Cervical Cancer Screening in Low
Resource Settings: A Cost Effectiveness Analysis in Nepalese Context
Aastha Bajracharya
Master Thesis
Department of Health Management and Health Economics
UNIVERSITY OF OSLO
May 2017II
Cervical Cancer Screening in Low
Resource Settings: A Cost Effectiveness Analysis in Nepalese Context
Aastha Bajracharya
Supervised by: Eline Aas
Thesis submitted as a part of the Master of Philosophy Degree in Health Economics, Policy and Management
Department of Health Management and Health Economics
UNIVERSITY OF OSLO
III
© Aastha Bajracharya 2017
Cervical Cancer Screening in Low Resource Settings: A Cost Effectiveness Analysis in Nepalese Context
Aastha Bajracharya http://www.duo.uio.no/
Print: Copycat, Nydalen
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Abstract
Background: Cervical cancer is a leading cause of cancer related mortality among women all over the world, with particularly high incidence in developing countries. It is the most common cancer among women in Nepal. Cervical cancer screening can be effective in reducing incidence and mortality due to cervical cancer. However, expansion of screening to low income settings remains a challenge. At present, there is no organized screening program in Nepal, but recently government announced that Pap smear tests will be made available free of cost in public hospitals. Studies from other countries indicate that Pap smear may not be the most cost effective strategy, especially in low resource settings. There is growing focus on Visual Inspection with Acetic Acid (VIA) and Human Papilloma Virus (HPV) Tests as more cost effective alternatives for Pap smear.
Objective: To compare cost effectiveness of three screening strategies VIA, Pap smear and HPV DNA test for cervical cancer screening in Nepal.
Method: A probabilistic decision tree model for one time screening of women at 30 years age was constructed where outcome was number of CIN2+ detected. Cost effectiveness analysis was carried out from societal perspective and hence both direct and indirect costs were included in analysis. The epidemiological data was obtained from literature. Uncertainty was explored by one-way, two-way and probabilistic sensitivity analysis. In addition, harm to benefit analysis was carried out to explore the additional number of colposcopy required per additional CIN 2+ detected. Budget impact analysis was carried out to explore the financial implication of implementing the screening program in Nepal from provider’s perspective.
Results: Among the three screening strategies, Pap smear was found to be not cost effective at any WTP threshold. VIA was found to be cost effective for WTP threshold below NRS 500,000 per CIN2+ detected and HPV Test was found to be cost effective for WTP threshold above NRS 500,000 per CIN2+ detected. In harms to benefit analysis, VIA was found to be least acceptable, whereas Pap smear was most acceptable strategy. In terms of budget impact, HPV test and VIA was found to be most costly and least costly strategies respectively.
Conclusion: Given the resource constraints, this study indicates that Pap smear may not be the right choice of screening strategy. VIA has more favourable outcomes, but there is need for more research as there is presence of a considerable decision uncertainty.
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Acknowledgement
My deepest gratitude to my supervisor, Eline Aas for her guidance and support through each and every step of this study. I came to you with very vague idea of what I wanted to do and you have guided me to materialise this thesis, which seemed impossible at times. Thank you for being patient with me and motivating me to keep going on.
Finding data for Nepal was the biggest challenge I had during the entire period of this study and I indebted to everyone who helped me in the process. I am thankful to Dr. Abha Hada and Dr. Sweta Shrestha for helping me with data and information about cervical cancer screening in Nepal. This study would have been impossible without the information they provided. I am also grateful to Punam Shakya for helping me obtain information about private hospitals, which helped me to gain much clearer understanding of the context of Nepal. I am much obliged to my father, Ratna Kaji Bajracharya for helping me find contact person in Ministry of Health, although getting information from there was an unsuccessful endeavour.
I would also like to thank the HEPAM department, my professors and fellow students. It was a wonderful learning experience.
I would like to thank my friend Enock for discussions and brainstorming sessions. Your feedback gave me much needed confidence at confusing moments. I am grateful to my friends Monimala, Gabriel, Anne Kathe, Aleksandra, Puja, Suchitra, Sunny and Siv Hege for cheering me up when I was stressed. Thank you Tara for the dinners!
I am very grateful to my family in Kathmandu as well as Mumbai for their constant support and encouragement. Thank you ever so much Surmeet, for always being there and believing in me. Many thanks for reading and editing my thesis as well. Lastly, to my Maa, thank you for being the wonderful person that you are.
Aastha Bajracharya May 2017
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Abbreviations
ASC-H Atypical squamous cells, cannot rule out high-grade lesion ASCUS Atypical squamous cells of undetermined significance
BIA Budget Impact Analysis
CBA Cost Benefit Analysis
CEA Cost Effectiveness Analysis
CEAC Cost Effectiveness Acceptability Curve CIN Cervical Intraepithelial Neoplasia
CUA Cost Utility Analysis
DALY Disability Adjusted Life Years
DNA Deoxyribonucleic Acid
DOHS Department of Health Services EHCS Essential Health Care Services
EVPI Expected Value of Perfect Information
GDP Gross Domestic Product
HPV Human Papilloma Virus
hrHPV High Risk Human Papilloma Virus
HSIL High-grade squamous intraepithelial lesion ICER Incremental Cost Effectiveness Ratio
LBC Liquid Based Cytology
LEEP Loop Electrosurgical Excision Procedure LSIL Low-grade squamous intraepithelial lesion
NHB Net Health Benefit
NMB Net Monetary Benefit
PSA Probabilistic Sensitivity Analysis QALY Quality Adjusted Life Years VIA Visual Inspection with Acetic Acid VILI Visual Inspection with Lugol’s Iodine
WHO World Health Organization
WTP Willingness to Pay
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Table of Contents
Abstract ... IV Acknowledgement ... V Abbreviations ... VII
1 Introduction ... 1
2 Background ... 4
2.1 Cervical Cancer ... 4
2.2 Background of Nepal ... 15
3 Theoretical Framework ... 21
3.1 Economic Evaluations ... 21
3.2 Decision Analysis ... 23
3.3 Analysis and Presentation of Results... 24
3.4 Uncertainty analysis ... 26
3.5 Value of information and expected value of perfect information ... 28
3.6 Budget Impact Analysis... 28
3.7 Economic Evaluation of Screening Programs ... 29
4 Methods ... 31
4.1 Model ... 31
4.2 Data ... 33
4.3 Analysis ... 37
4.4 Assumptions ... 39
5 Results ... 41
5.1 Cost Effectiveness Analysis ... 41
5.2 Sensitivity Analysis ... 42
5.3 Expected Value of Perfect Information ... 46
5.4 Harm to Benefit Analysis ... 48
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5.5 Budget Impact Analysis... 49
6 Discussions and Conclusions ... 54
6.1 Results of the study... 54
6.2 Limitations of the study ... 55
6.3 Strength of the Study ... 56
