1. A Cost-Effectiveness Analysis of Alternative Human papillomavirus ( HPV) Vaccination Strategies Elamin H. Elbasha Merck Research Laboratories, USA

2. 2 Presentation outline HPV infection and disease HPV vaccines Merck model Public health impact Economic impact Summary and conclusions

3. 3 HPV infection HPV is small, non-enveloped, encapsulated, double-stranded DNA virus HPV encodes two structural proteins L1 codes for major capsid protein L2 codes for minor capsid proteins Enormous HPV diversity More than 100 HPV genotypes More than 40 types infect ano-genital tract At least 13 high-risk types cause cervical cancer Ubiquitous Lifetime Risk of HPV infection up to 70% among sexually active Major risk factor for HPV acquisition: number of sexual partners

4. 4 Asymptomatic or common warts Neoplasm or external genital warts

5. 5 HPV infection life cycle Few months to few yearsUp to 20 years Goodman A., Wilbur D. C. Case 32-2003 — A 37-Year-Old Woman with Atypical Squamous Cells on a Papanicolaou Smear. N Engl J Med 2003; 349:1555-1564

6. 6 Conditions associated with HPV types 16, 18, 6,11 Clifford, BJ Ca 2003; Munoz Int J Cancer 2004; Brown J Clin Micro 1993; Carter Cancer Res 2001; Clifford Cancer Epi Biomarkers Prev 2005; Gissman Proc Natl Acad Science 1983; Kreimer Cancer Epidemiol Biomarkers Prev 2005 HPV 16, 18 Estimated attributable % – Cervical cancer70 % – High grade cervical abnormalities50 % – Low grade cervical abnormalities30 % – Anal cancer~70 % – Vulva / Vagina / Penile~40 % – Head and neck cancers~3-12 % HPV 6, 11 – Low grade cervical abnormalities10 % – Genital warts90 % – Recurrent respiratory papillomatosis (RRP)90 %

7. 7 Globocan 2002 By end of presentation, 16 women would die from cervical cancer Second most common cancer among women 274,000 deaths from cervical cancer in 2002

8. 8 Immunologic Basis for HPV vaccines L1 HPV major capsid protein self-assembles into empty virus-like particles (VLPs) In animal models of papillomavirus infection using species-specific VLPs Vaccination results in protection from infection and disease Efficacy associated with development of neutralizing antibodies Transfer of serum from vaccinated to unvaccinated animals transfers protective efficacy Protection is prophylactic, not likely to be therapeutic Protection is likely to be type-specific

9. 9 HPV vaccines Prepared from virus-like particles (non-infectious) Produced by recombinant technology Do not contain any live biological product or DNA GARDASIL ® [prophylactic quadrivalent HPV (6,11,16,18) vaccine] licensed in U.S. & other countries First vaccine to prevent cervical cancer, precancerous genital lesions, and genital warts Series of three injections over a six-month period Safe and highly efficacious CERVARIX ® [prophylactic bivalent HPV (16,18) vaccine] in final stages of clinical testing

10. 10 Research questions What are the epidemiologic consequences of HPV vaccination? What is the sensitivity of vaccine health impact (HPV, CIN, cervical cancer, genital warts) to: vaccine characteristics (e.g., duration of protection)? vaccination strategies (females and males, females-only, catch- up, etc.)? What is the cost-effectiveness of programs using a quadrivalent HPV (6/11/16/18) vaccine?

11. 11 Methods Direct and indirect ‘herd immunity’ effects of vaccination Describe transmission of the virus and resulting disease in a population Assess impact of vaccine on vaccinees and their contacts An integrated disease transmission model and cost- utility analysis Demographic model Behavioral model HPV infection and disease models Economic model US healthcare system data and perspective Assumes existing screening practices

12. 12 Infected, 16/18 types Susceptible X klib +S klib Death Infected, 6/11 types Coinfected New Entrants Immune, 16/18 types Immune, 6/11 types Immune, all 4 types Infected, 6/11 types Infected, 16/18 types Waning Immunity Death Infection 16/18 Infection 6/11 Infection 16/18 Infection 6/11/16/18 Clearance 16/18 Clearance 6/11 Infection 16/18 Infection 6/11 Clearance 16/18 Clearance 6/11 Clearance 16/18 Clearance 6/11/16/18 Infection 6/11 Transfer diagram, no vaccine compartments

13. 13 Infected, HR types Vaccinated V klib  ki V klib Infected, LR types Coinfected B klb  kl0b Immune, HR types Immune, LR types Immune, both types Infected, LR types Infected, HR types  ki V klib Transfer diagram, vaccine compartments

14. 14 Infected Y h,U h,P h Undetected CIN1Detected CIN1Treated & Infected Undetected CIN2Undetected CIN3Detected CIN2 Detected CIN3 Treated & Infected Treated & CuredInvasive Cancer Transfer diagram, CIN compartments

15. 15 Vaccine characteristics: data and assumptions Vaccine take (% of vaccinees with vaccine effect) HPV 16/18 100%, HPV 6/11 100% Vaccine degree of protection HPV 16/18, HPV 6/11: against infection 90% (CI:74  100) HPV 16/18, HPV 6/11: against disease 100% (CI:87  100) Vaccine duration of protection HPV 16/18, HPV 6/11: 10 years to lifetime Breakthrough infections Infectiousness and clearance same as natural infections

