Multicentric study of cervical cancer screening with human papillomavirus testing and assessment of triage methods in Latin America: the ESTAMPA screening study protocol

IntroductionHuman papillomavirus (HPV) testing is replacing cytology in primary screening. Its limited specificity demands using a second (triage) test to better identify women at high-risk of cervical disease. Cytology represents the immediate triage but its low sensitivity might hamper HPV testing sensitivity, particularly in low-income and middle-income countries (LMICs), where cytology performance has been suboptimal. The ESTAMPA (EStudio multicéntrico de TAMizaje y triaje de cáncer de cuello uterino con pruebas del virus del PApiloma humano; Spanish acronym) study will: (1) evaluate the performance of different triage techniques to detect cervical precancer and (2) inform on how to implement HPV-based screening programmes in LMIC.Methods and analysisWomen aged 30–64 years are screened with HPV testing and Pap across 12 study centres in Latin America. Screened positives have colposcopy with biopsy and treatment of lesions. Women with no evident disease are recalled 18 months later for another HPV test; those HPV-positive undergo colposcopy with biopsy and treatment as needed. Biological specimens are collected in different visits for triage testing, which is not used for clinical management. The study outcome is histological high-grade squamous intraepithelial or worse lesions (HSIL+) under the lower anogenital squamous terminology. About 50 000 women will be screened and 500 HSIL+ cases detected (at initial and 18 months screening). Performance measures (sensitivity, specificity and predictive values) of triage techniques to detect HSIL+ will be estimated and compared with adjustment by age and study centre.Ethics and disseminationThe study protocol has been approved by the Ethics Committee of the International Agency for Research on Cancer (IARC), of the Pan American Health Organisation (PAHO) and by those in each participating centre. A Data and Safety Monitoring Board (DSMB) has been established to monitor progress of the study, assure participant safety, advice on scientific conduct and analysis and suggest protocol improvements. Study findings will be published in peer-reviewed journals and presented at scientific meetings.Trial registration numberNCT01881659

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Human Papillomavirus Testing and Reporting Rates: Practices of Participants in the College of American Pathologists Interlaboratory Comparison Program in Gynecologic Cytology in 2006

Archives of Pathology & Laboratory Medicine ◽

10.5858/2008-132-1290-hptarr ◽

2008 ◽

Vol 132 (8) ◽

pp. 1290-1294 ◽

Cited By ~ 2

Author(s):

Ann T. Moriarty ◽

Mary R. Schwartz ◽

Galen Eversole ◽

Marilee Means ◽

Amy Clayton ◽

...

Keyword(s):

Human Papillomavirus ◽

Interlaboratory Comparison ◽

Low Grade ◽

Hpv Testing ◽

Squamous Intraepithelial Lesion ◽

Papanicolaou Test ◽

Frequency Distributions ◽

Squamous Cells ◽

Hpv Test ◽

Intraepithelial Lesion

Abstract Context.—Oncogenic, high-risk human papillomavirus (HR-HPV) testing is used to evaluate women who are older than 20 years with atypical squamous cells of undetermined significance (ASC-US) and in conjunction with a screening Papanicolaou test in women older than 30 years. Objectives.—To evaluate the 2006 laboratory practice data from laboratories incorporating human papillomavirus (HPV) testing with the Papanicolaou test. Design.—To use the College of American Pathologists (CAP) Supplemental Questionnaire Survey for 2006 to determine laboratory practices of participants in the CAP Interlaboratory Comparison Program in Cervicovaginal Cytology. Results.—A total of 679 laboratories responded to the questionnaire. Most (73%) refer HPV testing to reference laboratories. Nine percent perform HPV testing in cytology. Forty-five percent offer low-risk HPV (LR-HPV) testing. The most common reflex is ASC-US, although HR-HPV is also offered with low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), or any other Papanicolaou test result. Digene Hybrid Capture II is the most common method. Human papilloma virus median test volumes are 55 monthly. Frequency distributions of HPV test volumes are significantly different from those found in 2003. Laboratories performing in-house testing reported significantly higher monthly HPV volumes (P < .001). Median rates for HR-HPV positivity are 36.6% for ASC-US, 50.0% for atypical squamous cells, cannot exclude HSIL (ASC-H), and 4% for women 30 years of age and older in conjunction with a screening Papanicolaou test. Conclusions.—Reference HPV testing remains the most common pattern. The most common reflex indication is for ASC-US, but HPV testing is modified locally to include a variety of scenarios. LR-HPV testing is commonly offered despite its lack of clinical significance. These data form a baseline for ongoing monitoring of HPV testing practice trends.

