Journal List > J Gynecol Oncol > v.30(2) > 1148319

Termrungruanglert, Khemapech, Tantitamit, and Havanond: Cost effectiveness analysis of HPV primary screening and dual stain cytology triage compared with cervical cytology

Abstract

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.

References

1. Bruni L, Barrionuevo-Rosas L, Albero G, Serrano B, Mena M, Gómez D, et al. Human papillomavirus and related diseases in the world. Summary report [Internet]. Barcelona: ICO/IARC Information Centre on HPV and Cancer (HPV Information Centre);2017. July 27 [cited 2018 Jan 20]. Available from:. http://www.hpvcentre.net/statistics/reports/XWX.pdf.
2. Termrungruanglert W, Khemapech N, Tantitamit T, Sangrajrang S, Havanond P, Laowahutanont P. Cost-effectiveness analysis study of HPV testing as a primary cervical cancer screening in Thailand. Gynecol Oncol Rep. 2017; 22:58–63.
crossref
3. Ikenberg H, Bergeron C, Schmidt D, Griesser H, Alameda F, Angeloni C, et al. Screening for cervical cancer precursors with p16/Ki-67 dual-stained cytology: results of the PALMS study. J Natl Cancer Inst. 2013; 105:1550–7.
crossref
4. Wright TC Jr, Behrens CM, Ranger-Moore J, Rehm S, Sharma A, Stoler MH, et al. Triaging HPV-positive women with p16/Ki-67 dual-stained cytology: results from a sub-study nested into the ATHENA trial. Gynecol Oncol. 2017; 144:51–6.
crossref
5. Uijterwaal MH, Polman NJ, Witte BI, van Kemenade FJ, Rijkaart D, Berkhof J, et al. Triaging HPV-positive women with normal cytology by p16/Ki-67 dual-stained cytology testing: baseline and longitudinal data. Int J Cancer. 2015; 136:2361–8.
crossref
6. Wentzensen N, Fetterman B, Castle PE, Schiffman M, Wood SN, Stiemerling E, et al. p16/Ki-67 dual stain cytology for detection of cervical precancer in HPV-positive women. J Natl Cancer Inst. 2015; 107:djv257.
crossref
7. Ovestad IT, Dalen I, Hansen E, Loge JL, Dybdahl BM, Dirdal MB, et al. Clinical value of fully automated p16/Ki-67 dual staining in the triage of HPV-positive women in the Norwegian Cervical Cancer Screening Program. Cancer Cytopathol. 2017; 125:283–91.
crossref
8. World Bank Group. Population, total 2015 [Internet]. Washington, D.C.: World Bank Group;c2018. [cited 2018 Jan 8]. Available from:. http://data.worldbank.org/indicator/SP.POP.TOTL?view=chart.
9. Ministry of Public Health. Cervical cancer screening rate in women aged 30–60 years [Internet]. Muang Nonthaburi: Ministry of Public Health;c2018. [cited 2018 Jan 20]. Available from:. https://hdcservice.moph.go.th/hdc/reports/report.php?source=pformated/format1.php&cat_id=6966b0664b89805a484d7ac96c6edc48&id=4eab25b045dc0a9453d85c98dc2fdef0.
10. National Statistical Office; United Nations Children's Fund; Ministry of Public Health; National Health Security Office; Thai Health Promotion Foundation; International Health Policy Program. Thailand monitoring the situation of children and women: multiple indicator cluster survey 2012 [Internet]. Laksi Bangkok: National Statistical Office;c2013. [cited 2018 Jan 20]. Available from:. http://web.nso.go.th/en/survey/monitoring/data/monitoring_full_report_2012.pdf.
11. Schneider A, Hoyer H, Lotz B, Leistritza S, Kühne-Heid R, Nindl I, et al. Screening for high-grade cervical intraepithelial neoplasia and cancer by testing for high-risk HPV, routine cytology or colposcopy. Int J Cancer. 2000; 89:529–34.
crossref
12. Tantitamit T, Termrungruanglert W, Khemapech N, Havanond P. A model approach for assessing the benefits of HPV testing against cytology in screening for cervical cancer precursors in Thailand. Asian Pac J Cancer Prev. 2017; 18:1271–5.
13. Friedlander M, Grogan M. U.S. Preventative Services Task Force. Guidelines for the treatment of recurrent and metastatic cervical cancer. Oncologist. 2002; 7:342–7.
crossref
14. Mandelblatt JS, Lawrence WF, Womack SM, Jacobson D, Yi B, Hwang YT, et al. Benefits and costs of using HPV testing to screen for cervical cancer. JAMA. 2002; 287:2372–81.
crossref
15. United Nations, Department of Economic and Social Affairs, Population Division (UNPD). World population prospects: the 2015 revision, key findings and advance tables. New York, NY: United Nations;2015.
16. Wright TC Jr, Stoler MH, Sharma A, Zhang G, Behrens C, Wright TL, et al. Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV+ cytology-negative results. Am J Clin Pathol. 2011; 136:578–86.
crossref
17. Kulasingam SL, Benard S, Barnabas RV, Largeron N, Myers ER. Adding a quadrivalent human papillomavirus vaccine to the UK cervical cancer screening programme: a cost-effectiveness analysis. Cost Eff Resour Alloc. 2008; 6:4.
crossref
18. Myers ER, Green S, Lipkus I. Patient preferences for health states related to HPV infection: visual analog scales vs time trade-off elicitation. Proceedings of 21st International Papillomavirus Conference. 2004 Feb 20–27; Mexico City. International Papillomavirus Society;. 2004. Abstract 542.
19. Termrungruanglert W, Khemapech N, Havanond P, Pillsbury M, Shcheprov A, Numuang K, et al. Impact of vaccination: Health impact and cost-effectiveness to make informed policy decision on the introduction of human papillomavirus (HPV) vaccine to the national immunization Program (Nip) in Thailand. Value Health. 2014; 17:A737.
crossref
