Sekundärprophylaxe – HPV-Impfung nach Konisation Elmar A. Joura Medical University – Comprehensive Cancer Center Vienna, Austria Obergurgl, 4 Februar 2013

Outline Wirkt die HPV-Impfung nur bei jungen Mädchen? Konisation und Frühgeburtlichkeit Konisation und Krebsrisiko HPV- Impfung bei Erkrankten

Prophylactic efficacy against HPV 6,11,16,18-related CIN Subjects Previously Exposed to ≥1 Vaccine HPV Type at Day 1 Vaccine (N = 8,799) Placebo (N = 8,800) n Number of cases Rate* Observed efficacy 95% CI All HPV-Related CIN 2190 4 0.1 2184 32 0.8 87.5 (64.8, 96.8) By Lesion Type CIN 1 27 0.6 85.2 (57.5, 96.2) CIN 2 0.0 7 0.2 100.0 (30.5, 100.0) CIN 3/AIS 6 (14.9, 100.0) HPV-Related CIN Subjects are counted once in each applicable endpoint category. A subject may appear in more than one category. *Cases per 100 person years at risk. N = Number of subjects randomized to the respective vaccination group who received at least 1 injection and were seronegative and PCR negative to the relevant HPV type at enrollment; n = Number of subjects in the given population with at least 1 follow-up visit following 30 days after Day 1; CIN = cervical intraepithelial neoplasia.

Wirksamkeit nach HPV- Infektionen Seropositive Frauen Vaccine Placebo CIN n Cases Rate Efficacy (%) 95% CI HPV 6/11/16/18 1,243 0.0 1,283 7 0.2 100.0 (28.7, 100.0) Vaccine Placebo GW+VIN n Cases Rate Efficacy (%) 95% CI HPV 6/11/16/18 1,268 0.0 1,301 8 0.2 100% (39.5, 100.0) Olsson SE, Vaccine 2009

Prophylaktische Wirksamkeit Frauen 24-45a Persistant Infection or clinical endpoint related to HPV 6/11/16/18 Per-protocol analysis Age Gardasil Placebo % Reduction 95% CI P-value Cases pyr 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 35 to 45 Year-Olds 1,393 17 1,353 89% 52 - 99 PYR = person years at risk; CI = confidence interval. Munoz et al, Lancet 2009

In situ Carcinome Österreich 6400 Konisationen 30a Gebäralter  Frühgeburtsrisiko! Lancet 2006 <50a >50a

Meta-analysis of relative risk of perinatal mortality associated with excisional treatment for cervical intraepithelial neoplasia Fig 1 Meta-analysis of relative risk of perinatal mortality associated with excisional treatment for cervical intraepithelial neoplasia. *0.5 added to each cell of 2×2 contingency table because no cases were found in one of comparison groups. †Excluded because no events in both groups. In subtotals relative risks are pooled by treatment procedure (only computed in absence of significant heterogeneity between studies)‏ Arbyn M et al. BMJ 2008;337:bmj.a1284 ©2008 by British Medical Journal Publishing Group

Cumulative rates of invasive cervical cancer after CIN Cumulative rates of invasive cervical cancer over the follow-up period for all women in the cervical intraepithelial neoplasia (CIN) cohort, for women in the CIN cohort under active surveillance, for the comparison cohort (COMP), and for the comparison cohort under surveillance (COMP—under surveillance). We used the same definition as in the CIN cohort (ie, must have had a cervical cytology within the previous 2 years to be included for that year). Error bars = 95% confidence intervals. Melnikow J et al. JNCI J Natl Cancer Inst 2009;101:721-728

Incidence of vaginal and vulvar cancers after CIN 3 Vaginal cancer Vulvar cancer Edgren G et al, Lancet Oncology 2007

