Worldwide Impact of the Human Papillomavirus Vaccine

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1 Current Treatment Options in Oncology DOI /s Gynecologic Tumors Worldwide Impact of the Human Papillomavirus Vaccine Amy A. Hakim, MD, MS Tri A. Dinh, MD* Address *The Methodist Hospital, Houston, TX, USA ª Springer Science+Business Media, LLC 2009 Opinion statement Nearly 500,000 new cases of cervical cancer and 274,000 cervical cancer deaths are occurring worldwide each year. Approximately 80% of the 500,000 new cases occur in developing countries and this percentage is expected to increase to 90% by In developing countries, cervical cancer tends to affect relatively young poor women and is the single largest cause of years of life lost to cancer, since screening and treatment programs, and health care, in general, are relatively inaccessible to these women. Each 5-year delay in vaccinating women against HPV may lead to the deaths of 1.5 to 2 million women from cervical cancer in developing countries. The high efficacy of the two available cervical cancer vaccines and their proven ability to reduce the incidence of cervical cancer precursor lesions offer hope that the vaccine will have enormous worldwide impact and may dramatically reduce the cervical cancer burden. The current vaccines protecting against HPV-16 and HPV-18 may prevent up to 70% of new cervical cancers. Vaccine cross-reactivity for HPV-31, -33, -45, and -52 suggest that an even higher percentage of cervical cancers might be prevented with its use. Currently, the prohibitive cost of the vaccine precludes its widespread implementation. Cooperation between governments, international health organizations, and the vaccine industry is needed to overcome this significant barrier so that women are no longer denied a potentially life-saving advance. Worldwide HPV vaccination and cervical cancer screening should be made an international priority. Introduction Although cervical cancer is relatively uncommon in the United States, with only 11,070 new cases and 3870 deaths projected for 2008, nearly 500,000 new cases of cervical cancer and 274,000 deaths will, however, occur throughout the world [1 3]. Approximately 80% of the 500,000 new cases occur in developing countries and this percentage is expected to increase to 90% by 2020 [4]. In developing countries, cervical cancer tends to affect relatively young poor women and is the single largest cause of years of life lost to cancer [5 ], since screening and treatment programs are relatively inaccessible to these women. The human papillomavirus (HPV) is a necessary factor [6] in the development of cervical cancer, and is one of the most common sexually transmitted infections throughout the world. The virus quite often displays no early symptoms, and is the leading cause of vulvar, vaginal, cervical, anal, and penile cancers, as well the leading cause of anogenital warts.

2 Gynecologic Tumors HPV are non-enveloped, closed circular, doublestranded DNA viruses that infect epithelial cells [2, 6] and are members of the family of Papillomaviridae viruses. Approximately 100 strains of HPV have been detected with about 40 strains known to infect genital mucosa. Of these, 15 types are oncogenic [1, 7]. More than 99% of cervical cancers contain one or more of these genotypes [7]. HPV-16 and -18 are the most prevalent of the oncogenic types and are linked to 70% of cervical cancers diagnosed in the United States. In addition, nearly 300 million women worldwide harbor HPV DNA, one-third of whom carry genotypes 16 and/or 18 [8, 9]. This article reviews the data on the efficacy of the available HPV vaccines, describes the prevalence of HPV infections in different regions of the world, and discusses issues relevant to the worldwide adoption of the HPV vaccine, especially in developing countries. Current prevention for cervical cancer One of the most successful methods for preventing cervical cancer is screening with the conventional Papanicolaou (Pap) smear, which shows the presence of pre-cancerous cervical cells [2]. American Cancer Society statistics suggest that use of the Pap smear decreased the number of cervical cancer deaths between 1955 and 1992 by 74% [2, 10]. However, this method is not perfect as recent well-controlled clinical trials have found sensitivities of only 70 80% for conventional smears and 85 90% for liquid-based cytology [2, 11, 12]. A companion to the Pap smear is HPV DNA testing, using Digene Hybrid Capture Ò 2 (HC2) High-Risk HPV DNA Test. HPV DNA testing is approved by the U.S. Food and Drug Administration (FDA) and detects 13 high-risk types of HPV (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, and -68) [1]. Currently, its use is limited to the triage of patients with equivocal Pap tests (atypical squamous cells of undetermined significance (ASCUS)) and as an adjunct to a liquidbased cytology