1 Infección Enfermedades Asociadas PrevenciónVirus del Papiloma Humano Infección Enfermedades Asociadas Cáncer del Cuello Uterino Prevención CENTRO MEDICO IMBANACO Fundación Julio C. Reina Agosto 24, 2013

2 Virus del Papiloma HumanoConflicto de intereses: Participación como investigador principal en estudios clínicos de las vacunas tetravalente y nonavalente del Laboratorio M.S.D. U Libre Agosto 24, 2013

3 VIRUS DEL PAPILOMA HUMANO (VPH)Qué tan frecuente Como se adquiere Enfermedades asociadas Como se previene A quien vacunar: cuando

4 Qué tan frecuente es el VPH ?El VPH es una infección anogenital y orofaringea frecuente. Se estima que por lo menos el 50% de la población sexualmente activa adquiere el virus durante la vida. Se adquiere principalmente por contacto sexual. La mayoría de las infecciones son transitorias y no causan ningún problema de salud. ~10%-15%: crónicas, pueden progresar a pre-cáncer y cáncer. Centers for Disease Control and Prevention. Rockville, Md. 2004

5 Incidencia Anual de Enfermedades de Transmisión Sexual USA 15 a 24 años5000 4500 4000 3500 3000 2500 2000 1500 1000 500 4600 1900 Numero de infecciones (Miles) 1500 640 431 15 20 10 8.2 7.5 VPH VIH Sifilis Chlamydia Gonorrea Hepatitis B Trichomoniasis Herpes Genital Frazer IH y col. Pediatr Infect Dis J 2006;25:S61-S83

6 Prevalencia de VPH-DNA en Mujeres con Citología Normal30 Norteamerica Europa 25 Centro y Sur America Centro y Sur America 20 Prevalencia de VPH (%) 15 Europa 10 Norteamerica 5 < 25 25-34 35-44 45-54 > 54 Grupo de Edad SOURCE de Sanjosé S, et al. Lancet Infect Dis. 2007;7: :

7 Inicio de Actividad Sexual y Riesgo de Infección por VPHMujeres Adolescentes con solo un Compañero sexual1 Mujeres Estudiantes Universitarias2 10 40 50 70 60 30 20 70 N=242 60 N=603 40 Riesgo de Infección por VPH (%) Riesgo de Infección por VPH (%) 20 Key Point HPV infection can be quickly acquired after sexual debut. Background This slide illustrates the cumulative risk of HPV infection in a study in the United Kingdom of 242 adolescents 15–19 years of age (mean age, 17 years) by time since first intercourse.1 Female adolescents were recruited within 6 months of first sexual intercourse and had had only 1 sexual partner. In this study, the risk of acquiring cervical HPV was 46% at 3 years after first intercourse, and the median time from first intercourse to the first detection of HPV was only 3 months.1 Winer and colleagues evaluated US female university students (N=603; 18–20 years of age) at 4-month intervals between 1990 and At each visit, medical and sexual history information was collected and updated (including number of new sex partners). In addition, cervical and vulvovaginal samples were taken for HPV DNA analysis. Of the 553 enrolled women for whom there were adequate samples at enrollment and follow-up, 444 women were HPV DNA-negative at enrollment; 148 women were virgins. Ninety-four of the enrolled virgins became sexually active during the study. At 24 months, the cumulative incidence of HPV infection in women who initiated sexual activity during the study was 38.9% (95% CI, 29.4%–50.3%). The cumulative 24-month incidence of HPV in women who were sexually active at enrollment was 38.8% (95% CI, 33.3%–45.0%). Predictors of an increased risk of infection included intercourse with a new partner 5–8 months before a visit, having a partner known for <8 months before sex occurred (especially one who has had multiple sex partners), smoking, and oral contraceptive use.2 Although the majority of episodes of a type-specific infection may clear within 2 years, many young women either become reinfected with a new HPV type or presumably experience reactivation of their initial infection.3 References 1. Collins S, Mazloomzadeh S, Winter H, et al. High incidence of cervical human papillomavirus infection in women during their first sexual relationship. BJOG. 2002;109:96–98. 2. Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: Incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218–226. 3. Richardson H, Kelsall G, Tellier P, et al. The natural history of type-specific human papillomavirus infections in female university students. Cancer Epidemiol Biomarkers Prev. 2003;12:485–490. 36 45 60 24 12 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Meses después de la primera relación sexual Meses después de la primera relación sexual Adaptado de Collins et al.1 Adaptado de Winer et al.2 1. Collins S, Mazloomzadeh S, Winter H, et al. BJOG. 2002;109:96– Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: Incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218–226. Adapted by permission of Oxford University Press.

