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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.
Purpose
To describe the long-term (≥ 10 years) benefits of clinical human papillomavirus (HPV) DNA testing for cervical precancer and cancer risk prediction.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1200/JCO.2011.38.8389
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.
doi:10.1128/JCM.03432-13
PMCID: PMC4042749  PMID: 24671789
3.  A Comparison of Cervical and Vaginal Human Papillomavirus 
Sexually transmitted diseases  2007;34(11):849-855.
Objectives
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.
Results
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).
Conclusions
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.
doi:10.1097/OLQ.0b013e318064c8c5
PMCID: PMC3962831  PMID: 17621246
4.  Evaluation of clinical performance of a novel urine-based HPV detection assay among women attending a colposcopy clinic 
Background
Human papillomavirus (HPV) testing in urine offers a convenient approach for cervical cancer screening but has previously suffered from limited clinical sensitivity.
Objectives
We evaluated clinical performance of the prototype Trovagene HPV test, a novel polymerase chain reaction assay that targets the E1 region of the HPV genome and detects and amplifies short fragments of cell-free HPV DNA in urine.
Study design
We conducted a pilot study among seventy two women referred to colposcopy following abnormal screening. Participants provided a urine sample prior to clinician-collected cervical sampling and colposcopically-directed punch biopsy. Trovagene HPV test results on urine samples were compared with cervical and urine testing by Linear Array HPV Genotyping Test (LA-HPV) for detection of histologically-confirmed cervical precancerous lesions.
Results
There was high concordance between urine samples tested by the Trovagene HPV test and corresponding cervical (87.5%) and urine (81.9%) samples tested by LA-HPV. The Trovagene HPV test had high sensitivity (92.3% for detecting CIN2/3, and 100% for CIN3), comparable to LA-HPV testing on cervical samples (96.0% and 100%, respectively), and higher than LA-HPV testing on urine samples (80.8% and 90.0%, respectively). In this referral population, the specificity of the Trovagene urine HPV test was non-significantly lower (29% f CIN2/3 and 25% for CIN3) than corresponding estimates of LA-HPV testing on cervical (36% and 28%, respectively) and urine (42% and 38%, respectively) samples.
Conclusions
This pilot study suggests that the Trovagene HPV test has high sensitivity for urine-based detection of cervical precancer and merits evaluation in larger studies.
doi:10.1016/j.jcv.2014.04.016
PMCID: PMC4146457  PMID: 24881489
human papillomavirus; cervical cancer; urine; screening
5.  The Influence of Type-Specific Human Papillomavirus Infections on the Detection of Cervical Precancer and Cancer: A Population-based Study of Opportunistic Cervical Screening in the United States 
There are limited data on the prospective risks of detecting cervical precancer and cancer in United States (U.S.) 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 U.S. cervical cancer screening guidelines. Using data reported to the statewide passive surveillance systems of the New Mexico HPV Pap Registry, we measured the three-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 three-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+.
doi:10.1002/ijc.28605
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
6.  Reassurance Against Future Risk of Precancer and Cancer Conferred by a Negative Human Papillomavirus Test 
Primary human papillomavirus (HPV) testing (without concurrent Pap tests) every 3 years is under consideration in the United States as an alternative to the two recommended cervical cancer screening strategies: primary Pap testing every 3 years, or concurrent Pap and HPV testing (“cotesting”) every 5 years. Using logistic regression and Weibull survival models, we estimated and compared risks of cancer and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) for the three strategies among 1011092 women aged 30 to 64 years testing HPV-negative and/or Pap-negative in routine screening at Kaiser Permanente Northern California since 2003. All statistical tests were two sided. Three-year risks following an HPV-negative result were lower than 3-year risks following a Pap-negative result (CIN3+ = 0.069% vs 0.19%, P < .0001; Cancer = 0.011% vs 0.020%, P < .0001) and 5-year risks following an HPV-negative/Pap-negative cotest (CIN3+ = 0.069% vs 0.11%, P < .0001; Cancer = 0.011% vs 0.014%, P = .21). These findings suggest that primary HPV testing merits consideration as another alternative for cervical screening.
