Az előadás letöltése folymat van. Kérjük, várjon

Az előadás letöltése folymat van. Kérjük, várjon

A méhnyakrák elleni védőoltás hatékonysága és az eddig megszerzett tapasztalatok  Prof. Bánhidy Ferenc Az előadás a GlaxoSmithKline Kft. felkérésére készült.

Hasonló előadás


Az előadások a következő témára: "A méhnyakrák elleni védőoltás hatékonysága és az eddig megszerzett tapasztalatok  Prof. Bánhidy Ferenc Az előadás a GlaxoSmithKline Kft. felkérésére készült."— Előadás másolata:

1 A méhnyakrák elleni védőoltás hatékonysága és az eddig megszerzett tapasztalatok
 Prof. Bánhidy Ferenc Az előadás a GlaxoSmithKline Kft. felkérésére készült.

2 Miről fogok ma beszélni? /mai program/
Mik a Cervarix™ -al végzett klinikai vizsgálatok tapasztalatai ? immunogenitás, hosszú távú védettségi adatok hatékonyság biztonságossági profil Mik a széléskörű alkalmazás eddigi tapasztalatai ? Milyen szempontokat vegyünk figyelembe a vakcinációs program elindításakor ?

3 Today’s agenda Mik a Cervarix™ -al végzett klinikai vizsgálatok tapasztalatai ? immunogenicity, long-term protection data overall efficacy safety profile Mik a széléskörű alkalmazás eddigi tapasztalatai ? Milyen szempontokat vegyünk figyelembe a vakcinációs program elindításakor ?

4 Cervarix™ vizsgálatok: tények és számok, melyek az értékelés alapjai 
vizsgálati státusz 36 befejezett 12 jelenleg is zajló elsődleges végpontok 8 biztonságossági 5 biztonságossági és immunogenítási 25 immunogenitási 10 hatékonysági helyszín Öt kontinesen zajló 40 ország részvételével Bevont betegek száma > 80,000 Overview of all completed and ongoing Cervarix™ clinical trials . This presentation will focus on completed trials providing the main body of evidence for Cervarix™ in the European label. * Human Papillomavirus vaccine [Types 16, 18] (Recombinant, adjuvanted, adsorbed)

5 Cervarix™ trials: facts and figures to the evolution of the evidence
Trial status 36 completed 12 ongoing Primary endpoints 8 safety 5 safety and immunogenicity 25 immunogenicity 10 efficacy Location 5 continents Spanning > 40 countries Representing Subjects > 80,000 Overview of all completed and ongoing Cervarix™ clinical trials . This presentation will focus on completed trials providing the main body of evidence for Cervarix™ in the European label. * Human Papillomavirus vaccine [Types 16, 18] (Recombinant, adjuvanted, adsorbed)

6 Hosszantartó magas anti-HPV 18 és 16 teljes IgG ellenanyagszint
Hosszantartó magas anti-HPV 18 és 16 teljes IgG ellenanyagszint* 9,4 éves után követés (median 8.9 év) = természetes fertőzés utáni ellenanyag szint Up to 9.4 years (median 8.9) after first vaccination in study trial 001, all women were seropositive for HPV-16 antibodies reaching a plateau ~18 months following first vaccination, with titres several-fold above natural infection levels. GMT values for natural infection were obtained from subjects aged years evaluated in a phase III study (PATRICIA trial) who had developed a natural infection and cleared it prior to enrollment, i.e. subjects who were DNA negative and seropositive for the respective HPV type at enrollment (GMT levels corresponding to natural infection in the PATRICIA trial were 29.8 EL.U/mL (95% CI: [28.5; 31.0]) for HPV-16; measured by ELISA) For information: - Excellent retention for the brazilian cohort - 100% seropositivity against HPV-16 at 2 last timepoints for brazilian cohort Up to 9.4 years (median 8.9) after first vaccination in study trial 001, all women were seropositive for HPV-18 antibodies reaching a plateau ~18 months following first vaccination, with titres several-fold above natural infection levels. GMT values for natural infection were obtained from subjects aged years evaluated in a phase III study (PATRICIA trial) who had developed a natural infection and cleared it prior to enrollment, i.e. subjects who were DNA negative and seropositive for the respective HPV type at enrollment (GMT levels corresponding to natural infection in the PATRICIA trial were 22.6 EL.U/mL (95% CI: [21.6; 23.6]) for HPV-18; measured by ELISA) - 100% seropositivity against HPV-18 at 2 last timepoints for brazilian cohort PRE = pre-vaccination; * By ELISA. Combined analysis of trials 001/007/023 in the subcohort EMA. Cervarix®. European Summary of Product Characteristics, 2012

7 High and sustained anti-HPV 18 and 16 total IgG antibodies. up to 9
High and sustained anti-HPV 18 and 16 total IgG antibodies* up to 9.4 years (median 8.9 years) = Natural infection antibody levels Up to 9.4 years (median 8.9) after first vaccination in study trial 001, all women were seropositive for HPV-16 antibodies reaching a plateau ~18 months following first vaccination, with titres several-fold above natural infection levels. GMT values for natural infection were obtained from subjects aged years evaluated in a phase III study (PATRICIA trial) who had developed a natural infection and cleared it prior to enrollment, i.e. subjects who were DNA negative and seropositive for the respective HPV type at enrollment (GMT levels corresponding to natural infection in the PATRICIA trial were 29.8 EL.U/mL (95% CI: [28.5; 31.0]) for HPV-16; measured by ELISA) For information: - Excellent retention for the brazilian cohort - 100% seropositivity against HPV-16 at 2 last timepoints for brazilian cohort Up to 9.4 years (median 8.9) after first vaccination in study trial 001, all women were seropositive for HPV-18 antibodies reaching a plateau ~18 months following first vaccination, with titres several-fold above natural infection levels. GMT values for natural infection were obtained from subjects aged years evaluated in a phase III study (PATRICIA trial) who had developed a natural infection and cleared it prior to enrollment, i.e. subjects who were DNA negative and seropositive for the respective HPV type at enrollment (GMT levels corresponding to natural infection in the PATRICIA trial were 22.6 EL.U/mL (95% CI: [21.6; 23.6]) for HPV-18; measured by ELISA) - 100% seropositivity against HPV-18 at 2 last timepoints for brazilian cohort PRE = pre-vaccination; * By ELISA. Combined analysis of trials 001/007/023 in the subcohort EMA. Cervarix®. European Summary of Product Characteristics, 2012