6.4 Issues from related studies ... 57
6.5 Further Research ... 59
6.6 Conclusion ... 59
References ... 60
Appendix ... 66
List of Figures
Figure 2. 1 Development of Cervical Cancer ... 5Figure 3. 1 Cost Effectiveness Plane. ... 25
Figure 4.1. Decision Tree Model for Cervical Screening ... 32
Figure 5. 1 Cost Effectiveness Plane ... 42
Figure 5. 2 Cost Effectiveness plane for Probabilistic Analysis ... 44
Figure 5. 3 Cost Effectiveness Acceptability Curve ... 45
Figure 5. 4 Cost Effectiveness Acceptability Frontier ... 46
Figure 5. 5 Expected Value of Perfect Information ... 47
Figure 5. 6 Expected Value of Perfect Information for population ... 47
Figure 5. 7 Harm Benefit Plane ... 48
Figure 5. 8 Harm benefit Acceptability Curve (HBAC) ... 49
Figure 5. 9 Annual budget for screening strategies of 10 year time period ... 51
Figure 5. 10 Total number of CIN2+ detected annually for 10 year time period ... 51
Figure 5. 11 Scenario analysis for total cost for VIA ... 52
Figure 5. 12 Scenario analysis for total cost for Pap smear ... 53
Figure 5. 13 Scenario analysis for total cost for HPV DNA Test ... 53
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List of Tables
Table 2. 1 The Bethseda and CIN system from (Nayar, Wilbur, & Solomon, 2008) ... 10
Table 2. 2 FIGO staging system for cervical carcinoma and treatment ... 12
Table 4. 1 Epidemiological data ... 34
Table 4. 2 Cost for Cervical Cancer Screening ... 35
Table 5. 1 Costs, Effectiveness, Incremental Costs, Incremental Effects, Cost -Effectiveness Ratio and Incremental Cost effectiveness Ratio (ICER) for per woman screened ... 41
Table 5. 2: One-way sensitivity analysis for minimum and maximum values of parameters . 43 Table 5. 3Incremental harm, incremental benefits, harm benefit ratio and incremental harm benefits ratio (IHBR) ... 48
Table 5. 4 Resources used per 100000 women screened ... 50
Table 5. 5 Total resource used by screening strategies ... 50
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1 Introduction
Cervical cancer is a leading cause of death among women all over the world, with particularly high incidence in developing countries (Campos, Castle, Wright, & Kim, 2015; Goldie et al., 2005; Schiffman, Castle, Jeronimo, Rodriguez, & Wacholder, 2007). As of 2012, it accounts for 7.5% of all female cancer deaths and 87% of cervical cancer death occurs in less developed regions (Ferlay J et al., 2012). In addition to being the most prevalent cancer among women, its societal importance is heightened due to the fact that in average it affects women at young age, often when they are still raising families (Schiffman et al., 2007). The long time period taken for progression of cervical cancer precursors, known as cervical intraepithelial neoplasia (CIN), to invasive cancer gives good opportunity to detect and prevent cervical cancer mortality (T. C. Wright, Jr. & Kuhn, 2012). In many high-income countries, routine screening has reduced cervical cancer considerably (Kitchener, Castle, &
Cox, 2006; Schiffman et al., 2007; Vaccarella, Lortet-Tieulent, Plummer, Franceschi, & Bray, 2013). The implementation of routine screening program, however remains a challenging issue for developing countries, where the burden of cervical cancer related mortality is much higher, due to lack of health care delivery infrastructure, competing health priorities and limited budgets (Campos et al., 2015; R. Sankaranarayanan, Budukh, & Rajkumar, 2001).
The link between Human Papilloma Virus (HPV) and cervical cancer has been well established (Burd, 2003). It is well documented that 70% of cervical cancer are caused by HPV genotypes 16 and 18, and there are number of other HPV genotypes that are considered high risk HPV (Burd, 2003; Muñoz et al., 2003; Smith et al., 2007). Infection with high risk HPV (hrHPV) may cause change in infected cells that can lead to cervical intraepithelial neoplasia (CIN). CIN may progress from mild grade (CIN1) to moderate (CIN2) or micro invasive (CIN3) lesions. CIN1 indicates self-limited infection and mostly regresses on its own, whereas CIN 2 and CIN 3 (also known together as CIN2+), are considered as cancer precursors, which if left untreated may lead to invasive cancer.
Common screening methods widely used at present are cytology and HPV DNA tests.
Cytology involves microscopic study of cells collected from the outer opening of the cervix (also called transformation zone) to look for abnormalities (R. Sankaranarayanan, Gaffikin, Jacob, Sellors, & Robles, 2005). HPV DNA tests, on the other hand, detects presence the of carcinogenic HPV DNA in the cellular sample from cervix (Burd, 2003). In addition, there is
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growing focus on low cost visual methods for low resource settings (Mustafa et al., 2016).
Visual method involves observation of cervix with naked eye or magnifying glass after application of acetic acid (VIA) or Lugols Iodine to identify lesions (VILI) (Sauvaget, Fayette, Muwonge, Wesley, & Sankaranarayanan, 2011).
More recently, another preventive method, HPV vaccine has been developed for HPV16 and 18 as well as few other high risk types (Schiffman et al., 2007) and are being implemented both in developed and developing countries (ibid). However, screening is still necessary for two to three generation of women who are beyond vaccination age (Campos et al., 2015;
Goldie et al., 2005).
Although widely used in high-income countries, the use of cytology programs has proven to be challenging in low resource settings where health systems are not robust and quality cannot be assured (Goldie et al., 2005). Cytology requires greater human and financial resources to ensure accurate and reproducible results. In addition, there are greater chance of loss to follow up since results are not available quickly which negates the benefit of cytology program (WHO, 2013). HPV DNA testing is reported to have better performance than cytology, but it is still resource intensive for low income countries (R. Sankaranarayanan et al., 2005).
Therefore, there is growing emphasis on one and two visit screen-and-treat approaches that can be cost-effective in resource poor settings (Campos et al., 2015). The World Health Organization (WHO) recommends use of HPV DNA testing or VIA for cervical cancer screening in resource poor regions and countries that do not have screening program at place already (WHO, 2013).
Research Problem
Nepal, one of the poorest countries in South Asia, also has a high burden of cervical cancer. It is the leading cause of cancer related death among women (Ferlay J et al., 2012; Jha et al., 2009). There is no organized screening program for cervical cancer yet, and most of the screenings are opportunistic screenings. The participation of women in cervical screening is very low so far because of meagre health facilities in most of the rural areas, where 80%
population live. In addition there is lack of awareness and socio-cultural barriers associated to gynaecological diseases (A. Ranjit et al., 2016). In addition to that, being a low income country, the resources in health sector are very scarce. The government funded public health
3 system still struggles to provide basic health services to the whole population. The access to quality health facility is a challenge for majority of population (WHO, 2007) .
