Human Papillomaviruses (HPV): The Background, Current Status and Future of Vaccines to Prevent HPV Infection, Abnormal Genital Lesions and Cervical Cancer.

Human Papillomaviruses (HPV): The Background, Current Status and Future of Vaccines to Prevent HPV Infection, Abnormal Genital Lesions and Cervical Cancer Cosette M. Wheeler, PhD Departments of Molecular Genetics & Microbiology And Obstetrics & Gynecology University of New Mexico Health Sciences Center Albuquerque, New Mexico

Learning Objectives Identify risk factors for acquiring HPV infection
Discuss the causal relationship between HPv and cervical cancer and HPV and genital warts Identify recent clinical findings on HPV vaccines in development

Papillomaviruses are small DNA viruses that coevolved with ALL animals
HPV Life Cycle HPV Protein Expression Late genes L1&L2 Early Genes E6 & E7 Early Genes E4 & E5 Early Genes E1 & E2 Stratum Corneum Granulosum Spinosum Stratum Basale Basement Membrane

Natural history of CC: factors & co-factors
HPV INFECTION LSIL HSIL INVASIVE CANCER NORMAL Immune surveillance & response Genetic susceptibility Viral factors Smoking Parity OC use HIV Other STIs Sexual behavior Hygiene Condom use Circumcision Immunosuppresion Cervical inflammation HPV genotypes HPV variants Multiple types Viral load Viral integration Early AFSI High NOSP High-risk male partners C. trachomatis HSV-2

Incidence of Cervical HPV Detection in Women From the Time of Onset of Their First Sexual Relationship 0% 10% 20% 30% 40% 50% 60% 70% 6 12 18 24 30 36 42 48 Cervical HPV Detection Collins et al. Brit J Obstet Gynecol 2002;109: 96 to 98 Time since first intercourse (months)

Natural History of HPV 16/18-Related Cervical Neoplasia:
Estimated Median Age of Events Menarche Sexual debut HPV 16 or 18 cervical infection CIN ASC-US (atypical squamous cells of undetermined significance) CIS Micro-invasive Cervix Cancer Invasive Cervix Cancer Age in Years

Lifetime Risk of HPV Related Disease
Genital HPV Infection is the Most Common Viral STI Worldwide Lifetime risk of HPV infection for sexually active males and females ≥ 50% (80%) Estimated lifetime risk of developing genital warts ~ 10% 1, 2 Women participating in routine screening abnormal Pap smear: 35% CIN ~ 25% invasive cervical cancer: <1% Women without routine screening invasive cervical cancer: 3 to 4% 1) Franco, E. L., et al. in : New Developments in Cervical Screening and Prevention, Oxford, Blackwell Science, 1997: 2) Tortolero-Luna, G. Hematology and Oncology Clinics of North America, 13 (1), 1999:

HPV is a necessary cause of invasive cervical cancer worldwide
Prevalence of HPV DNA in over 1,000 cervical cancer biopsies from 22 countries : 99.7% J. Pathol. 189: 12-19, 1999

IARC International prevalence survey of HPV types in cervical cancer
Poland Canada Germany Spain USA Morocco Algeria Cuba Thailand The Philippines Mali Panama Benin Guinea Colombia Uganda Tanzania Brazil Indonesia Bolivia Paraguay Chile Argentina

Prevalence of HPV types in cervical cancer
Any HPV % HPV % HPV % 81 % HPV % % HPV % % HPV % HPV % HPV % HPV %

Geographical distribution of HPV types in cervical cancer
18 45 31 33 OTH

A vaccine that prevents HPV16- and 18-related intraepithelial lesions and neoplasms will be a major advance in anogenital cancer control

HPV Viral-Like Particle (VLP) Vaccines
Electron micrograph of VLP Schematic of HPV VLP HPV Neutralizing Epitopes Are Conformational and Reside in Pentameric (5 x L1) Capsomere Subunits Connected by Invading C-termini Modis Y et al (2002) Atomic Model of the Papillomavirus Capsid. EMBO;21:

