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1.  Inefficiencies and high-value improvements in U.S. cervical cancer screening practice: A cost-effectiveness analysis 
Annals of internal medicine  2015;163(8):589-597.
Background
Studies suggest that cervical cancer screening practice in the United States is inefficient. The cost and health implications of non-compliance in the screening process compared to recommended guidelines are uncertain.
Objective
To estimate the benefits, costs, and cost-effectiveness of current cervical cancer screening practice and assess the value of screening improvements.
Design
Model-based cost-effectiveness analysis.
Data Sources
New Mexico HPV Pap Registry; medical literature.
Target Population
Cohort of women eligible for routine screening.
Time Horizon
Lifetime.
Perspective
Societal.
Interventions
Current cervical cancer screening practice; improved compliance to guidelines-based screening interval, triage testing, diagnostic referrals, and precancer treatment referrals.
Outcome Measures
Reductions in lifetime cervical cancer risk, quality-adjusted life-years (QALYs), lifetime costs, incremental cost-effectiveness ratios (ICERs), incremental net monetary benefits (INMBs
Results of Base-Case Analysis
Current screening practice was associated with lower health benefit and was not cost-effective relative to guidelines-based strategies. Improvements in the screening process were associated with higher QALYs and small changes in costs. Perfect c4mpliance to a 3-yearly screening interval and to colposcopy/biopsy referrals were associated with the highest INMBs ($759 and $741, respectively, at a willingness-to-pay threshold of $100,000 per QALY gained); together, the INMB increased to $1,645.
Results of Sensitivity Analysis
Current screening practice was inefficient in 100% of simulations. The rank ordering of screening improvements according to INMBs was stable over a range of screening inputs and willingness-to-pay thresholds.
Limitations
The impact of HPV vaccination was not considered.
Conclusions
The added health benefit of improving compliance to guidelines, especially the 3-yearly interval for cytology screening and diagnostic follow-up, may justify additional investments in interventions to improve U.S. cervical cancer screening practice.
Funding Source
U.S. National Cancer Institute.
doi:10.7326/M15-0420
PMCID: PMC5104349  PMID: 26414147
2.  Deep sequencing of HPV16 genomes: A new high-throughput tool for exploring the carcinogenicity and natural history of HPV16 infection 
Papillomavirus research  2015;1:3-11.
For unknown reasons, there is huge variability in risk conferred by different HPV types and, remarkably, strong differences even between closely related variant lineages within each type. HPV16 is a uniquely powerful carcinogenic type, causing approximately half of cervical cancer and most other HPV-related cancers. To permit the large-scale study of HPV genome variability and precancer/cancer, starting with HPV16 and cervical cancer, we developed a high-throughput next-generation sequencing (NGS) whole-genome method. We designed a custom HPV16 AmpliSeq™ panel that generated 47 overlapping amplicons covering 99% of the genome sequenced on the Ion Torrent Proton platform. After validating with Sanger, the current “gold standard” of sequencing, in 89 specimens with concordance of 99.9%, we used our NGS method and custom annotation pipeline to sequence 796 HPV16-positive exfoliated cervical cell specimens. The median completion rate per sample was 98.0%.
Our method enabled us to discover novel SNPs, large contiguous deletions suggestive of viral integration (OR of 27.3, 95% CI 3.3–222, P=0.002), and the sensitive detection of variant lineage coinfections. This method represents an innovative high-throughput, ultra-deep coverage technique for HPV genomic sequencing, which, in turn, enables the investigation of the role of genetic variation in HPV epidemiology and carcinogenesis.
doi:10.1016/j.pvr.2015.05.004
PMCID: PMC4669577  PMID: 26645052
HPV16; HPV epidemiology; HPV genomics
3.  p16/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women 
Background:
Human papillomavirus (HPV)–based cervical cancer screening requires triage markers to decide who should be referred to colposcopy. p16/Ki-67 dual stain cytology has been proposed as a biomarker for cervical precancers. We evaluated the dual stain in a large population of HPV-positive women.
