Volume II. Health and Economic Outcomes of Human Papillomavirus (HPV) Vaccination in Selected Countries in Latin America:

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1 Volume II Health and Economic Outcomes of Human Papillomavirus (HPV) Vaccination in Selected Countries in Latin America: A PRELIMINARY ECONOMIC ANALYSIS 2008 A collaborative project of The Albert B. Sabin Vaccine Institute (SVI), Washington, DC, USA Harvard School of Public Health, Boston, MA, USA Institut Catalá d Oncología, Barcelona, Spain Pan American Health Organization (PAHO) Washington, DC, USA Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA Prepared by Dagna Constenla, Sue Goldie, Nelson Alvis, Meredith O Shea, Steven Sweet, Marite Valenzuela, Gabriel Cavada, Fernando de la Hoz, Emilia Koumans, Maria N Labbo, Cait Koss, Hector Posso Disclaimer The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention P age 119

2 TABLE OF CONTENTS VOLUME II EXECUTIVE SUMMARY CHAPTER 1 INTRODUCTION 1.1 BACKGROUND 1.2 STUDY AIMS CHAPTER 2 METHODS 2.1 ECONOMIC LITERATURE REVIEW 2.2 COST-EFFECTIVENESS ANALYSIS ANALYTIC OVERVIEW OVERVIEW OF MODELS PERSPECTIVE AND SCOPE OF THE ANALYSIS MODEL INPUTS SENSITIVITY ANALYSIS CHAPTER 3 RESULTS 3.1 DESCRIPTION OF ECONOMIC PAPERS REVIEWED 3.2 COST ANALYSIS COSTS OF TREATING PRECANCEROUS LESIONS AND CERVICAL CANCER DIRECT NONMEDICAL COSTS ASSOCIATED WITH PRECANCEROUS LESIONS AND CERVICAL CANCER OVERALL CANCER TREATMENT COSTS ECONOMIC EVALUATION HEALTH OUTCOMES FOR ADOLESCENT HPV 16 AND 18 VACCINATION COST-EFFECTIVENESS OF VACCINATION FINANCIAL IMPLICATIONS OF HPV 16 AND 18 VACCINATION CHAPTER 4 DISCUSSION 4.1 MAIN FINDINGS 4.2 REGIONAL CONTEXT 4.3 LIMITATION OF THE LITERATURE REVIEW 4.4 LIMITATIONS OF THE EPIDEMIOLOGICAL DATA 4.5 LIMITATIONS OF THE ECONOMIC STUDY REFERENCES P age 120

3 APPENDIXES Appendix A. Model comparison validation: Impact of HPV 16 and 18 vaccination on mean reduction in lifetime risk of cervical cancer Appendix B. Epidemiological parameters (tables) Appendix C. List of physicians interviewed Appendix D. Sample expert interview survey Appendix E. Summary of screening strategies across studied countries Appendix F. Summary of treatment of precancerous lesions across studied countries Appendix G. Diagnostic and staging procedures and treatment modalities of invasive cervical cancer by stage across studied countries Appendix H. Unit costs associated with the detection and treatment of precancerous lesions and treatment of cervical cancer by stage and country Appendix I. Costs of transportation and lost work time associated with precervical cancer and invasive cervical cancer by stage and country Appendix J. Vaccination cost per vaccinated girl and components of cost, expressed in different currencies by country P age 121

4 TABLES AND FIGURES Table 1. Treatment costs associated with precancerous lesions and cervical cancer (International dollars, 2005) Table 2. Direct nonmedical costs of precancerous lesions and cervical cancer (International dollars, 2005) Table 3. Cancer treatment cost estimates and model inputs (International dollars, 2005) Table 4. Adolescent HPV 16 and 18 vaccination: health outcomes Figure 1: Impact of HPV 16 and 18 vaccination on deaths averted for multiple birth cohorts for six Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico, and Peru) Table 5. Adolescent HPV 16 and 18 vaccination: CEA with assumption of lower-bound cancer costs and vaccine cost of I$25 (~I$5 per dose) Table 6. Adolescent HPV 16 and 18 vaccination: CEA with assumption of upper-bound cancer costs and vaccine cost of I$25 (~I$5 per dose) Table 7. Adolescent HPV 16 and 18 vaccination: CEA with assumption of lower-bound cancer costs and vaccine cost of I$50 (~I$12 per dose) Table 8. Adolescent HPV 16 and 18 vaccination: CEA with assumption of upper-bound cancer costs and vaccine cost of I$50 (~I$12 per dose) Table 9. Adolescent HPV 16 and 18 vaccination: CEA with assumption of lower-bound cancer costs and vaccine cost of I$75 (~I$20 per dose) Table 10. Adolescent HPV 16 and 18 vaccination: CEA with assumption of upper-bound cancer costs and vaccine cost of I$75 (~I$20 per dose Table 11. Affordability and budget implications of HPV 16 and 18 vaccination based on varying costs per vaccinated girl for 70% coverage of five birth cohorts P age 122