test in women >30 years of age. In addition to the proven efficacy of screening techniques listed above, there is now the possibility of primary prevention of cervical cancer via vaccination against HPV. There are two available vaccines, the bivalent vaccine, Cervarix Ò, covering HPV-16 and -18 developed by GlaxoSmithKline and the quadrivalent vaccine, Gardisilä, covering HPV-6, -11, -16, and -18 developed by Merck and Co., Inc. In the United States, only Gardisilä is currently licensed for use. However, it is expected that the U.S. FDA will approve the use of Cervarix Ò in the near future. These vaccines have the potential to prevent 70% of cervical cancers, and in the case of Gardisilä, 90% of genital warts over the next years. Indications for the cervical cancer vaccine HPV infection occurs shortly after a girl becomes sexually active, while cervical cancer from persistent HPV infections can take years to develop [4]. Ideally, vaccinating young girls before they become sexually active would result in maximum cervical cancer protection [4]. The FDA in the United States has approved Gardisilä for use in girls and women ages The Federal Advisory Committee on Immunization Practices (ACIP) recommends the starting the vaccine series between the ages of 11 and 12. For those who have not yet been vaccinated or received the full series of three vaccinations, catch-up vaccines may be given until age 26 [1].

3 Worldwide Impact of the Human Papillomavirus Vaccine Hakim and Dinh Efficacy of the HPV vaccine In anogenital cancers, exposure to HPV and the development of cancer precursor lesions can occur years before invasive cancer arises, so four of the largest studies have examined the efficacy of the HPV vaccine in relation to several endpoints including detection of new HPV DNA in cervicovaginal cells in women previously tested as HPV negative, persistent HPV DNA in cervicovaginal specimens during follow-up visits in women who were not positive for HPV DNA at baseline, abnormal Pap smears on liquid-based testing, or the presence of pre-cancerous cervical intraepithelial neoplasias (CIN) on cervical biopsies [9]. A double-blind phase II study of the monovalent HPV-16 vaccine in the United States published in 2002 included 2392 females ages years who received three doses of placebo or the HPV-16 vaccine [7]. The primary endpoint was HPV-16 infection, detected at two or more visits in women who were HPV-16 negative at study entry. After 17.4 months, the incidence of persistent HPV-16 infection was 3.8 per 100 woman-years at risk in the placebo group and 0 per 100 woman-years at risk in the vaccine group. Nine cases of HPV-16 linked CIN were found in the placebo group as compared to none in the vaccine group. The vaccine showed 100% efficacy after 3.5 years of follow-up [7]. A second study published in 2005 by Harper et al. was a double-blind multi-center, randomized placebo controlled trial of the bivalent HPV-14/-18 vaccine carried out to test its efficacy against incident infections with HPV-16 and HPV-18, with secondary aims being prevention of persistent infections, cytological abnormalities and cervical intraepithelial neoplasia (CIN) [8, 13]. The study participants were 1113 North American and Brazilian girls ages years who were HPV-16/-18 negative at study entry with a history of fewer than six sexual partners and who had normal pap smears. Study participants received either placebo or the vaccine at months 0, 1, and 6, and were followed for an average of 4.5 years. The efficacy was 96.9% for incident infection with HPV-16/-18, 94.3% for persistent HPV-16/-18 over 6 months and 100% for persistent HPV-16/-18 infection over 12 months [8, 13, 14]. In a combined evaluation of the initial efficacy trial [13] and the follow-up study [14], the vaccine efficacy was 100% for any type of CIN lesions associated with HPV-16/-18. No cases of CIN due to HPV-16/-18 were found in the vaccinated group [7, 14]. A randomized, placebo-controlled, double-blind trial, sponsored by Merck, evaluated the efficacy of Gardisilä, the quadrivalent vaccine against HPV-6, -11, -16, and -18, in preventing genital warts, vulvar or vaginal intraepithelial neoplasia, or cancer, and incident CIN, adenocarcinoma in situ, or cervical cancer [15]. The FUTURE I, The Females United to Unilaterally Reduce Endo/Ecto-Cervical Disease, enrolled 5455 women in 62 sites in the Americas, Europe, and Asia. The efficacy of the vaccine was 100% in the per protocol group, defined as subjects who completed the vaccine series within 12 months, were negative for HPV infection in the time period prior and during the vaccination series [15]. In the intention-to-treat general study population, which included all subjects, including those with current infection due to HPV-6, -11, -16, or -18, there was a 20% reduction in cervical lesions in the vaccine group as compared to the placebo group [15].