Methods:
One thousand five hundred and nine HPV-positive women screened with HPV/cytology cotesting at Kaiser Permanente California were enrolled into a prospective observational study in 2012. Dual stain cytology was performed on residual Surepath material, and slides were evaluated for dual stain–positive cells. Disease endpoints were ascertained from the clinical database at KPNC. We evaluated the clinical performance of the assay among all HPV-positive women and among HPV-positive, cytology-negative women. We used internal benchmarks for clinical management to evaluate the clinical relevance of the dual stain assay. We evaluated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the dual stain compared with Pap cytology. All statistical tests were two-sided.
Results:
The dual stain had lower positivity (45.9%) compared with cytology at an ASC-US threshold (53.4%). For detection of CIN2+, the dual stain had similar sensitivity (83.4% vs 76.6%, P = .1), and statistically higher specificity (58.9% vs 49.6%, P < .001), PPV (21.0% vs 16.6%, P < .001), and NPV (96.4% vs 94.2%, P = .01) compared with cytology. Similar patterns were observed for CIN3+. Women with a positive test had high enough risk for referral to colposcopy, while the risk for women with negative tests was below a one-year return threshold based on current US management guidelines.
Conclusion:
Dual stain cytology showed good risk stratification for all HPV-positive women and for HPV-positive women with normal cytology. Additional follow-up is needed to determine how long dual stain negative women remain at low risk of precancer.
doi:10.1093/jnci/djv257
PMCID: PMC4675094  PMID: 26376685
4.  Quality assurance of human papillomavirus (HPV) testing in the implementation of HPV primary screening in Norway: an inter-laboratory reproducibility study 
BMC Infectious Diseases  2016;16:698.
Background
Human papillomavirus (HPV) testing as primary screening for cervical cancer is currently being implemented in Norway in a randomized controlled fashion, involving three laboratories. As part of the quality assurance programme of the implementation, an evaluation of the inter-laboratory reproducibility of the HPV test was initiated, to ensure satisfactory HPV test reliability in all three laboratories.
Methods
The HPV test used is the cobas 4800 HPV Test, detecting 14 high-risk types with individual HPV genotype results for HPV16 and HPV18. In addition to the three laboratories involved in the implementation, the Norwegian HPV reference laboratory was included as a fourth comparative laboratory. A stratified sample of 500 cervical liquid based cytology (LBC) samples was used in the evaluation, with an aim towards a high-risk HPV positivity of ~25%. Samples were collected at one laboratory, anonymized, aliquoted, and distributed to the other laboratories.
Results
Comparison of the test results of all four laboratories revealed a 95.6% agreement, an 86.3% positive agreement and a kappa value of 0.94 (95% CI 0.92–0.97). For negative cytology specimens, there was a 95.8% overall agreement, a 67.4% positive agreement, and a kappa value of 0.88 (95% CI 0.80–0.93). For abnormal cytology specimens, there was a 95.8% overall agreement, a 95.5% positive agreement, and a kappa value of 0.86 (95% CI 0.71–0.97).
Conclusions
The study showed a high inter-laboratory reproducibility of HPV testing, implying satisfactory user performance and reliability in the laboratories involved in the implementation project. This is important knowledge and we recommend similar studies always to be performed prior to the introduction of new screening routines.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-016-2028-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-016-2028-7
PMCID: PMC5122146  PMID: 27881082
Human papillomavirus; HPV; Cervical cancer screening; HPV primary screening; HPV testing; Quality assurance; Cobas 4800 HPV Test; Inter-laboratory reproducibility
5.  Cervical Precancer Risk in HIV-Infected Women Who Test Positive for Oncogenic Human Papillomavirus Despite a Normal Pap Test 
Human immunodeficiency virus-infected women with a normal Pap result who nonetheless test positive for human papillomavirus (HPV) type 16 have a high risk of cervical precancer that may warrant immediate colposcopy, whereas those positive for other oncogenic HPV types are at moderate risk.
