Efficacy of Human Papillomavirus16 Vaccine to Prevent Cervical Intraepithelial Neoplasia: A Randomiz

1
Efficacy of Human Papillomavirus-16 Vaccine to
Prevent Cervical Intraepithelial Neoplasia A
Randomized Controlled Trial

• Journal Club
• Tina M. Cattrone, M.D., M.P.H.
• Family and Community Medicine

2
Outline

• HPV and cervical cancer
• Article review
• Valid study?
• Impact on practice
• Barriers to use
• How, when and where?
• Summary

3
Human papillomavirus (HPV)

• 200 subtypes, 15 associated with cervical cancer
• HPV type 16 accounts for 50.5 of cases1
• Persistent HPV infection? CIN 1-3 ? cervical
  cancer
• Long interval between initial infection and
  development of cancer

4
Cervical Cancer

• 2005 American Cancer Society estimates2
• Incidence 10,370/year
• Deaths 3710/year
• Estimated Lifetime cervical cancer risk
  3.67
• Highest rates in African American women3
• Peak incidence at age 50

5
Current Prevention Strategies

• Primary prevention
• Reduced exposure by changes in sexual practices
• Secondary prevention
• Pap smears for early detection
• HPV screening
• Laser, cryosurgery, LEEP excision and cervical
  conization for HPV-infected lesions

6
Vaccination as primary prevention?

• In 2002, Koutsky, et al. showed HPV 16 L1
  virus-like particle (VLP) vaccine prevented
  persistent HPV 16 infection during 1.5 years of
  follow-up4
• Bivalent HPV 16 and 18 VLP vaccine also effective
  for similar follow-up interval5
• Follow-up too short vaccine vs. routine
  resolution of viral disease

7
CIN as a surrogate marker

• CIN 2-3 is immediate precursor to cervical cancer
• Histologic changes can become apparent as soon as
  6-12 mos. after HPV 16 infection
• Study needed to determine whether vaccine
  protection 18 mos. and prevents CIN 2-3

8
CIN III Irregular distribution of immature,
hyperchromatic cells that replace normal
epithelium
9
Methods

• Randomized, multi-center placebo-controlled trial
  over 3.5 years
• 2391 women from 16 centers in US
• Women 16-23 years, no pregnant, no prior abnormal
  Pap tests, and lifetime hx of 0-5 male partners
• Randomized 11 ratio to receive IM HPV16 vaccine
  at day 1, month 2 and month 6

10
Methods, contd.

• Vaccine and placebo visually indistinguishable
• Participants and study staff blinded to group
  assignments
• At enrollment women underwent
• Pap smears with ThinPrep
• Cervical, external genital and cervicovaginal
  specimen collection for HPV16 DNA testing
• Serum HPV16 Antibody titers

11
Methods, contd.

• Follow-up at 7, 12, 18q6 months48 months
• Pap smear
• Specimen to check for HPV DNA
• HPV 16 serum Ab testing at all but 24 and 36
  month visits
• Women with HSIL, LSIL, ASCUS referred for
  colposcopy
• All women underwent colposcopy at 48-month visit

12
Methods, contd

• HPV 16-related CIN defined as follows
• Histology result of CIN 1,2 or 3 by path panel
  review
• Adjacent tissue biopsy or swab for HPV16 DNA (at
  least 2 out of 3 genes)
• Genital samples from visit before or after
  positive biopsy for HPV16 DNA
• All three required
• Persistent infection defined as HPV16 DNA
  positive on 2 visits at least 4 mos. apart or
  HPV16 DNA positive on last visit of record

13
Methods, contd

• Three patient populations analyzed
• Per-protocol group initially seronegative for
  HPV16 and throughout completed vaccination series
• Modified intention-to-treat (MITT)-1 group at
  least one vaccination and HPV negative at Day 1,
  including all protocol violators
• MITT-2 group all MITT-1 patients and those
  testing positive for HPV16 infection at enrollment

14
Results

• 84.9 of participants (2031/2391) completed the
  study
• Discontinuation of 360 women secondary to
• 9 clinical adverse events
• 189 lost to follow-up (7)
• 33 pregnancies
• 35 protocol deviations
• 94 consent withdrawal
• No significant difference in losses between
  vaccine and placebo groups

15
Demographics
16
Results Persistent HPV16 infection

• Per-protocol group 7 cases in vaccine recipients
  vs. 111 cases in placebo group
• Observed efficacy 94, P
• 7 cases in vaccine group were from patients who
  were positive at their last visit of record only.