4 Gynecologic Tumors A similar study, the FUTURE II study, enrolled 12,167 women ages in 13 countries to evaluate the efficacy of Gardisilä in the prevention of high-grade cervical dysplasia [16]. The endpoints were incidence of CIN 2/3, in situ adenocarcinoma, or invasive cancer [7] caused by HPV-16/-18. At 3 years, vaccine efficacy for the combined endpoints was 98% in the per protocol cohort and 44% in the intention-totreat population of women (with and without HPV-16/-18 at study entry) [16]. The study concluded that in women not infected with HPV-16/-18, those who were vaccinated with Gardisilä had a significantly lower incidence of high-grade intraepithelial lesions [16]. Similar excellent results were found in a study of 18,664 women ages years using the bivalent vaccine developed by GSK Pharmaceuticals, against HPV-16 and HPV-18 [17, 18 ]. The study enrolled women from 14 countries in North America, Latin America, Europe, and the Asian-Pacific Region [17, 18 ]. The efficacy of the vaccine in preventing high-grade (CIN 2+) lesions due to HPV-16 and HPV-18 was 100% [17, 18 ]. After a mean follow-up of 14.8 months, 21 of 23 CIN 2+ lesions were found in the control group and only two were found in the vaccine group [17, 18 ]. Cross reactivity Studies with Cervarix Ò, and employing HPV type specific virological endpoints of incident and persistent infection, demonstrate medium to long-term (up to 5.5 years) protection against new infection with HPV-45 and HPV-31, along with high levels of long-term protection against HPV-16 and HPV-18 infections [19]. These studies indicate that there is a cross-protective effect between closely related HPV types: HPV-16 and several closely related types [HPV-31 and HPV-52 (for a few years) and, possibly, HPV-33], and strongly between HPV-18 and -45 [19]. Worldwide strains of HPV and potential impact of the current HPV vaccines The two vaccines against HPV-16 and -18 have been approved for use in more than 80 countries [18 ], but are these vaccines adequate to prevent infection by HPV subtypes which cause the majority of cervical cancer cases worldwide? The following is a review of the distribution of cervical cancer disease burden and HPV infection, by HPV types, in countries where data are available. Mozambique In Mozambique, HPV-16 was uncommon and HPV-35 was the most prevalent type in one study [20]. Yet, in another study by Naucler et al. in 2004, of 74 women with invasive cervical cancer, HPV types 16 and 18 were present in 69% of samples [21]. These results suggest that the current HPV vaccines which target HPV-16 and -18 would have an impact on cervical cancer prevention in Mozambique. India Worldwide, 25% of all cervical cancer cases occur in India. It is the most common cancer diagnosis in Indian women with age-adjusted incidence rates, in some regions, as high as 47.2 per 100,000 person

5 Worldwide Impact of the Human Papillomavirus Vaccine Hakim and Dinh years. HPV-16 and -18 are the most common HPV types. Diaz et al. showed that vaccination of girls before age 12 will decrease the lifetime cancer risk by 44%, and screening of women over age 30 (three times during a lifetime with 70% coverage) will decrease the lifetime cancer risk by 21 33%. If vaccination and screening are combined a mean reduction of 56% to 63% in cervical cancer risk in India may result [22]. India, Bangladesh, Nepal, and Sri Lanka About one-third of the worldwide cervical cancer cases come from Indian subcontinent consisting of the countries of Indian, Bangladesh, Nepal, and Sri Lanka [22, 23]. Age-adjusted cervical cancer incidence and mortality rates range from 30.7 and 17.8 per 100,000 women in India, 27.6 and 14.8 per 100,000 women in Bangladesh, 17.2 and 9.5 per 100,000 women Sri Lanka, and 26.4 and 14.1 per 100,000 women in Nepal [23, 24]. In India, overall, 79.5% of cervical cancer cases were positive for HPV-16 and or HPV-18 [23]. HPV-16 is the most common type with