HPV Vaccine Programs Conducted in 3 Phases
Phase I in 300 subjects Immunogenicity and tolerability of a range of doses of monovalent HPV L1 VLP vaccines Phase II in 3,500 subjects Immunogenicity/tolerability of a range of HPV L1 VLP vaccine dose formulations Preliminary proof of efficacy Koutsky LA, Ault KA, Wheeler CM, Jansen KU, Barr E, Alvarez FB, Chiacchierini LM. Results from a phase II human papillomavirus virus-like particle vaccine efficacy trial. New England Journal of Medicine.2002; 347: Diane M Harper, Eduardo L Franco, Cosette Wheeler, Daron G Ferris, David Jenkins et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomized controlled trial. Lancet. 2004;364: Villa LL, Costa RLR, Petta CA, Andrade RP, Ault KA, Giuliano AR, Wheeler CM, Koutsky LA et al. A Double-blind, Placebo-controlled Efficacy Trial of a Prophylactic Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) Vaccine in Young Women. Lancet Oncology. 2005;6: Thus, the clinical program for the quadrivalent HPV vaccine has focused on evaluating vaccine efficacy against CIN 2/3 or worse. The clinical program has been conducted in 3 phases. Phase I studies in 300 subjects evaluated monovalent HPV vaccines. The Phase II studies expanded to 3500 subjects. The studies included a preliminary evaluation of vaccine efficacy, and a dose-ranging study of the quadrivalent vaccine. Finally, the Phase III studies are ongoing. They are evaluating the impact of the vaccine on rates of CIN 1, genital warts, and most importantly, CIN 2/3 or worse, related to vaccine HPV types.

HPV Vaccine Programs Conducted in 3 Phases (cont.)
Phase III in >20,000 subjects Efficacy of HPV L1 VLP vaccine vs. vaccine type-related CIN 1 Genital warts CIN 2/3+

HPV L1 VLP Phase III Vaccines
Quadrivalent HPV Types 6, 11, 16, 18 L1 VLP vaccine (Gardasil®, Merck Research Laboratories, West Point, PA.) – Phase II and III Reported Di-valent HPV Types 16 and 18 (Cervarix™, GlaxoSmithKline) – Phase II Reported

GSK Vaccine Efficacy: Persistent Infection (all samples)
Harper DM et al, The Lancet, 2004

Summary of HPV-001 Efficacy Data: HPV 16 and/or 18 Cervical Protection
Persistent Infection Incident Infection Cytology CIN Harper et al, The Lancet, 2004 Vaccine Efficacy 91% 100% 93% 100% *Analysis of incident/persistent infection and cytology performed in ATP cohort (cervical samples). Analysis of CIN performed in ITT cohort (DNA detected in tissue)

GSK Phase III Efficacy Studies
GSK efficacy study Global: North America, Latin America, Asia Pacific, Europe N = 18,000 (15-25 year old women) National Cancer Institute (NCI) efficacy study Population-based trial in Guanacaste, Costa Rica Clinical trial management – Allan Hildesheim (NCI PI), Rolando Herrero (Costa Rican PI) N ~12,000 (18-25 year old women) Both trials assessing CIN 2+ endpoints

Definitive evaluation of the impact of prophylactic HPV vaccination on cervical intraepithelial neoplasia grade 2 and 3 (CIN2/3), squamous cell carcinoma in situ (CIS), adenocarcinoma in situ (AIS) and cervical cancer has been recently reported for Merck quadrivalent HPV 6, 11, 16, and 18 VLP vaccine