8 VPH: Mecanismos de Transmisión e InfecciónContacto Sexual Relaciones sexuales1 Genital–genital, manual–genital, oral–genital2–4 La infección genital por VPH en virgenes es rara, pero puede resultar del contacto sexual sin penetración.2 El uso adecuado del condón aunque puede reducir el riesgo, no protege 100% de la infección.5 Rutas No Sexuales Madre a Recién Nacido (transmisión vertical)6 Fomitas (ej, ropa interior, guantes, forceps)7,8 Hipotético, no bien documentado. Raro. La mayoría de los infectados desconocen que están infectados y sin saberlo diseminan el virus.9 Key Point Because HPV infection is common and usually asymptomatic, most transmission may occur unknowingly. HPV infection is usually transmitted by sexual contact, commonly through sexual intercourse, although transmission can occur through nonpenetrative genital contact. Background The greatest behavioral risk for the acquisition of HPV infection is sexual contact, specifically the rate of new partners per month.1,2 Sexual intercourse is important in the transmission of HPV.2 Other types of genital contact (genital–genital, manual–genital, oral–genital), which may begin at an earlier age than penetrative intercourse, may also lead to HPV infection.1,3,4 A recent US study of 603 college-aged (19 years of age, average age at enrollment) women reported a 2-year genital HPV incidence rate of 39% among sexually active women and 8% among virginal women.1 Genital HPV infection in virgins is rare, but may result from nonpenetrative sexual contact.1 Proper condom use may help reduce the risk of genital warts, CIN 2 or CIN 3, and invasive cervical cancer, but is not fully protective against infection.5 Other nonsexual routes of HPV infection include vertical transmission (from a mother to a newborn baby), although this is rare.6 A potential consequence of vertical transmission of HPV is recurrent respiratory papillomatosis (RRP), epithelial growths in the respiratory tract. In the larynx, growths may cause hoarseness and airway obstruction, which is potentially fatal. This condition presents most often in children younger than 5 years of age; but it can also occur in adults.7 Transmission of HPV infection may occur via contact with fomites, such as undergarments, surgical gloves, and biopsy forceps. This route of transmission has been hypothesized but is not well documented and would be rare.8,9 Although it is clear that sexual contact is the major mode of HPV transmission, most individuals infected by HPV do not know they have the disease.10 Therefore, they may unknowingly spread the virus. References 1. Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Genital human papillomavirus infection: Incidence and risk factors in a cohort of female university students. Am J Epidemiol. 2003;157:218–226. 2. Kjaer SK, Chackerian B, van den Brule AJ, et al. High-risk human papillomavirus is sexually transmitted: Evidence from a follow-up study of virgins starting sexual activity (intercourse). Cancer Epidemiol Biomarkers Prev. 2001;10:101–106. 3. Fairley CK, Gay NJ, Forbes A, Abramson M, Garland SM. Hand–genital transmission of genital warts? An analysis of prevalence data. Epidemiol Infect. 1995;115:169–176. 4. Herrero R, Castellsagué X, Pawlita M, et al. Human papillomavirus and oral cancer: The International Agency for Research on Cancer multicenter study. J Natl Cancer Inst. 2003;95:1772–1783. 5. Manhart LE, Koutsky LA. Do condoms prevent genital HPV infection, external genital warts, or cervical neoplasia? A meta-analysis. Sex Transm Dis. 2002;29:725−735. 6. Smith EM, Ritchie JM, Yankowitz J, et al. Human papillomavirus prevalence and types in newborns and parents: Concordance and modes of transmission. Sex Transm Dis. 2004;31:57–62. 7. Kashima HK, Mounts P, Shah K. Recurrent respiratory papillomatosis. Obstet Gynecol Clin North Am. 1996;23:699–706. 8. Ferenczy A, Bergeron C, Richart RM. Human papillomavirus DNA in fomites on objects used for the management of patients with genital human papillomavirus infections. Obstet Gynecol. 1989;74:950–954. 9. Roden RB, Lowy DR, Schiller JT. Papillomavirus is resistant to desiccation. J Infect Dis. 1997;176:1076–1079. 10. Anhang R, Goodman A, Goldie SJ. HPV communication: Review of existing research and recommendations for patient education. CA Cancer J Clin. 2004;54:248–259. 1. Kjaer SK, Chackerian B, van den Brule AJ, et al. Cancer Epidemiol Biomarkers Prev. 2001;10:101– Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Am J Epidemiol. 2003;157:218– Fairley CK, Gay NJ, Forbes A, Abramson M, Garland SM. Epidemi ol Infect. 1995;115:169– Herrero R, Castellsagué X, Pawlita M, et al. J Natl Cancer Inst. 2003;95:1772–

9 VPH y Cancer Cervical Prevalencia de AND-VPH en más de biopsias de Cáncer Cervical de 22 paises: 99.7% El VPH es una causa necesaria para el Cancer Cervical Invasivo Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Muñoz Nubia. J Pathol. 1999; 89: 12-19

10 Co-factores en la Etiologá del Cáncer CervicalAlta Paridad C. Trachomatis Anticonceptivos VPH VHS-2 ESE Bajo Fumar VIH Dieta CANCER CERVICAL

11 Cáncer Relacionado con VPHCáncer cervical 100 % Cáncer de vagina 91–94 % Cáncer del ano 88–94 % Cáncer de vulva 40 % Cáncer de pene 40 % So the consequences of the continuum of a HPV infection related neoplasia is situated not only on the cervix, but also in the vagina, on the vulva, on the perianal skin, in the anal canal, in the nasopharynx and in men on the penis. Cáncer de orofaringe 35 % Cáncer de amigdalas ~50% Cáncer de cavidad oral 25 % Cáncer de laringe ~25% Muñoz N et al Vaccine Kreimer AR et al Cancer Epidemiology Biomarkers and Prevention 2005. Syrjanen S Journal of Clinical Pathology de Vuyst H, Int J Cancer 2009;124: 11 11

12 VPH y Papilomatosis Respiratoria Recurrente (PRR)Distribución Bimodal por Edad con 2 picos1: 2 a 4 años de edad (inicio infancia) 20 a 40 años de edad (inicio adulto) Causada usualmente por VPH tipos 6, 112 Transmisión: durante embarazo y/o canal del parto. Papilomas son masas de epitelio escamoso estratificado que pueden obstruir la via aerea si no son removidas.2 Histológicamente benigna, la PRR causa morbi-mortalidad fìsica y psicológica durante toda la vida debido a su naturaleza recurrente.2 Posible relación causal de la PRR en Cánceres de cabeza y cuello2-4 Key Point Recurrent respiratory papillomatosis (RRP) is a nonmalignant lesion of the larynx and trachea caused by HPV types 6 and 11. Background The age distribution of RRP is bimodal: the first peak in incidence occurs between 2 and 4 years of age (childhood-onset); the second occurs between ages 20 and 40 years (adult-onset).1 RRP is a benign lesion of the larynx and trachea caused by HPV types 6 and 11.2,3 Most studies indicate that RRP in children occurs after exposure of a child’s upper aerodigestive tract to the cervix and vagina of a mother with genital HPV infection at birth.2 Although lesions histologically and pathologically seem similar in children and adults, clinically, they behave very differently. In children, RRP may be life-threatening if the papillomas obstruct the airway and can be a devastating disease, occasionally necessitating up to 150 surgeries over a child’s lifetime. In contrast, adults with RRP usually only require a few surgical excisions to eliminate the disease.2,3 References 1. Derkay CS. Recurrent respiratory papillomatosis. Laryngoscope. 2001;111:57–69. 2. McClay JE. Recurrent respiratory papillomatosis. Available at: Accessed January 26, 2005. 3. Wiley DJ, Douglas J, Beutner K, et al. External genital warts: Diagnosis, treatment, and prevention. Clin Infect Dis. 2002;35(suppl 2):S210–S224. 1. Derkay CS. Laryngoscope. 2001;111:57– Abramson AL, Nouri M, Mullooly V, Fisch G, Steinberg BM. J Med Virol. 2004;72:473– Steinberg BM, DiLorenzo TP. Cancer Metastasis Rev. 1996;15:91– Szentirmay Z, Pólus K, Tamás L, et al. Cancer and Metastasis Reviews. 2005;24:19–34.

