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HPV???HPV??

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??????(Human Papilloma Virus) - HPV

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• ?????200???2,????80????????

1. Howley PM, Lowy DR. In Knipe DM, Howley PM,
eds. Philadelphia, Pa Lippincott-Raven
200121972229. 2. Schiffman M, Castle PE. Arch
Pathol Lab Med. 2003127930934.
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Normal Epidermis
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HPV Replication Transcription in the Epidermis

• Infects basal cells of dermal layer (low level of
  transcription replication)
• DNA amplification and capsid proteins made in the
  upper spinous layer
• Transcription increases in the spinous layer
• Squames released at surface to release viral
  particles

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HPV Transmission
Skin to Skin Contact
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HPV Types

• Two major phylogenetic branches, differing
  affinities for site of infection
• Cutaneous Keratinized squamous epithelium
  (genital nongenital)
• Mucosal Non-keratinized squamous epithelium
  (genital nongenital)

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Common Plantar Warts
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Common warts with thrombosed vessels (black
dots). (From Medical Microbiology, 4th ed.,
Murray, Rosenthal, Kobayashi Pfaller, Mosby
Inc., 2002, Fig. 49-4.
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Nongenital Mucosal
Laryngeal papilloma
Conjunctival papillomas
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Genital Warts
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HPV Mucosal Types Variants

• More than 30 types found in anogenital tract
• Low risk types rarely found in cancers, HPV 6
  11 are the most common types
• High risk types frequently found in cancers,
  HPV 16 18 are the most common types
• High risk types most prevalent in population,
  regardless of disease status
• Variants best characterized for HPV 16
• E6/E7 polymorphisms could modify oncogenicity
• Cross-reactive in ELISA assays

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Three Forms of HPV Infection

• Residential
• Usually minimally six weeks from exposure
• Can persist undetected for decades
• Can be LR or HR type
• Can be prevented with vaccination
• Episomal
• Virally active HPV located in the cell nucleus
• Separate from the human DNA
• Can be LR or HR type
• Can cause abnormal Pap tests
• Can be seen colposcopically
• Can be prevented with vaccination
• Integrated
• HPV DNA circle has opened and joined the human
  DNA
• Only HR types
• Causes abnormal Pap tests
• Seen colposcopically must be treated to prevent
  cancer
• Can be prevented with vaccination

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HPV Genome Episome
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Residential
16
Episomal vs. Integration
Episomal HPV 16
Integrated HPV 16
Releasing infectious particles into the cervical
and vaginal secretions
Basal Stem Cell
HPV Infection
CIN 2/3
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Duration of HPV Infection
HPV Types Months, median (95 CI)
Franco (1999) Oncogenic 8.1 (6.0 -12.6)
Woodman (2001) HPV 16 10.3 (6.8 - 17.3)
Woodman (2001) HPV 18 7.8 (6.0 12.6)
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EPIDEMIOLOGY OF HPV INFECTION

• LUDWIG/MCGILL COHORT STUDY
• Prevalence HPV 13.8
• Non-oncogenic 5 months
• Oncogenic 8 months
• 38.9 HPV () by 18 months
• Franco, et al. JID
  1999180-1415-23.

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???????????????(Human Papilloma Virus) - HPV

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• ????(????) HPV?6?11????gt90?????(??)??2,4
• ?????????HPV?????????,????????????

1. Schiffman M, Castle PE. Arch Pathol Lab Med.
2003127930934. 2. Wiley DJ, Douglas J, Beutner
K, et al. Clin Infect Dis. 200235(suppl
2)S210S224. 3. Muñoz N, Bosch FX, Castellsagué
X, et al. Int J Cancer. 2004111278285. 4.
Jansen KU, Shaw AR. Annu Rev Med.
200455319331.
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HPV???????

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HPV???????

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• Gross G, Pfister H. Med Microbiol Immunol (Berl).
  20041933544.
  2.
  Lillo FB. New Microbiol. 200528111118.
  
  
• 3. Frisch M, Glimelius B, van den Brule AJC, et
  al. N Engl J Med. 199733713501358.
  
  
• 4. Gillison ML, et al. J Natl Cancer Inst.
  200092709720.
  