Merck Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP Vaccine Dose-Ranging and Phase II Efficacy Study
Double-blind, placebo-controlled study In 1106 women aged 16 to 23 (U.S., Brazil, E.U.) Followed for 3 years, 6 month intervals 3 formulations of HPV vaccine or Placebo given at enrollment, Month 2, and Month 6 Group HPV 6 VLP (mg) HPV 11 VLP (mg) HPV 16 VLP (mg) HPV 18 VLP (mg) Total VLP (mg) Pbo *Low 20 40 120 Med 160 High 80 200 We conducted a large placebo-controlled study of HPV 16 vaccine in 2392 U.S. college women. We designed the study to have an early look at efficacy. We reasoned that such a proof-of-concept would justify the investment in a full scale Phase III program. In addition, each woman was to be followed for 4 years, so that we could also look at long-range impact of the vaccine. The primary endpoint of the study was persistent HPV 16 infection, or HPV 16-related CIN. Persistent infection means detection of HPV 16 virus in swabs of the women’s cervix or vagina on at least 2 consecutive visits. HPV 16-related CIN means a diagnosis of low-grade or high-grade pre-cancer on a tissue specimen obtained from an area of abnormality on the cervix, AND detection of HPV 16 virus in the same lesion. Since we believed that the vaccine was most effective as a preventative agent, we performed our main efficacy evaluation in women who had not been infected with HPV 16 at the time of vaccination. We also enrolled women who were already infected with HPV 16 to see if the vaccine could help clear the infection – but that is a story for another day. *GARDASIL® formulation

Quadrivalent HPV Vaccine Study: Results of Dose-Ranging Phase
1000 Geometric Mean Titer (mMU/mL) Placebo 20/40/40/20 mg 100 40/40/40/40 mg 80/80/40/80 mg 10 Levels after Natural Infection HPV 6 HPV 11 HPV 16 HPV 18

Quadrivalent HPV Vaccine Study: Anti-HPV 18 Immunogenicity Over 3
Quadrivalent HPV Vaccine Study: Anti-HPV 18 Immunogenicity Over 3.0 Years 10000 Per-Protocol Subjects (Phase III formulation) Baseline Seropositive & PCR Negative Subjects (Placebo Group) 1000 Serum cLIA GMT, mMU/mL 100 10 2 3 6 7 12 18 24 30 36 Time (Months)

Quadrivalent HPV Vaccine Study: Anti-HPV 16 Immunogenicity Over 3
Quadrivalent HPV Vaccine Study: Anti-HPV 16 Immunogenicity Over 3.0 Years Serum cLIA GMT, mMU/mL 2 3 6 7 12 18 24 30 36 Time (Months) 10 100 1000 10000 Per-Protocol Subjects (Phase III formulation) Baseline Seropositive & PCR Negative Subjects (Placebo Group)

Quadrivalent HPV Vaccine Study: Efficacy Evaluation by HPV Type
Per-Protocol Efficacy Cohort Vaccine Cases 4 3 1 71-97% 95% Confidence Interval 36 13 3 21 9 Placebo Cases Vaccine Efficacy 90% 100% 86% 89% P- Value <10–3 Endpoint HPV 6/11/16/18 Infxn, CIN, or GW HPV 6-related HPV 11-related HPV 16-related HPV 18-related We had the first look at efficacy in 2001, when women had been in the study for an average of 2 years. These are the results. A total of 41 women developed a persistent HPV 16 infection, with or without evidence of a cervical pre-cancer (CIN). All 41 cases occurred in the placebo group. Thus, the vaccine had 100% efficacy. The results were highly significant. Of the 41 women with new HPV 16 infections, 9 women had already developed HPV 16-related CIN in the placebo group. Five of these were CIN 1 and four were CIN 2/3 – so you see, women were already developing high grade lesions. The results were published in New England Journal of Medicine – and the accompanying editorial was extremely positive. On the strength of these data, we embarked on the Phase III program. But we didn’t stop the study there. Rather, we wanted to get an early read on long-term efficacy and cancer prevention. Such data would strengthen Merck’s request for priority review of the vaccine at FDA and EU agencies, a status which would shorten our timelines by 6 months. So, the study continued for another 3 years. Vaccine cases: HPV 16: 3 cases single positive at the last visit on record HPV 18: 1 case persistent HPV 18 infection Villa et al, Lancet Oncology 2005; 6:

