Should we adopt HPV vaccines for the prevention and control of cervical cancer in Thailand

1
Should we adopt HPV vaccines for the prevention
and control of cervical cancer in Thailand ?

• Supon Limwattananon, MPHM, PhD
• 23 February 2007

2
HPV vaccine
Human papillomavirus (HPV) infection is the
necessary cause of cervical cancer (1980)
Prof. Harald zur Hausen, MD (2005 Prince Mahidol
Awardee)

• Mercks Gardasil
• US FDA approved (8 June 2006)
• prevent persistent infection of HPV types 16, 18
  6, 11
• for girls and women 9-26 yr., recommended 11-12
  yr.
• 3 doses at 0, 2, 6 mo., 120/dose
• licensed in 50 countries (by 2006), mainly in
  private sectors
• GSKs Cervarix (against HPV types 16, 18)
• Expected approval by European EMEA in early 2007

3
What has been known about HPV vaccine

• No evidence on therapeutic efficacy
• The most cost-effective modality is to focus on
  girls or adolescent females
• Broad access to an HPV vaccine is an essential
  component in reducing the cervical cancer
  incidence and mortality. However, the impact of
  the vaccine will only be felt after 20 years.

4
Issues to be addressed before the adoption of
HPV vaccine into national program

• Vaccine profiles
• Safety adverse events following immunization
• Long-term efficacy and impacts
• Cost-effectiveness (as compared with existing
  screenings)
• Programmatic issues
• Immunization schedule vs. accessibility to health
  service
• Capacity of health systems to scale up the
  vaccine delivery
• Burden of disease versus financing capacity
• Public finance vs. voluntary private finance by
  households? WTP
• Long-term financial projection, fiscal
  capacity/budget impact analysis
• Socio-cultural, ethical dimensions
• Conservative concern, fear of disinhibition on
  sexual activity at early age
• Desire for privacy and confidentiality
• Equity issue

5
Evidence-based Efficacy of HPV Vaccine
6
RCT-based efficacy of HPV vaccinePrevention of
persistent infections and CIN1
(phase II)
Phase III trials Merck ? N America, L America,
Europe, Asia-Pacific GSK ? N America, L
America, Europe, Asia-Pacific
Source Lowy and Schiller (2006)
7
Global clinical trials of HPV vaccine
Norway
Denmark
Sweden
Finland
Canada
United Kingdom
Russia
Estonia
The Netherlands
China
Lithuania
Belgium
South Korea
Poland
Germany
Czech Republic
Japan
France
Taiwan
Portugal
Hong Kong
Spain
Italy
Greece
USA
Mexico
The Philippines
Honduras
Costa Rica
Panama
India
Senegal
Colombia
Thailand
Nigeria
Peru
Malaysia
Brazil
Australia
South Africa
8
HPV Epidemiology and Cervical Cancer
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Cervical Cancer and HPV Types
Source Franco et al. (2005)
Proportion of cervical cancers attributable to HPV
10
Distribution of HPV InfectionsHeterogeneity
across World Regions
Source Clifford et al. (2005)
11
Age-Standardized Prevalence of HPV Types
OREurope vs. Sub-Sahara for HPV 2.42 0.59 0.44
Source Clifford et al. (2005)
12
Age-Standardized HPV Prevalence 11-Country
Study (total N15,613 women aged 15-74 yr)
Location Percent (95 CI) Spain 1.4 (0.5
2.2) Vietnam, Hanoi 1.6 (0.7 2.4) Thailand,
Songkla 3.6 (1.9 5.4) Thailand,
Lampang 7.2 (5.3 9.2) Netherlands 7.7 (4.1
11.3) Italy 9.2 (7.5 11.0) Vietnam,
Ho Chi Minh 10.6 (8.7 12.4) Chile 11.9
(9.6 14.3) Korea 13.3 (4.7 21.9)
Colombia 13.9 (12.1 15.7) India 14.2
(12.0 16.4) Argentina 16.3 (13.7
18.9) Nigeria 25.6 (22.4 28.8) As
detected by GP5/6 PCR-based EIA HPV testing
Based on world standard population in 1966-cancer
incidence report
Source Clifford et al. (2005)
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HPV Vaccine and Model-based Impacts
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Impacts of HPV-16/18 Vaccine Efficacy on Invasive
Cancer, HSIL, LSIL Competing Risks
HPV-16/18 Other HPV types ( Efficacy) (Replaceme
nt)

