benefits from HPV vaccination?
• The magnitude of benefit from HPV vaccination in a country will depend on:
− the burden of HPV disease attributable to the genotypes against which the vaccines protect or, if confirmed, cross-protect;
− vaccine efficacy;
− achievable vaccine coverage;
− duration of protection.
• These factors may differ in different age groups and in populations with high HIV prevalence.
• Both direct protection of those vaccinated and indirect protection of others as a result of reduced HPV transmission in the community need to be considered when different vaccination strategies are evaluated.89, 92, 94
• The introduction of HPV vaccines may affect – positively or negatively – the effectiveness of screening programmes, which may have important consequences.94
• Poorly understood features of HPV epidemiology and natural history (e.g. age- and sex-specific transmission rates, duration of natural immunity, whether reactivation occurs, HPV genotype interaction, natural history of CIN2 and CIN3) hinder modelling work; better data are urgently required.
In general, the most important determinant of overall programme effectiveness will be the cov- erage of pre-adolescent girls with three doses of HPV vaccine. Direct protection of individuals would be expected to decline as age at vaccination increases, since HPV vaccines are prophylactic and
older women will be more likely to have had prior exposure to HPV. However, catch-up campaigns (sometimes used at the start of routine vaccination with a new vaccine) can hasten the decline in inci- dence and result in indirect protection of the popu- lation. Mathematical models can help to determine the costs and benefits of catch-up campaigns; these are likely to depend on the age-specific rates of HPV infection in different countries.
The potential gains from vaccinating males also need to be considered from a population perspec- tive, including indirect (reduced HPV transmission) and direct effects (e.g. prevention of genital warts, penile cancer, anal cancer, RRP, and certain head and neck cancers). The direct cancer prevention effect in boys will be less than in girls, as the inci- dence of HPV-related cancer is lower in men than in women. Results of dynamic simulation models of HPV transmission suggest that, if high coverage of females can be achieved, little additional reduc- tion in cervical cancer is gained by vaccinating males.94, 95 At lower coverage, vaccination of boys may contribute to controlling infection. However, because vaccination directly protects women, more gains may be derived per girl vaccinated than per boy vaccinated. Whether any additional benefits are worth the costs of vaccinating males can be evaluated further in different settings using math- ematical models. Validation of predictions based on these complex models will require long-term implementation studies. Furthermore, consider- ations of the acceptability and likely coverage of a strategy targeting girls only, against one including both sexes, will also be relevant in determining the usefulness of vaccinating boys.
The most important risk period for acquisition of HPV appears to be late adolescence and early adulthood. To obtain maximum benefit from vac- cines, protection must cover this period. The clini- cal trials have shown that efficacy is sustained for at least 4–5 years, and it seems likely that protection may last longer. Thus, declining vaccine efficacy is unlikely to be a major determinant of the benefits of a pre-adolescent programme, though data to confirm this are clearly required.
In countries with organized screening, it will be important to evaluate the effect of HPV vaccination on the screening programme. If those who have been vaccinated no longer attend for screening, because they (wrongly) believe that they are fully protected against cervical cancer, the number of deaths could even increase, especially if vac- cine protection wanes over time.94 It is important, therefore, to use the opportunity presented by the introduction of HPV vaccine to increase awareness of the need for screening.
15. What factors have most
influence on the estimated
costs of HPV vaccination?
• The cost of HPV vaccines is likely to be the major determinant of the cost of a vaccination programme.
• Delivery costs for HPV vaccines are likely to be much higher than for existing vaccines given to infants, since in most developing countries a new programme will be needed.
• Data on costs and coverage of different vac- cination strategies will be obtained from dem- onstration projects planned in four developing countries over the next 1–2 years.
The licensed vaccine is not yet widely available, but where it has been licensed, its current price is over US$100 per dose (i.e. over US$300 for the full course). Manufacturers have declared that they are willing to set different prices for countries with different economic conditions. The price of the vaccine is almost certainly going to be a major determinant of the cost and affordability of any vaccine programme.
Administration costs are likely to vary by country and region. Very few countries have universal programmes for delivering health care to pre- adolescents, so the costs of establishing and maintaining a new system for HPV vaccination are likely to be considerable.96 Demonstration projects
planned by the Program for Appropriate Technology in Health (PATH) in India, Peru, Uganda, and Viet Nam, will help to gather data on the costs of HPV vaccination programmes. If a two-dose schedule could be used, or if vaccines could be given at an earlier age, together with other vaccines (e.g. at school entry or even in infancy), the costs could be reduced. Evaluation of these options is therefore urgently needed.
