Literature review
Epidemiology of cervical cancer
Human papillomavirus (HPV) is responsible for various tumors and cancers, with cervical cancer being the most prevalent among women While HPV is associated with oropharyngeal, anal, and vulvar cancers, these types are excluded from certain studies due to their multiple causes The proportion of these cancers linked to HPV varies, and although over 200 HPV genotypes exist, only a select few are known to cause cancer The International Agency for Research on Cancer (IARC) has identified 12 high-risk HPV types that are classified as carcinogenic to humans, including types 16 and 18.
HPV infections primarily occur through sexual contact, but the human immune system often clears the infection within one to two years, with many individuals becoming uninfected within five years Typically, HPV does not present symptoms, and clearance is more common among young adults However, persistent HPV infections can lead to cancer, particularly when high-risk types are involved alongside a high viral load The progression from HPV infection to cervical cancer can take 15 to 20 years in women with normal immune systems, while it may only take 5 to 10 years in those with weakened immune systems This long preclinical phase underscores the importance of cervical cancer screening for early detection, which has proven effective over the years Many women with HPV and precancerous conditions can recover and clear the infection following treatment.
Burden of cervical cancer in the world and Southeast Asia region
The Global Burden of Disease Study reported that in 2017, approximately 601,000 women were diagnosed with cervical cancer, leading to 260,000 deaths Although detected cases slightly decreased to 570,000 in 2018, deaths rose to 311,000, making cervical cancer the fourth most common cancer among women Globally, the lifetime risk of developing cervical cancer is estimated at 1 in 65 women, with significantly higher risks in low social-demographic index (SDI) countries, where the risk is 1 in 40, compared to 1 in 106 in high SDI countries.
In 2007, cervical cancer was a major cause of cancer-related deaths among women globally A decade later, it remains prevalent in 50 countries and continues to be the leading cause of cancer deaths for women in 39 countries Furthermore, the incidence and mortality rates of cervical cancer have risen by 19% since 2007.
In 2017, cervical cancer accounted for 7.3% of global cancer cases, making it the third leading cause of cancer-related deaths, with a 15% increase in Disability-Adjusted Life Years (DALYs) lost According to the Global Cancer Observatory, the incidence of cervical cancer was projected to rank fourth in 2020.
Figure 1.1: Estimated number of new cases in 2020, females, all ages - Source: GLOBOCAN 2020 - Graph production:
Global Cancer Observation Retrieved from: https://gco.iarc.fr/today
Recent data highlights disparities in the incidence and mortality rates of cervical cancer between high-income and lower middle-income countries, primarily attributed to the availability of HPV vaccination and screening programs in the former.
Figure 1.2: Estimated number of new cases in 2020, High income (left) and Low middle income (right), females, all ages
- Source: GLOBOCAN 2020 - Graph production: Global Cancer Observation Retrieved from: https://gco.iarc.fr/today
In 2008, cervical cancer was the leading cause of cancer-related deaths among women in Southeast Asia, and a decade later, it remained a significant public health issue, ranking second in morbidity and mortality across all ages in the region In contrast, western Asia reported the lowest incidence rates, with fewer than 5 cases per 100,000 women The high prevalence of HIV among individuals aged 15 to 49 in Southeast Asia may contribute to the stark differences in cervical cancer rates between these subregions.
Burden of cervical cancer in Viet Nam
In Vietnam, cervical cancer was the fifth most common cancer and the seventh leading cause of cancer-related deaths in 2017 Recent estimates from the International Agency for Research on Cancer indicate a concerning prevalence of cervical cancer in the country from 2020 onwards.
Figure 1.3: Estimate number of prevalent cases - Source: GLOBOCAN 2020 - Graph production: Global Cancer
Observation Retrieved from: https://gco.iarc.fr/today
A literature review by Lam Duc Tam reveals significant variations in HPV infection rates across provinces, with Thua Thien Hue reporting the lowest at 0.9% and Ho Chi Minh City the highest at 19.97% Additionally, research by Arbyn et al indicates that cervical cancer ranks among the top three cancers affecting women under 45 in 176 countries, including Vietnam, largely due to the high percentage of women aged 30 and older.
A study conducted by Tran Kim Ngoc and colleagues revealed a significant rise in cervical cancer incidence in Vietnam, particularly among women aged 30 to 34, peaking in the 55 to 59 age group before gradually declining in older demographics This trend highlights the impact of HPV infection, which has been documented in various provinces across the country.
Between 1999 and 2017, the age-specific incidence rates of cervical cancer among women in Vietnam were documented, with rates expressed per 100,000 women This data, sourced from the Institute for Health Metrics and Evaluation, is derived from the Global Burden of Disease Study 2017 results and has been age-adjusted using the Vietnamese female population figures from both 1999 and 2017.
The cost of cervical cancer treatment varies by country and is often high, with late detection significantly reducing survival rates The global 5-year survival rate for cervical cancer ranges from below 40% to over 70%, largely influenced by the availability of HPV vaccination and screening programs Low- and middle-income countries (LMIC) experience notably lower survival rates due to the rarity of early detection, which is crucial for curing invasive cervical cancer Without the implementation of effective intervention programs, cervical cancer is poised to remain a significant public health challenge in Vietnam in the coming decades.
Strategy to eliminate cervical cancer in the world and Viet Nam
Global studies have shown that the HPV vaccine is effective for girls, while cervical screening is crucial for women's primary prevention The World Health Organization (WHO) recommends three key actions to eliminate cervical cancer: vaccinating girls before the age of 15, screening women with a high-performance test by age 35 and again by age 45, and providing treatment for women with precancerous conditions as well as managing those with invasive cancer.
High-income countries in the EU, USA, Canada, and Australia have implemented national strategies aimed at achieving and maintaining a target of fewer than four cases of cervical cancer per 100,000 women These strategies include comprehensive prevention programs that cover HPV vaccination for girls prior to the onset of sexual activity, as well as cervical cancer screening for women aged 25 and older, including those who have already been immunized.
In the United States, cervical cancer screening recommendations vary among institutions, but generally, women aged 21 to 65 should undergo screening at intervals of 3 to 5 years, depending on the testing method Women between 21 and 29 years old are advised to have cytology screenings every three years, while those aged 30 to 65 should prefer co-testing every five years Additionally, co-testing can be initiated for women starting at age 25.
(27) Besides common screening methods, the US Preventive Services Task Force
2012 recommended co-testing as a primary method for the 30-65 women age group
In Europe, cervical cytology and HPV testing are the primary methods for national screening strategies, with some countries adopting HPV testing as the main screening approach in line with European guidelines The target demographic for these screenings includes women aged 30 or 35 to 65 years Meanwhile, Australia has updated its National Cervical Screening Program, transitioning from biennial cytology screenings for women aged 20 to 65 to a five-year HPV testing protocol for women aged 25 to 74.