Background. Determining cervical precancer risk among human immunodeficiency virus (HIV)–infected women who despite a normal Pap test are positive for oncogenic human papillomavirus (oncHPV) types is important for setting screening practices.
Methods. A total of 2791 HIV-infected and 975 HIV-uninfected women in the Women's Interagency HIV Study were followed semiannually with Pap tests and colposcopy. Cumulative risks of cervical intraepithelial neoplasia grade 2 or greater (CIN-2+; threshold used for CIN treatment) and grade 3 or greater (CIN-3+; threshold to set screening practices) were measured in HIV-infected and HIV-uninfected women with normal Pap tests, stratified by baseline HPV results, and also in HIV-infected women with a low-grade squamous intraepithelial lesion (LSIL; benchmark indication for colposcopy).
Results. At baseline, 1021 HIV-infected and 518 HIV-uninfected women had normal Pap tests, of whom 154 (15%) and 27 (5%), respectively, tested oncHPV positive. The 5-year CIN-2+ cumulative risk in the HIV-infected oncHPV-positive women was 22% (95% confidence interval [CI], 9%–34%), 12% (95% CI, 0%–22%), and 14% (95% CI, 2%–25%) among those with CD4 counts <350, 350–499, and ≥500 cells/µL, respectively, whereas it was 10% (95% CI, 0%–21%) in those without HIV. For CIN-3+, the cumulative risk averaged 4% (95% CI, 1%–8%) in HIV-infected oncHPV-positive women, and 10% (95% CI, 0%–23%) among those positive for HPV type 16. In HIV-infected women with LSIL, CIN-3+ risk was 7% (95% CI, 3%–11%). In multivariate analysis, HIV-infected HPV16-positive women had 13-fold (P = .001) greater CIN-3+ risk than oncHPV-negative women (referent), and HIV-infected women with LSIL had 9-fold (P < .0001) greater risk.
Conclusions. HIV-infected women with a normal Pap result who test HPV16 positive have high precancer risk (similar to those with LSIL), possibly warranting immediate colposcopy. Repeat screening in 1 year may be appropriate if non-16 oncHPV is detected.
doi:10.1093/cid/civ569
PMCID: PMC4614409  PMID: 26187020
HIV; human papillomavirus; cervical cancer screening; Pap test
6.  Cervical Cancer Screening in Low-Resource Settings: A Cost-Effectiveness Framework for Valuing Tradeoffs between Test Performance and Program Coverage 
International journal of cancer  2015;137(9):2208-2219.
As cervical cancer screening programs are implemented in low-resource settings, protocols are needed to maximize health benefits under operational constraints. Our objective was to develop a framework for examining health and economic tradeoffs between screening test sensitivity, population coverage, and follow-up of screen-positive women, to help decision makers identify where program investments yield the greatest value. As an illustrative example, we used an individual-based Monte Carlo simulation model of the natural history of human papillomavirus (HPV) and cervical cancer calibrated to epidemiologic data from Uganda. We assumed once in a lifetime screening at age 35 with two-visit HPV DNA testing or one-visit visual inspection with acetic acid (VIA). We assessed the health and economic tradeoffs that arise between 1) test sensitivity and screening coverage; 2) test sensitivity and loss to follow-up (LTFU) of screen-positive women; and 3) test sensitivity, screening coverage, and LTFU simultaneously. The decline in health benefits associated with sacrificing HPV DNA test sensitivity by 20% (e.g., shifting from provider- to self-collection of specimens) could be offset by gains in coverage if coverage increased by at least 20%. When LTFU was 10%, two-visit HPV DNA testing with 80-90% sensitivity was more effective and more cost-effective than one-visit VIA with 40% sensitivity, and yielded greater health benefits than VIA even as VIA sensitivity increased to 60% and HPV test sensitivity declined to 70%. As LTFU increased, two-visit HPV DNA testing became more costly and less effective than one-visit VIA. Setting-specific data on achievable test sensitivity, coverage, follow-up rates, and programmatic costs are needed to guide programmatic decision making for cervical cancer screening.
