Cervical cancer screening in low- and middle-income countries: A systematic review of economic evaluation studies

Casas, Carmen Phang Romero; Albuquerque, Rita de Cassia Ribeiro de; Loureiro, Rafaela Borge; Gollner, Angela Maria; Freitas, Marina Goncalves de; Duque, Graciela Paula do Nascimento; Viscondi, Juliana Yukari Kodaira

doi:10.1016/j.clinsp.2022.100080

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Review articles • Clinics 77 • 2022 • https://doi.org/10.1016/j.clinsp.2022.100080 copy

Cervical cancer screening in low- and middle-income countries: A systematic review of economic evaluation studies

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Economic assessments are relevant to support the decision to incorporate more cost-effective strategies to reduce Cervical Cancer (CC) mortality. This systematic review analyzes the economic evaluation studies of CC prevention strategies (HPV DNA-based tests and conventional cytology) in low- and middle-income countries. Medline, EMBASE, CRD, and LILACS were searched for economic evaluation studies that reported cost and effectiveness measures of HPV DNA-based tests for CC screening and conventional cytology in women, without age, language, or publication date restrictions. Selection and data extraction were carried out independently. For comparability of results, cost-effectiveness measures were converted to international dollars (2019). Report quality was assessed using the CHEERS checklist. The Dominance Matrix Ranking (DRM) was used to analyze and interpret the results. The review included 15 studies from 12 countries, with cost-effectiveness analyzes from the health system’s perspective and a 3% discount rate. The strategies varied in age and frequency of screening. Most studies used the Markov analytical model, and the cost-benefit threshold was based on the per capita GDP of each country. The sensitivity analysis performed in most studies was deterministic. The completeness of the report was considered sufficient in most of the items evaluated by CHEERS. The Dominance Interpretation (DRM) varied; in 6 studies, the HPV test was dominant, 5 studies showed a weak dominance evaluating greater effectiveness of the HPV test at a higher cost, yet in 2 studies conventional cytology was dominant. Although the context-dependent nature of economic evaluations, this review points out the challenge of methodological standardization in the analytical models.

Keywords:
Economic evaluations; Cervical cancer; DNA tests for human papillomavirus

Highlights

Screening and early detection programs are a cornerstone of cervical cancer prevention.
Human papillomavirus DNA-based testing reduced the incidence of CC below per capita GDP.
Cost-effectiveness of HPV testing versus cytology in Low- and Middle-Income Countries.

Author, year	Country	Income classification (WB)	Study Type	Model	Perspective	Time horizon	Discount Rate	Population Age (years)	Index Test	Reference Test
Andrés-Gamboa (2008)	Colombia	Upper-middle	CEA	Markov decision model	Payer	Throughout life	3%	21‒69 (cytology) 30‒69 (HPV DNA)	HPV DNA	Cervical smear Pap smear
Beal (2014)	Mexico	Upper-middle	CEA, CA	Decision Tree Model	Healthcare system	3 to 5 years	5%	35–64	HPV DNA	Cervical smear Pap smear
Caetano (2006)	Brazil	Upper-middle	CEA	Decision Tree Model	Healthcare system	1 year	Without Information	25–59	HPV DNA	Cervical smear Pap smear
Campos (2015)	India, Nicaragua and Uganda	Lower-middle India and Nicaragua Low: Uganda	ACE, BIA	Microsimulation model	Health system and patient	Throughout life	3%	25–50	HPV DNA	Cervical smear Pap smear
Campos (2017)	Nicaragua	Medium-Low	CEA	Microsimulation model	Health system and patient	Throughout life	3%	30–59	HPV DNA	Cervical smear Pap smear
Flores (2011)	Mexico	Upper-middle	CEA	Decision Tree Model	Healthcare system	1 year	3%	20–80	HPV DNA	Cervical smear Pap smear
Goldie (2005)	South Africa, India, Peru, Kenya and Thailand	Upper-middle: South Africa, Peru and Thail and Lower-middle: India and Kenya	CEA	Markov decision model	Health system and patient	Throughout life	3%	1 × in life: 35 2 × in life: 35 and 40 3 × in life: 35, 40 and 45	Hybrid Capture II HPV test	Cervical smear Pap smear
Gutierrez-Delgado (2008)	Mexico	Upper-middle	CEA	Markov decision model	Payer	20years/intervention funding 100 years/health benefits	3%	25‒64 (cytology)	Hybrid Capture II HPV test 30‒69 (HPV DNA)	Cervical smear Pap smear
Levin (2010)	China	Upper-middle	CEA	Markov decision model	Health system and patient	Throughout life	3%	1 × in life: 35 2 × in life: 35 and 40 3 × in life: 35, 40 and 45	Hybrid Capture II HPV test and HPV DNA	Cervical smear Pap smear
Mandelblatt (2000).	Thailand	Upper-middle	CBA	Simulation model (Semi-Markov)	Health system and patient	Throughout life	3%	35–55	Hybrid Capture II HPV test	Cervical smear Pap smear
Nahvijou (2014)	Iran	Upper-middle	CMA	Decision Tree Model	Healthcare system	Without Information	Without Information	35 years	HPV DNA	Cervical smear Pap smear
Nahvijou (2016)	Iran	Upper-middle	CEA	Markov decision model	Healthcare system	Throughout life	3%	21–65	HPV DNA	Cervical smear Pap smear
Tantitamit (2015)	Thailand	Upper-middle	CEA	Decision Tree Model	Health system and patient	Without Information	Without Information	Without Information	Hybrid Capture II HPV test	Cervical smear Pap smear
Termrungruanglert (2017)	Thailand	Upper-middle	CEA	Markov decision model	Healthcare system	35 years	3%	35–65	HPV DNA with 16/18 genotyping	Cervical smear Pap smear
Termrungruanglert (2019)	Thailand	Upper-middle	ACE, BIA	Markov decision model	Healthcare system	10 years	3.5%	35–65	HPV DNA with 16/18 genotyping	Cervical smear Pap smear

