SBMF, São Paulo, 07 de maio de 2015 Impacto da vacinação contra Papilomavírus Humano (HPV) Luisa Lina Villa, PhD School of Medicine, Univ of São Paulo and Santa Casa São Paulo, Brazil
Disclosure: Consultant of Merck, Sharp and Dohme for the Quadrivalent HPV Vaccine Consultant of BD, QIAGEN and ROCHE for HPV DNA testing
Estimativa global de novos casos de doenças causadas por HPV em mulheres e homens Male Female Penile cancer 1 10,500 19,960 Vulvar & vaginal cancer 2 Anal cancer 1 13,000 14,300 Anal cancer 1 Head and neck cancer 2 42,000 18,000 Head and neck cancer 2 529,800 Cervical cancer 2 Genital warts 3 17,600,000 14,400,000 Genital warts 3 Parkin D et al. Vaccine. 2006 (penile, vulvar, anal, cervical cancers); WHO/ICO 2010 (head and neck cancer); De Vuyst H et al. Int J Cancer. 2009 (vaginal cancer); Greer CE et al. J Clin Microbiol. 1995 (genital warts). http://www.who.int/hpvcentre/en/. Accessed June 21, 2012. 3
Age specific incidence of cervical cancer in regions of America compared to the World South America Central America And the Caribbean World Northern America
Cervical Cancer: Estimated Annual Number of New Cases and Deaths by Age Group (Brazil, 2008 2025) 1 40.000 New Cases Deaths 0 64 yrs 65+ yrs 0 64 yrs 65+ yrs 37,464 17,788 30.000 24,562 +96% 11,055 +95% 20.000 10.000 +37% +41% 0 2008 2025 Year 2008 2025 Year 5 Projected burden in 2025 is estimated by applying current population forecasts for the country and assuming that current incidence rates of cervical cancer are constant over time. Data source: IARC, Globocan 2008. 1. HPV Information Centre. Human Papillomavirus and Related Cancers in Brazil. Summary Report Update. September 15, 2010. http://apps.who.int/hpvcentre/statistics/dynamic/ico/summaryreportsselect.cfm. Accessed March 2, 2011.
Componentes das Vacinas contra HPV Tipos HPV 6 11 16 18 16 18 Doses em μg 20/40/40/20 20/20 Produção de VLPs de L1 Adjuvante Levedura Amorphous aluminium hydroxyphosphate sulfate (Merck and Co., Inc.) Células de inseto AS04: Aluminium hydroxide + 3-deacylated monophosphoryl lipid A (MPL, Corixa/GSK) Adjuvante (dose) 225 μg 500 μg/50 μg 1. Villa LL, Costa RLR, Petta CA, et al. Lancet Oncol. 2005;6:671 678. 2. Harper DM, Franco EL, Wheeler C, et al. Lancet. 2004;364:1757 1765. GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
O que são as VLPs (Virus-Like Particles)?
VERRU GENITAIS INDICAÇÃO DA ANVISA CÂNCERES E LESÕES PRÉ-CANCEROSAS Bivalente Quadrivalente CONTRA HPVs: 16 e 18 Para mulheres de 10 a 25 anos 3 doses (0, 1 mês e 6 meses) CONTRA HPVs: 6, 11, 16 e 18 Para mulheres e homens de 9 a 26 anos 3 doses (0, 2 meses e 6 meses) COLO DO ÚTERO: previne 70% dos casos COLO DO ÚTERO: previne 70% dos casos VULVA: previne 44% dos casos VAGINA: previne 56% dos casos ÂNUS: previne 87% dos casos VERRUGAS GENITAIS: Previne 90% dos casos 1. Bula da vacina contra HPV oncogênico (16 e 18, recombinante, com adjuvante AS04) 2. Bula da vacina quadrivalente recombinante contra o HPV 6, 11, 16 e 18. 3. Gillison ML, Chaturvedi AK, Lowy DR. HPV prophylactic vaccines and the potential prevention of noncervical cancers in both men and women. Cancer 2008;113(10 Suppl):3036 46
Tumores causados por HPV 6 e 11: benignos mas de elevada morbidade 1. Jansen KU, Shaw AR. Annu Rev Med. 2004;55:319 331. 2. Koutsky L. Am J Med. 1997;102:3 8. 3. Franco EL, Villa LL, Richardson H, Rohan TE, Ferenczy A. In: Franco EL, Monsonego J, eds. Oxford, UK: Blackwell Science; 1997:14 22. 4. Tortolero-Luna G. Hematol Oncol Clin North Am. 1999;13:245 257, x. Derkay CS. Laryngoscope. 2001;111:57 69. Abramson AL, Nouri M, Mullooly V, Fisch G, Steinberg BM. J Med Virol. 2004;72:473 477
HPV vaccination Phase II and III trial findings already in the public domain. Safety and efficacy of VLP vaccines documented by numerous peer-reviewed publications in leading medical journals. Although clinical experience has just passed 8 years, the evidence base is one of the strongest in disease prevention. The standard of proof is far more rigorous than that used in the evaluation of candidate vaccines of the past. Possibly, the most scrutinized vaccine by the public and media concerning need and safety.