doi:10.1002/ijc.29594
PMCID: PMC4910518  PMID: 25943074
cancer screening; Human papillomavirus (HPV); HPV DNA tests; uterine cervical neoplasms; decision analysis
7.  A joint model of persistent human papillomavirus infection and cervical cancer risk: Implications for cervical cancer screening 
Summary
New cervical cancer screening guidelines in the US and many European countries recommend that women get tested for human papillomavirus (HPV). To inform decisions about screening intervals, we calculate the increase in precancer/cancer risk per year of continued HPV infection. However, both time to onset of precancer/cancer and time to HPV clearance are interval-censored, and onset of precancer/cancer strongly informatively censors HPV clearance. We analyze this bivariate informatively interval-censored data by developing a novel joint model for time to clearance of HPV and time to precancer/cancer using shared random-effects, where the estimated mean duration of each woman’s HPV infection is a covariate in the submodel for time to precancer/cancer. The model was fit to data on 9,553 HPV-positive/Pap-negative women undergoing cervical cancer screening at Kaiser Permanente Northern California, data that were pivotal to the development of US screening guidelines. We compare the implications for screening intervals of this joint model to those from population-average marginal models of precancer/cancer risk. In particular, after 2 years the marginal population-average precancer/cancer risk was 5%, suggesting a 2-year interval to control population-average risk at 5%. In contrast, the joint model reveals that almost all women exceeding 5% individual risk in 2 years also exceeded 5% in 1 year, suggesting that a 1-year interval is better to control individual risk at 5%. The example suggests that sophisticated risk models capable of predicting individual risk may have different implications than population-average risk models that are currently used for informing medical guideline development.
doi:10.1111/rssa.12101
PMCID: PMC4635446  PMID: 26556961
HPV; cancer screening; medical guidelines; risk modeling; joint modeling of longitudinal; survival data
8.  A Study of HPV Typing for the Management of HPV-Positive ASC-US Cervical Cytologic Results 
Gynecologic oncology  2015;138(3):573-578.
Background
In US cervical screening, immediate colposcopy is recommended for women with HPV-positive ASC-US (equivocal) cytology. We evaluated whether partial typing by Onclarity™ (BD) might identify HPV-positive women with low enough CIN3+ risk to permit 1-year follow-up instead.
Methods
The NCI-Kaiser Permanente Northern California Persistence and Progression Cohort includes a subset of 13,890 women aged 21+ with HC2 (Qiagen)-positive ASC-US at enrollment; current median follow-up is 3.0 years. Using stratified random sampling, we typed 2,079 archived enrollment specimens including 329 women subsequently diagnosed with CIN3+, 563 with CIN2, and 1,187 with
Results
The 3-year CIN3+ risk for all HC2-positive women with ASC-US was 5.2%; this establishes the “benchmark” risk for colposcopic referral. Hierarchically, 3-year cumulative risks for each typing channel were 16.0% for HPV16, 7.4% for HPV18, 7.0% for HPV31, 7.1% for grouped HPV33/58, 4.4% for HPV52, 3.9% for HPV45, 2.7% for HPV51, 1.6% for HPV39/68/35, and 1.3% for HPV59/56/66.
