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- 3. Inciden ţ a cancerului de col uterin pe plan mondial Î n fiecare an, î n lume, aprox. 500 000 femei sunt diagnosticate cu cancer de col uterin Ferlay J et al. Globocan 2002. IARC 2004. Age standardised rate (ASR) per 100,000 population (All ages) La fiecare 2 minute î n lume o femeie moare datorit ă cancerului de col uterin.
- 8. Rela ţ ia infec ţ i e HPV – c ancer Col uterin Anus Vulva/vagin Penis Gur ă Orofaringe 0 100 000 200 000 300 000 400 000 500 000 Cazuri HPV Total cazuri Vaccines: S.Plotkin et all. Saunders 2008
- 14. Cele mai des întâlnite tipuri de HPV î n cancerul cervical cu celule scuamoase 1 1. Mu ñoz N, Bosch FX, de Sanjosé S, et al. N Engl J Med . 2003;348:518–527. Pa c ient e cu Cancer Cervical cu Cell Scuamoase i nfect ate cu tipuri de HPV (%) 74%
- 15. Cele mai des întâlnite tipuri de HPV î n Adenocarcinomul Cervical 1 1. Andersson S, Rylander E, Larson B, et al. Oncol Rep . 2003;10:175–179. Pa c ient e HPV-Po z itive cu Adenocarcinom Cervical (%) 87%
- 17. Cancer Cervical Fumatul Diet a Utilizarea de lungă durată de OC* Co-factori potenţiali identificaţi şi implicaţi în carcinogeneza HPV 1 *OC = oral contraceptive 1. Castellsagué X, Mu ñoz N . J Natl Cancer Inst Monogr . 2003;31:20–28. Hormoni e ndogen i /Parit atea Factori Genetic i / Status ul Imun Co - infec ţie cu HIV şi alte infecţii cu transmitere s exual ă Trauma Cervical ă Variant e HPV Încărcătura Viral ă Integra rea Viral ă Infec ţia cu tipuri s pecific e HPV/ Co - infec ţie cu alte tipuri Mediul înconjurător sau Co-factori e xogen i Co - factor ii gazdei Co - factor i Viral i Infec ţia HPV
- 18. Screening Tratament Timp ani luni Infec ţ ie p ersistent ă cu HPV CIN = Cervical intraepithelial neoplasia E voluţi a natural ă a infectiei cu HPV oncogenice catre c ancer de col uterin Low-grade squamous intraepithelial lesions (LSILs) High-grade squamous intraepithelial lesions (HSILs) Carcinom Invaziv Epiteliu n ormal I nfectie HPV; koilocitoza CIN I CIN II CIN III
- 22. Epiteliu Normal Suprafata cervicala Membrana bazal ă Celule bazale (Stem) Celule Parabazale Strat scuamos Strat scuamos matur . . . . . . . Epiteliu Infectat Adaptat dupa Frazer IH. Nature Rev Immunol . 2004;4:46–54. Eliberarea virionilor cu celulele descuamate Infec ţi a celulelor bazale Integrare material genetic î n genomul celulei epiteliale Replicare de ADN viral Abia aici Virusul devine VIZIBIL pentru APC! Ciclul i nfec ţ ios al HPV ->
- 23. Ciclul infec ţ ios HPV : mecanism sofisticat de “camuflaj” pentru a nu fi detectat de sistemul imun 1-4 1.Stanley M. Vaccine 2006; 24: S106-13, 2.Tindle, Nat Rev Cancer 2002; 2, 59, 3.Stanley M. Vaccine 2006; 24: S16-22, 4. Stanley M. HPV Today 2007; 11: 1-16 Infec ţ ie localizat ă 1-4 Infectarea epiteliului prin micro abraziuni 1-4 F ă r ă viremie Intra î n celulele stratului bazal epitelial, integrarea AND-ului î n genomul celulei gazd ă 1-4 Replicare intracelular ă , r ă m â ne cantonat strict intraepitelial 1-4 Imunosupresie local ă 1-4 Utilizeaza ciclul natural al celulelor epiteliale pentru a produce si elibera noi virioni 1-4 Nu genereaza moarte celulara 1-4 F ă r ă inflama ţ ie, f ă r ă atrac ţ ia de celule imune Slab ă expunere c ă tre celulele prezentatoare de antigen = APC
- 24. Structura HPV Pentamer constituit din proteina L1 Proteina matriceal ă L2 & materialul genetic viral AD N Circular Virus relativ mic ce con ţ ine un AD N circular , dublu-catenar î n interiorul unei “cochilii” virale sferice (capsida)
- 25. Formarea HPV VLP Modelul structural al VLP de papillomavirus VLP (~20,000 kD) 72 Capsomere Capsomerul L1 (~280 kD) 5 x L1 Proteina L1 (55 – 57 kD) * VLP = Virus-like particle. 1.Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller JT. Proc Natl Acad Sci USA. 1992;89:12180–12184. 2. Syrjänen KJ, Syrjänen SM. Chichester, United Kingdom: John Wiley & Sons, Inc; 2000:11–51 .