8 Hosszú távú hatékonysági adatok a HPV/16,18-al szemben
TVC: Total Vaccinated Cohort 001/007/023TRIALS HPV 16/18-related CIN2+ Vaccine Control Vaccine efficacy n % (95% CI) Initial efficacy study 2.3 years1 3 NA* Combined analysis of initial efficacy study and extended follow-up 4.5 years2 5 100 (-7.7–100.0) 5.5 years3 7 100 (32.7–100.0) 6.4 years3 9 100 (51.3–100.0) In the subcohort, there were 223 women in the vaccine group and 213 women in the control group (at 8.4 years; Roteli-Martins et al. Hum Vaccin Immunother 2012; 8:1-8). At 9.4 years follow-up in the placebo group, there were 4 cases of 6-month persistent infection and 1 case of 12-month persistent infection. n = number of subjects reporting at least one event in each group. Kiterjesztett követési vizsgálat 9.4 év (közép érték 8.9) 437 nő bevonásával 4 A vakcina csoportban nem volt igazolt HPV 16/18 fertőzöttség, a placébó csoportban 4 esetben 6 hónapja fennállt a perzisztáló fertőzés, illetve 1 esetben már 12 hónapja*4 1. Harper D, et al. Lancet 2004; 364:1757–1765; 2. Harper D, et al. Lancet 2006; 367:1247–1255; 3. GlaxoSmithKline Vaccine HPV-007 Study Group. Lancet 2009; 374:1975–1985; 4. EMA. Cervarix®. European Summary of Product Characteristics 2012. CIN = Cervical Intraepithelial Neoplasia * The study was not powered to demonstrate a difference between the vaccine and the placebo group for this endpoint.

9 Long term efficacy data against HPV 16/18
TVC: Total Vaccinated Cohort 001/007/023TRIALS HPV 16/18-related CIN2+ Vaccine Control Vaccine efficacy n % (95% CI) Initial efficacy study 2.3 years1 3 NA* Combined analysis of initial efficacy study and extended follow-up 4.5 years2 5 100 (-7.7–100.0) 5.5 years3 7 100 (32.7–100.0) 6.4 years3 9 100 (51.3–100.0) In the subcohort, there were 223 women in the vaccine group and 213 women in the control group (at 8.4 years; Roteli-Martins et al. Hum Vaccin Immunother 2012; 8:1-8). At 9.4 years follow-up in the placebo group, there were 4 cases of 6-month persistent infection and 1 case of 12-month persistent infection. n = number of subjects reporting at least one event in each group. Extended follow-up to 9.4 years (mean 8.9) in a subcohort of 437 women4 No cases of infection or histopathological lesions associated with HPV 16 or HPV 18 in the vaccine group while in the placebo group, there were 4 cases of 6-month persistent infection and 1 case of 12-month persistent infection*4 1. Harper D, et al. Lancet 2004; 364:1757–1765; 2. Harper D, et al. Lancet 2006; 367:1247–1255; 3. GlaxoSmithKline Vaccine HPV-007 Study Group. Lancet 2009; 374:1975–1985; 4. EMA. Cervarix®. European Summary of Product Characteristics 2012. CIN = Cervical Intraepithelial Neoplasia * The study was not powered to demonstrate a difference between the vaccine and the placebo group for this endpoint.

10 Control (hepatitis A vaccine)
PATRICIA: Fázis III vizsgálatok, hatékonyság a 15 és 25 év közötti nők esetében Phase III efficacy trial* conducted in 14 countries from Europe, Asia-Pacific, North America, Latin America1 Randomization Cervarix End of study analysis3 Up to 48 months (mean follow-up 43.7 months) (TVC) Age 15–25 years N=18,644 Control (hepatitis A vaccine) Month 1 6 7 12 18 24 30 36 48 Visit 1 2 3 4 5 6 7 8 9 10 Largest efficacy trial for a licenced HPV vaccine Interim analysis2 Mean follow-up 14.8 months (TVC-E) Final analysis1 Mean follow-up 34.9 months (ATP-E cohort) * Trial 008 – NCT 1. Paavonen J, et al. Lancet 2009; 374: 301–314; 2. Paavonen J, et al. Lancet 2007; 369: 2161–70; 3. Lehtinen M, et al. Lancet Oncol 2012; 13:89–99.

11 PATRICIA: Phase III efficacy in women aged 15–25 years
Phase III efficacy trial* conducted in 14 countries from Europe, Asia-Pacific, North America, Latin America1 Randomization Cervarix End of study analysis3 Up to 48 months (mean follow-up 43.7 months) (TVC) Age 15–25 years N=18,644 Control (hepatitis A vaccine) Month 1 6 7 12 18 24 30 36 48 Visit 1 2 3 4 5 6 7 8 9 10 Largest efficacy trial for a licenced HPV vaccine Interim analysis2 Mean follow-up 14.8 months (TVC-E) Final analysis1 Mean follow-up 34.9 months (ATP-E cohort) * Trial 008 – NCT 1. Paavonen J, et al. Lancet 2009; 374: 301–314; 2. Paavonen J, et al. Lancet 2007; 369: 2161–70; 3. Lehtinen M, et al. Lancet Oncol 2012; 13:89–99.

12 PATRICIA: kohort vizsgálat
Total Vaccinated Cohort (TVC) N = 18,644 Received ≥ 1 dose Case counting ≥ 1 day post-Dose 1 Endpoints were evaluated irrespective of women’s baseline HPV DNA or serostatus TVC-naïve N = 11,641 (62% of TVC) Received ≥ 1 dose Case counting ≥ 1 day post-Dose 1 At Month 0: Negative cytology HPV DNA-negative for 14 HPV types* Seronegative for HPV 16 and 18 Approximates all young women: ≥ 1 dose Vaccine n = 5,822 Control n = 5,819 According-to-Protocol for efficacy (ATP-E) N = 16,162 (87% of TVC) Like the TVC but: Complied with protocol Received 3 doses TVC-naïve: approximates young women before sexual debut, the primary target population for organized vaccination programmes Approximates all young women: 3 doses Paavonen J, et al. Lancet 2009; 374:301–314. * 14 oncogenic HPV types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68.