Discussion
ASC-US linked to HPV16, HPV18, HPV31, or HPV33/58 warrants immediate colposcopy. Optimal management of women with HPV52 or HPV45 is uncertain. Risk of women with only HPV51, HPV39/68/35, or HPV59/56/66 might be low enough to recommend 1-year retesting permitting viral clearance. This strategy would defer colposcopy for 40% of women with HPV-positive ASC-US, half of whom would be cotest-negative at 1-year return. Approximately 10% of those with CIN3 diagnosable at enrollment would be delayed 1 year instead. Cost-effectiveness analyses are needed.
doi:10.1016/j.ygyno.2015.06.040
PMCID: PMC4556538  PMID: 26148763
ASC-US; HPV testing; cervical screening; triage
Background
The cobas® HPV Test (“cobas”, Roche Molecular Systems) detects HPV16 and HPV18 individually, and a pool of 12 other high-risk (HR) HPV types. The test is approved for 1) ASC-US triage to determine need for colposcopy, 2) combined screening with cytology (“co-testing”), and 3) primary HPV screening.
Methods
To assess the possible value of HPV16/18 typing, >17,000 specimens from a longitudinal cohort study of initially HPV-positive women (HC2, Qiagen) were retested with cobas. To study accuracy, cobas genotyping results were compared to those of an established method, the LINEAR ARRAY HPV Genotyping Test (LA, Roche Molecular Systems). Clinical value of the typing strategy was evaluated by linking the cobas results (supplemented by other available typing results) to 3-year cumulative risks of CIN3+.
Results
Grouped hierarchically (HPV16, else HPV18, else other HR types, else negative), the kappa statistic for agreement between cobas and LA was 0.86 (95%CI=0.86-0.87). In all 3 scenarios, HPV16-positive women were at much higher 3-year risk of CIN3+ than HPV16-negative women: women aged 21 and older with ASC-US (14.5%, 95%CI=13.5%-15.5% versus 3.5%, 95%CI=3.3%-3.6%); women aged 30 and older that were HPV-positive cytology-negative (10.3%, 95%CI=9.6%-11.1% versus 2.3%, 95%CI=2.2%-2.4%); and all women 25 and older that were HPV-positive (18.5%, 95%CI=17.8%-19.2% versus 4.3%, 95%CI=4.2%-4.4%).
Conclusion
The cobas and LA results show excellent agreement. The data support HPV16 typing.
Impact
HPV16 typing is useful in the management of HPV- positive/cytology-negative women in co-testing, of all HPV-positive women in primary HPV testing, and perhaps in the management of HPV-positive women with ASC-US.
doi:10.1158/1055-9965.EPI-14-1353
PMCID: PMC4560647  PMID: 26088703
In the United States high-risk HPV (HPV) testing is recommended for women with ASC-US cytology, and co-testing with cytology and HPV is a recommended option for screening women aged ≥30 years. No population-based data are available to examine utilization of HPV testing in the United States. Using the New Mexico HPV Pap Registry data resource, we describe population trends (2007–2012) in utilization and positivity rates for HPV testing as a routine co-testing screening procedure and for triage of ASC-US and other cytologic outcomes. For women aged 30–65 years co-testing increased from 5.2% in 2007 to 19.1% in 2012 (P< 0.001). Overall 82% of women with ASC-US cytology who did not receive co-testing also had an HPV test. HPV positivity was age and cytology result dependent but did not show time trends. For women with negative cytology, 64% received an additional screening test within 3 years if no co-test was done or if it was positive, but this was reduced to 47% with a negative co-test. Reflex HPV testing for ASC-US cytology is well established and occurs in most women. Evidence for reflex testing is also observed following other abnormal cytology outcomes. Co-testing in women aged 30–65 years has more than tripled from 2007 to 2012, but was still only used in 19.1% of women aged 30–65 years attending for screening in 2012. Women receiving co-testing had longer repeat screening intervals, but rescreening within 3 years is still very common even with co-testing.
doi:10.1002/ijc.29337
PMCID: PMC4737644  PMID: 25447979
high risk HPV testing; HPV co-testing; Cervical screening; utilization; outcome; and coverage; New Mexico; New Mexico HPV Pap Registry; United States
A pilot program introducing HPV testing as part of a public sector screening program was successfully and effectively implemented in a low-resource setting.
