1. Prophylactic HPV vaccines to prevent cervical cancer —but what else? Aimee R. Kreimer, Ph.D. kreimera@mail.nih.gov National Cancer Institute March 20, 2010 American Medical Writers Association Mid-Atlantic Chapter (AMWA-MAC)

2. Cervical Cancer History 1842: Italian investigator D. Rigoni-Stern reported that prostitutes had an unusually high rate of cervical cancer, while nuns had virtually no cases of the disease (vice versa for breast cancer). 1940’s: Papanicolaou develops his cytology test (Pap smear); cervical cancer rates decline by >75% in U.S. over the next ~50 years 1960’s-1980’s: Infectious agents implicated---HSV2

3. Cervical Cancer History 1974: Zur Hausen identifies human papillomavirus (HPV) DNA in cervical cancer tissue Late 1980s: Epidemiologic studies show association of HPV and cervical cancer; PCR assays developed Mid to Late 1990’s: ≥95% cervical CA’s have HPV DNA 2003: FDA approval of HPV DNA Test for CxCA Screening 2003-5: Vaccines based on Capsid Proteins Protect Against HPV infection and CIN

4. Summary of Today’s Talk Global Epidemiology of cervical cancer Etiology/biology Anatomy/physiology 2° prevention through screening 1° prevention through prophylactic vaccination –Details of the HPV vaccine

6. Cervical Cancer epidemiology Worldwide ~500,000 new cases per year –3 rd most common cancer in women Worldwide ~250,000 deaths per year –~1/10 th of all female cancer deaths Incidence and survival rates vary by race and geographical region

7. GLOBOCAN 2002 Age-standardized incidence and mortality rates of cervical cancer, 2002

8. The Primary Risk Factor for Cervical Cancer: Human Papillomavirus (HPV) Cervical Neoplasia risk factors

9. Risk factors for HPV acquisition –lifetime # of sexual partners –sexual practices of male partner Co-factors for progression –immunosuppression –other infectious agents (HSV-2, chlamydia) –Parity, oral contraceptives –smoking? dietary factors? genetics?

10. HPV Small DNA virus (~8000bp) More than 100 types identified based on the genetic sequence of the outer capsid protein L1

11. HPV epidemiology Most common viral sexually transmitted infection –MEN: oral cavity, penis, scrotum, urethra, anus –WOMEN: oral cavity, cervix, vagina, vulva, anus Manifestation of infection depends on the site of infection and the genotype of HPV –Carcinogenic  neoplasia and cancer of cervix, oropharynx, and anus; less likely to cause cancer at other sites, ex: HPV16 and 18 –Non-carcinogenic  anogenital warts, ex: HPV6 and 11

13. Secondary Prevention: Interrupting disease progression

14. In the right settings, cervical cancer can be prevented with a moderately sensitive test Forgiving disease: long pre-clinical detectable phase Almost all precancer can be treated when detected early With regular screening, an insensitive test will detect all but the most rapidly developing cases!

15. The Natural History of Disease Biologic Onset of Disease Disease detectable by screening Usual time of Diagnosis Outcome Symptoms Detectable preclinical phase Preclinical phase

16. Screening for precursor lesions and HPV infections Frequent pap smear cytology HPV DNA testing (age 30+) Treatment of precursor lesions by excisional therapy is > 95% effective Screening for cervical cancer

17. If Pap Smears successfully prevented cervical cancer in the mainstream U.S., why not use simply use them to screen everyone else? A.Three-visit cycle: 1. Cytology; 2. Colposcopy; 3. Treatment B.Cytology is an insensitive test (negative test = poor reassurance); repeat iterations (e.g., regular or annual Pap smears) are necessary. C.Cytology is a poorly reproducible (subjective) test and difficult to maintain performance D.Colposcopy is not as good as you think it is. E.Bottom Line: U.S. program costs billions of $ annually F.Tests with better test characteristics, less visits per cycle, fewer cycles per lifetime

18. % of Cancers Incremental Etiologic Contributions of HPV types

19. Cumulative Incidence of Cervical Precancer or Cancer (≥CIN3) after a Single Oncogenic HPV Test 30 Years and Older, Cytologically Normal Women Portland Sherman et al., JNCI, 2003

20. HPV16+ HPV18+ HPV+ HPV+/ HPV16-/18- HPV- Portland Khan et al., JNCI, 2005 HPV Test as Screening

21. HPV testing Pap testing Sensitive - 98% But not specific so high false+ rates Useful for equivocal Pap results Useful for certain ages Useful if can find persistent infection Useful for infrequent screening!

