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ACIP HPV Working Group


									Update and New Recommendations:

     Human Papillomavirus
                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

• Background
• US HPV Vaccination Program
• HPV Vaccines and Recommendations
    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

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

                   70                                         2007

                        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%



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
                                                         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)
      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)
      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        Placebo                        Efficacy
           Endpoints                                   N cases        N cases                       %      (CI)
           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

• 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


                                                 Bivalent HPV vaccine (N=12533)
                                                 Pooled controls (N=10730)



                         8                 7.2


                         2                              0.8     0.8

                                    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%
                                                                   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

      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

         – 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
• 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
         – 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
• 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
     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
                                                             cervical cancer
                                                             cervical cancer and wart
                                                 $300,000    cervical and other cancers
           Incremental cost effectivenss ratio

                                                             all outcomes






                                                            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

   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
            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
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
– 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

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