Atypical glandular cells in Pap tests: cytology-histology correlation and risk assessment with human papillopmavirus (HPV) testing.

INTRODUCTION: Atypical glandular cells (AGC) represent less than 1% of Pap test cases and include a variety of lesions in both the cervix and endometrium. The study aimed to investigate the cytology-histology correlation in AGC patients and to evaluate the clinical utility of hrHPV testing in this diagnostic context. MATERIALS AND METHODS: We identified 491 atypical glandular cells (AGC) cases in our quality analysis (QA) database of 336,064 Pap tests interpreted between March 1, 2013 and July 12, 2016. Of these, 251 cases had follow-up biopsies with hrHPV tests in 148 cases. RESULTS: The most common histologic diagnosis associated with AGC was normal/benign or low-grade lesions, comprising 55% of cervical biopsies and 24% of endometrial biopsies. High-grade lesions were identified in 21% of follow-up biopsies. In patients with AGC cytology, a positive hrHPV test significantly increased the likelihood of cervical HSIL or above lesions on biopsy by 26.4 times (OR = 26.4, 95% CI: 5.8-119.4, P < 0.0001). A positive genotyping result for HPV 16 dramatically increased the likelihood of cervical HSIL or above lesions on biopsy (OR = 84, 95% CI: 12.0-590.5, P < 0.0001). The HPV test had a negative predictive value of 97% (CI: 85%-100%). CONCLUSIONS: Our study confirms that AGC is a significant diagnosis with an overall risk for high-grade cervical or endometrial lesions as high as 21%. hrHPV testing with genotyping is an effective tool for identifying high-risk individuals within the AGC population, with excellent positive and negative predictive values. This approach is valuable for clinical risk stratification and differential diagnosis in patients with AGC cytology.

HPV-specific risk assessment of cervical cytological abnormalities.

BACKGROUND: Cytology and HPV genotype screening play an important role in cervical cancer detection. Whether multiple HPV genotyping can predict cytological lesions remains to be further studied. METHODS: Two thousand two hundred twenty-four females were analyzed for cytology and HPV genotypes test. The possibility of predicting cytological lesions by HPV genotypes test was evaluated by multivariate logistic regression and area under the receiver operator characteristic curve (AUC). RESULT: Abnormal cytological results were found in 479 participants. A total of 688 patients were detected with HPV infection, 619 with HR-HPV infection and 112 with LR-HRV infection. HPV-52 was found to be the most common type among these patients, and a relatively higher risk of cervical lesions was found in HPV positive females. HPV-16, 31, 33 and 58 were found to have significantly higher infection rates in patients with HSIL and higher lesions. The prediction model was developed based on age and HPV-specific genotypes, with the AUC of 0.73 for cytological abnormalities and 0.82 for HSIL and higher lesions. CONCLUSION: HPV-16, 31, 33 and 58 infection are significant risk factors for cervical lesions. Combined HPV genotypes test can effectively predict cytological abnormalities.

Quality of Actions to Control Cervical Cancer in Bahia, Brazil.

OBJECTIVE: To assess the quality of the actions to control cervical cancer (CC) and its correlates. METHODS: This is a cross-sectional study conducted from January to March 2019 in 19 municipalities in Bahia, Brazil, with a sample of 241 doctors and nurses from primary health care (PHC). Three dependent variables were chosen- "Performance of educational, promotion, prevention, and monitoring actions" (D1); "Access to diagnostic tests" (D2); "Non-occurrence of high grade cervical squamous intraepithelial lesions (HSIL)" (D3). Poisson regression with robust variance was used, adopting hierarchical input variables to estimate the prevalence ratios and confidence intervals of 95%. RESULTS: The following prevalence rates were found: D1  39.8% (95% CI: 33.8-46.2); D2  73.9% (95% CI: 67.9-79.1); and D3  46.4% (95% CI: 39.9-53.0). These dimensions remained associated with the dependent variables: D1- having professional training courses on the topic; consideration to ensure that collection takes place appropriately by a professional; and women having access to medical transport; D2- nurses treating low-grade lesions; D3- recording the Papanicolaou in electronic medical records; D1 and D2- professionals joining the service through public tender; D1 and D3- working in the PHC (≥ 2 years); D2 and D3- recording Papanicolaou in physical records; and performance of Papanicolaou by residents. CONCLUSION: Better trained professionals and professionals working in stable work arrangements are associated with comprehensive actions to control CC. Such strategies indicate that investments in work management result in a more organized PHC and more solution-centered work processes. Therefore, working in the PHC for a longer time and nurses performing more clinical actions (collection and treatment) are favored by such organizational actions. Investments in diagnostic support contribute to perceptions of more comprehensive actions to control CC. 
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Cervical testing beyond the screening target age - A register-based cohort study from Finland.