Author (Year)	Compared tracking strategies	Effective Measures	Types of costs	Currency (year)	Cost-effectiveness combined result	Exchange into international dollar (2019)	Cost-effectiveness threshold	Sensitivity analysis	Parameters Analyzed
Andrés-Gamboa	No tracking/ Conventional cytology/ DNA-HPV test	Years of life saved	Direct medical costs	US Dollar (2006)	USD44/ YSL	Int$77.42	USD 3,200	Without Information	Performance and costs of screening tests, diagnosis, and treatment costs for HSIL
Beal (2014)	Conventional cytology compared to: HR-HPV plus Conventional cytology; HR-HPV plus molecular screening; Co-testing	Number of missed cases of CIN 2, CIN 3 or cervical cancer avoided	Direct medical and non-medical costs	USD (2013)	ICER: HR-HPV plus Conventional Cytology USD 108.99; HR-HPV plus molecular screening USD 819; Co-testing USD-537	HR-HPV plus Conventional Cytology: Int $197.23 HR-HPV plus Molecular Screening: Int$1,482.03 Co-testing: Int $971.74	Willingness-to-pay 0 to 3,000 USD	Probability/ Monte Carlo Simulation	-
Caetano (2006)	Conventional cytology/ Cytology in liquid medium/ CH-HPV test/ CH-HPV with self collection/ Conventional cytology with CH-HPV/ Cytology in liquid medium with CH-HPV	Number of detected cases of precursor lesions with a high degree of malignancy or cervical cancer	Direct medical costs	Brazilian Real BRL (2005)	BRL 1,404.36/ detected case of cancer or high-grade precursor lesion	Int$1,309.68	Without Information	Univariate Deterministics	Costs of Compared Strategies
Campos (2015)	HPV-DNA testing (provider-collected [cervical] and self-collected [vaginal] sampling), Visual inspection with acetic acid (VIA)/Conventional cytology Screening strategies included several scenarios, varying both age at onset and frequency throughout life: 1x in life (25, 30, 35, 40, 45 or 50 years); 2x in life (25 and 35; 30 and 40 or 35 and 45 years); 3x in life (25, 35 and 45 years; 30, 35 and 40 years; 35, 40 and 45 years; or 30, 40 and 50 years)	Years of life saved	Direct medical costs	International Dollar Int $ (2011)	DNA-HPV test (cervical sampling) India: 1 × ICER in life (40 years: Int$330/YLS; 45 years: Int$190/YLS); 2 × in life (35 and 45 years: Int$390/YLS); 3 × in life (30, 35 and 40 years: Int$1,600/YLS; 30, 40 and 50 years: Int$580/YLS)	India: 1 × in life (40 years Int$402.53; 45 years Int$231.76); 2 × in life (35 and 45 years Int $475.72); 3 × in life (30, 35 and 40 years Int$1,951.68; 30, 40 and 50 years Int $707.49)	Int$ 5,240 GDP per capita in India	Probability/ Monte Carlo Simulation	Prevalence of age-specific high-risk HPV and age-specific incidence of cancer
					Nicaragua: ICER 2 × in life (30 and 40 years: Int$50/YLS); 3 × in life (30, 35 and 40 years: Int$ 180/YLS, 25, 35 and 45 years: Int$ 1200/YLS)	Nicaragua: 2 × in life (30 and 40 years Int $58.27); 3 × in life (30, 35 and 40 years Int $209.77; 25, 35 and 45 years Int$1,398.45)	Int$ 4,220 GDP per capita in Nicaragua
					Uganda: ICER 1 × in life (35 years: Int$ 160/ YLS; 40 years: I $120/YLS); 2 × in life (30 and 40 years: Int$210/YLS); 3 × in life (30, 40 and 50 years: Int$350/YLS)	Uganda: 1 × in life (35 years Int$166.32; 40 years Int$124.74); 2 × in life (30 and 40 years Int$ 218.29); 3 × in life (30, 40 and 50 years Int$ 2,165.77)	Int$1,370 GDP per capita in Uganda
