HPV- Impfung: Für wen? Ab wann? Elmar A. Joura Universitätsklinik für Frauenheilkunde Wien Krems, 21.02.2008
Outline Erkrankungen Frauen (16-26) Mädchen (9-15) Buben/Männer Sicherheit
HPV assoziierte Erkrankungen Frauen / Jahr in Europa ~2,000 Vulva/ Vagina CA 33,500 Zervix CA ~30,000 VIN / VAIN 2/3 163,000 CIN 2/3 VIN 1 554,000 CIN 1 250,000 CONDYLOME INFEKTIONEN RESP. PAPILLOME
Genital warts U.K. 300 250 Males Females 200 150 100 50 0 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000
A Study of 70,000 Women in the Nordic Countries 69.147 Frauen 18-45 a 10.6% kumulative Inzidenz 1.3% Prävalenz (letzte 12 mo) Alter 1. Auftreten 22 a (3-45) Risikofaktoren Anzahl der Sexualpartner Kondome, OC Rauchen Junges Alter Susanne Krüger Kjaer et. al. 2007 The Journal of Infectious Diseases
Trends in Vulvar Neoplasia VIN 3 Austria 20 15 1994-97 1985-88 10 5 0 20-30a 31-40a 41-50a 51-60a 61-70a 71-80a >80a Joura et al., J Reprod Med 2000
Mikroinvasives CA
Trends in Vulvar Neoplasia SCC: bimodal age-distribution 40 30 n 20 10 0 <30a 31-40a 41-50a 51-60a 61-70a 71-80a >80a Joura et al., J Reprod Med 2000
Zervixkarzinomkumulative Inzidenz 1983-2003 5,00 4,00 3,00 2,00 % 1,00 0,00 1983 1988 1993 1998 2003
In situ Carcinome Österreich 1983-2002 1200 6000 Konisationen 30a n 1000 800 600 400 200 <50a >50a Gebäralter 0 Frühgeburtsrisiko! Lancet 2006
CIN 3 - Carcinoma in situ
Produkte Gardasil HPV 6, 11, 16, 18 + AAHS Frauen 9-26, Knaben 9-15 Klinische Daten für Frauen 25-45 September 2006 Cervarix HPV 16, 18 + AS04 Frauen 10-25 Immunogenität 10-55 Oktober 2007 Australien (bis 45)
HPV 16/18-Related Cervical Disease Per-Protocol Efficacy Population 3 years follow-up post-dose 1 n= 20.583, 16-26yrs HPV 16/18- Related Cancer HPV 16/18- Related Surrogate GARDASIL Placebo % Efficacy 95% CI High Grade Cervical Dysplasia CIN 2/3 or AIS 1 85 99 93, 100 Squamous Cell Cervical Cancer Cervical Adenocarcinoma CIN 3 1 51 98 89, 100 AIS 0 7 100 31, 100 Ault KA, FUTURE II Study Group. Effect of prophylactic human papillomavirus L1 virus-like particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: A combined analysis of four clinical trials. Lancet 2007;369:1861 1968.
Efficacy HPV 6/11/16/18-associated Vulvar Disease- FUTURE I PP Population; Subjects were HPV 6, 11, 16, 18 naive up to month 7 End Point by Lesion Type GARDASIL * (n=2,261) Placebo * (n=2,279) Vaccine Efficacy CI HPV 6/11/16/18 VIN/VaIN, Genital Warts 0 60 100% 94 100 Genital warts 0 48 100% 92 100 VIN 1 or VaIN 1 0 9 100% 49 100 VIN 2/3 or VaIN 2/3 0 9 100% 49 100 *Subjects are counted once per row but may be counted in more than 1 row. Garland SM et al. New Engl J Med. 2007; 356:1928-1943.