- 26. Influenţa vârstei la înrolare asupra GMT neutralizanţi a nti-HPV 6 în luna 7 1 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Vârsta la includere (ani) 500 700 900 1,100 1,300 1,500 1,600 GMT neutralizanţi serici cu 95% CI , mMU/mL Studiile de eficienţă Imunogenicitate 1. Data on file, MSD. Numărul de subiecţi evaluabili (n) Vârsta 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 n 68 129 166 141 166 148 109 85 137 440 511 624 576 564 400
- 27. Rezultate: non-inferioritate in grupa 10 – 14 ani comparativ cu 15 – 25 ani GMC log (EU/ml) 100 % 100 % Imunogenicitate la luna 7: GMT si Rata de Seroconversie (SC) 1 10 100 1000 10000 100000 10-14 ani 15-25 ani HPV-16 Adapted from Pedersenet al. Journal of Adolesent Health (JAH). 40 (2007) 564–571 Valoare absoluta 17.273 EU Valoare absoluta 7.293 EU -> -> Seropositivity defined as titer ≥ 8 EU/ml GMT este dublu la grupa 10-14 ani
- 28. Rezultate: non-inferioritate in grupa 10 – 14 ani comparativ cu 15 – 25 ani GMC log (EU/ml) HPV-18 1 10 100 1000 10000 100000 10-14 ani 15-25 ani 100 % 100 % Adapted from Pedersenet al. Journal of Adolesent Health (JAH). 40 (2007) 564–571 Imunogenicitate la luna 7: GMT si Rata de Seroconversie (SC) Valoare absoluta 6.864 EU Valoare absoluta 3.319 EU -> -> -> Seropositivity defined as titer ≥ 7 EU/ml GMT este dublu la grupa 10-14 ani
- 29. Influenţa vârstei la înrolare asupra GMT neutralizanţi a nti-HPV 6 în luna 7 1 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Vârsta la includere (ani) 500 700 900 1,100 1,300 1,500 1,600 GMT neutralizanţi serici cu 95% CI , mMU/mL Studiile de eficienţă Imunogenicitate 1. Data on file, MSD. Numărul de subiecţi evaluabili (n) Vârsta 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 n 68 129 166 141 166 148 109 85 137 440 511 624 576 564 400
- 33. CMAJ • August 28, 2007 • 177(5)
- 35. CMAJ • August 28, 2007 • 177(5)
- 36. CMAJ • August 28, 2007 • 177(5)
- 37. Metaanaliză studii HPV CMAJ • August 28, 2007 • 177(5)
- 38. CMAJ • August 28, 2007 • 177(5)
- 39. Meta-analysis of serious adverse events and death in selected studies of prophylactic vaccination against HPV-related infection a nd disease CMAJ • August 28, 2007 • 177(5)
- 41. P â n ă la 6 , 4 ani: PROTEC Ţ IE SUS Ţ INUT Ă î n preven ţ ia Infec ţ iilor Persistente cu HPV-16/18 Analiza ATP pentru parametrii virologici n = numar de subjects care la care s-a raportat cel putin 1 eveniment in fiecare grup Analiza combinat ă a datelor: studiul ini ţ ial ş i follow-up extins Parametrii m ă sura ţ i pt HPV-16/18 Cervarix Control Eficacitatea Vaccinului n n % 95% CI Infec ţi e Incidental ă 4 70 95 87.4-98.7 Infec ţ ie Persistent ă la 6 luni 0 34 100 90.0 - 100 Infec ţ ie Persistent ă la 12 luni 0 20 100 81.8 - 100
- 42. P â n ă la 6 , 4 ani: PROTEC Ţ IE SUS Ţ INUT Ă preven ţ ia Infec ţ iilor Persistente ş i a leziunilor CIN determinate de HPV-16/18 Analiza combinat ă a datelor: studiul ini ţ ial ş i follow-up extins Analiza ATP pentru parametrii virologici ; Analiza ITT pt leziuni CIN n = numar de suiiec ţi care la care s-a raportat cel putin 1 eveniment in fiecare grup HPV-16/18 Endpoints Cervarix Control Eficacitatea Vaccinului n n % 95% CI Infec ţ ie Incidental ă 4 70 95 87.4-98.7 Infec ţ ie Persistent ă la 6 luni 0 34 100 90.0 - 100 Infec ţ ie Persistent ă la 12 luni 0 20 100 81.8 - 100 CIN1+ 0 15 100 73.4 - 100 CIN2+ 0 9 100 51.3 - 100
- 43. 100% Protec ţ ie - Confirmat ă an dup ă an preven ţ ia leziunilor CIN2+ determinate de HPV 16/18 1.Harper et al. Lancet. 2004; 364: 1757. 2.Harper et al. Lancet 2006; 367: 1247-55 3.Presentation Gall S, AACR, Los Angeles, April 14-18, 2007, abstract 4900 Analiza ITT n = numar de subjects care la care s-a raportat cel putin 1 eveniment in fiecare grup Studiu leziuni CIN2+ Legate de HPV 16/18 Cervarix TM Control Eficacitatea Vaccinului n n % 95% CI Studiul intial de eficacitate 27 luni 1 Analiza combinat ă a datelor: studiul ini ţ ial ş i follow-up extins 4 , 5 ani 2 5 , 5 ani 3 6 , 4 ani 0 3 100 NA 0 5 100 -7.7 - 100 0 7 100 32.7 - 100 0 9 100 51.3 - 100
- 44. 1.Harper et al. Lancet. 2004; 364: 1757. 2.Harper et al . Lancet 2006; 367: 1247-55 3.Presentation Gall S, AACR, Los Angeles, April 14-18, 2007, abstract 4900 100% Protec ţ ie - Confirmat ă an dup ă an preven ţ ia leziunilor CIN1+ determinate de HPV 16/18 Analiza ITT n = numar de sub i ec ţi care la care s-a raportat cel putin 1 eveniment in fiecare grup Studiu leziuni CIN 1+ Legate de HPV 16/18 Cervarix Control Eficacitatea Vaccinului n n % 95% CI Studiul initial de eficacitate 27 luni 1 Analiza combinat ă a datelor: studiul ini ţ ial ş i follow-up extins 4 , 5 ani 2 5 , 5 ani 3 6 , 4 ani 0 6 100 NA 0 8 100 42.4 - 100 0 11 100 61.5 - 100 0 15 100 73.4 - 100