13 PATRICIA: kohort vizsgálat
Total Vaccinated Cohort (TVC) N = 18,644 Received ≥ 1 dose Case counting ≥ 1 day post-Dose 1 Endpoints were evaluated irrespective of women’s baseline HPV DNA or serostatus TVC-naïve N = 11,641 (62% of TVC) Received ≥ 1 dose Case counting ≥ 1 day post-Dose 1 At Month 0: Negative cytology HPV DNA-negative for 14 HPV types* Seronegative for HPV 16 and 18 Approximates all young women: ≥ 1 dose Vaccine n = 5,822 Control n = 5,819 According-to-Protocol for efficacy (ATP-E) N = 16,162 (87% of TVC) Like the TVC but: Complied with protocol Received 3 doses TVC-naïve: a szervezett vakcinációs program első számú célcsoportja a nemi élet előtt álló nők voltak Approximates all young women: 3 doses Paavonen J, et al. Lancet 2009; 374:301–314. * 14 oncogenic HPV types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68.

14 CIN3 állapot, mint a méhnyak rákot kiváltó végpont
CIN2 egy elfogadott,végpont a méhnyak rák helyett1 lényegét tekintve ez egy heterogén mikroszkópikus diagnózis, a biológia jelentésére pedig ez még inkább igaz 5 Számos nem onkogén HPV törzs által okozott folyamat szintén CIN2 lézióként kerülhet diagnosztizálásra5 A CIN3 egy sokkal specifikusabb és szigorúbb végpont jobban elkülöníthető egy friss HPV fertőzéstől2 jobban reprodukálható diagnosztikus végpont, mint a CIN23,4 lényegesen gyakrabban alakul át méhnyak rákká4 1. Castle PE et al. Am J Epidemiol 2010; 171:155–63; 2. Moscicki A et al. Vaccine 2006; 24(Suppl 3):42-51; 3. Carreon JD et al. Int J Gynecol Pathol 2007; 26:441–446; 4. Lehtinen M et al. Lancet Oncol 2012; 13: Schiffman, Kjaer. JNCI Monographs 2003 ,No. 31;.

15 CIN3 as a surrogate endpoint for cervical cancer
CIN2 is considered an acceptable surrogate endpoint for cervical cancer1 There is substantial heterogeneity in the microscopic diagnosis and biologic meaning of CIN 2 lesions in particular.5 Some non-oncogenic HPV infections are capable of producing lesions diagnosed as CIN 2.5 CIN3 is a more specific and more stringent endpoint it can be reliably distinguished from a recently acquired HPV infection2 it is a more reproducible diagnostic endpoint than CIN23,4 it more frequently progresses to invasive cervical carcinoma4 1. Castle PE et al. Am J Epidemiol 2010; 171:155–63; 2. Moscicki A et al. Vaccine 2006; 24(Suppl 3):42-51; 3. Carreon JD et al. Int J Gynecol Pathol 2007; 26:441–446; 4. Lehtinen M et al. Lancet Oncol 2012; 13: Schiffman, Kjaer. JNCI Monographs 2003 ,No. 31;.

16 PATRICIA: hatékonysági eredmények a nagykockázatú HPV 16/18 ellen
End-of-study analysis1 TVC-naïve cohort végpont csoportok N n Vakcina hatékonysága, % (95% CI) CIN2+ Vaccine 5,466 1 99.0 (94.2–100.0) Control 5,452 97 CIN3+ 100.0 (85.5–100.0) 27 At 34.9 months, vaccine efficacy against HPV 16/18-associated CIN2+ was 92.9% (96.1% CI: 79.9–98.3) in the according-to-protocol cohort for efficacy (ATP-E) – primary endpoint2 1. Lehtinen M, et al. Lancet Oncol 2012; 13:89–99; 2. Paavonen J, et al. Lancet 2009; 374:301–314..

17 End-of-study analysis1
PATRICIA: Efficacy results against high grade lesions associated with HPV 16/18 End-of-study analysis1 TVC-naïve cohort Endpoint Group N n Vaccine efficacy, % (95% CI) CIN2+ Vaccine 5,466 1 99.0 (94.2–100.0) Control 5,452 97 CIN3+ 100.0 (85.5–100.0) 27 At 34.9 months, vaccine efficacy against HPV 16/18-associated CIN2+ was 92.9% (96.1% CI: 79.9–98.3) in the according-to-protocol cohort for efficacy (ATP-E) – primary endpoint2 1. Lehtinen M, et al. Lancet Oncol 2012; 13:89–99; 2. Paavonen J, et al. Lancet 2009; 374:301–314..

18 Invasive cervical cancer
Mit várhatunk egy vakcinától, ami csak a HPV 16/18-al szemben nyújt védelmet? HSIL/CIN2/3 Invasive cervical cancer 12% 8% 17% 7% 21% 37% 44% 54% HPV 16 HPV 18 HPV 31/45 egyéb ≈ 51% -át a CIN2,3 elváltozásnak a HPV 16/18 okozza ≈ 71%-át a méhnyakrák típusainak a HPV 16/18 okozza HSIL = high-grade squamous intraepithelial lesion. CIN = Cervical intraepithelial neoplasia. Adapted from: (accessed September 2012). CONFIDENTIAL

19 Invasive cervical cancer
What could we expect from a vaccine that protects only against HPV 16 and HPV 18? HSIL/CIN2/3 Invasive cervical cancer 12% 8% 17% 7% 21% 37% 44% 54% HPV 16 HPV 18 HPV 31/45 Other ≈ 51% of CIN2/3 lesions are caused by HPV 16 or HPV 18 ≈ 71% of cervical cancers are caused by HPV 16 or HPV 18 HSIL = high-grade squamous intraepithelial lesion. CIN = Cervical intraepithelial neoplasia. Adapted from: (accessed September 2012). CONFIDENTIAL

20 PATRICIA: a hatékonyság független a HPV törzs típusától
End-of-study analysis1 TVC-naïve cohort Endpoint Group N n Vaccine efficacy, % (95% CI) CIN2+ Vaccine 5,466 61 64.9 (52.7–74.2) Control 5,452 172 CIN3+ 3 93.2 (78.9–98.7) 44 A tapasztalt hatékonyság messze felülmúlja azt az értéket, ami elvárható volna egy csupán HPV 16/18 ellen védelmet biztosító vakcina esetében* *Based on a comparison with epidemiology data, which can vary in different regions2. 1. Lehtinen M, et al. Lancet Oncol 2012; 13:89–99; 2. WHO/ICO Information Centre on Human Papilloma Virus (HPV) and Cervical Cancer. Available at: (accessed September 2012).

