Model structure
A cost-analysis model was developed with Microsoft Excel®. The design and structure of the model as well as the parameters needed for the development of the analysis were defined by a multidisciplinary expert panel composed of 2 gynaecologists, 3 pathologists, 1 epidemiologist and 3 health economics specialists. A structured questionnaire that included the values identified in the scientific published literature was developed and filled by the expert panel. Subsequently, an expert meeting was carried out to validate and agree upon all the values used in the analysis.
Modelling
Two scenarios were considered to estimate the costs associated with the CCS for all Spanish populations covered by the screening programme, including the first colposcopy. The initial analysis was performed in women 35-65 years old, where the primary screening was performed with HPV testing (base case). The alternative analysis considered the subgroup of women 25-34, where the primary screening was carried out with LBC (alternative case).
A decision tree model was designed for the two scenarios considering the recommendations of the current screening guidelines available in Spain [13] (Figure 1).
The analysis started with the cohorts accessing the CCS. Along the simulation, women were transitioning between the different nodes according to the probability of event occurrence. For this economic analysis, the model stops after performance of the colposcopy in those women requiring it. The decision tree nodes represented events derived from the findings of their HPV, LBC, colposcopy, and biopsy results.
Furthermore, LBC was considered in the analysis for sample collection, allowing the reflex test to be performed in both scenarios, thus avoiding the collection of a new sample.
The probabilities needed were obtained from the available scientific epidemiological publications and clinical trials of HPV testing.
Study population
Following the recommendations of the Spanish guidelines for CCS [13,[i]], the primary HPV CCS included the Spanish population of women aged 35-65 years (base case), and the cytological screening included women aged 25-34 (alternative case).
The number of the different populations was obtained from the National Institute of Statistics for 2018 [[ii]]. It was assumed that all women in the target population would be invited to participate in the CCS. In accordance with the AFRODITA study [[iii]], it was considered that 70% of invited women would attend their screening appointment. Therefore, the final population assessed in the model was 7,263,529 Spanish women from ages 35 to 65 and 1,947,925 women from ages 25 to 34, assuming that all of them were asymptomatic.
HPV testing
Based on the expert panel recommendations, three molecular detection HPV tests were considered in the analysis: one HPV mRNA test [Aptima human papillomavirus assay (Hologic, Inc., San Diego, USA)] and two HPV DNA tests [Hybrid Capture 2 high-risk HPV DNA test (Qiagen, Gaithersburg, MD, USA) and Cobas 4800 HPV test (Roche Molecular Diagnostics, Pleasanton, CA, USA)].
The Hybrid Capture 2 (HC2) high-risk HPV DNA test is considered the gold standard of HPV assays, as its performance was validated in many randomized controlled trials. HC2 collectively detects 13 high-risk (hr) HPV genotypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68). Aptima human papillomavirus (AHPV) is an in vitro nucleic acid amplification test for the qualitative detection of E6/E7 viral transcript mRNA from 14 hr HPV types in cervical smear samples. The hr HPV types detected by the assay are 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. Likewise, the Cobas 4800 test detects the same 14 hr HPV genotypes as the AHPV assay. However, while the Roche assay detects hr HPV DNA, the Aptima assay detects hr HPV oncogenic mRNA expression and is designed to be more specific in identifying clinically significant hr HPV infections that are likely to lead to high-grade squamous dysplasia and neoplasia.
In the model, two different scenarios were compared: scenario 1, AHPV versus HC2; and scenario 2, AHPV versus Cobas 4800. Although some of these HPV tests give, in addition to the overall result for all included hr HPV types (positive/negative), the partial result for HPV 16 and HPV 18. This partial result was not taken into account in this study. The current analysis only considers the overall result for all three HPV tests.
Clinical data
A literature review was conducted in Medline through PubMed to identify publications regarding the clinical evidence in this field and to extract the probabilities needed. The search strategy is shown in Appendix 1 and Appendix 2.
An initial selection of 1,408 localized references was performed by reading the title and abstract. Subsequently, 80 studies were considered relevant for this analysis and were selected and reviewed in full text. The probabilities of the different clinical data included in the analysis were obtained from the most relevant clinical studies. Among all publications, those studies that provided data from direct comparisons between the selected HPV tests were prioritized.
In this sense, the prevalence of HPV for base case was obtained from a transversal head-to-head study about HPV tests in a screening population [[iv]]. This study showed rates of 7.5%, 11.50% and 12.40% for AHPV, HC2 and Cobas 4800, respectively (Table 1).
Regarding the proportion of women with abnormal LBC after a positive HPV test result, several studies were identified [[v],[vi],[vii]]. These transition probabilities are shown in Table 1.
For the alternative case, the prevalence of women with abnormal LBC was 6.5% [25]. Other transition probabilities for the different nodes considered in the decision tree model for this subgroup of women from 25-34 years are shown in Table 1.
Costs
The analysis was carried out from the perspective of the Spanish National Health System (NHS); therefore, only direct health care costs were included, comprising HPV and diagnostic test costs (LBC, colposcopy, and biopsy costs). Figure 1 describes when and which of each of the health care resources were considered.