Recently government has announced that public health facilities will provide Pap smear test free of cost to the public (RSS, 2017). Studies carried out in other countries however show that Pap smear might not be the most cost effective test for cervical cancer screening. Based on this context, this study aims carry out a cost effectiveness analysis (CEA) for primary cervical cancer screening in Nepal. Three strategies VIA, cytology based on Pap smear and HPV DNA testing will be compared in terms of cost and effectiveness for screening women who are 30 years once in lifetime. The study is carried out from societal perspective for Nepal, and therefore cost associated with health sector as well as patient’ cost and productivity losses are compared for the three strategies. The outcome of CEA is number of CIN2+ detected. The cost effectiveness is determined on basis of Incremental Cost Effectiveness Ratio (ICER), which can be defined as additional cost per CIN2+ detected for a given strategy as compared to next most costly strategy. In addition, budget impact analysis (BIA) has been carried out to understand the financial consequence of adopting a screening program for Nepal.
Structure of Thesis
This thesis has been organized into six chapters. The following chapter starts with brief background on cervical cancer and screening methods with special focus on low-income countries. This is followed by an overview on socio-economic situation, health care system and scenario of cervical cancer screening in Nepal. In Chapter 3, the theoretical framework for the study is presented followed by detailed discussion of the methods used for this study in Chapter 4. Chapter 5 presents the results of the study. Lastly, in Chapter 6 discussion and conclusion of the study is presented.
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2 Background
2.1 Cervical Cancer
Epidemiology and Risk Factors
Cervical cancer is the fourth most common cancer in women, and the seventh overall, with an estimated 528,000 new cases and 266,000 deaths in 2012 worldwide. Majority of cervical cancer deaths occur in the less developed regions (Ferlay J et al., 2012). HPV is found to be present in 99.7% of cervical cancer in the world (Walboomers et al., 1999). Out of over 100 strains of HPV, 15 has been classified as high risk for cervical cancer (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) (Muñoz et al., 2003) .
Infection with HPV is necessary condition for cervical cancer but whether infection with high risk HPV develops into cervical cancer depends on number of additional factors (Burd, 2003).
HPV is commonly transmitted sexually and among women HPV infection is most common in between ages of 18 to 30 (Burd 2003) and the average age of diagnosis of pre cancer varies from 25 to 35, depending on first exposure to HPV (for which average societal age at first intercourse can act as proxy) and on the intensity of screening (Schiffman et al., 2007).
However, cervical cancer is more common in women older than 35 years suggesting infection at younger age and slow progression to cancer (Burd, 2003). Higher risk of infection with HPV is associated with sexual activity starting at young age and high total number of sexual partners, whereas progression of HPV infection to invasive cancer is determined by mostly by HPV type and other risk factors that include genetic predisposition, presence of conditions that impair cell mediated immunity such as HIV, smoking and multiple pregnancy (Burd, 2003; Schiffman et al., 2007; Waggoner, 2003).
Cervical cancer arises in four steps – HPV transmission, viral persistence, progression of persistently infected cells to pre cancer and invasion (Schiffman et al., 2007). The diagnosis, therapeutic measures and secondary preventive strategies are based on natural history of cervical cancer as a continuous single disease process progressing gradually from mild cervical intraepithelial neoplasia (CIN1) to more severe neoplasia and invasive lesions (CIN2 and CIN3 or CIN2+) and to more invasive disease. The risk from progression from mild to
5 moderate dysplasia is very low ( 1% per year) whereas progression of moderate to severe is higher( 16% within 2 year and 25% with 5 year) (Burd, 2003).
Most mild to moderate dysplasia are likely to regress than progress. The median time to clearance of HPV infection detected during screening studies is 6 to 18 months (Schiffman et al., 2007). In other cases, it can progress gradually form mild cervical intraepithelial neoplasia (CIN1) to more severe degrees of neoplasia (CIN2+), which if left untreated can progress to invasive cancer. About 80% of invasive cancers are squamous cell carcinoma and 20% are glandular cell carcinoma or adenocarcinoma (Waggoner, 2003). Various stages of cervical cancer is presented in the Figure 2.1.
Figure 2. 1 Development of Cervical Cancer (Source: Schiffman et al., 2007)
Cervical Cancer Screening
Screening of disease involves test or examination that can identify the existence of a particular disease in a population at high risk with no or minimum symptoms (Collaco &
Zardo, 2008). The principles of screening, according to WHO are, that the conditions should be an important health problem, there should be accepted treatment for patients with recognized disease as well as facilities for diagnosis and treatment, recognizable latent or early symptomatic stage, existence of suitable test or examination which is acceptable to the
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population, adequate understanding of natural history of the condition, including development from latent to declared disease, agreed policy on whom to treat as patient, economically balanced cost of case finding in relation to possible expenditure on medical care as a whole and case finding should be a continuous process and not a once for all project (Wilson &
Jungner, 1968). It can be said that screening for cervical cancer meets many of these principles. Cervical cancer, as discussed earlier, is quite common and associated with significant mortality, hence suitable for mass screening. In addition, effective treatment exists for pre-cancerous and early invasive state, making screening much beneficial than treatment of disease (Koliopoulos et al., 2007). Since it takes more than 10 years from detection of CIN 2 or CIN3 to development into invasive cervical cancer, the screening gives ample time to detect and treat before it develops into invasive cancer (T. C. Wright, Jr. & Kuhn, 2012).
In high resource countries, cervical cancer prevention involves screening, triage of equivocal results, colposcopically guided biopsy of abnormal screening results and treatment and post treatment follow up (Schiffman et al., 2007; T. C. Wright, Jr. & Kuhn, 2012). Screening policies differ widely among countries in terms of tests used, targeted age, screening interval and total number of scheduled screening examination (van den Akker-van Marle, van Ballegooijen, van Oortmarssen, Boer, & Habbema, 2002). As mentioned in chapter 1, the effectiveness of cervical cancer screening in preventing invasive cancer in high income countries has been well accepted. Although studies examining the effectiveness of screening programs in developing countries are not as common, there is growing evidence that screening can be effective in low resource setting as well. For example, a randomized controlled trail in rural India showed that the risk of cervical cancer mortality is reduced by 35% even with single screening (Peirson, Fitzpatrick-Lewis, Ciliska, & Warren, 2013).
Sensitivity and specificity are two main indices used to assess the efficacy of screening tests.
Sensitivity of the test refers to ability to correctly identify those with disease, whereas specificity refers to the ability to identify those without the disease (Collaco & Zardo, 2008;
Grimes & Schulz, 2002). Sensitivity can be defined as probability of a positive test result given that the disease is present and specificity can be defined as probability of a negative test result given that a disease is absent. Sensitivity and specificity are two independent values and tests may have high sensitivity and low specificity or vice versa, as well as high value or low value for both. The strength of test depends on how high its sensitivity and specificity is.
(Hunink et al., 2001) In addition, for screening program to be effective, the coverage and
7 availability of treatment are two important requirements; whereas the age to start, number of screenings and intervals depends upon affordability and social demands (Schiffman et al., 2007).
As discussed briefly in Chapter 1, the commonly used screening tests are cytology, HPV DNA testing and visual methods such as VIA and VILI. Three tests that are evaluated in this study are further described in detail below.
