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. Course 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 Invasive cervical cancer is the stage of disease that follows CIN 3. In this stage, neoplastic epithelial cells have invaded the stroma underlying the epithelium. Background These colposcopic findings of invasive cervical cancer demonstrate exophytic raised lesions with raised and rolled out margins and the appearance of atypical vessels. 1 The colposcopy images on the right show coarse and irregular mosaic lesions indicative of invasive carcinoma of the cervix. Photos and description courtesy of Dr. J. Monsonego. 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 The CIN grading system classifies dysplasia into 3 categories based on histological changes. Although CIN caused by HPV infection often clears without treatment, the likelihood of progression to invasive cancer is greater in more severe grades (CIN 2/3). Background The CIN grading system classifies dysplasia into 3 categories based on histological changes: CIN 1 includes mild dysplasia and condyloma (anogenital warts), CIN 2 includes moderate dysplasia, and CIN 3 includes severe dysplasia and carcinoma in situ (CIS). 1 These lesions are graded based on the extent of abnormal proliferation of the basal layer of the cervical epithelium. In mild dysplasia (CIN 1), proliferation occurs up to the lower third of the epithelium. In moderate dysplasia (CIN 2), proliferation occurs up to the upper two thirds; and in severe dysplasia/CIS (CIN 3), the entire epithelium is abnormal. 1 When stratified into the various grades of severity, the composite data from a review indicate that the approximate likelihood of regression of CIN 1 is 60%, persistence is 30%, progression to CIN 3 is 10%, and progression to invasion is 1%. The corresponding approximations for CIN 2 are 40%, 40%, 20%, and 5%, respectively. The likelihood of CIN 3 regressing is 33% and progressing to invasion greater than 12%. 2 References 1. Bonnez W. Papillomavirus. In: Richman DD, Whitley RJ, Hayden FJ, eds. Clinical Virology . 2nd ed. Washington, DC: American Society for Microbiology Press; 2002:557 – 596. 2. Ostor AG. Natural history of cervical intraepithelial neoplasia: A critical review. Int J Gynecol Pathol . 1993;12:186–192.
Key Point More than 90% of anogenital warts are associated with HPV Types 6 and 11. Anogenital warts may be painful and embarrassing to treat. Many patients experience recurrence after treatment. Background More than 90% of anogenital warts are associated with HPV Types 6 and 11. 1 Studies have shown that up to 30% of genital warts cases spontaneously regress within 4 months. 2 Nevertheless, diagnosis of anogenital warts tends to create concern and anxiety in patients and may engender lifestyle changes with regard to sexual relationships. In addition, treatment may be painful and embarrassing. 3 External genital warts are very contagious; more than 75% of sexual partners develop warts when exposed. 4 Chemical treatments for anogenital warts include podofilox, imiquimod, podophyllin resin, trichloroacetic acid, and interferons; however, treatment with interferons is no longer recommended for routine use. Current ablative therapies include treatment with cryotherapy, surgical removal, and laser treatment. 5 Genital wart recurrence rates vary greatly. Approximate wart recurrence rates for various treatments are 5% – 30% for podofilox, 5% – 50% for laser treatment, 15% for imiquimod, 20% for surgical excision, 20% – 40% for cryotherapy, 20% – 65% for podophyllin resin, and 35% for trichloroacetic acid. 5 References 1. Jansen KU, Shaw AR. Annu Rev Med. 2004;55:319 –331. 2. Lacey CJN. Therapy for genital human papillomavirus-related disease. J Clin Virol . 2005;32(suppl):S82−S90. 3. Maw RD, Reitano M, Roy M. An international survey of patients with genital warts: Perceptions regarding treatment and impact on lifestyle. Int J STD AIDS . 1998;9:571–578. 4. Soper DE. Genitourinary infections and sexually transmitted diseases. In: Berek JS, ed. Novak’s Gynecology. 13th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2002:453 – 470. 5. Kodner CM, Nasraty S. Management of genital warts. Am Fam Physician . 2004;70:2335–2342.