20. National Institute for Health and Care Excellence. NICE process and methods guides. Guide to the methods of technology appraisal 2013. London: National Institute for Health and Care Excellence;2013.
21. Ogilvie GS, van Niekerk D, Krajden M, Smith LW, Cook D, Gondara L, et al. Effect of screening with primary cervical HPV testing vs cytology testing on high-grade cervical intraepithelial neoplasia at 48 months: the HPV FOCAL randomized clinical trial. JAMA. 2018; 320:43–52.
crossref
22. Tjalma WA, Kim E, Vandeweyer K. The impact on women's health and the cervical cancer screening budget of primary HPV screening with dual-stain cytology triage in Belgium. Eur J Obstet Gynecol Reprod Biol. 2017; 212:171–81.
crossref
23. World Health Organization. Macroeconomic and health: investing in health for economic development: report for the commission on macroeconomics and health. Geneva: World Health Organization;2001.
24. Wright TC Jr, Stoler MH, Behrens CM, Apple R, Derion T, Wright TL. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol. 2012; 206:46. e1–11.
crossref
25. Cox JT, Castle PE, Behrens CM, Sharma A, Wright TC Jr, Cuzick J. Athena HPV Study Group. Comparison of cervical cancer screening strategies incorporating different combinations of cytology, HPV testing, and genotyping for HPV 16/18: results from the ATHENA HPV study. Am J Obstet Gynecol. 2013; 208:184. e1–11.
crossref
26. Luyten A, Scherbring S, Reinecke-Lüthge A, Braun BE, Pietralla M, Theiler K, et al. Risk-adapted primary HPV cervical cancer screening project in Wolfsburg, Germany–experience over 3 years. J Clin Virol. 2009; 46(Suppl 3):S5–10.
27. Petry KU, Menton S, Menton M, van Loenen-Frosch F, de Carvalho Gomes H, Holz B, et al. Inclusion of HPV testing in routine cervical cancer screening for women above 29 years in Germany: results for 8466 patients. Br J Cancer. 2003; 88:1570–7.
crossref
28. Klug SJ, Hukelmann M, Hollwitz B, Düzenli N, Schopp B, Petry KU, et al. Prevalence of human papillomavirus types in women screened by cytology in Germany. J Med Virol. 2007; 79:616–25.
crossref
29. Cuzick J, Myers O, Hunt WC, Saslow D, Castle PE, Kinney W, et al. Human papillomavirus testing 2007–2012: co-testing and triage utilization and impact on subsequent clinical management. Int J Cancer. 2015; 136:2854–63.
30. Smith JS, Lindsay L, Hoots B, Keys J, Franceschi S, Winer R, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer. 2007; 121:621–32.
crossref
31. World Bank Group. Death rate, crude (per 1,000 people) 2014 [Internet]. Washington, D.C.: World Bank Group;c2018. [cited 2018 Jan 20]. Available from:. http://data.worldbank.org/indicator/SP.DYN.CDRT.IN.
32. Chen T, Jansen L, Gondos A, Emrich K, Holleczek B, Luttmann S, et al. Survival of cervical cancer patients in Germany in the early 21st century: a period analysis by age, histology, and stage. Acta Oncol. 2012; 51:915–21.
crossref
33. Holowaty P, Miller AB, Rohan T, To T. Natural history of dysplasia of the uterine cervix. J Natl Cancer Inst. 1999; 91:252–8.
crossref
34. Insinga RP, Dasbach EJ, Elbasha EH. Epidemiologic natural history and clinical management of human papillomavirus (HPV) disease: a critical and systematic review of the literature in the development of an HPV dynamic transmission model. BMC Infect Dis. 2009; 9:119.
crossref
35. Insinga RP, Dasbach EJ, Elbasha EH, Liaw KL, Barr E. Progression and regression of incident cervical HPV 6, 11, 16 and 18 infections in young women. Infect Agent Cancer. 2007; 2:15.
crossref
36. Insinga RP, Perez G, Wheeler CM, Koutsky LA, Garland SM, Leodolter S, et al. Incident cervical HPV infections in young women: transition probabilities for CIN and infection clearance. Cancer Epidemiol Biomarkers Prev. 2011; 20:287–96.
crossref
37. Kataja V, Syrjänen K, Mäntyjärvi R, Väyrynen M, Syrjänen S, Saarikoski S, et al. Prospective follow-up of cervical HPV infections: life table analysis of histopathological, cytological and colposcopic data. Eur J Epidemiol. 1989; 5:1–7.
crossref
38. Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005; 97:1072–9.
crossref
39. Matsumoto K, Yasugi T, Oki A, Fujii T, Nagata C, Sekiya S, et al. IgG antibodies to HPV16, 52, 58 and 6 L1-capsids and spontaneous regression of cervical intraepithelial neoplasia. Cancer Lett. 2006; 231:309–13.
crossref
40. Bulkmans NW, Berkhof J, Bulk S, Bleeker MC, van Kemenade FJ, Rozendaal L, et al. High-risk HPV type-specific clearance rates in cervical screening. Br J Cancer. 2007; 96:1419–24.
crossref
41. Termrungruanglert W, Havanond P, Khemapech N, Lertmaharit S, Pongpanich S, Khorprasert C, et al. Cost and effectiveness evaluation of prophylactic HPV vaccine in developing countries. Value Health. 2012; 15:S29–34.
crossref
42. Lier D, Jacobs P. An economic analysis of the introduction of liquid-based cytology (LBC) and human papillomavirus (HPV) testing in Alberta [Internet]. Calgary: Alberta Cervical Cancer Screening Program;c2018. [cited 2018 Jan 20]. Available from:. https://www.albertahealthservices.ca/findhealth/service.
43. Termrungruanglert W, Havanond P, Khemapech N, Lertmaharit S, Pongpanich S, Jirakorbchaipong P, et al. Model for predicting the burden and cost of treatment in cervical cancer and HPV-related diseases in Thailand. Eur J Gynaecol Oncol. 2012; 33:391–4.