13 VIRUS DEL PAPILOMA HUMANO (VPH)Qué tan frecuente Como se adquiere Enfermedades asociadas Como se previene A quien vacunar: cuando

14 VPH Prevención Tamizaje Vacunas 14

15 Por qué la necesidad de vacunación contra VPH?A pesar de las estrategias de tamizaje, la incidencia y mortalidad del cáncer cervical continúan siendo altas Estimated Cervical Cancer Incidence Worldwide in 2008 GLOBOCAN 2008, International Agency for Research on Cancer

16 Vacunas VPH : ComposiciónMezcla recombinante of 2 (16,18) o 4 (6,11,16,18)* partículas similares al VPH Características estructurales y antigénicas similares al VPH Esquema de vacunación : tiempo 0, 2m, 6m: 0.5 ml I.M. Mujeres: 9–45* años, Hombres: 9–25 años

17 Inmunogenicidad en Adolescentes : ResultadosSeroconversión en % Prueba NIÑAS Y NIÑOS 10–15 años (95% CI) (n=506) MUJERES 16–23 años (95% CI) (n=511) Anti-VPH 6 100 (99.1%,100%) 100 (98.9%,100%) Anti-VPH 11 Anti-VPH 16 100 (98.8%,100%) Anti-VPH 18 99.1 (97.4%,99.8%) Key Point The proportions of subjects who seroconverted were comparable in each of the 3 groups in this Phase III study. Seroconversion to anti-VPH 6, VPH 11, and VPH 16 was observed in 100% of subjects. Rates of seroconversion to anti-VPH 18 were 100% in girls 10–15 years of age, 99.8% in boys 10–15 years of age, and 99.1% in women 16–23 years of age. Background The percentage of subjects who seroconverted at Month 7 was evaluated in each of the 3 groups in this Phase III study.1 The seroconversion rates were evaluated in a noninferiority analysis in which the noninferiority criteria were an upper bound of 95% CI for the fold ratio in geometric mean titers between the 2 groups (adolescents/adults) of >0.5 for each VPH type; and an upper bound of 95% CI for the difference of percent seroconversions (adolescent-adult) >5% for each VPH type.1,2 This study demonstrated that the rates of seroconversion to anti-VPH 6, 11, 16, and 18 were comparable among groups and those of 10 to 15-year-old subjects were noninferior (P<0.001) compared with the seroconversion rates observed among young women and older adolescent girls.1,2 GARDASIL® is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. References 1. Data on file, MSD. 2. Nolan T, Block SL, Reisinger KS, et al. Comparison of the immunogenicity and tolerability of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine in male and female adolescents and young adult women. Presented at: European Society for Paediatric Infectious Diseases (ESPID). Valencia, Spain; May 18–20, 2005. Seroconversión > 99% al mes 7 CI = confidence interval *A P value <0.025 supports a conclusion that the specific type anti-VPH response in 10–15-year-old females or males was non-inferior to the response in 16–23 year old females. 17

18 Objetivos de las Vacunas GARDASIL® 6,11,16,18 - CERVARIX ® 16,18Tipo Mujeres Hombres 6/11 G ® 90% : Verrugas genitales 5 -25% : Lesiones cervicales de bajo riesgo NIC1 90% : PRR 90%: Verrugas genitales Transmisores a mujeres 90% : PRR 16/18 G® C® 25% : Lesiones cervicales de bajo riesgo NIC1 70% : Lesiones cervicales de alto riesgo NIC 2-3 70% : Cáncer cervical 70% : Cánceres anogenitales 70% : NIA 2/3 (HSH) 70% : Cáncer anal (HSH) 50% : Cáncer de pene Transmisores a mujeres 18

19 EFECTIVIDAD de GardasilDisminución de Verrugas Genitales después del inicio de vacunación en Australia IPV 2009 CONTEXTO: Programa de vacunación VPH en Australia (aproximadamente un 70% de cobertura) Cohorte de niñas de años en las escuelas Programa de catch-up en niñas de años (desde abril 2007) Mujeres 26 años en atención primaria (desde julio 2007) OBJETIVO: Determinar si el programa de vacunación australiano VPH tiene un impacto en la presencia de verrugas genitales, al cabo de un año de su implementación. MEDIDA DE LAS VARIABLES PRINCIPALES: Ratios de prevalencia clínicos (RR) y IC 95% se calcularon según la proporción de nuevos pacientes con verrugas genitales y se estratificaron según género, edad, y grupo de riesgo para la combinación de los años comparados con 2008. DISEÑO: Estudio retrospectivo que compara la proporción de nuevos pacientes con verrugas genitales en el Melbourne Sexual Health Centre (MSHC) desde Enero 2004 a Diciembre 2008. Fairley Full paper submitted 2009

20 NIC 2/3 o AIS relacionado VPH 16/18 100EFICACIA: Vacuna Tetravalente NIC 2/3 o AIS Mujeres entre 16 y 26 años Población: Por Protocolo Vacuna Placebo 95% CI n Casos Eficacia (%) Valor P PP NIC 2/3 o AIS relacionado VPH 16/18 8487 8460 53 100 (93–100) < 0.001 NIC 2 36 (89–100) NIC 3 or AIS 32 (88–100) PP = received 3 vaccinations within 1 year; no major protocol violations; VPH 16/18 sero(-) at day 1 and VPH 16/18 DNA(-) day 1 to month 7; cases counted starting after month 7. CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ.