21 End-of-study analysis1
PATRICIA: Efficacy against high-grade lesions irrespective of HPV type in the lesion End-of-study analysis1 TVC-naïve cohort Endpoint Group N n Vaccine efficacy, % (95% CI) CIN2+ Vaccine 5,466 61 64.9 (52.7–74.2) Control 5,452 172 CIN3+ 3 93.2 (78.9–98.7) 44 This efficacy was more than would be expected from a vaccine that is only efficacious against HPV 16/18* *Based on a comparison with epidemiology data, which can vary in different regions2. 1. Lehtinen M, et al. Lancet Oncol 2012; 13:89–99; 2. WHO/ICO Information Centre on Human Papilloma Virus (HPV) and Cervical Cancer. Available at: (accessed September 2012).

22 End-of-study analysis
Mit jelent az a 93 % ? PATRICIA: hatékonyság CIN3 lézióban, a vakcinában szereplő illetve nem szereplő törzsek esetében End-of-study analysis TVC-naïve cohort csak a HPV 16/18-al összefüggésben levő 93.2% csökkenés A HPV 16/18-al összefüggésbe hozható, illetve egyéb a vakcinában nem szereplő törzsekkel is összefüggésbe hozható Number of cases A vakcinában nem szereplő, illetve HPV- vel összefüggésbe nem hozható Lehtinen M, et al. Lancet Oncol 2012; 13:89–99;

23 End-of-study analysis
Mit jelent az a 93 % ? PATRICIA: Efficacy against CIN3+ lesions associated with vaccine and non-vaccine types End-of-study analysis TVC-naïve cohort Associated with HPV-16/18 only 93.2% reduction Associated with HPV-16/18 and co-infected with a non-vaccine type Number of cases Associated with non-vaccine type or no HPV detected Lehtinen M, et al. Lancet Oncol 2012; 13:89–99;

24 PATRICIA: A vizsgálat alatti CIN 3 léziók kummulatív incidenciája független volt a HPV törzs típusától End-of-study analysis TVC-naïve cohort HAV (Control) HPV (Vaccine) A vakcina átfogó hatékonysága: ·2% (78·9–98·7) Incidence (cumulative) idő(hónapok) Lehtinen M, et al. Lancet Oncol 2012; 13:89–99. * Throughout the 48-month follow-up period.

25 PATRICIA:. Cumulative incidence of CIN3+ lesions over. time
PATRICIA: Cumulative incidence of CIN3+ lesions over time*, irrespective of HPV type in the lesions End-of-study analysis TVC-naïve cohort HAV (Control) HPV (Vaccine) Overall vaccine efficacy: ·2% (78·9–98·7) Incidence (cumulative) Time (months) Lehtinen M, et al. Lancet Oncol 2012; 13:89–99. * Throughout the 48-month follow-up period.

26 PATRICIA: a citológiai eltérések csökkenése
TVC-naïve cohort End-of-study analysis Reduction (%) ASC-US ASC-US HR+ or greater ASC-US HR+ LSIL ASC-H HSIL Vaccine efficacy (%) 95% CI 19.7 11.0–27.5 27.3 20.7–33.3 29.0 19.1–37.7 –32.0 – 75.9 –78.1 Vaccine: number of cases (events) 679 (791) 907 (1428) 400 (465) 650 (926) 16 (16) 17 (17) Control: number of cases (events) 831 (1005) 1215 (1999) 554 (663) 847 (1248) 34 (34) 41 (42) ASC-US=atypical squamous cells of undetermined significance. ASC-US HR+=ASC-US which were positive for high-risk HPV DNA. ASC-US HR+ or greater=ASC-US HR+, LSIL, ASC-H, HSIL, and atypical glandular cells. LSIL=low-grade squamous intraepithelial lesions. ASC-H=atypical squamous cells, cannot exclude HSIL. HSIL=high-grade intraepithelial lesions. Lehtinen M, et al. Lancet Oncol 2012; 13:89–99.

27 PATRICIA: Reduction in cytological abnormalities
TVC-naïve cohort End-of-study analysis Reduction (%) ASC-US ASC-US HR+ or greater ASC-US HR+ LSIL ASC-H HSIL Vaccine efficacy (%) 95% CI 19.7 11.0–27.5 27.3 20.7–33.3 29.0 19.1–37.7 –32.0 – 75.9 –78.1 Vaccine: number of cases (events) 679 (791) 907 (1428) 400 (465) 650 (926) 16 (16) 17 (17) Control: number of cases (events) 831 (1005) 1215 (1999) 554 (663) 847 (1248) 34 (34) 41 (42) ASC-US=atypical squamous cells of undetermined significance. ASC-US HR+=ASC-US which were positive for high-risk HPV DNA. ASC-US HR+ or greater=ASC-US HR+, LSIL, ASC-H, HSIL, and atypical glandular cells. LSIL=low-grade squamous intraepithelial lesions. ASC-H=atypical squamous cells, cannot exclude HSIL. HSIL=high-grade intraepithelial lesions. Lehtinen M, et al. Lancet Oncol 2012; 13:89–99.

28 End-of-study analysis
PATRICIA: a kolposzkópos beavatkozások és méhnyakon történő kimetszések számának csökkenése End-of-study analysis TVC-naïve cohort Group N n Efficacy, % (95% CI) kolposzkópos beavatkozások Vaccine 5,466 672 29.0 (21.6–35.8) Control 5,452 933 méhnyakon történő kimetszések 43 70.2 (57.8–79.3) 143 Severe preterm delivery <32/34 weeks Extreme low birth weight (<1000g) A konizációt követően magasabb a koraszülések kockázata.2 Konizáció után:csökken az átlagos kihordási idő,gyakrabban fordul elő idő előtti burokrepedés,koraszülésre jellemző laborértékek, neonatalis kórházi kezelés, A CIN miatti beavatkozások( diatermia,krioterápia) utáni terhességek esetében igaz: emelkedik a perinatalis mortalitás, koraszülések száma, alacsony születési súly, 1. Lehtinen M, et al. Lancet Oncol 2012; 13:89–99., 2 Bruinsma FJ, Quinn MA. BJOG Aug;118(9): Van Hentenryck M et al Eur J Obstet Gynecol Reprod Biol May;162(1):16-20, 4 Arbyn et al BMJ 2008;337:a1284.