Campos (2017)	Conventional cytology w/3 years, with referral for colposcopy if ASCUS or worse result/ DNA-HPV test w/5 years, with referral for cryotherapy for HPV-positive eligible/ DNA-HPV test w/5 years, with referral for screening with visual inspection with acetic acid (VIA) for HPV-positive/ DNA-HPV test w/5 years, with referral to conventional cytology for HPV-positive	Years of life saved	Direct medical and non-medical costs	US Dollar U$ (2015)	USD320/ YLS	Int$ 969.36	USD 2,090 GDP per capita	Univariate Deterministics	Test performance, colposcopy performance, screening coverage, visit compliance, eligibility for cryotherapy after a positive screening and screening test, treatment effectiveness, discount rate, and costs
Flores (2011)	No screening/ Conventional cytology/ Self-collection DNA-HPV test/ DNA-HPV test administered by the doctor/ DNA-HPV test administered by the doctor plus Conventional cytology	Number of detected cases of high grade, cervical intraepithelial neoplasm or cervical cancer	Direct medical costs	US Dollar U$ (2008)	USD 9,352.00/ case detected	Int$ 21,581.07	Without Information	Univariate Deterministics	Performance and costs of screening tests and treatment costs
Goldie (2005)	Strategies vary according to the number of clinic visits, frequency of screening, and specific ages.	Years of life saved	Direct costs (medical and non-medical) and programme costs	International Dollar Int$ (2000)	Lifetime tracking (1, 2, 3 times, respectively) Costs/ YLS India = D; D; 24.32 Kenya = D; 70.15; 110.35 Turkey = 3.2; 9.54; 24.12 South Africa = 4.92; 11.52; 25.91 Thailand = 2.67; 4.86; 10.32	India: 3 × in life Int $37.58, Kenya: 2 × in life Int$197.22; 3 × in life Int$ 310.24 Peru: 1 × in life Int$ 5.47; 2 × in life Int$ 16.31; 3 × in life Int$41.24 South Africa: 1 × in life Int$5.30; 2x in life Int$ 12.40; 3 × in life Int$ 27.89 Thailand: 1 × in life Int$ 3.44; 2 × in life Int$6.26; 3 × in life Int$ 13.29	Int$2,330 GDP per capita in IndiaI Int$1,005 GDP per capita in Kenya Int$4,747 GDP per capita in Peru Int$9,486 GDP per capita in South Africa Int$6,373 GDP per capita in Thailand	Univariate Deterministics	Costs associated with invasive cancer treatment and target age of screening, while the choice between strategies was sensitive to test characteristics and screening costs.
Gutierrez-Del-gado (2008)	Strategies include 10 scenarios: 3 with screening by conventional Cytology, DNA-HPV Test (CH) or combined; and 7 with HPV vaccine	Years of life saved	Direct medical costs	Mexican Peso Mex$ (2006)	Conventional cytology by the Program, 80% coverage = ICER: Mex $16,678/YLS DNA-HPV w/3 years, 80% coverage = ICER: Mex$ 21,914/ YLS	Conventional cytology by the Program, 80% coverage: Int$3,078.93 DNA-HPV with 3 years, 80% coverage: Int$ 4,045.55	Mex$ 88,688 GDP per capita	Univariate Deterministics	The frequency and cost of tracking for the HC-HPV test and the discount rate
Levin (2010)	Conventional cytology/ DNA-HPV test (CH-HPV, Rapid HPV test)	Years of life saved, Number of cancer cases avoided	Direct costs (medical and non-medical) and programme costs	US Dollar U$ (2005)	$50/ YLS for a single lifetime screening using county-level HPV DNA rapid testing compared to no screening.	DNA-HPV rapid test 1 × in life: Int$ 140.65 2 × in life: Int$ 225.04 3 × in life: 421.95	USD 1,702GDP per capita	Univariate Deterministics	Costs associated with invasive cancer, treatment of precan-cerous lesions, and screening test costs.
Levin (2010)	The strategies varied according to age, screening frequency, number of clinic visits (1, 2 or 3) and service delivery configuration (city, county or national)	Years of life saved, Number of cancer cases avoided	Direct costs (medical and non-medical) and programme costs	US Dollar U$ (2005)	$80 and $150/ YLS two or three times in a lifetime, with the same strategy, respectively		USD 1,702GDP per capita	Univariate Deterministics