Low- and middle-income countries (LMIC) encounter significant challenges in establishing cervical screening programs due to socioeconomic factors and limited resources, despite cervical cancer being a leading cause of death among women High-income nations are able to implement HPV vaccination programs for pre-adolescent girls prior to the onset of sexual activity, largely due to the high costs associated with the HPV vaccine Without international assistance, LMICs struggle with budget constraints that hinder their ability to meet vaccination needs In Vietnam, research conducted by Hoang et al assessed the cost-effectiveness of HPV vaccines, Cervarix and Gardasil, for pre-adolescent girls, revealing important insights into the economic viability of vaccination efforts.
HUPH vaccination against HPV would be cost-effective only if Vietnam could negotiate the price of vaccine at 4.55 USD per dose However, with the actual vaccine price in
In 2017, the cost per Disability-Adjusted Life Year (DALY) averted was $8000, highlighting the need for cost-effective strategies in low- and middle-income countries (LMIC) Many authors advocate for cervical cancer screening in these regions due to its high cost-effectiveness A literature review indicates that a one-time cervical screening for women aged 35 and older can significantly reduce cervical cancer prevalence, especially in the absence of HPV vaccination Scientific studies confirm that early cervical cancer screening can lower morbidity and mortality rates for decades to come However, the search for an appropriate screening method in LMIC continues, hampered by inadequate facilities and resource shortages.
In Vietnam, the Ministry of Health (MOH) approved a national action plan for cervical cancer prevention and control for 2016-2025, along with guidelines established in 2019 This plan is funded through international aid and other sources, as cervical screening and vaccination are not covered by the national health insurance program The guidelines outline six screening pathways for women aged 21 to 65, including cervical cytology, HPV testing, and colposcopy, with co-testing allowing for extended screening intervals of 5 years compared to the 2- or 3-year intervals of other methods However, the lack of public budget coverage means that out-of-pocket payments can hinder access to cervical cancer screening.
Since its introduction in Vietnam in 2009, the HPV vaccine has not been included in the national vaccination program With support from the Bill & Melinda Gates Foundation, 6,358 girls received three doses of the vaccine in two provinces However, there is currently no data available on the number of girls who have voluntarily chosen to receive the HPV vaccine.
The HPV vaccine is priced at approximately 46 USD, but the total cost for three doses can be at least three times higher Furthermore, women of childbearing age show a low willingness to pay for the HPV vaccine for their children upon learning its actual price.
Figure 1.5: the proportion of nonvaccinated women willing to receive the HPV vaccine before and after knowing its price
As of now, there are no published reports on the national action plan for the prevention and control of cervical cancer, and studies on the percentage of Vietnamese women undergoing cervical cancer screening or their preferred screening methods are lacking The current practices of cervical cancer screening among Vietnamese women remain unclear The national action plan aims to achieve a screening rate of 60 percent for women aged 30 to 54 by 2025, suggesting that currently, only about 30 percent of the targeted women are being screened.
In 2021, the cost of HPV testing is generally higher than that of colposcopy and cervical cytology As a result, women may opt for the more affordable cytology method for cervical screening, especially considering the lower effectiveness of colposcopy in the early detection of cervical cancer.
Cervical screening methods
Cervical cancer screening commonly utilizes cervical cytology, colposcopy, and HPV testing, which can be employed individually or in combination Typically, HPV testing is paired with cervical cytology (co-testing) or colposcopy Cervical cytology is the original method used for screening cervical cancer, and it involves two processes for specimen preparation.
Cervical cytology can be performed using conventional smear (Pap smear) or liquid-based cytology (LBC), with results interpreted according to the 2014 Bethesda system The Colposcopy method, which utilizes acetic acid or Lugol’s iodine for cervix inspection, categorizes results as negative or positive; however, it is not recommended as a primary cervical screening method due to its low effectiveness in detecting early HPV infection symptoms Instead of identifying cervical cancer or abnormal cells, the HPV test focuses on detecting high-risk HPV types in women through cell samples Screening strategies for cervical cancer vary among countries based on their financial capabilities to ensure early detection and prevention.
Cervical cytology has long been recognized as a primary global screening method, but due to inadequate healthcare facilities, colposcopy has emerged as a viable alternative Liquid-based cytology (LBC) represents an advanced form of cervical cytology, demonstrating significantly higher efficacy in detecting squamous cell carcinoma recurrence compared to the traditional Pap smear Over the past two decades, the shift towards HPV testing has highlighted its importance in screening and post-treatment follow-up, leading to increased HPV vaccination coverage However, the prevalence of lesions in vaccinated populations may reduce the sensitivity and positive predictive value of cytology Unlike morphological assessments, HPV tests focus on identifying genomic types to pinpoint patients at risk for cervical cancer Nonetheless, existing HPV tests can produce a considerable number of false positives, potentially resulting in unnecessary treatments for healthy women, which can undermine screening program outcomes without proper cytology triage Recent studies indicate that co-testing is more cost-effective than using cervical cytology or HPV testing alone, as it reduces screening cycles throughout women's lifespans while maintaining high detection rates for cervical cancer.
Target age group and screening interval
Cervical cancer screening age recommendations vary by country, typically ranging from 20 or 25 to 60 or 65 years in high-income nations The screening frequency is generally every two to three years for cytology and every five years for HPV testing or co-testing The World Health Organization advises that women in low- and middle-income countries (LMIC) should undergo screening at least twice by the age of 35.
The WHO recommends that cervical cancer screening programs target women aged 30 to 60, initiating screenings five years before the age at which cervical cancer incidence begins to rise Additionally, the HPV vaccine plays a crucial role in the prevention and management of cervical cancer, highlighting the importance of comprehensive healthcare strategies over the past 45 years.
Women in high-income countries can undergo cervical cancer screening every three to five years as per their national programs, while low- and middle-income countries (LMIC) face financial and resource limitations that hinder similar strategies The World Health Organization recommends that women aged 35-54 in LMICs with a sufficient screening history and no abnormal results may discontinue screening due to a low risk of HPV infection An adequate screening history is characterized by three consecutive negative cytology results or two negative co-testing results within the last ten years, with the latest test conducted within the past five years.
In addition, there is limited evidence about the optimal age when to stop screening
The recommended age for cervical screening in each country should be determined by its specific incidence of cervical cancer, taking into account the experiences of other countries that have implemented similar screening programs.
A 2016 National Survey on Reproductive and Sexual Health revealed that Vietnamese youth engage in their first sexual intercourse at an average age of 18.7 years, with a concerning lack of knowledge about safe sex practices Additionally, research by Tran Kim Ngoc et al highlights the age-specific incidence rates of cervical cancer in Vietnam from 1999 to 2017, indicating a significant public health concern.
HUPH rate began to rise in the 30-35 age group and reached the highest number in the 55-
The Ministry of Health (MOH) guidelines recommend cervical cancer screening for women aged 21 to 65, prioritizing those at risk between 30 and 50 years old This research proposes an optimal screening age of 25 to 55 years to facilitate early diagnosis and treatment Co-testing, which combines cervical cytology and HPV testing, has proven to be more cost-effective than using either method alone, allowing for extended screening intervals from 3 to 5 years Following MOH and WHO recommendations, the researcher aims to develop a study involving 1,000 women aged 25 to 55, conducting screenings every five years over a 30-year period.