HPV-18 the second most common [23]. HPV-31, -33, -35, -39, -45, -51, -52, -52, -56, -58, -59, and -68 (descending order) are also common types of HPV found in India [23, 25 30]. In theory, cervical cancer in India could be reduced by % by introducing an HPV vaccine covering HPV-16 and -18 with 100% efficacy [23]. Currently, data on HPV-type prevalence from Bangladesh, Sri Lanka, and Nepal are lacking since there are no comprehensive formal screening programs in these countries. One study, in Sri Lanka, however, showed that 11 of 15 cases of squamous cell cancer of the cervix contained HPV-16 [23, 31]. Latin America and the Caribbean HPV prevalence has been estimated to be 84.9% in women with highgrade squamous intraepithelial lesions of the cervix in the Latin American Countries (LAC) and 89.7% in those with invasive cervical cancer [32, 33]. HPV-16 and -18 are found in 65% of cervical cancers in LAC and HPV-6 and -11 are found in 90% of genital warts in the region [32]. In 2002, there were an estimated 72,000 new cases of cervical cancer and 33,000 deaths in LAC, making cervical cancer the second most common cancer (after breast cancer) in women in these regions [24, 32]. Registries are still in their infancy, but cervical cancer incidence appears highest in Bolivia, Haiti, Nicaragua, Paraguay, Peru, and El Salvador, and lowest in the Bahamas, Costa Rica, Cuba, Puerto Rico, and Uruguay [32]. Asia Pacific Region Half (250,000) of the world s cervical cancer cases come from the Asia Pacific Region [24, 32, 34]. Age-adjusted incidence rates for cervical cancer range from 2.4 per 100,000 person years at risk in Jiashan, China, to 28.9 in Chiang Mai, Thailand [34]. Prevalence of HPV varies in the region, as well. In Vietnam, a population-based random sample of married women revealed that prevalence of HPV in Ho Chi Minh City, in the South, was five times higher (10.9%), than in Hanoi

6 Gynecologic Tumors (the Northern Capital of Vietnam) [34 36]. In the Asia Pacific Region, while the majority of cervical cancer is due to HPV-16 and -18, HPV-58 and -52 also play major roles in cancer cases [34, 36]. Southeastern Europe (Albania, Bosnia & Herzegovina, Bulgaria, Croatia, Cyprus, Greece, Former Yugoslavian Republic of Macedonia, Moldova, Romania, Serbia & Montenegro) There are nearly 9000 new cancer cases and 4600 cervical cancer deaths in Southeastern Europe each year [24, 37, 38]. Most of these countries have had organized cervical cancer screening for decades. Croatia, for example, has had organized cervical cancer screening since Since that time, cervical cancer incidence rates have dropped from 26 to 14/100,000 woman-years, but cervical cancer incidence rates have been constant over the last 15 years [37, 39, 40]. In descending order, HPV types 16, 31, 6/11, 33, 18, 52, 45, and 58 are the most prevalent in Croatia [41]. United States In the United States, there are 11,070 new cervical cancer cases and 3,870 deaths projected for High-risk strains of HPV include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 73, and 82. Approximately, 75% of cervical cancers in the United States are squamous cell and approximately 25% are adenocarcinomas [1]. HPV-16 is found in nearly 68% of squamous cell cancers and HPV-18 is found in nearly 83% of adenocarcinomas [2, 6]. HPV-16 and -18 are the most common of the oncogenic types and are found in 70% of cervical cancers diagnosed in the United States [2]. Other regions worldwide Munoz et al. studied HPV types present in 3607 women in 25 countries with incident cervical cancer [42]. HPV DNA was found in 96% of specimens, and 30 different strains were detected. In descending order, HPV-16, -18, -45, -31, -33, -52, -58, -35, -59, -56, -39, , -68, and 66 were detected in the specimens. The study suggests that a higher proportion of cervical cancers positive for HPV-16 are found in northern Africa and a higher proportion of cervical cancers positive for HPV-18 are