29 End-of-study analysis
PATRICIA: Reduction in colposcopy referrals and cervical excision procedures End-of-study analysis TVC-naïve cohort Group N n Efficacy, % (95% CI) Colposcopy referrals Vaccine 5,466 672 29.0 (21.6–35.8) Control 5,452 933 Cervical excision procedures 43 70.2 (57.8–79.3) 143 Severe preterm delivery <32/34 weeks Extreme low birth weight (<1000g) Women treated using excisional treatments are at a higher risk of preterm birth.2 Women post-conization: significant reduction in mean gestational age at delivery, higher rate of premature rupture of the membrane, premature onset of labor, premature delivery and neonatal hospitalization including ICU admission3 Women who become pregnant after treatment for CIN with cold knife conisation and radical diathermy have an increased risk of perinatal mortality, severe preterm delivery, and extreme low birthweight infants4 1. Lehtinen M, et al. Lancet Oncol 2012; 13:89–99., 2 Bruinsma FJ, Quinn MA. BJOG Aug;118(9): Van Hentenryck M et al Eur J Obstet Gynecol Reprod Biol May;162(1):16-20, 4 Arbyn et al BMJ 2008;337:a1284.

30 Cervarix™: biztonságossági profil
A vizsgálatok 30 ezer, éves nő bevonásával történtek A vakcinával kapcsolatba hozható mellékhatások többsége enyhe és középes fokú volt, és átmeneti jellegű A leggyakoribb az oltás helyén fellépő reakció, fejfájás, izomfájdalom volt A Cervarix esetében a terhességben történő alkalmazásra vonatkozó adatok nem elégségesek, ezért a készítményt nem javasolt terhesség alatt alkalmazni A GSK folyamatosan monitorozza az oltás után fellépő oltási reakciókat, mellékhatásokat MHRA = Medicines and Healthcare products Regulatory Agency EMA. Cervarix®. European Summary of Product Characteristics, 2012.

31 Cervarix™: Safety profile
Safety was monitored in clinical studies enrolling ≈ 30,000 subjects aged 10–72 years who had received Cervarix™ or control The majority of vaccine-related adverse reactions were of mild to moderate severity and were not long lasting The most common were injection site reactions, headache and myalgia Data on Cervarix™ administered during pregnancy are insufficient to recommend use of the vaccine during pregnancy A GSK folyamatosan monitorozza az oltás után fellépő oltási reakciókat, mellékhatásokat MHRA = Medicines and Healthcare products Regulatory Agency EMA. Cervarix®. European Summary of Product Characteristics, 2012.

32 Cervarix® vakcina átfogó vizsgálatok: biztonságossági analízis
11 vizsgálat, azonos oltási sémával, hasonló módon értékelve 25 21.4 AS04-adjuvanted bivalent HPV vaccine (N = 16,142) 19.4 20 Control (N = 13,811) 15 mellékhatást jelentő nők , % of population 10 Rates of solicited local and general symptoms were higher in the Cervarix™ group than in the control group. However, this did not affect compliance with the three-dose schedule, which was high in all age groups and did not differ between groups (93.4% for Cervarix™ versus 92.5% for pooled controls). No clinically relevant differences were seen between Cervarix™ and pooled control groups in rates of SAE (2.8% versus 3.1%), MSC (19.4% versus 21.4%), NOCD (1.7% in both groups) or NOAD (0.4% versus 0.3%). Similarly, no differences in rates of withdrawals due to adverse events or SAE were observed between groups. Reference Descamps D et al. Human Vaccines 2009; 5:1–9. July 2010 5 2.8 3.1 1.7 1.7 0.4 0.3 Medically új tünet új tünet significant jelentett > 1 SAE Krónikus betegség autoimmun condition betegség Descamps D, et al. Hum Vaccin 2009; 5:1–9. SAE = severe adverse event.

33 Cervarix® vaccine pooled studies: safety analysis
Eleven studies with the same vaccination schedule and similar methodology of safety assessment 25 21.4 AS04-adjuvanted bivalent HPV vaccine (N = 16,142) 19.4 20 Control (N = 13,811) 15 Women reporting events, % of population 10 Rates of solicited local and general symptoms were higher in the Cervarix™ group than in the control group. However, this did not affect compliance with the three-dose schedule, which was high in all age groups and did not differ between groups (93.4% for Cervarix™ versus 92.5% for pooled controls). No clinically relevant differences were seen between Cervarix™ and pooled control groups in rates of SAE (2.8% versus 3.1%), MSC (19.4% versus 21.4%), NOCD (1.7% in both groups) or NOAD (0.4% versus 0.3%). Similarly, no differences in rates of withdrawals due to adverse events or SAE were observed between groups. Reference Descamps D et al. Human Vaccines 2009; 5:1–9. July 2010 5 2.8 3.1 1.7 1.7 0.4 0.3 Medically Women New-onset New-onset significant reporting > 1 SAE chronic disease autoimmune condition disease Descamps D, et al. Hum Vaccin 2009; 5:1–9. SAE = severe adverse event.

34 Label update based on the VIVIANE trial
VIVIAN Interim Efficacy Analysis (M48) women >25years: The section 5.1 Pharmacodynamic properties of the SmPC has been updated efficacy data in women aged 26 years and above 6-month persistent infection data Immunogenicity data EU Commission Decision issued on September 17, 2012 CONFIDENTIAL

35 Label update based on the VIVIANE trial
VIVIAN Interim Efficacy Analysis (M48) women >25years: The section 5.1 Pharmacodynamic properties of the SmPC has been updated efficacy data in women aged 26 years and above 6-month persistent infection data Immunogenicity data EU Commission Decision issued on September 17, 2012 CONFIDENTIAL