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Assessing the value of human papillomavirus vaccination in Gavi-eligible low-income and middle-income countries

BMJ Global Health ◽

10.1136/bmjgh-2020-003006 ◽

2020 ◽

Vol 5 (10) ◽

pp. e003006

Author(s):

Jessica Ochalek ◽

Kaja Abbas ◽

Karl Claxton ◽

Mark Jit ◽

James Lomas

Keyword(s):

Human Papillomavirus ◽

Low Income ◽

Hpv Vaccination ◽

Cost Effective ◽

Health Impact ◽

Healthcare Intervention ◽

Human Papillomavirus Vaccination ◽

Middle Income ◽

Maximum Price ◽

Healthcare Interventions

IntroductionEstimating the value of providing effective healthcare interventions in a country requires an assessment of whether the improvement in health outcomes they offer exceeds the improvement in health that would have been possible if the resources required had, instead, been made available for other healthcare activities in that country. This potential alternative use of the same resources represents the health opportunity cost of providing the intervention. Without such assessments, there is a danger that blanket recommendations made by international organisations will lead to the adoption of healthcare interventions that are not cost effective in some countries, even given existing donor mechanisms intended to support their affordability.MethodsWe assessed the net health impact to 46 Gavi-eligible countries of achieving one of the WHO’s proposed 90-70-90 targets for cervical cancer elimination, which includes 90% coverage of human papillomavirus (HPV) vaccination among girls by 15 years of age, using published estimates of the expected additional benefits and costs in each country and estimates of the marginal productivity of each healthcare system. We calculated the maximum price each country could afford to pay for HPV vaccination to be cost effective by assessing the net health impact that would be expected to be generated at different potential prices.ResultsAt Gavi negotiated prices, HPV vaccination offers net health benefits across most Gavi-eligible countries included in this study. However, if Gavi-eligible countries faced the average price faced by non-Gavi eligible countries, providing HPV vaccination would result in reduced overall population health in most countries.ConclusionEstimates of the net health impact of providing a healthcare intervention can be used to assess the benefit (or lack of) to countries of adhering to global guidance, inform negotiations with donors, as well as pricing negotiations and the value of developing new healthcare interventions.

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Clinical Human Papillomavirus Detection Forecasts Cervical Cancer Risk in Women Over 18 Years of Follow-Up

Journal of Clinical Oncology ◽

10.1200/jco.2011.38.8389 ◽

2012 ◽

Vol 30 (25) ◽

pp. 3044-3050 ◽

Cited By ~ 61

Author(s):

Philip E. Castle ◽

Andrew G. Glass ◽

Brenda B. Rush ◽

David R. Scott ◽

Nicolas Wentzensen ◽

...

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

Cancer Risk ◽

Clinical Test ◽

Low Grade ◽

Hpv Testing ◽

Pap Testing ◽

Health Maintenance ◽

Hpv Test

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.

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Comparison of Human Papillomavirus Detection in Urine and Cervical Samples Using High-Risk HPV DNA Testing in Northern Thailand

Obstetrics and Gynecology International ◽

10.1155/2016/6801491 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Surapan Khunamornpong ◽

Jongkolnee Settakorn ◽

Kornkanok Sukpan ◽

Suree Lekawanvijit ◽

Narisara Katruang ◽

...

Keyword(s):

Human Papillomavirus ◽

High Risk ◽

Hpv Testing ◽

Dna Testing ◽

Northern Thailand ◽

Cervical Sample ◽

Hpv Dna ◽

Hpv Dna Testing ◽

Hpv Test ◽

High Risk Hpv

Objective. To evaluate the performance of high-risk human papillomavirus (HPV) DNA testing in urine samples compared to that of cervical sample testing in Northern Thailand. Methods. Paired urine and cervical samples were collected during the follow-up of women with a previous positive HPV test. HPV testing was performed using the Cobas 4800 HPV Test. Linear Array assay was used for genotyping in selected cases. Results. Paired urine and cervical samples were obtained from 168 women. Of 123 paired samples with valid results, agreement in the detection of high-risk HPV DNA was present in 106 cases (86.2%), with a kappa statistic of 0.65 (substantial agreement). Using the cervical HPV results as a reference, the sensitivity of urine HPV testing was 68.6% (24/35) and the specificity 93.2% (82/88). For the detection of histologic high-grade squamous intraepithelial lesion or worse (HSIL+), the sensitivity of urine HPV testing was 80.0% (4/5) and the specificity 78.0% (92/118). Conclusion. Although urine HPV testing had a rather low sensitivity for HPV detection, its sensitivity for histologic HSIL+ detection was high. For clinical use of urine HPV testing, standardization of specimen collection and processing techniques or application of a more sensitive test, especially in the detection of HPV52 and HPV58, is necessary.