doi:10.1093/jnci/dju153
PMCID: PMC4111283  PMID: 25038467
7.  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.
doi:10.1016/j.jviromet.2007.06.001
PMCID: PMC2683347  PMID: 17673302
Cervical Cancer; Human Papillomavirus (HPV); HPV genotypes; Cervical Precancer; Cervical Intraepithelial Neoplasia Grade 3 [CIN3]; screening; PCR
8.  A Population-based Evaluation of Cervical Screening in the United States: 2008–2011 
Background
Cervical screening consumes substantial resources, but little is known about utilization in the United States or compliance with guideline recommendations.
Methods
To describe population screening coverage, utilization and outcomes and examine time trends from 2008 to 2011, cervical cytology reports from women residing in New Mexico (981,063 tests from 511,381 women) were evaluated.
Results
From 2008–2011 cervical screening utilization decreased at all ages, but especially in younger women, with a two-thirds reduction at ages 15–20 years. 94% of women aged 25–29 years were screened within 48 months but coverage decreased at older ages, to 69% at 45–49 years and 55% at 60–64 years. Intervals between screening tests were significantly longer in 2011 compared to 2008 (hazard ratio = 1.23, 95% CI = 1.22–1.24) although the commonest rescreening interval was 13 months. In 2011, 91.9% of screening tests for women aged 21–65 years were negative, 6.6% showed minor abnormalities, and 1.0% high grade abnormalities.. High grade abnormality rates were relatively constant over time, but minor abnormalities and atypical cells cannot rule out high-grade (ASC-H) were increasing.
Conclusion
This population-based evaluation of cervical screening shows high coverage under the age of 40 years but lower levels in older women. Screening under age 21 years is becoming less common and screening intervals are lengthening, reflecting updates in national screening guidelines.
Impact
Assessment of cervical screening intervals and population outcomes is essential for accurately estimating the impact and effectiveness of changing recommendations and vaccination against human papillomavirus infections.
doi:10.1158/1055-9965.EPI-13-0973
PMCID: PMC4011954  PMID: 24302677
Cervical screening; utilization; outcome; coverage; New Mexico
9.  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
10.  Polycyclic Aromatic Hydrocarbon-DNA Adducts in Cervix of Women Infected with Carcinogenic Human Papillomavirus Types: An Immunohistochemistry Study 
Mutation research  2007;624(0):114-123.
Among women infected with carcinogenic human papillomavirus (HPV), there is a 2- to 5-fold increased risk of cervical precancer and cancer in women who smoke compared to those who do not smoke. Because tobacco smoke contains carcinogenic polycyclic aromatic hydrocarbons (PAHs), it was of interest to examine human cervical tissue for PAH-DNA adduct formation. Here, we measured PAH-DNA adduct formation in cervical biopsies collected in follow-up among women who tested positive for carcinogenic HPV at baseline. A semi-quantitative immunohistochemistry (IHC) method using antiserum elicited against DNA modified with r7, t8-dihydroxy-t-9, 10-oxy-7, 8, 9, 10-tetrahydrobenzo[a]pyrene (BPDE) was used to measure nuclear PAH-DNA adduct formation. Cultured human cervical keratinocytes exposed to 0, 0.153, or 0.331 μM BPDE showed dose-dependent increases in r7, t8, t9-trihydroxy-c-10-(N2deoxyguanosyl)-7, 8, 9, 10-tetrahydrobenzo[a]pyrene (BPdG) adducts. For BPdG adduct analysis, paraffin-embedded keratinocytes were stained by IHC with analysis of nuclear color intensity by Automated Cellular Imaging System (ACIS) and, in parallel cultures, extracted DNA was assayed by quantitative BPDE-DNA chemiluminescence immunoassay (CIA). For paraffin-embedded samples from carcinogenic HPV-infected women, normal-appearing cervical squamous epithelium suitable for scoring was found in samples from 75 of the 114 individuals, including 29 cases of cervical precancer or cancer and 46 controls. With a lower limit of detection of 20 adducts/108 nucleotides, detectable PAH-DNA adduct values ranged from 25 to 191/108 nucleotides, with a median of 75/108 nucleotides. PAH-DNA adduct values above 150/108 nucleotides were found in 8 samples, and in 3 samples adducts were non-detectable. There was no correlation between PAH-DNA adduct formation and either smoking or case status. Therefore, PAH-DNA adduct formation as measured by this methodology did not appear related to the increased risk of cervical precancer and cancer among carcinogenic HPV-infected smokers.