  5. Derkay CS. Laryngoscope.
  20011115769.

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HPV Infection and Cervical Cancer
Carcinogenic by epidemiologic definition
HPV type Odds Ratio
16 59 182
18 12 231
45 4.8 148
31 3.7 71.5
33,35,51,52,58,59 31-146
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• ??HPV 6?11???(????)?????HPV??

Wang H, Qiao YL. Int J STD AIDS. 19(10)680-4,
2008
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??????????1

• ??HPV 6?11????89.3

1. Paul K.S. Chan and etc., Journal of Clinical
Virology (2008) P 1-4.
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HPV??????????????????????
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UW Students

• A UW study found that more than 60 of college
  women became infected over 5 years.

SOURCE GRAPH ADAPTED FROM R. L. WINER ET AL.,
AMERICAN JOURNAL OF EPIDEMIOLOGY 157, 218 (2003)
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HPV???????????
S Strauss et. el, Contamination of environmental
surfaces by genital human papillomavirus, Sex
Transm Inf 2002 78 135-138
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1. Soper DE. In Berek JS, ed. Novaks Gynecology.
   13th ed. Lippincott Williams Wilkins,
   2002453-470.

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Anthony Wisdom, 1989 A color atlas of sexually
transmitted diseases. Year Book Medical
Publishers, Chicago, 296pp.
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TCA
EF
CRYO
ALEX FERENCZY, MD
Traditional provider administered
LASER
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Home therapies
All have adverse events burning to scarring
ALEX FERENCZY, MD
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HPV Vaccination
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Vaccines on the Horizon
SOURCE Merck and GSK. Science Magazine, Vol.
308, Issue 5722, pages 618-621 , 29 April 2005
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Randomized Controlled Trials Phase II - HPV
Vaccines
Quadrivalent Vaccine1 Bivalent Vaccine2
Reference Villa LL et al., Lancet Oncology Online, April 7, 2005 Harper DM et al., Lancet 3641757-1765, November 2004
Vaccine Type Quadrivalent HPV-6/11/16/ 18 VLP, L1 capsid component Bivalent HPV-16 and HPV-18 VLP , L1 capsid component
Manufacturing Yeast Insect Cells (Baculovirus)
Concentration 20 µg HPV 6 40 µg HPV 11 40 µg HPV 16 20 µg HPV 18 20 µg HPV 16 20 µg HPV 18
Adjuvant 225 µg Aluminum Hydroxyphosphate Sulfate 500 µg Aluminum Hydroxide with 50 µg 3-deacylated monophosphoryl lipid A (AS04)
1Villa LL, et al. Lancet Oncol.
20056271-278. 2Harper DM, et al. Lancet.
20043641757-1765.
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Quadrivalent Vaccine1 Bivalent Vaccine2
Dose and Administration 0.5 ml, intramuscular 0.5 ml, intramuscular
Schedule 0, 2, 6 months 0, 1, 6 months
Trial Size 277 vaccinees, 275 placebo 560 vaccinees, 553 placebo
Site US, Brazil, Europe US, Canada, Brazil
Age Range of Women 16-23 years 15-25 years
Key Eligibility Requirements No history of cervical lesions, few sexual partners No history of cervical lesions, few sexual partners
Duration Up to 35 months Up to 27 months
Primary Endpoint Persistent Type-Specific HPV Persistent Type-Specific HPV
1Villa LL, et al. Lancet Oncol.
20056271-278. 2Harper DM, et al. Lancet.
20043641757-1765.
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ATP Group Quadrivalent Vaccine1 Bivalent Vaccine2 (cx/cxvag samples)
Efficacy in Preventing Persistent Vaccine Specific HPV type Infections 89 (95 CI 70-97 P/V 47/6 events) 100 (95 CI 77-100 P 16 events)
HPV 6 100 (95 CI 68-100 P 13 events) Not a Study Aim
HPV 11 NS (P 3 events) Not a Study Aim
HPV 16 86 (95 CI 54-97 P/V 21/3 events) 100 (95 CI 72-100 P 13 events)
HPV 18 89 (95 CI 21-100 P/V 9/1 events) 100 (95 CI 7-100 P 4 events)
1Villa LL, et al. Lancet Oncol.
20056271-278. 2Harper DM, et al. Lancet.
20043641757-1765.
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ITT Group Quadrivalent Vaccine1 Bivalent Vaccine2 (cx/cxvag samples)
Efficacy in Preventing type specific associated Cytologic Abnormalities Not Reported 94 (95 CI 70-98)
Efficacy in Preventing Any type specific associated Lesions 100 (95 CI 56-100) 10 placebo events 100 (95 CI 16-100) 6 placebo events
CIN Lesions 100 (95 CI 32-100) (7 events) 100 (6 events)
External Genital Warts 100 No CI (4 events) Not a Study Aim
1 Villa et al. Lancet Oncol. 20056271-278. 2
Harper et al. Lancet. 20043641757-1765.
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Quadrivalent Vaccine1 Bivalent Vaccine2
Acceptable rate of adverse events Yes Yes
Serious Adverse Events No No
Seroconversion 100 100
Specific Titers compared to Natural Infection at Month 7 10 times greater for HPV 6 10 times greater for HPV 11 100 times greater for HPV 16 20 times greater for HPV 18 200 times greater for HPV 16 100 times greater for HPV 18
Specific Titers compared to Natural Infection at follow-up 27 months 1.4 times greater for HPV 6 No greater for HPV 11 20 times greater for HPV 16 6 times greater for HPV 18 18 month 100 times greater for HPV 16 10 times greater for HPV 18
1 Villa et al. Lancet Oncol. 20056271-278. 2
Harper et al. Lancet. 20043641757-1765.
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Efficacy of HPV Vaccines forHPV 16 or 18 () CIN
2,3
Phase III Trial
Quadrivalent Vaccine1
Per protocol analysis P/V (n5258/5301) 100 95 CI 76, 100 P/V 21/0
Intention-to-treat P/V (n5766/5736) 97 95 CI 83, 100 P/V 36/1
Skjeldestad FE, et al. IDSA. San Francisco, 2005.
Abstract LB-8a.
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Recommendations
The Advisory Committee on Immunization Practices
(ACIP)