Key Point Although most HPV infections are transient and asymptomatic, certain HPV types (eg, 16 and 18) are more likely to persist than other types. Background HPV infections are mostly transient. 1 The gradual development of an effective cell - mediated immune response is presumed to be the likely mechanism for HPV DNA clearance. 2 In a study of 608 college women, the median duration of new HPV infections was 8 months. 3 By 12 months after the incident infection, in about 70% of the women, HPV infection was no longer detected; and by 24 months, approximately 91% appeared to be cleared of HPV. 3 The incidence of high - risk HPV types was similar to the incidence of other types. 3 Virus types more likely to persist included HPV AE7, 16, 18, 61, and 73. 3 This study found that oncogenic HPV types are more likely to persist than nononcogenic types, but even these infections generally clear within 2 years. 3 References 1. Meijer CJLM, Helmerhorst TJM, Rozendaal L, van der Linden JC, Voorhorst FJ, Walboomers JMM. HPV typing and testing in gynaecological pathology: Has the time come? Histopathology . 1998;33:83 – 86. 2. Schiffman M, Kjaer SK. Chapter 2: Natural history of anogenital human papillomavirus infection and neoplasia. J Natl Cancer Inst Monogr . 2003;31:14 – 19. 3. Ho GYF, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med . 1998;338:423–428.
Key Point While the vast majority of subjects enrolled in the efficacy trials were negative to all 4 vaccine types at enrollment, those who were positive to at least 1 type were eligible for efficacy analysis. Background These efficacy studies did not include a screening phase; thus, some subjects were positive to 1 or more vaccine HPV types at baseline. These subjects were included in the overall efficacy analyses for GARDASIL ® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine], but only with respect to the types for which they were naïve at baseline. 1 An analysis was conducted in this subset of subjects who were seropositive or PCR-positive to at least 1 vaccine HPV type, to determine whether a woman who is positive to 1 or more vaccine HPV types prior to vaccination derives benefit from the vaccine against disease caused by the remaining vaccine HPV types. 1 While nearly three-quarters of the enrolled subjects were negative to all 4 vaccine types at enrollment, 27% were positive to at least 1 of the 4 vaccine types. Ninety-three percent of subjects had 1 or none of the HPV vaccine types at enrollment. Reference 1 . Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package XXXXXXX.
Key Point This study demonstrated that a monovalent HPV 16 L1 vaccine was highly immunogenic, producing elevated anti-HPV 16 levels at the completion of the vaccination regimen. Background In a randomized, double-blind, placebo-controlled study, 2,391 women (16 to 23 years of age), received either 40 μ g HPV 16 L1 VLP vaccine or placebo at Day 1, Month 2, and Month 6. Serum HPV 16 antibody titer was measured by competitive radioimmunoassay (cRIA). 1 After immunization, HPV 16 serum antibody geometric mean titer (GMT) peaked at Month 7 (1,519 milli-Merck units [mMU]/mL), declined through Month 18 (202 mMU/mL), and remained relatively stable between Month 30 and Month 48 (128 – 150 mMU/mL). 1 The duration of protection of GARDASIL ® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] is unknown beyond 48 months. Because there were few disease cases in subjects naïve to vaccine types at baseline in the group that received GARDASIL, it has not been possible to establish minimum anti- HPV 6, 11, 16, and 18 antibody levels that protect against clinical disease caused by these types. Reference 1 . Mao C, Koutsky LA, Ault KA, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol . 2006;107:18 – 27.
Key Point The effect of the variation of the dosing regimen on GMTs was evaluated. Background It is recommended that the 3 doses of GARDASIL ® [Quadrivalent Human Papillomavirus (HPV Types 6, 11, 16, 18) Recombinant Vaccine] are administered at 0, 2, and 6 months. To determine the impact of early or delayed dosing, anti-HPV GMTs were evaluated at 1 month Postdose 3 among subjects who received Dose 2 between Month 1 and Month 3 and subjects who received Dose 3 between Month 4 and Month 8. All subjects evaluated in the PPE populations of the Phase II and III studies received the 3-dose regimen of GARDASIL within a 1-year period, regardless of the interval between doses. GMTs were evaluated in subjects who received dosing ±1 month for Dose 2 (ie, Month 1 to Month 3 in the vaccination regimen) and ±2 months for Dose 3 (ie, Month 4 to Month 8 in the vaccination regimen). These data indicate that dosing within 1 month for Dose 2 and within 2 months for Dose 3 resulted in only a small effect on the antibody levels across all 4 vaccine types. Therefore, administering the second and third doses of GARDASIL to Patient 1, one month after the recommended time, should result in only small differences in levels of antibodies to HPV 6/11/16/18, compared with the levels observed in patients who received Doses 2 and 3 on schedule. Package Insert/p. 6/ Table 4 Package Insert/p. 6/ lines 175-176 Package Insert/p. 6/ Table 4 Package insert/ p.13/lines 412-416
Lesotho hpv vaccine 2012
Preventing Cervical Cancer in Lesotho Sejojo Phaaroe
Cervical Cancer Worldwide Disease Burden• 2nd most common cancer in women worldwide• Number one cause of cancer-related deaths in women in the developing world• Annual disease burden – 493,000 cases – 273,500 deaths• 90% of cervical cancer cases in the developing world
Base Programs on the Needs of our People50% of young people between 15 and 24 years of age will DIE within the next 10 years!