In developing countries, cervical cancer is the leading cause of cancer death in women; it is estimated that 91% of all HPV-related cancer deaths in the world are due to cervical cancer. HPV vaccines are very effective in preventing infection and disease resulting from vaccine- related HPV genotypes in women who are negative for both HPV DNA and serum antibodies at the time of first vaccination. Protection lasts for at least 5 years and probably much longer. Data are not yet available on the safety and efficacy of HPV vaccines in Africa, or in populations with high HIV prevalence. HPV vaccines will reduce, but not eliminate, the risk of cervical cancer. Screening programmes will still be needed to prevent cervical cancer, even after HPV vaccines are introduced, although the procedures used for screening may need to be adapted.97 The primary target group for HPV vaccines is likely to be pre- adolescent girls (e.g. aged 9–12 years), but the cost-effectiveness of vaccinating other groups needs to be evaluated. Further data on regional and country variations in HPV epidemiology, the
Conclusions
natural history and transmission of HPV infection, the mechanism and duration of protection by HPV vaccines, and the costs and effectiveness of different strategies for vaccination and screening will improve predictions of the benefits to come from these new vaccines.98, 99 More information on the cost-effectiveness of different strategies will become available to guide policy-makers once the price of the vaccine itself is known for countries at different income levels, and when associated delivery costs have been assessed. If a two-dose schedule could be used, or if HPV vaccines could be given at an earlier age with other vaccines (e.g. at school entry or even in infancy), vaccine delivery could be greatly facilitated. Innovative methods will be needed to finance the introduction of HPV vaccines.100 The introduction of HPV vaccines will create opportunities to strengthen health systems. Such opportunities should be taken through the rapid establishment of new partnerships for vaccine delivery, financing and monitoring of impact.7
1. zur Hausen H. Papillomaviruses in human cancer. Appl Pathol. 1987;5:19–24.
2. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–19.
3. Hobbs CG, Sterne JA, Bailey M, Heyderman RS, Birchall MA, Thomas SJ. Human papillomavirus and head and neck cancer: a systematic review and meta-analysis. Clin Otolaryngol. 2006;31:259–266.
4. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med. 1997;102:3–8.
5. Chew GK, Cruickshank ME, Rooney PH, Miller ID, Parkin DE, Murray GI. Human papillomavirus 16 infection in adenocarcinoma of the cervix. Br J Cancer. 2005;93:1301–1304.
6. Department of Immunization, Vaccines and Biologicals. Vaccine introduction guidelines. Adding a vaccine to a national
immunization programme: decision and implementation. Geneva: World Health Organization; 2005 (WHO/IVB/05.
18).
7. WHO, UNFPA. Preparing for the introduction of HPV vaccines. Policy and programme guidance for countries. Geneva: World Health Organization; 2006 (WHO/RHR/06.11).
8. World Health Organization. Comprehensive cervical cancer control. A guide to essential practice. Geneva; 2006. 9. de Villiers EM. Papillomavirus and HPV typing. Clin Dermatol. 1997;15:199–206.
10. International Agency for Research on Cancer. Human papillomaviruses. Lyon; 2006 (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 90).
11. Munoz N, Bosch FX, De Sanjose S, Herrero R, Castellsague X, Shah KV et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518–527.
12. Parkin DM, Bray F. The burden of HPV-related cancers. Vaccine. 2006;24 (Suppl 3):S11–S25.
13. Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB. Cancer incidence in five continents. Volume VIII. Lyon: International Agency for Research on Cancer; 2002 (IARC Scientific Publications No. 155).
14. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2000: Cancer incidence, mortality and prevalence worldwide, Version
1.0. Lyon: IARC Press; 2001 (IARC Cancer Base No. 5).
15. Mathers CD, Shibuya K, Boschi-Pinto C, Lopez AD, Murray CJ. Global and regional estimates of cancer mortality and incidence by site: I. Application of regional cancer survival model to estimate cancer mortality distribution by site. BMC
Cancer. 2002;2:36.
16. Shibuya K, Mathers CD, Boschi-Pinto C, Lopez AD, Murray CJ. Global and regional estimates of cancer mortality and incidence by site: II. Results for the global burden of disease 2000. BMC Cancer. 2002;2:37.