5 ABBREVIATIONS CDC CEA CIN CI5C DALY GDP GLOBOCAN IRAC HPV HPV DNA ICER Centers for Disease Control and Prevention Cost-Effectiveness Analysis Cervical intraepithelial neoplasia Cancer Incidence in Five Continents Disability-Adjusted Life Year Growth Domestic Product Global Burden of Cancer International Agency for Research on Cancer Human Papillomavirus Human Papillomavirus Deoxyribonucleic Acid (Screening Test) Incremental Cost-Effectiveness Ratio I$ International Dollar LAC LEEP MeSH PAHO PPP QALY SVI VIA Latin America and the Caribbean Loop Electrosurgical Excision Procedure Medical Subject Headings Pan American Health Organization Purchasing Power Parity Quality-Adjusted Life-Year Sabin Vaccine Institute Visual Inspection using Acetic Acid (Screening Method) VILI Visual Inspection using Lugol s Iodine (Screening Method) P age 123

6 WHO YLD YLL YLS World Health Organization Years Lived with Disability Years of Life Lost Years of Life Saved P age 124

7 EXECUTIVE SUMMARY Background and Aim Human Papillomavirus (HPV) is a virus associated with cervical cancer and other malignancies. Although high-risk HPV types 16 and 18 are two of the most common cancer-causing HPV types, responsible for more than 70% of invasive cervical cancer, variation exists both in the age-related prevalence of HPV and in the proportions of HPV 16 and 18 associated with cancer. Recently, vaccines against HPV types 16 and 18 have created opportunities for primary prevention in areas where organized secondary prevention with screening has been difficult. The aim of this document is to provide estimates of the health and economic outcomes of HPV vaccination in selected countries in Latin America. The findings will be used to inform national health authorities about the burden of HPV and the economic value of implementing an HPV vaccination program in selected countries of the region. This document is the second of a two-part report; the first part is a meta-analysis of the burden of HPV in Latin America and the Caribbean; this second part is a cost-effectiveness study of HPV vaccination. This document complements the meta-analysis (described elsewhere) and provides specific economic information for six selected countries in Latin America. Although some of the epidemiologic estimates from the two documents may differ because of differences in methods, the reports should be viewed as complementary in aiding understanding of HPV infection and its financial and human cost in Latin American and Caribbean countries. Methods We synthesized available data to estimate the cost-effectiveness of vaccination for HPV 16 and HPV 18 in six selected countries in Latin America (Argentina, Brazil, Chile, Colombia, Mexico, and Peru). We conducted a comprehensive literature review of epidemiologic data in countries of the region to gain information about age-specific rates of cervical cancer incidence and mortality and about distribution of HPV 16 and HPV 18 associated with cervical cancer. We researched national treatment guidelines to establish treatment practices for precancerous lesions and cervical cancer in each country. To further determine cervical cancer treatment by stage and cost of care, we conducted surveys in several countries of the region in person and by telephone or . These surveys contained specific questions about screening for precancerous lesions and about diagnosis and treatment of cervical cancer. In addition, surveys P age 125

8 were conducted from which we derived assumptions about the costs required to vaccinate preadolescent girls against HPV. To conduct the cost-effectiveness projections, we used an Excel-based model developed as a companion model to a previously validated microsimulation model of HPV infection and cervical cancer. The Excel-based model relies on simplified assumptions to explore the costs and benefits of vaccination and is less data intensive than a comprehensive microsimulation model; as such, it is an appropriate tool if its use is restricted to generating broad qualitative insights into the potential benefits of vaccination against HPV 16 and HPV 18 for preadolescent girls in the six selected countries. This model cannot compare screening costs and benefits with those of vaccination. To provide contextual insights into the benefits and cost-effectiveness of vaccination compared with screening and of vaccination combined with screening, we also show results from previously published models developed by Goldie et al. for selected countries for which adequate epidemiologic data were available to conduct empirical calibration. These previously published models evaluate the cost-effectiveness of prevention strategies that include both vaccination and screening. Model outcomes include the following measures: reduction in lifetime risk for cervical cancer, number of averted cervical cancer cases and deaths from cervical cancer, number of years of life saved (YLS), number of averted disability-adjusted life years (DALYs), and lifetime costs. Although not age-weighted, DALYs reflect the disability weight and duration estimates for cervical cancer as provided in the Global Burden of Disease study conducted by the World Health Organization (WHO) [119]. This report describes the performance of vaccination strategies by using incremental costeffectiveness ratios, which are defined as the additional cost of a specific strategy, divided by its additional benefit (life expectancy gain per woman). Each cost-effectiveness ratio is compared with that of the next most costly strategy. Results are presented in International dollars (I$, 2005) for broad comparison across countries, and financial costs are also expressed in local currency and U.S. dollars for use by local and regional decision makers. We followed recommendations from several published sources for economic evaluations and adopted a modified societal perspective and discounted future costs and life years by 3% annually. P age 126