found in south Asia, while HPV-45 is dominant in cervical cancers in sub-saharan Africa and HPV-31 is dominant in cervical cancers in Central/South America [42]. Considerations for the worldwide introduction of the HPV vaccine Policymakers considering the introduction of the HPV vaccine for primary prevention of cervical cancer will have to consider which HPV strains are the most common cause of cervical cancer in a particular country. In order to implement HPV vaccination, a country needs an adequate health care infrastructure to introduce and sustain an immunization program for adolescents [5 ]. Cost-effectiveness of the HPV vaccine is the key issue as the vaccine would necessarily compete for scarce health care funding with screening programs for breast and cervical cancer, and programs for childhood immunizations, and

7 Worldwide Impact of the Human Papillomavirus Vaccine Hakim and Dinh control of diseases such as malaria, or acute respiratory illnesses [5, 43 ]. In addition, there may be perceived social barriers to the introduction of a vaccine that prevents a cancer caused by a virus that is sexually transmitted. How could the HPV vaccine be introduced? School-based or community-based immunization programs, so that the HPV vaccine is given along with other immunizations such as measles mumps, rubella, tetanus, meningococcus, and typhoid is one method [5 ]. Price barriers to introduction of the HPV vaccine Price may present the biggest barrier to introduction of the HPV vaccine in developing countries. Agnosti and Goldie [5 ] describe cost considerations for the HPV vaccine in Brazil. They note that at $5 per dose (excluding program costs, administration, and wastage), the cost-effectiveness ratio at $5 per dose would be less than $150 per year of life saved [4, 44]. The combination of vaccination with screening women three times during their lifetimes would meet the criteria for a very cost-effective treatment [5, 44]. However, if the price of the HPV vaccine was $100 per dose, it would not be as cost-effective as screening women three times in their lifetimes. For countries with a gross domestic product of less than $1000 per capita, the cost of the HPV vaccine would not be cost-effective unless it were as low as $1 to $2 [5 ]. Financing mechanisms to introduce the vaccine in developing countries In the United States, the quadrivalent vaccine by Merck costs $360 for the series of three vaccine doses, independent of costs of administration. This is potentially an insurmountable barrier in developing countries with gross domestic products of less than $1000 per capita, and even in middle-income countries such as Indonesia, China, and India [5 ]. In some low-income countries, total health expenditure per capita per year is only about $29 [43, 45]. Thus, a vaccine costing $100 is an exorbitant luxury. Tiered pricing or differential pricing is one method that some vaccine companies employ in order to sell a vaccine worldwide [43 ]. This is a practice where vaccine companies sell vaccines at lower prices to developing countries, and sell the same vaccines at higher prices to middle-income and developed countries [43 ]. Pooled procurement also has improved access to needed vaccines [43 ]. UNICEF and the Pan-American Health Organization (PAHO) have each purchased large amounts of vaccines for developing countries in Latin American as well as in other regions [43 ]. The GAVI Alliance (previously known as the Global Alliance for Vaccines and Immunization) is a partnership of national governments of industrialized and developing countries, the World Health Organization, the World Bank, UNICEF, the Bill and Melinda Gates Foundation, the vaccine industry, public health institutions, and nongovernmental organizations. It provides financial and technical support for vaccination programs in developing countries and will be essential in facilitating the introduction of the HPV vaccine worldwide [5 ].