Cytology
Cytology involves collection of cervical cell samples form transformation zone of the cervix by health personnel such as nurse or a doctor, who prepares and fixes the smear, followed by processing, staining and reading by a cytotechnician. Finally, a cytopathologist supervises and reports the result (R. Sankaranarayanan et al., 2005). Conventional cytology also known as Papanicolaou (Pap) smear is primary method used widely to detect cervical cancer (Burd, 2003). After its development in 1940s, Pap smear gained wide application mostly during 1960s among several developed countries (Collaco & Zardo, 2008; Cuzick et al., 2008).
Incidence and mortality associated with cervical cancer has fallen in many developed countries due to introduction of wide overage organized screening programs (Kitchener et al., 2006; Schiffman et al., 2007; Vaccarella et al., 2013). The efficacy of Pap smear screening has never been established through randomized trails, but the marked reduction in incidence and mortality from cervical cancer before and after introduction of screening programs in the countries with organized screening program has been considered as non-experimental support for the effectiveness of cervical screening (Collaco & Zardo, 2008; Jack Cuzick et al., 2008;
R. Sankaranarayanan et al., 2001). An improved method, known as Liquid based cytology (LBC) was developed later and has been used widely as well (Burd, 2003).
The problem with conventional Pap smear is high false negative rate, which can be as high as 20 to 30%. The monolayer cytology or liquid based cytology (LBC) was developed to reduce false negative results (Burd, 2003). Although it is more costly than standard Pap smear, some studies report better sensitivity for LBC (Burd, 2003; R. Sankaranarayanan et al., 2005). In LBC, the cells collected from cervix are suspended in fluid medium, which is processed to provide a uniform thin layer of cells in slide. However, there are other studies that report that sensitivities and specificity of liquid based cytology is not significantly different from
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conventional cytology (Marc Arbyn et al., 2008; Schiffman et al., 2007). The advantage of liquid based cytology is that it has fewer insufficient samples and microscopic interpretation is facilitated by the uniform spread of epithelial cells in a thin layer and reduced problems of air-drying, uneven thickness and presence of debris. Furthermore, additional test, such as triage HPV DNA testing can be performed on the remnant after cytological examination, thereby reducing follow up costs (Marc Arbyn et al., 2008; R. Sankaranarayanan et al., 2005;
Schiffman et al., 2007).
On basis of clinical performance, cervical cytology has relatively low sensitivity for pre cancer and cancer, and various studies have reported wide variety of sensitivity ranging from 30% to over 80%, which could be due to subjective nature of cytological interpretation (Kitchener et al., 2006; R. Sankaranarayanan et al., 2005). The success of cytology is partly due to repeated screening, wide coverage and availability of treatment of women with positive result (Kitchener et al., 2006; R. Sankaranarayanan et al., 2005). Adjunct tests such as HPV DNA test has been used to improve the sensitivity of cytology. The combination of cytology with HPV DNA testing is reported to have sensitivity of 94 % or greater (Wright et al.2004 as quoted in (R. Sankaranarayanan et al., 2005).
HPV DNA testing
The well-established link between oncogenic HPV and development of CIN2+ has given rise in use of high risk HPV (hrHPV) genotype testing. A number of studies have also shown that HPV DNA test is more sensitive and more reproducible that cytology and has high negative predictive value, allowing for increasing the gaps between screening for women testing negative, which allows to reduce the cost of screening. There is growing evidence that it can become alternative to cytological screening and many countries in the developed world have already started to use it as adjunct to cytology. The development of a more affordable self- sampling HPV DNA testing has given the possibility of its use in developing countries, although its sensitivity as compared to clinician collected HPV DNA test is still under speculation (T. C. Wright, Jr. & Kuhn, 2012).
HPV DNA test in clinical practice got its first application for women with abnormal Pap smear referred for colposcopy (Collaco & Zardo, 2008). Studies show that HPV DNA testing can be cost effective and sensitive for detection of precancerous lesions in women with
9 equivocal cytology and commonly used for triage of equivocal cytology in USA (Schiffman et al., 2007). HPV DNA testing also has greater reproducibility than cytology. Although not commonly in practice as cytology yet, the International Agency for Research on Cancer has endorsed the use of HPV DNA testing alone as an option for primary cervical screening.
There are four assays used commonly which gives roughly same results Hybrid Capture 2, the MY09/MY11 primer set and its improvements like PGMY; the GP5+/GP6+ primer set; and SPF10/LiPA PCR-based methods (Schiffman et al., 2007). Globally, the most widely used hrHPV DNA test is the Hybrid Capture 2 HPV Assay (HC2) (Qiagen, Gaithersburg, MD, USA9), and its sensitivity is often used as benchmark for other HPV DNA test. A new hrHPV DNA test modelled on HC2 has been developed for low incomes resource setting, known as care HPV TM (T. C. Wright, Jr. & Kuhn, 2012).
However, since infection with HPV is not a disease in itself, HPV DNA testing will have to be restricted to detecting clearly carcinogenic HPV types in order to prevent over diagnosis, as it could create false anxiety among women about risk of cancer. The commonly used HPV DNA tests so far are however costly and need to be done in specialized laboratories. The new tests for low resource regions are currently under validation studies (Schiffman et al., 2007)
Visual Inspection with Acetic Acid (VIA)
Visual Inspection with Acetic Acid (VIA), also known as cervicoscopy is one of the least costly and easiest screening approaches. It involves examination of the cervix application of 3-5% dilute solution of acetic acid using cotton swab or spray in the transformation zone of the cervix. VIA result is considered positive if acetowhite areas appear in the applied area (Sauvaget et al., 2011; T. C. Wright, Jr. & Kuhn, 2012). It can be also performed using low magnification to inspect cervix, in which case it is called VIA with magnification (VIAM) and with Lugol’s Iodine (VILI). VIA does not require laboratory settings and can give immediate results (M. Arbyn et al., 2008; R. Sankaranarayanan et al., 2005; Sauvaget et al., 2011).
The performance of VIA reported in various studies have been found to be vary from 40% to 90% sensitivity to CIN2+ (Denny, Quinn, & Sankaranarayanan, 2006; Schiffman et al., 2007). Wright and Kuhn (2012) suggests that although the sensitivity of VIA varies across different studies, there is considerable evidence that it can be considered reasonable
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alternative for cytology in developing countries. This is because general evidence is that it is more sensitive than cytology and it does not require expensive laboratory setting (ibid). In addition, since it can provide immediate results, if combined with treatment such as cryotherapy, it can be used as one visit screen and treat option, saving time and cost associated with multiple visits (ibid). Although it sounds straightforward, there are number of problems associated with VIA. The disadvantages of VIA are that it is subjective and more difficult to ensure quality control, its performance declines substantially with age of women over 40 and its specificity is lower than that of cytology (T. C. Wright, Jr. & Kuhn, 2012).
Acetowhitening is non-specific cervical finding because other conditions than CIN2 + lesions such as immature squamous metaplasia or reparative conditions may have acetowhitening, hence can lead to over referral and over treatment (R. Sankaranarayanan et al., 2005; T. C.
Wright, Jr. & Kuhn, 2012). Good training to providers and sustained quality assurance are needed to ensure VIA is effective (Jack Cuzick et al., 2008).