Unitary costs were obtained from the available scientific literature or regional public information [21,[viii],[ix]] and from a national database of health care costs [[x]]. All costs included in the model were expressed in euros for 2019, updating the costs obtained from the literature based on the Spanish general consumer price index, if needed [[xi]].
Table 1 shows the unitary costs of the direct health care resources included in the model.
Sensitivity analysis
Several univariate sensitivity analyses (SAs) were performed to incorporate the uncertainty into the analysis and to observe the effect of these modifications on the results. The following parameters were varied individually: 1) One-way SA was carried out considering a possible reduction in the women from 35-65 years of age who would attend their screening appointment, assuming that 36.3% of these women attended the CCS in private practice [23] and that 44.6% of first screening attendees used the public sector. In all cases, an organized CCS with an individual invitation to the target women was considered. 2) To represent a range for the most plausible results of the clinical data regarding women from 35-65 years with a positive HPV result, a univariate SA was performed with the studies showing the largest [16,[xii]] and smallest [[xiii],[xiv]] differences between the test considered in the analysis. 3) Finally, primary LBC, colposcopy and biopsy unitary costs were modified considering the alternative values identified in the literature [21,[xv]]. An additional scenario was performed with the upper and lower values of these health resources, obtained by applying the standard deviation (SD) to the mean value (Table 1).
[i] López de Argumedo González de Durana M, Bayón Yusta JC, Mateos del Pino M. Impacto de la implantación de un programa de cribado poblacional de cáncer de cérvix, siguiendo las recomendaciones europeas (prueba/intervalo) en relación a la situación actual. Ministerio de Sanidad, Servicios Sociales e Igualdad. Servicio de Evaluación de Tecnologías Sanitarias del País Vasco; 2016. Informes de Evaluación de Tecnologías Sanitarias: OSTEBA.
[ii] Instituto Nacional de Estadística. Proyecciones de población 2016-2066. Población residente en España a 1 de enero, por sexo, edad y año. En: INEbase [Internet]. Madrid: Instituto Nacional de Estadística; 2018. Available at: www.ine.es
[iii] Puig-Tintoré LM, Castellsagué X, Torné A, et al. Coverage and factors associated with cervical cancer screening: results from the AFRODITA study: a population-based survey in Spain. J Low Genit Tract Dis. 2008;12(2):82-9.
[iv] Cuzick J, Cadman L, Mesher D, et al. Comparing the performance of six human papillomavirus tests in a screening population. Br J Cancer. 2013;108(4):908-13.
[v] Granados R, Tellez-Safina H, Solis I, et al. Cervical cancer screening cotesting with cytology and MRNA HPV E6/E7 yields high rates of CIN2+ lesions in young women. Diagn Cytopathol. 2017;45(12):1065-1072.
[vi] Passamonti B, Gustinucci D, Giorgi Rossi P, et al. Cervical human papilloma virus (HPV) DNA primary screening test: Results of a population-based screening programme in central Italy. J Med Screen. 2017;24(3):153-162.
[vii] Gage JC, Katki HA, Schiffman M, et al. Age-stratified 5-year risks of cervical precancer among women with enrollment and newly detected HPV infection. Int J Cancer. 2015;136(7):1665-71.
[viii] Orly de Labry Lima A, Epstein D, García Mochón L, Ruiz Aragón J, Espín Balbino J. Análisis de coste-efectividad de la prueba de citología cervicovaginal. Prog Obstet Ginecol. 2012;55(7):304-11.
[ix] Resolución de la Dirección Gerencia del Hospital Universitario de Getafe, por la que se adjudica el contrato de suministros de citología líquida para el Hospital Universitario de Getafe. Hospital Universitario de Getafe; 2018.
[x] Oblikue Consulting. Base de datos de costes sanitarios eSalud [eSalud Health Cost database] [Internet]. Barcelona: Oblikue Consulting; 2019. Available at: http://www.oblikue.com/bddcostes/
[xi] Instituto Nacional de Estadística. Índices de Precios al Consumo [consulted January 2019]. Available at: http://www.ine.es/varipc/
[xii] Rebolj M, Preisler S, Ejegod DM, et al. Disagreement between human papillomavirus assays: an unexpected challenge for the choice of an assay in primary cervical screening. PLoS One. 2014;9(1):e86835.
[xiii] Cook DA, Smith LW, Law J, et al. Aptima HPV Assay versus Hybrid Capture(®) 2 HPV test for primary cervical cancer screening in the HPV FOCAL trial. J Clin Virol. 2017;87:23-29.
[xiv] White C, Reynolds S, Naik P, et al. HPV Primary Screening Pilot Study: molecular testing of potential triage strategies for HPV-positive women. Oral Abstract presented at The British Society for Colposcopy and Cervical Pathology, 2017 May 3-5, Cardiff, Wales.
[xv] Diaz M, de Sanjose S, Ortendahl J, et al. Cost-effectiveness of human papillomavirus vaccination and screening in Spain. Eur J Cancer. 2012;46(16):3973-85.