Objective
In a primary human papillomavirus (HPV) screening program, we compared the 6-month follow-up among colposcopy and noncolposcopy-based management strategies for screen-positive women.
Materials and Methods
Women aged 30 to 49 years were screened with HPV DNA tests using both self-collection and provider collection of samples. Women testing positive received either (1) colposcopy management (CM) consisting of colposcopy and management per local guidelines or (2) screen-and-treat (ST) management using visual inspection with acetic acid to determine cryotherapy eligibility, with eligible women undergoing immediate cryotherapy. One thousand women were recruited in each cohort. Of these, 368 (18.4%) of 2000 women were recruited using a more intensive outreach strategy. Demographics, HPV positivity, and treatment compliance were compared across recruitment and management strategies.
Results
More women in the ST cohort received treatment within 6 months compared with those in the CM cohort (117/119 [98.3%] vs 64/93 [68.8%]; p < .001). Women recruited through more intensive outreach were more likely to be HPV positive, lived in urban areas, were more educated, and had higher numbers of lifetime sexual partners and fewer children.
Conclusions
Women in the CM arm were less likely to complete care than women in the ST arm. Targeted outreach to underscreened women successfully identified women with higher prevalence of HPV and possibly higher disease burden.
doi:10.1097/LGT.0000000000000188
PMCID: PMC4819528  PMID: 26890683
careHPV; human papillomavirus; cervical cancer; screening program; Latin America
It is unclear whether a woman's age influences her risk of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) upon detection of HPV. A large change in risk as women age would influence vaccination and screening policies. Among 972,029 women age 30-64 undergoing screening with Pap and HPV testing (Hybrid Capture 2, Qiagen, Germantown, MD, USA) at Kaiser Permanente Northern California (KPNC), we calculated age-specific 5-year CIN3+ risks among women with HPV infections detected at enrollment, and among women with “newly detected” HPV infections at their second screening visit. 57,899 women (6.0%) had an enrollment HPV infection. Among the women testing HPV negative at enrollment with a second screening visit, 16,724 (3.3%) had a newly detected HPV infection at their second visit. Both enrollment and newly detected HPV rates declined with age (p<.001). Women with enrollment vs. newly detected HPV infection had higher 5-year CIN3+ risks: 8.5% vs. 3.9%, (p<.0001). Risks did not increase with age but declined slightly from 30-34 years to 60-64 years: 9.4% vs. 7.4% (p=0.017) for enrollment HPV and 5.1% vs. 3.5% (p=0.014) for newly detected HPV. Among women age 30-64 in an established screening program, women with newly detected HPV infections were at lower risk than women with enrollment infections, suggesting reduced benefit vaccinating women at older ages. Although the rates of HPV infection declined dramatically with age, the subsequent CIN3+ risks associated with HPV infection declined only slightly. The CIN3+ risks among older women are sufficiently elevated to warrant continued screening through age 65.
doi:10.1002/ijc.29143
PMCID: PMC4314342  PMID: 25136967
Human Papillomavirus (HPV); cancer prevention; cytology; cervical intraepithelial neoplasia (CIN); Hybrid Capture 2 (HC2); age
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
Journal of virological methods  2013;189(1):167-171.
The current method of transporting self-collected cervicovaginal specimen for HPV DNA testing relies on liquid based medium, which is challenging and expensive to transport. A novel, dry storage and transportation device, Whatman indicating FTA™ Elute Cartridge, avoids some of the pitfalls of liquid-based medium. This method has been shown to be comparable to liquid-based collection medium, but relative performance of self-collected (SC) and clinician-collected (CC) samples onto FTA cards has not been reported. The objective of this study is to compare the analytic performance of self- and clinician-collected samples onto FTA cartridges for the detection of carcinogenic HPV using Linear Array. There was a 91% agreement, 69% positive agreement, and kappa of 0.75 between the clinician-collected and self-collected specimens for detection of any carcinogenic HPV genotype. When the HPV results were categorized hierarchically according to cervical cancer risk, there was no difference in the distribution of the HPV results for the clinician- and self-collected specimens (p = 0.7). This study concludes that FTA elute cartridge is a promising method of specimen transport for cervical cancer screening programs considering using self-collected specimen and HPV testing. Larger studies with clinical endpoints are now needed to assess the clinical performance.