Reporting and Management of Screening Results
The commonly used system for reporting the results of cytology are the Bethesda system and CIN system shown in table 2.2. For details on the reporting system Nayar, et al (2008) can be referred.
Table 2.1 The Bethseda and CIN system from (Nayar, Wilbur, & Solomon, 2008)
The Bethseda system The CIN system
Negative for intraepithelial lesions or malignancy(NILM) Normal Atypical squamous cells of undetermined significance
(ASCUS)
Atypical squamous cells, cannot rule out HSIL (ASC-H)
Low-grade squamous intraepithelial lesion (LSIL) CIN1 High-grade squamous intraepithelial lesion (HSIL) CIN2/CIN3
Carcinoma
Since there are number of countries which have organized cytology based screening programs, the management of abnormal cytological results are in many countries also systematic. Patients with normal results from the primary screening go back to screening at
11 normal intervals. Patients with abnormal screening reports may be asked to repeat the test or combination of tests, also called “triage” test. Different countries have different triage routines with cytology, HPV DNA testing or combination of two tests, and/or colposcopy which have different advantages and disadvantaged including differences in sensitivities and specificities of tests and convenience to the patients (Wright et al., 2002).
Patients with results showing HSIL or CIN2+ are usually evaluated with colposcopy and colposcopy directed biopsy to confirm diagnosis. Colposcopy involves examination of cervix with bright filtered light under 10-15 times magnification following application of 3% acetic acid solution. If colposcopy does not give clear results or if clear visualization is not possible, cervical cone biopsy is done (Burd, 2003). Colposcopy has been commonly used as reference standard for diagnosing precancerous lesion and also to make distinction such as CIN1, CIN2 or CIN3. Clinicians rely on colposcopy and colposcopy directed biopsy to determine presence or absence of invasive cancer, find area of highest degree of disease and direct the biopsy for histological diagnosis. In cases where biopsy sample suggest micro invasion or the patient does not have grossly apparent invasive cancer, a conisation or cone biopsy is required (Waggoner, 2003). Information of location and extent of disease obtained from colposcopy is also important for planning treatment. However, sensitivity of colposcopy has not advanced, given the weak correlation between visual changes and disease severity. The reproducibility of colposcopy is said to be low. It also has high false negative rate because it can miss CIN3 lesions that are smaller and involve fewer quadrants of the cervix. Sensitivity of colposcopy increases if more than one non-random biopsy is taken (Schiffman et al., 2007).
Treatment of Cervical Cancer
Cervical cancer originates from transformation zone of the cervix and spreads to regional lymph nodes (Petignat & Roy, 2007; Schiffman et al., 2007). Clinical presentation depends mainly on the location and extent of diseases, with pre cancers or early stages being asymptomatic. Symptoms include bleeding caused by contact or spontaneously due to tumour, pain in lymph nodes, foul smelling vaginal discharge or backache (Petignat & Roy, 2007). The infection with oncogenic HPV types could stay latent and symptomless for a time.
The primary diagnostic tool for cervical cancer has been cytology and histology (Burd, 2003).
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The treatment of pre-cancer that is commonly used at present is to treat entire transformation zone of cervix of women diagnosed with equivocal (CIN2) or more definite (CIN3) pre cancer. Colposcopy cannot usually ascertain the worst site of pathology and presence of lesion indicates that the entire transformation zone is at risk. Cone shaped excision and cryotherapy are commonly used first options for intraepithelial lesions of the cervix. Loop electrosurgical excision procedure (LEEP) or large loop excision of the transformation zone are popular procedures used because it can be done as an outpatient with local anaesthesia and removes only small part of cervical stroma. But these procedures increases risk of premature deliveries as shown by recent studies. Cryotherapy is a low cost and effective method, widely used in low resource settings since it can be done without local anaesthesia or electricity, although it can lead to discharge during recovery and some possibility of infection. Cold knife cone is used when more extended tissue removal is required. Women treated successfully usually have negative HPV DNA test and those who have negative test after 4 to 6 months have no significant risk of recurrence. Cytology and HPV DNA testing are used to assess cure after treatment (Schiffman et al., 2007).
Cervical cancer is clinically staged using The International Federation of Gynaecology and Obstetrics (FIGO) staging system. Managing the disease depends in which stage the patient is. Table2.2 briefly outlines the commonly used treatment for cervical cancer during various stages (Petignat & Roy, 2007; Waggoner, 2003).
Table 2. 2 FIGO staging system for cervical carcinoma and treatment
Stage Details Treatment
0 Carcinoma in situ or CIN 3
I Invasive carcinoma, confined to cervix Hysterectomy, conisation, radiation, radical trachelectomy, chemoradiotherapy
II Tumour extension beyond cervix to vagina but not to lower third of vagina or Parametrial invasion
Radical hysterectomy, radiotherapy, radical trachelectomy, chemoradiotherapy
III Tumour extension to lower third of vagina or pelvic side wall
Chemoradiotherapy
IV Tumour invasion into bladder or rectum or distant metastasis
Chemoradiotherapy, palliative care,
13 Clinical staging also gives prognostic indicator for survival with cervical carcinoma. For patients in stage IA, 5 year disease free survival approaches 100%, for IA1 and IIB lesions, it is 70-85%, 50–70% for stages IB2 and IIB, 30–50% for stage III, and 5–15% for stage IV (Waggoner, 2003). Lower survival is associated with metastases to pelvic and para-aortic lymph nodes (ibid).
Cervical Cancer Screening in Developing Countries
Although organized cervical cancer screening has been proven to be effective in saving significant number of lives in developed world, there are a number of barriers to expand them into developing world such as competing health care needs, limited human and financial resources, poorly developed health care services, gender related barriers, political instability, widespread poverty. Even when they are present in developing countries, they are often of poor quality, inadequate and inefficient, as a result of which there has been limited impact(R.
Sankaranarayanan et al., 2001)
The screening programs that have been successful so far in developed countries are resource intensive by nature (Denny et al., 2006). This is especially true for cytology based screening, as it requires intensive infrastructure to obtain Pap smear and transport them to laboratories for processing and interpretation. Training cytotechnologist and pathologists needs to be extensive along with quality assured cytological laboratories as cytology is a subjective test and is poorly reproducible. In addition, there is necessity for systems to follow up women with abnormal cytological results and provisions of quality assured colposcopy, pathology and treatment services. This it becomes labour intensive and experience of developed countries is that it requires time to establish high quality cytology program, so although consumables are not costly cytology program becomes costly in total. In addition, to ensure that cytology based programs are effective in reducing death from cervical cancer requires that women are screening frequently as sensitivity of single cytology has been found to be quite low. Furthermore, one cytology test requires at least three visits, which can be problematic in rural and remote settings. This can be expensive and time consuming, leading to high loss to follow-up. Hence the effectiveness of cytology has been found to be low in developing countries and it is often considered not very cost effective low resource setting.
(Jack Cuzick et al., 2008; Denny et al., 2006; Kitchener et al., 2006; Mezei et al., 2017; T. C.
Wright, Jr. & Kuhn, 2012).