Lesotho Disease Burden• QEII data – 1April2006 – 31March2007 – 680 cervical cancer referrals – If 25-33% of population seek out treatment at the national referral hospital then 2000-2800 women may have late stage disease in Lesotho• Leribe and Mohale’s Hoek Referrals* – 1Jan2005 – 31March2006 – Retrospective analysis of cytology and hystology archives – Age Standardized Incidence Rate (ASIR) 66.7:100,000 women
Cervical Cancer by Age90% of cervical cancer cases were in women over age 39
Human Papillomavirus (HPV) Infection• HPV is the most common sexually transmitted infection• Causes 99% of cervical cancer cases worldwide• 100 different types of HPV, 40 types affect the genital tract• Types 16 & 18 cause 70% of cervical cancer cases
Cancer definition Cancer is a neoplastic proliferation of abnormal cells, invading surrounding tissue and giving distance metastases Cancer of the breast is the neoplastic proliferation of cells and tissues in the breast Abnormal proliferation starts with the genetic aberration in a single cell genetic material, which grows and give a clone of abnormal cells A number of factors contribute into the cellular disturbance
Correlation of ASIR rates in Southern AfricaCOUNTRY ASIR Sited PublicationSouth Africa 32.1 : 100 000 Freddy Sitas et al 1993Mali 21.0 : 100 000 Bayo et al 1990Uganda 43.6 : 100 000 Wabbinga et al 1993Gambia 13 : 100 000 Bah 1990Senegal 9 : 100 000 Bah et al 1988Lesotho 66.7 : 100 000 S. Phaaroe et al 2007Senegal & Gambia are Moslem areas( Low in Gambia)Zimbabwe 67:100 000 ( Dr Cronje – Oncology specialist : SebetaMemorial Lecture LMA AGM 8/7/06
Prevention Strategies PAP smear screening HPV testing Direct Visual Inspection Acetic acid –VIA HPV vaccine
P s y c h o lo g ic a l B io lo g ic a l/ C o u n s e li n g S o c ia l M e d ic a l C o n f li c t R e s o lu t i o n S tre n g th e n - P h a rm a c o - F a m i ly W H A T K IN D T h e ra p y C o m m u n it y O F S O L U T IO N ? E c o n o m ic E d u c a tio n L e g i s l a t iv e (la w ) N ew Jobs F in is h e d O u t la w F i r e a r m sH ig h S c h o o l M o r e P r is o n s / L o n g e r S e n te n c e s
National stake holders S. Phaaroe MM.T S. Phaaroe .T C.T(IAC), MIBMS C.T(IAC), MIBMS PSBH- REPORT Boston Education/Information-Magnitude of cancer PSBH- REPORT Boston University 2005 University 2005 Well women Well women groups/ church/ groups/ church/ Gyaenacology, Gyaenacology, women in Law, women in Law, Oncology, Oncology, every body, every body, Radiology, Radiology, Support groups/ Support groups/ Pharmacy etc Pharmacy etc men leagues men leagues Chiefs, local Chiefs, local government, government, FAMILY H, ED, FAMILY H, ED, CYTOPATHOLOGY village councils, CYTOPATHOLOGY village councils, PLANNING & PLANNING & BIOMEDICAL NETWORKS BIOMEDICAL NETWORKS Men’s clinics, Men’s clinics, SCIENCE SCIENCE private clinics RESEARCH LAB RESEARCH LAB private clinics linkage with is the central Technology Technology linkage with is the centralLBCN NGO’S in aahealth organ INCUBATION INCUBATION NGO’S in health organ system CENTRES, CENTRES, system SMME’s , ,Joined SMME’s Joined Bilateral Bilateral LEGAL EMPLOYMENT commissions/ commissions/ Education , , Education LEGAL EMPLOYMENT agreements Academic centers SYSTEMS, Policy SYSTEMS, Policy FORCE/ FORCE/ agreements Academic centers of excellence & makers, makers, Government Government of excellence & other Research International International Institutions Institutions other Research institutions conventions, conventions, Insurance Levy, Insurance Levy, institutions Regional Regional Businesses & Businesses & strategies strategies Industry Industry
Disease Burden HPV types 6, 11, 16, & 18HPV Type Approximate Disease Burden 70% of cervical cancer, AIS, CIN 3,16 and 18 VIN 2/3, and VaIN 2/3 cases 50% of CIN 2 cases 35%–50% of all CIN 1, VIN 1,6, 11, 16, and 18 and VaIN 1 cases 90% of genital warts cases
HPV Type Prevalence WorldwideClifford GM, Smith JS, Plummer M, Munoz N, Franceschi S. Human papillomavirus types in invasivecervical cancer worldwide: a meta-analysis. Br J Cancer. 2003;88: 63-73.
