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Vaccines for the 21st Century: A Tool for Decisionmaking APPENDIX 11 Human Papillomavirus Human papillomavirus (HPV) infects stratified squamous, metaplastic squamous, and columnar epithelial cells. The majority of human papillomavirus cells are self-limited, but there is now a clear correlation between malignant tumors and the development of a subset of infections that involve oncogenic viruses. Specific types of HPV tend to infect different types of epithelia and produce different clinical and pathogenic manifestations. The two distinct types of cells are mucosal HPV infection and cutaneous HPV infection. Genital tract HPV is thought to be currently the most common sexually transmitted viral infection in the United States. Genital warts occur on the vulva, vagina, cervix, penis, and anus. In addition to being a common STD, genital HPV infection is of considerable importance in the pathogenesis role of epithelial cancers of the female and male genital tracts. DISEASE BURDEN Epidemiology For the purposes of the calculations in this report, the committee estimated that there are 1 million new infections of human papillomavirus (HPV) each year in the United States in males and females between the ages of 15 and 29 years of age. New infections are equally divided between males and females.

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Vaccines for the 21st Century: A Tool for Decisionmaking Disease Scenarios For the purposes of the calculation in this report, the committee assumed that approximately half of women with HPV infection experience a 3-month episode of limited or severe genital warts and the other half experience recurrences of limited or severe genital warts. Health utility indices (HUI) associated with those episodes range from .85 to .95. It was assumed that 10% of women with HPV infections develop cervical dysplasia due to the infection. It was also assumed that cancers that develop secondary to HPV infection occur with an average lag of 25 years from time of infection. Cervical cancers were separately described as carcinoma in situ, locally invasive at diagnosis, and advanced at diagnosis. Treatment phases and follow-up phases are included, with HUI and duration of that state ranging from 4 months of treatment at an HUI of .8 to 16 years of life spent at an HUI of .9. Sequelae of HPV infection of men was assumed to parallel to a great degree that in women: several scenarios of genital warts and penile cancers. HUI and duration of time in the specific disease states show the same ranges as for women. Table A11–1 shows the disease states for both men and women. COST INCURRED BY DISEASE Table A11–2 summarizes the health care costs incurred by HPV infections. For the purposes of the calculations in this report, it was assumed that women with genital warts incur costs associated with physician visits and diagnostics. More severe cases were assumed to involve more frequent physician visits. It was assumed that approximately half of women with mild recurrent warts and all of the women with extensive recurrent warts visit a physician four times per year. It was assumed that women with cervical dysplasia incur costs associated with specialist visits, diagnostics, and follow-up visits for 1.5 years. It was assumed that cervical carcinoma in situ was associated with multiple visits, advanced diagnostics, and ambulatory surgery during the treatment phase. During the 2-year follow-up, it was assumed that all patients receive 3 follow-up visits; and diagnostics per year. Treatment for locally invasive cervical cancer was assumed to be associated with physician visits, diagnostics, hospitalization, including costs for surgeons/anesthesiologists; and radiation therapy. The 2-year follow-up phase was assumed to include quarterly physician and diagnostic evaluation. Advanced cervical cancer was associated with similar treatment costs as for locally invasive cancer, but with increased physician visits during both the treatment phase and the follow-up phase. Treatment patterns for acute and chronic (recurring genital warts and penile cancers) sequelae of HPV infection in men were assumed to be similar to that of treatment patterns in women.

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Vaccines for the 21st Century: A Tool for Decisionmaking Table A11–1 Disease Scenarios for Women and Men for HPV Infection   No. of Cases % of Cases Committee HUI Values Duration (years) WOMEN   Genital warts, limited 237,500 47.5%   minor physical discomfort   0.95 0.2500 (3 months) Genital warts, limited but recurring 237,500 47.5%   minor physical discomfort (2 recurrences per year for 10 years)   0.90 0.5000 (6 months/year) Genital warts, extensive 12,500 2.5%   same physical discomfort   0.85 0.2500 (3 months) Genital warts, extensive and recurring 12,500 2.5%   some physical discomfort (2 recurrences per year for 10 years)   0.85 0.5000 (6 months/year) Cervical dysplasia 50,000 10.0% 0.97 1.5000 (18 months) All Cancers: assume average 25-year lag from infection Cervical cancer—carcinoma in situ 25,000 5.0%   treatment phase   0.80 0.3333 (4 months) posttreatment phase (follow-up)   0.97 2.0000 (2 years) Cervical cancer—locally invasive at diagnosis 5,000 1.0%   treatment phase (surgery, radiation, chemotherapy)   0.79 0.3333 (4 months) posttreatment phase (follow-up)   0.90 16.7349 (years remaining) Cervical cancer—advanced at diagnosis 2,500 0.5%   treatment phase (surgery, radiation, chemotherapy)   0.62 0.3333 (4 months) posttreatment phase (follow-up and sequelae e.g., infertiity, sexual dysfunction, urinary dysfunction)   0.62 3.0000 (3 years) premature death (by 3 years after diagnosis)   0.00 15.7265 (years lost)