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Studies have found HPV DNA testing and VIA to be more effective and cost effective for developing countries and are gaining attention as more effective methods in resource poor setting (Jack Cuzick et al., 2008; Denny et al., 2006; Goldie et al., 2005; R.
Sankaranarayanan et al., 2001; T. C. Wright, Jr. & Kuhn, 2012). Furthermore, WHO also has recommended the use of VIA or HPV DNA testing in resource poor setting where there are no pre-established screening program (WHO, 2013). Study by Sankaranarayanan et al (2001) reports that sensitivity of VIA to detect high grade lesions was similar or higher than that of Pap smear, although specificity was found to be lower. In study by Arbyn et al. (2008) effectiveness of VIA is reported to be higher than HPV DNA test or cytology, but they also report that sensitivity of VIA is inconsistent across the studies, which indicates that there is considerable subjectivity in interpretation of results and hence has lower reproducibility.
Furthermore, the high sensitivities reported in many studies may have been overestimated due to correlation with colposcopy, which is also a visual method (M. Arbyn et al., 2008).
Systematic review by Mezei et al (2017) shows that once in lifetime HPV DNA testing was most cost effective screening strategy when compared with VIA and cytology. Although HPV DNA test is more costly, it is reported to have better effectiveness in most studies (Mezei et al., 2017; T. C. Wright, Jr. & Kuhn, 2012). It is highly sensitive and reproducible, and women who are test negative by HPV DNA testing do not need to be rescreened before 6 years.
However, high unit costs and requirement of relatively sophisticated laboratories makes it a challenge for HPV DNA test to be implemented in low resource settings (T. C. Wright, Jr. &
Kuhn, 2012).
In addition to effective tests, in order to ensure that screening programs works to reduce incidence and mortality, screening should also be followed up by triage of equivocal results, colposcopically guided biopsy of abnormal screening results, decision whether to treat, treatment and post treatment follow-up (Schiffman et al., 2007). Colposcopy may not be available in primary care setting and may create problem of access in low resource settings (T. C. Wright, Jr. & Kuhn, 2012). Furthermore, although it immediately informs presence or absence of significant disease but it can be uncomfortable procedure and can create false concerns about the disease, potential for over diagnosis and over treatment (Wright et al., 2002).
Choosing appropriate screening test is important part of effective screening programs. A good quality and highly sensitive test is important in low resource settings because tests requiring
15 frequently repeated screening is not affordable. From the patient’s perspective as well, tests requiring several revisits for diagnostic evaluations and treatment can act as barrier for participation. Specificity of the tests needs to be high to control the chances of over treatment.
Hence sustainable screening programs that targets high risk women for one or two screening with highly sensitive test with broad coverage are necessary to ensure cervical cancer incidence and mortality is reduced (R. Sankaranarayanan et al., 2001; T. C. Wright, Jr. &
Kuhn, 2012).
2.2 Background of Nepal
Socio-economic and political context
Landlocked between two Asian giants India and China, Nepal is a low income country with an area of 147,181 square kilometres and a population of about 26.5 million people in (CBS, 2015). The country can be divided into three distinct ecological zones running from east to west, consisting of Mountains, Hills and Terai (Rai, Rai, Hirai, Abe, & Ohno, 2001).
Administratively it is divided into 75 districts and 14 zones. Over 80% of the population live in rural areas (CBS, 2014b). The census of 2011 has identified 125 ethnic groups and 123 spoken languages. The national literacy rate is 67%. (CBS, 2014b). Infant mortality rate 32 per 1000 live births and life expectancy at birth is 66.6 years and 44.4% population below 19 years(UN, 2016).
The GDP per capita is 752 US $ (MoF, 2016) (1 US dollars ≈ 100 NRS) and 25.2% people are living below national poverty line (CBS, 2015). There has been a notable progress in health, education and other social services in the past two decades; however, Nepal’s level of human development remains low. According to the Global Human Development Report of 2015, Nepal ranks 145th in the Human Development Index (HDI)(UNDP, 2015). Being a mountainous country with 77% of its land covered by hills and mountains and 35% of land lying above 4800 meters, its difficult terrain is one of the major reasons of low infrastructure development (MOHP, Era, & International, 2012). Like most other low-income countries, agriculture is the major driver of economy contributing over 31% to GDP in 2015/2016 (MoF, 2016), and employing 61% of all the employed population (NLSS, 2011). Another important source of income accounting for 29.1% of GDP in 2011 is remittances (MoF,
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2016). Due to weak performance of the rain dependent agriculture sector and industrial sector disturbed by political instability and energy crisis, GDP growth has mostly remained under 5% in the past decade (MoF, 2016).
Health Care system in Nepal
The development of health sector in Nepal is relatively recent. The country’s first medical hospital, Bir hospital was established in 1889 in Kathmandu (DoHS, 2014). Until 1950 there were only handful of doctors in the entire country (Rai et al., 2001). The first national level health policy was the General Health Plan of 1956 (ibid). Since then, the past six decades has seen marked progress in providing basic health services to the population (DoHS, 2014). The health sector opened up for private investment a little over two decades ago and since then there has been growing participation of private sector in curative services, mostly in urban areas. In addition, there are about four dozen pharmaceutical companies that produce 40%
medicine requirement and the country produces most of the human resources working in health sector (DoHS 2014).
Nepal’s health care facilities can be categorized into private and public facilities. Public health services are delivered through facilities under Department of Health Services (DoHS).
The DoHS under Ministry of Health is responsible for delivering preventive, promotive, diagnostic and curative health services throughout the country. At regional level, there are five regional health directorates that provided technical backstopping as well as program monitoring to districts. The public health service is hierarchical and delivered through health posts, primary health care canters (PHCC), districts hospitals, zonal hospitals, sub regional hospitals, regional hospitals and central level hospitals. Health posts are the first institutionalized contact point for basic health services. There are 3805 health posts, 202 PHCCs or health centres, 75 district hospitals, 20 zonal hospitals, 3 regional hospitals, 3 sub- regional hospitals and 6 central hospitals (DoHS, 2015). The private health facilities are mostly limited around urban areas, where as public health facilities have better network all around the country. There are also non-governmental organizations and community based organizations that work in health sector through community hospitals, camps and so on.
(Karkee & Kadariya, 2013; Mishra, Khanal, Karki, Kallestrup, & Enemark, 2015).
17 District hospitals play a key role in providing outpatient, inpatient and emergency services throughout the country. They also serve as backbone of country’s health services since they are the primary referral point after the primary health care centres. District hospitals have facilities of childcare, maternal care, communicable and non-communicable diseases related services, pathology tests and diagnostic services, X-ray services. They are run by committees formed with members from local bodies and civil societies and financially sustained through government budget and user fees (DoHS, 2015).
In terms of policy, Nepal has comprehensive framework of health policies and plans. For example the national health policy of 1991 aims at the extending the primary health care to rural population. The second long term health plan( 1997-2017) has focus on the health status of women, rural population, poor and underprivileged and marginalized, focus more on low cost high impact Essential Health Care Services (EHCS). Under Free EHCS Program that was started in 2007, government health facilities provides free primary health care services, basic secondary care services and 70 essential medicines (WHO, 2007).