High prevalence of HPV 16 in South African women with cancer of the cervix andcervical intraepithelial neoplasia• Cervical cancer biopsies 82% contained type 16 and 10% type 18• 56.6% of CIN (cervical intraepithelial neoplaysia) lesions contained type 16 Kay P, Soeter R, Nevin J, Denny L, et al. High prevalence of HPV 16 in South African women with cancer of the cervix and cervical intraepithelial neoplasia. J Medical Virology 2003;71:265-273.
Gardasil®• Non-infectious, recombinant, quadrivalent vaccine• Prepared from highly purified virus-like particles (VLPs) of the major capsid protein (L1) protein• Contains no DNA• Protects against HPV types 6, 11, 16 & 18• Three separate IM injections – 1st dose: at elected date – 2nd dose: 2 months after the 1st dose – 3rd doses: 6 months after the 1st dose
Gardasil® Registration• Registered in 100 countries• U.S., all 27 member countries of the European Union, Mexico, Australia, Taiwan, Canada, New Zealand, and Brazil• U.S. FDA approval in June 2006• Africa registration: South Africa, Togo, Chad, Uganda• 26 million doses distributed worldwide• 11 million doses distributed in the U.S.
Clinical Trials• FUTURE I & FUTURE II studies• Phase III, prospective, double-blind, placebo controlled trials in 29 countries• Females ages 15 - 26
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] GARDASIL Is Efficacious Against HPV 16– and 18–Related CIN 2/3 or AIS GARDASIL Placebo 60 53 50 40 n=8,460 Related Cases 30 100% 20 Efficacy 10 n=8,487 0 0 CIN 2/3 or AIS 16- to 26-year-old females naïve to the relevant vaccine HPV type at enrollment and through 30 days Postdose 3 Over a period of 2 to 4 years Analysis included Protocol 005. CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ. 22
GARDASIL® (Quadrivalent Human Papillomavirus [HPV Types 6, 11, 16, 18] Recombinant Vaccine) Invasive Cervical Carcinoma From IARC, 2003.1 24
GARDASIL® (Quadrivalent Human Papillomavirus [HPV Types 6, 11, 16, 18] Recombinant Vaccine) Classification of Histological Findings CIN 1 CIN 1 CIN 2 (moderate CIN 3 Invasive (condylom (mild CIN 1 Normal a) dysplasia) dysplasia) (severe dysplasia/CIS) Cancer Histology of squamous cervical epithelium 1 Basal cell Basal membrane CIN caused by HPV can clear without treatment; however, rates of regression are dependent on grade of CIN. 25
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] GARDASIL Is Efficacious Against HPV 6/11/16/18–Related VIN and VaIN GARDASIL Placebo 12 10 10 8 Related Cases n=7,741 6 100% 4 Efficacy 2 n=7,769 0 0 VIN 2/3 or VaIN 2/3 16- to 26-year-old females naïve to the relevant vaccine HPV type at enrollment and through 30 days Postdose 3 Over a period of 2 to 4 years VIN = vulvar intraepithelial neoplasia; VaIN = vaginal intraepithelial neoplasia. Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package 20651717(3)-GRD. 27
GARDASIL® (Quadrivalent Human Papillomavirus [HPV Types 6, 11, 16, 18] Recombinant Vaccine) HPV and Anogenital Warts HPV 6 and 11 responsible for >90% of anogenital warts Infectivity >75% Treatment can be painful and embarrassing.4 Topical and surgical therapies are available for genital warts Recurrence rates vary greatly. 1. Jansen KU, Shaw AR. Annu Rev Med. 2004;55:319–331. 2. Soper DE. In: Berek JS, ed. Novak’s Gynecology. 13th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2002:453–470. 3. Lacey CJN. J Clin Virol. 2005;32(suppl):S82–S90. 4. Maw RD, Reitano M, Roy M. Int J STD AIDS. 1998;9:571–578. 5. Kodner CM, Nasraty S. Am Fam Physician. 2004;70:2335–2342. 28
HPV Clearance In a study of 608 college women, 70% of new HPV infections cleared within 1 year and 91% within 2 years. Median duration of infection = 8 months Certain HPV types are more likely to persist (eg, HPV 16 and HPV 18). Women with HIV are unable to clear the infectionSchiffman J Natl Cancer Inst Monogr. 2003;31:14–19.Ho N Engl J Med. 1998;338:423–428. 31