Cost-effectiveness analysis of co-testing for cervical cancer screening
A review of 82 articles published in the PubMed database from 2011 to December 2021 highlights the efficacy and effectiveness of the co-testing method for cervical cancer detection, with 13 studies assessing its cost-effectiveness compared to other interventions Among these, six studies employed the Markov model for evaluation, although the use of lifetime cycles was not clearly specified, and only one study utilized monthly cycles, suggesting that most authors likely adopted 1-year cycles In addition to the Markov model, various methodologies such as the "Policy1-Cervix" model, decision trees, the FOCAL trial, retrospective cohort studies, and budget impact analyses were identified in research from countries including China, Thailand, Canada, the USA, and Germany.
The epidemiological development of cervical cancer is characterized by seven distinct health states: (i) HPV negative (HPV -), (ii) high-risk HPV infection (HPV hr+), (iii) mild cervical intraepithelial neoplasia (CIN 1), (iv) moderate cervical intraepithelial neoplasia (CIN 2), (v) cervical intraepithelial neoplasia or carcinoma in situ (CIN 3), (vi) cervical cancer (CC), and (vii) death.
In Vietnam, research on the cost-effectiveness of cervical cytology is limited, with only two studies conducted—one by Suba et al in 2001 and another by Kim et al in 2008 Suba et al identified cervical cytology as the optimal screening method at the time, primarily due to the lack of alternative screening options However, their study's comparison of pap smear to no screening may not be as relevant for current policymakers and users Conversely, Kim et al focused on the cost-effectiveness of HPV vaccination combined with cervical screening every five years, finding it cost-effective if the vaccination cost per girl is below 25 USD Currently, there is a scarcity of studies evaluating the cost-effectiveness of cervical screening methods in Vietnam, particularly regarding newer tools like co-testing A comparative analysis of co-testing and cervical cytology could provide valuable insights for selecting the most effective primary screening method for cervical cancer in Vietnam.
Research conceptual framework
In 2019, Vietnam introduced six cervical cancer screening options for women aged 21 to 65, but the absence of a recommended cost-effective primary screening method may result in inefficient resource use Given the scarcity of healthcare resources, prioritizing an efficient screening approach is essential This concept underpins health economics, prompting the researcher to explore cost-effectiveness in cervical cancer screening.
HUPH analysis of cervical cancer screening for women aged 25 to 55 years old in Viet Nam The conceptual framework for my study is outlined in the graph below
Figure 1.6: The conceptual framework of the study
+ Quality adjusted life years + Mortality
HPV (-), HPV hr(+), CIN1/2/3, Cervical cancer
+ Literature review + Secondary data + Expert consultation
Research methodology
Research methodology for the objective 1
Research articles or reports that satisfied the following criteria were selected for literature review:
- Types of studies: CEA study
- Participants: Women aged 25 to 55 years old
- Full text report written by English and Vietnamese
Research articles published between 2011 and December 2021 were sourced from various bibliographic databases, including the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Gynecological Cancer Collaborative Review Group (CGCG) trial register, PubMed, and Web of Science Additionally, unpublished or grey literature was examined, adhering to specific inclusion criteria from doctoral and master's theses available in the libraries of universities in Sweden and Hanoi University of Public Health in Vietnam.
The search query in bibliographic databases utilized terms such as "cost effectiveness analysis" (CEA) and "cervical cancer" or "cervical intraepithelial neoplasia" (CIN), along with keywords related to screening and co-testing After eliminating duplicates, the selected studies were assessed for quality using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement Subsequently, eligible papers were compiled into a summary table (annex 5), which included details such as publication year, methodology, model, objectives, target population, perspective, willingness to pay, cycle and time horizon, discount rates, interventions, comparators, sources of input parameters, and results.
Research methodology for the objective 2
- Cost – effectiveness analysis: May 2022 – July 2022
As mentioned in the previous part, the incidence of cervical cancer in Viet Nam increased rapidly by age from women 30 to 34 years old and peaked in the 55 –
59 age group before decreasing gradually in older age groups The development of
Cervical cancer (CC) typically develops after a prolonged period following HPV infection, while the average age of first sexual initiation among Vietnamese youth is 18.7 years Consequently, this research focuses on women aged 25 to 55, who are at a heightened risk for cervical cancer due to insufficient HPV vaccination coverage and the absence of reimbursement from Vietnam's national health insurance.
The co-testing method has demonstrated greater cost-effectiveness compared to traditional cytology and HPV tests for routine cervical cancer (CC) screening, particularly until women reach a certain age limit However, low- and middle-income countries (LMICs) face challenges in implementing routine CC screening due to resource constraints The World Health Organization (WHO) and previous studies suggest that conducting at least three consecutive CC screenings is a viable strategy for women in LMICs This research aims to evaluate the cost-effectiveness of the co-testing method within the context of Vietnam, comparing it to the cytology method, which has been recognized for its cost-effectiveness for over a decade Utilizing a Markov model, the study will analyze cervical cancer screening strategies for Vietnamese women aged 25 to 55, focusing on three consecutive screenings with a five-year interval for the co-testing method versus five screenings with a two-year interval for the cytology method.
- The 25-29 group was screen at the age of 25, 30 and 35 by the co-testing method, and at the age of 25, 27, 29, 31, 33 by the cytology method
- The 30-34 group was screen at the age of 30, 35 and 40 by the co-testing method, and at the age of 30, 32, 34, 36, 37 by the cytology method
As mentioned in the chapter 1, most of CEA study on co-testing method used the Markov model for their evaluation The model was built based on natural
The epidemiology of cervical cancer (CC) development was examined through a review of medical literature and findings from randomized control trials and retrospective cohort studies Consequently, the researcher opted to employ a Markov model for the cost-effectiveness analysis (CEA) study Additionally, consultations with clinical experts and various natural history models of high-risk HPV infections leading to oncogenesis were conducted for adjustments Other models exhibited similar health states, and four clinical experts provided no objections to the proposed Markov model, although they recommended incorporating information regarding ASC-US, HSIL, and LSIL results from cytology tests Following the Ministry of Health's treatment guidelines, women with ASC results were considered for further analysis.
The US follows a similar follow-up pathway for HPV positive women, where those with LSIL and HSIL results are treated as CIN 1 and CIN 2/3, respectively Consequently, there was no need to modify the Markov model, which is based on the work of Felix, J C et al.
In 2016, a simulation was conducted to model the natural progression of HPV infection over one-year cycles, focusing on the cost-effectiveness of cervical screening using the co-testing method in comparison to the cytology method.
