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Update and New Recommendations: Human Papillomavirus Vaccines NetConference November 12, 2009 Lauri E. Markowitz, MD Centers for Disease Control and Prevention The findings and conclusions in this presentation are those of the author(s) and do not necessarily represent the views of the Centers for Disease Control and Prevention Overview • Background • US HPV Vaccination Program • HPV Vaccines and Recommendations Background Human Papillomavirus (HPV) • Non enveloped DNA virus • >100 different types identified • ~40 types are sexually transmitted • “Low-risk” types (6, 11 and others) • Genital warts and recurrent respiratory papillomatosis • “High-risk” types (16, 18 and others) • Cervical and other anogenital cancers • Subset of oral cavity and oropharyngeal cancers Percentage of Cervical Cancers Attributed to the Most Frequent HPV Types in All Regions of the World HPV 16 54.4% HPV 18 15.9% HPV 33 4.3% HPV 45 3.7% HPV 31 3.6% HPV 58 3.3% HPV 52 2.5% HPV 35 1.7% HPV 59 1.0% HPV 56 0.7% HPV 51 0.7% HPV 39 0.6% 0% 10% 20% 30% 40% 50% 60% Smith et al. Int J Cancer 2007 Two Licensed HPV Vaccines Quadrivalent Bivalent Manufacturer Merck GlaxoSmithKline Brand Name Gardasil Cervarix Licensed in US 2006 2009 VLP types HPV 6,11,16,18 HPV 16,18 VLP – virus like particle US HPV Vaccination Program Advisory Committee on Immunization Practices (ACIP) Recommendations for Quadrivalent HPV Vaccine, 2006 Routine vaccination Females age 11 or 12 years Catch-up Females age 13 through 26 years > 26 million doses of quadrivalent HPV vaccine distributed in the US through 9/09 Estimated 1+ Dose HPV Vaccination Coverage, Females 13-17 Years National Immunization Survey 2007 and 2008 100 90 80 70 2007 Percent 60 2008 50 40 30 20 10 0 13 14 15 16 17 Age (yrs) National Immunization Survey. MMWR 2008;57 National Immunization Survey. MMWR 2009;58 Estimated Vaccination Coverage with 1+ HPV Vaccine among Adolescent Girls, 2008 National Coverage = 37% D.C. 50-59% 40-49% 30-39% 20-29% 10-19% Source: CDC. National, state, and local area vaccination coverage among adolescents aged 13-17 years---United States, 2008. New Policy Issues ACIP – October 2009 • Bivalent HPV vaccine for females • Quadrivalent HPV vaccine for males Two Licensed HPV Vaccines for Use in Females Quadrivalent (Merck) Bivalent (GSK) Licensed in US 2006 2009 VLP types HPV 6/11/16/18 HPV 16/18 Trichoplusia ni insect cell line Saccharomyces cerevisiae Producer cells infected with L1 recombinant (yeast) - expressing L1 baculovirus AS04: AAHS: 500 µg aluminum hydroxide Adjuvant 225 µg aluminum 50 µg 3-O-deacyl-4’- hydroxyphosphate sulfate monophosphoryl lipid A Schedule* 0,2,6 months 0,1,6 months VLP – virus like particle *in clinical trials HPV Vaccine Efficacy Vaccine HPV Type CIN2+ According to Protocol or Per Protocol Control or Vaccine Vaccine/ Vaccine Placebo Efficacy HPV type N cases N cases % (CI) Bivalent* HPV 16/18 7344 4 7312 56 93% (80, 98) HPV 16 6303 2 6165 46 96% (83,100) HPV 18 6794 2 6746 15 87% (40, 99) Quadrivalent** HPV 16/18 7738 2 7714 100 98% (93,100) HPV 16 6647 2 6455 81 98% (91,100) HPV 18 7382 0 7316 29 100% (87,100) *According to protocol population: females 15-25 yrs, received all three doses, cases counted day one after dose 3, normal or low grade cytology at baseline; mean follow-up: 2.9 yrs. 96.1% CIs **Per protocol population: females 16-26 yrs, received all three doses, cases counted day one after dose 3; mean follow-up: 3.5 yrs; 95% CIs CIN2+: cervical intraepithelial neoplasia grade 2 or higher or adenocarcinoma in situ Paavonen et al. Lancet 2009; Kjaer et al. Cancer Prev Res 2009 HPV Vaccine Efficacy HPV 6,11,16, or 18 Related Lesions Per Protocol Vaccine Vaccine/ Vaccine Placebo Efficacy Endpoints N cases N cases % (CI) Quadrivalent** VIN/VaIN2+ 7900 0 7902 23 100% (83,100) Genital warts 6718 2 6647 186 99% (96,100) **HPV 6,11,16,18 related; Per protocol population: females 16-26 yrs, received all three doses, cases counted day one after dose 3; mean follow-up: 3.5 yrs; 95% CIs CIN2+: cervical intraepithelial neoplasia grade 2 or higher or adenocarcinoma in situ VIN: vulvar intraepithelial neoplasia; VaIN: vaginal intraepithelial neoplasia Kjaer et al. Cancer Prev Res 2009. Dillner et al. 2009 in press HPV Vaccines Efficacy and Immunogenicity • High efficacy for prevention of vaccine type related CIN2+ among those without evidence of infection • No evidence of waning protection through follow-up period • No therapeutic efficacy • Almost all vaccinees develop antibody, with titers higher than those after natural infection • Minimum protective