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Vaccines for the 21st Century: A Tool for Decisionmaking   No. of Cases % of Cases Committee HUI Values Duration (years) MEN   Genital warts, limited 237,500 47.5%   minor physical discomfort   0.90 0.2500 (3 months) Genital warts, limited but recurring 237,500 47.5%   minor physical discomfort (2 recurrences per year for 10 years)   0.90 0.5000 (6 months/year) Genital warts, extensive 12,500 2.5%   some physical discomfort   0.85 0.2500 (3 months) Genital warts, extensive and recurring 12,500 2.5%   some physical discomfort (2 recurrences per year for 10 years)   0.85 0.5000 (6 months/year) All Cancers: assume average 25-year lag from infection Penile cancer—carcinoma in situ 25,000 5.0%   treatment phase   0.80 0.3333 (4 months) post-treatment phase (follow-up)   0.97 2.0000 (2 years) Penile cancer—locally invasive at diagnosis 5,000 1.0%   treatment phase (surgery, radiation, chemotherapy)   0.80 0.3333 (4 months) post-treatment phase (follow-up)   0.90 16.7349 (years remaining) Penile cancer—advanced at diagnosis 2,500 0.5%   treatment phase (surgery, radiation, chemotherapy)   0.62 0.3333 (4 months) post-treatment phase (follow-up and sequelae e.g., infertility, sexual dysfunction, urinary dysfunction)   0.62 3.0000 (3 years) premature death (by 3 years after diagnosis)   0.00 15.7265 (years lost)

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Vaccines for the 21st Century: A Tool for Decisionmaking Table A11–2 Health Care Costs Associated with HPV Disease in Women and Men   % with Care Cost per Unit Units per Case Form of Treatment WOMEN   Genital warts, limited   minor physical discomfort 100% $50 3 physician a   100% $50 1 diagnostic a Genital warts, limited but recurring   minor physical discomfort 50% $50 4 physician a/year 2 recurrences per year for 10 years 50% $50 1 diagnostic a Genital warts, extensive   some physical discomfort 100% $50 3 physician a Genital warts, extensive and recurring   some physical discomfort 100% $50 4 physician a/year 2 recurrences per year for 10 years 100% $50 1 diagnostic a Cervical dysplasia   treated precancerous condition 100% $650 1 physician c plus diagnostic c follow-up period 100% $100 6 physician b All Cancers: assume average 25-year lag from infection Cervical cancer—carcinoma in situ treatment phase 100% $50 5 physician a   100% $500 1 diagnostic c 100% $1,000 1 ambulatory surgery post-treatment phase (follow-up) 100% $50 3 physician a/year   100% $50 3 diagnostic a/year Cervical cancer-locally invasive at diagnosis treatment phase (surgery, radiation, chemotherapy) 100% $100 2 physician b   100% $500 2 diagnostic c 100% $4,000 1 hospitalization 100% $500 2 surgeons/anesthesiologist 100% $5,000 1 radiation follow-up 10% $100 4 physician b/year   10% $50 4 diagnostic a/year

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Vaccines for the 21st Century: A Tool for Decisionmaking   % with Care Cost per Unit Units per Case Form of Treatment Cervical cancer—advanced at diagnosis treatment phase (surgery, radiation, chemotherapy) 100% $100 5 physician b   100% $500 2 diagnostic c 100% $4,000 1 hospitalization 100% $5,000 1 radiation 100% $500 2 surgeon/anesthesiologist 100% $50 12 physician a 100% $50 3 medication b post-treatment phase (follow up and sequelae (e.g., infertility, sexual dysfunction, urinary dysfunction) 100% $100 6 physician b/year   100% $50 6 diagnostic a/year MEN   Genital warts, limited   minor physical discomfort 100% $50 1 physician a minor physical discomfort; recurrences for 10 years 100% $50 2 physician a/year Genital warts, extensive   some physical discomfort 100% $50 2 physician a Genital warts, extensive and recurring some physical discomfort 100% $50 2 physician a 2 recurrences per year for 10 years 100% $50 2 physician a/year All Cancers: assume average 25-year lag from infection Penile cancer—carcinoma in situ treatment phase 100% $50 1 physician a   50% $1,000 1 ambulatory surgery 100% $100 1 diagnostic b 50% $4,000 1 hospitalization 100% $500 2 surgeon/anaesthiologist post-treatment phase (follow-up) 100% $100 2 physician b/year Penile cancer—locally invasive at diagnosis treatment phase (surgery, radiation, chemotherapy) 100% $100 1 physician b   100% $4,000 1 hospitalization 100% $500 2 surgeon/anesthesiologist 50% $5,000 1 radiation