8 Gynecologic Tumors The health and economic impact of the HPV vaccine in countries where it has been introduced: the U.S. and Indian experiences Using epidemiologic and demographic data and models of HPV-16 and -18 transmission and carcinogenesis, Kim and Goldie compared health and economic outcomes of different HPV vaccination strategies: primary vaccination of girls at age 12, and catch-up vaccination programs for older girls and women up to 18, 21, or 26 years of age [46 ]. Assuming that the vaccine provides lifelong immunity, the cost of vaccinating 12-year-old girls was $43,000 per quality-adjusted life year (QALY) when compared with present screening practices [46 ]. The cost of extending a temporary catch-up program for girls to 18 years of age is $97,300 per QALY. The cost of extending the vaccine to age 21 years is $120,400 per QALY, and extending the vaccine to age 26 years is $152,700 per QALY [46 ]. This model makes the important assumption that the vaccine provides lifelong immunity and the authors conclude that vaccinating all women under the age of 21 makes economic sense, especially when the vaccine may prevent other non-cervical HPV-related illnesses [46 ]. Using similar mathematical modeling, Diaz and colleagues calculated the incremental cost-effectiveness ratios (I$ (Indian Dollars)/YLS (Year of Life Saved)) for several cervical cancer prevention strategies: vaccination of pre-adolescent (before age 12), screening of women over age 30, and the combination of vaccination and screening. Assuming 70% coverage, the mean reduction in lifetime cervical cancer risk was 44% (range 28 57%) with HPV-16 and -18 vaccination alone, and 21 33% with screening three times per lifetime. The combination of vaccination with screening, three times per lifetime or 2-visit HPV testing, reduced the lifetime cervical cancer risk by 56 63%. With a cost per vaccinated girl of I$10 (per dose cost of I$2), pre-adolescent vaccination and screening using either VIA or HPV testing is cost-effective with India s gross domestic product I$3452 per capita used as a threshold [21]. The authors conclude that a program to administer a low-cost HPV vaccine with intermittent cervical screening is cost-effective and may decrease deaths from cervical cancer by one half [21]. The HPV vaccine should be introduced worldwide and its introduction could have significant worldwide impact Each 5-year delay in vaccinating women against HPV may lead to the deaths of 1.5 to 2 million women from cervical cancer in developing countries [5 ]. The high efficacy of the two available cervical cancer vaccines and their proven ability to reduce the incidence of cervical cancer precursor lesions offer hope that the vaccine will have enormous worldwide impact and may dramatically reduce the cervical cancer burden. The current vaccines protecting against HPV-16 and HPV-18 may prevent up to 70% of new cervical cancers and their cross-reactivity for HPV-31, -33, -45, and -52 suggest that an even higher percentage of the cervical cancers might be prevented. Currently, the prohibitive cost of the vaccine precludes its widespread implementation. Cooperation between governments, international health organizations, and the vaccine industry is needed to overcome this significant barrier so that women are no longer denied a