- 45. FUTURE II: Rezultatele primare ale eficienţei PP (per-protocol) = au primit toate cele 3 doze de vaccin ; fără abateri de la protocol ; HPV sero(-) în ziua 1 şi HPV DNA(-) din ziua 1 până în luna 7; cazurile au fost cuantificate după luna 7 şi durata medie de urmărire a fost de 1.5 ani după încheierea regimului de vaccinare . FUTURE = Females United to Unilaterally Reduce Endo/Ectocervical Disease CIN = neoplazie cervicală intraepitelială AIS = adenocarcinom in situ Populaţie per-protocol Eficienţa în boala cauzată de HPV 16/18 SILGARD ™ Placebo Eficienţă (%) CI Valoa-rea P n Cazuri n Cazuri CIN 2/3 sau AIS 5301 0 5258 21 100 (76–100)* <0.001
- 46. FUTURE II: Rezultate secundare ale eficienţei MITT (modified intention to treat) = a primit ≥1 doză de vaccin ; HPV sero(-) şi HPV DNA(-) în ziua 1; cazurile au fost cuantificate după 30 de zile de la prima vaccinare . Populaţie MITT Durata de urmărire: 2 ani după prima vaccinare FUTURE = Females United to Unilaterally Reduce Endo/Ectocervical Disease CIN = cervical intraepithelial neoplasia AIS = adenocarcinoma in situ Eficienţa în boala cauzată de HPV 16/18 SILGARD ™ Placebo Eficienţa (%) CI Valoarea P n Cazuri n Cazuri CIN 2/3 sau AIS 5736 1 5766 36 97 (83–100) <0.001
- 47. Mai mult decât atât !
- 48. P â n ă la 6 , 4 ani PROTEC Ţ IE Î NCRUCI Ş AT Ă sus ţ inut ă î n preven ţ ia infec ţ iei incidentale cu tipurile HPV 45 & 31 Analiza ATP HPV-16, 18, 45 si 31: sunt responsabile de 80% dintre carcinoamele squamocelulare si > 80% dintre adenocarcinoame Analiza combinata a datelor: studiul initial si follow-up extins n = numar de subjects care la care s-a raportat cel putin 1 eveniment in fiecare grup Tip de HPV Cervarix Control Eficacitatea Vaccinului n n % 95 % CI HPV-45 5 21 78 39.3-93.4 HPV-31 13 30 60 20.5-80.7
- 49. Siguranta Reproducerii *Totals do not include blinded outcomes, ectopic pregnancies. N = number of subjects with pregnancies included in each group; n = number of subjects reporting at least one event in each group ITT analysis Follow-up extins Sarcini / rezultatele sarcinilor* Cervarix N=130 Control N=131 n % n % Sarcina in evolutie 4 3.1% 9 6.9% Sugar normal 104 80.0% 90 68.7% Avort Spontan * 10 7.7% 15 11.5% Avort la cerere 6 4.6% 5 3.8% Avort incomplet 1 0.8% 3 2.3% Fat nascut mort 1 0.8% 1 0.8% Sugar anormal 1 0.8% 5 3.8% Nastere prematura 2 1.5% 2 1.5%
- 50. In general, un bun profil de siguranta pana la 6.4 ani Analiza ITT Follow-up extins *ex.diabet zaharat, boli autoimune N = numar de subiecti inclusi in fiecare grup; n = numar de subjects care la care s-a raportat cel putin 1 eveniment in fiecare grup Nu sunt motive de îngrijorare Vaccin (N=393) n Control (N=383) n Evenimente adverse Femei cu cel putin un eveniment advers raportat 110 (28%) 126 (32.9%) Numar de Evenimente Adverse raportate 149 202 New Onset Chronic Disease (NOCD)* Aparitia de boli cronice de novo Femei cu cel putin un eveniment NOCD raportat 18 (4.6%) 21(5.5%) Numar de Evenimente NOCD raportate 21 23 Evenimente adverse severe ( EAS) Femei cu cel putin un EAS raportat 31 (7.9%) 39 (10.2%) Numar de Evenimente EAS raportate 36 46
- 56. VĂ MULŢUMESC !
Notas do Editor
- Global incidence The incidence of cervical cancer varies widely around the world, with the highest incidence in developing countries. Incidence rates exceeding > 30 cases per 100 , 000 population occur in Latin America and Sub-Saharan Africa with lower incidences observed in Western Europe, North America and Japan. The incidence rates for each country are available from the IARC database. The main reason for these variations in incidence is the availability of screening programmes in developed countries but not in poorer developing countries. Screening can detect the early signs of cervical cancer, allowing for prompt treatment to prevent the development of invasive and potentially fatal cervical cancer. It is important to understand that these figures are not necessarily accurate everywhere. They are sourced from WHO and IARC data , which varies in quality depending on country. Data from Finland, for example, will be perfect because they have good records systems and all cancers are routinely reported. In India, by contrast, very few centres report into data sources and in some areas of Africa, incidence figures are an estimate only due to the lack of availability of cancer registries or other reporting mechanisms . Likewise, t he incidence in China is reported to be low, but may be due to under-reporting . Reference: Ferlay J et al . Globocan 2002. IARCPress 2004.