OBJECTIVE: It has been proposed that cervical cancer screening should be continued in women with previous abnormal results or irregular attendance. We examined the coverage and factors that might influence cervical testing beyond the age range of the organized cervical screening programme in Finland. The national programme invites women in every five years least until the age of 60. After the stopping age, only opportunistic service is available. METHODS: Data on cervical testing were collected from the Mass Screening Registry and providers of opportunistic Pap/HPV-testing and were linked with information on socio-economic variables. The study included 373,353 women who had at least one invitation to the national screening programme between ages 50-60 years, and who were aged 65-74 years in the follow-up period 2006-2016. Multivariable binomial regression models were conducted to determine associations. RESULTS: Altogether 33% of the study population had been tested at least once at ages 65-74 years. Previous regular screening attendance (adjRR 1.70; 95% CI 1.67-1.73) and earlier abnormal results (adjRR 2.08; 95% CI 2.04-2.12) were most clearly related to higher testing adherence at older age. Other factors related to higher testing adherence were urban area of residence, domestic mother tongue, high education level, and high socio-economic status. CONCLUSION: Testing at older age was frequent with normal results, whereas only a small proportion of women with earlier abnormal results or irregular attendance were tested. The upper age limit of the national programme should be raised to 65 years, and the invitations thereafter should be targeted to selected high-risk groups.

Cost-effectiveness analysis of primary human papillomavirus testing in cervical cancer screening: Results from the HPV FOCAL Trial.

The Human Papillomavirus FOr CervicAL cancer (HPV FOCAL) trial is a large randomized controlled trial comparing the efficacy of primary HPV testing to cytology among women in the population-based Cervix Screening Program in British Columbia, Canada. We conducted a cost-effectiveness analysis based on the HPV FOCAL trial to estimate the incremental cost per detected high-grade cervical intraepithelial neoplasia of grade 2 or worse lesions (CIN2+). A total of 19,009 women aged 25 to 65 were randomized to one of two study groups. Women in the intervention group received primary HPV testing with reflex liquid-based cytology (LBC) upon a positive finding with a screening interval of 48 months. Women in the control group received primary LBC testing, and those negative returned at 24 months for LBC and again at 48 months for exit screening. Both groups received HPV and LBC co-testing at the 48-month exit. Incremental costs during the course of the trial were comparable between the intervention and control groups. The intervention group had lower overall costs and detected a larger number of CIN2+ lesions, resulting in a lower mean cost per CIN2+ detected ($7551) than the control group ($8325), a difference of -$773 [all costs in 2018 USD]. Cost per detected lesion was sensitive to the costs of sample collection, HPV testing, and LBC testing. The HPV FOCAL Trial results suggest that primary HPV testing every 4 years produces similar outcomes to LBC-based testing every 2 years for cervical cancer screening at a lower cost.

Cost-Effectiveness of Offering Cervical Cancer Screening with HPV Self-Sampling among African-American Women in the Mississippi Delta.