21 EFICACIA: Vacuna Tetravalente Neoplasia Intraepitelial Vaginal Mujeres entre 16 y 26 años Población por protocolo Vacuna (n = 8,392) Placebo (n = 7,914) Casos Tasa* Eficacia 95% IC NIVa 1-3 0.0 19 0.2 100 (80, 100) VPH 6 9 0.1 (54, 100) VPH 11 2 (<0, 100) VPH 16 8 (48, 100) VPH 18 3 PP = received 3 vaccinations within 1 year; no major protocol violations; VPH 16/18 sero(-) at day 1 and VPH 16/18 DNA(-) day 1 to month 7; cases counted starting after month 7. CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ.

22 Gardasil®: Prevention of HPV 16/18 CIN 2/3 and AISCombined results from 4 phase II/III trials END OF STUDY– Per Protocol Population ~4 year follow up in women 16 – 26 years 100% (0/73) 95% CI 97%* (2/63) 95% CI 100% (0/7) 95% CI Cases Gardasil, Cases Placebo CIN CIN AIS 0 7 n (GARDASIL®)= 8,493 n (placebo)= ,464 *2 cases of CIN 3 most likely not causally related to HPV 16. HPV 16 identified at a single time point only. One case was an infection with HPV 52 already at inclusion in study; the other case was baseline HPV 51 positive and a co-infection with HPV 56

23 Reduction in Abnormal Pap tests Regardless of Causal HPV type – HPV naïve population↓45% % Reduction ↓36% ↓22% ↓17% ASC-US HR + LSIL ASC-H HSIL Cases Placebo Cases Vaccine Muñoz N et al JNCI 2010;102(5):325

24 Reduction in Cervical Procedures Regardless of Causal HPV type –HPV naïve population↓42% % Reduction ↓22% ↓20% Colposcopy Cervical Biopsy Definitive therapy Cases Placebo Cases Vaccine Muñoz N. et al JNCI 2010

25 Mujeres con infección previa: Gardasil protege frente a los otros tipos vacunales no expuestosEficacia(%) 95% CI CIN 2/3 y AIS 100 (55, 100) Verrugas Genitales y Neoplasias Vulvares y Vaginales (VIN 1-3 y VaIN 1-3) 94 (81, 99) Mujeres seropositivas para uno o más tipos de la vacuna: Gardasil es EFICAZ frente a las enfermedades causadas por el resto de tipos VPH incluidos en la vacuna. The Future II Study Group. Prophylactic Efficacy of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Women with Virological Evidence of HPV Infection. J Infect Dis. 2007;196(10):

26 Nonserious AEs Reported for qHPV Vaccine to VAERS 2006–2008 Compared With 2006–2011(N=12,424)1,a Slade 2009: p752B; Gee 2011: p9A (N=18,569)2 % Total reported AEsb Slade BS et al. JAMA. 2009;302:750–757. Gee J. Presented at: Advisory Committee on Immunization Practices Meeting; October 25, 2011; Atlanta, GA. aTotal includes 772 SAEs. bAEs coded using MedDRA preferred terms; more than 1 code may have been assigned to a single event. AE=adverse event; MedDRA=Medical Dictionary for Regulatory Activities; qHPV=quadrivalent human papillomavirus; SAE=serious AE; VAERS=Vaccine Adverse Event Reporting System. 1. Slade BS et al. JAMA. 2009;302:750– Gee J. Presented at: Advisory Committee on Immunization Practices Meeting; October 25, 2011; Atlanta, GA.

27 Perfil de seguridad en estudios clinicos y post-comercialización

28 Resumen de EAs publicado en JAMA1Sistema VAERS (US) Resumen de EAs publicado en JAMA1 “Basados en la revisión de información disponible por la FDA y el CDC, la vacuna de HPV continúa siendo segura y efectiva, y sus beneficios sobrepasan los riesgos” 1http://www.cdc.gov/vaccinesafety/Vaccines/HPV/jama.html 28

29 Pregnancy Registry in United States, France, Canada: 5-Year ResultsGoss 2012 Abstract: p1B Goss 2012 Abstract: p1C Pregnancy Registry in United States, France, Canada: 5-Year Results Lievano 2012 (DOF): slide4A Goss 2012 Abstract: p1A FDA PAC 2012: p4A Prospective Reports (n=2,286)a Background Data of Unexposed Population Number of exposed pregnancies with known outcomes 1,5911 – Spontaneous abortionb rate 6.4%1 ~15%3 Fetal death ratec 0.9%3 0.62–1%3 Live births 1,3831 Total number of neonates 1,3913 Major birth defect 2.4%3 2.67%3 Analysis covers 5 years postlicensure (June 2006 to May 2011)1,2 No adverse signal was detected1,2 Rates of congenital anomalies and miscarriages within background rates1,2 qHPV vaccine use during pregnancy is not recommended1 Lievano 2012 (DOF): slide5C Goss 2012 Abstract: p1D FDA PAC 2012: p5A Lievano 2012 (DOF): slide5A Lievano 2012 (DOF): slide4C Goss 2012 Abstract: p1D Lievano 2012 (DOF): slide5B Footnote a: Goss 2012 Abstract: p1E Footnote b & c: Lievano 2012 (DOF): slide 3B Goss MA et al. Presented at: EUROGIN International Multidisciplinary Congress; July 8–11, 2011; Prague, Czech Republic. Abstract SS 8-3. Gardasil Pediatric Utilization and Safety Review for the Pediatric Advisory Committee Meeting — May 7-8, Food and Drug Administration website. Committees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UC M pdf. Accessed February 6, 2013. Data on File, MSD _____. aProspective data were received before birth, without known outcomes. bSpontaneous abortions prior to week 20. cFetal deaths after at least week 20. qHPV=quadrivalent human papillomavirus. 1. Goss MA et al. Presented at: EUROGIN International Multidisciplinary Congress; July 8–11, 2011; Prague, Czech Republic. Abstract SS Gardasil Pediatric Utilization and Safety Review for the Pediatric Advisory Committee Meeting — May 7-8, Food and Drug Administration website. Committees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM pdf. Accessed February 6, Data on File, MSD _____.

