Cervical cancer screening program based on primary DNA-HPV testing in a Brazilian city: a cost-effectiveness study protocol.

BACKGROUND: The causal relationship between high-risk (hr) HPV infection and precancerous lesions or cervical cancer has led to the development of strategies to increase screening performance and prevent this cancer. The increased sensitivity of DNA-HPV testing compared to cervical cytology favors DNA-HPV testing as a primary screening test. Cervical cancer screening in Brazil is opportunistic, and this cancer remains a considerable health problem with a high proportion of diagnoses in advanced stages. This paper aims to describe the design and implementation of the Cervical Cancer Screening Program with primary DNA-HPV testing (CCSP-HPV) planned for Indaiatuba City (SP), Brazil; the strategies to achieve higher population coverage; and a study protocol for cost-effectiveness analyses. METHODS: The CCSP-HPV was designed based on successful guidelines that replaced cervical cytology-based screening by the DNA-HPV test performed at 5-year intervals. The screening will be performed for the female population aged 25-64 years cared for by the public health system and aim to reach 80% coverage after completing the first round. The chosen DNA-HPV test detects 14 hr-HPV types and genotypes HPV-16 and 18. All women with a negative test will be reassessed after five years. Women showing a positive test for HPV-16 and/or 18 will be referred for colposcopy. Those showing the other 12 hr-HPV types will be tested by cytology, and if any abnormality is detected, they will also be referred for colposcopy. The histopathologic evaluation will be reviewed by a pathologist panel and aided by p16 immunohistochemistry. A cost-effectiveness analysis will be performed by a Markov model comparing the cost of the new program and the screening performed by conventional cytology five years prior (2011-2016). DISCUSSION: The new screening program is considered a breakthrough for public health regarding cervical cancer, which is the third leading cause of cancer death among Brazilian women. Achieving at least 80% coverage will have the possibility to change this scenario. The proposed program will provide a modern cervical cancer screening method for women, and information about cost-effectiveness will help other similar places support the decision of implementing cervical cancer screening using the DNA-HPV test.

The cost-effectiveness of human papillomavirus self-collection among cervical cancer screening non-attenders in El Salvador.

Cervical cancer screening with human papillomavirus (HPV) DNA testing has been incorporated into El Salvador's national guidelines. The feasibility of home-based HPV self-collection among women who do not attend screening at the clinic (i.e., non-attenders) has been demonstrated, but cost-effectiveness has not been evaluated. Using cost and compliance data from El Salvador, we informed a mathematical microsimulation model of HPV infection and cervical carcinogenesis to conduct a cost-effectiveness analysis from the societal perspective. We estimated the reduction in cervical cancer risk, lifetime cost per woman (2017 US$), life expectancy, and incremental cost-effectiveness ratio (ICER, 2017 US$ per year of life saved [YLS]) of a program with home-based self-collection of HPV (facilitated by health promoters) for the 18% of women reluctant to screen at the clinic. The model was calibrated to epidemiologic data from El Salvador. We evaluated health and economic outcomes of the self-collection intervention for women aged 30 to 59 years, alone and in concert with clinic-based HPV provider-collection. Home-based self-collection of HPV was projected to reduce population cervical cancer risk by 14% and cost $1210 per YLS compared to no screening. An integrated program reaching 99% coverage with both provider- and home-based self-collection of HPV reduced cancer risk by 74% (compared to no screening), and cost $1210 per YLS compared to provider-collection alone. Self-collection facilitated by health promoters is a cost-effective strategy for increasing screening uptake in El Salvador.

A mobile-phone based high-resolution microendoscope to image cervical precancer.

Nearly 90% of cervical cancer cases and deaths occur in low- and middle-income countries that lack comprehensive national HPV immunization and cervical cancer screening programs. In these settings, it is difficult to implement screening programs due to a lack of infrastructure and shortage of trained personnel. Screening programs based on visual inspection with acetic acid (VIA) have been successfully implemented in some low-resource settings. However, VIA has poor specificity and up to 90% of patients receiving treatment based on a positive VIA exam are over-treated. A number of studies have suggested that high-resolution cervical imaging to visualize nuclear morphology in vivo can improve specificity by better distinguishing precancerous and benign lesions. To enable high-resolution imaging in low-resource settings, we developed a portable, low-cost, high-resolution microendoscope that uses a mobile phone to detect and display images of cervical epithelium in vivo with subcellular resolution. The device was fabricated for less than $2,000 using commercially available optical components including filters, an LED and triplet lenses assembled in a 3D-printed opto-mechanical mount. We show that the mobile high-resolution microendoscope achieves similar resolution and signal-to-background ratio as previously reported high-resolution microendoscope systems using traditional cameras and computers to detect and display images. Finally, we demonstrate the ability of the mobile high-resolution microendoscope to image normal and precancerous squamous epithelium of the cervix in vivo in a gynecological referral clinic in Barretos, Brazil.