9 To enable country-specific payors to differentiate cost-effectiveness results (i.e., information on value for money from a long-term perspective) and affordability (i.e., information on financial costs and budget limitations over a short time), we provide crude estimates of the financial costs of vaccination. Findings HPV is a relatively common infection affecting an estimated 20 million people in the United States and causing annually nearly half a million cases of cervical cancer worldwide. Cervical caner is caused by certain types of HPV, mainly types 16 and 18. According to the World Health Organization, cervical cancer accounts for more than 2.5 million years of life lost (YLL) each year. Based on available data for six countries, the total direct medical cost per case for screening ranged from I$10 to I$81 per woman and from I$534 to I$1,402 per woman for treatment of precancerous lesions. Highest screening costs occurred in Argentina, and highest treatment costs occurred in Brazil. These costs were mainly attributed to the cost of specialist consultation (in the case of screening) and hospital stay (in the case of treating precancerous lesions). The cost of cervical cancer treatment was much higher than precancerous lesion treatment and ranged from I$3,745 (Peru) to I$14,438 (Argentina) per woman, with highest costs for more advanced stages of cervical cancer. The majority of this treatment cost was attributed to the costs of hospital stay and palliative care. Using an Excel-based model to evaluate the clinical benefits of vaccination in the six selected countries of the region and assuming 70% vaccination coverage by 12 years of age, lifelong immunity, and 100% efficacy against HPV types 16 and 18, we found that HPV vaccination reduced cancer incidence by approximately 40% in Mexico and Chile, and by more than 50% in Argentina. With vaccination, almost 45,000 cancer deaths and 74,000 cervical cancer cases could be averted over the lifetime of a single birth cohort, compared to outcomes with no intervention. Most averted cases and deaths would appear in Brazil, where cervical cancer is more common than in other countries of the region. When 10 birth cohorts are considered, assuming 70% coverage, we would expect to prevent nearly half a million deaths over the lifetime of the vaccinated girls in the region. If cancer costs were reduced and cost per vaccinated girl were I$100, the Excel model s assessment of the cost-effectiveness ratio for preadolescent vaccination, compared with no intervention (no screening or vaccination), shows that the cost per saved life-year from a societal perspective would range from I$670 (Chile) to I$1,500 (Mexico). At lower costs of I$75 per Page 127

10 vaccinated girl (I$20 per dose), I$50 per vaccinated girl (I$12 per dose), and I$25 per vaccinated girl (I$5 per dose), the cost per saved year of life would range from I$420 (Chile) to I$1,040 (Mexico), I$180 (Chile) to I$580 (Mexico), and I$10 (Brazil) to I$160 (Peru), respectively. At I$25 per vaccinated girl (I$5 per dose), vaccination was cost saving in Chile and Argentina. Because these results were generated for vaccination only, the incremental ratios appear more attractive than they would if the baseline for comparison was screening. For example, previously published independent models that include screening as well as vaccination show that as the cost per vaccinated girl approximates I$100, vaccination plus screening (at ages 35, 40, and 45) is more effective than vaccination alone, although the incremental cost-effectiveness ratio increases (i.e., becomes less attractive) with higher vaccine costs. For example, in Mexico, a combined vaccination and screening strategy at I$75, I$100, and I$360 per vaccinated girl (using 2-visit HPV DNA testing) results in costs of I$1,530, I$1,780, and I$7,070 per YLS, respectively, compared with cost-effectiveness ratios of the next best strategy. According to published data, at the vaccine price of I$360 per girl (the approximate current 2008 U.S. vaccine price) screening, with or without vaccination, used as the main cervical cancer prevention option in countries able to provide screening, was generally more cost-effective than vaccination alone. As the cost per vaccinated girl declines, however, preadolescent vaccination followed by screening three times per lifetime may be the most effective option in countries able to provide both. In the poorest countries in this region, vaccination alone, if available for a markedly reduced price and if widespread coverage of young girls is achievable, may be the most feasible option to reduce cervical cancer. Although vaccination appears to be cost-effective according to the criterion of the incremental cost-effectiveness ratio being less than the per capita Gross Domestic Product (GDP) of a specific country, vaccination may not be affordable. Even an intervention that provides good value for invested resources may have prohibitive financial requirements that cannot be met by the health care systems of countries studied. For those six countries, the financial costs would be $270 million (present value discounted 3% annually) to vaccinate five birth cohorts at 70% coverage with a cost per vaccinated girl of I$25. At a cost of I$50 per vaccinated girl, the financial costs of vaccinating just five birth cohorts at 70% coverage would be nearly $600 million; at a cost of I$360 per vaccinated girl, the cost would be more than $4 billion. These estimates of costs for broad coverage show the important difference between cost-effectiveness and affordability. Limitations of this analysis include gaps in our understanding of the natural history of HPV, uncertainties about the epidemiology and temporal trends of cervical cancer in many countries, P age 128

11 lack of high-quality data on screening, costs associated with HPV-related diseases, and access to and costs of cervical cancer treatment for many countries. Data are lacking on the cost of initiating, enhancing, and maintaining a new adolescent vaccination program and on the longterm efficacy of the vaccine (i.e., whether it will provide life-long immunity). For countries with ongoing screening, the cost-effectiveness of vaccination strategies, either alone or combined with screening, is heavily dependent on assumptions about the quality, coverage, effectiveness, and costs of screening. Collecting these data will be critical for facilitating evidence-based vaccine decisions. P age 129