The Markov model operates under several key assumptions: it considers 1,000 undiagnosed women aged 25-55, all of whom are engaging in sexual behavior and have not been diagnosed with CIN 1/2/3 or cervical cancer (CC), and will undergo cervical cancer screening through co-testing and cytology methods Additionally, none of the participants have received HPV vaccinations or undergone hysterectomy, and all are expected to participate in screening programs Furthermore, it is assumed that 100 percent of detected cases, including HPV positive, CIN1, CIN2, CIN3, and CC, will receive appropriate treatment Health outcomes are measured using QALY weights, and the Markov model is structured around health states informed by the history of natural HPV infection.
In the progression of cervical health, individuals may experience various states: State A indicates an HPV negative status (HPV -), while State B signifies a high-risk HPV infection (HPV +) Progressing to State C, mild cervical intraepithelial neoplasia (CIN 1) may develop, followed by State D, which represents moderate cervical intraepithelial neoplasia (CIN 2) State E is characterized by cervical intraepithelial neoplasia or carcinoma in situ (CIN 3), leading to State F, where cervical cancer (CC) is present Ultimately, State G denotes death, with this progression occurring over a cycle of one year.
Figure 2.1: Markov model of Felix, J C et al (2016)
The study assesses the cost-effectiveness of cervical cancer (CC) screening for Vietnamese women aged 25 to 55 by comparing co-testing with the traditional cytology method over a 30-year period The target group will undergo cervical screening three times using the co-testing method at five-year intervals, while the alternative method will involve five screenings every two years A Microsoft Excel template is utilized to conduct the simulation and calculate the incremental cost-effectiveness ratio (ICER).
Following the initial screening, women were categorized into four conditions based on test performance, identifying true/false negatives and true/false positives for HPV cases They were then divided into two subgroups: detected and undetected As highlighted in the literature review, women with HPV infections and precancerous conditions (CIN1/2/3) often experience recovery and significant clearance of the infection post-treatment Consequently, undetected women across all health states continued to follow the natural history of HPV development.
Death from CC and other causes*
*Patients can enter all-cause death state from any of the health states
Cervical cancer progression from state A to state F follows a normal trajectory, with women detected through screening receiving treatment and adhering to standard progression and regression transition probabilities In accordance with Ministry of Health guidelines, false positive HPV cases undergo triage tests twice within a year Women screened using the co-testing method will be re-screened with co-testing, while those screened via the cytology method will be re-evaluated with an HPV test.
2.2.5 Time horizon, cycle length and analytical perspective:
The study involved a cohort of 1,000 women aged 25, monitored annually until they reached the maximum screening age Due to time constraints, the researcher utilized a provider perspective for the cost-effectiveness analysis.
After adjusting all costs for inflation to the year 2021 and applying a discount rate of 3% for Vietnam, an Incremental Cost-Effectiveness Ratio (ICER) is calculated to assess the efficiency of the co-testing method compared to the cytology method The ICER represents the ratio of the additional costs incurred by using the co-testing method to the Quality-Adjusted Life Years (QALYs) gained According to WHO recommendations, an ICER below 1 to 3 times the GDP per capita indicates that the evaluated method may be considered cost-effective In 2020, the World Bank reported Vietnam's GDP per capita as 2,785.7 USD.
The exchange rate for converting VND to USD was set at 22,860 VND per USD by Vietcombank Consequently, the GDP per person is calculated to be 63.68 million VND, equivalent to 2,786 USD, while three times the GDP per person amounts to 191.04 million VND, or 8,357 USD.
2.2.7 Input parameter and data sources:
The input parameters identified through a literature review and secondary data were validated and refined through consultations with experts The researcher conducted interviews with a cancer specialist, reproductive health experts, and an additional authority in the field.
HUPH finance and national health insurance collaborated with cancer and reproductive health specialists to enhance understanding of cervical cancer development, patient QALY weights across various health states, and transition probabilities between these states They also evaluated the specificity and sensitivity of cervical cancer screening methods and treatment scenarios using the Markov model Additionally, the financial team assisted researchers in updating treatment costs in line with the latest Ministry of Health regulations.
Ethical issues
The research proposal received approval from the Ethical Committee of Hanoi University of Public Health Participants were informed about the study's objectives and had the right to consent or decline participation This study utilized existing databases without any clinical intervention, ensuring that the customs and habits of participants were not affected No personally identifiable information was used or shared in the research report All participant information was collected and stored in accordance with confidentiality guidelines, being used solely for research purposes.
2022, the ethical issues of the study were approved and accepted by the Ethical Committee of Hanoi University of Public health following the letter no 154/2022/YTCC-HD3 (Annex 8)
Results
The literature review of cost-effectiveness studies of cervical cancer screening for
screening for women by the co-testing method
A comprehensive search of bibliographic databases, including The Cochrane Central Register of Controlled Trials, The Cochrane Gynecological Cancer Collaborative Review Group trial register, PubMed, and Web of Science, yielded 82 articles on the efficacy and cost-effectiveness of the co-testing method for cervical cancer detection from 2011 to December 2021 After applying selection criteria, 13 studies were included in the literature review, with 11 focusing on cost-effectiveness analysis of the co-testing method in cervical screening programs Additionally, two studies that combined budget impact and cost-effectiveness analysis were also included Studies that were observational or randomized control trials without a cost-effectiveness analysis were excluded Due to the lack of studies targeting the proposed screening age of 25-55, those with broader age intervals were selected A summary of the selected studies is provided in Table 1, with detailed information in Annex 5.
Figure 3.1 PRISMA diagram for literature reviews
Thirteen studies were conducted across various countries, including the Netherlands, USA, Ireland, Korea, Germany, Greece, British Columbia, Canada, Australia, and China, to evaluate the cost-effectiveness of cervical cancer interventions Among these, seven articles utilized Cost-Effectiveness Analysis (CEA) with Markov modeling, while the remaining six employed the “Policy1-Cervix” platform, the MISCAN-Cervix model, decision tree modeling, prospective trials, retrospective cohort studies, or a combination of Markov and decision tree models Although some researchers did not clearly specify their costing perspective, it is generally assumed that most studies adopted the payer perspective for measuring direct medical costs associated with cervical screening algorithms, with only two studies applying a societal perspective in their cost analysis.