Antibody levels among non-cases vs
Antibody levels among non-cases vs. single case of persistent HPV 18 infection (vaccine recipients) 10000 ____ Non-Cases for HPV 18 combined Subject A ….. 1000 Serum cLIA GMT, mMU/mL 100 10 Detection of HPV 18 DNA 2 3 6 7 12 18 24 30 36 Time (Months) No evidence that HPV vaccine titers are any different in cases compared to non-cases – No minimum protective antibody level known

Phase III Trial of Prophylactic Quadrivalent HPV 6, 11, 16, 18 L1 Virus-Like Particle (VLP) Vaccine - Merck: Prevention of Cervical Intraepithelial Neoplasia (CIN) and External Genital Lesions (EGL) – FUTURE I Prevention of Cervical Intraepithelial Neoplasia (CIN) 2/3 including Adeno- and Squamous-cell Carcinoma in situ (CIS) -FUTURE II General Trial Population Impact

FUTURE II Clinical Protocol
Randomized, double-blind, placebo-controlled study in 12,167 women aged 16 to 26 enrolled in 13 countries 1:1 randomization to Gardasil™ or placebo ThinPrep™ Pap tests, swabs for HPV DNA taken at Day 1 and Months 7, 12, 24, 36, 48, and sera tested at Day 1 in all subjects Mandatory colposcopy and definitive therapy algorithm based on standard of care All Pap tests and biopsies processed and read at a central laboratory Expert Pathology panel read all slides for endpoint determination We conducted a large placebo-controlled study of HPV 16 vaccine in 2392 U.S. college women. We designed the study to have an early look at efficacy. We reasoned that such a proof-of-concept would justify the investment in a full scale Phase III program. In addition, each woman was to be followed for 4 years, so that we could also look at long-range impact of the vaccine. The primary endpoint of the study was persistent HPV 16 infection, or HPV 16-related CIN. Persistent infection means detection of HPV 16 virus in swabs of the women’s cervix or vagina on at least 2 consecutive visits. HPV 16-related CIN means a diagnosis of low-grade or high-grade pre-cancer on a tissue specimen obtained from an area of abnormality on the cervix, AND detection of HPV 16 virus in the same lesion. Since we believed that the vaccine was most effective as a preventative agent, we performed our main efficacy evaluation in women who had not been infected with HPV 16 at the time of vaccination. We also enrolled women who were already infected with HPV 16 to see if the vaccine could help clear the infection – but that is a story for another day.

HPV 16/18-Related CIN 2, CIN 3 (includes CIS), AIS, or Cervical Cancer
FUTURE I and II Trial Primary Disease Endpoints: HPV 6/11-Rleated Extragenital Lesions HPV 16/18-Related CIN 2, CIN 3 (includes CIS), AIS, or Cervical Cancer Fixation, Processing & Paraffin Embedding Cervical Biopsy 1 2 5 4 3 6 7 12 9 8 13 11 10 Prepare Consecutive Sections Extraction of DNA for HPV Multiplex PCR 3 7 5 Diagram for Biopsy Thinsectioning. 1 2 12 13 H&E Staining and Histology HPV 6/11/16/18 PCR Positive Wart/CIN - FUTURE I + CIN 2/3, AIS, Cancer – FUTURE II Vaccine Type PCR Negative No Case Case

Statistical Plan Primary Efficacy Evaluation in Per-Protocol (PP) Population received 3 vaccinations within 1 year no major protocol violations HPV 16/18 sero(-) at Day 1 and HPV 16/18 DNA(-) Day 1 to Month 7 Cases counted starting after Month 7 Supportive analysis in Modified intention to treat (MITT) population received ≥1 vaccination HPV 16/18 sero(-) and HPV 16/18 DNA(-) at Day 1 Cases were counted starting 30 days after Day 1 Timing of efficacy analyses Interim analyses when 19 endpoint cases seen in PP population PP population efficacy tested at a=0.0204 For the HPV 16/18-related CIN 2, CIN 3 (includes CIS), AIS, or cervical cancer endpoint in the PP population, 97.96% CI reported. All other CIs are 95%.