Prophylactic Efficacy Against HPV 16 or 18- Related VIN 2/3 or VaIN 2/3 Type Specific Per-Protocol Population(s) GARDASIL (N = 9075) Placebo (N = 9,075) n Cases n Cases %Efficacy 95% CI HPV 16 or 18- related VIN 2/3 7,771 0 7,742 8 100 (42, 100) HPV 16 or 18- related VaIN 2/3 7,771 0 7,742 7 100 (31, 100) An additional 4 cases of HPV 6 or 11-related VIN 2/3 or VaIN 2/3 (not also associated with 16 or 18) were observed in the placebo group (none such cases in the vaccine group). The Lancet2007;369:1693-1702 Joura EA & Future Investigators
The Lancet2007;369:1693-1702 Cumulative Incidence (%) 0.5 0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 Figure 2. Time Since Day 1 (in Months) Placebo GARDASIL Vaccine At-risk 9,087 8,830 8,715 8,620 8,488 8,310 4,342 Total Cases 0 2 3 4 7 8 8 Placebo At-risk 9,087 8,850 8,722 8,640 8,509 8,320 4,387 Total Cases 0 1 6 10 16 24 31 Cumulative Incidence (%) 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 Time Since Day 1 (in Months) Placebo GARDASIL Vaccine At-risk 9,087 8,830 8,714 8,615 8,480 8,300 4,332 Total Cases 0 2 4 9 15 18 23 Placebo At-risk 9,087 8,847 8,715 8,630 8,494 8,303 4,374 Total Cases 0 4 13 20 31 41 49
Phase III efficacy study HPV008: Efficacy against HPV-16/18 CIN2+ (TVC-E) Pre-specified Case Definition based on PCR detection in lesion only Endpoint Group N n Cervarix Efficacy (97.9% CI) % LL UL P-value CIN2+ HPV- 16/18 Cervarix Control 7788 7838 2 21 90.4 53.4 99.3 <0.0001 CIN2+ HPV-16 Cervarix Control 6701 6717 1 15 93.3 47.0 99.9 0.0005 CIN2+ HPV-18 Cervarix Control 7221 7258 1 6 83.3-78.8 99.9 0.1249 Paavonen J et al. Lancet 2007
4- Jahresergebnisse Gardasil CIN2/3 und AIS, Frauen 16 26 Combined results from 4 phase II/III trials ~4 year follow up - Per Protocol Population (END OF STUDY) 100% 100% 97% 100% 75% 95% CI 95-100 95% CI 88-100 95% CI 31-100 50% 25% 0% HPV 16/18 CIN 2 HPV 16/18 CIN 3 HPV 16/18 AIS n (GARDASIL ) = 8493; n (placebo) = 8464 Joura & Future Investigators ICACT Paris 5.2.2008
Interpretation 100% Effekt in idealer Population jung low risk HPV naiv Keinen therapeutischen Effekt Effekt in HPV+ Frauen Zeit Herdenimmunität
Safety and Persistent Immunogenicity of a Quadrivalent HPV 6, 11, 16, 18 L1 Virus-Like Particle Vaccine in Preadolescents and Adolescents 1781 Mädchen und Buben 9-15 Dreiteilige Impfung 99.5% Serokonversion Lokale Reaktionen 75 vs. 50% Fieber 7 vs. 6% Nach 18 Monaten: 91-99% seropositiv Reisinger KS, Pediatr Infect Dis J. 2007 Mar;26(3):201-9.
