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 People
50% of young people between 15 and 24 years of age will DIE within the next 10 years!
Disease Burden in Lesotho
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
*Phaaroe, 2007
Cervical Cancer by Age
90% 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 Africa COUNTRY ASIR Sited Publication
South Africa 32.1 : 100 000 Freddy Sitas et al
1993 Mali 21.0 : 100 000 Bayo et al 1990 Uganda 43.6 : 100 000 Wabbinga et al 1993 Gambia 13 : 100 000 Bah 1990 Senegal 9 : 100 000 Bah et al 1988 Lesotho 66.7 : 100 000 S. Phaaroe et al 2007 Senegal & Gambia are Moslem areas ( Low in Gambia) Zimbabwe 67:100 000 ( Dr Cronje – Oncology specialist : Sebeta Memorial Lecture LMA AGM 8/7/06
Prevention Strategies PAP smear screening
HPV testing
Direct Visual InspectionDirect Visual Inspection Acetic acid –VIA Acetic acid –VIA
HPV vaccine
Education
FinishedH igh School
Psychological
CounselingConflict
Resolution
Social
Strengthen-Fam ily
Com m unity
Economic
New JobsLegislative (law) Outlaw F irearm s
M ore Prisons/Longer Sentences
W KS ?
H A T IN DO F O L U T IO N
Biological/Medical
Pharm aco-Therapy
National stake holders Education/Information-Magnitude of cancer
Gyaenacology, Oncology, Radiology, Pharmacy etc
Gyaenacology, Oncology, Radiology, Pharmacy etc
FAMILY H, ED, PLANNING & Men’s clinics, private clinics linkage with NGO’S in a health system
FAMILY H, ED, PLANNING & Men’s clinics, private clinics linkage with NGO’S in a health system
Education , Academic centers of excellence & other Research institutions
Education , Academic centers of excellence & other Research institutions
Chiefs, local government, village councils, NETWORKS
Chiefs, local government, village councils, NETWORKS
LEGAL SYSTEMS, Policy makers, International conventions, Regional strategies
LEGAL SYSTEMS, Policy makers, International conventions, Regional strategies
EMPLOYMENT FORCE/ Government Institutions Insurance Levy, Businesses & Industry
EMPLOYMENT FORCE/ Government Institutions Insurance Levy, Businesses & Industry
Technology INCUBATION CENTRES, SMME’s , Joined Bilateral commissions/ agreements
Technology INCUBATION CENTRES, SMME’s , Joined Bilateral commissions/ agreements
CYTOPATHOLOGY BIOMEDICAL SCIENCE RESEARCH LAB is the central organ
CYTOPATHOLOGY BIOMEDICAL SCIENCE RESEARCH LAB is the central organ
Well women groups/ church/ women in Law, every body, Support groups/ men leagues
Well women groups/ church/ women in Law, every body, Support groups/ men leagues
S. Phaaroe M.T
C.T(IAC), MIBMS
PSBH- REPORT Boston University 2005
S. Phaaroe M.T
C.T(IAC), MIBMS
PSBH- REPORT Boston University 2005
LBCN
Disease BurdenHPV types 6, 11, 16, & 18
6, 11, 16, and 186, 11, 16, and 18
70% of cervical cancer, AIS, CIN 3, 70% of cervical cancer, AIS, CIN 3, VIN 2/3, and VaIN 2/3 casesVIN 2/3, and VaIN 2/3 cases
50% of CIN 2 cases50% of CIN 2 cases16 and 1816 and 18
Approximate Disease BurdenApproximate Disease BurdenHPV TypeHPV Type
35%35%––50% of all CIN 1, VIN 1, 50% of all CIN 1, VIN 1, and VaIN 1 casesand VaIN 1 cases
90% of genital warts cases90% of genital warts cases
HPV-Related Disease Development
Clifford GM, Smith JS, Plummer M, Munoz N, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer. 2003;88: 63-73.
HPV Type Prevalence Worldwide
High prevalence of HPV 16 in South African women with cancer of the cervix and cervical 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
• Age indication: females ages 9-26
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
22
53
0
10
20
30
40
50
60
CIN 2/3 or AIS
GARDASIL Placebo
GARDASIL Is Efficacious Against HPV 16– and 18–Related CIN 2/3 or AISR
elat
ed C
ases
100% Efficacy
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.
0
CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ.