36 Legutóbbi módosítás 2013. március 27
Indikáció (4.1) : A Cervarix vakcina 9 éves kortól adva egyes onkogén Humán papillomavírus (HPV) típusok által okozott perzisztáló fertőzés, premalignus genitalis (cervicalis, vulvaris és vaginalis) léziók és a cervix carcinoma prevenciójára szolgál. A javallatot alátámasztó adatokkal kapcsolatos fontos információkért lásd a 4.4 és az 5.1. pontot. Egyéb változások : Becslések szerint a HPV-16 és a HPV-18 felelős a méhnyakrák kb. 70%-áért és a HPV-vel összefüggő nagyfokú vulvaris és vaginalis intraepithelialis neoplasiák 70%-áért. Egyéb onkogén HPV típusok szintén okozhatnak méhnyakrákot (kb. 30% arányban). A HPV-45, -31 és -33 a három leggyakoribb, vakcina által le nem fedett típus, amelyeket a laphám eredetű méhnyakrákokban (12,1%) és az adenocarcinomákban (8,5) kimutattak. A 4.1 pontban szereplő „premalignus genitalis laesiók” kifejezés a nagyfokú Cervicalis Intraepithelialis Neoplasiának (CIN2/3), a nagyfokú vulvaris intraepitheliális neoplasiának (VIN2/3) és a nagyfokú vaginalis intraepithelialis neoplasiának (VaIN2/3) felel meg.  A vizsgálati elemzés végén az ATP-kohortban a vakcina-csoportban 2 HPV-16-tal vagy HPV-18-al összefüggő VIN2+ vagy VaIN2 esetet, míg a kontroll-csoportban 7 esetet figyeltek meg. A vizsgálat nem rendelkezett olyan statisztikai erővel, hogy ezekben a végpontokban bizonyítsa a különbséget a vakcina- és a kontoll-csoport között

37 Következtetések Fázis II, III, vizsgálatok az elmúlt tíz évben: Folyamatosan magas HPV 16/18 elleni ellenanyagszintek, (9,4 év, medián 8,9 év) Magas hatékonyság a HPV 16/18 törzsekkel szemben CIN2+/CIN3+ lézióban 99% and 100% HPV 16/18 ellen CIN2+ and CIN3+,esetén (TVC-naïve) A vakcina 93.2%-os hatékonysága CIN3+ esetén független a HPV törzs típusától (TVC-naïve cohort) Cervarix™ általánosságban jól tolerálható, megfelelő klinikai biztonságossági profillal rendelkezik * In an analysis of CIN3+ lesions, conducted irrespective of HPV type, Cervarix™ showed 93% efficacy (95% CI: 78.9–98.7)

38 Conclusions In Phase II and III studies conducted over a period of approximately 10 years, Cervarix™ has demonstrated: Consistently high HPV 16/18 antibody levels up to 9.4 years (median 8.9 years) Sustained high efficacy against HPV 16/18 related CIN2+/CIN3+ lesions 99% and 100% against HPV 16/18 CIN2+ and CIN3+, (TVC-naïve 93.2% vaccine efficacy against CIN3+ in the TVC-naïve cohort, irrespective of HPV type* Cervarix™ is generally well tolerated with a clinically acceptable safety profile * In an analysis of CIN3+ lesions, conducted irrespective of HPV type, Cervarix™ showed 93% efficacy (95% CI: 78.9–98.7)

39 Első hatékonysági adatok Angliából, Skóciából
3 éves tender ( ) Magas átoltottság elérése 80% a 12/13 éves lányok esetében >50% felzárkóztatóan 17 éves korig HPV vakcina és daganat regiszter + figyelőszolgálat kezdeményezése: HPA (England) and HPS (Scotland) szervezett méhnyak rák szűrés indul: 25 éves kortól, Anglia 20 éves kortól, Skócia

40 First Cervarix effectiveness data from UK England and Scotland
Three-year tender ( ) High coverage achieved 80% for 12/13 year-old girls >50% for catch-up to age 17 HPV vaccine and cancer registries + surveillance initiated by HPA (England) and HPS (Scotland) Organized cervical cancer screening starting at age 25 in England at age 20 in Scotland

41 Csökkenő HPV fertőzés a fiatal nők körében a HPV immunizációt követően Angliában
célok: monitorozni a HPV elleni immunizáció korai hatásait fiatal, szexuálisan aktív nők esetében (HPV törzsek alakulása) eredmények: In 2008, the prevalence was 19.1% in year olds, and lower at older ages. következtetések:ez a nyílvánvaló csökkenése a HPV 16/18 fertőzéseknek nagyjából megfelel az elvárásoknak ami a HPV átoltottságnak (catch-up cohorts) , és a vakcina hatékonyságának tulajdonítható a méhnyakrákkal szemben. életkor (év) HPV 16/18 Prevalencia Becsült átoltottság P value for trend 16-18 9.3% 56% 0.002 19-21 12.5% 19% 22-24 17.4% 0% Mesher et al. Abstract presented at IPVC 2012

42 Reduction in HPV infection in young women following introduction of HPV immunisation in England
Objectives: To monitor the early impact of the HPV immunisation programme on type-specific HPV infections in sexually active young women in England Results: In 2008, the prevalence was 19.1% in year olds, and lower at older ages. Conclusions: This apparent reduction in HPV16/18 infection is broadly consistent with expectations based on HPV immunisation coverage (for catch-up cohorts) and vaccine efficacy against cervical infection. Age (yrs) HPV 16/18 Prevalence Estimated Coverage P value for trend 16-18 9.3% 56% 0.002 19-21 12.5% 19% 22-24 17.4% 0% Mesher et al. Abstract presented at IPVC 2012

43 a bemutatott és biztosított magas lefedettség a kétkomponensű HPV vakcina által, a HPV 16/18 és a hozzá közeli törzsek prevalenciáját csökkentette Skóciában A program első három évében Skóciában, a 3 adag oltóanyagot a éves lányok több, mint 90%-a megkapta Az iskolát éppen elhagyók között kevesebben lettek beoltva (30-50% részesült oltásban), ez kedvezőbb, mint Angliában ennek a korcsoportnak az oltottsága Az előzetes analízisek alapján elmondható, hogy a vakcina csökkentette a HPV 16/18 törzsek prevalenciáját, és kereszt védelmet biztosít más magaskockázatú törzsekkel szemben is (31,33, 45) Cuschieri et al. Abstract presented at IPVC 2012 CONFIDENTIAL

44 Introduction and sustained high coverage of the HPV bivalent vaccine in Scotland leads to a reduction in prevalence of HPV 16/18 and closely related types For the first three years of the programme in Scotland, routine HPV vaccine uptake of all 3 doses has been sustained at the high levels (>90%) in the age group. Among school leavers where there was lower uptake (between %), coverage still compares favourably with previous vaccines targeted at this age group in the UK. Az előzetes analízisek alapján elmondható, hogy a vakcina csökkentette a HPV 16/18 törzsek prevalenciáját, és kereszt védelmet biztosít más magaskockázatú törzsekkel szemben is (31,33, 45) Cuschieri et al. Abstract presented at IPVC 2012 CONFIDENTIAL