17. Schiffman M, Solomon D. Findings to date from the ASCUS-LSIL Triage Study (ALTS). Arch Pathol Lab Med. 2003;127:946–949.
18. Greer CE, Wheeler CM, Ladner MB, Beutner K, Coyne MY, Liang H et al. Human papillomavirus (HPV) type distribution and serological response to HPV type 6 virus-like particles in patients with genital warts. J Clin Microbiol. 1995;33:2058–2063.
19. Koshiol JE, Laurent SA, Pimenta JM. Rate and predictors of new genital warts claims and genital warts-related healthcare utilization among privately insured patients in the United States. Sex Transm Dis. 2004;31:748–752. 20. Winer RL, Kiviat NB, Hughes JP, Adam DE, Lee SK, Kuypers JM et al. Development and duration of human
papillomavirus lesions, after initial infection. J Infect Dis. 2005;191:731–738.
21. Chin-Hong PV, Vittinghoff E, Cranston RD, Browne L, Buchbinder S, Colfax G et al. Age-related prevalence of anal cancer precursors in homosexual men: the EXPLORE study. J Natl Cancer Inst. 2005;97:896–905.
22. Kjaer SK, Munk C, Tran TN, Tryggvadottir L, Sparen P, Dasbach E, Liaw K-L, Nygaard J, Nygaard M. The burden of genital warts. A study of nearly 70,000 women from four Nordic countries. Proceedings of European Research
Organization on Genital Infection and Neoplasia (EUROGIN), April 23–26 2006, Paris, France (Abstract SS21-04).
23. Silverberg MJ, Thorsen P, Lindeberg H, Grant LA, Shah KV. Condyloma in pregnancy is strongly predictive of juvenile- onset recurrent respiratory papillomatosis. Obstet Gynecol. 2003;101:645–652.
24. Derkay CS, Hester RP, Burke B, Carron J, Lawson L. Analysis of a staging assessment system for prediction of surgical interval in recurrent respiratory papillomatosis. Int J Pediatr Otorhinolaryngol. 2004;68:1493–1498. 25. Ho GY, Burk RD, Klein S, Kadish AS, Chang CJ, Palan P et al. Persistent genital human papillomavirus infection as a
risk factor for persistent cervical dysplasia. J Natl Cancer Inst. 1995;87:1365–1371.
26. Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998;338:423–428.
27. Franco E, Villa L, Rohan T, Ferenczy A, Petzl-Erler M, Matlashewski G. Design and methods of the Ludwig-McGill longitudinal study of the natural history of human papillomavirus infection and cervical neoplasia in Brazil. Ludwig- McGill Study Group. Rev Panam Salud Publica. 1999;6:223–233.
28. Moscicki AB, Shiboski S, Broering J, Powell K, Clayton L, Jay N et al. The natural history of human papillomavirus infection as measured by repeated DNA testing in adolescent and young women. J Pediatr. 1998;132:277–284. 29. Moscicki AB, Schiffman M, Kjaer S, Villa LL. Updating the natural history of HPV and anogenital cancer. Vaccine.
2006;24 (Suppl 3):S42–S51.
30. Ostor AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol. 1993;12:186– 192.
31. Munoz N, Bosch FX, Castellsague X, Diaz M, De Sanjose S, Hammouda D et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer. 2004;111:278–285.
32. Clifford GM, Smith JS, Aguado T, Franceschi S. Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: a meta-analysis. Br J Cancer. 2003;89:101–105.
33. Clifford GM, Smith JS, Plummer M, Munoz N, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer. 2003;88:63–73.
34. Clifford G, Franceschi S, Diaz M, Munoz N, Villa LL. HPV type-distribution in women with and without cervical neoplastic diseases. Vaccine. 2006;24 (Suppl 3):S26–S34.
35. Smith JS, Lindsay L, Keys J, Hoots B, Winer R, Franceschi S, Clifford G. HPV type distribution in invasive cervical cancer and high-grade cervical neoplasia: an update of meta-analyses and identification of global data gaps. Int J
Cancer. 2007; in press.
36. Castellsague X, Diaz M, De Sanjose S, Munoz N, Herrero R, Franceschi S et al. Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors: implications for screening and prevention. J Natl Cancer Inst. 2006;98:303–315.