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]
n=8,487
n=8,460
23
GARDASIL® (Quadrivalent Human Papillomavirus [HPV Types 6, 11, 16, 18] Recombinant Vaccine)
Cervical Intraepithelial Neoplasia- VIAM
CIN 1 CIN 2 CIN 3
VIA-
24
GARDASIL® (Quadrivalent Human Papillomavirus [HPV Types 6, 11, 16, 18] Recombinant Vaccine)
Invasive Cervical Carcinoma
From IARC, 2003.1
25
GARDASIL® (Quadrivalent Human Papillomavirus [HPV Types 6, 11, 16, 18] Recombinant Vaccine)
Classification of Histological Findings
CINCIN11 NormalNormal
CIN 1CIN 1
(condylo(condyloma)ma)
CIN 1CIN 1
(mild (mild dysplasiadysplasia
))
CIN 2 CIN 2 (moderat(moderat
e e dysplasiadysplasia
))
CIN 3CIN 3
(severe (severe dysplasia/CIS)dysplasia/CIS)
Invasive Invasive CancerCancer
Histology Histology of of squamous squamous cervical cervical epitheliumepithelium11
Basal cell
Basal membrane
CIN caused by HPV can clear without treatment; however, rates of CIN caused by HPV can clear without treatment; however, rates of regression are dependent on grade of CIN.regression are dependent on grade of CIN.
26
27
10
0
2
4
6
8
10
12
VIN 2/3 or VaIN 2/3
GARDASIL Placebo
GARDASIL Is Efficacious Against HPV 6/11/16/18–Related VIN and VaIN
Rel
ated
Cas
es
100% Efficacy
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.
VIN = vulvar intraepithelial neoplasia; VaIN = vaginal intraepithelial neoplasia.
0
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]
n=7,741
n=7,769
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
28
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 Infectivity >>75%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.
29
Genital & Anal warts
30
HPV-Related Disease Development
31
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 infection
Schiffman J Natl Cancer Inst Monogr. 2003;31:14–19. Ho N Engl J Med. 1998;338:423–428.
32
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
Cervical Cancer and HIV
33
4 1
8391
0
10
20
30
40
50
60
70
80
90
100
CIN 1, CIN 2/3 or AIS Genital Warts
GARDASIL Placebo
GARDASIL Is Efficacious Against HPV 6/11/16/18–Related Lesions
Rel
ated
Cas
es
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
99% Efficacy
95% Efficacy
n=7,861
n=7,858
n=7,899
n=7,897
CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ.
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]
34
27% of subjects had evidence of prior exposure to or ongoing infection with at least 1 of the4 vaccine HPV types.
20%
Subjects Exposed to Any Vaccine HPV Type at Enrollment
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
Baseline HPV Status
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]
Efficacy Studies—Combined Population
Naïve to all 4 types
Positive to 1 type
Positive to 2 types
Positive to 3 types
Positive to 4 types
93% of subjects were naïve to ≥3 vaccine HPV types (6, 11, 16, or 18) at enrollment.
1.2%
0.1%
6%
73%
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.
35
*Evaluated only the HPV 16 L1 VLP vaccine component of GARDASIL.GMT = Geometric mean titer; cRIA = Competitive radioimmunoassay.
684 684 663 649 609 533 481
680 680 661 638 604 532 489
Number of Subjects
Months Since Enrollment
Adapted from Mao C, Koutsky LA, Ault KA, et al. Obstet Gynecol. 2006;107:18–27.
GARDASIL Maintained Type-Specific,Neutralizing Antibody Responses
0 7 12 18 30 42 481
10
100
1,000
3,0005,000
Ser
um c
RIA
GM
T*,
mM
U/m
L
GARDASIL (Per Protocol) Per-Protocol Placebo
Vaccination
Ph II–P005 Proof of Principle 16- to 23-year-old women
The durationof protectionof GARDASIL is unknown beyond 48 months.
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]
36
0
500
1,000
1,500
2,000
2,500
3,000
3,500
16 18 6 11 16 18 6 11
Early On Time Late
Variation in Dosing Regimen for GARDASIL
*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.
Summary of Geometric Mean Titers (GMTs)
Anti-HPV Types
Variability in Dose 2*
Variability in Dose 3†
GM
Ts
1 M
onth
Pos
tdos
e 3
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
EPI Information and Data Flow