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

Size: px

Start display at page:

Download "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"

Gervais Fields
5 years ago
Views:

1 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, San Francisco General Hospital University of California San Francisco I have no conflicts of interest. Collaborative effort with Karen Smith-McCune, MD, PhD A case Focus You perform a Pap test in a 24-year-old G1P1 woman that is interpreted as low-grade squamous intraepithelial lesion (LSIL). She asks whether she should receive the HPV vaccine. She reports having had 4 lifetime sexual partners. She is trying to become pregnant. - Background - Focus on Gardasil - US vaccination guidelines: areas of conflict - Trial primary outcomes and populations, results of FUTURE studies (Gardasil) - Effect of vaccination on pregnancy outcomes - Potential effect of vaccination stratified by risk factors: age, number of lifetime sexual partners, abnormal cervical cytology - Counseling sexually experienced women about HPV vaccination 1

2 Background: HPV and Cervical Cancer 1960s: Epidemiological associations of cervical cancer and sexual transmissibility 1970s: Evidence of viral implication: HSV, HPV 1980s: HPV highly associated with CIN, cervical cancer (ORs >100); 13 to 18 different HPV types are considered oncogenic 1990s: HPV testing has high sensitivity for CIN 2000s: Development of a vaccine targeting highestrisk types 2008: zur Hausen awarded Nobel Prize in Physiology or Medicine for work in HPV/cervix cancer Background: vaccination HPV vaccines composed of the major viral capsid protein L1 assembled into virus-like particles. Principle of vaccination: generate blocking antibodies HPV virions, thereby preventing infection. Vaccination has no known therapeutic effect on established HPV infections or established HPV-associated genital warts, CIN or cancer. Background: vaccination HPV Vaccine Time-line Quadrivalent HPV vaccine, Gardasil, targets 2 oncogenic types (HPV 16 and 18) and 2 nononcogenic types associated with genital warts (HPV 6 and 11) Gardasil: first HPV vaccine approved by the US FDA; Cervarix approved late 2009 (targets HPV 16,18) HPV 16 and 18 associated with up to 70% of cervical cancer cases worldwide A vaccine targeting these HPV types expected to prevent a majority of cervical cancers May 2005 June 2006 August 2006 January 2007 March 2007 May 2007 September 2009 October 2009 March 2010 Phase II trial published FDA approves tetravalent vaccine HPV 6/11/16/18 (Gardasil) ACIP provisional recommendations ACOG endorsement of ACIP ACS recommendations ACIP final recommendations Interim Phase III trials published Some final Phase III trials published FDA: Cervarix approved; Gardasil approved for men and boys Final Phase III trials published for Gardasil 2

Current US Guidelines: The Conflict CDC- Advisory Committee on Immunization Practices (ACIP) - Recommend vaccination of 11-12 year old girls - Recommend catch-up vaccination up to the age of 26 -

3 Current US Guidelines: The Conflict CDC- Advisory Committee on Immunization Practices (ACIP) - Recommend vaccination of year old girls - Recommend catch-up vaccination up to the age of 26 - Vaccination can begin as young as age 9 years -Provisional recommendation (December 2009): The 3-dose series of quadrivalent HPV vaccine may be given to males aged 9 through 26 years to reduce their likelihood of acquiring genital warts. Ideally, vaccine should be administered before potential exposure to HPV through sexual contact. 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 - not recommended for use in pregnancy 3

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.