doi:10.1016/j.mrfmmm.2007.04.008
PMCID: PMC4383290  PMID: 17583755
Automated Cellular Imaging System; BPDE-DNA antiserum; smoking; chemiluminescence immunoassay; human keratinocytes
11.  A New Method to Address Verification Bias in Studies of Clinical Screening Tests: Cervical Cancer Screening Assays as an Example 
Journal of clinical epidemiology  2013;67(3):343-353.
Objective
Studies to evaluate clinical screening tests often face the problem that the “gold standard” diagnostic approach is costly and/or invasive. It is therefore common to verify only a subset of negative screening tests using the gold standard method. However, under-sampling the screen-negatives can lead to substantial overestimation of the sensitivity and underestimation of the specificity of the diagnostic test. Our objective was to develop a simple and accurate statistical method to address this “verification bias”.
Study Design and Setting
We developed a weighted generalized estimating equation approach to estimate, in a single model, the accuracy (e.g., sensitivity/specificity) of multiple assays as well as simultaneously compare results between assays while addressing verification bias. This approach can be implemented using standard statistical software. Simulations were conducted to assess the proposed method. An example is provided using a cervical cancer screening trial that compared the accuracy of human papillomavirus and Pap tests, with histological data as the gold standard.
Results
The proposed approach performed well in estimating and comparing the accuracy of multiple assays in the presence of verification bias.
Conclusion
The proposed approach is an easy to apply and accurate method for addressing verification bias in studies of multiple screening methods.
doi:10.1016/j.jclinepi.2013.09.013
PMCID: PMC3946800  PMID: 24332397
clinical screening tests; sensitivity; specificity; weighted generalized estimating equations; verification bias
12.  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
doi:10.1128/JCM.05979-11
PMCID: PMC3264159  PMID: 22162556
Journal of Clinical Microbiology  2015;53(4):1277-1281.
Few studies have compared the cobas HPV test to the Aptima HPV assay (AHPV) and the Aptima HPV 16 18/45 genotype assay (AHPV GT) for high-risk human papillomavirus (hrHPV) detection, clinical performance in detecting cervical intraepithelial neoplasia grade 2 (CIN2) or more severe (CIN2+) diagnoses, and risk stratification by partial HPV genotyping. The cobas HPV test is a DNA test that separately and concurrently detects HPV16, HPV18, and a pool of 12 other hrHPV types. AHPV is an RNA test for a pool of 14 hrHPV genotypes, and AHPV GT is an RNA test run on AHPV-positive results to detect HPV16 separately from HPV18 and HPV45, which are detected together. In a population of patients (n = 988) referred for colposcopy because of a cervical Pap cytology result of atypical squamous cells of undetermined significance (ASC-US), a cervical scrape specimen was taken, placed into a ThinPrep Pap test vial containing PreservCyt liquid cytology medium, and tested in a blinded fashion with cobas and AHPV and with AHPV GT for AHPV-positive results. The final diagnoses were based on a consensus panel review of the biopsy specimen histology. AHPV and cobas were equally sensitive for CIN2+ diagnoses (89.4% each; P = 1.000), and AHPV was more specific than cobas (63.1% versus 59.3%; P ≤ 0.001). The percent total agreement, percent positive agreement, and kappa value were 90.9%, 81.1%, and 0.815, respectively. Risk stratification using partial HPV genotyping was similar for the two assays. AHPV and AHPV GT had similar sensitivity and risk stratification to cobas HPV, but they were more specific than cobas HPV.