17
Results HPV 16-related CIN

• Per protocol group
• Placebo 12/750 (1.6)
• NO cases in vaccine population
• MITT-1 group
• Placebo 32/843 (3.8) developed CIN 1 or worse
• NO cases in vaccine population
• P-value
• MITT-2 group
• Placebo 42/1050 (4) developed CIN
• Vaccine 7/1017 (0.7) developed CIN
• P-value

18
Results CIN and abnormal Paps

• Per protocol group No statistical significance
  for overall incidence of CIN1 or CIN2-3 caused by
  any HPV type.
• Observed efficacy was 31 (95 CI
• No significant difference in incidence of
  abnormal Pap tests among placebo or vaccine
  recipients (AS-CUS or worse)

19
Are the results of the study valid?

• Was the assignment of patients to treatments
  randomized? Yes!
• Were all enrolled patients accounted for at its
  conclusion? Yes!
• RCT? Double-blinded, placebo controlled trial
• Similar placebo and intervention demographics?
  Yes!

20
Treatment Effect

• How large was the treatment effect in patients
  who completed the protocol ?
• Persistent HPV16 infection
• RRR 94 (95 CI 88 - 98)
• ARR .14 (95 CI .11 - .16)
• NNT 7 (95 CI 6 - 9)
• HPV 16-related CIN 2 or worse
• RRR 100 (95 CI NA)
• ARR .016 (95 CI .007 - 025)
• NNT 63 (95 CI 8 - 143)

21
Study Limitations

• Does HPV16 vaccine provide protection against
  infection beyond 3.5 years after vaccination?
• Impact of vaccination on women who already had
  HPV 16 infection at enrollment?
• and some authors Merck
• Still need long-term study to show vaccination
  prevents cervical cancer

22
Impact on Practice

• Potential for reduced
• HPV infection
• Incidence of cervical cancer
• Possible reduced frequency for recommended
  cervical cytological testing
• Decrease in healthcare costs
• Pap tests and treatment of CIN costs estimated
  3.6 billion

23
Impact on Patients

• Potential harms
• Adverse reactions not seen in study
• Hypothetical concerns about
• Reductions in safe sex practices
• Reductions in patients coming for screenings
• Misconceptions that vaccine prevents against more
  than just HPV

24
Barriers to Use

• Policy dilemmas
• Should it be recommended or mandated?
• HPV is associated with specific behavioral risk
  vs. other communicable diseases prevented with
  vaccines
• Females only?
• At what age?
• How to ensure access for disadvantaged and
  uninsured?

25
Vaccine acceptability at different proposed ages
of vaccination.
6Factors that are Associated with Parental
Acceptance of Human Papillomavirus Vaccines A
randomized Intervention Study of Written
Information About HPV. Dempsey AF, et al.
Pediatrics
26
Acceptance

• Parental acceptance
• Statistically significant differences in vaccine
  variability between age categories of children6
• More likely to accept if
• child was female,
• parent had experience with genital warts
• Physician recommendation
• Influence of peer group
• Increased perception of childs risk
• Perception of benefit to society and child

27
Independent predictors of HPV vaccine
acceptability among patients. (Dempsey, et al.)
28
How, when and where?

• Final FDA date is June 8, 2006
• FDA approval vote was on May 18, 2006 Yes
• 9-25 year olds
• Females only
• Advisory committee on Immunization Practices
  (ACIP) meeting in June for specific age
  recommendation
• June availability?
• Series of 3 shots for app. 400
• Undecided who will cover costs and how much

29
Summary

• Clear evidence that vaccine prevents persistent
  infection and CIN 2-3
• Future likely holds long-term study looking at
  cervical cancer as outcome
• Many questions exist with the introduction of
  vaccine!

30
Questions? Comments?
31
References

• Munoz N, Bosch FX, de Sanjoe S,et al.
  Epidemiologic classification of human
  papillomavirus types associated with cervical
  cancer. N Engl J Med 2003348518-527.
• American Cancer Society. Cancer facts and figures
  2005. Am Cancer Soc 20051-60.
• Freeman HP, Wingrove BK. Excess cervical cancer
  mortality a marker for low access to health care
  in poor communities. National Cancer Institute,
  Center to Reduce Cancer Health Disparities, May
  (05-5282) 2005. p. 1-79.
• Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr
  E, Alvarez FB, et al. A controlled trial of human
  papillomavirus type 16 vaccine. N Engl J Med
  20023471645-51.
• Harper DM, Franco EL, Wheeler CM, Ferris DG,
  Jenkins D, Schuind A, 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 20043641757-65.
• Dempsey AF, Zemet GD, Davis RL, Koutsky L.
  Factors that are associated with parental
  acceptance of human papillomavirus vaccines A
  randomized intervention study of written
  information about HPV. Pediatrics 2005
  17(5)1487-1493.
• Review article
• Mao C, Koutsky LA, Ault KA, Wheeler CM, Brown DR,
  Wiley DJ, Alvarez FB, Bautista OM, Jansen
• KU, Barr E. Efficacy of Human Papillomavirus-16
  Vaccine to Prevent Cervical Intraepithelial
• Neoplasia A Randomized Controlled Trial.
  Obstetrics and Gynecology 2006 107(1)18-27.