Grand Round Ut 031808
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Cervical Cancer- Beginning of the End? Nadeem Zafar, MD Assistant Professor and Associate Program Director University of Tennessee at Memphis
Mummy Speak……………………
Penile lesion related to intercourse- 1st century AD Tissue from a paravulval skin lesion in a 16th- century mummy of noblewoman Mary of Aragon- direct evidence of HPVs 18 and alsoJC9813 DNA (HPV with low oncogenic potentialrecently identified) Lancet 2003; 362: 1160
Papanicolaou Smear George Papanicolaou Greek physician and anatomist (1883- 1962) Discoverer of "Pap Smear“ First report of validity of vaginal smears- 1928 Appropriate stain developed and reported 1943 Boston conference 1948Cytology is recognized
Historical Perspective
ACS president at the turn of the century described cervical cancer as “hopeless” Within Papanicolaou’s lifetime- 50% reduction from cervical cancer mortality Thousands of woman-lives saved since Cervical cancer #2 most common cancer in women worldwide 500,000 new cases and 290,000 deaths/year (#3 Killer) 2007: US-11,000 (250 TN) new cases and 3800 deaths
HPV and Cancer
Persistent HPV well recognized as a cause of majority of cervical cancer High Risk HPV: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and 73 Vulvar and Vaginal, Oral and Pharyngeal/Tonsillar, Anal, Penile
HPV Structure
Non-enveloped virus Genome- three major regions Early region (E1-8) genes >>> transcription, plasmid replication, transformation Late region>>> major (L1), minor (L2) capsid proteins Control region >>> regulatory elements for transcription and replication
HPV At Cellular Level
Enters the body through epithelial trauma Needs differentiated cells for replication Replication in the cellular nucleus Early region expressed in basal (replicating cells) but cannot be transmitted Late-region genes expressed in superficial cells > capsid formation > transmission Episomal: extrachromosomal/plasmid > Benign disease- HPV 6 and 11 Integrated into host chromosome in high grade lesions- E6 and E7 genes implicated- HPV 16 and 18
HPV At Cellular Level
From Beutner, KR et al, "Human Papillomavirus and Human Disease." Am J Med 1997; 102(5A):9-15.
HPV Vaccine
June 2006- CDC (Advisory Committee on Immunization Practices-ACIP) recommended vaccination against HPV FDA approves Gardasil- Merck Vaccine Recommendations- Vaccinate girls aged 11-12, recommended age 13-26 but as early as 9!!!! 3 shots- 0,2 and 6 months. Cost $120/shot (x 3), currently $126/shot Cost related to calculated savings/year
How is Gardasil Made
L1 Capsid Protein spontaneously selfassemble into virus-like particles (VLPs) that resemble authentic HPV virions Gardasil contains recombinant VLPs assembled in Saccharomyces sp. from the L1 proteins of HPVs 6, 11, 16 and 18 VLPs lack the viral DNA- cannot induce cancer VLP antibody response protects recipients from becoming infected with the HPV types represented in the vaccine
Expected Impact of HPV Vaccine
Up to 70% reduction in HPVassociated cervical carcinoma Up to 90% reduction in warts Impact on other HPV associated diseases?
What we know of so far…..
The immunity against HPV types 16, 18 (and 6 and 11 for Gardasil ®) remains good at 5 years- no need for a booster Some evidence of cross protection against HPV 31 and 45 for Cervarix ® Improved cervical cancer prevention when boys are inoculated Minimal side effects- mainly local pain (VAERS) Data on women >26 years of age?
HPV Vaccine is Very Effective So What’s The Problem?
Problem #1 >> Cost
$378/course (3 shots) and no administration reimbursement Preventive healthcare capitation Additive to Pap Screening Governments expected to sponsor the indigent/underinsured- For 14,000 women/year- $5.34 Million x 10 years (TN only) Financial chaos, War on Terror
Problem #2 >> First STD Vaccine!
BLOG-WATCH
SATAN’S HPV VACCINE BEING PUSHED HARD BY DOCTORS Posted on March 15, 2008 by WHY
In response to
No-Brainer Syndrome: Using the HPV Vaccine and Male Circumcision to Fight Disease
Wednesday, Jun. 21, 2006
Defusing the War Over the "Promiscuity" Vaccine By Nancy Gibbs
When my 11-year-old got her tetanus shot during her checkup last week, her pediatrician did not tell her that it was now safe to go dance barefoot on rusty nails… The New Scientist in Britain quoted the Family Research Council's Bridget Maher warning that "giving the HPV vaccine to young women could be potentially harmful, because they may see it as a license to engage in premarital sex" More than 100 lawmakers to write to the CDC to warn about playing politics with what should be purely scientific judgments At a time when government data shows 70% of girls having had intercourse by the time they're 18, the need for a vaccine seemed self-evident
Problem #3 >> Aggressive Marketing!