BACKGROUND: African-American women in the United States have an elevated risk of cervical cancer incidence and mortality. In the Mississippi Delta, cervical cancer disparities are particularly stark. METHODS: We conducted a micro-costing study alongside a group randomized trial that evaluated the efficacy of a patient-centered approach ("Choice" between self-collection at home for HPV testing or current standard of care within the public health system in Mississippi) versus the current standard of care ["Standard-of-care screening," involving cytology (i.e., Pap) and HPV co-testing at the Health Department clinics]. The interventions in both study arms were delivered by community health workers (CHW). Using cost, screening uptake, and colposcopy adherence data from the trial, we informed a mathematical model of HPV infection and cervical carcinogenesis to conduct a cost-effectiveness analysis comparing the "Choice" and "Standard-of-care screening" interventions among un/underscreened African-American women in the Mississippi Delta. RESULTS: When each intervention was simulated every 5 years from ages 25 to 65 years, the "Standard-of-care screening" strategy reduced cancer risk by 6.4% and was not an efficient strategy; "Choice" was more effective and efficient, reducing lifetime risk of cervical cancer by 14.8% and costing $62,720 per year of life saved (YLS). Screening uptake and colposcopy adherence were key drivers of intervention cost-effectiveness. CONCLUSIONS: Offering "Choice" to un/underscreened African-American women in the Mississippi Delta led to greater uptake than CHW-facilitated screening at the Health Department, and may be cost-effective. IMPACT: We evaluated the cost-effectiveness of an HPV self-collection intervention to reduce disparities.

Human Papillomavirus Same Genotype Persistence and Risk: A Systematic Review.

OBJECTIVE: The aim of the study was to examine whether high-grade cervical intraepithelial neoplasia (CIN) was more closely associated with human papillomavirus (HPV) same-genotype persistence (SGTP) versus clearance of prior infection with a subsequent infection by a new genotype (genotype switch [GS]), clearance of HPV infection, or acquisition of a new HPV infection after a negative infection status, during a follow-up testing subsequent to abnormal screening results. MATERIALS AND METHODS: MEDLINE, Cochrane Library, Health Technology Assessment, and clinicaltrials.gov were searched from January 2000 to July 2019 for prospective controlled trials and observational studies of women and retrospective studies using HPV assays with extended- or full-genotype reporting. The primary outcome was high-grade CIN after at least 2 rounds of testing. Overall quality of evidence for the risk estimate outcomes was assessed. Of the 830 identified abstracts, 66 full-text articles were reviewed, and 7 studies were included in the synthesis. The study protocol was registered with the PROSPERO International Prospective Register of Systematic Reviews (CRD42018091093). RESULTS: Continued HPV-positive women falls in 2 equally large groups: SGTP and GS. Sensitivity, positive predictive value, and positive likelihood ratio of SGTP were significantly higher than for GS. Human papillomavirus genotypes may be ranked into 3 tiers (immediate colposcopy, follow-up testing, return to routine screening), according to associated risk of persistence for high-grade CIN and to prevailing clinical action thresholds. CONCLUSIONS: There is moderately high-quality evidence to support the clinical utility of SGTP to improve risk discrimination for high-grade CIN compared with qualitative HPV testing without genotype-specific information.

Introducing human papillomavirus (HPV) primary testing in the age of HPV vaccination: projected impact on colposcopy services in Wales.

OBJECTIVE: To determine the demand for colposcopy in the Cervical Screening Wales programme after the introduction of human papillomavirus (HPV) cervical screening, which coincided with the start of screening of women vaccinated against HPV types 16/18. DESIGN: The study used a computational model that assigns screening and screening-related colposcopy events to birth cohorts in individual calendar years. SETTING: Cervical Screening Wales. POPULATION: Women aged 25-64 years from birth cohorts 1953-2007. METHODS AND MAIN OUTCOME MEASURES: We estimated the numbers of colposcopies and high-grade cervical intraepithelial lesions (CIN2+) within Cervical Screening Wales in 2018-32, using official population projections for Wales and published estimates of the effects of HPV screening and vaccination. RESULTS: Vaccination will reduce the number of colposcopies by 10% within the first 3-4 years after the national roll-out of HPV screening, and by about 20% thereafter. The number of screening colposcopies is estimated to increase from 6100 in 2018 and peak at 8000 (+31%) in 2021, assuming current screening intervals are maintained. The numbers of CIN2+ lesions follow similar patterns, stabilising at around 1000 diagnoses per year by 2026, approximately 60% lower than at present. Extending the screening intervals to 5 years for all women shows similar trends but introduces peaks and troughs over the years. CONCLUSIONS: Vaccination will not fully prevent an increase in colposcopies and detected CIN2+ lesions during the first 2-3 years of HPV-based screening but the numbers are expected to decrease substantially after 5-6 years. TWEETABLE ABSTRACT: HPV-based cervical screening will initially increase colposcopy referral. In 6 years, this increase will be reversed, partly by HPV vaccination.