- HPV is the most common sexually transmitted disease in the US Diferenta intre infectia incidentala – AND in secretii Are semnificatie daca gasesc la 6 luni acelasi HPV 50% contractează infecţia ăn primii 3 ani de la debutul vieţii sexuale. Moscicki AB. 2005
- Key Point There are many different types of HPV; of the 15 – 20 oncogenic types, HPV 16 and HPV 18 account for the majority of cervical cancers. Background Papillomaviruses such as HPV are nonenveloped, double-stranded DNA viruses. 1 More than 100 HPV types have been detected, 2 with >80 types sequenced and classified. 3 Approximately 30 – 40 types of HPV are anogenital, of which 15 –20 types are oncogenic. 2,3 HPV Types 16 and 18 are oncogenic and account for about two thirds of all cervical cancers—the next 5 most prevalent types (31, 33, 45, 52, 58) account for only an additional 18% of cases. 4 Other oncogenic HPV types include 35, 39, 51, and 56. 5 HPV Types 6 and 11 are nononcogenic and are associated with external anogenital warts and recurrent respiratory papilloma (RRP). 3,6 References 1. Howley PM. Papillomaviruses and their replication. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology . 4th ed. Philadelphia, Pa: Lippincott-Raven; 2002:2197–2229. 2. Schiffman M, Castle PE. Human papillomavirus: Epidemiology and public health. Arch Pathol Lab Med . 2003;127:930–934. 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. 4. Clifford GM, Smith JS, Aguado T, Franceschi S. Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: A meta-analysis. Br J Cancer . 2003:89;101–105. 5. Mu ñ oz N, Bosch FX, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med . 2003;348:518–527. 6. Abramson AL, Nouri M, Mullooly V, Fisch G, Steinberg BM. Latent human papillomavirus infection is comparable in the larynx and trachea. J Med Virol . 2004;72:473 – 477.
- Pana in 90 – mai multe teorii In 1990 – hpv – ccu relatie dem
- Key Point Infection with HPV will typically clear, but some infections with high-risk HPV types may ultimately lead to cervical cancer via a number of intermediate steps. Background Following initial HPV infection, the course of progression to cervical cancer depends on the type of HPV. Low-risk HPV types (such as HPV 6 or 11) have a negligible risk of progressing, but may persist. 1 Persistent HPV infection is the detection of the same HPV type in follow-up visits 6–12 months apart in women who were naive for that particular HPV type at baseline. 2 High-risk types (such as types HPV 16 and 18) are often associated with CIN 2 or higher lesions. 1 The strong association of HPV 16 with CIN 2 or greater suggests that lesions caused by this infection evolve to CIN 2 without a prolonged period as CIN 1. Some CIN 3 cases may arise from oncogenic HPV infections without evolving from CIN 1. 1 In a cohort study of 241 women with initially negative cervical cytologic smears, most women who developed CIN 2/3 never had evidence of preceding CIN 1. In these women, detection of high-risk HPV was a better predictor of the development of CIN 2/3 than was detection of CIN 1. 3 Incident HPV infection is the new detection of HPV infection in women who were previously HPV-negative. Although common in sexually active persons, more than 90% of infections are spontaneously cleared by the immune system within approximately 1 year without treatment. 2 Approximately 60% of CIN 1 lesions (or low-grade dysplasia), the most common clinical manifestation of cervical HPV infections, regress without treatment, and about 10% can progress to CIN 2 and CIN 3. 2,4 CIN 2 (moderate-grade dysplasia) also can regress; however women with CIN 2 are still at risk for developing invasive cervical cancer. In a meta-analysis of studies on the natural history of CIN, it was estimated that 22% of CIN 2 lesions that were not treated will progress. *,2 CIN 3 lesions (high-grade precancerous lesions and carcinoma in situ) are more likely to persist or progress to cancer, with regression being less common. 2 When HPV infection does progress to CIN in young adult women, 1 study reported that the time from detection of HPV infection to progression to cervical and vaginal SIL can be rapid (4 and 8 months, respectively). 5 However, in another study, a substantial proportion of women with high-risk HPV infections who were cytomorphologically normal at recruitment developed CIN 2 or 3 within 5 years of infection. 6 In general, CIN occurs at least a decade earlier than invasive cancer, supporting a concept of the temporal evolution of cervical cancer. 4 Based on a Markov model that approximated age-specific incidence of cervical cancer and HPV infection–associated events, the peak prevalence of LSIL is at 28 years of age, at 42 years of age for HSIL, and at 48 years of age for cervical cancer. 7 *Some studies have shown that CIN 2 may represent a heterogeneous group, including both lesions that regress and those that progress. This may be due to a misclassification of CIN 1 as CIN 2. 2 References 1. Pinto AP, Crum CP. Natural history of cervical neoplasia: Defining progression and its consequence. Clin Obstet Gynecol . 2000;43:352–362. 2. Pagliusi SR, Aguado MT. Vaccine . 2004;23:569–578. 3. Koutsky LA, Holmes KK, Critchlow CW, et al. A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. N Engl J Med . 1992;327:1272–1278. 4. Östö r AG. Natural history of cervical intraepithelial neoplasia: A critical review. Int J Gynecol Pathol . 1993;12:186–192. 5. Winer RL, Kiviat NB, Hughes JP, et al. Development and duration of human papillomavirus lesions, after initial infection. J Infect Dis . 2005;191:731–738. 6. Rozendaal L, Walboomers JMM, van der Linden JC, et al. PCR-based high-risk HPV test in cervical cancer screening gives objective risk assessment of women with cytomorphologically normal cervical smears. Int J Cancer . 1996;68:766–769. 7. Myers ER, McCrory DC, Nanda K, Bastian L, Matchar DB. Mathematical model for the natural history of human papillomavirus infection and cervical carcinogenesis. Am J Epidemiol . 2000;151:1158–1171.