Subject Characteristics FUTURE II
Vaccine (N = 6087) Placebo (N = 6080) Mean age (yrs) 20.0 19.9 Age range (yrs) 15 to 26 Region North America 460 (8%) 456 (7%) Latin America 1599 (26%) 1594 (26%) Asia-Pacific 92 (2%) 89 (2%) Europe 3936 (64%) 3941 (65%) Mean Age 1st intercourse among non- virgins (~93.4%) 16.6 Median Lifetime # of sex partners 2 Using hormonal contraception 3613 (59.4%) 3614 (59.5%)

Subject Accounting FUTURE II
Vaccine Placebo Population to which category applies (N = 6,087) (N = 6,080) PP MITT Received ≥ 1 Injection 6,082 6,075 Included in PP 5,301 5,258 Included in MITT 5,736 5,766 Reason for exclusion General protocol violations 275 315 X Sero (+) and/or DNA (+) to HPV 16 at Day 1 954 964 at or before Month 7 1,012 1,162 Sero (+) and/or DNA (+) to HPV 18 397 405 443 548 No post-Month 7 follow-up (16/18) 25/35 25/36

Clinical Serious Adverse Experience (AE) Summary (Days 1 to 15 Following Any Vaccination Visit)
Vaccine (N=6075) Placebo (N=6076) n (%) Subjects with follow-up 6019 6031 Number (%) of subjects with: serious AE 17 (0.3) 16 serious vaccine-related AE 3 (<0.1) 2 discontinuation due to a serious AE 1 discontinuation due to a serious vaccine-related AE discontinuation due to death* (0) *Deaths: one drug overdose and one traffic accident

Efficacy Results in PP Efficacy – FUTURE II
Average 17 Months After Completion of the Vaccination Regimen Vaccine (N=6,082) Placebo (N=6,075) Efficacy (%) CI p-Value Endpoint n Cases CIN 2/3 or AIS HPV 16/18-related 5,301 5,258 21 100 (76– 100) < 0.001 HPV 16-related 4,552 4,405 16 (75– 100) HPV 18-related 5,051 4,968 8 (42– 100) By lesion type (worst diagnosis)- All in the Placebo group CIN 2 5 CIN 3 15 AIS 1 Last week, we unblinded the study, after a total of 4 years of follow-up. The results are shown here, and they are as exciting as the primary results. The overall efficacy was 94%. For the same endpoint that were used in the first analysis, that is HPV 16 persistent infection or HPV 16-related CIN, the efficacy remained 100%. 26 women developed cervical abnormalities related to HPV 16. Of these 12 developed high-grade pre-cancer, the last stage of cervical abnormality prior to frank cancer. Furthermore, these results show the durability of the vaccine’s efficacy. Now I want to discuss the final line here. This end-of-study analysis differed from the first analysis because it included the last visits in the study. So although our endpoints were persistent infection and CIN related to HPV 16, they also included detection of HPV 16 on the last visit on record without a requirement for detection on 2 visits. Here, there were 19 cases in the placebo group and 7 cases in the vaccine group. Now these cases do not necessarily represent true infection –single time detection of HPV 16 in the cervicovaginal tract is a mixed bag of transient infection, deposition of HPV from an infected partner, or contamination from instruments used in GYN offices. However, since women with HPV 16 detection on the very last visit in the study were not followed for another visit, we couldn’t tell whether they had persistent infection or not. One thing we do know is that none of the 7 vaccine cases had evidence of CIN or pap test abnormalities, suggesting contamination. CIN 3 includes squamous-cell carcinoma in situ (CIS); AIS = adenocarcinoma in situ (AIS) PP = received 3 vaccinations within 1 year; no major protocol violations; HPV 16/18 sero(-) at Day 1 and HPV 16/18 DNA(-) Day 1 to Month 7; Cases counted starting after Month 7