Cost-effectiveness analysis of repeated self-sampling for HPV testing in primary cervical screening: a randomized study.

BACKGROUND: Human papillomavirus (HPV) testing is recommended in primary cervical screening to improve cancer prevention. An advantage of HPV testing is that it can be performed on self-samples, which could increase population coverage and result in a more efficient strategy to identify women at risk of developing cervical cancer. Our objective was to assess whether repeated self-sampling for HPV testing is cost-effective in comparison with Pap smear cytology for detection of cervical intraepithelial neoplasia grade 2 or more (CIN2+) in increasing participation rate in primary cervical screening. METHODS: A cost-effectiveness analysis (CEA) was performed on data from a previously published randomized clinical study including 36,390 women aged 30-49 years. Participants were randomized either to perform repeated self-sampling of vaginal fluid for HPV testing (n = 17,997, HPV self-sampling arm) or to midwife-collected Pap smears for cytological analysis (n = 18,393, Pap smear arm). RESULTS: Self-sampling for HPV testing led to 1633 more screened women and 107 more histologically diagnosed CIN2+ at a lower cost vs. midwife-collected Pap smears (€ 229,446 vs. € 782,772). CONCLUSIONS: This study resulted in that repeated self-sampling for HPV testing increased participation and detection of CIN2+ at a lower cost than midwife-collected Pap smears in primary cervical screening. Offering women a home-based self-sampling may therefore be a more cost-effective alternative than clinic-based screening. TRIAL REGISTRATION: Not registered since this trial is a secondary analysis of an earlier published study (Gustavsson et al., British journal of cancer. 118:896-904, 2018).

Use of the Aptima mRNA high-risk human papillomavirus (HR-HPV) assay compared to a DNA HR-HPV assay in the English cervical screening programme: a decision tree model based economic evaluation.

OBJECTIVE: To estimate the impact of using the Aptima messenger RNA (mRNA) high-risk human papilloma virus (HR-HPV) assay versus a DNA HR-HPV assay in a primary HPV cervical screening programme. DESIGN: One hypothetical cohort followed for 3 years through HPV primary cervical screening. SETTING: England. PARTICIPANTS: A hypothetical cohort of women aged 25-65 years tested in the National Health Service (NHS) Cervical Screening Programme (CSP) for first call or routine recall testing. METHODS: A decision tree parameterised with data from the CSP (2017/18) and the HORIZON study. Uncertainty analyses were conducted using data from the FOCAL and GAST studies, other DNA HPV tests in addition to one-way and probabilistic sensitivity and scenarios analyses, to test the robustness of results. INTERVENTIONS: Aptima mRNA HR-HPV assay and a DNA HR-HPV assay (cobas 4800 HPV assay). MAIN OUTCOME MEASURES: Primary: total colposcopies and total costs for the cohort. Secondary: total HPV and cytology tests, number lost to follow-up. RESULTS: At baseline for a population of 2.25 million women, an estimated £15.4 million (95% credibility intervals (CI) £6.5 to 24.1 million) could be saved and 28 009 (95% CI 27 499 to 28 527) unnecessary colposcopies averted if Aptima mRNA assays are used instead of a DNA assay, with 90 605 fewer unnecessary HR-HPV and 253 477 cytology tests performed. These savings are due to a lower number of HPV positive samples in the mRNA arm. When data from other primary HPV screening trials were compared, results indicated that using the Aptima mRNA assay generated cost savings and reduced testing in every scenario. CONCLUSION: Using the Aptima mRNA assay versus a DNA assay would almost certainly yield cost savings and reduce unnecessary testing and procedures, benefiting the NHS and women in the CSP.