30 Consenso de las Autoridades de Salud Global (FDA, CDC, WHO, EMA, ECDC)CDC Male VAERS 2012: p10C CDC Male VAERS 2012: p10D Gee ACIP 2011: p6A ECDC 2012: p2A,B; p12A Los estudios de monitoreo de seguridad de la vacuna Tetravalente no han mostrado eventos adversos significantes tanto en mujeres como en hombres1–6 Después de la aprobación de la vacuna para los hombres, los eventos adversos han sido similares a los presentados en los ensayos clínicos de las mujeres1 Recomiendan continuar el monitoreo de la seguridad de la vacuna Tetravalente contra el VPH en los dos generos1–6 CDC Male VAERS 2012: p10E Gee ACIP 2011: p6A FDA PAC 2012: p14A,B ECDC 2012: p13A WHO 2009: p39A,B EMA 2011: p2A; p3A Harrington T. Presented at: National Foundation of Infectious Diseases 15th Annual Conference on Vaccine Research; 7–9 May, 2012; Baltimore, MD. Presentation 3B. Gee J. Presented at: Advisory Committee on Immunization Practices Meeting; October 25, 2011; Atlanta, GA. Gardasil Pediatric Utilization and Safety Review for the Pediatric Advisory Committee Meeting — May 7-8, Food and Drug Administration website. terials/PediatricAdvisoryCommittee/UCM pdf. Accessed February 6, World Health Organization (WHO). Wkly Epidemiol Rec. 2009;84:37–40. Gardasil: Procedural steps taken and scientific information after the authorisation. European Medicines Agency website. _Procedural_steps_taken_and_scientific_information _after_authorisation/human/000703/WC pdf. Accessed February 6, 2013. European Centre for Disease Prevention and Control. Introduction of HPV vaccines in EU countries – an update. Stockholm: ECDC; / _gui_hpv _vaccine_update.pdf. Accessed February 6, 2013. CDC=Centers for Disease Control and Prevention; ECDC=European Centre for Disease Prevention and Control; EMA=European Medicines Agency; FDA=Food and Drug Administration; qHPV=quadrivalent human papillomavirus; WHO=World Health Organization. 1. Harrington T. Presented at: National Foundation of Infectious Diseases 15th Annual Conference on Vaccine Research; 7–9 May, 2012; Baltimore, MD. Presentation 3B. 2. Gee J. Presented at: Advisory Committee on Immunization Practices Meeting; October 25, 2011; Atlanta, GA. 3. Gardasil Pediatric Utilization and Safety Review for the Pediatric Advisory Committee Meeting — May 7-8, Food and Drug Administration website. Accessed February 6, World Health Organization (WHO). Wkly Epidemiol Rec. 2009;84:37– Gardasil: Procedural steps taken and scientific information after the authorisation. European Medicines Agency website. _Procedural_steps_taken_and_scientific_information _after_authorisation/human/000703/WC pdf. Accessed February 6, European Centre for Disease Prevention and Control. Introduction of HPV vaccines in EU countries – an update. Stockholm: ECDC; / _gui_hpv _vaccine_update.pdf. Accessed February 6, 2013.

31 A que edad vacunar? Temprano en la adolescencia:Después del debut sexual, el riesgo acumulativo a 5 años para contagiarse con el VPH es 50-60% Europa: 20-40% de los adolescentes habían iniciado actividad sexual a 15 años1 Brasil: 32% de las mujeres y 47% de los hombres habían iniciado actividad sexual <14 años.

32 % de Relaciones Sexuales por Edad 200537% 24% 12% 4% 2% ENDS, Profamilia 2005 32

33 Iniciación de Relaciones Sexuales Adolescentes – Aguablanca 2005-06≤ 12 años: 42% ≤ 14 años: 90% Reina JC Programa Adolescentes Embarazadas-Aguablanca (Archivo personal)

34 Virus del Papiloma HumanoLos Milagros en Medicina son el Fruto de la Investigación Gracias

35

36

37 EFICACIA Neoplasia Intraepitelial Vaginal Mujeres entre 16 y 26 años Población por protocoloVacuna (n = 8,392) Placebo (n = 7,914) Casos Tasa* Eficacia 95% IC NIVa 1-3 0.0 19 0.2 100 (80, 100) VPH 6 9 0.1 (54, 100) VPH 11 2 (<0, 100) VPH 16 8 (48, 100) VPH 18 3 PP = received 3 vaccinations within 1 year; no major protocol violations; VPH 16/18 sero(-) at day 1 and VPH 16/18 DNA(-) day 1 to month 7; cases counted starting after month 7. CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ.