- Key Point Well-demarcated, dense, opaque, acetowhite areas in the transformation zone of the cervix often determine the colposcopic diagnosis of CIN. Background Low-grade CIN is often seen as thin, smooth acetowhite lesions with well-demarcated, but irregular, feathery or digitating or angular margins, as is observed in this example of CIN 1 (see arrow). In comparison to high-grade lesions, many low-grade CIN lesions show mildly dense, less extensive and less complex acetowhite areas close to or abutting the squamocolumnar junction. 1 High-grade lesions show well demarcated, regular margins, which sometimes have raised and rolled out edges. High-grade lesions, like the CIN 2 and CIN 3 examples shown, have a thick, dull, opaque or greyish-white appearance. Coarse punctation (see a) and mosaics (see b) can be observed in the CIN 2 colposcopy image. High-grade CIN may also sometimes extend into the endocervical canal. As CIN lesions become more severe, their surfaces become less smooth and less reflective of light, as in normal squamous epithelium. 1 Reference 1. Sellors JW, Sankaranarayanan R, eds. Colposcopy and Treatment of Cervical Intraepithelial Neoplasia. A Beginner’s Manual. Lyon, France: International Agency for Research on Cancer; 2003.
- Key Point HPV Types 16 and 18 are the most common HPV types found in women with squamous cell cervical cancer. Background Although many HPV types are known, only a few of them cause the majority of cervical cancers. 1 ,2 Together, HPV Types 16, 18, 45, 31, and 33 account for ~80% –90 % of squamous cell carcinomas. 1 ,2 In a pooled analysis of 11 case-control studies from 9 countries, Mu ñoz and colleagues evaluated the risk associated with HPV by type. 1 The analysis included 1918 women with histologically confirmed squamous cell cervical cancer and 1928 controls. Cervical cells were collected for detection of HPV DNA and typing in a central laboratory by polymerase chain reaction (PCR)–based assays . HPV DNA was detected in 1739 of the 1918 women with cervical cancer (90.7%) and in 259 of the 1928 control women (13.4%). The most common HPV types were Types 16 (58.9%), 18 (15.0%), and 45 (5.9%). The researchers classified these 3 HPV types, as well as Types 31, 33, 35, 39, 51, 52, 56, 58, 59, 68, 73, and 82 as high risk for cervical cancer. In addition HPV Types 26, 53, and 66 were classified as probable high risk. 1 References 1. Mu ñoz N, Bosch FX, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med . 2003;348:518–527. 2. Bosch FX, de Sanjos é S. Chapter 1: Human papillomavirus and cervical cancer—Burden and assessment of causality. J Natl Cancer Inst Monogr . 2003;31:3 – 13.
- Key Point HPV Type 18 is the most frequently occurring type in cervical adenocarcinomas. Background HPV Type 16 is the most common type present in cervical squamous carcinomas. 1,2 In contrast to squamous carcinomas, HPV Type 18 is the predominating type in cervical adenocarcinomas. 2 In a study of 173 cervical adenocarcinomas, 68% were positive for HPV. Among the HPV-positive tumors, HPV Type 18 was most prevalent (52%), followed by HPV Type 16 (35%) and HPV Type 45 (7.7%). 2 HPV Types 31, 42, and 59 comprise an additional 2.7%. 2 References 1. Mu ñoz N, Bosch FX, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med . 2003;348:518–527. 2. Andersson S, Rylander E, Larson B, et al. Types of human papillomavirus revealed in cervical adenocarcinomas after DNA sequencing. Oncol Rep . 2003;10:175 – 179.
- Key Point Although HPV infection is necessary for the development of cervical cancer, progression to cancer is probably influenced by a combination of host, environmental, and virological factors. Background HPV infection alone may not be sufficient to cause cervical cancer. Other host, environmental, and virological cofactors may exist that influence the risk of progression from cervical HPV infection to cervical cancer. 1 Based on key studies on HSIL and cervical cancer conducted among HPV-positive women, it can be concluded that high parity, smoking, and, less consistently, long-term oral contraceptive use are cofactors that may modulate the risk of progression risk of progression from HPV infection to HSIL/cervical cancer. 1,2 Coinfection with HIV is also a known cofactor of HPV progression. 1,2 Other possible cofactors for HPV progression identified include coinfection with sexually transmitted infections (other than HIV) and diet. 1 – 4 Viral cofactors, including high viral load, 1,5 and host cofactors, including genetic disposition and endogenous hormones 1,2 are also considered possible cofactors for HPV progression. References 1. Castellsagu é X , Mu ñ oz N. Cofactors in human papillomavirus carcinogenesis—Role of parity, oral contraceptives, and tobacco smoking. J Nat l Can cer Inst Monogr . 2003;31:20–28. 2. American Cancer Society. Detailed guide: Cervical cancer. Available at: www.cancer.org/docroot/CRI/content/CRI_2_4_2X_What_are_the_risk_factors_for_cervical_cancer_8asp?sitearea= Accessed January 24, 2006. 3. Smith JS, Herrero R, Bosetti C, et al. Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer. J Natl Cancer Inst . 2002;94:1604–1613. 4. Smith JS, Muñoz N, Herrero R, et al. Evidence for Chlamydia trachomatis as a human papillomavirus cofactor in the etiology of invasive cervical cancer in Brazil and the Philippines. J Infect Dis . 2002;185:324–331. 5. Moberg M, Gustavsson I, Wilander E, Gyllensten U. High viral loads of human papillomavirus predict risk of invasive cervical carcinoma. Br J Cancer . 2005;92:891–894.