12 CHAPTER 1 INTRODUCTION 1.1 Background According to the Centers for Disease Control and Prevention (CDC), approximately 20 million people are currently infected with Human Papillomavirus (HPV) [105]. HPV is a virus that causes genital warts and has been associated with cervical cancer and other malignancies. Cervical cancer is the second most frequent malignant neoplasia affecting women worldwide, accounting for approximately 10% of overall cancer incidence among women [106]. Cervical cancer is also the primary cause of cancer-related deaths among women. In 2000, 470,606 cases and 233,372 deaths associated with cervical cancer were reported [2, ]. The majority (80%) of this burden arises in less developed countries, where cervical cancer is the leading malignancy in women [107,108,110]. Recent estimates from the World Health Organization (WHO) suggest that in the Latin American and Caribbean region, cervical cancer accounts for 2.5 million years of life lost (YLL) [2], 72,000 cases, and 38,000 deaths. The estimated age-adjusted incidence rates for cervical cancer are 32.6 per 100,000 women in the Caribbean, 30.6 per 100,000 women in Central America, and 28.6 per 100,000 women in South America [2]. Cervical cancer is fully preventable when early detection and screening programs are available. However, despite these programs effectiveness and low cost, they have proven to be relatively unsuccessful in Latin America and the Caribbean (LAC). This lack of success is due in part to the apparent absence of well-organized screening programs, which are difficult to implement in lowresource settings [111]. Another reason these programs are unsuccessful is because women with abnormal cytology results are not always tracked [111]. In Mexico, fewer than 13 percent of potentially preventable cases have been averted despite having a screening program in place for more than 20 years. Costa Rica is another country where screening programs have met with limited success. Only a small number of prevented cases have been reported since national screening programs were established forty years ago. The potential benefits of HPV vaccination are considerable. Currently, two vaccines are available that are designed to protect against the two most aggressive types of HPV. The first vaccine, Gardasil (quadrivalent) (Merck & Co., Inc., Whitehouse Station, New Jersey, USA), was approved by the U.S. Food and Drug Administration in The second vaccine, Cervarix (bivalent) (GlaxoSmithKline [GSK] Biologicals, Inc., Rixensart, Belgium), was approved in Australia by the Therapeutic Goods Administration of Australia in Persons most likely to P age 130

13 benefit from these vaccines are young girls and preadolescents (starting at age 9) who have not yet become sexually active. However, even if women are vaccinated with these recently approved vaccines, they will still need a regular Papanicolaou (Pap) smear and, depending on their age, an HPV DNA test because HPV vaccines do not reduce the risk for cervical cancer completely. Approximately 15 types of the HPV virus can cause cervical cancer. Gardasil and Cervarix are designed to protect against two HPV types that are responsible for 70% of all cervical cancers [112]. Gardasil also protects against HPV types 6 and 11, which cause genital warts. Researchers in a 2006 study published in the online edition of Lancet found that Cervarix also prevented infection with HPV strains 31 and 45, which, together with strains 16 and 18, cause more than 80% of cervical cancer cases [9]. Recently GSK announced that it would begin a trial to determine whether Cervarix provides better protection against cervical cancer than Gardasil [113]. 1.2 Study aims The aims of this report are to briefly review the economic evidence for cervical cancer screening and HPV vaccination, to provide an estimate of the cost of cervical cancer screening and treatment in six selected countries of the LAC region (Argentina, Brazil, Chile, Colombia, Mexico, and Peru), and to estimate the health and economic outcomes of HPV vaccination. This study is the second part of a two-part report available to policy makers for evaluating the feasibility of implementing an HPV vaccination program in these countries. The first part of the report focuses on a meta-analysis of the burden of HPV in Latin America and the Caribbean. Available data, not necessarily derived only from the meta-analysis, were used to develop projections of the costeffectiveness of HPV vaccination; hence, differences may be observed in number of cases and deaths in the two parts of the report. P age 131

14 CHAPTER 2 METHODS This section begins with a description of the economic literature review, including the search strategy. The literature review description is followed by a brief discussion of the methods and model framework, perspective and scope of the analysis, model inputs, and sensitivity analyses. 2.1 Economic literature review We conducted an economic literature review simultaneously with the systematic review of epidemiologic studies described in the first part of this report. References with relevant economic data were included to provide a critical overview of the economic issues related to HPV and to assess the implications for prevention strategies (e.g., screening and vaccination). We identified relevant studies, including general economics papers, studies on the burden or cost of illness, economic evaluations, and official reports from countries in the region. Most of these papers were published in English or Spanish from 2003 through Much of the published literature and some of the completed study reports in the public domain were obtained from the PubMed- MEDLINE, Bireme-MEDLINE, Bireme-LILACS, SciELO, and the COCHRANE library databases. Manual bibliographic searches revealed additional articles. Articles that were not true economic evaluations (e.g., reviews of applied studies, commentaries, or editorials without original data) were excluded, as were some articles that substantially replicated results from other articles. Due to the limited range of published studies originating in LAC, studies from North America and Europe were included. We also considered studies containing only abstracts as well as work in the process of being published. The medical subject heading (MeSH) terms used to survey the literature on the cost of HPV included costs, cost analysis, cost of illness, cost-benefit analysis. MeSH terms used to survey the literature on the economics of vaccines included costs, cost analysis, cost of illness, hospital costs, cost control, cost-effectiveness analysis, cost-benefit analysis, cost savings, delivery of health care, drug costs, economic value of life, healthcare costs, HPV and vaccination. Based on predefined inclusion and exclusion criteria, we abstracted full-text peer-reviewed studies for the final economic analysis. We reviewed the selected studies for country of P age 132