Efficacy Results in MITT Population FUTURE II
Average 24 Months After the First Vaccination Vaccine (N=6,082) Placebo (N=6,075) Efficacy (%) CI p-Value Endpoint n Cases CIN 2/3 or AIS HPV 16/18-related 5,736 1 5,766 36 97 (83– 100) < 0.001 HPV 16-related 4,944 4,957 28 96 (78– 100) HPV 18-related 5,477 5508 11 100 (60– 100) By lesion type (worst diagnosis) CIN 2 10 CIN 3 23 AIS 4 Last week, we unblinded the study, after a total of 4 years of follow-up. The results are shown here, and they are as exciting as the primary results. The overall efficacy was 94%. For the same endpoint that were used in the first analysis, that is HPV 16 persistent infection or HPV 16-related CIN, the efficacy remained 100%. 26 women developed cervical abnormalities related to HPV 16. Of these 12 developed high-grade pre-cancer, the last stage of cervical abnormality prior to frank cancer. Furthermore, these results show the durability of the vaccine’s efficacy. Now I want to discuss the final line here. This end-of-study analysis differed from the first analysis because it included the last visits in the study. So although our endpoints were persistent infection and CIN related to HPV 16, they also included detection of HPV 16 on the last visit on record without a requirement for detection on 2 visits. Here, there were 19 cases in the placebo group and 7 cases in the vaccine group. Now these cases do not necessarily represent true infection –single time detection of HPV 16 in the cervicovaginal tract is a mixed bag of transient infection, deposition of HPV from an infected partner, or contamination from instruments used in GYN offices. However, since women with HPV 16 detection on the very last visit in the study were not followed for another visit, we couldn’t tell whether they had persistent infection or not. One thing we do know is that none of the 7 vaccine cases had evidence of CIN or pap test abnormalities, suggesting contamination. Single case of HPV 16-related CIN 2 (Month 24) in vaccine group. HPV 16 DNA detected at Month 7. MITT = received ≥1 vaccination; HPV 16/18 sero(-) and HPV 16/18 DNA(-) at Day 1 Cases were counted starting 30 days after first vaccination

Efficacy Results in MITT Population FUTURE I
Average 26 Months After Completion of the Vaccination Regimen Vaccine (N=2,240) Placebo (N=2,258) Efficacy (%) CI p-Value Endpoint Cases HPV6/11/16/18-CIN 2 57 97 87%,100% P<0.001 HPV 6-related CIN 1 12 92 43%,100% HPV 11-related CIN 6 100 15%,100% HPV 16-related CIN 32 88%,100% HPV 18-related CIN 13 49%,100% Last week, we unblinded the study, after a total of 4 years of follow-up. The results are shown here, and they are as exciting as the primary results. The overall efficacy was 94%. For the same endpoint that were used in the first analysis, that is HPV 16 persistent infection or HPV 16-related CIN, the efficacy remained 100%. 26 women developed cervical abnormalities related to HPV 16. Of these 12 developed high-grade pre-cancer, the last stage of cervical abnormality prior to frank cancer. Furthermore, these results show the durability of the vaccine’s efficacy. Now I want to discuss the final line here. This end-of-study analysis differed from the first analysis because it included the last visits in the study. So although our endpoints were persistent infection and CIN related to HPV 16, they also included detection of HPV 16 on the last visit on record without a requirement for detection on 2 visits. Here, there were 19 cases in the placebo group and 7 cases in the vaccine group. Now these cases do not necessarily represent true infection –single time detection of HPV 16 in the cervicovaginal tract is a mixed bag of transient infection, deposition of HPV from an infected partner, or contamination from instruments used in GYN offices. However, since women with HPV 16 detection on the very last visit in the study were not followed for another visit, we couldn’t tell whether they had persistent infection or not. One thing we do know is that none of the 7 vaccine cases had evidence of CIN or pap test abnormalities, suggesting contamination. MITT = received ≥1 vaccination; HPV 16/18 sero(-) and HPV 16/18 DNA(-) at Day 1 Cases were counted starting 30 days after first vaccination CIN 3 includes squamous-cell carcinoma in situ (CIS); AIS = adenocarcinoma in situ (AIS)