Impacto das vacinas contra HPV Curto prazo (meses) Taxas de infecção por HPV Incidência de verrugas genitais Intermediário (anos) Redução da incidência de lesões cervicais (NIC) Longo prazo (décadas) Incidência e mortalidade por câncer cervical, anal, outros tumores anogenitais e câncer de orofaringe Brotherton JM et al. Expert Rev Anti Infect Ther. 2011;9(8):627-639.
Impacto da vacinação contra HPV: Australia Redução de verrugas genitais em mulheres % of new patients diagnosed with GW (women <21 yo) 25% 20% 16,90% 18,80% Start of vaccination programme (Apr 07) 20,90% 18,60% VCR>70% 15% 10% 5% 6,00% 4,50% 1,90% -90% 0% July 2004-June 2005 July 2005-June 2006 July 2006 - June 2007 July 2007- June 2008 July 2008 - June 2009 July 2009 - June 2010 July 2010 - June 2011 In Australia, 90% reduction of new episode of genital warts since start of vaccination with Gardasil in young girls < 21 years old No reduction of GW incidence in groups not eligible for free HPV vaccination programme, i.e non-residents women >21 years old, males > 21 years old, and men having sex with men (MSM) VCR: Vaccine Coverage rate: >70% Adapted from Read TRH et al. Sex Transm Infect 2011
Proportion with genital warts % Impacto da vacinação em HOMENS (Australia) Proportion of men with genital warts by gender of sexual partners, by half year 2004-2010 18 16 14 12 p-trend=0.35 p-trend<0.001 10 8-35% 6 4 2 0 p-trend=0.03 Pre-vaccine period p-trend=0.19 Vaccine period Half year Heterosexual men Men who have sex with men
Impacto da vacina quadrivalente na Austrália: 5 anos após Dados de vigilância epidemiológica nacional da Australia (antes e após Introdução da vacina em mulheres de 10 a 26 anos) Redução de verrugas genitais foram observadas em -93% em mulheres até 21 anos de idade -73% em mulheres entre 21 e 30 anos -82% em homens heterossexuais menores de 21 anos -51% em homens heterossexuais entre 21 e 30 anos Pouca ou nenhuma redução em homens homossexuais, bissexuais e HSH ou em mulheres e homens acima de 30 anos Ali et al., BMJ 2013)
Impacto da vacina quadrivalente de HPV em programas públicos Australia New Zealand Denmark Sweden USA Germany Type of Program (start year) Coverage (youngest females) Decline in GW in youngest females School- and clinic-based (2007) School- and clinic-based (2008) Clinic-based (2008-2009) Clinic-based (2006-2007) Clinic-based (2006) Clinic-based (2007) 83% 52% 85% 32% 32% 40% 93% 63% 90% 41% 35% 47% Decline in high-grade abnorm. Decline in target HPV prevalence Herd protection for males Y - Y - [Less HPV 16/18] 67% - 49% - 56% - +++ ++ 0 + + - -
Impacto das vacinas contra HPV Curto prazo (meses) Taxas de infecção por HPV Incidencia de verrugas genitais Intermediário (anos) Redução de 50% dos casos de NIC3 e Redução da incidencia de lesões cervicais (NIC) AIS em jovens mulheres Australianas Largo prazo (décadas) Incidencia e mortalidade por câncer cervical, anal, Gertig et al., BMC Medicine 2013, outros tumores anogenitais y orofaringe apresentado no EUROGIN 6 nov 13)
WHO Recommendations The WHO recognizes the importance of cervical cancer and other HPV-related diseases as global health problems, and recommends HPV vaccines should be introduced as part of a coordinated strategy to prevent these diseases, that includes: Education about reducing behaviors that increase disease risk Cervical cancer screening Diagnosis and treatment of precancerous lesions and cancer Vaccination should not be deferred if screening is not available
México (desde 2008; 2011) Honduras (2012) Países con vacunación universal (6 implementada + 2 planeada) Bolivia (2009) Países con vacunación subnacional o proyectos pilotos (10) Organización Panamericana de la Salud Colombia (2011, 2012) Panamá (2008) Perú (piloto desde 2006) HPV vaccine introduction Americas, October 2012 2013, 2014 Uruguay, Chile, Canada (2007) USA (2006) Bermuda (2007) Cayman Islands & Haiti (2009) Guyana & Suriname (2do semestre 2012) DF, Manaus Argentina (2011) Courtesy of Andrea Vicari, PAHO Brazil (2014) Departamentos franceses (2007) Territorios británicos (2008) Municipios holandeses (2009) Proyecto de Inmunización Integral de la Familia
HPV Vaccination in Latin America: Opportunities and Challenges Competing public health priorities for vaccines and immunization Ensure broad vaccine delivery while maintaining cervical cancer screening (explore alternative technologies and screening intervals) Establish surveillance systems to monitor vaccine effectiveness Education: Improving understanding of cervical cancer and HPV is key Andrus et al., Vaccine 26S (2008): L80-7.