Cost-effectiveness of HPV-based cervical cancer screening in the public health system in Nicaragua.

OBJECTIVES: To evaluate the cost-effectiveness of human papillomavirus (HPV) DNA testing (versus Papanicolaou (Pap)-based screening) for cervical cancer screening in Nicaragua. DESIGN: A previously developed Monte Carlo simulation model of the natural history of HPV infection and cervical cancer was calibrated to epidemiological data from Nicaragua. Cost data inputs were derived using a micro-costing approach in Carazo, Chontales and Chinandega departments; test performance data were from a demonstration project in Masaya department. SETTING: Nicaragua's public health sector facilities. PARTICIPANTS: Women aged 30-59 years. INTERVENTIONS: Screening strategies included (1) Pap testing every 3 years, with referral to colposcopy for women with an atypical squamous cells of undetermined significance or worse result ('Pap'); (2) HPV testing every 5 years, with referral to cryotherapy for HPV-positive eligible women (HPV cryotherapy or 'HPV-Cryo'); (3) HPV testing every 5 years, with referral to triage with visual inspection with acetic acid (VIA) for HPV-positive women ('HPV-VIA'); and (4) HPV testing every 5 years, with referral to Pap testing for HPV-positive women ('HPV-Pap'). OUTCOME MEASURES: Reduction in lifetime risk of cancer and incremental cost-effectiveness ratios (ICER; 2015 US$ per year of life saved (YLS)). RESULTS: HPV-based screening strategies were more effective than Pap testing. HPV-Cryo was the least costly and most effective strategy, reducing lifetime cancer risk by 29.5% and outperforming HPV-VIA, HPV-Pap and Pap only, which reduced cancer risk by 19.4%, 12.2% and 10.8%, respectively. With an ICER of US$320/YLS, HPV-Cryo every 5 years would be very cost-effective using a threshold based on Nicaragua's per capita gross domestic product of US$2090. Findings were robust across sensitivity analyses on test performance, coverage, compliance and cost parameters. CONCLUSIONS: HPV testing is very cost-effective compared with Pap testing in Nicaragua, due to higher test sensitivity and the relatively lower number of visits required. Increasing compliance with recommended follow-up will further improve the health benefits and value for public health dollars.

High-resolution microendoscopy: a point-of-care diagnostic for cervical dysplasia in low-resource settings.

Cervical cancer is the third leading cause of cancer-related death among women in low-to-middle income countries. Pap testing and pathological services are difficult to implement under these settings. Alternative techniques for the diagnosis of cervical precancer in these settings are needed to reduce the burden of the disease. The objective of this study was to evaluate the diagnostic accuracy of a low-cost, high-resolution microendoscope imaging system in identifying precancerous lesions of the cervix in vivo. A retrospective study of 59 patients undergoing colposcopy for an abnormal Pap test was performed at Hospital de Câncer de Barretos in Brazil. All patients underwent colposcopy as per standard of care, and acetowhite lesions were recorded. High-resolution microendoscopy (HRME) images were obtained from one colposcopically normal region and from all lesions observed on colposcopy. Biopsies of abnormal areas were obtained and reviewed by three independent, blinded pathologists and compared with HRME findings. The mean nuclear area and the median nuclear eccentricity were calculated from HRME images acquired from each site. A diagnostic algorithm to distinguish histopathologically diagnosed cervical intraepithelial neoplasias of grade 2 or more severe lesions (high grade) from less severe lesions (low grade) was developed using these parameters. A test of trend was used to analyze the relationship between HRME positivity and severity of histopathogical diagnosis. Fisher's exact test was used to analyze differences in HRME positivity between high-grade and low-grade lesions. Evaluable images were obtained from 108 of 143 discrete sites. Of these, 71 sites were colposcopically normal or low grade according to histopathology and 37 were diagnosed as high grade on the basis of histopathology. Using the mean nuclear area and the median nuclear eccentricity, HRME images from 59 colposcopically abnormal sites were classified as high grade or low grade with 92% sensitivity and 77% specificity compared with histopathological findings. Increasing HRME positivity showed a significant trend with increasing severity of diagnosis (Ptrend<0.001). We found a strong association (P<0.001) between HRME positivity and a histopathological diagnosis of cervical intraepithelial neoplasia of grade 2 or higher. HRME demonstrated an accurate in-situ diagnosis of high-grade dysplasia. In low-resource settings in which colposcopy and histopathology services are severely limited or unavailable, HRME may provide a low-cost, accurate method for diagnosis of cervical precancer without the need for biopsy, allowing for a single 'screen-and-treat' approach.