4 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. Limited effect of vaccination on overall incidence of CIN 2/3 in women with 2-4 lifetime partners No data about efficacy in women with >4 lifetime partners No cost-effectiveness data in year old Disease associated with HPV vaccine types Intention to treat population (ITT) Unrestricted susceptible population (US) Per protocol susceptible population (PPS) Naïve at entry for relevant HPV types and throughout vaccination period All 3 doses; no major protocol violations Case counting at month 7 Everyone Naïve at entry At least 1 dose Disease associated with any HPV type Histology Primer Cervical intraepithelial neoplasia (CIN) is pre-invasive Graded based on proportion of epithelium involved CIN 1: indicates active HPV infection; treatment discouraged since spontaneous resolution is high CIN 2: most are treated, but about 40% resolve over 6 month period; treatment may be deferred in young women CIN 3: the most proximal cancer precursor Adenocarcinoma in situ (AIS) is also widely considered a cancer precursor. 4

Phase II trial of Gardasil: 2005 Phase III trials of Gardasil Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) Two, multi-centered, double-blind, placebo-controlled trial

5 Phase II trial of Gardasil: 2005 Phase III trials of Gardasil Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) Two, multi-centered, double-blind, placebo-controlled trial sponsored by Merck FUTURE I FUTURE II - Double-blind, placebo-controlled trial sponsored by Merck (N=552) - Modified intention-to-treat analysis: CIN associated with vaccine-hpv types: 7 (placebo) vs. 0 (vaccine) External genital warts: 4 (placebo) vs. 0 (vaccine) - Per-protocol analysis: CIN associated with vaccine-hpv types: 3 (placebo) vs. 0 (vaccine) External genital warts: 3 (placebo) vs. 0 (vaccine) Ages % sexually experienced N 5,455 12,167 Setting 62 sites in 16 countries 90 sites in 13 countries Exclusions Pregnancy, h/o abnormal Pap tests, genital warts; >5 lifetime partners Pregnancy, h/o abnormal Pap tests, genital warts; >5 lifetime partners Enrollment Jan 2002 to March 2003 June 2002 to May 2003 Interim results May 10, 2007 disease associated with HPV 6,11,16 or 18: 55% (2.6, 5.7%; 32) 98% (0.08, 3.3%; 21) 100% (0, 2.6%, 38) FUTURE I: CIN 1, 2, 3, AIS Intention to treat (ITT) Unrestricted susceptible (UnS) Per protocol susceptible population (PPS) disease regardless of HPV type: 20% (12, 15.4%, 29) Vulvar, vaginal, perianal lesions reduced by 34% (3.8% vs. 5.8%; NNT=50). Numbers on parentheses are absolute risks over ~3 years, vaccine vs placebo, with NNT for benefit. 5

6 FUTURE I: Adverse Events Interim results May 10, 2007 No difference in vaccine-related events, discontinuation rates or death Injection site event: 87% vs 77% (NNT=10) Pyrexia: 13.5% vs 10.2% (NNT=30) Vulvar cancer diagnosed in 1 woman in the vaccine group (age 22). disease associated with HPV 16 or 18: 44% (1.4, 2.4%; 93) 95% (0.05, 1.05%; 100) 98% (0.02, 0.8%; 164) FUTURE II: CIN 2,3,AIS Intention to treat (ITT) Unrestricted susceptible (UnS) Per protocol susceptible population (PPS) disease regardless of HPV type: 17% (3.6, 4.4%; 128) Cumulative incidence of CIN 2,3,AIS associated with HPV 16 or 18 (FUTURE II) Numbers on parentheses are absolute risks over ~3 years, vaccine vs placebo, with NNT for benefit. NEJM 2007;356; Figure 1 6

Cumulative incidence of CIN 2/3/AIS associated with any HPV type (FUTURE II) FUTURE II: Adverse Events Similar injection-site adverse events as in FUTURE I Pregnancy outcomes (combined FUTURE I and

7 Cumulative incidence of CIN 2/3/AIS associated with any HPV type (FUTURE II) FUTURE II: Adverse Events Similar injection-site adverse events as in FUTURE I Pregnancy outcomes (combined FUTURE I and II) Congenital anomalies: no difference EDC within 30 days of vaccination: 5 cases in the vaccine group versus 0 in the placebo group (risk difference 4.5%; NNT=23); no pattern among the types of anomalies; these results final (Obstet Gynecol 2009) - Pregnancy registry has been established NEJM 2007;356; Figure 1 Pooled results of North American women from a Phase II trial of a monovalent (HPV 16), a Phase II trial of the quadrivalent vaccine, and interim results from the Phase III trials FUTURE I and II >5500 women, average follow-up 2.5 years NB: Be generally cautious in interpreting subgroup analyses. 7