- infectia cu HPV Oncogenic & progresia catre cancer ce col uterin It takes years for cervical lesions to develop. Most infections will be transient. However, some may persist and a persistent infection is a necessary cause for cervical cancer. The progressive development of cellular changes from HPV infection to cervical cancer is shown visually on this slide. It starts with infecton of the basal cell layers of the epithelium by HPV. The whole process generally takes 10 –4 0 years, although , in very few cases , it may only take 1 – 2 years. 1 CIN I changes can arise within 3 months of infection , CIN II within 6 months and CIN III within 1 – 2 years. As shown in the slide, abnormal infected cells and CIN I can also be termed low-grade squamous intraepithelial lesions (LSILs), while CIN II and CIN III can also be termed high-grade squamous intraepithelial lesions (HSILs). 1,2 Cytological screening works by detecting cells scraped from the surface of these lesions , which are then classified as LSIL or HSIL by cytology. In addition, there are cytology categories of ASC-US (atypical squamous cells of uncertain significance) for abnormal cell changes thought to show possible minor, low-grade changes, and ASC-H for abnormal cells that might show high-grade abnormality. There is also a pathway to glandular (adeno) carcinoma that includes adenocarcinoma in situ (AIS) and atypical glandular cells of undetermined significance (AGUS) . References Burd EM. Clin Microbiol Rev 2003;16:1 – 17. Solomon D et al. JAMA 2002;287:2114 –9 .
- 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 et al evaluated US female university students (N=603; 18 – 20 years of age) at 4-month intervals between 1990 and 2000. 1 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 most HPV infections may clear within 2 years, many young women may 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. 2/ Winer/p. 218/ abstract; col 1/¶2; p. 220; col 1/¶2, 3. 1/ Collins/p. 96/col 1/¶2; Table 1; p. 97; col 1/¶2; Figure 1; p. 96/ abstract. 3/ Richardson/p. 485/abstract. 1/ Collins/p. 96/abstract; p. 97/Figure 1. 2/Winer/ p. 221/Figure 2
- Key Point In 2003, the American College of Obstetrics and Gynecology (ACOG) provided new HPV screening recommendations. Background In 2003, the American College of Obstetrics and Gynecology issued its most recent revision of cervical cancer screening guidelines. These guidelines focus on age and prior history of abnormal cytology as key criteria for determination of screening frequency. The revised ACOG guidelines indicate that screening can begin later than previously suggested: approximately 3 years after initiation of sexual intercourse, but no later than 21 years of age. It is also recommended that for women ≥ 30 years of age who have had a negative test result on both HPV DNA and Pap smear tests, rescreening should occur no more frequently than every 3 years. More frequent screening may be required in women with human immunodeficiency virus (HIV) infection or other immunosuppression, and in those who were exposed to diethylstilbestrol (DES) in utero . 1 Reference 1. American College of Obstetrics and Gynecology. ACOG Practice Bulletin: Cervical Cytology Screening. Int J Gynecol Obstet . 2003;83:237 – 247.
- Value of cervical screening Regular cytology screening involving Pap smear testing (or liquid-based cytology) can be effective in identifying the development of cervical cancer, enabling treatment to be given at an early stage. A well-implemented screening programme can reduce the incidence of cervical cancer in a country by approximately 80%. 1 This still means that 20% of cancers, particularly adenocarcinomas , are evading screening. In most cases, however, the screening programme enables the detection of abnormal cells at an early stage. These can be monitored and, if necessary, treated or removed to prevent their progression, eventually, to the development of cervical cancer. Of course, this process is stressful for the women involved, particularly for those who have positive smears and need follow-up investigations or treatment, causing the fear of premature death from cervical cancer. However, there is good evidence that regular screening of appropriate women with the Pap test reduces mortality from cervical cancer. 2 Screening visits will provide an ideal opportunity for integrating vaccination with current screening programmes. Reference s : Schiller JT et al . Nat Rev Microbiol 2004; 2: 343 – 7. National Cancer Institute. Screening for cervical cancer. Available at: http://www.meb.uni-bonn.de/cancer.gov/CDR0000062756.html. Limitations of cervical screening Although useful if fully implemented, a cytology-based screening programme does have limitations. It cannot prevent infection with oncogenic HPV or the subsequent development of pre-cancerous lesions. It is also a very expensive and demanding system to set up and maintain. Even if fully implemented, the system depends upon the accuracy of the cytologists or pathologists who examine the smears – up to 30% false-negative results have been recorded. 1 Another limitation of the Pap smear procedure is that approximately 8% of specimens received are inadequate. 2 In addition, many women are affected by the anxiety of having positive smears and the need for follow-up investigations or treatment. 3,4 Adenocarcinomas are more difficult to detect than squamous cell carcinomas using cytology screening, because they tend to be deeper in the cervical tissue. With a Pap smear or other cytology screening, cells are removed only from the surface of the cervix. False-negative and false-positive results are fairly common. False-negative results can allow cervical cancer to continue to develop, while false-positive results only lead to a repeat smear test being undertaken. The risk of false-negative results is greatest for adenocarcinomas, which are unlikely to be detected by Pap smear screening until they are at an advanced stage. Adenocarcinomas are particularly associated with persistent HPV 18 infections. Women can also suffer anxiety, discomfort and complications from the actual procedures involved in the initial screen as well as any follow-up investigations and therapeutic interventions. Reference s : Renshaw AA et al . Arch Pathol Lab Med 2004; 128: 153–7. Burd EM. Clin Microbiol Rev 2003; 16: 1 – 17. Bell S et al . Prev Med 1995; 24: 610 – 16. Lerman C et al . Am J Obstet Gynecol 1991; 165: 658 – 62.
