivity for detecting AIN3.
Molecular features of anal disease categories are similar to those of corresponding cervical lesions. Biomarkers evaluated for cervical cancer screening may be used for primary anal cancer screening or to decide who should require immediate treatment vs. expectant management.
PMCID: PMC4144865  PMID: 23018436
anal cancer screening; HIV; human papillomavirus; human papillomavirus mRNA; MSM; p16
American Journal of Epidemiology  2009;171(2):155-163.
Misclassification of exposure and surrogate endpoints of disease can obscure causal relations. Using data from the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS, 1997–2001), the authors explored the impact of exposure (human papillomavirus (HPV) detection) and endpoint (histologic cervical precancer) classification on their mutual association. Women referred into this study with an atypical squamous cells of undetermined significance Papanicolaou test with satisfactory results for all 4 HPV tests were included in this analysis (n = 3,215; 92.2%). HPV testing results were related to different definitions of cervical precancer, based on paired, worst 2-year histologic diagnoses, by calculating clinical sensitivity, specificity, and odds ratios. The authors found that HPV test sensitivity increased and specificity decreased with increasing certainty of cervical precancer, with HPV testing having the highest sensitivity (92%–98%) and lowest specificity (46%–54%) for consensus cervical intraepithelial neoplasia grade 3 (CIN 3). The overall accuracy of each HPV test, as measured by odds ratios, was greatest for consensus CIN-3 diagnoses, from 2- to 4-fold greater than for a less stringent precancer definition of any diagnosis of CIN 2 or more severe. In summary, there was convergence of greater certainty of carcinogenic HPV with greater certainty of a precancerous diagnosis, such that all 4 HPV tests almost always tested positive in women most likely to have cervical precancer. Finding increasingly strong associations when both test and diagnostic misclassification are reduced is a useful sign of “true association” in molecular epidemiology.
PMCID: PMC2878104  PMID: 20007673
cervical intraepithelial neoplasia; misclassification; papillomavirus infections; uterine cervical neoplasms
A population sample of 10,049 women living in Guanacaste, Costa Rica was recruited into a natural history of human papillomavirus (HPV) and cervical neoplasia study in 1993–4. At the enrollment visit, we applied multiple state-of-the-art cervical cancer screening methods to detect prevalent cervical cancer and to prevent subsequent cervical cancers by the timely detection and treatment of precancerous lesions. Women were screened at enrollment with 3 kinds of cytology (often reviewed by more than one pathologist), visual inspection, and Cervicography. Any positive screening test led to colposcopic referral and biopsy and/or excisional treatment of CIN2 or worse. We retrospectively tested stored specimens with an early HPV test (Hybrid Capture Tube Test) and for >40 HPV genotypes using a research PCR assay. We followed women typically 5–7 years and some up to 11 years. Nonetheless, sixteen cases of invasive cervical cancer were diagnosed during follow-up. Six cancer cases were failures at enrollment to detect abnormalities by cytology screening; three of the six were also negative at enrollment by sensitive HPV DNA testing. Seven cancers represent failures of colposcopy to diagnose cancer or a precancerous lesion in screen-positive women. Finally, three cases arose despite attempted excisional treatment of precancerous lesions. Based on this evidence, we suggest that no current secondary cervical cancer prevention technologies applied once in a previously under-screened population is likely to be 100% efficacious in preventing incident diagnoses of invasive cervical cancer.
PMCID: PMC2766540  PMID: 19569231
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.
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.
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.
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.
HPV genotyping in HPV-positive women with minor cytological abnormalities will likely not alter clinical management. Adding HPV45 to genotyping assays is not warranted.
PMCID: PMC3687215  PMID: 23603204
HPV testing; cervical intraepithelial neoplasia; cervical cytology; risk stratification
Journal of Clinical Microbiology  2014;52(6):2089-2095.
High-risk human papillomavirus (hrHPV) testing is now being introduced as a potential primary screening test for improved detection of cervical precancer and cancer. Current U.S. Food and Drug Administration-approved tests are batch tests that take several hours to complete. A rapid, non-batch test might permit point-of-care (POC) testing, which can facilitate same-day screen and management strategies. For a non-batch, random-access platform (GeneXpert; Cepheid, Sunnyvale, CA), a prototype hrHPV assay (Xpert) has been developed where testing for 14 hrHPV types can be completed in 1 h. In the first clinical evaluation, Xpert was compared to two validated hrHPV tests, the cobas HPV test (cobas, Roche Molecular Systems) and Hybrid Capture 2 (hc2, Qiagen), and to histologic outcomes using specimens from colposcopy referral populations at 7 clinical sites in the United States (n = 697). The sensitivity of Xpert for cervical intraepithelial neoplasia grade 2 or more severe diagnoses (CIN2+) (n = 141) was equal to that of cobas (90.8% versus 90.8%, P = 1) and greater than that of hc2 (90.8% versus 81.6%, P = 0.004). Xpert was more specific than cobas (42.6% versus 39.6%, P = 0.02) and less specific than hc2 (42.6% versus 47.7%, P < 0.001). Similar results were observed for cervical intraepithelial neoplasia grade 3 or higher (CIN3+) (n = 91). HPV16 detection by Xpert identified 41.8% of the CIN2+ specimens with a positive predictive value (PPV) of 54.6%. By comparison, HPV16 detection by cobas identified 42.6% of the CIN2+ specimens with a PPV of 55.0%. hrHPV detection by the Xpert demonstrated excellent clinical performance for identifying women with CIN2+ and CIN3+ that was comparable to that of currently available clinically validated tests.