Cervical cancer screening coverage, management of squamous intraepithelial lesions and related costs in France.

Until 2018, cervical cancer screening in France was an unorganized individual screening, with the exception of some pilot programs in some territories. We aimed to assess, before the implementation of organized cervical cancer screening and human papillomavirus (HPV) nonavalent vaccine introduction in the vaccination schedule in 2018, (i) the individual cervical cancer screening coverage, (ii) the management of squamous intraepithelial lesions (SIL) and (iii) the related costs. We used the Système National des Données de Santé (SNDS) (Echantillon Généraliste de Bénéficiaires [EGB] and Programme de Médicalisation des systèmes d'information [PMSI]) to assess the cervical screening coverage rate in France between January 1st, 2012 and December 31st, 2014, and to describe diagnostic investigations and therapeutic management of SIL in 2013. After extrapolation to the general population, a total of 10,847,814 women underwent at least one smear test over the 3-year study period, corresponding to a coverage rate of 52.4% of the women aged 25 to 64 included. In 2013, 126,095 women underwent HPV test, 327,444 women underwent colposcopy, and 9,653 underwent endocervical curettage; 31,863 had conization and 12,162 had laser ablation. Besides, 34,067 women experienced hospital stays related to management of SIL; 25,368 (74.5%) had high-grade lesions (HSIL) and 7,388 (21.7%) low-grade lesions (LSIL). Conization was the most frequent in-hospital therapeutic procedure: 89.5% (22,704) of women with an in-hospital procedure for HSIL and 64.7% (4,781) for LSIL. Mean cost of smear test, colposcopy and HPV tests were around 50€. Total cost for hospital stays in 2013 was estimated at M41€, or a mean cost of 1,211€ per woman; 76% were due to stays with HSIL. This study highlights the low coverage rate of individual cervical cancer screening and a high burden related to SIL management.

Histomorphologic assessment and distribution of high-risk human papillomavirus (HPV) types in cervical high-grade squamous intraepithelial lesions with unusual histomorphologic features.

In rare cases, equivocal histomorphology ('deceiving dysplasia') does not allow immediate diagnosis of cervical high-grade squamous intraepithelial lesion (HSIL). We studied whether these cases are correlated with specific high-risk human papillomavirus (hr HPV) types. During 2011-2017, 39 cases of p16-positive cervical tissue biopsies with unusual ('deceiving') dysplastic histomorphology were identified and matched with the same number of controls (typical HSIL samples). Histomorphological characteristics were reviewed blindly and HPV testing was performed using the clinically validated RealTime test (Abbott) and Anyplex HPV 28 (Seegene). HPV 16 and HPV 31 were the two most frequent HPV types in both groups, although minimum, proportional, hierarchical and any etiological attribution estimates for HPV 16 were significantly lower in the deceiving group (13.2%, 21.3%, 23.7% and 23.7%) than in the control group (32.4%, 48.1%, 48.6% and 48.6%). In addition, the distribution of other hr HPV types differed between the two study groups, with five HPV types (HPV 56, 58, 59, 73 and 82) detected only in the deceiving group. Histomorphologic review of both groups (regardless of HPV type) confirmed significant differences in nuclear atypia, maximum lesion thickness and cellularity, although these were diminished when cross-comparisons between HPV16/18 and non-HPV16/18 cases pooled from both study groups were evaluated. Different attribution estimates for HPV 16, HPV 16/18 and non-16/18 hr HPV types in deceiving and control groups were observed, in particular for HPV 16. However, an unusual (deceiving) histomorphology may also depend on unknown HPV-related molecular changes.

Reducing overtreatment associated with overdiagnosis in cervical cancer screening-A model-based benefit-harm analysis for Austria.