Cost analysis of different cervical cancer screening strategies in Mexico.

OBJECTIVE: To compare the costs and number of undetected cases of four cervical cancer screening strategies (CCSS) in Mexico. MATERIALS AND METHODS: We estimated the costs and outcomes of the following CCSS: a) conventional Papanicolaou smear (Pap) alone; b) high-risk human papilloma virus testing (HR-HPV) as primary screening with Pap as reflex triage; c) HR-HPV as primary screening with HPV-16/18 typing, liquid-based cytology (LBC) and immunostaining for p16/Ki67 testing as reflex triage, and d) co-testing with HR-HPV and LBC with HPV-16/18 typing and immunostaining for p16/Ki67 as reflex triage. The outcome of interest was high-grade cervical lesions or cervical cancer. RESULTS: HR-HPV testing, HPV typing, LBC testing and immunostaining is the best alternative because it is the least expensive option with an acceptable number of missed cases. CONCLUSIONS: The opportunity costs of a poor quality CCSS is many false negatives. Combining multiple tests may be a more cost-effective way to screen for cervical cancer in Mexico.

Cost of the Cervical Cancer Screening Program at the Mexican Social Security Institute.

OBJECTIVE: To estimate the annual cost of the National Cervical Cancer Screening Program (CCSP) of the Mexican Institute of Social Security (IMSS). MATERIALS AND METHODS: This cost analysis examined regional coverage rates reported by IMSS. We estimated the number of cytology, colposcopy, biopsy and pathology evaluations, as well as the diagnostic test and treatment costs for cervical intraepithelial neoplasia grade II and III (CIN 2/3) and cervical cancer. Diagnostic test costs were estimated using a micro-costing technique. Sensitivity analyses were performed. RESULTS: The cost to perform 2.7 million cytology tests was nearly 38 million dollars, which represents 26.1% of the total program cost (145.4 million). False negatives account for nearly 43% of the program costs. CONCLUSION: The low sensitivity of the cytology test generates high rates of false negatives, which results in high institutional costs from the treatment of undetected cervical cancer cases.

Should endocervical curettage routinely be performed at the time of colposcopy? A cost-effectiveness analysis.

OBJECTIVES: Endocervical curettage (ECC) has been used with colposcopy-directed biopsy to increase diagnostic sensitivity for detecting cellular abnormality. Our objective was to determine if routine ECC was cost-effective compared with colposcopy alone in women with atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion cervical cytology, who are older and younger than 50 years. MATERIALS AND METHODS: We generated a cost-effectiveness model using outcomes from cervical screening including repeat Pap smears, colposcopy, and loop electrosurgical excision procedure. Cervical cancer costs, survival, as well as incidence and complications after loop electrosurgical excision procedure (preterm birth, cervical stenosis, dysmenorrhea, amenorrhea, and infertility) were modeled. Cost and probability values were obtained from published literature and Medicare databases. Direct medical costs were analyzed in 2011 US dollars. Effectiveness outcomes were cervical cancer deaths and incident cases of cancer prevented. Model robustness was evaluated using probabilistic sensitivity analysis. RESULTS: For women older than 50 years, routine ECC is the dominant strategy (less expensive and more effective at reducing cervical cancer deaths/incidence). For women younger than 50 years, routine ECC costs $96,737 more per cervical cancer death prevented. Cost per incident cancer case prevented ranged from $21,894 (local spread or greater) to $235,873 (distal spread). Sensitivity analysis confirmed these conclusions. In women older than 50 years, routine ECC was always the most likely cost-effective choice. In women younger than 50, routine ECC was most likely cost-effective for all willingness-to-pay thresholds greater than $80,000 to prevent 1 cancer death. CONCLUSIONS: In women older than 50 years, routine ECC is favored over colposcopy alone because this strategy is cost saving and reduces the number of cancer deaths and incident cancer cases. For women younger than 50 years, cost-effectiveness is dependent on willingness to pay to prevent 1 cancer death but still seems to be cost-effective.