12) Records removed due to unable access to full text (n = 20)
Not written in English (n = 2) Randomized control trial studies (n = 5)
Identification of studies via databases
Ident if ica ti o n Scre en ing Incl ud ed
Records excluded due to not analysis cost-effectiveness of co- testing (n = 32)
Reports not retrieved due to analysis of clinical benefits (n = 27)
To conclude, a majority of records applied the Markov model for their decision model under the provider perspective to inform recommendations for policy makers
Table 3.1: List of selected studies
No Article Authors Published year
1 Cost- effectiveness analysis of primary human papillomavirus testing in cervical cancer screening:
Results from the HPV FOCAL Trial
2 Health economic evaluation of primary human papillomavirus screening in urban populations in
3 Economic evaluation of HPV DNA test as primary screening method for cervical cancer: A health policy discussion in Greece
4 Screening capacity and cost-effectiveness of the human papillomavirus test versus cervicography as an adjunctive test to Pap cytology to detect high- grade cervical dysplasia
5 Primary HPV testing versus cytology-based cervical screening in women in Australia vaccinated for HPV and unvaccinated: effectiveness and economic assessment for the
Jie-Bin Lew et al,
6 The budget impact of cervical cancer screening using HPV primary screening
7 A model to evaluate the costs and clinical effectiveness of human papilloma virus screening compared with annual Papanicolaou cytology in
Karl Ulrich Petry et al,
8 Optimal Cervical Cancer Screening in Women
9 The Clinical and Economic Benefits of Co-Testing
Versus Primary HPV Testing for Cervical Cancer
10 Cervical Cancer Screening in Partly HPV
11 Cost Effectiveness of Human Papillomavirus-
16/18 Genotyping in Cervical Cancer Screening
12 Long-term costs of introducing HPV-DNA post- treatment surveillance to national cervical cancer screening in Ireland
13 Screening for Cervical Cancer: A Modeling Study for the US Preventive Services Task Force
Five out of thirteen studies on cervical cancer screening strategies were conducted in the United States, generally modeling a theoretical cohort of women aged 25 or 30 over a 40-year period, regardless of HPV vaccination status Notably, Shalini L Kulasingam et al developed a Markov model that tracked women from ages 12 to 100, aligning with the US Preventive Services Task Force recommendations Additionally, only one study by Jane J Kim et al examined screening strategy differences in a vaccinated cohort starting at ages 25 or 30 Other research from the Netherlands, Ireland, Germany, Greece, British Columbia, Canada, and the US focused on cohorts aged 25 to 65.
Research from Australia and China reveals notable differences in HPV screening practices The Australian study examined a cohort aged 10 to 84 years, while the Chinese study focused exclusively on unvaccinated women, as there is no HPV vaccination program in place in China The age range for screening intervals varied across studies, typically starting at 25 years and ending at 65 years However, some studies suggest that offering screening services to women over 65 may not provide significant benefits.
Table 3.2: Cervical cancer screening age interval
No Article Country Starting age
1 Cost- effectiveness analysis of primary human papillomavirus testing in cervical cancer screening:
Results from the HPV FOCAL Trial
2 Health economic evaluation of primary human papillomavirus screening in urban populations in
3 Economic evaluation of HPV DNA test as primary screening method for cervical cancer: A health policy discussion in Greece
4 Screening capacity and cost-effectiveness of the human papillomavirus test versus cervicography as an adjunctive test to Pap cytology to detect high- grade cervical dysplasia
5 Primary HPV testing versus cytology-based cervical screening in women in Australia vaccinated for HPV and unvaccinated:
No Article Country Starting age
Finished age effectiveness and economic assessment for the
6 The budget impact of cervical cancer screening using HPV primary screening
7 A model to evaluate the costs and clinical effectiveness of human papilloma virus screening compared with annual Papanicolaou cytology in
8 Optimal Cervical Cancer Screening in Women
9 The Clinical and Economic Benefits of Co-Testing
Versus Primary HPV Testing for Cervical Cancer
10 Cervical Cancer Screening in Partly HPV
11 Cost Effectiveness of Human Papillomavirus-
16/18 Genotyping in Cervical Cancer Screening
12 Long-term costs of introducing HPV-DNA post- treatment surveillance to national cervical cancer screening in Ireland
13 Screening for Cervical Cancer: A Modeling Study for the US Preventive Services Task Force
Authors developed various screening scenarios based on age for initiating and concluding screenings, transitioning to new tests, and determining intervals for routine screenings in accordance with national guidelines Typically, HPV-based and co-testing strategies are compared to cytology-based strategies However, a study by Adam Keane et al used no screening scenario as a comparator, while Jane J Kim et al suggested a specific threshold for evaluation.
$50,000 to $200,000 per QALY gained as reference range for cost-effectiveness assessment
Countries have developed cervical cancer (CC) screening strategies that are either based on cytology or HPV testing These strategies can utilize cytology tests, HPV tests, or a combination of both, along with other tests The approaches to CC screening vary significantly across different regions.
HUPH evaluates the implementation of front-line screening and triage tests for positive cases across different countries In summary, studies typically assess the cost-effectiveness of eight distinct pathways.
CC screening: (i) primary cytology (pap or LBC) triage with HPV test or colposcopy;
(ii) primary cytology triage with co-testing or HPV test; (iii) primary HPV test triage with cytology or colposcopy; (iv) primary HPV genotyping test (with or without HPV
The article discusses various triage methods for cervical cancer screening, including cytology, colposcopy, and primary co-testing with or without genotyping Notably, one study by Karl Ulrich Petry et al utilized p16/Ki-67 dual-stained cytology as a biomarker in HPV testing to detect high-grade CIN and cervical cancer The interventions and comparators from each study are detailed in table 3.3, highlighting that screening frequency for women ranged from 1 to 12 times based on different strategies Additionally, Steffie K Naber et al recommended a three-time consecutive screening approach for unvaccinated women aged 35-59 to evaluate its cost-effectiveness.
Screening test Interval Screening test
1 Cost- effectiveness analysis of primary human papillomavirus testing in cervical cancer screening:
Primary HPV testing with reflex LBC (co-testing)
2 Health economic evaluation of primary human papillomavirus screening in urban populations in China
(i) primary cytology (pap or LBC) triage with colposcopy
(ii) Primary HPV DNA test with cytology triage
(iii) primary HPV genotyping test (with HPV 16/18) triage with colposcopy
Screening test Interval Screening test
(iv) primary co-testing triage with colposcopy
(v) Primary HPV DNA test with HPV 16/18 genotyping, and cytology triage
(vi) Primary cytology test with HPV DNA triage
(vii) Colposcopy and biopsy management
HPV DNA test as primary screening method for cervical cancer: A health policy discussion in
Cytology (current practice) 1 year or 3 years
Cytology 1 year the HPV test with simultaneous HPV 16 and
3 years or 5 years the HPV test with reflex 16 and 18 genotyping
3 years or 5 years the HPV test with no genotyping
Co-testing with cytology and the HPV test with simultaneous 16 and 18 genotyping
Co-testing with cytology and the HPV test with reflex
Co-testing with cytology and the HPV test with no genotyping
4 Screening capacity and cost-effectiveness of the human papillomavirus test versus cervicography as an adjunctive test to Pap cytology to detect high- grade cervical dysplasia cervicography (TeleCervico system) + pap
Not mention HPV test genotyping
5 Primary HPV testing versus cytology-based cervical screening in women in Australia vaccinated for HPV and unvaccinated: primary cytology (pap) triage with colposcopy
3-yearly intervals for ages 25-49 years and 5- yearly intervals for conventional cytology, no HPV triage testing
Screening test Interval Screening test
Interval effectiveness and economic assessment for the National Cervical
Screening Program ages 50-64 years primary cytology (LBC) triage with colposcopy
3-yearly intervals for ages 25-49 years and 5- yearly intervals for ages 50-64 years
Primary HPV genotyping test triage with cytology and colposcopy with cytology triage of all oncogenic HPV positive women
5 years primary co-testing triage with colposcopy
6 The budget impact of cervical cancer screening using HPV primary screening primary HPV genotyping test with HPV 16, 18 and 12 hr HPV triage with cytology or colposcopy
3 or 5 years primary cytology (pap or LBC) triage with HPV testing or colposcopy
3 years primary co- testing without genotyping triage with colposcopy or co-testing again
Co-testing with genotyping triage with colposcopy or co-testing again
7 A model to evaluate the costs and clinical a positive HPV test followed by Pap cytology
Screening test Interval Screening test
Interval effectiveness of human papilloma virus screening compared with annual
In Germany, a positive HPV test is followed by p16/Ki-67 dual-stained cytology If the test is HPV-16/18-positive, a colposcopy is recommended For other HPV subtypes, p16/Ki-67 dual-stained cytology is performed Co-testing with HPV and Pap is also utilized in the screening process.