Efficacy Results in MITT Population FUTURE I
Average 26 Months After Completion of the Vaccination Regimen Vaccine (N=2,240) Placebo (N=2,258) Efficacy (%) CI p-Value Endpoint Cases HPV 6/11/16/18-EGL 3 59 95 84%,99% P<0.001 HPV 6-related EGL 2 34 94 77%,99% HPV 11-related EGL 1 14 93 53%,100% HPV 16-related EGL 10 100 70%,100% HPV 18-related EGL 7 30%, 100% Last week, we unblinded the study, after a total of 4 years of follow-up. The results are shown here, and they are as exciting as the primary results. The overall efficacy was 94%. For the same endpoint that were used in the first analysis, that is HPV 16 persistent infection or HPV 16-related CIN, the efficacy remained 100%. 26 women developed cervical abnormalities related to HPV 16. Of these 12 developed high-grade pre-cancer, the last stage of cervical abnormality prior to frank cancer. Furthermore, these results show the durability of the vaccine’s efficacy. Now I want to discuss the final line here. This end-of-study analysis differed from the first analysis because it included the last visits in the study. So although our endpoints were persistent infection and CIN related to HPV 16, they also included detection of HPV 16 on the last visit on record without a requirement for detection on 2 visits. Here, there were 19 cases in the placebo group and 7 cases in the vaccine group. Now these cases do not necessarily represent true infection –single time detection of HPV 16 in the cervicovaginal tract is a mixed bag of transient infection, deposition of HPV from an infected partner, or contamination from instruments used in GYN offices. However, since women with HPV 16 detection on the very last visit in the study were not followed for another visit, we couldn’t tell whether they had persistent infection or not. One thing we do know is that none of the 7 vaccine cases had evidence of CIN or pap test abnormalities, suggesting contamination.

General Clinical Trial Population Impact of Gardasil
Average 24 Months After the First Vaccination Vaccine Placebo Reduction(%) 95% CI Endpoint n Cases HPV 16/18 CIN 2/3 or AIS 9831 122 9896 201 39 (23– 52) VIN 2/3 and VaIN 2/3 8954 8 8962 26 69 (30– 88) HPV 6,11,16,18-related CIN, CIN 2/3, AIS HPV 6,11,16,18-related genital warts 8814 170 58 8846 317 184 46 (35–56) (58-77) Last week, we unblinded the study, after a total of 4 years of follow-up. The results are shown here, and they are as exciting as the primary results. The overall efficacy was 94%. For the same endpoint that were used in the first analysis, that is HPV 16 persistent infection or HPV 16-related CIN, the efficacy remained 100%. 26 women developed cervical abnormalities related to HPV 16. Of these 12 developed high-grade pre-cancer, the last stage of cervical abnormality prior to frank cancer. Furthermore, these results show the durability of the vaccine’s efficacy. Now I want to discuss the final line here. This end-of-study analysis differed from the first analysis because it included the last visits in the study. So although our endpoints were persistent infection and CIN related to HPV 16, they also included detection of HPV 16 on the last visit on record without a requirement for detection on 2 visits. Here, there were 19 cases in the placebo group and 7 cases in the vaccine group. Now these cases do not necessarily represent true infection –single time detection of HPV 16 in the cervicovaginal tract is a mixed bag of transient infection, deposition of HPV from an infected partner, or contamination from instruments used in GYN offices. However, since women with HPV 16 detection on the very last visit in the study were not followed for another visit, we couldn’t tell whether they had persistent infection or not. One thing we do know is that none of the 7 vaccine cases had evidence of CIN or pap test abnormalities, suggesting contamination. General Population = received ≥1 vaccination; HPV 16/18 sero(+/-) and HPV16/18 DNA(+/-) at Day 1 - Cases were counted starting 30 days after first vaccination – Gardasil® Trial Population had no more than 4 lifetime sex partners AND an average of only 2

Summary A 3-dose regimen of Gardasil ® was 100% effective in preventing HPV 16/18-related CIN 2/3 and AIS in women who were HPV 16/18-naïve at enrollment and HPV 16/18 DNA(-) through the vaccination regimen Efficacy remained high (97%) in MITT population (received ≥ 1 vaccination; includes protocol violators but which excluded women previously exposed to HPV vaccine types) General trial population impact of Gardasil® was significantly reduced compared to PP or MITT when women who had already been exposed to HPV vaccine types in the past (sero+) or who were currently infected with vaccine types (HPV DNA PCR+) were included There is no clear evidence that Gardasil® or any other HPV vaccine provides benefit to women who are currently infected or have been infected in the past with HPV vaccine types Administration of Gardasil® was generally safe and well-tolerated CIN 2-3 is clinically relevant endpoint. Although long term follow-up is not possible (always treated), presumably will prevent HPV 16 related cancer.