A general concern exists that cervical cancer screening using human papillomavirus (HPV) testing may lead to considerable overtreatment. We evaluated the trade-off between benefits and overtreatment among different screening strategies differing by primary tests (cytology, p16/Ki-67, HPV alone or in combinations), interval, age and diagnostic follow-up algorithms. A Markov state-transition model calibrated to the Austrian epidemiological context was used to predict cervical cancer cases, deaths, overtreatments and incremental harm-benefit ratios (IHBR) for each strategy. When considering the same screening interval, HPV-based screening strategies were more effective compared to cytology or p16/Ki-67 testing (e.g., relative reduction in cervical cancer with biennial screening: 67.7% for HPV + Pap cotesting, 57.3% for cytology and 65.5% for p16/Ki-67), but were associated with increased overtreatment (e.g., 19.8% more conizations with biennial HPV + Papcotesting vs. biennial cytology). The IHBRs measured in unnecessary conizations per additional prevented cancer-related death were 31 (quinquennial Pap + p16/Ki-67-triage), 49 (triennial Pap + p16/Ki-67-triage), 58 (triennial HPV + Pap cotesting), 66 (biennial HPV + Pap cotesting), 189 (annual Pap + p16/Ki-67-triage) and 401 (annual p16/Ki-67 testing alone). The IHBRs increased significantly with increasing screening adherence rates and slightly with lower age at screening initiation, with a reduction in HPV incidence or with lower Pap-test sensitivity. Depending on the accepted IHBR threshold, biennial or triennial HPV-based screening in women as of age 30 and biennial cytology in younger women may be considered in opportunistic screening settings with low or moderate adherence such as in Austria. In organized settings with high screening adherence and in postvaccination settings with lower HPV prevalence, the interval may be prolonged.

Economic evaluation of HPV DNA test as primary screening method for cervical cancer: A health policy discussion in Greece.

BACKGROUND: HPV test appears to be more effective in cervical cancer (CC) screening. However, the decision of its adoption as a primary screening method by substituting the established cytology lies in the evaluation of multiple criteria. Aim of this study is to evaluate the economic and clinical impact of HPV test as primary screening method for CC. METHODS: A decision tree and a Markov model were developed to simulate the screening algorithm and the natural history of CC. Fourteen different screening strategies were evaluated, for women 25-65 years old. Clinical inputs were drawn from the HERMES study and cost inputs from the official price lists. In the absence of CC treatment cost data, the respective Spanish costs were used after being converted to 2017 Greek values. One-way and probabilistic sensitivity analyses were conducted. RESULTS: All screening strategies, that offer as primary screening method triennial HPV genotyping (simultaneous or reflex) alone or as co-testing with cytology appear to be more effective than all other strategies, with regards to both annual CC mortality, due to missed disease (-10.1), and CC incidence(-7.5) versus annual cytology (current practice). Of those, the strategy with HPV test with simultaneous 16/18 genotyping is the strategy that provides savings of 1.050 million euros annually. However, when the above strategy is offered quinquennially despite the fact that outcomes are decreased it remains more effective than current practice (-7.7 deaths and -1.3 incidence) and more savings per death averted (1.323 million) or incidence reduced (7.837 million) are realized. CONCLUSIONS: HPV 16/18 genotyping as a primary screening method for CC appears to be one of the most effective strategies and dominates current practice in respect to both cost and outcomes. Even when compared with all other strategies, the outcomes that it generates justify the cost that it requires, representing a good value for money alternative.

Clinical evaluation and budget impact analysis of cervical cancer screening using cobas 4800 HPV screening technology in the public sector of South Africa.