Good value for money according to thresholds of $50 000 to $200 000 per quality-adjusted life- year (QALY) gained Women vaccinated with
Cytology when 21 and switch to HPV test when 30
3 years for cytology and 5 years for HPV test
Cytology when 21 and switch to cotest test when 30
3 years for cytology and 5 years for cotest
HPV test 3 years, 4 years, 5 years,
Screening test Interval Screening test
Cytology when 21 and switch to HPV test when 30
3 years for cytology and 3-5 years for HPV test
Cytology when 21 and switch to HPV test when 30
3 years for cytology and 5 years for cotest
Co-testing: Pap (ThinPrep Pap Test and Aptima HPV Assay, Hologic, Inc.) plus HPV mRNA testing with genotyping for HPV 16/18
HPV DNA testing with genotyping for HPV 16/18 and reflex cytology (cobas®
HPV test, Roche Di- agnostics US) (HPV primary)
10 Cervical Cancer Screening in Partly HPV Vaccinated
(A) primary HPV screening with reflex cytol- ogy triage and cytology triage after six months (future Dutch screening program),
(B) primary cytology with reflex HPV triage,
(C) combined primary HPV and cytology (i.e co- testing) with HPV triage after 12 months,
The study evaluates the incremental cost-effectiveness ratio (ICER) of screening unvaccinated women using a primary cytology approach combined with HPV triage, comparing it to a strategy optimized for vaccinated women The analysis considers screening intervals ranging from 5 to 20 years and lifetime screenings varying from 1 to 12.
Screening test Interval Screening test
Interval cytology triage after 18 months (current Dutch screening program)
(1) primary cytology (pap or LBC) triage with HPV testing or colposcopy/ cytology with reflex HPV testing for atypical squamous cells of undetermined significance (ASC-US);
(2) primary co-testing without genotyping) triage with colposcopy or co- testing again/co-testing with cytology and HPV testing;
(3) primary HPV test triage with cytology pap /HPV with reflex to cytology
(4) primary HPV genotyping test (with HPV 16/18) triage with cytology or colposcopy/HPV with 16/18 genotyping and reflex cytology (ASC-US threshold)
12 Long-term costs of introducing HPV-DNA post-treatment surveillance to national cervical cancer screening in Ireland co-testing (cytology plus human papillomavirus DNA testing)
2 semi-annual Cytology at 6 months post- treatmen t, then at
18 months and annually , for 5-10 years thereafte r
Cancer: A Modeling Study for the US Preventive
Co-testing: human papillomavirus DNA testing in conjunction with cytology
The costing perspective in various studies primarily focused on healthcare service payers, with a social perspective identified in the works of Steffie K Naber et al and Jane J Kim et al In contrast, Juan C Felix et al and Ian Cromwell et al concentrated solely on direct medical costs for service delivery To assess the costs of screening tests, researchers utilized fee schedules sanctioned by national medical authorities, while treatment costs were derived from published studies and validated by at least two clinical experts to establish average treatment and follow-up costs for cervical cancer across all states Notably, Anastasios Skroumpelos et al relied on Spanish data, converting it for their Greek analysis due to data limitations Additionally, a positive discount rate of 3% to 5% was applied to both QALYs and costs, although the rationale for these rates was not specified in the studies.
Authors calibrated transition probabilities and QALY weights using data from large population trials and clinical facilities Notably, the ATHENA trial provided epidemiological estimates for the US screening population, including unvaccinated women Jane J Kim et al explored optimal screening pathways for vaccinated women using data from the New Mexico HPV Pap Registry and the National Health and Nutrition Examination Survey Additionally, a study from the Netherlands validated data from the Costa Rica Vaccine Trial and the PATRICIA trial, which assessed the clinical benefits of the HPV vaccine in women who were HPV naive at enrollment This research enabled an analysis of the cost-effectiveness of screening among pre-vaccinated, vaccinated, and unvaccinated women.
The HERMES study in Greece utilized clinical, epidemiological, and diagnostic test performance data for multicentric cervical screening, although the target population remains unknown due to inaccessible trial details In British Columbia, Canada, the HPV-FOCAL trial conducted a randomized controlled trial on Human Papillomavirus testing for cervical cancer screening Both the ATHENA and HPV-FOCAL trials examined HPV testing as a primary screening method in the US, with the ATHENA trial specifying the Cobas HPV Test for performance evaluation In Ireland, data from CervicalCheck, established in 2008, was analyzed to assess the clinical and economic advantages of co-testing in post-treatment cervical cancer surveillance Additionally, studies in Australia and China gathered data from various healthcare facilities, with Australia collecting nationwide data and China focusing on Shenzhen and other cities in the Pearl River Delta region of Guangdong province.
The studies showed that co-testing proved its cost-effectiveness in preventing
Co-testing for cervical cancer (CC) screening demonstrated the lowest incidence and high performance in detecting early stages of CC, resulting in a higher number of quality-adjusted life years (QALYs) gained, despite not being statistically significant However, it also incurred the highest cost per screened woman, which is a critical factor for policymakers Most studies indicated that HPV test-based screening strategies are more cost-effective than co-testing due to reduced costs In contrast, cytology-based screening methods, such as the Pap test and liquid-based cytology (LBC), were found to be less effective, as primary HPV test scenarios resulted in fewer deaths from missed diagnoses, as highlighted in the majority of research.
HUPH not only reduced costs but also extended screening intervals and enhanced Quality-Adjusted Life Years (QALYs) Research by Steffie K Naber et al indicated that screening intervals could be extended to 6 years for pre-vaccinated cohorts and 12 years for vaccinated cohorts, surpassing the previous recommendation of 5 years While cervical cancer screening strategies utilizing primary HPV tests were found to be more effective than cytology, they resulted in a higher number of referrals to colposcopy per prevented death, particularly among unvaccinated women when herd immunity reached 100 percent.
Parameter inputs for CEA of the co-testing method
The ATHENA study provides valuable insights into the prevalence of high-risk HPV types within the general population, particularly in a context similar to Vietnam, where HPV vaccination coverage is notably low at just 2%.