15 evaluation, publication year, vaccine strategies assessed, study design, method of evaluation, cost measures, perspective, and period of analysis used. We report results are as they were presented in the literature. That is, no adjustments of expenditures or savings to present value were made. 2.2 Cost-effectiveness analysis Analytic overview We synthesized the available data to estimate the incremental cost-effectiveness ratios (ICERs) of HPV vaccination for six countries in Latin America (Argentina, Brazil, Chile, Colombia, Mexico, and Peru). These countries were selected because of their available epidemiologic and economic data and their willingness and ability to participate. Each country s economic, social, and political climates were also considered, although these factors did not necessarily affect inclusion. The models we used integrated health burden estimates and economic burden estimates generated by this study to develop country-level estimates of the value for money represented by the investment in and use of the existing HPV vaccines (Gardasil and Cervarix ). These vaccines are the only ones that may help guard against diseases caused by HPV types 16 and 18, which together cause 70% of cervical cancer cases [3]. Both are given as three injections over six months. Gardasil is recommended for use in girls and young women 9 26 years of age, and Cervarix is recommended for use in girls and young women years of age. We conducted a comprehensive literature review of epidemiologic data in countries in the region to gather information about age-specific cervical cancer incidence rates and the distribution of HPV 16 and HPV 18 in cervical cancer cases [11]. We describe the performance of vaccination strategies by using incremental cost-effectiveness ratios, defined as the additional cost of a specific strategy, divided by its additional benefit (per life expectancy gain per woman), compared with the next most costly strategy. Results are presented in international dollars (2005) for purposes of broad comparison across countries, and financial costs are also expressed in local currency and U.S. dollars to assist local and regional decision makers. All future costs and health benefits were discounted at an annual rate of 3% [114]. P age 133

16 To provide information that enables country-specific payors to differentiate cost-effectiveness results (i.e., information on value for money from a long-term perspective) and affordability (i.e., information on financial costs and budget limitations over a short time horizon), we provide crude estimates of the financial costs of vaccination. As an approximate benchmark and for comparison purposes only, we used the per capita Gross Domestic Product (GDP) as a threshold and assumed that vaccination strategies costing less than a country s per capita GDP might be cost-effective Overview of models To conduct the cost-effectiveness projections, we used an Excel-based model developed as a companion model to a previously validated microsimulation model of HPV infection and cervical cancer [115]. The Excel-based model relies on simplified assumptions identified as reasonable by comparing results of this model s projected benefits and cost-effectiveness to those generated by the more complex microsimulation model. An exercise to demonstrate the validity of comparing simplified assumptions appears in Appendix A and has been published [11]. The Excel-based model may be used to explore the costs and benefits of vaccination and is less data intensive than the comprehensive microsimulation model; as such, the Excel-based model is an appropriate tool provided its use is restricted to generating broad qualitative insights into the potential benefits of vaccinating preadolescent girls against HPV 16 and HPV 18. The Excelbased model follows cohorts from birth to death (100 years). The microsimulation model is described elsewhere [115]. Model outcomes include reductions in the lifetime risk for cervical cancer, the number of averted deaths from cervical cancer, and lifetime costs. Outcomes also include increases in number of averted cases of cervical cancer, years of life saved (YLS), and disability-adjusted life years (DALYs) averted. DALYs reflect the disability weight and duration estimates for cervical cancer as provided in WHO s Global Burden of Disease study [121], although the DALYs are not age weighted. After integrating the epidemiologic data, we assumed the following: (1) the overall mean duration of time between development of invasive cancer and death is 6 years but may vary from 2 to 10 years; (2) distribution of cervical cancer by stage in an unscreened population is 30% local, 40% regional, and 30% distant, although stage distribution varied in sensitivity analyses; (3) ratio of P age 134

17 mortality to incidence varies by country, with the poorest countries (e.g., Haiti) having mortality to incidence ratios of 80% (range, 60% 90%) and other countries having ratios of about 60% (range, 40% 80%); and (4) cancer incidence has not appreciably changed with low levels of effective cervical cytology screening. Because our goal is to identify the avertable burden and potential cost-effectiveness of vaccination against HPV 16 and 18 and because the model did not include screening, we do not examine strategies that include both vaccination and screening. For practical reasons, we assumed that scaling up cervical cytology to a high coverage level and a high-quality screening program are not realistic options. We also assumed the following about the performance of the HPV vaccine: (1) the vaccine effectively prevents HPV 16 and 18 in girls without previous infection and provides longlasting protection against HPV 16 and 18; (2) the vaccine, even at high coverage rates, does not alter the risk of cervical cancer associated with HPV types other than 16 and 18; and (3) successful coverage is defined as completion of a three-dose course by a girl. We assumed 70% population coverage, although we varied coverage from 0% to 90%. Results are presented for a strategy for 2007 of 70% vaccination of a single birth cohort of preadolescent girls (i.e., 12 years old), using a 100% effective vaccine at a cost ranging from I$25 to I$360 per vaccinated girl. To provide insights into the benefits and cost-effectiveness of vaccination relative to screening and of vaccination combined with screening, we summarized selected results from previously published models developed by Goldie et al. for a few countries with adequate epidemiologic data to conduct empirical calibration. These previously published models evaluated the costeffectiveness of strategies that included both vaccination and screening [11] Perspective and scope of the analysis We performed the analysis from a modified societal perspective, which considered all direct medical and nonmedical costs borne by governments and families (costs for cancer treatment included women s time and transportation costs). We also considered the health care system in the base case analysis and included costs borne by medical facilities, providers of health care, and other facilities and providers of vaccine-related services. P age 135