8 Stratified analyses: ITT, outcomes regardless of causal HPV type (% reduction) Information pending Enrollment CIN 1+ CIN 2+ Genital lesions Age (NS) 44.8 (NS) 39.1 (NS) ASC-US+ cytology 5.5 (NS) 14.7 (NS) <0 (NS) Final results from Phase 3 trials, including effects of vaccination on overall rates of CIN 3+ (regardless of HPV type) Effect on abnormal Pap tests, colposcopy, cervical treatments (LEEPs); NB: potential for large cost savings Final subgroup analyses Cost-effectiveness analyses Barr et al AJOG 2008 interventions: Abnormal Pap tests vs Colposcopy 9.59 vs FUTURE I and II: Final results Intention to Treat disease regardless of HPV type CIN vs 4.19 CIN vs Cumulative incidence of CIN 3/AIS associated with any HPV type (FUTURE I and II) Definitive treatment 1.97 vs 2.56 Warts, VIN or VAIN 0.76 vs 1.59 No additional cancers. JNCI March 2010 JNCI March

9 outcomes associated with HPV 6, 11, 16 or 18: 31% 75% 3,819 sexually experienced women ages 24-35, interim results: infection 6 months duration, CIN 1+, external genital lesion Intention to treat (ITT) Unrestricted susceptible (UnS) outcomes regardless of HPV type: outcomes associated with HPV 6, 11, 16 or 18: 30% (NS) 82% 3,819 women 24-35, interim results: CIN 1+*, external genital lesion only Intention to treat (ITT) Unrestricted susceptible (UnS) outcomes regardless of HPV type: 91% Per protocol susceptible population (PPS) 92% Per protocol susceptible population (PPS) Lancet, on-line June 2, 2009 *Most were CIN 1. Lancet, on-line June 2, 2009 Gardasil versus Cervarix No head-to-head comparison for clinical outcomes (e.g., CIN) Effect on genital warts presumed to be less for Cervarix (HPV 16 and 18 only) Immunogenicity studies pending Summary On one hand, the vaccine has high efficacy certain HPV types that cause an important lifethreatening disease and it appears safe; delaying vaccination may mean that many women will miss an opportunity for long-lasting protection. On the other hand, a cautious approach may be warranted in light of important unanswered questions about overall vaccine effectiveness, duration of protection, and adverse effects that may emerge over time. HPV vaccination has the potential for profound public health benefit if the most optimistic scenario of benefit is realized. Sawaya GF, Smith-McCune K. HPV vaccination more answers, more questions. N Engl J Med ;(19):

10 Back to the case Counseling A 24-year-old G1P1 woman Pap test is low-grade squamous intraepithelial lesion (LSIL) Reports having had 4 lifetime sexual partners Trying to become pregnant Current US guidelines conflict (An abnormal Pap test may indicate that she is unlikely to benefit; vaccination safety in this clinical situation unknown) (Reported number of lifetime sexual partners may substantially diminish vaccination benefit) Seems prudent to counsel avoidance of vaccination while she is trying to conceive pending more data Cervical cancer is a rare outcome in women undergoing routine screening; she should continue to undergo screening as recommended An informal poll Would you recommend vaccination in this patient? What if she were not trying to get pregnant? What if she had a normal cytology test? What if she had only one lifetime partner? 10

The HPV vaccine: what we know versus what we hope

The HPV vaccine: what we know versus what we hope Karen Smith-McCune Associate Professor University of California San Francisco email: kmccune@cc.ucsf.edu 415-476-7882 I have no financial conflicts of