Source Goldie et al. (2003)
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Impact of HPV eradication on cervical cancer
reductionPopulation attributable risk (PAR)
P(RR-1) / 1 P(RR-1)
RRcancer50
PAR83
P10 HPV prevalence
Source Franco et al. (2005)
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Impact on HPV prevalence (y) by vaccine coverage
(p), basic reproductive no. (R0), population at
risk, natural immunity (z)
(SIS model)
(y)
susceptible-infected-susceptible
model susceptible-infected-removed model
, R06.0 , R02.67 , R02.0 , R01.0
(y)
25 at risk
R01.25, z0
R020, z75
(p)
(p)
(SIS model)
(SIS model)
(y)
(y)
R02.0 R018/14
7.5 at risk R03.0
Non-linear decline!
(p)
(p)
y (R01)/R0 p z number of population at
risk
Source Garnett et al. (2006)
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HPV-16/18 Vaccine and Cervical Cancer Effective
Coverage is Matter
Effectiveness Coverage
Source Goldie et al. (2003)
18
Impact of HPV-16, 18 vaccine on infection
deathwithout (A B) and with (C D) screening
Assumptions 5-yr type-specific immunity after
natural infection, Life-long immunity after
vaccination at age 12 with 70 coverage, 100
efficacy in preventing HPV-16 -18 infection
Source Garnett et al. (2006)
19
Impact of age at vaccination on HSIL (A)
vaccine protection duration on death (B)
HPV-16, 18 vaccine
HPV-16 vaccine, with 70 coverage
Source Garnett et al. (2006)
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(No Transcript)
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Effectiveness of HPV-16/18 Vaccine over
TimeLagged Benefit
Benefit later
Invest now!
at 13 yr.
Source Goldie et al. (2003)
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HPV Vaccine and Financing
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The Vaccine Pipeline
Source WHO (2006)
24
All Vaccines, One Country Vaccine Portfolio Cost
vs. Government Health Expenditure
Source GAVI Alliance (2006)
25
Financing Childhood Vaccines

• How much we spent on childhood vaccine?
• All public financed (household pays none),
• MOPH budget for childhood vaccine procurement
  US17.5 million per year
• 10 Antigens provided for EPI
• OPV, BCG, DTP, MMR, HB, and JE
• Influenza for healthcare workers
• Cost per dose as purchased by MOPH
• HB US1
• JE US2-4
• Influenza US6-7

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Projected cost of HPV vaccine scaling up
US360 cost/vaccinated girl
20 covered birth cohort/yr
10 covered birth cohort/yr
US90 cost/vaccinated girl
20 covered birth cohort/yr
10 covered birth cohort/yr
MOPHs current vaccine budget
Estimate of 12-yr. girls is based on 1-10 yr
female population structure in 2005
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Financing Cervical Cancer Prevention 2005,
Thailand

• In the process of achieving full coverage of Pap
  smear VIA cryotherapy to all Thai women aged
  gt 30 years every 5 years,
• Financed by National Health Security Office
  (NHSO) for the whole population (including
  government employee scheme, SHI)
• Budget allocation FY2005 US3 per Pap smear or
  VIA
• National target 2005 0.7 million population
• Pap smear target 600,000 women (in all 76
  provinces)
• VIA still limited, 100,000 women (in 4 pilot
  provinces)
• Current performance
• 62 coverage (NHSO, 2005)
• Scale up to 1.35 million target in 2006

NSOs RH survey of 35-59 yr. female (2006) ?
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Economic Evaluation of Cervical Cancer Prevention
and Control
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Cervical cancer screeningCost-Effectiveness
Analysis -Thailand

• Major study by Mandelblatt J, et al. (J Natl
  Cancer Inst, 2002)
• Strategy Age Frequency
• VIA with treatment by cryosurgery 20 - 70 yr
  Every 5 or 10 yr
• VIA with referral to regional hospital 35 - 55
  yr Every 5 or 10 yr
• Pap smear alone 35 45 yr Twice
• HPV DNA testing alone 35 yr Once
• VIA HPV test 45 yr Once
• Pap smear HPV test
• Health care cost Screening test
  property
• (in 2000-US) Sensitivity Specificity
• (LSIL/gtHSIL) (gtLSIL)
• VIA 0.92 57.5/76.9 65.4
• Pap smear 7.50 19.6/46.2 94.5
• HPV test 30 55.6/78.7 79.2