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Cervical Visual Inspection with Acetic Acid (VIA) and Oncogenic Human Papillomavirus Screening in Rural Indigenous Guatemalan Women: Time to Rethink VIA

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph182312406 ◽

2021 ◽

Vol 18 (23) ◽

pp. 12406

Author(s):

Anne Jeffries ◽

Consuelo M. Beck-Sagué ◽

Ariel Bernardo Marroquin-Garcia ◽

Michael Dean ◽

Virginia McCoy ◽

...

Keyword(s):

Acetic Acid ◽

Human Papillomavirus ◽

Visual Inspection ◽

Clinical Laboratory ◽

Precancerous Lesions ◽

World Health ◽

Low Grade ◽

Hpv Testing ◽

Abnormal Cytology ◽

Hpv Test

Single-visit “screen-and-treat” strategies using visual inspection with acetic acid (VIA) and cryotherapy (liquid nitrous oxide ablation) in low-resource settings are commonly used to detect and treat precancerous lesions for cervical cancer prevention. This study compared VIA sensitivity and specificity in rural indigenous Guatemalan communities, to that of oncogenic human papillomavirus (HPV) testing for detection of precancerous changes, using cytology as the reference standard. Between 3–8 September 2017, trained nurses examined 222 women aged 23–58 years with VIA. Specimens for liquid-based cytology and HPV testing were obtained prior to VIA with a cytobrush and transported in PreservCyt to a US clinical laboratory. VIA and HPV test sensitivities were assessed as proportions of women with abnormal cytology that had abnormal VIA or HPV results, respectively, and specificities, as proportions with normal cytology with normal VIA or negative HPV tests. Of 222 women, 18 (8.1%) had abnormal cytology (1 carcinoma in a participant who received VIA-based cryotherapy in 2015, 4 high- and 5 low-grade squamous intraepithelial lesions, and 8 atypical squamous cells of undetermined significance (ASCUS)). Excluding ASCUS, sensitivities of VIA and HPV were 20.0% and 100%, respectively. VIA-based screening may not be acceptable for detecting precancerous lesions, and field cryotherapy for preventing malignancy. The World Health Organization recommended in 2021 “…using HPV DNA detection as the primary screening test rather than VIA or cytology.”

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De-implementation and Substitution of Clinical Care Processes: Stakeholder Perspectives on the Transition to Primary Human Papillomavirus (HPV) Testing for Cervical Cancer Screening

10.21203/rs.3.rs-318847/v1 ◽

2021 ◽

Author(s):

Erin E Hahn ◽

Corrine Munoz-Plaza ◽

Danielle Altman ◽

Chunyi Hsu ◽

Nancy Cannizzaro ◽

...