45 Következtetések: These reports provide evidence of the early impact on HPV 16/18 infection as well as HPV 31, 33, 45, with high coverage, following implementation of Cervarix Results are reassuring and seem to be consistent with vaccine efficacy seen in clinical trials Further analyses on abnormal Pap and CIN expected in the coming years CONFIDENTIAL

46 Következtetések: ez a riport még egyértelműbbé teszi a Cervarix vakcina alkalmazása kapcsán a HPV 16/18 illetve a 31, 33, 45 törzsek esetében a korai hatást. Az eredmények megnyugtatóak, és egybevágnak azzal, amit a hatékonyságról a klinikai vizsgálatok mutatnak További analízisek várhatóak a jövőben (Pap, CIN elemzés) CONFIDENTIAL

47 Milyen szempontokat mérlegelünk méhnyakrák elleni vakcináció esetén?
Minél több méhnyakrákot előzzön meg (hatékonyság) Védjen hosszú távon Csökkentse a méhnyakon végzett kisműtétek számát Legyen biztonságos

48 Átoltottsági tapasztalatok
Highest coverage typically achieved through school-based programmes The majority of national immunization programmes are not achieving high enough coverage levels to significantly reduce the burden of disease European Centre for Disease Prevention and Control. Introduction of HPV vaccines in EU countries – an update. Stockholm: ECDC; 2012; CDC. MMWR 2012, 61:671–677; Fagot JP, et al. Vaccine 2012; 29:3610–3616; Statens Serum Institut Available at: (accessed April 2013); Istituto Superiore di Sanità (ISS) Available at: (accessed April 2013). New Zealand Ministry of Health Available at: (accessed April 2013); Norwegian Institute for Public Health. Vaccination statistics for Available at: (accessed April 2013); Department of Health and Ageing Available at: (accessed April 2013); Department of Health. Annual HPV vaccine coverage in England in 2010/ Available at: (accessed April 2013); Smittskyddsinstitutet Available at: (accessed April 2013); NCCID. Purple Paper: HPV vaccination: understanding the impact on HPV disease Available at: (accessed April 2013); BCCDC. Grade 6 Students with Up-to-date Immunizations, British Columbia Available at: (accessed April 2013); CDC. MMWR 2011, 60:1382–1384. 1. European Centre for Disease Prevention and Control. Introduction of HPV vaccines in EU countries – an update. Stockholm: ECDC; 2012; 2. CDC. MMWR 2012, 61:671–677; 3. Fagot JP, et al. Vaccine 2012; 29:3610–3616; 4. Statens Serum Insitut 2010; 5. Istituto Superiore di Sanità (ISS). 2012; New Zealand Ministry of Health 2012; 7. Norwegian Institute for Public Health 2013; 8. Department of Health and Ageing 2013; 9. Department of Health 2012; 10. Smittskyddsinstitutet 2013; 11. NCCID. 2011; 12. BCCDC. 2012; 13. CDC. MMWR 2011, 60:1382–1384.

49 Átoltottsági tapasztalatok
A legnagyobb lefedettséget az iskolai programok biztosítják A NIP-ok többsége nem biztosít olyan fokú lefedettséget, hogy az a betegség okozta gazdasági terheket jelentősen mérsékelné. European Centre for Disease Prevention and Control. Introduction of HPV vaccines in EU countries – an update. Stockholm: ECDC; 2012; CDC. MMWR 2012, 61:671–677; Fagot JP, et al. Vaccine 2012; 29:3610–3616; Statens Serum Institut Available at: (accessed April 2013); Istituto Superiore di Sanità (ISS) Available at: (accessed April 2013). New Zealand Ministry of Health Available at: (accessed April 2013); Norwegian Institute for Public Health. Vaccination statistics for Available at: (accessed April 2013); Department of Health and Ageing Available at: (accessed April 2013); Department of Health. Annual HPV vaccine coverage in England in 2010/ Available at: (accessed April 2013); Smittskyddsinstitutet Available at: (accessed April 2013); NCCID. Purple Paper: HPV vaccination: understanding the impact on HPV disease Available at: (accessed April 2013); BCCDC. Grade 6 Students with Up-to-date Immunizations, British Columbia Available at: (accessed April 2013); CDC. MMWR 2011, 60:1382–1384. 1. European Centre for Disease Prevention and Control. Introduction of HPV vaccines in EU countries – an update. Stockholm: ECDC; 2012; 2. CDC. MMWR 2012, 61:671–677; 3. Fagot JP, et al. Vaccine 2012; 29:3610–3616; 4. Statens Serum Insitut 2010; 5. Istituto Superiore di Sanità (ISS). 2012; New Zealand Ministry of Health 2012; 7. Norwegian Institute for Public Health 2013; 8. Department of Health and Ageing 2013; 9. Department of Health 2012; 10. Smittskyddsinstitutet 2013; 11. NCCID. 2011; 12. BCCDC. 2012; 13. CDC. MMWR 2011, 60:1382–1384.

50 Átoltottság – Magyarország 2012. december
12-28 év: 11,4% 12-18 év: 26,1% 19-28 év: 4,9% eddig összesen oltott a két vakcinával teljes oltási sort kapott kislány, hölgy :

51 Cervarix in vaccination programs
Cervarix is currently used in national immunisation programmes in: Netherlands, Peru, Panama, Argentina, Iceland, Izrael, Mexico and regional programmes in Italy, Spain, Monaco, Belgium and Bermuda amongst others 100%-ban támogatott Németország, Franciaország, Románia, Bulgária, Csehország Cervarix has been selected as vaccine for British Columbia's new cervical cancer prevention program for young women 51

52 A Cervarix az oltási programban
Cervarixot a következő államokban alkalmazzák a NIP kapcsán: Hollandia, Peru, Panama, Argentina, Izland, Izrael, Mexikó, Olaszország egyes régióiban,Spanyolország, Monaco, Belgium, Bermuda 100%-ban támogatott: Németország, Franciaország, Románia, Bulgária, Csehország A Cervarixra esett a választás a British Columbiában induló új méhnyak rák megelőzési programban, melynek célcsoportja a fiatal lányok 52