doi:10.1128/JCM.03558-14
PMCID: PMC4365215  PMID: 25653409
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.
doi:10.1128/JCM.03517-13
PMCID: PMC4136172  PMID: 24899025
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.
doi:10.1093/aje/kwr016
PMCID: PMC3145395  PMID: 21571873
biological markers; censored data; life change events; menopause; premenopause; survival analysis
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.
doi:10.1158/1055-9965.EPI-13-0053
PMCID: PMC4306595  PMID: 23632816
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.
doi:10.1093/infdis/jiq116
PMCID: PMC3071125  PMID: 21343148
Obstetrics and gynecology  2014;123(1):49-56.
Objective
To investigate the risk of cervical precancer and cancer associated with detection of human papillomavirus (HPV) 6, 11, and 42.
Methods
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).
Results
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.
Conclusion
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.
doi:10.1097/AOG.0000000000000013
PMCID: PMC3926945  PMID: 24463663
Background
New World Health Organization guidelines recommend high-risk human papillomavirus (hrHPV) screen-and-treat strategies for cervical cancer prevention. We describe risk of, and risk factors for, testing hrHPV positive in a pilot study of hrHPV screen-and-treat conducted in Rwanda.
Methods
A total of 2,964 women, 1,289 HIV-infected (HIV [+]) and 1,675 HIV-uninfected (HIV [-]), aged 30-60 years and living in Rwanda were enrolled in 2010. Cervical specimens were collected and tested by careHPV, a DNA test for a pool of 14 hrHPV types. Prevalence with binomial 95% confidence intervals (95% CI) and determinants of testing hrHPV positive were calculated.
Results
hrHPV prevalence was higher in HIV [+] (31.8%, 95% CI = 29.2-34.4%) than HIV [-] women (8.2%, 95% CI = 6.7-9.8%; P < 0.0001). Among HIV [+] women, there was a significant trend (ptrend <0.001) of higher hrHPV prevalence with lower CD4 cell count, with the highest hrHPV prevalence among those with <200 CD4 cell counts (45.5%, 95% CI = 34.8-56.4%). In multivariate analysis of HIV [+] women, testing hrHPV positive was positively associated CD4 count of <200 cells/μL, history of 3 or more sexual partners, and history of using hormonal contraception, and negatively associated with older age. In HIV [-] women, testing hrHPV positive was negatively associated only with older age groups of 45-49 and 50-60 years and surprisingly was not associated with lifetime number of sexual partners.
Conclusion
hrHPV prevalence is high in HIV [+], especially in women with the lowest CD4 cell counts, which may have implications for utilizing hrHPV-based screening strategies such as screen-and-treat in these high-risk subgroups.
doi:10.1186/1750-9378-9-40
PMCID: PMC4413542  PMID: 25926864
HPV; HIV; Cervical cancer; Screening
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.
doi:10.1093/infdis/jit374
PMCID: PMC3814839  PMID: 23908478
anal cancer; human papillomavirus (HPV); human immunodeficiency virus (HIV); men who have sex with men (MSM); anal intraepithelial neoplasia (AIN)
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.
doi:10.1016/j.vaccine.2013.07.026
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+.
doi:10.1002/ijc.28605
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+).
doi:10.1002/ijc.28616
PMCID: PMC4232922  PMID: 24248915
HPV; triage; cervical cancer; careHPV; developing countries; E6
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.
doi:10.1093/aje/kwp390
PMCID: PMC2878104  PMID: 20007673
cervical intraepithelial neoplasia; misclassification; papillomavirus infections; uterine cervical neoplasms

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