doi:10.1016/j.jviromet.2012.11.010
PMCID: PMC4763924  PMID: 23370404
FTA cartridge; Self-collection; Cervical cancer; Human papillomavirus (HPV)
We have developed and evaluated a next-generation bisulfite sequencing (NGS) assay to distinguish HPV16 cervical precancer (CIN2-3; N=59) from HPV16-positive transient infections (N=40). Cervical DNA was isolated and treated with bisulfite and HPV16 methylation was quantified by (1) amplification with barcoded primers and massively parallel single molecule sequencing and (2) site-specific pyrosequencing. Assays were evaluated for agreement using intraclass correlation coefficients (ICC). Odds ratios (OR) for high methylation vs. low methylation were calculated. Single site pyrosequencing and NGS data were correlated (ICC=0.61) and both indicated hypermethylation was associated with precancer (ORs of 2-37). Concordant NGS and pyrosequencing results yieled ORs that were stronger when compared to using either assay separately. Within the L1 region, the ORs for CIN2-3 were 14.3 and 22.4 using pyrosequencing and NGS assays, respectively; when both methods agreed the OR was 153. NGS assays provide methylation haplotypes, termed methyl-haplotypes from single molecule reads: cases had increased methyl-haplotypes with ≥ 1 methylated CpG site(s) per fragment compared to controls, particularly in L1 (P=3.0×10−8). The maximum discrimination of cases from controls for a L1 methyl-haplotype had an AUC of 0.89 corresponding to a sensitivity of 92.5% and a specificity of 73.1%. The strengthening of the OR when the two assays were concordant suggests the true association of CpG methylation with precancer is stronger than with either assay. As cervical cancer prevention moves to DNA testing methods, DNA based biomarkers, such as HPV methylation could serve as a reflex strategy to identify women at high risk for cervix cancer.
doi:10.1002/ijc.29119
PMCID: PMC4262737  PMID: 25081507
HPV16; methylation; next-generation sequencing; pyrosequencing; cervical precancer
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
Background
The New Mexico HPV Pap Registry was established to measure the impact of cervical cancer prevention strategies in the United States. Prior to widespread HPV vaccine implementation, we established the baseline prevalence for a broad spectrum of HPV genotypes across the continuum of cervical intraepithelial neoplasia (CIN) and cancer.
Methods
A population-based sample of 6,272 tissue specimens were tested for 37 HPV genotypes. The number of specimens tested within each diagnostic category was: 541 negative, 1,411 CIN grade 1 (CIN1), 2,226 CIN grade 2 (CIN2), and 2,094 CIN grade 3 (CIN3) or greater. Age-specific HPV prevalence was estimated within categories for HPV genotypes targeted by HPV vaccines.
Results
The combined prevalence of HPV genotypes included in the quadrivalent and nonavalent vaccines increased from 15.3% and 29.3% in CIN1 to 58.4% and 83.7% in CIN3, respectively. The prevalence of HPV types included in both vaccines tended to decrease with increasing age for CIN1, CIN2, CIN3, and squamous cell carcinoma, most notably for CIN3 and SCC. The six most common HPV types in descending order of prevalence were HPV-16, −31, −52, −58, −33, and −39 for CIN3 and HPV-16, −18, −31, −45, −52, and −33 for invasive cancers.
Conclusions
Health economic modeling of HPV vaccine impact should consider age-specific differences in HPV prevalence.