18 2.2.4 Model inputs Health outcomes The primary outcome measures considered for both models were the total health-care and nonhealth-care costs of cervical cancer and the disease burden and societal costs averted by vaccination. Number of cases of cervical cancer, number of deaths from cervical cancer, YLSs, disability-adjusted life years (DALYs) averted, and lifetime costs (in 2005 international dollars) were also calculated. ICERs compare the difference in cost with and without HPV vaccination over the difference in health outcome with and without HPV vaccination. For the cost-effectiveness analyses, medical costs averted by vaccination were subtracted from costs invested in vaccination and then divided by the health outcome. An example of the relationship between cost and health outcome is described by the following ICER: ICER = Vaccine related costs averted disease costs DALYs averted by vaccination Epidemiologic data For our companion Excel-based model, which is intended to provide broad qualitative insight into the potential benefits of HPV vaccination, we used cervical cancer incidence rates and prevalence of HPV 16 and 18 among women with cervical cancer. Cervical cancer incidence rates were drawn from GLOBOCAN 2002 (the WHO database containing estimates of incidence and mortality for the year 2002) [119] or from cancer registry data available in Cancer Incidence in Five Continents (CI5C) [110]. CI5C incidence data cover entire national populations or samples of these populations from selected regions. We applied data hierarchically according to quality, with the best data considered to be those from CI5C followed by data from GLOBOCAN 2002 (see Appendix B for rates). We used a meta- P age 136

19 analysis to estimate the proportion of HPV 16 and HPV 18 in cervical cancer cases 1 [116]. For those countries with specific information in the meta-analysis, we used the provided estimate or the pool of estimates for the country if more than one citation was included. For those countries without specific information, we devised a regional pool. Smith et al. include both single- and multiple-type HPV infections [116]; women with multiple HPV types are counted more than once, so the overall prevalence of HPV types totals more than 100%. Specifically, women with both HPV 16 and 18 are counted twice; therefore, the HPV 16 and 18 distribution is inflated. To avoid that overestimate, we used a hierarchical classification in which multiple types are assigned according to the most common type, and women are counted only once. For example, a woman with both HPV types 16 and 18 is classified as HPV 16. This classification implies that the prevalence of HPV 16 remains the same, but the prevalence of HPV 18 decreases, thus altering the HPV16/18 distribution. The prevalence of HPV 18 was corrected for cervical cancer cases with multiple types 16 and 18 when this information was reported (provided by the International Agency for Research on Cancer). The final prevalence of HPV 18 that we report is the prevalence presented in the Smith et al. meta-analysis less the prevalence of women with both types. For those studies with multiple types but no specific information, we used a 3.3% correction (i.e., overall average of prevalences from articles with available information on multiple types 16 and 18). Because cancer prevalence is thought to be underestimated in some of these data sources, we conducted sensitivity analyses to explore the implications of underreporting and underestimation. The model relies on detailed population data by age for each country. Demographic estimates for age-group specific population size and age-group specific life expectancy were drawn from United Nations World Population Prospects 2004 data [117] and from 2004 WHO life tables [118]. We assumed that the average age at initiation of sexual activity and the levels of other risk factors remained constant over the time horizon. DALYs In addition to estimating numbers of cases and deaths, we expressed the disease burden in DALYs, which provide a standardized measure of disease burden that allows for cross-disease comparisons of burden [119]. DALY estimate includes two components: YLL due to premature mortality and years lived with disability (YLD). Calculations of YLL were based on country-specific 1 Estimates of the proportion of HPV 16 and HPV 18 in cervical cancer derived from the Sabin Vaccine Institute meta- P age 137

20 mean life expectancies for girls 9 and 12 years of age (Excel model) [118]. For the calculation of YLD, we considered morbidity only from disease severe enough to require medical care. We calculated YLD by using default disability weights from WHO s Global Burden of Disease study [119] and WHO s guidelines for cost-effectiveness studies [120]. The calculated DALYs reflect the disability weight and duration estimates for cervical cancer as provided in the Global Burden of Disease [121]. This calculation is not age weighted and uses an annual discount rate of 3%. Use of health services for early detection of precancerous lesions and treatment of cervical cancer National guidelines for the detection of precervical cancer and treatment of cervical cancer were available for each of the six selected countries. Most of these guidelines were published by government-sponsored institutions that focused on early detection and treatment of cervical cancer in each country. We used these guidelines to derive resource-use profiles 2 for each country. We used the resource-use profiles to learn about treatment practices in each country and to help identify the level of input of each resource in the treatment of precancerous lesions and cervical cancer. National guidelines generally included what, in theory, is provided to and for patients who are at risk for precancerous lesions or who are diagnosed with cervical cancer. The information in these guidelines was not always complete. To augment this information, we contacted HPV researchers in nine countries and asked them to respond to a survey. We visited some of these researchers in Argentina, Brazil, Chile, and Colombia and corresponded with others by telephone or . We surveyed health care providers to determine HPV treatment by stage and cost of care. In addition, we reviewed conference abstracts, and, with the help of the Pan American Health Organization (PAHO), we contacted national Ministries of Health in nine countries in the region to identify additional information about cervical cancer treatment. The survey sent to health researchers contained specific questions about screening for precancerous lesions and about the diagnosis and treatment of cervical cancer. Most of the experts interviewed were obstetricians, oncologists, or primary care physicians working in the analysis were not available at the time of the analysis. 2 Resource use profiles included diagnosis for precervical cancer, treatment for precervical cancer, diagnosis and staging for invasive cervical cancer, treatment of invasive cervical cancer by stage, follow-up treatment by stage, and palliative care by stage. P age 138