• Routine vaccination
• Catch-up vaccination
• Special situations
• Precautions and contraindications

CDC Policy
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HPV Vaccine Recommendations
(1) Routine Vaccination

• ACIP recommends that HPV vaccine be routine given
  for girls when they are 1112 years old
• ACIP allows for vaccination of girls beginning at
  9 years old.

CDC Policy
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HPV Vaccine Recommendations
(2) Catch-up Vaccination

• ACIP recommends that HPV vaccine (GARDASIL) is
  indicated in females aged 13-26 years for the
  prevention of CIN, cervical cancer, and infection
  caused by HPV 6, 11, 16 and 18.

 Immunization Catch-Up (ICU)
CDC Policy
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VFC ( Vaccines for Children )

• The Vaccines for Children (VFC) Program
  automatically covers vaccines recommended by the
  Advisory Committee on Immunization Practices
  (ACIP) and approved by the Centers for Disease
  Control and Prevention (CDC).

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What are we vaccinated ?
Quadrivalent Vaccine1 Bivalent Vaccine2
Quadrivalent HPV Vaccine 6,11,16, 18 VLP, L1 capsid component Bivalent HPV 16 and 18 VLP , L1 capsid component
20 µg HPV 6 40 µg HPV 11 40 µg HPV 16 20 µg HPV 18 20 µg HPV 16 20 µg HPV 18
225 µg Aluminum Hydroxyphosphate Sulfate 500 µg Aluminum Hydroxide with (MPL) 50 µg 3-deacylated monophosphoryl lipid A (AS04)
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How to vaccinate?

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HPV Vaccine

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• GARDASIL?????????,??????
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• No Drugs interaction steroid, hormone,
  immunosuppressive drugs ?
• May vaccinate combined with other vaccination

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Clinical Schedule

• Schedule 0, 2, 6 months?0.5 CC ?
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• Payment
• Consultation fee ? 200500 NT dollars
• Self-pay profit ? 5

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??HPV???????????

• ??HPV??????90.4 ?HPV 6/11/16/18??????????
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????????? (FDA) ??????????HPV?? ???HPV??6?11??????
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TUA LectureThe Efficacy of Quadrivalent (Types
6/11/16/18) HPV Vaccine Against HPV-related
Genital disease and Infection in Young Men -
Protocol 020 2009.08
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1. Lacey CJN. J Clin Virol 200532(suppl)S82-S90.

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