38 EFICACIA Condilomas y verrugas genitales Población por protocoloVacuna (n = 8,392) Placebo (n = 7,914) Casos Tasa* Eficacia 95% CI Condiloma 1 <0.1 90 0.8 99 (94, 100) Condiloma Vaginal 8 0.1 100 (47, 100) Condiloma Vulvar 87 0.7 Lo sujetos se cuentan una vez en cada categoría que de Endpoint que aplique. Un Sujeto puede aparecer en más de una categoría. *Casos por 100 personas año a riesgo. n = recibieron las vacunaciones en 1 año; no mayores violaciones del protocolo ; VP 6, 11, 16 o 18 sero(-) at Day 1 and VPH 6, 11, 16 o 18 DNA(-) desde día 1 hasta un mes post dosis 3; Conteo se iicia 1 mes post dosis 3

39 Evaluación de Seguridad: Días 1 a 15 Siguiendo cualquier vacunación1Placebo (n=4064) n % n % 1/Data on file/ VRBPAC briefing document/p 75/ Table 24. Sujetos con seguimiento 6069 – 3994 – Número (%) de sujetos: 73.4 En sitio de Inyección AEs 5035 83.0 2932 1/Data on file/ VRBPAC briefing document/p75/ Table 24; p. 72/ ¶2. Eventos serios SAEs totales 37 0.6 26 0.7 Eventos Seios relacionados con Vacuna AEs* 1 0.0 0.0 Key Point The vaccine was generally well tolerated, with no significant differences between GARDASIL® and placebo regarding AEs. Background This slide presents the summary of clinical AEs reported from day 1 to day 15, following any study vaccination for the detailed safety population. Overall, the proportions of subjects reporting AEs were comparable between the 2 vaccination groups. In the group that received GARDASIL® , 83% of subjects reported injection-site AEs, compared with 73.4% of placebo recipients.1 Few subjects reported a serious AE. The proportions of subjects who reported serious AEs were comparable between the 2 vaccination groups. Few subjects discontinued due to an AE.1 Ten patients in the GARDASIL® group (overall safety population) died at any time during the clinical trials. None of the deaths were considered by the investigators to be vaccine or procedure related.1 The most common cause of death was motor vehicle accident (4 subjects who received GARDASIL® and 3 placebo subjects), followed by overdose/suicide (1 subject who received GARDASIL® and 2 subjects who received placebo), and pulmonary embolus/deep-vein thrombosis (1 subject who received GARDASIL® and 1 placebo subject). In addition, there were 2 cases of sepsis, 1 case of pancreatic cancer, and 1 case of arrhythmia in the group that received GARDASIL® , and 1 case of asphyxia in the placebo group. The events reported were consistent with events expected in healthy adolescent and adult populations.2 The most frequently reported serious AEs for GARDASIL® , compared to placebo and regardless of causality, were2: Headache (0.03% GARDASIL® vs 0.02% placebo) Gastroenteritis (0.03% GARDASIL® vs 0.01% placebo) Appendicitis (0.02% GARDASIL® vs 0.01% placebo) Pelvic inflammatory disease (0.02% GARDASIL® vs 0.01% placebo) One case of bronchospasm and 2 cases of asthma were reported as serious AEs that occurred during days 1 to 15 of any vaccination visit.2 GARDASIL® is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. References GARDASIL® Prescribing Information. Merck & Co., Inc., Whitehouse Station, NJ, USA. Data on file, MSD. Muertes** 1 0.0 1 0.0 Descontinuación debida a AE 11 0.2 6 0.2 1/Data on file/ VRBPAC briefing document/p74/¶2; p.75/ ¶1. Descontinuación debida a SAE 2 0.0 2 0.1 Descontinuación debida a SAE relacionado con Vacuna 0.0 0.0 1/Data on file/ VRBPAC briefing document/p.75/ ¶1. *Determined by the investigator to be possibly, probably, or definitely related to the vaccine. **None of the deaths were considered by the investigators to be vaccine or procedure related. 1. Data on file, MSD. 1/Data on file/ VRBPAC briefing document/p77/¶2. Sin diferencias significativas entre ambos grupos 2/Package Insert/p. 12/Lines 2/Package Insert/p. 12/Lines 2/Package Insert/p. 12/Lines 39

40 Resumen de EAs publicado en JAMA1Sistema VAERS (US) Resumen de EAs publicado en JAMA1 “Basados en la revisión de información disponible por la FDA y el CDC, la vacuna de HPV continúa siendo segura y efectiva, y sus beneficios sobrepasan los riesgos” 1http://www.cdc.gov/vaccinesafety/Vaccines/HPV/jama.html 40

41 VAERS Reporting for qHPV VaccineOriginal Report1 2009 Update2 2011 Update3 Time frame June 1, 2006–Dec 31, 2008 June 1, 2006–June 1, 2009 June 1, 2006–Sept 15, 2011 Doses distributed >23 million >25 million >40 million AEs 12,424 14,072 20,096 SAEs 6.2% 7% 7.2% Deaths 32 (20 confirmed) No association by PRR 43 (26 confirmed) No unusual clustering to suggest causality 71 (34 confirmed) No patterns in verified deaths Other Disproportional reporting of syncope and VTE was noted with data mining methods 42 reports of GBS 56 reports of VTE CDC concluded increased reporting of qHPV vaccine versus other vaccines 43 reports of anaphylaxisa (20 serious) 12 confirmed; all treated and recovered No confirmed deaths No new AE concerns or clinical patterns identified compared with previous analyses Slade 2009: p750A; p751B; p752A,F; p755B,C,D Gee 2011: p6A; 11A; 12A; 14A; Block 2010: p99A; p100A-D Slade 2009: p754A Slade BS et al. JAMA. 2009;302:750–757. Block SL et al. Pediatr Infect Dis J. 2010;29:95–101. Gee J. Presented at: Advisory Committee on Immunization Practices Meeting; October 25, 2011; Atlanta, GA. aReports coded with MedDRA terms: anaphylactic shock, anaphylactic reaction, anaphylactoid shock, anaphylactoid reaction. AE=adverse event; CDC=Centers for Disease Control and Prevention; GBS=Guillain-Barré syndrome; medDRA=Medical Dictionary for Regulatory Activities; PRR=proportional reporting ratio; qHPV=quadrivalent human papillomavirus; SAE=serious AE; VAERS=Vaccine Adverse Event Reporting System; VTE=venous thromboembolism. 1. Slade BS et al. JAMA. 2009;302:750– Block SL et al. Pediatr Infect Dis J. 2010;29:95– Gee J. Presented at: Advisory Committee on Immunization Practices Meeting; October 25, 2011; Atlanta, GA.