(106) For progression and regression transition probabilities, the data from the study
The article "Screening for Cervical Cancer: A Decision Analysis for the U.S Preventive Services Task Force" by Juan C Felix et al discusses the use of decision tree models in studies from Korea and China to evaluate the cost-effectiveness of cervical cancer screening methods However, these approaches are not applicable to my Markov model analysis.
Most studies reviewed in the literature calculated transition probabilities based on epidemiological data from the past 15 years, primarily from Western countries, during which the HPV vaccine was not available to inform the natural progression of cervical cancer (CC) However, the data set lacked a comprehensive range of values and did not include transition probabilities from CIN2 to CIN3 To address this gap, data from the study "The predicted effect of changes in cervical screening practice in the UK: Results from a modelling study" was utilized.
“Effectiveness and cost-effectiveness of eliminating cervical cancer through a tailored optimal pathway: a modelling study” (109,110) were taken The transition probabilities were presented in the table 3.6
The data collected was validated through consultations with four clinical experts Due to the lack of available data in Vietnam, the experts were unable to offer comments for data adjustments Nevertheless, data from a randomized control trial conducted in a population with low HPV vaccine coverage, published in the Cochrane Central Register of Controlled Trials, serves as a suitable and reliable reference source.
3.2.2 Effectiveness of co-testing and cytology method
After conducting a thorough search in bibliographic databases such as the Cochrane Database of Systematic Reviews, PubMed, and Web of Science, the researcher identified a total of 25 articles focused on the effectiveness of co-testing and 50 articles on the effectiveness of cytology Ultimately, four reports were selected based on their abstracts and summary information.
Figure 3.2: PRISMA diagram for test effectiveness
Identification of studies via databases
Ident if ica ti o n Scre en ing Incl ud ed
Records excluded due to not analysis test effectiveness (n 1 = 18
Recent analyses of co-testing performance in cervical cancer (CC) screening and post-treatment recurrence detection reveal that co-testing outperforms cytology alone in sensitivity but falls short in specificity Specifically, pooled results from Tong Li et al indicate a sensitivity of 0.937 and specificity of 0.858, surpassing the findings of Mamiko Onuki et al., which reported a sensitivity of 0.92 and specificity of 0.76 The diagnostic value from Tong Li et al has been utilized for the cost-effectiveness analysis of this study, as it focuses on CC screening, whereas Onuki et al provided data relevant to post-treatment scenarios.
The effectiveness of the cytology method is supported by data from Alejandra Castanon et al., who focused on assessing its sensitivity In contrast, Teruhiko Terasawa et al highlighted varying ratios of sensitivity and specificity among different screening tests, rather than reporting cytology performance in cervical cancer screening separately For specificity data, Alejandra Castanon et al referenced the study by Tong Li et al The results regarding the effectiveness of cytology and co-testing are summarized in Table 3.5.
The systematic review of reports and selected records did not clarify whether co-testing utilized the same or separate specimens, nor did it address the differences in test effectiveness based on the sampling process The Ministry of Health's guidelines also failed to mention these aspects According to the National Cancer Institute's guidelines, the same sample can be used for HPV testing Additionally, a search of bibliographic databases revealed no records indicating that the sampling process for co-testing impacted test effectiveness, suggesting that specimen preparation may not be a significant concern in co-testing.
The collected data was reviewed by clinical experts for their recommendations One expert proposed reducing the sensitivity of the cytology test to 0.7 for base case analysis However, the researcher opted to retain the original data, as the lower range of cytology sensitivity was 0.78, which closely aligned with the expert's suggestion This data will be analyzed in the one-way DSA.
Table 3.4: List of systematic review studies about co-testing and cytology effectiveness
No Article Authors Published year
1 Posttreatment human papillomavirus testing for residual or recurrent high-grade cervical intraepithelial neoplasia: a pooled analysis
2 Diagnostic value of combination of HPV testing and cytology as compared to isolated cytology in screening cervical cancer: A meta-analysis
1 Systematic Review and Meta-Analysis of Individual
Patient Data to Assess the Sensitivity of Cervical
Cytology for Diagnosis of Cervical Cancer in Low- and Middle-Income Countries
2 Comparative accuracy of cervical cancer screening strategies in healthy asymptomatic women: a systematic review and network meta‑analysis
Currently, there is a lack of Vietnamese data on QALY weights for various states in the Markov model Cost-effectiveness analyses of cervical cancer screening using the co-testing method in China, Taiwan, and Thailand have relied on utility weights derived from clinical trials conducted in countries like the USA and Canada.
The UK is set to calculate Incremental Cost-Effectiveness Ratios (ICERs), with research conducted by Warner K H et al focusing on Vietnamese women The authors derived Quality-Adjusted Life Years (QALYs) for various cervical conditions (CIN 1, CIN 2, CIN 3, and cervical cancer) using data from Canadian and US population surveillance, employing the standard gamble method To prevent overestimation of utility for cervical cancer, the QALY for the cervical cancer state was calculated as an average of QALY weights across different treatment phases according to FIGO stages Clinical experts did not provide recommendations for the proposed data, as HPV-positive patients with CIN 1/2/3 can significantly improve their health post-treatment without hindering their daily activities, including sexual life Thus, using average QALY weights for cervical cancer patients is deemed reasonable given the varying health conditions associated with different cervical cancer states.
3.2.4 Cost for co-testing method, cytology method and cervical cancer treatment from provider perspective
Costing parameters for cervical cancer treatment services in Vietnam were derived from a study by Nguyen, A D et al., which focused on medical resources at central hospitals in 2017 from a provider perspective The treatment costs for cervical cancer varied by severity, but the costs for CIN 1, CIN 2, and CIN 3 were similar, leading to the use of average costs for these scenarios To conduct a health economic evaluation, the 2017 costs were adjusted to 2021 based on the Consumer Price Index published by the Vietnam General Statistics Office Additionally, the costs for cytology and co-testing methods were sourced from price lists provided by K Hospital and the National Hospital of Obstetrics and Gynecology.
The treatment services related to CC were reviewed by clinical experts, and the revised list included published costs per service based on financial expert consultation Overall, the updated costs showed only slight variations compared to the study by Nguyen, A D et al The researcher adjusted the treatment costs for analysis, accounting for a 20% fluctuation in costs affecting the change in ICER.