antibody titer is not known HPV Vaccine Cross Protection • Data suggest the vaccines may provide protection against HPV types other than those in the vaccine • Types examined are those phylogenetically related to HPV 16 and 18 • Analyses of CIN2+ endpoints are difficult to interpret due to co-infections • Bivalent vaccine may have more cross protection than the quadrivalent vaccine Bivalent HPV Vaccine Safety Assessment • Evaluations for • solicited symptoms -- Safety diary cards for 7 days following injection -- 30 days following injection in subset • unsolicited symptoms • medically significant conditions • new onset autoimmune disorders and chronic diseases All females during study • serious adverse events period • pregnancy outcomes • Integrated safety analysis from 11 trials of bivalent HPV vaccine involving ~30,000 females • Meta-analysis of autoimmune diseases from trials of AS04 containing vaccines involving ~68,000 subjects Bivalent HPV Vaccine SAEs and New Onset Autoimmune Disorders Pooled Safety Database*, Females 10-25 years 20 18 Bivalent HPV vaccine (N=12533) 16 Pooled controls (N=10730) 14 12 Percent 10 8 7.2 6.4 6 4 2 0.8 0.8 0 SAEs Potential new onset autoimmune disorders SAE – serious adverse event *Entire observation period Current Understanding of HPV Vaccines in Females Attribute Bivalent Quadrivalent Protection against HPV 16/18 related CIN2+* >93% >98% Protection against HPV 6/11 related genital - >98% lesions Some types Some types Cross-protection against CIN2+ due to high phylogenetically related phylogenetically related risk types other than HPV 16,18 to HPV 16 and 18 to HPV 16 Seroconversion to vaccine types >99% >99% Geometric mean antibody titers bivalent > quadrivalent Duration of protection Unclear if any differences Local reactogenicity bivalent > quadrivalent *Quadrivalent vaccine - also demonstrated protection against VIN2/3 and VaIN2/3 ** http://www.cdc.gov/vaccines/programs/vfc/cdc-vac-price-list.htm Provisional Recommendations* for Vaccination of Females ACIP recommends routine vaccination of females aged 11 or 12 years with 3 doses of HPV vaccine. The vaccination series can be started as young as 9 years of age. HPV vaccination is also recommended for females aged 13 through 26 years who have not been previously vaccinated or who have not completed the full vaccination series. Ideally, vaccine should be administered before potential exposure to HPV through sexual contact. – ACIP recommends vaccination with either the bivalent HPV vaccine or the quadrivalent HPV vaccine for prevention of cervical cancers and precancers. – ACIP recommends vaccination with the quadrivalent HPV vaccine for prevention of cervical cancers and precancers, vulvar and vaginal cancers and precancers, and genital warts. *final recommendations pending CDC/HHS review and approval Harmonization of Age Groups, Dosing Schedule and Minimal Intervals* • The quadrivalent HPV vaccine and bivalent HPV vaccine are each administered in a 3-dose schedule • The second dose should be administered 1-2 months after the first dose; the third dose should be administered 6 months after the first dose • Minimal intervals similar for two vaccines *final recommendations pending CDC/HHS review and approval Provisional Recommendation*: Interchangeability of Vaccines ACIP recommends that the HPV vaccine series be completed with the same HPV vaccine product whenever possible However, if vaccination providers do not know or have available the HPV vaccine product previously administered, either HPV vaccine product can be used to continue or complete the series to provide protection against HPV 16 and 18 *final recommendations pending CDC/HHS review and approval Provisional Recommendation*: Precautions and Contraindications • HPV vaccines are not recommended for use in pregnant women; pregnancy testing is not needed before vaccination – Any exposure to vaccine during pregnancy should be reported to the appropriate vaccine pregnancy registry: • 1-800-986-8999 (quadrivalent HPV vaccine) • 1-888-452-9622 (bivalent HPV vaccine) • HPV vaccines are contraindicated for persons with immediate hypersensitivity to any vaccine component – Quadrivalent HPV vaccine is contraindicated for persons with a history of immediate hypersensitivity to yeast – Bivalent HPV vaccine in prefilled syringes is contraindicated for persons with anaphylactic latex allergy *final recommendations pending CDC/HHS review and approval Quadrivalent HPV Vaccine for Males HPV Epidemiology in Men • Men have similar prevalence of HPV infection, and possibly higher acquisition, compared to women • Burden of diseases and cancers in