Cytology remains the mainstay of cervical cancer screening in South Africa (SA), however false negative rates are 25-50%. In contrast, human papillomavirus (HPV) screening techniques have higher sensitivity for cervical cancer precursors. The cobas® 4800 HPV test detects pooled high-risk HPV types and individual genotypes HPV 16 and 18. Using a mathematical budget impact model, the study objective was to evaluate the clinical and budget impact of replacing primary liquid-based cytology (LBC) with primary HPV-based screening strategies. In SA, current LBC screening practice recommends one test every ten years, followed by large loop excision of the transformation zone (LLETZ) if indicated. HPV testing can be performed from an LBC sample, where no additional consultations nor samples are required. In the budget impact model, LBC screening for 2 cycles (one test every ten years) was compared to cobas® 4800 HPV test for 2 cycles (one test every 5 years). The model inputs were gathered from literature and primary data sources. Indicative prices for LBC and cobas® 4800 HPV test were R189 and R457, respectively. Model results indicate that best outcomes for detection of disease were seen using cobas® 4800 HPV test. Forty-eight percent of cervical cancer cases were detected compared to 28% using LBC, and 50% of cervical intraepithelial neoplasia (CIN) 2 and CIN3 cases, compared to 25% with LBC. The budget impact analysis predicted that the cost per detected case of CIN2 or higher would be R 56,835 and R46,980 for the cobas® 4800 HPV and LBC scenarios, respectively. This equates to an incremental cost per detected case of CIN2 or higher of R9 855. From this model we conclude that a primary HPV screening strategy will have a significant clinical impact on disease burden in South Africa.

A direct comparison of four high-risk human papillomavirus tests versus the cobas test: Detecting CIN2+ in low-resource settings.

Low-cost, accurate high-risk human papillomavirus (HR-HPV) tests are needed for cervical cancer screening in limited-resource settings. More than 200 cervical cytological specimens from hospital patients were collected and analyzed for a real-world study. We evaluated the analytical and clinical performance of four widely used HR-HPV test (Tellgen, Hybribio, Liferiver, and Sansure) based on real-time polymerase chain reaction technology platforms, compared with the cobas test. Cervical intraepithelial neoplasia grade 2 or worse lesions (CIN2+) were set as the disease endpoint, and all the five HPV tests were performed with equal sensitivity (McNemar's test; P = 0.971) and specificity (McNemar's test; P = 0.953). All genotyping using the INNO-LiPA HPV test showed that HPV-16, -52, and -54 were the most common types among CIN2+ cases. Overall, the four HR-HPV tests analyzed appear to be as effective as the cobas HPV test in both agreement and clinical performance. Therefore, each of these low-cost HPV test kits could be implemented in limited-resource settings to accelerate the control of cervical cancer. However, we suggest that there is a need to further standardize and optimize testing around clinical sensitivity and specificity.

Cost-effectiveness evaluation of HPV self-testing offered to non-attendees in cervical cancer screening in Switzerland.

OBJECTIVE: About 30% of women who are eligible for cervical cancer (CC) screening remain un-screened or under-screened in Switzerland. HPV testing on self-collected vaginal samples (Self-HPV) has shown to be more sensitive than cytology while also reaching non-attendees. The objective of this study was to explore the cost-effectiveness of offering Self-HPV to non-attendees in Switzerland. METHODS: A recursive decision-tree with one-year cycles was used to model the life-long natural HPV history. Markov cohort simulations were used to assess the expected outcomes from the model. The outcomes of three strategies were compared with the absence of screening: Self-HPV and triage with colposcopy (Self-HPV/colpo), Self-HPV and triage with Pap cytology (Self-HPV/PAP), cytological screening and triage with HPV (PAP/HPV). Sensitivity analyses for the key parameters of the model were conducted to check the robustness of findings. RESULTS: Offering a Self-HPV screening to non-attendees could prevent 90% of CC and 94% of CC-related deaths in the study population. The current cytology-based program could reduce by 83% the number of CC cases and by 88% the number of CC-related deaths over the population's lifetime. Compared to the absence of screening, incremental cost-effectiveness ratios (ICER) were estimated to be, per saved Quality Adjusted Life Year (QALY), 12413US$ for the strategy Self-HPV/colpo, 11138US$ for the strategy Self-HPV/Pap and 22488US$ for the strategy PAP/HPV. CONCLUSIONS: Offering Self-HPV as a CC screening strategy to non-attendees in Switzerland is a cost-effective solution that is associated with a reduction of CC cases and related deaths. Self-HPV is more cost-effective than the currently used cytology-based screening.

