HPV- Impfung: Für wen? Ab wann? Elmar A. Joura Universitätsklinik für Frauenheilkunde Wien. Krems,

Transkript

1 HPV- Impfung: Für wen? Ab wann? Elmar A. Joura Universitätsklinik für Frauenheilkunde Wien Krems,

2 Outline Erkrankungen Frauen (16-26) Mädchen (9-15) Buben/Männer Sicherheit

3 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

4 Genital warts U.K Males Females

5 A Study of 70,000 Women in the Nordic Countries Frauen 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 The Journal of Infectious Diseases

6 Trends in Vulvar Neoplasia VIN 3 Austria a 31-40a 41-50a 51-60a 61-70a 71-80a >80a Joura et al., J Reprod Med 2000

7 Mikroinvasives CA

8 Trends in Vulvar Neoplasia SCC: bimodal age-distribution n <30a 31-40a 41-50a 51-60a 61-70a 71-80a >80a Joura et al., J Reprod Med 2000

9 Zervixkarzinomkumulative Inzidenz ,00 4,00 3,00 2,00 % 1,00 0,

10 In situ Carcinome Österreich Konisationen 30a n <50a >50a Gebäralter 0 Frühgeburtsrisiko! Lancet 2006

11 CIN 3 - Carcinoma in situ

12 Produkte Gardasil HPV 6, 11, 16, 18 + AAHS Frauen 9-26, Knaben 9-15 Klinische Daten für Frauen September 2006 Cervarix HPV 16, 18 + AS04 Frauen Immunogenität Oktober 2007 Australien (bis 45)

13 HPV 16/18-Related Cervical Disease Per-Protocol Efficacy Population 3 years follow-up post-dose 1 n= , 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 , 100 Squamous Cell Cervical Cancer Cervical Adenocarcinoma CIN , 100 AIS , 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:

14 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 % Genital warts % VIN 1 or VaIN % VIN 2/3 or VaIN 2/ % *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:

15 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, , (42, 100) HPV 16 or 18- related VaIN 2/3 7, , (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: Joura EA & Future Investigators

16 The Lancet2007;369: Cumulative Incidence (%) 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 Placebo At-risk 9,087 8,850 8,722 8,640 8,509 8,320 4,387 Total Cases Cumulative Incidence (%) 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 Placebo At-risk 9,087 8,847 8,715 8,630 8,494 8,303 4,374 Total Cases

17 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 < CIN2+ HPV-16 Cervarix Control CIN2+ HPV-18 Cervarix Control Paavonen J et al. Lancet 2007

18 4- Jahresergebnisse Gardasil CIN2/3 und AIS, Frauen 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 % CI % CI % 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

19 Interpretation 100% Effekt in idealer Population jung low risk HPV naiv Keinen therapeutischen Effekt Effekt in HPV+ Frauen Zeit Herdenimmunität

20 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 Mar;26(3):201-9.

21 Immunogenität Block SL, et al. Pediatrics 2006 Serum clia GMT with 95% CI, mmul Immunogenicity Bridge Efficacy Program Age at enrolment (yrs)

22 HPV- Impfung für Männer Condylome > Risikofaktor für die Partnerin (RR 10!) Herdenimmunität Males Females

23 HPV- Erkrankungen Männer USA 7000 Karzinome HNO 1700 Analkarzinome 2/ / MSM (HIV-) 1200 Peniskarzinome Condylome 3300 juv. respirat. Papillomatose

24 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, ,654 91% < to 34 Year-Olds 2 1, ,301 92% < to 45 Year-Olds 2 1, ,353 89% <0.001 PYR = person years at risk; CI = confidence interval. Luna & FUTURE Investigators IPV 2007 Beijing

25 Study HPV014: GMCs and seroconversion rates after complete vaccination at month years years years GMC (EU/ml) % 100% 100% 100% 100% 100% 100% 100% years 1 HPV-16 HPV-18 Primary and secondary study objectives met Schwarz T, ASCO, 2006 ATP cohort, Seronegative at entry, month 7 results

26 Summary of Safety- Gardasil 1. Garland SM et al. New Engl J Med The FUTURE II Study Group. New Engl J Med Injection site AE Pain Systemic AE Serious AE Vaccine (n=2,673) FUTURE I 1 Placebo (n=2,672) Vaccine (n=6,019) FUTURE II 2 Placebo (n=6,031) Serious vaccine-related AE < <0.1 <0.1 Discontinuation due to serious AE Discontinuation due to serious vaccine-related AE <0.1 Discontinuation due to death* *None of the deaths were judged by the research investigator to be vaccine- or placebo-related. Data are presented a percentages, AE = Adverse Event

27 Study HPV012 Study: Safety - Cervarix % Doses followed by symptoms Adapted from Pedersenet al. Journal of Adolesent Health (JAH). 40 (2007) Any Symptoms General Symptoms Local Symptoms yrs yrs Solicited symptoms within 7 days (Total Vaccinated Cohort) No serious adverse events related to vaccination

28 Unklare Todesfälle D: Inzidenz 1-3/ ! 2007: 22 Kein Anstieg nach >2 Mio Dosen NW: 189 Ö: 15-19a Frauen 60 Todesfälle/ Jahr 2006: 3 Ungeklärte Todesfälle Dosen NW: 13

29 Vaccine Adverse Event Reporting System (VAERS) Mai Dosen (US) 1763 reports 4 Todesfälle 1 Myocarditis 2 Thromboembolien Hintergrundinzidenz 3-30/ Grippe + MRSA 13 Fälle Guillain Barre Syndrom Hintergrundinzidenz 1-2/ Mio Dosen 8 Todesfälle (geklärt)

30 Basisinzidenzen von vermeintlichen Nebenwirkungen 3/ binnen 24h wegen Asthma/ Allergie intensivpflichtig! 2/ binnen 1 Woche Erstmanifestation eines Diabetes 10/ binnen 6 Wochen wegen Autoimmunerkrankung hospitalisiert Siegrist CA, Pediatric Infect Dis J 11/2007

31 Zervixkarzinom Inzidenz Screening 120 Cervical Cancer Incidence Rate per 100,000 women Brazil UK Age