42 Nonserious AEs Reported for qHPV Vaccine to VAERS 2006–2008 Compared With 2006–2011(N=12,424)1,a Slade 2009: p752B; Gee 2011: p9A (N=18,569)2 % Total reported AEsb Slade BS et al. JAMA. 2009;302:750–757. Gee J. Presented at: Advisory Committee on Immunization Practices Meeting; October 25, 2011; Atlanta, GA. aTotal includes 772 SAEs. bAEs coded using MedDRA preferred terms; more than 1 code may have been assigned to a single event. AE=adverse event; MedDRA=Medical Dictionary for Regulatory Activities; qHPV=quadrivalent human papillomavirus; SAE=serious AE; VAERS=Vaccine Adverse Event Reporting System. 1. Slade BS et al. JAMA. 2009;302:750– Gee J. Presented at: Advisory Committee on Immunization Practices Meeting; October 25, 2011; Atlanta, GA.

43 Pregnancy Registry in United States, France, Canada: 5-Year ResultsGoss 2012 Abstract: p1B Goss 2012 Abstract: p1C Pregnancy Registry in United States, France, Canada: 5-Year Results Lievano 2012 (DOF): slide4A Goss 2012 Abstract: p1A FDA PAC 2012: p4A Prospective Reports (n=2,286)a Background Data of Unexposed Population Number of exposed pregnancies with known outcomes 1,5911 – Spontaneous abortionb rate 6.4%1 ~15%3 Fetal death ratec 0.9%3 0.62–1%3 Live births 1,3831 Total number of neonates 1,3913 Major birth defect 2.4%3 2.67%3 Analysis covers 5 years postlicensure (June 2006 to May 2011)1,2 No adverse signal was detected1,2 Rates of congenital anomalies and miscarriages within background rates1,2 qHPV vaccine use during pregnancy is not recommended1 Lievano 2012 (DOF): slide5C Goss 2012 Abstract: p1D FDA PAC 2012: p5A Lievano 2012 (DOF): slide5A Lievano 2012 (DOF): slide4C Goss 2012 Abstract: p1D Lievano 2012 (DOF): slide5B Footnote a: Goss 2012 Abstract: p1E Footnote b & c: Lievano 2012 (DOF): slide 3B Goss MA et al. Presented at: EUROGIN International Multidisciplinary Congress; July 8–11, 2011; Prague, Czech Republic. Abstract SS 8-3. Gardasil Pediatric Utilization and Safety Review for the Pediatric Advisory Committee Meeting — May 7-8, Food and Drug Administration website. Committees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UC M pdf. Accessed February 6, 2013. Data on File, MSD _____. aProspective data were received before birth, without known outcomes. bSpontaneous abortions prior to week 20. cFetal deaths after at least week 20. qHPV=quadrivalent human papillomavirus. 1. Goss MA et al. Presented at: EUROGIN International Multidisciplinary Congress; July 8–11, 2011; Prague, Czech Republic. Abstract SS Gardasil Pediatric Utilization and Safety Review for the Pediatric Advisory Committee Meeting — May 7-8, Food and Drug Administration website. Committees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM pdf. Accessed February 6, Data on File, MSD _____.

44 US Postlicensure Safety Surveillance Study: Primary ResultsKlein 2012: pE5B; pE7B Klein 2012: pE5B; pE7C Goldstone 2012: p401A,B Gee Vaccine 2011: p5C FDA PAC 2012: p4C Quadrivalent HPV vaccine may be associated with 2 AEs:a Same day syncope1 Skin infection during 2 weeks after vaccination (some cases may have been injection-site reactions)1 No other safety signals identified1 Several studies show vaccination, not specific to vaccine, is related to syncope in this age group1-4 Klein 2012: pE6A; pE7D Klein 2012: pE5C; pE7A Klein NP et al. Arch Pediatr Adolesc Med. 2012;166:1140–1148. Goldstone SE et al. Exper Rev Vaccines. 2012;11: 395–406. Gee J et al. Vaccine. 2011;29:8279–8284. Gardasil Pediatric Utilization and Safety Review for the Pediatric Advisory Committee Meeting — May 7-8, Food and Drug Administration website. terials/PediatricAdvisoryCommittee/UCM pdf. Accessed February 6, aAs observed in the overall safety population. AE=adverse event. 1. Klein NP et al. Arch Pediatr Adolesc Med. 2012;166:1140– Goldstone SE et al. Exper Rev Vaccines. 2012;11: 395– Gee J et al. Vaccine. 2011;29:8279– Gardasil Pediatric Utilization and Safety Review for the Pediatric Advisory Committee Meeting — May 7-8, Food and Drug Administration website. Accessed February 6, 2013.

45 US Postlicensure Safety Surveillance Study: Autoimmune Safety Results1No clear safety signal for autoimmune conditions found after qHPV vaccination Vaccination timing, dose sequence, and age were not associated with disease onset for prespecified autoimmune conditions Condition Vaccinated Nonvaccinated Incidence Rate Ratio (95% CI) Incidence/100,000 Person-Years Graves’ disease 18.2 25.8 0.72 (0.50–1.01) Hashimoto’s disease 104.8 81.1 1.29 (1.08–1.56) Type 1 diabetes 10.3 18 0.57 (0.47–0.73) ITP 6.8 5.9 1.16 (0.85–1.83) JRA 3.4 7.7 0.48 (0.26–0.91) MS 2.5 1.37 (0.74–3.2) Optic neuritis 5.7 3.9 1.45 (1.00–2.91) Other demyelinating CNS diseases 1.1 1.6 0.71 (0.38–2.13) RA 4.6 7 0.71 (0.39–1.45) SLE 11.4 1.07 (0.69–1.6) Uveitis 8 11.9 0.67 (0.49–1.02) Chao 2012: p199A; p200A; p201 A 1. Chao C et al. J Intern Med. 2012;271:193–203. CI=confidence interval; CNS=central nervous system; ITP=immune thrombocytopenia; JRA=juvenile rheumatoid arthritis; MS=multiple sclerosis; qHPV=quadrivalent human papillomavirus; RA=rheumatoid arthritis; SLE=systemic lupus erythematosus. 1. Chao C et al. J Intern Med. 2012;271:193–203.