53 Nemzeti immunizációs Programok: Európa és Észak- Amerika
Age 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Gross national income (US$)9 Macedonia Free vaccination is available to all females 9–26 years old from approved government and private gynaecology clinics 4,130 Liechtenstein Vaccination of females 9–26 years old is reimbursed by the obligatory scheme of health insurers 97,990 USA 47,930 Greece 28,400 Canada1,2 43,640  France 42,000 Switzerland1 55,510  Belgium1,4 44,570  UK 46,040 Luxembourg 69,390  Germany1 42,710  Sweden5 50,910 Norway 87,340  Netherlands1 49,340 Denmark1 58,800 Spain3,6 1–2 cohorts of girls 11–15y 31,930 Romania 8,280 Italy6 5 out of 21 regions: 15y (1 region); 16 y (3 regions); 18+25y (1 region) 35,460 Ireland7 49,770 Portugal 20,680 Slovenia 24,230 Latvia8 11,860 1Older women on individual basis; 2Quebec: vaccination 10–13y in school and 14–17y through HCP, no province funding above 18y; 3Regional administration; 4Recommendation for one primary cohort between 10–13y in reality is administered at 12y with catch-up increased to 18y; 5Vaccination 12y in school and 13–18y on-demand through HCP, funding of 13–18y by National Pharmaceutical Products Insurance Programme; 6Some regions have included additional catch-up; 7Recommendations for vaccination of females 9–26y; 8Vaccination starts September 2010; 9Gross national income per capita, 2008, Atlas method (http://siteresources.worldbank.org/DATASTATISTICS/Resources/GNIPC.pdf) Main age Catch-up Bonanni P, et al. Human Vaccines 2011; 7: 128–135

54 National immunisation programmes: Europe & North America
Age 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Gross national income (US$)9 Macedonia Free vaccination is available to all females 9–26 years old from approved government and private gynaecology clinics 4,130 Liechtenstein Vaccination of females 9–26 years old is reimbursed by the obligatory scheme of health insurers 97,990 USA 47,930 Greece 28,400 Canada1,2 43,640  France 42,000 Switzerland1 55,510  Belgium1,4 44,570  UK 46,040 Luxembourg 69,390  Germany1 42,710  Sweden5 50,910 Norway 87,340  Netherlands1 49,340 Denmark1 58,800 Spain3,6 1–2 cohorts of girls 11–15y 31,930 Romania 8,280 Italy6 5 out of 21 regions: 15y (1 region); 16 y (3 regions); 18+25y (1 region) 35,460 Ireland7 49,770 Portugal 20,680 Slovenia 24,230 Latvia8 11,860 1Older women on individual basis; 2Quebec: vaccination 10–13y in school and 14–17y through HCP, no province funding above 18y; 3Regional administration; 4Recommendation for one primary cohort between 10–13y in reality is administered at 12y with catch-up increased to 18y; 5Vaccination 12y in school and 13–18y on-demand through HCP, funding of 13–18y by National Pharmaceutical Products Insurance Programme; 6Some regions have included additional catch-up; 7Recommendations for vaccination of females 9–26y; 8Vaccination starts September 2010; 9Gross national income per capita, 2008, Atlas method (http://siteresources.worldbank.org/DATASTATISTICS/Resources/GNIPC.pdf) Main age Catch-up Bonanni P, et al. Human Vaccines 2011; 7: 128–135

55

56 End-of-study analysis TVC-naïve cohort; CIN2+
PATRICIA: Efficacy against CIN2+ lesions associated with vaccine and non-vaccine types End-of-study analysis TVC-naïve cohort; CIN2+ 64.9% reduction (95% CI: 52.7 to 74.2) Number of cases 1 (1.6%) Associated with HPV-16/18 only Associated with HPV-16/18 and co-infected with a non-vaccine type Associated with non-vaccine type or no HPV detected 1. Lehtinen M, et al. Lancet Oncol 2012; 13:89–99.

57 Vaccine efficacy against CIN2+ and CIN3+ associated with 12 non-vaccine HPV types* (TVC-naïve)
Wheeler CM, et al. Lancet Oncol 2011; in press.

58 End-of-study analysis
PATRICIA: Efficacy results against CIN2+ lesions associated with non-vaccine oncogenic HPV types* TVC-naïve cohort; CIN2+ Vaccine Control Efficacy, % (95% CI) N Cases A9 species HPV 31 5,466 3 5,452 28 89.4 (65.5–97.9) HPV 33 5 82.3 (53.4–94.7) HPV 35 1 6 83.4 (-36.6–99.6) HPV 52 14 20 30.4 (-45.0–67.5) HPV 58 9 36.1 (-58.6–75.6) A7 species HPV 39 11 72.9 (-2.7–95.1) HPV 45 8 100 (41.7–100) HPV 59 2 100 (-429.6–100) HPV 68 54.8 (-41.2–87.7) Other HPV 51 30 70.2 (35.6–87.6) HPV 56 7 100 (31.0–100) HPV 66 End-of-study analysis The PATRICIA study was not designed to study efficacy against individual non-vaccine oncogenic HPV types. Vaccine efficacies with lower limit of CI > 0. * With or without co-infection with HPV 16/18. Wheeler CM, et al. Lancet Oncol 2012; 13:100–110.

59 Cervical cancers cases reduction from Cervarix overall efficacy
Cancer cases: IARC/Globocan HPV distribution: WHO/ICO (http://www.who.int/hpvcentre) – weighted distribution (sum all HPV = 100%), Eastern Europe data; Vaccine efficacy overall: Lehtinen Lancet Oncology 2012; Vaccine efficacy against HPV-16/18: Harper, D. M. et al. Lancet 2004;364(9447) - Paavonen, J. et al. The Lancet 2009;374 (9686)

60 Cervical Cancer deaths reduction from Cervarix overall efficacy
Cancer deaths: IARC/Globocan HPV distribution: WHO/ICO (http://www.who.int/hpvcentre) – weighted distribution (sum all HPV = 100%), Eastern Europe data; Vaccine efficacy overall: Lehtinen Lancet Oncology 2012; Vaccine efficacy against HPV-16/18: Harper, D. M. et al. Lancet 2004;364(9447) - Paavonen, J. et al. The Lancet 2009;374 (9686)


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