- Key Point Virus-like particles spontaneously assemble when the HPV L1 protein is overexpressed in several different cell types. Virus-like particles consist of 72 capsomeres, each of which is composed of 5 L1 molecules. Background When overexpressed in mammalian, 1 insect, 2 yeast, 3 or bacterial cells, 4 the papillomavirus L1 protein spontaneously assembles to form VLPs that are devoid of the oncogenic viral genome . 5 High-resolution cryoelectron microscopic analysis has determined that the HPV structure consists of 72 pentameric capsomeres, each composed of 5 L1 molecules. 2,6 References Hagensee ME, Yaegashi N, Galloway DA. Self-assembly of human papillomavirus type 1 capsids by expression of the L1 protein alone or by coexpression of the L1 and L2 capsid proteins. J Virol . 1993;67:315 –322 . Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller JT. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci USA . 1992;89:12180–12184. Jansen KU, Rosolowsky M, Schultz LD, et al. Vaccination with yeast-expressed cottontail rabbit papillomavirus (CRPV) virus-like particles protects rabbits from CRPV-induced papilloma formation. Vaccine . 1995;13:1509–1514. Nardelli-Haefliger D, Roden R, Balmelli C, Potts A, Schiller J, De Grandi P. Mucosal but not parenteral immunization with purified human papillomavirus type 16 virus-like particles induces neutralizing titers of antibodies throughout the estrous cycle of mice. J Virol . 1999;73:9609–9613. 5. Roden R, Wu T-C. Preventative and therapeutic vaccines for cervical cancer. Expert Rev Vaccines. 2003;2:495–516. 6. Baker TS, Newcomb WW, Olson NH, Cowsert LM, Olson C, Brown JC. Structures of bovine and human papillomaviruses. Analysis by cryoelectron microscopy and three-dimensional image reconstruction. Biophys J . 1991;60:1445 – 56.
- Key Point Higher antibody responses to HPV 6 type was observed in adolescent males and females compared with adult women. Background An evaluation of the duration of anti-HPV levels induced by GARDASIL ® in 9- to 15- year-old boys and girls is ongoing. To date it has been observed that 1 month after the last vaccination (Month 7) neutralizing anti-HPV GMT levels for all 4 types are higher in young adolescents compared with older adolescents and young women (the age range in which the efficacy of GARDASIL was demonstrated). A similar profile is observed 1 year after the last vaccination dose. 1 This slide presents an example at Month 7 for neutralizing anti-HPV 6 GMTs by age at first vaccination in the per-protocol immunogenicity population of the Phase III integrated immunogenicity data set for 9- to 15-year-old boys, 9- to 17-year-old girls, and 18- to 26-year-old women (protocols 011, 012, 015, 016, 018). GARDASIL is a registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Reference 1. Data on file, MSD.
- GMT = Geometrical Medium Titer
- Key Point Higher antibody responses to HPV 6 type was observed in adolescent males and females compared with adult women. Background An evaluation of the duration of anti-HPV levels induced by GARDASIL ® in 9- to 15- year-old boys and girls is ongoing. To date it has been observed that 1 month after the last vaccination (Month 7) neutralizing anti-HPV GMT levels for all 4 types are higher in young adolescents compared with older adolescents and young women (the age range in which the efficacy of GARDASIL was demonstrated). A similar profile is observed 1 year after the last vaccination dose. 1 This slide presents an example at Month 7 for neutralizing anti-HPV 6 GMTs by age at first vaccination in the per-protocol immunogenicity population of the Phase III integrated immunogenicity data set for 9- to 15-year-old boys, 9- to 17-year-old girls, and 18- to 26-year-old women (protocols 011, 012, 015, 016, 018). GARDASIL is a registered trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Reference 1. Data on file, MSD.
- Key Point The clinical program for the HPV vaccine development has included over 25,000 patients. Background The clinical program to develop the quadrivalent HPV vaccine from Merck & Co, Inc. has included ~29,000 subjects: Phase I studies: ~300 subjects evaluated monovalent HPV vaccines. 1-4 Phase II studies: Expanded to ~3,500 subjects. These studies included a preliminary evaluation of vaccine efficacy and a dose-ranging study of the quadrivalent vaccine. 5,6 Phase III studies: Ongoing with the chosen quadrivalent vaccine formulation GARDASIL™. These studies include an evaluation of the impact of the vaccine on rates of CIN 1, genital warts, and most importantly, CIN 2/3 or worse, related to vaccine HPV types. 7 GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. References Fife KH, Wheeler CM, Koutsky LA, et al. Dose-ranging studies of the safety and immunogenicity of human papillomavirus type 11 and type 16 virus-like particle candidate vaccines in young healthy women. Vaccine . 2004;22:2943–2952. Poland GA, Jacobson RM, Koutsky LA et al. The immunogenicity and reactogenicity of a novel vaccine to human papillomavirus 16: Results of a 2-year randomised controlled clinical trial. Mayo Clin Proc . 2005;80:601–610. Ault KA, Giuliano AR, Edwards RP, Tamms G, Kim LL, Smith JF, Jansen KU, Allende M, Taddeo FJ, Skulsky D, Barr E. A phase I study to evaluate a human papillomavirus (HPV) type 18 L1 VLP vaccine. Vaccine . 2004;22:3004–3007. Brown DR, Bryan JT, Schroeder JM, et al. Neutralisation of human papillomavirus type 11 (HPV-11) by serum from women vaccinated with yeast-derived HPV-11 L1 virus-like particles: Correlation with competitive radioimmunoassay titre. J Infect Dis 2001;184:1183–1186. 5. Villa LL, Costa RLR, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: A randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol . 2005;6:271–278. 6. Koutsky LA, Ault KA, Wheeler CM, et al. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347:1645–1651. 7. Data on file, MSD.