Other Important Take Home Messages I
It is critical that vaccinated and un-vaccinated women continue being screened under current early detection guidelines Current first generation HPV vaccines do not protect against over 12 HPV types that cause ~30% of invasive cervical cancer Duration of HPV vaccine immunity is unknown and how and when booster immunizations will be recommended is unknown Public health and policy efforts are needed to ensure access and encourage high HPV vaccine coverage for all racial, ethnic, and socioeconomic groups, and particularly for girls/women of color, immigrants, those living in rural areas, low-income and uninsured women, and others who have limited access to health care services

Other Important Take Home Messages II
Clinical trials for Gardasil were not conducted in a general population of women (limited inclusion for lifetime sex # of partners and abnormal Pap history) although universal vaccination of women aged was recommended It is likely that the reduction in disease in a random general population will be less than that observed in the general Gardasil trial populations – US population average number of sex partners is ~ ≥ 4 for women ages 21-26 HPV 16/18 CIN 2/3 or AIS % (23– 52) VIN 2/3 and VaIN 2/ % (30– 88) HPV 6,11,16,18-related CIN, CIN 2/3, AIS 46% (35–56) HPV 6,11,16,18-related genital warts 69% (58-77)

Other Important Take Home Messages III
In many cases women may be paying for HPV vaccines themselves - The potential benefit diminishes with increasing number of lifetime sexual partners Vaccination of women over age 26 and of males is not currently recommended HPV testing is not recommended prior to vaccination – current tests are not type-specific and even if and when type-specific HPV tests become available, single tests do not accurately measure current infections and CANNOT assess past exposure

Some Remaining Questions
Given competing health care demands and limited resources, is it rational to vaccinate the general population of women ages many who have already been exposed (currently infected ) or whom are presumed immune and who should be attending screening programs ? Will HPV vaccination give a false sense of protection and result in modification of screening behaviors or practices that will undermine the anticipated benefits of HPV vaccines? There are no data to provide evidence for changes in screening of vaccinated women - however will financial constraints or alternate interests drive lengthening of Pap smear screening intervals to allow HPV vaccine expenditures ? As changes in practices continue, will providers implement somewhat costly active screening reminders and pursue missed screens in support of the changing environment and potential problems as we move forward ?

Other Key Issues If HPV vaccines are shown effective in men, will they be recommended given cost benefit and benefit to overall disease outcomes appear to be minimal based on modeling if penetration in women is high Will women at greatest risk for this disease be provided to access to HPV vaccines – developing world, impoverished

Required Go-Forward Surveillance and Research
Ongoing research and surveillance should be conducted in diverse populations, including research on duration of protective immunity, population- and lesion-based changes in type-specific prevalence for the full spectrum of carcinogenic and non-carcinogenic genital HPV types, changes in Pap test performance characteristics, changes in screening practices and behaviors, comprehensive surveillance for reproductive toxicities, increasing vaccine coverage and acceptability, and impact on safe sexual behavior.

Human Papillomaviruses (HPV): The Background, Current Status and Future of Vaccines to Prevent HPV Infection, Abnormal Genital Lesions and Cervical Cancer.

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Human Papillomaviruses (HPV): The Background, Current Status and Future of Vaccines to Prevent HPV Infection, Abnormal Genital Lesions and Cervical Cancer.

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Presentation on theme: "Human Papillomaviruses (HPV): The Background, Current Status and Future of Vaccines to Prevent HPV Infection, Abnormal Genital Lesions and Cervical Cancer."— Presentation transcript:

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