Fig. 1.
A model of the patient flow through a cervical cancer screening. CIN, cervical intraepithelial neoplasia; FU, follow up; HPV, human papillomavirus.
jgo-30-e17f1.tif
Fig. 2.
Screening model. (A) Cytology: screening with conventional cytology. (B) HPV/dual stain: HPV DNA test with genotyping 16&18 plus triage with p16/Ki-67 dual stain. ASCUS, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; ICC, invasive cervical cancer. * Women with negative colposcopy return to routine screening, women with CIN or ICC were referred to treatment.
jgo-30-e17f2.tif
Fig. 3.
The prevalence of preinvasive cervical cancer, cervical cancer, and mortality rate from cancer. CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus.
jgo-30-e17f3.tif
Table 1.
Data of HPV infection and cancer based on published reference
Clinical parameters Input value
The performance of screening test [24,25]  
 Cytology (threshold = ASCUS)  
 Sensitivity of cytology for CIN2 53.20%
 Sensitivity of cytology for CIN3 57.70%
 Sensitivity of cytology for ICC 57.70%
 Specificity of cytology 73.40%
HPV testing  
 Sensitivity of pooled hrHPV testing for CIN2 86.40%
 Sensitivity of pooled hrHPV testing for CIN3 89.90%
 Sensitivity of pooled hrHPV testing for ICC 89.90%
 Specificity of pooled hrHPV testing 62.70%
 Sensitivity of genotyping 16/18 for CIN2 43.60%
 Sensitivity of genotyping 16/18 for CIN3 53.40%
 Sensitivity of genotyping 16/18 for ICC 59.20%
 Specificity of genotyping 16/18 91.90%
Dual staining (pooled HPV triage)  
 Sensitivity for CIN2 86.80%
 Sensitivity for CIN3 89.80%
 Specificity for CIN2+ 71.40%
 Sensitivity for ICC 93.80%
Epidemiology data [11,24,26–31]  
 Prevalence of hrHPV 5.6%
 Prevalence of HPV16 and 18 1.7%
 Prevalence of CIN1 0.6%
 Prevalence of CIN2 0.3%
 Prevalence of CIN3 0.8%
 Prevalence of invasive cervical cancer 0.075%
 % of HSIL+ population that is HPV+ 88.4%
 % of LSIL population that is HPV+ 61.5%
 % of ASCUS population that is HPV+ 21.4%
 % CIN1 that are hrHPV 16/18 13.6%
 % CIN2 that are hrHPV 16/18 23.1%
 % CIN3 that are hrHPV 16/18 50.3%
 % of ICC that are hrHPV 16/18 75.0%
 General population annual death rate 0.800%
Natural history parameters  
 Progression [17,26,32–39]  
  Well to hrHPV infection 3.20%
  Transformation from hrHPV (12 types)  
   to CIN1 9.10%
   to CIN2 0.10%
   to CIN3 0.10%
  Transformation from hrHPV 16/18  
   to CIN1 7.30%
   to CIN2 2.20%
   to CIN3 2.00%
  Progression from CIN1  
   to CIN2 3.10%
   to CIN3 0.90%
  Progression from CIN2 (base case assumes CIN2 does not progress directly to ICC)  
   to CIN3 4.20%
   to ICC 0.00%
   CIN3 to ICC 4.50%
  Annual mortality rate for cervical cancer 8.30%
 Regression [32,35,39,40]  
  Regression from hrHPV (12 types) to.  
   with NORMAL smear to well 58.60%
   with BORDERLINE/MILD smear to well 45.60%
  Regression from hrHPV 16/18 to.  
   with NORMAL smear to well 43.80%
   with BORDERLINE/MILD smear to well 21.80%
  Regression from CIN1  
   to well 21.20%
   to hrHPV 2.40%
  Regression from CIN2  
   to well 9.40%
   to CIN1 9.40%
  Regression from CIN3  
   to well 3.80%
   to CIN1 1.60%

