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

Wichai Termrungruanglert; Nipon Khemapech; Tanitra Tantitamit; Piyalamporn Havanond

doi:10.3802/jgo.2019.30.e17

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

Original Article

J Gynecol Oncol 2019;30(2):e17.

Published online: 4 March 2019

DOI: https://doi.org/10.3802/jgo.2019.30.e17

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

Wichai Termrungruanglert^1,, Nipon Khemapech¹, Tanitra Tantitamit², Piyalamporn Havanond¹

¹Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

²Department of Obstetrics and Gynecology, Faculty of Medicine, Srinakharinwirot University, Nakhonnayok, Thailand

Correspondence to Wichai Termrungruanglert Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, 1873 Rama IV Road, Pathumwan, Bangkok 10330, Thailand. E-mail: wichaiterm@yahoo.com

Presentation This study has been presented in European Research Organisation on Genital Infection and Neoplasia (EUROGIN 2017) Congress during Oct 8–11, 2017 at Amsterdam

RAI Exhibition and Convention Centre, Amsterdam, Noord Holland, Netherlands.

Funding Funding for development of this article was partially provided by Roche Diagnostics (Thailand). The views expressed in this article are those of the authors and are not endorsed by the sponsor.

Conflict of Interest A grant for this study was partially provided by Roche Diagnostics (Thailand). The views expressed in this article are those of the authors and are not endorsed by the sponsor.

Received 3 July 2018 Revised 19 October 2018 Accepted 23 October 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.

Keywords: Cervical Cancer, Cost-Effectiveness Analysis, Cytology, Biomarkers, Cancer Screening, Human Papillomavirus DNA Tests

References

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Fig. 1.

A model of the patient flow through a cervical cancer screening. CIN, cervical intraepithelial neoplasia; FU, follow up; HPV, human papillomavirus.

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.

Fig. 3.

The prevalence of preinvasive cervical cancer, cervical cancer, and mortality rate from cancer. CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus.

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.

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