Immunogenität Block SL, et al. Pediatrics 2006 Serum clia GMT with 95% CI, mmul 1600 1500 1300 1100 900 700 500 Immunogenicity Bridge Efficacy Program 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Age at enrolment (yrs)
HPV- Impfung für Männer Condylome > Risikofaktor für die Partnerin (RR 10!) Herdenimmunität 300 250 200 Males Females 150 100 50 0 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000
HPV- Erkrankungen Männer USA 7000 Karzinome HNO 1700 Analkarzinome 2/100.000 35/100.000 MSM (HIV-) 1200 Peniskarzinome 500.000 Condylome 3300 juv. respirat. Papillomatose
Primary efficacy Persistant Infection or clinical endpoint related to HPV 6/11/16/18 Per-protocol analysis Age Cases Gardasil pyr Cases Placebo pyr % Reduction 95% CI P-value All Subjects 4 2,721 41 2,654 91% 74 98 <0.001 24 to 34 Year-Olds 2 1,329 24 1,301 92% 67-99 <0.001 35 to 45 Year-Olds 2 1,393 17 1,353 89% 52-99 <0.001 PYR = person years at risk; CI = confidence interval. Luna & FUTURE Investigators IPV 2007 Beijing
Study HPV014: GMCs and seroconversion rates after complete vaccination at month 7 10000 15-25 years 1000 26-35 years 36-45 years GMC (EU/ml) 100 10 100% 100% 100% 100% 100% 100% 100% 100% 46-55 years 1 HPV-16 HPV-18 Primary and secondary study objectives met Schwarz T, ASCO, 2006 ATP cohort, Seronegative at entry, month 7 results
Summary of Safety- Gardasil 1. Garland SM et al. New Engl J Med. 2007. 2. The FUTURE II Study Group. New Engl J Med. 2007. Injection site AE Pain Systemic AE Serious AE Vaccine (n=2,673) 86.8 85.3 65.3 1.8 FUTURE I 1 Placebo (n=2,672) 77.4 75.4 63.7 1.7 Vaccine (n=6,019) 84.4 83.0 61.4 0.7 FUTURE II 2 Placebo (n=6,031) 77.9 75.8 60.0 0.9 Serious vaccine-related AE <0.1 0.0 <0.1 <0.1 Discontinuation due to serious AE 0.1 0.1 0.1 0.1 Discontinuation due to serious vaccine-related AE 0.0 0.0 0.0 <0.1 Discontinuation due to death* 0.1 0.1 0.1 0.1 *None of the deaths were judged by the research investigator to be vaccine- or placebo-related. Data are presented a percentages, AE = Adverse Event
Study HPV012 Study: Safety - Cervarix % Doses followed by symptoms Adapted from Pedersenet al. Journal of Adolesent Health (JAH). 40 (2007) 564 571 100 90 80 70 60 50 40 30 20 10 0 Any Symptoms General Symptoms Local Symptoms 15-25 yrs 10-14 yrs Solicited symptoms within 7 days (Total Vaccinated Cohort) No serious adverse events related to vaccination
Unklare Todesfälle D: Inzidenz 1-3/100.000! 2007: 22 Kein Anstieg nach >2 Mio Dosen NW: 189 Ö: 15-19a Frauen 60 Todesfälle/ Jahr 2006: 3 Ungeklärte Todesfälle 100.000 Dosen NW: 13
Vaccine Adverse Event Reporting System (VAERS) Mai 2007-5.000.000 Dosen (US) 1763 reports 4 Todesfälle 1 Myocarditis 2 Thromboembolien Hintergrundinzidenz 3-30/100.000 1Grippe + MRSA 13 Fälle Guillain Barre Syndrom Hintergrundinzidenz 1-2/100.000 13 Mio Dosen 8 Todesfälle (geklärt)
Basisinzidenzen von vermeintlichen Nebenwirkungen 3/100.000 binnen 24h wegen Asthma/ Allergie intensivpflichtig! 2/100.000 binnen 1 Woche Erstmanifestation eines Diabetes 10/100.000 binnen 6 Wochen wegen Autoimmunerkrankung hospitalisiert Siegrist CA, Pediatric Infect Dis J 11/2007
Zervixkarzinom Inzidenz Screening 120 Cervical Cancer Incidence Rate per 100,000 women 100 80 60 40 20 Brazil UK 0 0-5- 10-15- 20-25- 30-35- 40-45- 50-55- 60-65- 70-75- 80-85+ Age