Cost effectiveness analysis of HPV primary screening and dual stain cytology triage compared with cervical cytology.

OBJECTIVES: To assess the clinical and cost-effectiveness of human papillomavirus (HPV) primary screening triage with p16/Ki-67 dual stain cytology compared to cytology. METHODS: We conducted an Excel®-based budget impact model to estimate the preinvasive and invasive cervical cancer cases identified, mortality rate, direct medical costs, quality-adjusted life years (QALYs) and the incremental cost-effectiveness analysis of two strategies from the healthcare payer perspective. The study population is a cohort of women 30-65 years of age presenting for cervical screening. RESULTS: HPV primary screening triage with p16/Ki-67 dual stain showed higher sensitivity without losing specificity compared to conventional Pap smear. The improving the screening performance leads to decrease the prevalence of precancerous lesion, annual incidence and mortality of cervical cancer. The incidence of cervical cancer case detected by new algorithm compared with conventional method were 31,607 and 38,927, respectively. In addition, the new algorithm was more effective and more costly (average QALY 24.03, annual cost $13,262,693) than conventional cytology (average QALY 23.98, annual cost $7,713,251). The incremental cost-effective ratio (ICER) per QALY gained was $1,395. The sensitivity analysis showed if the cost of cytology and HPV test increased three times, the ICER would fall to $303/QALY gained and increased to $4,970/QALY gained, respectively. CONCLUSION: Our model results suggest that screening by use of HPV genotyping test as a primary screening test combined with dual stain cytology as the triage of HPV positive women in Thai population 30-65 years old is expected to be more cost-effective than conventional Pap cytology.

Budget impact analysis of cervical cancer screening in Portugal: comparison of cytology and primary HPV screening strategies.

BACKGROUND: Primary Human Papilloma Virus (HPV) testing is the currently recommended cervical cancer (CxCa) screening strategy by the Portuguese Society of Gynecology (SPG) clinical consensus. However, primary HPV testing has not yet been adopted by the Portuguese organized screening programs. This modelling study compares clinical benefits and costs of replacing the current practice, namely cytology with ASCUS HPV triage, with 2 comparative strategies: 1) HPV (pooled) test with cytology triage, or 2) HPV test with 16/18 genotyping and cytology triage, in organized CxCa screenings in Portugal. METHODS: A budget impact model compares screening performance, clinical outcomes and budget impact of the 3 screening strategies. A hypothetical cohort of 2,078,039 Portuguese women aged 25-64 years old women is followed for two screening cycles. Screening intervals are 3 years for cytology and 5 years for the HPV strategies. Model inputs include epidemiological, test performance and medical cost data. Clinical impacts are assessed with the numbers of CIN2-3 and CxCa detected. Annual costs, budget impact and cost of detecting one CIN2+ were calculated from a public healthcare payer's perspective. RESULTS: HPV testing with HPV16/18 genotyping and cytology triage (comparator 2) shows the best clinical outcomes at the same cost as comparator 1 and is the most cost-effective CxCa screening strategy in the Portuguese context. Compared to screening with cytology, it would reduce annual CxCa incidence from 9.3 to 5.3 per 100,000, and CxCa mortality from 2.7 to 1.1 per 100,000. Further, it generates substantial cost savings by reducing the annual costs by €9.16 million (- 24%). The cost of detecting CIN2+ decreases from the current €15,845 to €12,795. On the other hand, HPV (pooled) test with cytology triage (comparator 1) reduces annual incidence of CxCa to 6.9 per 100,000 and CxCa mortality to 1.6 per 100,000, with a cost of €13,227 per CIN2+ detected with annual savings of €9.36 million (- 24%). The savings are mainly caused by increasing the length of routine screening intervals from three to five years. CONCLUSION: The results support current clinical recommendations to replace cytology with HPV with 16/18 genotyping with cytology triage as screening algorithm.