- Key point The primary aim of the FUTURE II study (Females United to Unilaterally Reduce Endo/Ectocervical Disease) was to demonstrate protection with GARDASIL™ against biopsy-confirmed precancerous and cancerous lesions. Background This multinational study evaluated the impact of HPV (types 6, 11, 16, 18) L1 VLP vaccine on the rates of CIN 2/3 and cervical cancer. Vaccine or placebo was given at day 1, month 2, and month 6 to 12,167 randomized women 16–23 years of age. Pap tests and HPV swabs were taken at day 1 and months 7, 12, 24, 36, and 48. Colposcopy referral was algorithm-based, and biopsies were HPV typed. The primary end point was the combined incidence of HPV 16/18-related CIN 2/3, adenocarcinoma in situ (AIS), or cancer (read by blinded pathology panel). 1 The primary efficacy hypothesis for the FUTURE II study states that the quadrivalent HPV (types 6, 11, 16, 18) L1 VLP vaccine reduces the incidence of HPV 16/18-related CIN 2/3 or worse, compared with placebo. 1 GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Reference 1. Data on file, MSD.
- Key point According to the statistical plan for the FUTURE II study, the primary analysis was done in the per-protocol population. An analysis in a pre-specified modified intention-to-treat population aimed at assessing the efficacy of GARDASIL™ in a population that may be closer to real-life settings. Background In the FUTURE II study, analyses were done in a per-protocol (PP) population (subjects received 3 doses, had no major protocol violations, were HPV 16/18 seronegative at day 1 and HPV 16/18 DNA negative from day 1 through month 7) and in a pre-specified modified intention-to-treat (MITT) population (subjects received ≥1 dose and were HPV 16/18 negative at day 1). End point counts began at month 7 and day 30 in the PP and MITT analyses, respectively. 1 An interim analysis was done when ≥19 end point cases were seen in PP population, and PP population efficacy was tested at the = 0.0204 (2-sided level). 1 This occurred on average after 2 years post first vaccination. For the HPV 16/18-related CIN 2/3 (includes CIS), AIS, or cervical cancer end point in the PP population, 97.96% CI was reported. For the MITT analyses, CIs were 95%. 1 GARDASIL is a t rademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Reference 1. Data on file, MSD.
- Key point Results from the FUTURE II study show that GARDASIL™ was 100% efficacious against high-grade precancerous and noninvasive cancerous cervical lesions related to HPV 16 and 18 in a population of female subjects naïve to these types until completion of vaccination. Background In this study, prophylactic quadrivalent HPV vaccination with GARDASIL prevented 100% of HPV 16/18-related high-grade cervical precancerous and noninvasive cervical cancers (CIN 2/3 and AIS) in female subjects who were not infected with HPV 16 and 18 at enrollment and who remained free of infection through the completion of the vaccine regimen. 1 The analysis was completed on average 2 years after first vaccination. 1 This intervention is expected to reduce the risk of cervical cancer. 1 GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Reference 1. Data on file, MSD. Data on file; Memo 015 p. 4 Table 1. Data on file; Memo 015 p. 4/Table 1 footnote. 2.5 Clinical Overview p. 18 ¶ 3 Data on file; Memo 015 p. 4 Table 1. Data on file; 2.5 Clinical Overview p. 18 ¶ 3 Data on file; Memo 015 p. 2 ¶1
- Key point In a secondary analysis of the FUTURE II (Females United to Unilaterally Reduce Endo/Ectocervical Disease) study, GARDASIL™ was 97% efficacious against high-grade precancerous and noninvasive cancerous cervical lesions related to HPV 16 and 18 in an analysis conducted on a pre-specified modified intention-to-treat population and starting 30 days after the first vaccination. Background A secondary analysis of FUTURE II evaluated the incidence of CIN 2/3 and AIS in a broader group of women. This analysis started 30 days after administration of the first dose of GARDASIL or placebo, and included all of the women in the primary analysis group, as well as women who may have become infected with HPV 16 or 18 during the vaccination period, and women who may have violated the protocol in significant ways (for example, by missing certain protocol visits or vaccine doses). It should be noted though that the vast majority of subjects received all three doses. On average, these women were followed for 24 months after the first vaccination . In this group, GARDASIL reduced the risk of developing high-grade precancer and noninvasive cancer (CIN 2/3 or AIS) associated with HPV types 16 and 18 by 97% (n=5736); one case was observed in the vaccine group compared with 36 in the placebo group (n=5766). 1 This intervention is expected to reduce the risk of cervical cancer. 1 GARDASIL is a t rademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Reference 1. Data on file, MSD.