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

Clinical Practice ◽

Cancer Screening ◽

Cervical Cancer Screening ◽

Readiness To Change ◽

Barriers And Facilitators ◽

Hpv Testing ◽

Cost Cutting ◽

Hpv Test

Abstract Background: New cervical cancer screening guidelines recommend primary human papillomavirus (HPV) testing for women age 30-65 years. Healthcare organizations are preparing to de-implement the previous recommended strategies of Pap testing or co-testing (Pap plus HPV test) and substitute primary HPV testing. However, there may be significant challenges to replacement of this entrenched clinical practice, even with an evidence-based substitution. We sought to identify stakeholder-perceived barriers and facilitators to this substitution within a large healthcare system, Kaiser Permanente Southern California.Methods: We conducted semi-structured qualitative interviews with clinician, administrative and patient stakeholders regarding: (a) acceptability and feasibility of the planned substitution; (b) perceptions of barriers and facilitators, with an emphasis on those related to the de-implementation/implementation cycle of substitution; and (c) perceived readiness to change. Our interview guide was informed by the Consolidated Framework for Implementation Research (CFIR). Using a team coding approach, we developed an initial coding structure refined during iterative analysis; the data were subsequently organized thematically into domains, key themes, and sub-themes using thematic analysis, followed by framework analysis informed by CFIR.Results: We conducted 23 interviews: 5 patient and 18 clinical/administrative. Clinicians perceived that patients feel more tests equals better care, and clinicians and patients expressed fear of missed cancers (“…it’ll be more challenging convincing the patient that only one test is…good enough to detect cancer.”). Patients perceived practice changes resulting in “less care” are driven by desire to cut costs. In contrast, clinicians/administrators viewed changing from two tests to one as acceptable and a workflow efficiency (“…It’s very easy and half the work.”). Stakeholder-recommended strategies included focusing on the increased efficacy of primary HPV testing and developing clinician talking points incorporating national guidelines to assuage ‘cost-cutting’ fears. Conclusions: Substitution to replace an entrenched clinical practice is complex. Leveraging available facilitators is key to ease the process for clinical and administrative stakeholders—e.g., emphasizing the efficiency of going from two tests to one. Identifying and addressing clinician and patient fears regarding cost-cutting and perceived poorer quality of care is critical for substitution. Multicomponent and multilevel strategies for engagement and education will be required.Trial registration: ClinicalTrials.gov #NCT04371887

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Assessment of a new low-cost, PCR-based strategy for high-risk human papillomavirus DNA detection for cervical cancer prevention

BMC Infectious Diseases ◽

10.1186/s12879-019-4527-9 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Pedro Surriabre ◽

Andrea Torrico ◽

Tania Vargas ◽

Fuantina Ugarte ◽

Patricia Rodriguez ◽

...

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

High Risk ◽

Low Income ◽

Low Cost ◽

Low Income Countries ◽

Hybrid Capture ◽

Hpv Test ◽

Novel Strategy ◽

Level Of Agreement

Abstract Background HPV test implementation as a primary screening tool has the potential to decrease cervical cancer incidence as shown by several studies around the world. However, in many low-resource settings, the HPV test introduction has been backed down mainly due to its price. In this study, we present a novel low-cost strategy involving simple devices and techniques for high-risk human papillomavirus (HR-HPV) detection. The analytical performance to detect HR-HPV infections of this novel strategy was assessed by comparing it with the Hybrid Capture 2 system (HC2), which is used as gold standard. Methods Paired-cervical samples were collected from 541 women assisting to gynecological services in an outpatient clinic. One sample was transported in the Hybrid Capture Standard Transport Medium for HR-HPV detection by the HC2. The second sample was transported on glass slide for detection by PCR-based techniques (GP-EIA, BSGP-EIA and pU 1 M-L/2R). Results The level of agreement between the PCR-based techniques and HC2 system was determined with the Cohen’s kappa value. The kappa values between HC2 and GP-EIA, BSGP-EIA and pU 1 M-L/2R were 0.71 (CI 95% 0.63–0.78), 0.78 (CI 95% 0.71–0.84) and 0.63 (CI 95% 0.55–0.72), respectively. However, when the results from both BSGP-EIA and pU 1 M-L/2R were combined, the level of agreement with HC2 was increased to 0.82 (CI 95% 0.76–0.88), reflecting a very good agreement between the two HR-HPV detection strategies. Furthermore, the sensitivity of both techniques combined was also increased compared to the BSGP-EIA (88.7% vs 77.4%) and the pU (88.7 vs 60.9%) without penalizing the specificity obtained with the BSGP-EIA (95.1% vs 96.9%) and the pU (95.1% vs 96.5%). Conclusions This novel strategy, combining two PCR-based techniques for HR-HPV detection, could be useful for cervical cancer screening in self-collected samples in low-income countries.

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Combining Human Papillomavirus Testing or Cervicography With Cytology to Detect Cervical Neoplasia

Archives of Pathology & Laboratory Medicine ◽

10.5858/2004-128-1257-chptoc ◽

2004 ◽

Vol 128 (11) ◽

pp. 1257-1262

Author(s):

Michelle Howard ◽

John W. Sellors ◽

Alice Lytwyn ◽

Paula Roth ◽

James B. Mahony

Keyword(s):