Impact
Population-based HPV prevalence in CIN is not well described but is requisite for longitudinal assessment of vaccine impact and to understand the effectiveness and performance of various cervical screening strategies in vaccinated and unvaccinated women.
doi:10.1158/1055-9965.EPI-14-0775
PMCID: PMC4294978  PMID: 25363635
human papillomavirus prevalence; age-specific HPV prevalence; HPV vaccine impact; cervical intraepithelial neoplasia grade 1, 2, 3; cervical cancer; community pathology diagnoses; cervical screening performance; United States
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
BMC Public Health  2015;15:1058.
Background
Cervical cancer is the third most commonly occurring cancer among women and the fourth leading cause of cancer-related deaths in women worldwide, with more than 85 % of these cases occurring in developing countries. These global disparities reflect the differences in cervical cancer screening rates between high-income and medium- and low-income countries. At 19 %, El Salvador has the lowest reported screening coverage of all Latin American countries. The purpose of this study is to identify factors affecting public sector HPV DNA-based cervical cancer screening participation in El Salvador.
Methods
This study was nested within a public sector screening program where health promoters used door-to-door outreach to recruit women aged 30–49 years to attend educational sessions about HPV screening. A subgroup of these participants was chosen randomly and questioned about demographic factors, healthcare utilization, previous cervical cancer screening, and HPV knowledge. Women then scheduled screening appointments at their public health clinics. Screening participants were adherent if they attended their scheduled appointment or rescheduled and were screened within 6 months. The association between non-adherence and demographic variables, medical history, history of cancer, sexual history, birth control methods, and screening barriers was assessed using Chi-square tests of significance and logistic regression.
Results
All women (n = 409) enrolled in the study scheduled HPV screening appointments, and 88 % attended. Non-adherence was associated with a higher number of lifetime partners and being under-screened—defined as not having participated in cervical cancer screening within the previous 3 years (p = 0.03 and p = 0.04, respectively); 22.8 % of participants in this study were under-screened.
Conclusions
Adherence to cervical cancer screening after educational sessions was higher than expected, in part due to interactions with the community-based health promoters as well as the educational session itself. More effective recruitment methods targeted toward under-screened women are required.
doi:10.1186/s12889-015-2360-7
PMCID: PMC4609068  PMID: 26474762
HPV; Community health promoters; Cervical cancer; Adherence; Screening; Underserved populations; Education
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
Obstetrics and gynecology  2012;120(5):1117-1123.
OBJECTIVE
All national organizations now recommend that women be screened for cervical cancer beginning at age 21 years, regardless of age of sexual initiation; however, studies have shown that providers continue to screen much earlier than recommended. Two federal cancer surveillance systems were used to quantify the burden of invasive cervical carcinoma among women younger than 40 years of age.
METHODS
We examined combined data from the National Program of Cancer Registries and the Surveillance, Epidemiology, and End Results Program covering 92% of the U.S. population. We calculated the age-adjusted incidence of cervical carcinoma among women younger than age 40 years by age, race, ethnicity, and histology for the time period of 1999–2008.
RESULTS
For women younger than age 40 years, 78% of the cervical cancer cases were diagnosed in women aged 30–39, 21% were diagnosed in women 20–29 years of age, and 1% was diagnosed in women younger than age 20 years. There was an average of 3,063 cases of invasive cervical carcinomas annually from 1999 through 2008, with an average of 14 carcinomas per year (rate of 0.15 per 100,000 females) among those aged 15–19 years, and 125 carcinomas per year (rate of 1.4 per 100,000 females) among those aged 20–24 years.
CONCLUSION
Cervical cancer is very rare in young women. Widespread implementation of Pap testing over the past four decades has detected very few cases of cervical cancer in women younger than 25 while potentially causing harm with unnecessary follow-up interventions.
LEVEL OF EVIDENCE
III
PMCID: PMC4540330  PMID: 23090530
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
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
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

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