The HPV vaccine: what we know versus what we hope

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1 The HPV vaccine: what we know versus what we hope Karen Smith-McCune Associate Professor University of California San Francisco

2 I have no financial conflicts of interest

3 Objectives Discuss current recommendations for vaccination from CDC and ACS Discuss currently available data regarding vaccine safety and efficacy

HPV L1 Protein Self-Assembles Into VLPs 1. Berzofsky JA, et al. J Clin Invest. 2004;114:450 462. 2. Kirnbauer R, et al.

4 HPV L1 Protein Self-Assembles Into VLPs 1. Berzofsky JA, et al. J Clin Invest. 2004;114: Kirnbauer R, et al. Proc Natl Acad Sci USA. 1992;89: Modis Y, et al. EMBO J. 2002;21:

6 HPV Vaccine Time-line May, Phase II trial published (N=552) June FDA approves Gardasil June 29, ACIP provisional recommendations for the use of the quadrivalent HPV vaccine May 10, Interim Phase III trials published

7 CDC- Advisory Committee on Immunization Practices Recommend vaccination of year old girls Recommend catch-up vaccination up to the age of 26 Vaccination can begin as young as 9 years

8 American Cancer Society Similar recommendations as ACIP EXCEPT- In women ages 18-26, decision to vaccinate should be based on a discussion about sexual history. -Cancer 2007

9 Unanswered questions: Will the vaccine reduce rates of cervical cancer? - Rare outcome - Surrogates: CIN 2+, CIN 3+? - Longitudinal outcomes of prospective cohorts in Scandinavia (the Nordic cohort ) will provide data on cancer but the results will not be available for several decades

10 Unanswered questions: Will the vaccine reduce overall rates of cervical cancer precursors (CIN and AIS)?

11 Intention to treat population (ITT) Unrestricted susceptible population (US) Per protocol susceptible population (PPS) Everyone Naïve to vaccine HPV types at entry Disease associated with HPV vaccine types Naïve throughout vaccination period Disease associated with any HPV type

12 Efficacy against disease associated with HPV 16 or 18: 44% 95% Future II: CIN 2,3,AIS Intention to treat (ITT) Unrestricted susceptible (UnS) Efficacy against disease regardless of HPV type: 17% (1-31%) Not reported 98% Per protocol susceptible population (PPS) Not reported NEJM 2007;356; Table 3

13 Why is vaccine efficacy so modest in overall population? some women were already infected with vaccine HPV types vaccine does not prevent infection with other HPV types it will take time for true overall efficacy to manifest

14 Cumulative incidence of CIN 2,3,AIS associated with HPV 16 or 18 (FUTURE II) NEJM 2007;356; Figure 1

15 Cumulative incidence of CIN 2/3/AIS associated with any HPV type (FUTURE II) NEJM 2007;356; Figure 1

16 Related to HPV 16 and 18 Related to any HPV

17 Unanswered questions What is the effect of vaccination on disease associated with nonvaccine HPV types? What is the effect of vaccination on rates of CIN 3+

18 Lesions associated with vaccine HPV types: FUTURE I Intention to treat (ITT) Unrestricted susceptible (US) Per protocol susceptible (PPS) 40 Vaccine CIN 3/AIS Placebo 0 0 lesions Absolute risk reduction 1.0% 1.1% 0.3%

19 Lesions regardless of HPV types Intention to treat (ITT) Unrestricted susceptible (US) Lesions regardless of HPV types Per protocol susceptible (PPS) Vaccine CIN 3/AIS lesions Placebo % Absolute risk reduction -0.1% 78

20 Unanswered questions How long will vaccine protection last? - Unknown, but follow-up for 5 years in a small cohort shows continued protection (Villa et al 2006 Br Med J)

21 Unanswered questions: Is the vaccine safe? - Vaccine was well-tolerated in year olds - Major side-effect was reaction at the injection site judged to be mild or moderate by 94% of vaccine recipients - One case of vulvar cancer reported in a 22 year old who received the vaccine. - Final trial results are not yet reported.

22 National guidelines established Phase 3 trial results not yet reported

23 HPV Vaccinemanaging expectations Since the vaccine targets only 2 of the 15 oncogenic HPV types, women must continue to get Pap smears at the same intervals as currently recommended

24 HPV Vaccinemanaging expectations Since the overall effect of the vaccine on reduction of CIN/AIS rates is small (17% reduction), women must be counseled to get regular Pap smears and be aware that they still have a significant risk of abnormal Paps and CIN despite vaccination

25 HPV Vaccinemanaging expectations Since the duration of efficacy of the vaccine is unknown, women must be counseled that booster shots may be necessary

26 States with laws mandating vaccination Laws passed: Nevada, New Hampshire, Virginia, Kentucky Laws pending:colorado, Connecticut, DC, Illinois, Kansas, Massachusetts, Michigan, Missouri, Minnesota, New Jersey, Ohio, Oklahoma, South Carolina, Vermont, West Virginia

29 HPV Vaccine Time-line May, Phase II trial published (N=552) June FDA approves Gardasil June 29, ACIP provisional recommendations for quadrivalent HPV vaccine May 10, Interim Phase III trials published the use of the

30 CDC- Advisory Committee on Immunization Practices Special circumstances: -can be given to women with equivocal or abnormal Pap tests -can be given to lactating women -can be given to immunocompromised women although response to vaccine and vaccine effectiveness may be less than in immunocompetent women

31 CDC- Advisory Committee on Immunization Practices Special circumstances not recommended for use in pregnancy

32 Future II: CIN 2,3/AIS Intention to treat (ITT) Risk of disease: Vaccine: 3.6% Placebo: 4.4% Unrestricted susceptible (UnS) Per protocol susceptible population (PPS) 129 women need to be vaccinated to prevent 1 case of CIN 2,3/AIS NEJM 2007;356; Table 3

34 Intention to treat population?? Per protocol susceptible population (PPS) Disease associated with HPV vaccine types 100% vaccine efficacy

35 HPV Vaccinemanaging expectations Since the overall effect of the vaccine on cancer rates is unknown, women must be counseled to get regular Pap smears

Focus. A case. I have no conflicts of interest. HPV Vaccination: Science and Practice. Collaborative effort with Karen Smith-McCune, MD, PhD 2/19/2010

Focus. A case. I have no conflicts of interest. HPV Vaccination: Science and Practice. Collaborative effort with Karen Smith-McCune, MD, PhD 2/19/2010 HPV Vaccination: Science and Practice George F. Sawaya, MD Professor Department of Obstetrics, Gynecology and Reproductive Sciences Department of Epidemiology and Biostatistics Director, Colposcopy Clinic,