Human Papillomavirus ◽

Cervical Intraepithelial Neoplasia ◽

Intraepithelial Neoplasia ◽

Low Grade ◽

Invasive Squamous Cell Carcinoma ◽

Hpv Testing ◽

Cross Sectional ◽

Hpv Test ◽

Atypical Cells ◽

Sectional Analysis

Abstract Context.—Cervicography and oncogenic human papillomavirus (HPV) testing have been proposed for improving the accuracy of cervical cancer screening. Objective.—To examine whether cervicography and HPV testing can improve beyond chance the detection of cervical intraepithelial neoplasia (CIN) 2 or 3 in women with atypical cells of undetermined significance or low-grade squamous intraepithelial lesions on cytology. Design.—Cross-sectional analysis. Oncogenic HPV testing by Hybrid Capture II assay or cervicography combined with cytology was compared with the reference standard of colposcopy with directed biopsy. Setting.—Community family practices. Participants.—Three hundred four women with low-grade cytologic abnormality. Main Outcome Measures.—The gain in accuracy for detecting histologic CIN 2 or 3 or carcinoma. Because an adjunct test may improve sensitivity by chance alone, the sensitivity or specificity if the second test performed randomly was estimated. Results.—Cervical intraepithelial neoplasia 2 or 3 was found in 11.8% (36/304) of the women and invasive squamous cell carcinoma in 0.3% (1/304). The sensitivity of cytology for detecting CIN 2 or 3 was 73.0% and increased by 21.6% to 94.6% with the addition of a cervigram showing a low-grade lesion or higher or a positive HPV test result. These gains were reduced to 8.1% and 10.8% above the sensitivities expected if the additional tests performed randomly. The corresponding specificities decreased from 49.1% to 32.2% and 33.0%. There was insufficient power to determine whether observed sensitivities were statistically significantly higher than the expected sensitivities. Conclusion.—Adjunctive HPV testing or cervicography may provide similar gains in sensitivity, but they can appear misleadingly large if chance increases are not taken into account.

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Longitudinal Clinical Performance of the RNA-Based Aptima Human Papillomavirus (AHPV) Assay in Comparison to the DNA-Based Hybrid Capture 2 HPV Test in Two Consecutive Screening Rounds with a 6-Year Interval in Germany

Journal of Clinical Microbiology ◽

10.1128/jcm.01177-18 ◽

2018 ◽

Vol 57 (1) ◽

Cited By ~ 4

Author(s):

Thomas Iftner ◽

Klaus-Joachim Neis ◽

Alejandra Castanon ◽

Rebecca Landy ◽

Barbara Holz ◽

...

Keyword(s):

Human Papillomavirus ◽

Clinical Performance ◽

Absolute Risk ◽

Intraepithelial Neoplasia ◽

Cross Sectional ◽

Predictive Values ◽

Hybrid Capture ◽

Hpv Test ◽

Hybrid Capture 2 ◽

The Absolute

ABSTRACT Longitudinal data on the E6/E7 mRNA-based Aptima human papillomavirus (AHPV) assay exceeding three years in comparison to the gold standard Digene Hybrid Capture 2 (HC2) test are not available. We previously reported the cross-sectional data of the German AHPV Screening Trial (GAST) in which 10,040 women were recruited and tested by liquid-based cytology, the HC2 assay, and the AHPV assay. Four hundred eleven test-positive women were followed for up to six years. In addition, 3,295 triple-negative women were screened after a median time of six years. Overall, 28 high-grade cervical intraepithelial neoplasia (CIN3) cases were detected. The absolute risk of developing high-risk HPV-positive CIN3+ over six years among those women that tested negative at baseline was 2.2 (95% confidence interval [95% CI], 1.0 to 4.9) and 3.1 (95% CI, 1.7 to 5.7) per 1,000 women screened by the HC2 and the AHPV tests; the additional risk for those with AHPV-negative compared with HC2-negative results was 0.9 (95% CI, −0.2 to 2.1) per 1,000. In comparison, the absolute risk following a negative LBC test was 9.3 (95% CI, 2.9 to 30.2). The relative sensitivity of AHPV compared to HC2 was 91.5% for CIN3+, and the negative predictive values were 99.8% (95% CI, 99.5 to 99.9%) for HC2 and 99.7% (95% CI, 99.4 to 99.8%) for AHPV. Our data show that the longitudinal performance of the AHPV test over six years is comparable to the performance of the HC2 test and that the absolute risk of CIN3+ over six years following a negative AHPV result in a screening population is low. (This study is registered at ClinicalTrials.gov under registration number NCT02634190.)

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