22. Current Recommendations in US Women 30 Years and Older Cytology Negative Oncogenic HPV- Oncogenic HPV+ Repeat Tests in 3 Years Repeat Tests in 6-12 Months Oncogenic HPV Testing

23. Concerns about Screening Using HPV Tests Will the tests include the right types and proper thresholds for positivity? Will screening be used incorrectly, e.g., among young women? Will the companies act and price fairly? Will the “winner” be the best test? How can “home-brew” assays be quality- controlled or discouraged?

24. Primary Prevention: Prophylactic vaccination

25. Current Prophylactic Vaccines are Based on Purified Papillomavirus-Like Particles (VLPs) Empty viral capsid composed of the L1 major virion protein Non-infectious and non-oncogenic (Subunit vaccine)

26. HPV VLP Vaccines ManufacturerMerckGlaxoSmithKline Trade nameGardasil®Cervarix™ HPV types6,11,16,1816,18 Theoretic coverage 70% of CxCa 90% GW 70% of CxCa AdjuvantAlumASO4 (Alum+MPL) Dosing Schedule0, 2, 6 months0, 1, 6 months

27. Phase III Trials--Main Results Design: double blind, placebo controlled trials of >10,000 women Main Finding: protection against cervical precancer caused by HPV16/18 among women naïve to these types during the vaccination period: VE ~100% Tolerability: slightly more injection site pain than control vaccine Immunogenicity: 99.5% seroconversion with titers 10-50 fold higher than natural infection Safety: no evidence of elevated adverse events among vaccinees

28. How durable is protection?

29. Serum HPV16 antibody titers post- vaccination plateau at levels higher than in natural infection Vaccinees Naturally infected Uninfected From Mao et al, Obstet Gynecol 107:18-27, 2006

30. Can the vaccine be used to treat existing infections and/or disease?

31. Vaccine efficacy among women already infected with HPV16 or 18 Vaccine efficacy against viral clearance: 2.5% (95% CI -9.8 to 13.5%) HPV vaccination does not accelerate viral clearance among those infections No evidence of a therapeutic effect of this vaccine Hildesheim et al. JAMA 2007; 298(7):743-53

32. Does the vaccine protect against other HPV types? (cross-protection)

33. Efficacy Against 12 month persistent HPV infection Other High Risk HPV Types GSK HPV16/18 Vaccine ITT Analysis; ca. >700 per arm: 3.5 yr follow-up* HPV Type# Vaccine# Placebo Efficacy (95%CI) 451027 63 (18-85) 312110279 (66-88) 333150 38 (18-85) 521501435 (-34-18) 586456-15 (-71-23) 30 53 56 66 51 26 34 45 39 68 18 35 16 31 58 33 52 High-risk HPV types X X *Paavonen et al, Lancet 2009

34. Does the vaccine protect against HPV infections at other anatomic sites?

35. Site Attributable to HPV (%) Of which, HPV16/18 (%) Total Cancers Attributable to HPV % of all cancers Cervix10070492,800 4.54 Penis406326,30010,5000.1 Vulva, vagina408040,00016,0000.15 Anus909230,40027,3000.25 Mouth395274,30082000.08 Oropharynx128952,10062000.06 All sites 10,862,500561,1005.17 Burden of HPV in all cancers Adapted from Parkin and Bray, Vaccine 2006

36. Protection against other cancers Vaginal/vulvar- 100% VE Anal- studies on-going Penile- high protection against penile precancer Oral- no data yet

37. Important considerations ~ $375 for the 3 dose series in the USA Requires a cold chain and 3 visits It doesn’t protect women with past infection Still have to screen for other carcinogenic types (~30% of cancer)

38. How do we integrate HPV vaccination into current screening programs? (goal: maximize impact in a cost- effective manner)

40. Summary of Vaccine Findings in Young Women High level prevention of precancerous cervical lesions when administered to females without infection by vaccine-type HPVs –Not therapeutic Generally safe and well-tolerated –Cannot cause infection or cancer (b/c only contains 1 protein from each targeted type) High antibody titers sustained for ~8 years Additional results –High efficacy for prevention of HPV-related vaginal/extra-genital lesions

41. Summary of questions that still need addressed How long is the duration of protection (past 10 yrs)? Will the vaccine protect against infections and disease at other anatomic sites? Will the vaccine work in special populations (i.e.: HIV-positive)? How should the vaccine be integrated into existing screening programs? How should the vaccine be introduced in countries without screening programs?