Method Base case Lower range
Upper range Distribution Source Sensitivity Co-testing 0.937 0.925 0.948 Beta Li T et al, (113)
Cytology 0.809 0.78 0.838 Beta Castanon A et al, (114)
Specificity Co-testing 0.858 0.855 0.860 Beta Li T et al, (113)
Cytology 0.951 0.949 0.953 Beta Li T et al, (113)
Upper range Distribution Source Well, HPV (-) or
CIN 1 0.97 0.87 1 Beta Huh W K et al, (115)
CIN 2 0.97 0.87 1 Beta Huh W K et al, (115)
CIN 3 0.97 0.87 1 Beta Huh W K et al, (115)
ICC 0.71 0.64 0.78 Beta Huh W K et al, (115)
Upper range Distribution Source Treatment of
Co-testing 73.91 $ Gamma Hospital price list
HPV hr 0,267 0,134 0,099 0,076 0,066 0,066 0,041 0,305 Beta Felix J C et al, Wright T C et al, (21,106) Annual transition probabilities
Progression for detected and undetected cases
HPV hr (-) to HPV hr (+) 0,05 0,01 0,01 0,01 0,01 0,005 0 0,17 Beta Felix J C et al, Kulasingam
S L et al, (21,116) HPV hr (+) to CIN1 0,054 0,054 0,054 0,054 0,054 0,054 0,0527 0,1121 Beta Felix J C et al, Wright T C et al, (21,106,109) HPV hr (+) to
0,006 0,006 0,006 0,006 0,006 0,006 0,0045 0,0075 Beta Felix J C et al, Kulasingam
S L et al, (21,116) CIN1 to CIN2/CIN3 0,02 0,02 0,02 0,02 0,02 0,02 0,001 0,06 Beta Felix J C et al, Kulasingam
S L et al, (21,116) CIN2/CIN3 to ICC 0,01 0,01 0,01 0,01 0,01 0,01 0,001 0,04 Beta Felix J C et al, Kulasingam
S L et al, (21,116) CIN2 to CIN3 0,0389 0,0389 0,0797 0,0797 0,1062 0,1062 0,0389 0,1062 Beta Canfell K et al, (110)
HPV hr (+) to HPV hr (-) 0,5 0,25 0,25 0,15 0,15 0,05 0,05 0,5 Beta Felix J C et al, (21)
CIN1 to HPV hr (+)/(-) 0,1 0,1 0,06 0,06 0,06 0,06 0,058 0,27 Beta Felix J C et al, Kulasingam
S L et al, (21,116) CIN2/CIN3 to CIN1 0,03 0,03 0,03 0,03 0,03 0,03 0,001 0,19748 Beta Felix J C et al, Kulasingam
S L et al, (21,116) CIN2/CIN3 to HPV hr (-) 0,03 0,03 0,03 0,03 0,03 0,03 0,001 0,19748 Beta Felix J C et al, Kulasingam
S L et al, (21,116) CIN3 to CIN2 0,0135 0,0135 0,0135 0,0135 0,0135 0,0135 0,01013 0,01688 Beta Xia C et al, (109)
4 Please see annex 6 to explain how to use transition probabilities and distribution calculation
CEA results – co-testing 3 times v.s cytology 5 times
3.3.1 Incremental cost-effectiveness ratio (ICER)
The study indicates that co-testing is not cost-effective compared to cytology for a simulation cohort of 1,000 women, as shown in Table 3.9 In five age groups (25-29, 35-39, 40-44, 45-49, and 50-55), co-testing is less favorable, with higher costs and lower QALYs Although for women aged 30-34, co-testing presents a lower cost than cytology, transitioning to co-testing would result in a loss of QALYs This alternative could be considered cost-effective if the savings per QALY lost exceeded the threshold; however, the WHO recommended threshold of 2,786 USD far surpasses the actual savings of only 3 USD.
The cytology test is less effective than the co-testing method in reducing the incidence of cervical cancer (CC) and cervical intraepithelial neoplasia (CIN) cases Specifically, co-testing can prevent 887 cases of CIN 1/2/3 and 32 cases of CC, while cytology only prevents 627 CIN cases and 24 CC cases across all age groups compared to no screening However, co-testing results in nearly double the number of false positive cases compared to cytology Additionally, costs for older age groups significantly decreased, as the model only simulated the cohort until they reached 55 years old, resulting in fewer follow-up cycles and lower overall expenses.
Table 3.9: Cost, QALY weights and ICER between alternatives (3% discount)
Co-testing 3 times Cytology 5 times Difference cytology v.s co-testing
3.3.2.1 One-Way Deterministic Sensitivity Analysis (DSA)
The top 15 factors significantly influencing the Incremental Cost-Effectiveness Ratio (ICER) across different age groups are presented in Annex 7 Furthermore, the researcher examined the impact of variations in the number of cervical cancer screenings using the cytology method on the ICER.
The analysis of the top 15 inputs across different age groups reveals significant variations, with the Tornado diagrams indicating that the Incremental Cost-Effectiveness Ratio (ICER) is most influenced by the transition probability from HPV hr(-) to HPV hr(+) and the prevalence of HPV hr among the general female population While the cost and effectiveness of screening tests have minimal effects on ICER changes in most age groups, the 50-55 age group stands out, where co-testing costs rank third, and HPV and cytology test costs are sixth and seventh, respectively Notably, the treatment cost of cervical cancer (CC) significantly impacts the ICER, ranking second in the 35-39 age group and third in the 25-29, 30-34, and 40-44 age groups, while it ranks fourth for women aged 45-49 However, in the 50-55 age group, treatment costs exert little influence on ICER changes.
A comparative analysis of cost-effectiveness between three consecutive co-testing and three consecutive cytology screenings for women aged 25-30 reveals that the co-testing method, with a cost of \$1,202 and QALYs of 24.18, outperforms the cytology method, which costs \$955 and yields 22.55 QALYs The incremental cost-effectiveness ratio (ICER) for co-testing is \$152 per QALY gained, significantly below the GDP per capita of \$2,786 Additionally, 1,000 Monte Carlo simulations conducted under uncertainty conditions indicate that the frequency of screening has a substantial effect on the ICER.
Figure 3.3 illustrates the cost-effectiveness planes for 1,000 Monte Carlo simulations and the corresponding cost-effectiveness acceptability curves (CEAC) The incremental cost-effectiveness ratio simulations exhibit variability in both the north-west and south-west quadrants These graphs demonstrate that the strategy of screening CC three consecutive times is effective.
HUPH testing is primarily influenced by the comparator, with CEACs indicating that sensitivity analyses from both PSA and DSA are robust The probability of the Incremental Cost-Effectiveness Ratio (ICER) remaining below the willingness to pay (WTP) threshold in Vietnam, set at 1 to 3 times GDP per capita, is significant However, the co-testing method shows a cost-effectiveness probability of only 40% to 50% across all age groups, dropping to nearly 0% as the WTP threshold increases to $1,200, indicating it is not cost-effective at this level In contrast, the cytology method demonstrates a higher likelihood of cost-effectiveness, with probabilities ranging from 40% to 60% across all age groups, and approaches 100% at the WTP threshold, confirming its cost-effectiveness at a WTP of around $1,200, which is below 1 GDP ($2,786).
Women aged 25 to 29: CE plane and CEA Curve
Women aged 30 to 34: CE plane and CEA Curve
Women aged 35 to 39: CE plane and CEA Curve
Women aged 40 to 44: CE plane and CEA Curve
Women aged 45 to 49: CE plane and CEA Curve
Women aged 50 to 55: CE plane and CEA Curve