The percentage share of health expenditure is 5.8% of GDP, which accounts to 1.27 billion USD (WHO, 2014). However almost half of the health budget is funded by international donors. The 2014 Annual Report of DoHS reports that 48,47% budget of DoHS was from the international donors (DoHS, 2015). The health expenditure about 40 USD per capita per year and 60% health expenditure is private, out of which, almost 48% of health expenditure is out of pocket payment (WHO, 2014).
The health care system in Nepal faces multiple challenges. Although the basic health services are available free of cost in public hospitals, they are very limited in range and quality is sub- par and in most facilities the users have reported shortage of medicines, expired medicines and limited human resources (K.C., Heydon, & Norris, 2015). Therefore, the poor and disadvantaged do not have affordable access to wide range of health services. The burden of non-communicable disease is growing in Nepal, including cancer and the capability of hospitals in many districts is still questionable. In addition outpatient department coverage in public health facilities are low and stagnating, along with critical shortage of medical personnel, staff absence, lack of relevant skills, maintaining quality and availability of drugs and location of standard physical facilities in some areas. All these factors contribute to high out of the pocket costs for low quality services which are not available where and when needed (WHO, 2007).
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Cervical cancer in Nepal
India, Bangladesh, Nepal and Sri Lanka contribute to one third of global cancer burden but lacks uniform or vigorous control measure (Rengaswamy Sankaranarayanan et al., 2008).
Cervical Cancer is one of leading cause of cancer related death among women in Nepal. In 2012, the number of women were diagnosed with cervical cancer was 2332 (Ferlay J et al., 2012) and more than 50% of patients died from the disease (Cancer, 2016). A 10 year retrospective study carried out in a cancer hospital found that 29% of all cancers were cervical carcinoma (Jha et al., 2009). Another hospital survey carried out in western Nepal reports that cervical cancer is the second leading cancer type for females (19.7% of all cancers ), with lung cancer as the leading cancer (20% of all cancer) (Binu et al., 2007). The peak incidence in age group is found to be between 41-50 years old and most common histopathological type was found to be squamous cell carcinoma non keratinizing type (87.63%) (Pathak, Pun, Shrestha, Bastola, & Bhatta, 2013) (Dhakal & Pradhan, 2009). Over 80% of cervical cancer patients had late diagnosis (stage IIB or more) and 90% of patients had symptoms misinterpreted in initial consultation with health care provider (Gyenwali, Pariyar, & Onta, 2013).
A study by International Agency for Research on Cancer (IARC) reported a prevalence of 8.6%, 6.1%, and 1.9% for any HPV, HR-HPV types, and HPV16, respectively among 932 married women aged 15–59 years from a general population in a city in the south-central part of Nepal. This study also reported that HPV positivity was significantly higher in women living in slums, women with lower levels of education, greater number of sexual partners and women whose husbands have extramarital sexual relationship (Sherpa et al., 2010). It should be noted that there are about 9.1 million women over 15 years old, 6.3 million women above 25 years (CBS, 2014a). This indicates a very large number of women that could be at risk.
Nepali national cervical cancer screening guidelines developed in 2010 recommends to screen at least 50% women aged 30-60 years every 5 years for cervical cancer (DoHS, 2015). It also mentions that the DoHS aims to implement nationwide screening using visual inspection with acetic acid by trained nurses and doctors. In women with signs of precancerous lesions, cryotherapy using compressed carbon dioxide will be used to treat the lesion (DoHS, 2015).
There is no follow up report regarding this plan yet. So far, due to poor level of awareness, lack of nationwide screening program, limited health care resources, and inadequate access to
19 health care due to financial and geographical barriers, very few women undergo screening and most cases of cervical cancer are presented at very late stage of the disease. Lack of laboratory services, trained pathologists, especially in rural Nepal, high cost limits are few of the challenges for low screening rates (Anju Ranjit et al., 2016).
Most screenings are in Nepal at present opportunistic screenings, and are carried out for women visiting gynaecology outpatient department for complaints such as vaginal discharge or severe pain (Pradhan, Giri, & Rana, 2008). In a survey carried out by Ranjit and colleagues, it was found that out of random sample of 829 women between ages 21 to 65 years interviewed; only 5% had undergone a Pap smear test. Their survey showed that literacy level and whether a woman lived in rural or urban area had significant association with having a cervical test (A. Ranjit et al., 2016). In addition, nature of early symptoms determined time of diagnosis. Symptoms involving unusual bleeding were less associated with late diagnosis. This can be attributed to cultural sensitivity and shyness when it comes to sexual and reproductive health due to which women do not discuss problems until the symptoms gets worse such as bleeding accompanied by severe pain (Gyenwali et al., 2013;
Pathak et al., 2013).
From January 2017, Government has announced free Pap smear in all District hospitals in Nepal1. In view of this, other alternatives should be explored with regard to cost effectiveness.
VIA has been considered as cost effective alternative in low resource setting. In addition, compared to no screening, one-time screening has been shown to significantly reduce lifetime risk of cervical cancer. There are also recommendations for cervical smears at prenatal care visits, periodic mobile services, screening for HPV with self-administered swab and primary prevention through HPV vaccination(Goldie et al., 2005).
Being a developing country, the effective use of health care expenditure is an important issue.
There is no universal health insurance and most of the health care expenditure is out of pocket payment in Nepal. Furthermore, government’s EHCS does not cover cancer related treatments or procedure. Treatment of cancer is expensive in any setting, and even more so in a low income country like Nepal. The cost of treatment is further aggravated by the fact that it is not easily available. As reported by Bhatt et al. (2009), there are only five hospitals with radiotherapy facilities all over the country, which makes accessing cancer treatment even
1 According to notice published in Department of Health Service’s website Pap Smear is free in all public hospitals from January 2017. http://tabucs.mohp.gov.np/mohp/Pap_Smear.pdf
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more costly. It may be hence worthwhile to invest in a screening program to reduce incidence of cervical cancer.
However, given limited resources, a sophisticated screening program, with multiple tests and necessity of frequent screening is not feasible in low resource settings as also shown by other studies (Jack Cuzick et al., 2008; Goldie, Kim, & Myers, 2006; Rengaswamy Sankaranarayanan et al., 2008; R. Sankaranarayanan et al., 2001; Sauvaget et al., 2011).
Based on this background, this study aims to find out what kind of cervical cancer screening will be most cost effective for Nepal.
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3 Theoretical Framework
3.1 Economic Evaluations
Economic evaluation can be defined as “the comparative analysis of alternative courses of action in terms of both their costs and consequences” (Drummond, Sculpher, Torrance, O'Brien, & Stoddart, 2005, p. 9). Economic evaluation in health is necessary because resources are scarce and there is need to make structured deliberation of factors involved in a decision to commit these scarce resources to one use instead of other. A good economic evaluation helps a decision maker to clearly identify the relevant alternatives, determine a viewpoint of evaluation and measure uncertainty associated with decision making to certain extent. Economic evaluation involves identification, measurement, valuation and comparison of costs and consequences of alternatives being considered (Drummond et al., 2005).