16. 16 Vaccination strategies DescriptionDefinition A. Routine 12-year-old females Vaccinate females before reaching age 12 B. Routine 12-year-old females and males Vaccinate females and males before reaching age 12 C. 12-year-old females + 12– 24-year-old females catch-up Strategy A + a temporary catch-up program targeting 12–24-year-old females D. 12-year-old females and males + 12–24-year-old females catch-up Strategy B + a temporary catch-up program targeting 12–24-year-old females E. 12-year-old females and males + 12–24-year-old females and males catch-up Strategy B + a temporary catch-up program targeting 12–24-year-old females and males

17. 17 Vaccination penetration rates: assumptions Routine 12-year olds increase vaccine penetration linearly from 0% in Year 0 to 70% in Year 5 and after Catch-up 12  24-year olds All cohorts (12  24): increase vaccine penetration linearly from 0% in Year 0 to 50% in Year 5 Program stops after 5 years

18. 18 Impact of vaccination strategies diagnosed HPV 16/18-related cervical cancer incidence, females (12+y), lifelong duration

19. 19 Impact of vaccination strategies diagnosed HPV 16/18-related CIN 2/3 incidence- females (12+y) lifelong duration

20. 20 Impact of vaccination strategies diagnosed HPV 6/11/16/18-related CIN 1 incidence - females (12+y) lifelong duration

21. 21 Impact of vaccination strategies diagnosed HPV 6/11-related genital warts incidence - females (12+y) lifelong duration

22. 22 Impact of vaccination strategies diagnosed HPV 6/11-related genital warts incidence - males (12+y) lifelong duration of protection

23. 23 Cumulative quality-adjusted life years

24. 24 Cumulative costs

25. 25 Cost-effectiveness analysis of HPV vaccination strategies* Discounted totalIncremental StrategyCostsQALYsCostsQALYs$/QALYs** No vaccination72,659,3022,698,711–– 12-year-old females74,042,9902,699,1781,383,687467$2,964 12-year-old females and males78,707,8252,699,3274,664,835149dominated 12-year-old females + 12  24-year- old females catch up 74,815,6672,699,3433,892,15916$4,666 12-year-old females and males + 12  24-year-old females catch up 79,746,3572,699,4614,930,690118$41,803 12-year-old females and males + 12  24-year-old females and males catch up 81,761,2102,699,5062,014,85345$45,056 * Assumes cost of vaccination series is $360 and duration of protection is lifelong. ** Compared with the preceding non-dominated strategy.

26. 26 Sensitivity analysis: Impact of vaccination strategies diagnosed HPV 16/18-related CIN 2/3 incidence- females (12+y) 10-years duration vs. lifetime

27. 27 Impact of Vaccination Strategy Cervical Cancer Incidence - Females (12–85y) Lifelong duration, 50% coverage

28. 28 Impact of Vaccination Strategy Cervical Cancer Incidence - Females (12–85y) Lifelong duration, 90% coverage

29. 29 Sensitivity analyses: Incremental cost-effectiveness ratio ($/QALY) vs. duration of protection & cost Input range/Program Vaccination costs $300$500 Vaccine duration of protection: lifelong 12-year-old females + 12  24-year-old females catch up 2,4229,900 12-year-old females & males + 12  24- year-old females & males catch up 36,16165,810 Vaccine duration of protection: 10- Years 12-year-old females + 12  24-year-old females catch up 16,19432,619 12-year-old females & males + 12  24- year-old females & males catch up 44,56279,115

30. 30 Sensitivity analyses: Incremental cost-effectiveness ratio ($/QALY) vs. vaccine coverage and cost Input range/Program Vaccination costs $300$500 Vaccine coverage: 50% 12-year-old females + 12  24-year- old females catch up 2,056 9,271 12-year-old females & males + 12  24-year-old females & males catch up 28,84553,479 Vaccine coverage: 90% 12-year-old females + 12  24-year- old females catch up 2,92510,739 12-year-old females & males + 12  24-year-old females & males catch up 82,241142,830

31. 31 Limitations & outstanding research questions Vaccine characteristics (e.g., duration of protection) are influential Need more and better epidemiologic and natural history of disease data to support model Need to analyze the impact on other important HPV-related diseases such as vulvar and vaginal neoplasias and cancers, recurrent respiratory papillomatosis Need to reflect the indirect costs of HPV-related disease Need to model HPV types interaction/cross protection If screening practices change, the model can reflect the shifting impact of vaccination

32. 32 Summary A prophylactic quadrivalent HPV vaccine can substantially reduce the incidence of cervical cancer, CIN, and genital warts Catch up vaccination can provide earlier and greater reductions in HPV-related disease Vaccinating males and females before age 12 combined with a temporary 12  24-year olds catch up program can be cost-effective and efficiently added to current screening programs

33. 33 Acknowledgement Erik J. Dasbach, PhD Ralph P. Insinga, PhD Merck Research Laboratories, USA