men include genital warts, recurrent respiratory papillomatosis, anal, penile, oral cavity and oropharyngeal cancers – Burden of HPV related cancers less than in females • Transmission high between sex partners Men who have Sex with Men (MSM) • Greater burden of HPV-related outcomes including genital warts, anal precancers and anal cancers – Anal cancer: 2 per 100,000 in men and 35 per 100,000 in MSM (HIV negative) – Currently no routine recommendations for anal cancer screening • Immunization of females would likely have minimal impact on infection/disease in this population Hong PV, et al. Clin Infect DIs 2002. Johnson LG, et al. Cancer 2004, Simatherai, et al. Sex Transm Inf 2009 Quadrivalent HPV Vaccine Efficacy Study in Men • Study population – Heterosexual men (HM) • 3463: 16-23 year olds – Men having sex with men (MSM) • 602: 16-26 year olds • Primary objectives: Efficacy for 6/11/16/18-related – Main study: HM + MSM • External genital warts • Penile/perianal/perineal precancers lesions and cancer – Sub-study: MSM • Anal precancer lesions and cancer Quadrivalent HPV Vaccine Efficacy Prevention of HPV 6, 11-related Genital Warts, Males 16-26 years Vaccine Placebo % Efficacy Endpoint n/N n/N (95% CI) Genital warts 3/1245 28/1244 89 (66, 98) Interim Analysis; per-protocol efficacy population, mean follow-Up 2.2 yrs, received all three doses of vaccine; naïve to vaccine type at baseline Ref: BLA, Presentation for VRBPAC Meeting, Sept 9, 2009 FDA Licensure: Indications for Quadrivalent HPV Vaccine in Males • Prevention genital warts due to HPV types 6 and 11 • Approved for use in males aged 9 through 26 years http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm094042.htm Published Cost-Effectiveness Studies of Male HPV vaccination, US & UK Study Incremental cost per QALY of vaccinating 12-year-old males Taira et al. (2004), US ≈ $442,000 (70% coverage) ≈ $41,000 (30% coverage) Elbasha et al. (2007), US ≈ $128,000 (90% coverage) ≈ $42,000 (70% coverage) ≈ $24,000 (50% coverage) Jit et al. (2008), UK ≈ $1 million (80% coverage) Kim et al. (2009), US ≈ $91,000 (75% coverage, high efficacy scenario) ≈ $62,000 (50% coverage, high efficacy scenario) QALY: Quality-adjusted life year. UK results were converted to US dollars. Results not updated for inflation. Impact of Disease Outcomes on Cost Effectiveness Ratios for Male HPV Vaccination in the US $350,000 cervical cancer cervical cancer and wart $300,000 cervical and other cancers Incremental cost effectivenss ratio all outcomes $250,000 $200,000 $150,000 $100,000 $50,000 $0 vaccination of girls only vaccination of girls and boys (90% efficacy) Adapted from Kim and Goldie. BMJ 2009 Cost Effectiveness of Male Vaccination: Summary • Cost-effectiveness depends on vaccine coverage of females – Most favorable when coverage of females is low • Cost-effectiveness depends on what health outcomes are included – Cost-effectiveness of vaccination appears most favorable when including all potential health outcomes Provisional Recommendations* for Vaccination of Males Recommendations: Quadrivalent HPV vaccine may be given to males aged 9 through 26 years to reduce their likelihood of acquiring genital warts. Quadrivalent HPV vaccine would be most effective when given before exposure to HPV through sexual contact. Vaccines for Children (VFC): Quadrivalent HPV vaccine for males approved to be included in VFC enabling health care providers to obtain and provide vaccine but not actively promoting vaccination. *final recommendations pending CDC/HHS review and approval Affirmative and Permissive Recommendations Under a VFC Resolution Action Affirmative Permissive recommendation recommendation Provider expected to offer Yes No vaccine proactively to VFC- eligible child Provider expected to vaccinate Yes Yes, if provider VFC-eligible child on request stocks vaccine, else refer Provider may offer vaccine Yes Yes proactively to VFC-eligible child Immunization programs expected Yes No to promote recommendation Uptake is measure of program or Yes No provider performance Summary – Progress in vaccine implementation • Further efforts are needed to increase uptake; information, educations efforts as well as other strategies will be helpful – Two HPV vaccines available for use in females – Permissive recommendation for quadrivalent HPV vaccine for males with inclusion in the VFC program – Policy issues that need to be addressed next year • Further data on quadrivalent HPV vaccine in males • HPV vaccine in women over age 26 • Review of new data as available from ongoing studies and post licensure monitoring Thank you
"ACIP HPV Working Group"