Costs implies value of the resources used in treatment or intervention, which should include health care resources and social care resources (Gray, Clarke, Wolstenholme, & Wordsworth, 2011). Health costs includes all the tangible resources that are used to provide health care (Briggs, Claxton, & Sculpher, 2006). According to Drummond et al, costs consumed in health programs comprises of four component : health sector costs such as drugs, equipment, hospitalization, physician visits and costs associated with continuing care; other sectors cost such as other public agencies depending upon the kind of disease; patient and family resources which could be out of pocket payment, various co-payments, costs associated with home care and finally productivity losses associated with disease (Drummond et al., 2005).
The cost here reflects opportunity cost, i.e. benefits or utility from other alternatives forgone by selecting the given alternative. Inclusion of range costs depends on the perspective taken during economic evaluation, such as patient perspective, health care perspective and societal perspective (Drummond et al., 2005).
The consequences or outcomes can be measured by change in patient’s health state, other values created by the program as well as the costs saved from the health intervention. The change in health state can be measured in terms of effect (for example life years saved), or valued in terms of health state preferences and willingness to pay (Drummond et al., 2005).
There are number of types of economic evaluation depending upon how the consequences are
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measured, valued and compared (Drummond et al., 2005; Gray et al., 2011). The most commonly carried out economic evaluation are cost effectiveness analysis, cost benefit analysis and cost utility analysis.
In cost effectiveness analysis (CEA), outcomes are measured in natural units such as life years saved, number of episode free days or number of cancer detected. CEA therefore compares alternatives in which costs related to a single common effect that may differ in magnitude. Result of CEA can be expressed in terms of cost per unit of effect or effect per unit cost. CEA is of most use in situation where decision is to be made from limited range of option in a given field under limited budget. It is mostly recommended to use final outcomes, such as life years saved, but in cases where intermediate outcomes are used, it is recommended that the link between final and intermediate outcome be established (Drummond et al., 2005).
Cost Utility Analysis (CUA) uses utilities as a measure of the value of programs effect.
Utilities in health indicates the preferences individuals or society may have for any particular set of health outcomes. Results are expressed in terms of the cost per healthy year or cost per quality adjusted life year (QALY) gained by undertaking one program instead of another.
Using QALY as measure of outcome helps to include both quality and quantity of health change in a single measure, and also helps to compare intervention having different types of health effect, which is not easily accomplished by CEA (Drummond et al., 2005),
Cost Benefit Analysis CBA measures cost and consequences of both alternatives in monetary terms. Results are expressed in the form of ratio of cost to benefits or as sum representing the net benefit or loss of one program over another (Drummond et al., 2005). CBA can provide both absolute and relative benefit of the programmes. The advantage of CBA is that in principle it allows the comparison of interventions across sectors, although assigning monetary value to health benefits is still a challenging task in itself (ibid).
Health programs or intervention may have different time profile for both costs and consequences. Due to existence of time preference, which means individuals as well as society attaches more value to costs and consequences now, it is necessary to discount both cost and consequences. This is done using a standard discount rate which is either a predetermined national rate or popular rate of 5% used in literature (Drummond et al., 2005).
23 WHO recommends use of 3% for both costs and consequences, with recommended testing from 0% to 6% for sensitivity of the result (WHO, 2003).
3.2 Decision Analysis
One of the most important aspect of economic evaluations is accounting for uncertainty involved in decision-making. Decision analytic modelling allows for variability and uncertainty associated with all decisions (Briggs et al., 2006). Decision analysis is defined as a systematic approach to decision making under uncertainty (ibid). Decision analytic modelling is useful in economic evaluations as it provides framework for combining various types of evidence, such as effectiveness evidence, resource use data and in cases of CBA and CUA, quality of life and utility related data for all relevant options. Randomized trials rarely compare all relevant options and data is often taken from multiple sources. In addition, there is need to link intermediate to final endpoints and need to extrapolate results over appropriate time horizon beyond the trial follow up period. Also in some cases, there is need for results of randomized trials to be applicable in decision making context, for example when evidence is not applicable in routine practice, for making evidence relevant in another location or different subgroup of patients. In cases where decision are to be made in absence of formal evidence and on basis of assumptions and judgements, decision analysis provides an explicit analytical framework within which this can be done (Drummond et al., 2005).
Decision trees and Markov models are commonly used decision models (Drummond et al., 2005). For this study, a decision tree model of primary cervical cancer screening has been constructed. The square decision node at the start of the decision tree indicates the decision point between the alternatives and each branch emerging from the decision represents the alternates that can be chosen. The circular chance node represents the point where two or more alternative events can happen to the patient. These alternates are shown by the branches coming out from the chance nodes. Each branch as probability associated with it, which shows the probability of a particular event occurring at a chance node. As we move from left to right branches, probabilities on right are conditional probabilities depended on probabilities to the left of the nodes. The routes of mutually exclusive sequence of events are called pathways, which end at triangular nodes. Each branch has cost and outcome associated with it. The expected costs and outcomes for each are calculated by multiplying the costs and outcomes associated with probability of moving through that pathway(Briggs et al., 2006).
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Decision analytic models can be deterministic or probabilistic. Deterministic model uses point estimates for input parameters, and the output of the model is also a point estimate. On the other hand, probabilistic models use probability distribution for input parameters. The distribution assigned to parameter depends on its character, for example beta distribution are used for input parameters that are probabilities, dirichlet distribution for multinomial data, gamma distribution for cost data and log normal distribution for utilities and relative risks.
The output of probabilistic models gives a distribution of costs and outputs (Briggs et al., 2006).
3.3 Analysis and Presentation of Results
The alternative options in economic evaluation are compared in terms of incremental costs and effects, expressed as incremental cost effectiveness ratio (ICER), which are defined as additional cost per extra unit of effect from the more effective treatment (Briggs et al., 2006).
If a new treatment or intervention costs less with more effect, it is considered dominant and hence more cost effective. However, in cases where new intervention is more costly but has more effects as well, the intervention having higher ICER as compared to next most effective strategy is said to be having extended dominance (Drummond et al., 2005; Gray et al., 2011).
ICER can be represented as given equation below:
ICER = 𝐶2−𝐶1
𝐸2−𝐸1
=
∆𝐶∆𝐸 (i)In the above equation, the numerator is the difference in costs or incremental cost (ΔC= C2- C1) between two interventions and the denominator is the difference in effects or incremental effect (ΔE=E2-E1). In cases where there are more than two alternatives being compared, the dominated and extendedly dominated options are excluded. Among the non-dominated options, ICER is calculated by ranking interventions from least costly to most costly comparing each option with next more costly and more effective option. The ICERs are presented in Cost Effectiveness (CE) plane. The line joining non dominated options in the CE plane is known as cost effectiveness (CE) frontier and options lying internal to this frontier are not cost effective. In probabilistic analysis, the costs and effects will have several estimates in the cost effectiveness plane (Briggs et al., 2006; Drummond et al., 2005).