Prevention of cervical cancer in women with ASCUS in the Brazilian Unified National Health System: cost-effectiveness of the molecular biology method for HPV detection.

This study aimed to assess the performance of PCR as a means of detecting HPV 16/18 compared to the single probe-based PCR for detecting high-risk HPV, and evaluate these methods for detecting cervical intraepithelial neoplasia (CIN) in follow-ups for ASCUS testing. It also compares the costs of cytology, PCR methods, colposcopy and biopsy in the Brazilian Unified National Health System. Of the 81 patients with ASCUS, 41 (50.6%) tested positive for HPV 16/18 in PCR testing and 47 (58.02%) tested positive for high-risk HPV with single probe-based PCR testing. The negative predictive value was 93.75% for HPV 16/18 PCR and 100% for single probe-based PCR in cases that progressed to high-grade CIN. The annual costs of patient referral were the following: R$2,144.52 for referral of patients with ASCUS cytology for colposcopy; R$6,307.44 for referral of patients with ASCUS cytology and PCR positive for HPV 16/18 or colposcopy; R$3,691.80 for referral of patients with ASCUS cytology with single probe-based PCR positive for high-risk HPV. Therefore, cost per user can be reduced by performing single probe-based PCR for high-risk HPV on patients with ASCUS.

Prevention of cervical cancer in women with ASCUS in the Brazilian Unified National Health System: cost-effectiveness of the molecular biology method for HPV detection / Prevenção de câncer de colo uterino em pacientes com ASCUS no Sistema Único de Saúde: custo-efetividade de método de biologia molecular para HPV

This study aimed to assess the performance of PCR as a means of detecting HPV 16/18 compared to the single probe-based PCR for detecting high-risk HPV, and evaluate these methods for detecting cervical intraepithelial neoplasia (CIN) in follow-ups for ASCUS testing. It also compares the costs of cytology, PCR methods, colposcopy and biopsy in the Brazilian Unified National Health System. Of the 81 patients with ASCUS, 41 (50.6%) tested positive for HPV 16/18 in PCR testing and 47 (58.02%) tested positive for high-risk HPV with single probe-based PCR testing. The negative predictive value was 93.75% for HPV 16/18 PCR and 100% for single probe-based PCR in cases that progressed to high-grade CIN. The annual costs of patient referral were the following: R$2,144.52 for referral of patients with ASCUS cytology for colposcopy; R$6,307.44 for referral of patients with ASCUS cytology and PCR positive for HPV 16/18 or colposcopy; R$3,691.80 for referral of patients with ASCUS cytology with single probe-based PCR positive for high-risk HPV. Therefore, cost per user can be reduced by performing single probe-based PCR for high-risk HPV on patients with ASCUS.

Os objetivos deste estudo foram avaliar o desempenho do PCR para detecção de HPV 16/18 versus PCR sonda única para a detecção de HPV de alto risco, avaliar estes métodos na detecção de neoplasia intraepitelial cervical (NIC) no seguimento de ASCUS, e comparar os custos de citologia, métodos de PCR, colposcopia e biópsia no Sistema Único de Saúde. Das 81 pacientes com ASCUS, 41 (50,6%) foram positivas para o HPV 16/18 PCR, e 47 (58,02%) foram positivas para PCR sonda única para HPV de alto risco. O valor preditivo negativo foi de 93,75% para HPV 16/18 PCR e 100% para PCR sonda única em casos que evoluíram para NIC de alto grau. Os custos anuais encaminhando todas as pacientes com ASCUS para a colposcopia, encaminhando à colposcopia as pacientes com ASCUS e PCR positivo para HPV 16/18 e encaminhando à colposcopia aquelas pacientes com ASCUS e PCR sonda única para HPV de alto risco positivo foram de R$2.144,52, R$6.307,44 e R$3.691,80, respectivamente. Considerando eventual redução dos custos para utilização em grandes quantidades, este método poderia ser realizado em ASCUS.

Cervical cancer screening among HIV-infected women: an economic evaluation in a middle-income country.