Mandelblatt (2002)	Strategies include 7 scenarios: 3 with screening per test: Conventional Cytology, VIA Test??, DNA-HPV Test and Combined Tests	Years of life saved	Direct medical and non-medical costs	US Dollar U$ (2000)	Incremental ratio ($/YL) All strategies saved lives, at costs ranging from $121 to $6,720/ YLS	Variation from Int$ 621.47 to Int$ 34,514.67	Without Information	Probability/ Monte Carlo Simulation	Individual parameters: sensitivity and test cost, prevalence rates; and parameter combinations: two-or three-way sensitivity analysis at reasonable intervals to examine the robustness of model results
Nahvijou (2014)	Conventional cytology/ DNA-HPV test with conventional cytology	Not applicable^a	Direct medical costs	International Dollar Int$ (2010)	Total cost/woman: Conventional cytology = $36.1; DNA-HPV Test USD 174.0	Conventional cytology: Int$ 18.84 DNA-HPV Test: Int$ 90.81	per capita GDP of the Without Information country	Without Information	Without Information
Nahvijou (2016)	11 screening strategies compared to no screening, varying both age at onset for Conventional cytology (21, 30, 35 years), for DNA-HPV Test (30, 35 years) and the interval between tests for Conventional cytology (3, 5, 10 years) for DNA-HPV Test (5, 10 years)	Life Years Saved, Quality Adjusted Life Years (QALY)	Direct medical costs	International Dollar Int$ (2013)	ICER $8,875/QALY compared to no tracking	Int$ 23,281.74	USD 6,631 GDP per capita	Univariate Deterministics	Performance and Costs of Tracking Tests
Tantitamit (2015)	Women Population with ASCUS results: Repeat conventional cytology/ Screening with DNA-HPV test/Immediate colposcopy	Number of CIN 2+ cases detected	Direct medical costs	Thai Baht ₿ (2013)	Health system: ICER = 56,048 THB/additional case of CIN 2+ detected Patient: ICER = 62,712 THB/ additional case of CIN 2+ detected	Health system: Int$ 4.62 Patient: Int$ 5.17	USD 6,168.30 GDP per capita	Univariate Deterministics	Tracking Strategies Costs
Termrungruanglert (2017)	DNA-HPV test with 16/18 genotyping, with referral for colposcopy if positive or return to routine screening within 5 years/ HR-HPV test w/5 years, colposcopy for women with positive result/ Conventional cytology, followed by colpos-copy if the result is ASCUS or worse	Number of detected cases of CIN 2, CIN 3 and cervical cancer per 100,000 women	Direct medical costs	Thai Baht ₿ (2016)	ICER test DNA-HPV with 16/18 genotyping: –360.810 THB (dominated) HR-HPV test: 41,075.1 THB/ Case detected Conventional cytology: -11,511.8 THB (dominated)	DNA-HPV test with 16/18 genotyping: Int $-29.51HR-HPV test: Int$ 3,358.97 Conventional cytology: Int$ -941.39	USD 5,904.20 GDP per capita	Univariate Deterministics	Prevalence of HPV infection in strategies 1 and 2, sensitivity of conventional cytology in strategy 3, discount rate and costs of all screening tools
Termrungruanglert (2019)	DNA-HPV test/double staining with 16/18 genotyping/ Conventional cytology	Number of pre-invasive and invasive cervical cancer cases identified quality-adjusted life years (QALY)	Direct medical costs	US Dollar U$ (2018)	ICER = USD1,395/QALY earned	Int$ 3,672.46	USD5,901 GDP per capita	Univariate Deterministics	Tracking Strategies Costs

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[1] *Corresponding author. E-mail address:carmen.romero@cdts.fiocruz.br (C.P.R. Casas).