PMCID: PMC4042758  PMID: 24719440
Journal of virological methods  2008;151(2):298-300.
The impact of 6-month storage of cervical specimens under alkaline conditions that occurs as the result of Hybrid Capture 2 testing on human papillomavirus (HPV) genotyping is not well documented. To examine this issue, 143 frozen hc2-positive specimens in specimen transport medium were selected at random from each of the following groups: specimens stored for 6 months, 4 months, and 2.5 months under alkaline pH (pH 12–13) and specimens stored 1 month at neutral pH (pH 6–7) as controls (one control specimen was missing results). Specimens were tested in a masked fashion for 19 HPV genotypes (HPV6, 11, 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, and 82) using a prototype, research-use-only GP5+/6+ L1 consensus PCR method and multiplex hybridization using Luminex® xMAP® for detection of specific HPV genotypes. There were no statistical differences in the number of HPV genotypes detected, number of carcinogenic HPV genotypes detected, or in the signal strength among HPV-positive results across groups. Six-month frozen storage of cervical specimens at alkaline pH had little impact on testing for HPV genotypes among hc2-positive women using this HPV genotyping method.
PMCID: PMC2577906  PMID: 18571737
Human Papillomavirus (HPV); HPV genotypes; PCR
No evidence-based clinical management recommendations exist for women with an endocervical curettage (ECC) cervical intraepithelial neoplasia (CIN) grade 1 (CIN1) result when the concurrent cervical biopsy is not high-grade. For women with these pathology findings, we assessed their short-term risk of high-grade histopathology diagnosis in the Calgary Health Region where ECC was routinely performed.
Materials and Methods
We analyzed pathology and colposcopy reports from 1902 referral colposcopies where both ECC and biopsies were normal or CIN1. We calculated the short-term risk of CIN2 or more severe (CIN2+) detected 12–24 months after colposcopy. Pearson chi-square tests or Fisher’s exact tests were used to compare risks of a CIN2+ diagnosis between combinations of test results and strata of risk factors.
The short-term risk of CIN2+ was the same following a CIN1 biopsy and CIN1 ECC (4.9% of 1389 vs. 5.0% of 359, respectively, P=.37). Compared to low-grade referral cytology, the risk of CIN2+ following high-grade cytology was elevated significantly for CIN1 ECC (13.3% vs. 3.3%, P<.01) and non-significantly for CIN1 biopsy (7.1% vs. 4.6%, P=.12).
Following low-grade cytology, the short-term risk of a high-grade histologic diagnosis in women with either CIN1 ECC or biopsy is equivalent, suggesting similar management. A CIN1 ECC may warrant different management in the context of high-grade referral cytology.
PMCID: PMC3608705  PMID: 23343702
cervical intraepithelial neoplasia; colposcopy; curettage; diagnosis; endocervical sampling
Journal of lower genital tract disease  2013;17(5 0 1):S78-S84.
After excisional treatment, CIN2+ can recur. It is not clear how many negative post-treatment Pap or cotest results are needed to assure adequate safety against CIN2+, prior to return to extended retesting intervals.
We observed 5-year risks of CIN2+, and outcomes for 3 follow-up management strategies after treatment (Pap alone, HPV alone, and cotesting) for 3273 women aged 25 and older who were treated for CIN2, CIN3, or AIS between 2003–2010 at Kaiser Permanente Northern California.
Five-year risks of recurrent CIN2+ after treatment varied both by antecedent screening test result and the histology of the treated lesion. The risk ranged from 5% for CIN2 preceded by HPV-positive/ASC-US or LSIL to 16% for CIN3/AIS preceded by AGC/ASC-H/HSIL+ (p<0.0001). However, after post-treatment negative tests, risks were lowered and similar regardless of antecedent screening test and histology of treated disease. The 5-year recurrent CIN2+ risk associated with a negative post-treatment cotest (2.4%) was lower than that of an HPV-negative test alone (3.7%, p=0.3) or Pap-negative result alone (4.2%, p=0.1). Two negative post-treatment tests of each kind conferred slightly lower 5-year CIN2+ risk than one (Pap-negative: 2.7% vs. 4.2%, p=0.2; HPV-negative: 2.7% vs. 3.7%, p=0.7; HPV-negative/Pap-negative: 1.5% vs. 2.4%, p=0.8). The 5-year CIN2+ risk associated with 2 negative cotests of 1.5% (95%CI 0.3% to 7.2%) approached the 0.68% risk associated with a negative Pap test during routine screening.
Women with antecedent AGC/ASC-H/HSIL+ Pap results or those treated with CIN3/AIS had a substantial risk of developing CIN2+ after treatment. Based on the principle of “benchmarking to implicit risk thresholds”, after negative test results following treatment, no subgroup of women achieved risk sufficiently low risk to return to 5-year routine screening. However, negative cotests after treatment provided more reassurance against recurrent CIN2+ than either negative Pap tests or HPV tests alone.
PMCID: PMC3616418  PMID: 23519309
Human Papillomavirus (HPV); cancer prevention; Pap; cervical intraepithelialneoplasia (CIN); Hybrid Capture 2 (HC2); post-treatment; test of cure

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