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Vaccines for the 21st Century: A Tool for Decisionmaking   % with Care Cost per Unit Units per Case Form of Treatment Penile cancer—locally invasive at diagnosis   50% $5,000 1 chemotherapy post-treatment phase (follow-up) 100% $50 1 physician a/year Penile cancer—advanced at diagnosis treatment phase (surgery, radiation, chemotherapy) 100% $100 1 physician b   100% $4,000 1 hospitalization 100% $500 2 surgeon/anesthesiologist 50% $5,000 1 radiation 50% $5,000 1 chemotherapy post-treatment phase (follow-up and sequelae (e.g., infertility, sexual dysfunction, urinary dysfunction) 100% $100 6 physician b/year VACCINE DEVELOPMENT The committee assumed that it will take 7 years until licensure of a HPV vaccine and that $360 million needs to be invested. Table 4–1 summarizes vaccine development assumptions for all vaccines considered in this report. VACCINE PROGRAM CONSIDERATIONS Target Population For the purposes of the calculations in this report, it is assumed that the target population for this vaccine male and female adolescents (age 12). It was assumed that 50% of the target population would utilize the vaccine. Vaccine Schedule, Efficacy, and Costs For the purposes of the calculations in this report, it was estimated that this vaccine would cost $100 per dose and that administration costs would be $10 per dose. Default assumptions of a 3-dose series and 75% effectiveness were accepted. Table 4–1 summarizes vaccine program assumptions for all vaccines considered in this report.

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Vaccines for the 21st Century: A Tool for Decisionmaking RESULTS If a vaccine program for HPV were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the QALYs gained would be 180,000. Using committee assumptions of less than ideal efficacy and utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the QALYs gained would be 48,000. If a vaccine program for HPV were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the health care costs saved would be $530 million. Using committee assumptions of less than ideal efficacy and utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the health care costs saved would be $140 million. If a vaccine program for HPV were implemented today and the vaccine was 100% efficacious and utilized by 100% of the target population, the annualized present value of the program cost would be $1.2 billion. Using committee assumptions of less than ideal efficacy and utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the program cost would be $435 million. Using committee assumptions of time and costs until licensure, the fixed cost of vaccine development has been amortized and is $10.8 million for a HPV vaccine. If a vaccine program were implemented today and the vaccine were 100% efficacious and utilized by 100% of the target population, the annualized present value of the cost per QALY gained is $4,000. Using committee assumptions of less than ideal utilization and including time and monetary costs until a vaccine program is implemented, the annualized present value of the cost per QALY gained is $6,000. See Chapters 4 and 5 for details on the methods and assumptions used by the committee for the results reported. READING LIST CDC, NCID. National Registry Established for Pediatric Recurrent Respiratory Papillomatosis. URL http://www.cdc.gov/ncidod/focus/vol6no2/dvrd.htm (accessed September 26, 1997). Institute of Medicine. The Hidden Epidemic: Confronting Sexually Transmitted Diseases. Eng TR, Butler WT (eds.). Washington, DC: National Academy Press, 1997. Miller BA, Kolonel LN, Bernstein L, et al. (eds). Racial/Ethnic Patterns of Cancer in the United States 1988–1992, National Cancer Institute. NIH Pub. No. 96–4104. Bethesda, MD, 1996. Stoeckle MY. Human Herpesvirus 6 and Human Herpesvirus 7. In: Principles and Practice of Infectious Diseases. GL Mandell,, JE Bennett, Dolin R eds. New York, NY: Churchill Livingstone, 1995, pp. 1377–1400.

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Vaccines for the 21st Century: A Tool for Decisionmaking U.S. Bureau of the Census. Statistical Abstract of the U.S.: 1995 (115th edition). Washington, D.C. 1995. Ventura SJ, Martin JA, Mathews TJ, et al. Advance Report of Final Natality statistics, 1994. Monthly Vital Statistics Report 1996; 44.

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