ASCUS, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; hrHPV, high-risk human papillomavirus; ICC, invasive cervical cancer.

Table 2.
Details of total direct medical costs
Cost parameters Input value (USD*)
Screening costs [41]  
 Office visit (routine/repeat screening) 2.00
 Cytology test (lab fee) 5.30
 Cytology test (professional fee) 3.00
 HPV DNA test 17.00
 P16/Ki-67 Dual staining 35.00
Diagnosis costs [41]  
 Office visit (diagnostic follow-up) 12.86
 Colposcopy plus biopsy 21.42
 CINtec® p16 Histology 25.37
Treatment costs [41–43]  
 Treatment for CIN2/CIN3 1,292.00
 Treatment for ICC 7,403.00
  • Stage IA1 1,206.29
  • Stage IA2–IIA 2,904.94
  • Stage IIB–IVA 163,334.63
  • Stage IVB 9,168.74
 End of life cancer treatment cost 10,019.00
Discounting rate [20]  
 Discount rate for cost 0.035
 Discount rate for health outcomes 0.035

CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; ICC, invasive cervical cancer.

* The currency used was US dollar (US Dollar exchange rate on May 3,2018; 1 USD = 35 THB);

The treatment for invasive cervical cancer cost was the weighted average of cervical cancer at different stages (stage I, 0.37; stage II, 0.19; stage III, 0.33; and stage IV, 0.11) [43].

Table 3.
Screening performance, cost, average QALY and ICER per QALY gained
Variables Cytology HPV/dual stain  
Screening performance based on colposcopy population      
 Number of screening cycles 20 20  
 Total colposcopy population (per screening cycle) 270,487 220,535 −18.5%
 False positive (per screening cycle) 249,800 194,562 −22.1%
 False negative (per screening cycle) 16,350 5,452 −66.7%
 Sensitivity (≥CIN2) 55.85% 82.65% 48.0%
 Specificity (≥CIN2) 95.48% 96.47% 1.0%
Screening performance and total number of cancer/precancer cases detected      
 Screening performance (%)      
  Cervical cancer detected 57.7% 88.9% 54.1%
  CIN3 detected 57.7% 85.2% 47.7%
  CIN2 detected 53.2% 79.2% 49.0%
 Total number of cancer/precancer cases detected      
  Cervical cancer detected 38,927 31,607 −18.81%
  CIN3 Detected 213,218 257,188 20.62%
  CIN2 Detected 161,582 230,669 42.76%
Total annual cost, average QALY and ICER per QALY gained      
 Total cost $771,325,070 $1,326,269,261  
 Annual cost $7,713,251 $13,262,693  
 Per person per year (over total screening population) $1 $2  
 Per member per year (over total population) $0 $0  
 Average QALY 23.98 24.03  
 ICER per QALY gained $1,395  

CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year.

TOOLS
Similar articles