9 Worldwide Impact of the Human Papillomavirus Vaccine Hakim and Dinh References and Recommended Reading potentially life-saving medical advancement. Worldwide HPV vaccination and cervical cancer screening should be made an international priority. Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Centers for Disease Control and Prevention: Quadrivalent human papillomavirus vaccine. Recommendations of the Advisory Committee on Immunization Practices. MMWR 2007, 56(Early Release): ACOG Practice Bulletin: Practice Bulletin: Clinical management guidelines for obstetricians-gynecologists. Number 61, April Human papillomavirus. Obstet Gynecol 2005, 105: Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, CA Cancer J Clin 2005, 55: doi: /canjclin Pagliusi SR, Teresa Aguado M: Efficacy and other milestones for human papillomavirus vaccine introduction. Vaccine 2004, 23: doi: / j.vaccine Agosti JM, Goldie SJ: Introducing HPV vaccine in developing countries key challenges and issues. N Engl J Med 2007, 356(19): This is a thought-provoking companion article to the FU- TURE I and FUTURE II NEJM studies discussing the key challenges to introducing the HPV vaccine in developing countries. 6. Bosch FX, Lorncz A, Munoz N, Meijer CJ, Shah KV: The causal relation between human papilloma virus in cervical cancer. J Clin Pathol 2002, 55: Koutsky LA, Ault KA, Wheeler CM, et al.: A controlled trial of human papillomavirus type 16 vaccine. N Engl J Med 2002, 347: Bayas J-M, Costas L, Munoz A: Cervical cancer indications, efficacy, and side effects. Gynecol Oncol 2008, 110:S11 S De Sanjose S, Diaz M, Catellsague X, et al.: Worldwide prevalence and genotype distribution of cervical human papilloma virus DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis 2007, 7(7): Jemal A, Tiwari RC, Murray T, et al.: Cancer statistics, CA Cancer J Clin 2004, 54: Clavel C, Masure M, Bory JP, et al.: Human papillomavirus testing in primary screening for the detection of high-grade cervical lesions: a study of 7932 women. Br J Cancer 2001, 84: Hutchison ML, Zahniser DJ, Sherman ME, et al.: Utility of liquid-based cytology for cervical cancer screening: results of a populations-based study conducted in a region of Costa Rica with a high incidence of cervical carcinoma. Cancer 1999, 87: Harper DM: Impact with Cervarix on subsequent HPV-16/18 infection and cervical disease in women years of age. Gynecol Oncol 2008, 110:S11 S Harper DM, Franco EL, Wheeler CM, et al.: Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomized control trial. Lancet 2006, 367: Garland SM, Hernandez-Avila M, Wheeler CM, et al.: Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007, 356: Future II Study Group.: Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007, 356: Paavanen J, Jenkins D, Bosch FX, et al.: Efficacy of a prophylactic adjuvant bivalent L1 virus-like particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase II double-blind, randomized controlled trial. Lancet 2007, 369: Herzog TJ, Huh WK, Downs LS, Smith JS, Monk BM: Initial lessons learned in HPV vaccination. Gynecol Oncol 2008, 109:S4 S11. This is an excellent article examining patients and parents awareness and attitudes of HPV vaccination in the United States and describing misperceptions and barriers such as costs related to the worldwide introduction of the HPV vaccine. 19. Jenkins D: A review of cross-protections against oncogenic HPV by an HPV-16/18 ASO4-adjuvanted cervical cancer vaccine: importance of virological and clinical endpoints and implications for mass vaccination in cervical cancer prevention. Gynecol Oncol 2008, 110:S18 S Castellsague X, Mendez C, Loscertales MP, et al.: Human papillomavirus genotypes in rural Mozambique. Lancet 2001, 358: Naucler P, Mabota da Costa F, Ljungberg O, Bugalho A, Dillner J: Human papillomavirus genotypes in cervical cancers in Mozambique. J Gen Virol 2004, 85: Diaz M, Kim JJ, Albero G, Clifford G, Bosch FX, Goldie SJ: Health and economic impact of HPV-16 and-18 vaccination and cervical cancer screening in India. Br J Cancer 2008, 99: Sankaranarayanan R, Bhatla N, Gravitt PE, et al.: Human papillomavirus infection and cervical cancer prevention in India, Bangladesh, Sri Lanka, and Nepal. Vaccine 2008, 26S:M43 M Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN Cancer incidence, mortality, and prevalence worldwide. IARC Cancer Base No 5 Version 2.0. Lyon: IARC Press; 2004.