21 public sector, but we also interviewed physicians working in the private sector. Fourteen physicians responded to the surveys. Appendix C provides a list of all physicians interviewed. Surveys were originally developed in English and were translated into Spanish and Portuguese to facilitate physicians responses. Appendix D contains an example of the Spanish version of the survey. The surveys contained two sets of questions: the first set addressed practices used in the early detection of precancerous lesions; the second set addressed diagnosis and treatment practices (acute and long-term care) for invasive cervical cancer by stage (i.e., stages IA1, IA2, IB1, IB2, IIA, IIB, IIIA-IIIB, IVA, and IVB). Although we were unable to include a comparative screening strategy for the Excel-based model, we made a substantial effort to identify screening information (e.g., coverage, protocols, guidelines, and costs) for the following reasons: (1) to provide qualitative comparisons to vaccination outcomes, (2) to conduct future cost-effectiveness analyses using more complex models that can accommodate simulation of primary and secondary prevention, and (3) to provide useful information to countries for comparison of financial costs associated with screening with financial costs required for vaccination. We reviewed studies including both screening and vaccination. We also summarize selected results from previously published models developed by Goldie et al. for some countries having adequate epidemiologic data for conducting empirical calibration. These previously published models evaluated the cost-effectiveness of strategies that included both vaccination and screening [11]. The information we gathered from the surveys regarding screening strategies was consistent with the information provided in the national guidelines. For example, in Argentina, women undergo cervical cytology (with Pap smears) during their first screening visit and return for results in a second visit. If results are negative, women are screened once every three years. If results are positive, women are screened every six months for three years. In Brazil, women undergo initial screening in the first visit; those with positive results undergo colposcopy/biopsy in a second visit, which is followed by treatment of abnormalities at a tertiary clinical site in a third visit. In Chile, cervical cytology is performed in the majority of women every six months to rule out falsenegative results.women with negative screens are screened every three years. In Colombia, women undergo a Pap smear every three years. Screen-negative women undergo a second Pap smear a year later to confirm a negative result. If the second Pap smear is negative, a Pap smear P age 139

22 is scheduled every three years after the second negative test. However, if the second Pap smear is positive, women undergo a Pap smear three times a year. Women in Mexico are offered a screening protocol similar to Argentina s. In Peru, women undergo a screening test (90%, Pap smear; 5%, HPV DNA testing; 3%, visual inspection using acetic acid [VIA]; and 2%, visual inspection using Lugol s iodine [VILI]). Those women with positive results undergo a screening test every six months. The test is repeated again and, if results are negative, a test is scheduled once every three years thereafter. Appendix E summarizes the screening recommendations and current practices of studied countries. Treatment of precancerous lesions depends on the lesions size and type and may include cryosurgery, loop electrosurgical excision procedure (LEEP), cold knife conization, or simple hysterectomy. According to information from the surveys, precancerous lesions are generally treated on an outpatient basis. The classification system of cervical intraepithelial neoplasia (CIN) is used in the studied countries to provide information about the precancerous condition of the cervix. After initial screening, screen-positive women generally undergo a gynecological exam, colposcopy, and directed biopsy to determine whether they are suitable for follow-up or same-day treatment such as cryosurgery or LEEP. Biopsy-confirmed CIN 1 lesions are generally followed by colposcopy and cytology every six months until the lesion regresses to normal or until evidence of progression appears. Only a small proportion of women in these countries with CIN 1 lesions require treatment. In contrast, all biopsy-confirmed CIN 2 and 3 lesions in the studied countries require treatment because of the potential of these lesions to progress to invasive cervical cancer. Women undergoing treatment for CIN 2 and 3 lesions are generally treated as outpatients; however, certain procedures such as cold knife conization require general or regional anesthesia, and women undergoing these procedures may need to be admitted to a hospital. Treatment of complications resulting from procedures such as cold knife conization is also reported in these countries. Women treated for precancerous lesions in the studied countries generally return for a follow-up visit two to six weeks after treatment for a gynecological examination and discussion of results of histopathology (in cases involving LEEP and cold knife conization) and at six and twelve months for a screening test and coloscopy and directed biopsy (in cases of persistent lesions). Appendix F summarizes the treatment of precancerous lesions in studied countries. Staging is required for women who have a histologic diagnosis of cervical cancer. For the studied countries, the International Federation of Gynecology and Obstetrics staging system is recommended for staging invasive cervical cancer. This classification system is based on tumor Page 140

23 size and on the extent of spread of disease in the pelvis and distant organs. Like precancerous lesions, treatment of invasive cervical cancer depends on lesion size and type. The most common tests and procedures performed for staging and treatment of invasive cervical cancer in the studied countries included vaginal and rectal examination, abdominal ultrasound, cystoscopy, proctoscopy, cone biopsy, chest x-ray, computerized tomography scan of abdomen and pelvis, magnetic resonance imaging of pelvis, and blood tests. Appendix G describes methods used for cervical cancer staging in the studied countries. Once the extent of the cancer s growth is assessed, several treatment modalities can be performed, including surgery, radiotherapy, and chemotherapy. For the studied countries, the most commonly reported surgical procedures include simple abdominal hysterectomy for treatment of stage IA1 and radical hysterectomy or pelvic lymphadenectomy or both for treatment of stages IA2 to IIA. Length of stay in the hospital for a surgical procedure varies by country but averages seven to ten days. Surgical procedures are generally performed in a tertiary-level hospital and require about two to three hours. Most of these procedures were performed to effect a cure, but most countries (Brazil, Chile, Colombia, Mexico, and Peru) reported palliative surgery to relieve symptoms, particularly at advanced stages of cervical cancer. Radiotherapy (teletherapy, brachytherapy) was commonly reported for treatment of stages IB1 through IVB. However, in countries like Brazil, Chile, and Colombia, use of radiotherapy was reported for treatment as early as stages IA1 and IA2. For treatment of stages IA1 through IIA, radiotherapy was sometimes used concurrently with surgery. For bulkier tumors and for women with extensive lymph node involvement, radiotherapy was used as the sole treatment. Teletherapy was generally used in addition to brachytherapy. Radiotherapy sessions were generally given five days a week for about five weeks in a tertiary-level hospital. Women receiving radiotherapy were either admitted to a hospital or were treated as outpatients. For women admitted to a hospital for radiotherapy, the length of stay varied between two and three days, depending on the dose rate. For all studied countries, palliative therapy was commonly reported to relieve symptoms. A third treatment modality for invasive cervical cancer is chemotherapy. The most commonly used drug in the studied countries was cisplatin. Chemotherapy was generally given for the treatment of bulkier tumors; however, in Brazil, Chile, and Colombia, chemotherapy was reported as being used in early stages of cervical cancer, specifically stage IA2 (Brazil) and stage IB2 (Chile and Colombia). Cisplatin is generally given concurrently with surgery or radiation or both. P age 141