Due to the recent widespread availability of highly active antiretroviral therapy (HAART) in middle-income countries, there has been an increase in life expectancy for women on HAART, but no corresponding decrease in cervical cancer incidence. This study evaluates the optimal cervical cancer screening strategy for HIV-infected women in a middle-income country. We developed a mathematical model, which simulates the natural history of the HPV infection, as well as the HIV-mediated immunosupression among women in Brazil. Our model was calibrated using data from the IPEC/FIOCRUZ Women's HIV-infected cohort. The model compares the lifetime effects, costs and cost-effectiveness of strategies combining cytology, HPV DNA test and colposcopy at different screening intervals for different CD4 count strata (27 strategies in total). We found that the strategy with the best cost-effectiveness profile (cost-effectiveness ratio-U$4,911/year of life saved [YLS] and probability of being cost-effective-86%) was HPV testing followed by cytology triage every year for all HIV infected women, considering a very cost-effective threshold given by Brazil's GDP per capita (US$8,625/YLS). The results were robust to changes in the input parameters as demonstrated in one-way, scenario, threshold and probabilistic sensitivity analysis. Our study indicates that annual HPV testing followed by cytology triage for all HIV-infected women is likely to be very cost-effective in a middle-income country like Brazil. The results reflect the synergic effect of using a highly sensitive screening test (HPV DNA test) in sequence with a highly specific test (cytology).

Economic evaluation of strategies for managing women with equivocal cytological results in Brazil.

In Brazil, current management of women with screening results of atypical squamous cells of undetermined significance (ASC-US) is to offer repeat testing at 6-month intervals. Alternative management strategies that have been adopted in many high-income settings are to offer immediate colposcopy referral or to utilise human papillomavirus (HPV) DNA testing as a triage for colposcopy referral, and to consider different strategies according to women's age. The objective of our study was to evaluate the lifetime cost effectiveness in terms of cost per years of life saved (YLS) of these alternative strategies for a middle income setting. A Markov model was developed using data from the Ludwig-McGill cohort and calibrated to independent observational datasets and local cost estimates obtained. In the base-case analysis, repeat cytology was the least costly strategy but also the least effective. Based on the WHO threshold for very cost-effective interventions, HPV triage for women above 30 years-old was the strategy with the highest probability of being cost effective. HPV triage including younger women with ASCUS results would also be a cost-effective option. Whilst there was a slight further gain in effectiveness with immediate colposcopy referral, it was also more expensive and did not appear to be cost effective. Threshold analysis indicated that an HPV test would have to be more than twice as expensive as a cytology test for HPV triage to no longer be cost effective. In conclusion, our results indicate that in middle income settings HPV triage is likely to be the optimal strategy for managing women presenting with ASC-US results.

[Overuse of colposcopy service in Mexico]. / Sobreutilización del servicio de colposcopia en México.

BACKGROUND: Cervicouterine cancer is one of the main public health problems in Mexico. Several problems related to the low effectiveness of the Program of Opportune Detection of Cervicouterine Cancer have been identified, among them: low cover of the disease detection and absence of quality control in the detection, diagnosis and treatment of it. In Mexico the quality control problem in cytology has been taken with success, but the opposite occurs with colposcopy practice. For that reason this service is overused by patients with low risk cancer and is not accessible for the high risk population. OBJECTIVE: To evaluate the association between cervicouterine cancer knowledge and satisfaction with the service regarding the use and intention of adherence to it for the follow-up and treatment, as well as analyze the resources used for this attention. PATIENTS AND METHODS: A transversal study was done from May to December, 2002. It included all the patients who went to the Colposcopy Service in three hospitals. 1,606 patients were interviewed, from them 443 cases were first-time visits and 1,163 were subsequent ones. RESULTS: In a multivariate model we observed that the real utility knowledge of cervicovaginal cytology increases the probability that women come back to the Colposcopy Service (OR 2.0, Cl 95%: 1.57, 2.54). Patients who know their diagnosis when it is dysplasia or cancer are more likely to become attached to their follow-up than those who do not know it. 91% of the users (1,463) had two or more cervicovaginal cytolgies done, and 49% (787) had eight or more. Patients who know the purpose and utility of the biopsy had a 4.4 fold probability of become subsequent than those that do not know such information (Cl 95%: 1.72 to 11.35). CONCLUSIONS: Nowadays colposcopy clinics treat 70% of the patients who are subsequent and that have normal reports of cytology. This shows us an overuse of the service, with the consequent service, monetary and opportunity costs for women. More studies should be done to reformulate the rule that controls the treatment of these patients, and incorporate follow-up guidelines according to the natural history of the disease in Mexican women.