46 US CDC Vaccine Safety Datalink RCA1: Safety ResultsGee 2011: p4A; p2E 600,558 doses administered during 164 weeks 416,942 doses in youths 9–17 years old 183,616 doses in adults 18–26 years old No increased risk with qHPV vaccine of: Guillain-Barré syndrome Stroke Venous thromboembolism Appendicitis Anaphylaxis Seizure or new-onset seizures Syncope Allergic reaction Gee 2011: p4A,C 1. Gee J. Vaccine. 2011;29:8279–8284 CDC=Centers for Disease Control and Prevention; qHPV=quadrivalent human papillomavirus; RCA=rapid cycle analysis. 1. Gee J. Vaccine. 2011;29:8279–8284.

47 Protocol 018 Extension Study: Study DesignSaah 2012 IPV 018 poster: p1A,B OBJECTIVE: Evaluate the long-term safety, tolerability, and effectiveness of qHPV vaccine in male and female subjects 9 to 15 years old at enrollment in the base study1,2 Reisinger 2007: p2A,B qHPV vaccine Current analysis at 96 months EVG Months Randomized to GARDASIL: n=1,184 EVG: n=1,179 Base Study: Boys and girls 9-15 years of age (N=1,781) Long-Term Follow-Up Study (N=1,661) CVG Reisinger KS et al. Pediatr Infect Dis J. 2007;26:201–209. Saah A et al. Presented at: 28th International Papillomavirus Conference; November 30–December 6, 2012; San Juan, Puerto Rico. Randomized to placebo: n=597 CVG: n=482 Months Saline placebo qHPV vaccine CVG=catch-up vaccination group; EVG=early vaccination group; qHPV=quadrivalent human papillomavirus. 1. Reisinger KS et al. Pediatr Infect Dis J. 2007;26:201– Saah A et al. Presented at: 28th International Papillomavirus Conference; November 30–December 6,2012; San Juan, Puerto Rico.

48 US FDA: Post-licensure Review1FDA PAC 2012: p3A Reviewed data from VAERS reports, VSD study, and manufacturer’s active surveillance programs for PAC meeting in May 2012 Conclusions: 94% of VAERS reports were NOT serious Most frequently reported AEs: headache, syncope, dizziness, nausea, injection site reactions Safety signals for syncope and cellulitis likely attributable to injection method and targeted adolescent population, NOT the vaccine itself No safety signals identified for prespecified autoimmunune diseases Overall pregnancy outcomes similar to those expected in the general population, with no unusual patterns in congenital anomalies or deaths Found no new safety concerns for qHPV vaccine Recommended continued safety monitoring FDA PAC 2012: p4B FDA PAC 2012: p4C FDA PAC 2012: p4D FDA PAC 2012: p5A FDA PAC 2012: p14A FDA PAC 2012: p14B 1. Gardasil Pediatric Utilization and Safety Review for the Pediatric Advisory Committee Meeting — May 7-8, Food and Drug Administration website. MeetingMaterials/PediatricAdvisoryCommittee/UCM pdf. Accessed February 6, 2013. AE=adverse event; FDA=Food and Drug Administration; PAC=Pediatric Advisory Committee; qHPV=quadrivalent human papillomavirus; VAERS=Vaccine Adverse Event Reporting System; VSD=Vaccine Safety Datalink. 1. Gardasil Pediatric Utilization and Safety Review for the Pediatric Advisory Committee Meeting — May 7-8, Food and Drug Administration website. MeetingMaterials/PediatricAdvisoryCommittee/UCM pdf. Accessed February 6, 2013.

49 Inmunogenicidad en Adolescentes : ResultadosSeroconversión en % Prueba NIÑAS Y NIÑOS 10–15 años (95% CI) (n=506) MUJERES 16–23 años (95% CI) (n=511) Anti-VPH 6 100 (99.1%,100%) 100 (98.9%,100%) Anti-VPH 11 Anti-VPH 16 100 (98.8%,100%) Anti-VPH 18 99.1 (97.4%,99.8%) Key Point The proportions of subjects who seroconverted were comparable in each of the 3 groups in this Phase III study. Seroconversion to anti-VPH 6, VPH 11, and VPH 16 was observed in 100% of subjects. Rates of seroconversion to anti-VPH 18 were 100% in girls 10–15 years of age, 99.8% in boys 10–15 years of age, and 99.1% in women 16–23 years of age. Background The percentage of subjects who seroconverted at Month 7 was evaluated in each of the 3 groups in this Phase III study.1 The seroconversion rates were evaluated in a noninferiority analysis in which the noninferiority criteria were an upper bound of 95% CI for the fold ratio in geometric mean titers between the 2 groups (adolescents/adults) of >0.5 for each VPH type; and an upper bound of 95% CI for the difference of percent seroconversions (adolescent-adult) >5% for each VPH type.1,2 This study demonstrated that the rates of seroconversion to anti-VPH 6, 11, 16, and 18 were comparable among groups and those of 10 to 15-year-old subjects were noninferior (P<0.001) compared with the seroconversion rates observed among young women and older adolescent girls.1,2 GARDASIL® is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. References 1. Data on file, MSD. 2. Nolan T, Block SL, Reisinger KS, et al. Comparison of the immunogenicity and tolerability of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine in male and female adolescents and young adult women. Presented at: European Society for Paediatric Infectious Diseases (ESPID). Valencia, Spain; May 18–20, 2005. Seroconversión > 99% al mes 7 CI = confidence interval *A P value <0.025 supports a conclusion that the specific type anti-VPH response in 10–15-year-old females or males was non-inferior to the response in 16–23 year old females. 49