37. Clifford GM, Rana RK, Franceschi S, Smith JS, Gough G, Pimenta JM. Human papillomavirus genotype distribution in low-grade cervical lesions: comparison by geographic region and with cervical cancer. Cancer Epidemiol
Biomarkers Prev. 2005;14:1157–1164.
38. Myers ER, McCrory DC, Nanda K, Bastian L, Matchar DB. Mathematical model for the natural history of human papillomavirus infection and cervical carcinogenesis. Am J Epidemiol. 2000;151:1158–1171.
39. Castle PE, Schiffman M, Herrero R, Hildesheim A, Rodriguez AC, Bratti MC et al. A prospective study of age trends in cervical human papillomavirus acquisition and persistence in Guanacaste, Costa Rica. J Infect Dis. 2005;191:1808– 1816.
40. Munoz N, Mendez F, Posso H, Molano M, van den Brule AJ, Ronderos M et al. Incidence, duration, and determinants of cervical human papillomavirus infection in a cohort of Colombian women with normal cytological results. J Infect
Dis. 2004;190:2077–2087.
41. Schiffman MH. Recent progress in defining the epidemiology of human papillomavirus infection and cervical neoplasia. J Natl Cancer Inst. 1992;84:394–398.
42. Kjaer SK, Chackerian B, van den Brule AJ, Svare EI, Paull G, Walbomers JM et al. High-risk human papillomavirus is sexually transmitted: evidence from a follow-up study of virgins starting sexual activity (intercourse). Cancer
Epidemiol Biomarkers Prev. 2001;10:101–106.
43. Winer RL, Lee SK, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218–226.
44. Smith EM, Johnson SR, Ritchie JM, Feddersen D, Wang D, Turek LP et al. Persistent HPV infection in postmenopausal age women. Int J Gynaecol Obstet. 2004;87:131–137.
45. Fairley CK, Gay NJ, Forbes A, Abramson M, Garland SM. Hand-genital transmission of genital warts? An analysis of prevalence data. Epidemiol Infect. 1995;115:169–176.
46. Antonsson A, Karanfilovska S, Lindqvist PG, Hansson BG. General acquisition of human papillomavirus infections of skin occurs in early infancy. J Clin Microbiol. 2003;41:2509–2514.
47. Rintala MA, Grenman SE, Jarvenkyla ME, Syrjanen KJ, Syrjanen SM. High-risk types of human papillomavirus (HPV) DNA in oral and genital mucosa of infants during their first 3 years of life: experience from the Finnish HPV Family Study. Clin Infect Dis. 2005;41:1728–1733.
48. Rintala MA, Grenman SE, Puranen MH, Isolauri E, Ekblad U, Kero PO et al. Transmission of high-risk human papillomavirus (HPV) between parents and infant: a prospective study of HPV in families in Finland. J Clin
Microbiol. 2005;43:376–381.
49. Clifford GM, Gallus S, Herrero R, Munoz N, Snijders PJ, Vaccarella S 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;366:991–998.
50. Strickler HD, Burk RD, Fazzari M, Anastos K, Minkoff H, Massad LS et al. Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women. J Natl Cancer Inst. 2005;97:577– 586.
51. De Sanjose S, Valls I, Paz CM, Lloveras B, Quintana MJ, Shah KV et al. Human papillomavirus and human immunodeficiency virus infections as risk factors for cervix cancer in women prisoners. Med Clin (Barc). 2000;115:81–84 (in Spanish).
52. Castellsague X, Munoz N. Cofactors in human papillomavirus carcinogenesis-role of parity, oral contraceptives, and tobacco smoking. J Natl Cancer Inst Monogr. 2003;31:20–28.
53. Franceschi S, Herrero R, Clifford GM, Snijders PJ, Arslan A, Anh PT et al. Variations in the age-specific curves of human papillomavirus prevalence in women worldwide. Int J Cancer. 2006; 119: 2677–2684.
54. Herrero R, Castle PE, Schiffman M, Bratti MC, Hildesheim A, Morales J et al. Epidemiologic profile of type-specific human papillomavirus infection and cervical neoplasia in Guanacaste, Costa Rica. J Infect Dis. 2005;191:1796– 1807.
55. Castle PE, Schiffman M, Herrero R, Hildesheim A, Rodriguez AC, Bratti MC et al. A prospective study of age trends in cervical human papillomavirus acquisition and persistence in Guanacaste, Costa Rica. J Infect Dis. 2005;191:1808–1816.