24 Five to six cycles of chemotherapy were generally administered to women who undergo chemotehrapy. Women treated with surgery or radiotherapy generally return for follow-up visits every three months for the first two years. Several tests are performed during these follow-up visits, including vaginal and rectal examination and Pap smears. Appendix G provides a summary of the treatment modalities of invasive cervical cancer by stage and country. Costs associated with precancerous lesions and cervical cancer treatment Low estimates for treatment costs were determined by using methods of indirect estimation previously used by others in the absence of primary data [115,122]. We compared these estimates to the data we collected in our study sites: Argentina, Brazil, Chile, Colombia, Mexico, and Peru. The costs for cervical cancer treatment represent an average treatment cost per case and are assumed to be realized at around median survival time after cancer onset. Every detected cancer case is assumed to incur cancer treatment costs. The base case value was estimated by using data collected separately. Because we accepted the favorable assumption that women with detected cancer have access to care in the latter estimation procedure, we refer to the treatment cost of all detected cases as the upper treatment cost estimate, and we vary it widely in sensitivity analyses. Methods of collecting cost data and of conducting surveys to assess clinical practice assumptions are documented below. Costs are presented in 2005 international dollars, a currency that provides a means of translating and comparing costs among countries, taking into account differences in purchasing power. Costs are also presented in local currency and in U.S. dollars for local and regional decision makers. For the latter, we needed to distinguish tradable from nontradable goods. Vaccine, wastage, and freight are considered tradable goods. Whether expressed in local currency units or in U.S. dollars, they are converted by using exchange rates of the U.S. dollar to local currency units. Administration and vaccine support are considered local nontradable goods. To express nontradable goods in local currency units, we converted them from international dollars by using purchasing power parity (PPP) exchange rates. When expressing administration and vaccine support in U.S. dollars, the local currency units are converted by using U.S. dollar exchange rates. P age 142

25 Health care costs Cost-generating events were estimated based on two main sources: country-specific management guidelines and expert surveys. The unit cost for detection of precancerous lesions and treatment of invasive cervical cancer was based on estimates provided by the finance departments of local hospitals and national administrative data in each studied country. Unit cost estimates associated with the detection and treatment of precancerous lesions and the treatment of cervical cancer by stage and by country are summarized in Appendix H. The cost per stay as an inpatient was calculated by multiplying the per diem rate by length of stay and adding the cost of diagnostics and medications. The per diem rate includes the accommodation and administration costs (i.e., costs of the bed, building, utilities, maintenance, administration, and equipment), food, and personnel. Mean hospital lengths of stay were derived from combined physician surveys and varied by stage: 1.17 and 2.67 days for precancerous lesions CIN1 and CIN2, respectively; 2.50 days for stage IA1; 3.30 days for stages IA2 and IB1; 5.17 days for stage IB2; 4.17 days for stage IIA; 3.67 days for stage IIB; 2.00 days for stages IIIA IIIB; 1.83 days for stage IVA; and 2.83 days for stage IVB. The cost per outpatient visit was based on the cost of visiting a general practitioner, a nurse, or a specialist (obstetrician or oncologist). According to physicians surveyed, 50% of women with precancerous lesions have an average of one to two outpatient visits with a general practitioner, 66% are seen by the nurse once or twice, and 78% are seen once or twice by the obstetrician or oncologist. An estimated 79% of women with invasive cervical cancer are seen in the outpatient setting. The majority (99%) of this outpatient care is for staging of cervical cancer, 56% is for treatment, and 100% is for follow-up and palliative care. An average of 2.67, 4.26, 4.50, 12.67, 6.50, 7, 17.67, 20.17, 21.17, and outpatient visits were reported for cervical cancer screening, stage CIN1, stage CIN2, stage IA1, stage IA2, stage IB1, stage IB2, stage IIA, stage IIB, and stages IIIA IV, respectively. The majority of these outpatient visits were for palliative care treatment. Unit cost estimates for outpatient visits were based on the average provided by the finance departments of public institutions and administrative sources. The total screening and diagnostic cost per woman was calculated by first multiplying the number of each test used by the frequency of its use, multiplying that number by each test s unit cost, and then summing the total cost for all tests administered to each woman. Unit cost estimates for screening and diagnostic tests were based on the average given by the finance departments of public institutions and administrative sources described previously. Page 143