Cervical Cancer and HIV CIN is common in HIV infected women because: HIV infected women likely to have persistent HPV Persistent infection leads to cervical cancer Do ARTs Lower the Risk of Cervical Cancer? Multiple studies yield mixed results Incidence of cervical cancer appears to be unchanged in the ART era Those on ART are more likely to have persistent HPV So, probably no . . . therefore other treatment needed 32
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] GARDASIL Is Efficacious Against HPV 6/11/16/18–Related Lesions GARDASIL Placebo 100 91 90 83 80 70 60 n=7,861 n=7,899 Related Cases 50 95% 99% 40 Efficacy Efficacy 30 20 n=7,858 n=7,897 10 4 1 0 CIN 1, CIN 2/3 or AIS Genital Warts 16- to 26-year-old females naïve to the relevant vaccine HPV type at enrollment and through 30 days Postdose 3 Over a period of 2 to 4 years CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ. 33
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] Subjects Exposed to Any Vaccine HPV Type at Enrollment Efficacy Studies—Combined Population 93% of subjects were Baseline HPV Status naïve to ≥3 vaccine HPV types (6, 11, 16, Naïve to all 4 types or 18) at enrollment. 73% Positive to 1 type 20% 27% of subjects had Positive to 2 types evidence of prior 6% exposure to or Positive to 3 types ongoing infection Positive to 4 types with at least 1 of the 1.2% 4 vaccine HPV types. 0.1% 73% of subjects were naïve to all 4 vaccine HPV types. Among subjects who were positive to a vaccine HPV type, most were positive to only 1 type. Exclusion criteria: 6 or more sexual partners Data available on request from Merck & Co., Inc., Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package 20651717(4)-GRD. 34
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine] GARDASIL Maintained Type-Specific, Neutralizing Antibody Responses Ph II–P005 Proof of Principle 16- to 23-year-old women 5,000 GARDASIL (Per Protocol) 3,000 Per-Protocol Placebo Serum cRIA GMT*, mMU/mL 1,000 The duration of protection 100 of GARDASIL is unknown beyond 48 months. 10 Vaccination 1 0 7 12 18 30 42 48 Months Since Enrollment Number of 684 684 663 649 609 533 481 Subjects 680 680 661 638 604 532 489 *Evaluated only the HPV 16 L1 VLP vaccine component of GARDASIL. GMT = Geometric mean titer; cRIA = Competitive radioimmunoassay. Adapted from Mao C, Koutsky LA, Ault KA, et al. Obstet Gynecol. 2006;107:18–27. 35
Variation in Dosing Regimen for GARDASIL Summary of Geometric Mean Titers (GMTs) Early On Time Late 3,500 3,000 GMTs 1 Month Postdose 3 2,500 Variability in Variability in Dose 2* Dose 3† 2,000 1,500 1,000 500 0 16 18 6 11 16 18 6 11 Anti-HPV Types*Dose 2 (Postdose 1): Early = 36–50 days Postdose 1; On Time = 51–70 days; Late = 71–84 days.† Dose 3 (Postdose 2): Early = 80–105 days Postdose 2; On Time = 106–137 days; Late = 138–160 days. 36
Gardasil® Access Program• Merck donates 3 million doses – U.S. price = $125/dose• For GAVI-eligible countries• This is NOT a clinical trial or and experiment• Providing access to a new & expensive vaccine for developing countries• Free doses will go to those countries that can demonstrate implementation projects
Lesotho Strategy• The HPV Vaccine will be piloted in Leribe and Mohales’Hoek districts• Target population: Females Aged 9-18 years• School-based and Facility Based strategies will be used facilitated by the public health nurses with the assistance of the hospital staff• Estimated Starting period : February 2009• Follow established vaccine distribution system• Monitoring and evaluation- through current system