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Cost-effectiveness of cervical cancer screening
Thailand
Dominance strategy
Source Mandelblatt J et al. (J Natl Cancer Inst,
2002)
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Cost-Effectiveness of HPV-16/18 VaccinePrevious
CEA Studies
Reference case Goldie et al. (2004) Kulasingam
et al. (2003) Vaccine Regimen 3-dose series
3-dose series Age 12 yr 12
yr Coverage 100 100 Efficacy 90 90 Dur
ation of efficacy Lifetime 10
yr Cost US100/dose US200/3 doses (US
IOMs assumption) (US IOMs assumption) Screening
Conventional or liquid cytology Conventional
cytology Age 18, 21, 25, 30, 35 yr 18, 22,
24, 26, 30 yr Interval every 1, 2, 3, 5
yr every 1, 2, 3, 5 yr Compliance 100 100
Sensitivity specificity 66 97
(conventional) 55.6 95.7 84 88
(liquid) Cost US15-51 (conventional) US45
US28-64 (liquid) Diagnosis and
treatment Colposcopy biopsy US436 US436 CIN
1/CIN2-3 US1,264/2,833 US2,010/3,546 Cervical
cancer stage I US21,533 US20,524
stage II/III US23,046/27,067 US31,485
stage IV US36,912 US46,851
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Cost-Effectiveness of HPV-16/18 VaccineGoldie et
al. (2004)
Vaccine Screen q 1 y 18C, 18L y.o.
Vaccine Screen q 2 y 21, 18C, 18L y.o.
Vaccine Screen q 3 y 25, 21 y.o.
Vaccine Screen q 5 y 30, 25, 21 y.o.
Screen q 5 y 35, 30, 25 y.o.
Doing nothing
18C Conventional cytology screening at age 18
years old 18L Liquid-based cytology screening
at age 18 years old
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Cost-Effectiveness of HPV-16/18
VaccineKulasingam et al. (2003)
Vaccine Screen q 1 y 22, 18 y.o.
Vaccine Screen q 2 y 24, 18 y.o.
Screen q 1 y 18 y.o.
Vaccine Screen q 3 y 26, 18 y.o.
Vaccine Screen q 5 y 30, 18 y.o.
Vaccine
Screen q 2 y 18 y.o.
Doing nothing
Screen q 3 y 18 y.o.
Screen q 5 y 18 y.o.
Dominance strategy
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Cost-Effectiveness of HPV-16/18 Vaccine
Intervention Doing Screening Screening Age _at_
interval nothing only vaccine Expected
QALYs25.9112 Screen start 30 yr _at_ 5
yr -----------------------? IE0.0584
QALYs ICER3,562/QALY Screen as above
Vaccine -----------------------------------------
----------? IE0.0781 QALYs ICER6,569/QAL
Y -----------------------? IE0.0197
QALYs ICER15,482/QALY Screen
start 25 yr _at_ 5 yr -----------------------? IE
0.0653 QALYs ICER4,456/QALY Screen as
above Vaccine --------------------------------
-------------------? IE0.0807 QALYs ICER
7,348/QALY -----------------------? IE0.015
4 QALYs ICER19,610/QALY
IEIncremental effectiveness, ICERIncremental
cost-effectiveness ratio (in 2002US/QALY) Source
Adapted from Goldie et al. (2004)
35
Cost-Effectiveness of HPV-16/18 Vaccine
Intervention Doing Screening Screening Age _at_
interval nothing only vaccine Expected
LYs28.7120 Screen start 18 yr _at_ 5
yr -----------------------? IE0.0330
LYs ICER6,030/LY Screen as above
Vaccine -----------------------------------------
----------? IE0.0379 LYs ICER9,182/LY
-----------------------? IE0.0049
LYs ICER30,408/LY Screen start 18 yr _at_
2 yr -----------------------? IE0.0438
LYs ICER12,283/LY Screen as above
Vaccine -----------------------------------------
----------? IE0.0458 LYs ICER15,044/LY
-----------------------? IE0.0020
LYs ICER75,500/LY Screen start 18 yr _at_
1 yr -----------------------? IE0.0484
LYs ICER23,326/LY Screen as above
Vaccine -----------------------------------------
----------? IE0.0492 LYs ICER25,996/LY
-----------------------? IE0.0008
LYs ICER187,500/LY
IEIncremental effectiveness, ICERIncremental
cost-effectiveness ratio (in 2001 US/LY) Source
Adapted from Kulasingam et al. (2003)
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Cost-Effectiveness of HPV-16/18 Vaccine Garnett
et al. (2006)
SScreening age 30/35 yr q 5 yr 3 times/lifetime
3-dose wastage delivery programmatic costs
Assumptions Model calibrated to Brazils
epidemiology outcomes Life-long immunity after
vaccination at age 12 with 70 coverage, 100
efficacy in preventing HPV-16 -18 infection
37
Benchmarking of various decision based on cost
effectiveness

• Renal Replacement Therapy (RRT)
• Cost per life year saved (Teerawattananon et al.,
  2005)
• Peritoneal dialysis US10,170
• Hemo-dialysis US10,490
• Antiretroviral Therapy (ART)
• Cost per life year saved (Lertiendumrong et al.,
  2005)
• Antiretroviral therapy US590
• Breast Cancer Therapy
• Cost per QALY gained (Limwattananon et al., 2005)
• Adjuvant chemotherapy Paclitaxel US18,450
• Adjuvant hormonal therapy Anastrozole US36,390
• 
  Letrozole US11,060
• 
  Exemestane US8,570
• Monoclonal antibody (MBC) Trastuzumab
  US118,210
• GNI for Thailand
• US 2,540 per capita (WDR2006)

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Scientific questions yet to be answered

• Minimum doses, alternative dosage schedules
• Optimal age for vaccination in children lt 9 yr
• Efficacy in women gt 26 yr (15-55 yr ASCO2006),
  men of all ages, HIV-positive female (studies
  under way!)
• Years of protection beyond the documented 4.5-5
  yr
• Cross-protection against other oncogenic HPV
  types (esp., the next most prevalent HPV 45, 31)

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Recommendations

• Produce country-specific evidence on the policy
  options and financial implications to control
  cervical cancer, taking into account health
  system context, existing screening programs, and
  fiscal space.
• In view of prohibitive cost of vaccine, priority
  and support should be given to improve screening
  capacity until we have more evidence and the
  vaccine becomes affordable
• If the vaccine is proven cost-effective, upon the
  current screening programs
• Estimate and secure the demand
• Active role of partners to negotiate vaccine
  price to be affordable
• Support to scale up vaccine program