56. Clifford GM, Goncalves MA, Franceschi S. Human papillomavirus types among women infected with human immunodeficiency virus: a meta-analysis. AIDS. 2006; 20: 2337–2344.
57. Strickler HD, Palefsky JM, Shah KV, Anastos K, Klein RS, Minkoff H et al. Human papillomavirus type 16 and immune status in human immunodeficiency virus-seropositive women. J Natl Cancer Inst. 2003;95:1062– 1071.
58. Palefsky JM, Gillison ML, Strickler HD. HPV vaccines in immunocompromised women and men. Vaccine. 2006;24 (Suppl 3):S140–S146.
59. Palefsky J. Human papillomavirus-associated malignancies in HIV-positive men and women. Curr Opin Oncol. 1995;7:437–441.
60. Palefsky JM. Human papillomavirus infection and anogenital neoplasia in human immunodeficiency virus-positive men and women. J Natl Cancer Inst Monogr. 1998;23:15–20.
61. Vaccarella S, Franceschi S, Herrero R, Munoz N, Snijders PJ, Clifford GM et al. Sexual behavior, condom use, and human papillomavirus: pooled analysis of the IARC human papillomavirus prevalence surveys. Cancer Epidemiol
Biomarkers Prev. 2006;15:326–333.
62. Vaccarella S, Herrero R, Dai M, Snijders PJF, Meijer CJLM, Thomas JO et al. Reproductive factors, oral contraceptive use and HPV infection: pooled analysis of the IARC HPV Prevalence Surveys. Cancer Epidemiol Biomarkers Prev. 2006; 15:2148–2153.
63. Jamison JH, Kaplan DW, Hamman R, Eagar R, Beach R, Douglas JM Jr. Spectrum of genital human papillomavirus infection in a female adolescent population. Sex Transm Dis. 1995;22:236–243.
64. Young TK, McNicol P, Beauvais J. Factors associated with human papillomavirus infection detected by polymerase chain reaction among urban Canadian aboriginal and non-aboriginal women. Sex Transm Dis. 1997;24:293–298. 65. Winer RL, Hughes JP, Feng Q, O’Reilly S, Kiviat NB, Holmes KK et al. Condom use and the risk of genital human
papillomavirus infection in young women. N Engl J Med. 2006;354:2645–2654.
66. Partridge JM, Koutsky LA. Genital human papillomavirus infection in men. Lancet Infect Dis. 2006;6:21–31. 67. Chin-Hong PV, Vittinghoff E, Cranston RD, Buchbinder S, Cohen D, Colfax G et al. Age-specific prevalence of anal
human papillomavirus infection in HIV-negative sexually active men who have sex with men: the EXPLORE study. J
Infect Dis. 2004;190:2070–2076.
68. Stanley M. Immune responses to human papillomavirus. Vaccine. 2006;24 (Suppl 1):S16–S22.
69. Carter JJ, Koutsky LA, Hughes JP, Lee SK, Kuypers J, Kiviat N et al. Comparison of human papillomavirus types 16, 18, and 6 capsid antibody responses following incident infection. J Infect Dis. 2000;181:1911–1919.
70. Koshiol J, Schroeder J, Jamieson DJ, Marshall SW, Duerr A, Heilig CM et al. Smoking and time to clearance of human papillomavirus infection in HIV-seropositive and HIV-seronegative women. Am J Epidemiol. 2006;164:176–183. 71. Koshiol JE, Schroeder JC, Jamieson DJ, Marshall SW, Duerr A, Heilig CM et al. Time to clearance of human
papillomavirus infection by type and human immunodeficiency virus serostatus. Int J Cancer. 2006;119:1623– 1629.
72. Ferguson M, Heath A, Johnes S, Pagliusi S, Dillner J. Results of the first WHO international collaborative study on the standardization of the detection of antibodies to human papillomaviruses. Int J Cancer. 2006;118:1508–1514. 73. Pagliusi SR, Dillner J, Pawlita M, Quint WG, Wheeler CM, Ferguson M. International Standard reagents for
harmonization of HPV serology and DNA assays-an update. Vaccine. 2006;24 (Suppl 3):S193–S200.
74. Zhou J, Sun XY, Stenzel DJ, Frazer IH. Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles. Virology. 1991;185:251–257.