Incidence of anal cancers after CIN 3 Edgren G et al, Lancet Oncology 2007

Fig 1 Study design for assessing effect of quadrivalent HPV vaccine on incidence of subsequent HPV related disease among women who had undergone surgery for cervical disease or who were diagnosed with vulvar or vaginal disease. Fig 1 Study design for assessing effect of quadrivalent HPV vaccine on incidence of subsequent HPV related disease among women who had undergone surgery for cervical disease or who were diagnosed with vulvar or vaginal disease. Subsequent disease was measured from 60 days after surgery or diagnosis Joura E A et al. BMJ 2012;344:bmj.e1401 ©2012 by British Medical Journal Publishing Group

Fig 2 Participant flow through study. Joura E A et al. BMJ 2012;344:bmj.e1401 ©2012 by British Medical Journal Publishing Group

Fig 3 Incidence of HPV related disease detected ≥60 days after cervical surgery or diagnosis of vulvar or vaginal disease among women who did not receive quadrivalent HPV vaccine (that is, placebo recipients). Fig 3 Incidence of HPV related disease detected ≥60 days after cervical surgery or diagnosis of vulvar or vaginal disease among women who did not receive quadrivalent HPV vaccine (that is, placebo recipients)‏ Joura E A et al. BMJ 2012;344:bmj.e1401 ©2012 by British Medical Journal Publishing Group

Fig 4 Time to detection of any HPV related disease (A) or vulvar or vaginal disease (B) after cervical surgery; and of any HPV related disease (C) or any cervical disease (D) after diagnosis of vulvar or vaginal disease. Fig 4 Time to detection of any HPV related disease (A) or vulvar or vaginal disease (B) after cervical surgery; and of any HPV related disease (C) or any cervical disease (D) after diagnosis of vulvar or vaginal disease. Case counting began 60 days after surgery or diagnosis Joura E A et al. BMJ 2012;344:bmj.e1401 ©2012 by British Medical Journal Publishing Group

Percent Reduction (95% CI) GARDASIL: FUTURE I/II End-of-Study Results Incidence of HPV Disease After a Cervical Excisional Procedure1 1/Huh SGO slide 14 ↓79% ↓65%a Percent Reduction (95% CI) ↓47%a ↓46.2%a (22, 63) (3.5, 71) (20, 86) (49, 93) aIrrespective of HPV type. CI = confidence interval; CIN = cervical intraepithelial neoplasia; GW = genital warts; VaIN = vaginal intraepithelial neoplasia; VIN = vulvar intraepithelial neoplasia. 1. BMJ 2012, Elmar A Joura&al for the Future I and II Study group 17 17

Cervarix post treatment Konisation nach Impfung 190 Cervarix 264 Plazebo 1 vs 9 CIN 2+ VE 88% (14.8-99.7) 12 vs 22 CIN 1+ VE 42.6% (-21 – 74) Garland SM, Eurogin 2011, Lissabon

Time to recurrence of high-grade AIN among vaccinated and unvaccinated oncogenic HPV–infected MSM with a history of high-grade AIN (n = 105) Time to recurrence of high-grade anal neoplasia among vaccinated and unvaccinated oncogenic human papillomavirus–infected men who have sex with men with a history of high-grade anal neoplasia, New York City, April 2007–April 2011 (n = 105). Swedish K A et al. Clin Infect Dis. 2012;cid.cir1036

Was ist der biologische Hintergrund dieser klinischen Wirksamkeit? Schutz gegen anderen HPV- Typ1 Anamnestischer Response in seropositiven Frauen Impfung verhindert Neuinfektion/ Reaktivierung2,3 Kreuzprotektion: 32.5% (95%CI: 6.0, 51.9)4 Kein therapeutischer Effekt! 1) J Infect Dis 2007; 196:1438-1446; 2) Vaccine 2007; 25:4931-4939; 3) Human Vaccines 2009; 5:696-704; 4) J Infect Dis 2009; 199:926-935.

Conclusion Patienten mit HPV- assoziierten Erkrankungen haben ein erhöhtes Risiko für weitere Erkrankungen Frauen nach Konisation haben ein erhöhtes Karzinomrisiko HPV- Impfung senkt das Risiko für weitere Erkrankung signifikant HPV impfung senkt das Risiko für weitere Konisation um 65-88% Impfung kann schon vor der Behandlung begonnen werden!