10 Gynecologic Tumors 25. Franceschi S, Rajkumar R, Snijders PJ, et al.: Papillomavirus infection in rural women in southern India. Br J Cancer 2005, 92: Clifford GM, Galluss S, Herrero R, et al.: Worldwide distribution of human papillomavirus types in cytologically normal women in the international agency for research on cancer HPV prevalence surveys: a pooled analysis. Lancet 2005, 366: Sankaranarayanan R, Nene BM, Dinshaw KA, et al.: A cluster randomized control trial of visual, cytology, and human papillomavirus screening for cancer of the cervix in rural India. Int J Cancer 2005, 116: Sankaranarayanan R, Chatterji R, Shastri SS, et al.: Accuracy of human papillomavirus testing in primary screening of cervical neoplasia: results from a multicenter study in India. Int J Cancer 2004, 112: Sowjanya AP, Jain M, Poli UR, et al.: Prevalence and distribution of high-risk human papilloma virus (HPV) types in invasive squamous cell carcinoma of the cervix and in normal women in Andhra Pradesh, India. BMC Infect Dis 2005, 5: Laikangbam P, Sengupta S, Bhattacharya P, et al.: A comparative profile of the prevalence and age distribution of human papilloma virus type 16/18 infections among three states of India with focus on northeast India. Int J Gynecol Cancer 2007, 17(1): De Silva R, Karunaratne K, Mendis LN, Ramesh R, Chow VT: PCR detection and typing of human papilloma virus DNA in squamous carcinoma of the cervix in a cohort of Sri Lankan women. Ceylon Med J 2006, 51: Munoz N, Franco EL, Herrero R, et al.: Recommendations for Cervical cancer prevention in Latin America and the Caribbean. Vaccine 2008, 26S:L96 L Smith JS, Lindsay L, Hoots B, et al.: Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer 2007, 121(3): Goldie SJ, Diaz M, Kim S-Y, Levin CE, Van Minh H, Kim JJ: Mathematical models of cervical cancer prevention in the Asia Pacific Region. Vaccine 2008, 26S:M17 M Pham Th, Nguyen TH, Herrero R, et al.: Human Papilloma Virus infection among women in South and North Vietnam. Int J Cancer 2003, 104(2): Clifford GM, Smith JS, Plummer M, Munoz N, Franceschi S: Human papilloma virus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer 2003, 88(1): Grce M, Davies P, Anttila A, et al.: Report on the 2007 International workshop on Human papillomaviruses and consensus recommendations for cervical cancer prevention. Cent Eur J Pub Health 2008, 16(1): Arbyn M, Primix-Zakelj M, Raifu AO, et al.: The burden of cervical cancer in South-East Europe at the beginning of the 21st century. Coll Antropol 2007, 31(Suppl 2): Znaor A, Strnad M: Cervical cancer in Croatia; state of the art and possibilities for prevention. Coll Antropol 2007, 31(Suppl 2): Croatian National Institute of Public Health Zagreb ; No Milutin-Gasperov N, Sabol I, Halec G, Matovina M, Grce M. Retrospective study of the prevalence of high-risk human papilloma viruses among Croatian women. Coll Antropol 2007, 31 (suppl 2): Munoz N, Bosch FX, Castellsague X, et al.: Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 2004, 111: Batson A, Meheus F, Brooke S: Chapter 26: innovative financing mechanisms to accelerate the introduction of HPV vaccines in developing countries. Vaccine 2006, 24(S3): This is a comprehensive article on the ways that vaccines are financed in countries worldwide and specifically on how the HPV vaccine could be financed in developing countries. 44. Garnett GP, Kim JJ, French K, Goldie SJ: Chapter 21: modeling the impact of HPV vaccines on cervical cancer and screening programmes. Vaccine 2006, 24(Suppl 3):S178 S World Bank Development Data. worldbank.org/hnpstats/query/default.html. 46. Kim JJ, Goldie SJ: Health and economic implications of HPV vaccination in the United States. N Engl J Med 2008, 359(8): This study identifies the bottom line of introducing the HPV vaccine in the United States by looking at its costeffectiveness ratio in dollars per quality-adjusted life-year gained compared with current screening practice. Such cost effectiveness modeling will be the basis for examining the introduction of the vaccine in countries worldwide..