Screening after HPV vaccine introduction HPV test as primary screening tool followed by triage: Detects cervical carcinogenesis earlier than cytology -> longer latency -> safer approach HPV test is more sensitive and less subjective Performance less dependent on prevalence of infection and disease Cytology will have a better performance in a scenario of high prevalence of lesions such as in the case of triage of HPV positive women
HPV Vaccination and beyond To establish a monitoring and surveillance system that: Standardizes methodologies for large-scale use Communicates the impact of vaccination (vaccine efectiveness) in cervical screening programmes by raising awareness of successful existing programs HPV testing has the potential to perform better as a primary screening test, followed by cytology triage for those tested HPV positive 22
Steps in Natural History Cervical cancer prevention: a comprehensive approach Risk Factor Sexual Behaviour Cancer Precursor Primary Prevention (HPV Vaccination) HPV and CIN Secondary Prevention (Screening) Integration of Primary and Secondary Prevention: Shared resources, common surveillance systems, record linkage Invasive Cancer Incidence Courtesy of Eduardo Franco
Conclusions - I To achieve maximum impact of cervical cancer control through primary and secondary prevention 1 Ideally, all eligible women will be immunized All women should be encouraged to participate in cervical cancer screening, regardless of immunization status Fully integrated screening and vaccine programs are needed; each alone will not reach all women 24 1. Howlett RI et al. Prev Med. 2009;48:432 437.
Conclusions - II Unequivocal and large body of evidence in favor of HPV-based preventive strategies. Unknowns: age and frequency of screening, triage tests (secondary screening), cost of the program, technologies choice and standardization Health professionals serving as opinion leaders should understand the arguments against HPVbased strategies and be prepared to oppose them based on scientific facts.
Perspectives Development of better triage methods Biomarkers: p16, Ki67 MCMs, TOP2 Methyation Other Ongoing studies on different screening algorithms
HPV 16 53.5 HPV 18 17.2 HPV 45 6.7 HPV 31 2.9 HPV 33 2.6 HPV 52 2.3 HPV 58 2.2 HPV 35 1.4 HPV 59 1.3 Nonavalent: 90.1 HPV 56 1.2 Decavalent: 91.3 HPV 51 1.0 HPV 39 0.7 HPV 68 0.6 HPV 73 0.5 HPV 82 0.3 Vaccine Composition % Monovalent: 53.5 Bivalent: 70.7 Trivalent: 77.4 Tetravalent: 80.3 NONAVALENT vaccine = 2 LR types, 7 High-risk types Clinical trials performed in young women worlwide Pentavalent: 82.9 Hexavalent: 85.2 Heptavalent: 87.4 Octavalent: 88.8 First results presented at EUROGIN Firenze (IT), November 5, 2013: HIGH EFFICACY IN THE PREVENTION OF INFECTION AND CERVICAL NEOPLASIA 0 caused 20 by 40the 9 60 HPV vaccine 80 100 types Adapted from: Munoz et al., IJC 2004
Eight in 10 adolescent girls in the Americas have access to HPV vaccine, following its introduction in Brazil The WHO Global Advisory Committee on Vaccine Safety reaffirmed the vaccine s safety Washington, D.C., March 20, 2014 (PAHO/WHO)
Thank you Muito Obrigada luisa.villa@icesp.org.br llvilla@incthpv.org.br