Problem #3 >> Aggressive Marketing!
Quest for mandatory vaccination Rick Perry (Texas Governor) mandates HPV vaccination in middle school girls starting 2008 Mike Toomey, Perry’s formal chief of staff, a lobbyist for Merck Women in Government (WIG) (advocacy group) strongly pushing for GardasilMerck Corporate Donor Diane White Delisis- state director for WIG- Mother-in-law of the current Perry Chief of Staff Perry’s attempt backfires
Problem #3 >> Aggressive Marketing!
Mandatory Vaccination takes liability away from Merck if Gardasil ® proven dangerous in future (experience from Viaoxx debacle) Merck suspends marketing campaign to make Gardasil ® mandatory Cervarix ® coming up for FDA approval- competition
New Vaccines
Richard Schlegel (Georgetown University) and Bob Garcea (University of Colorado) making a new HPV 16 vaccine (later 6 viruses) Football-shaped VLP vs. building blocksequally immunogenic In Bacteria vs. Fungus Un-refrigerated powder- distribution To be manufactured in India (1/10 cost or even $1/shot)- Gardasil ® being provided in the 3rd world without profit
Tennessee Response
Chapter No. 921 PUBLIC ACTS, 2006 1 CHAPTER NO. 921, SENATE BILL NO. 3678 By Bowers, Burks Substituted for: House Bill No. 3549 By Marrero, Sontany, Lois DeBerry, Rowe, Henri Brooks, John Deberry, Sherry Jones, Cooper, Favors, Coleman, Armstrong, Tindell, Langster, Hargrove, Moore, Brown, Ulysses Jones AN ACT to amend Tennessee Code Annotated, Title 68, relative to establishing the..
Tennessee Cervical Cancer Elimination Task Force- Report Due April 1, 2008
Where does Tennessee Stack Up?
Bottom 5 Chlamydia: Memphis #1 amongst metropolitan areas (810.8/100,000 people vs. 366.4 national avg.) Gonorrhea: #1 (370 cases/100,000 people vs. 131.1 national avg.) Syphilis: #2 (48.5 cases/100,000 people vs. 18 national avg.)
Source: CDC
Recommendations
Pilot study- Top 10 TN counties with cervical cancer- in 5 years entire state Vaccination through VFC and support for qualified women 19-26 (appropriation bill) Educational effort Oversight LBC and continued screening
National Legislative Trend
Enactment of cervical cancer “elimination” task force No mandatory screening but robust education effort/campaigns State funding for the indigent/underinsured- New Hampshire- $5 Million for 2008 Mandating insurance companies to pay up for HPV vaccination
Missouri Legislation- 02/26/08
National Legislative Efforts- Status
Acrobat Document
Prevention vs. Elimination
Certain- much improved prevention Elimination- Total elimination not realistic but efficiency of pap as a screening test (funding) would be challenged
Needed Research
Would HPV vaccination make girls and boys more promiscuous? Government’s responsibility if voluntary vaccination is not accepted- should government pay for subsequent care? Vaccine cross-coverage against other high risk types (Cervarix- HPV 31/45) Vaccination in boys- time and cost factors Reduction in Types 16/18- impact on other high risk HPV types- evolutionary trends (there we go again) vs. intelligent creation
Impact on Cytology
Impact on Gynecologic Cytology
Liquid-based cytology Image-guided cytology Vaccination Closure of cytotech schools
Impact on Surgical Pathology
Decreased number of cervical biopsies (including cones) Decreased number of biopsies from oral mucosa/pharynx/tonsil, vulva and vagina, penis and anal area
Since Pap Smear Gave Life to Cytopathology- Would Pap Smear Kill It Too?
Mummy Speak……………………
Penile lesion related to intercourse- 1st century AD Tissue from a paravulval skin lesion in a 16th- century mummy of noblewoman Mary of Aragon- direct evidence of HPVs 18 and alsoJC9813 DNA (HPV with low oncogenic potentialrecently identified) Lancet 2003; 362: 1160
Papanicolaou Smear George Papanicolaou Greek physician and anatomist (1883- 1962) Discoverer of "Pap Smear“ First report of validity of vaginal smears- 1928 Appropriate stain developed and reported 1943 Boston conference 1948Cytology is recognized
Historical Perspective
ACS president at the turn of the century described cervical cancer as “hopeless” Within Papanicolaou’s lifetime- 50% reduction from cervical cancer mortality Thousands of woman-lives saved since Cervical cancer #2 most common cancer in women worldwide 500,000 new cases and 290,000 deaths/year (#3 Killer) 2007: US-11,000 (250 TN) new cases and 3800 deaths
HPV and Cancer
Persistent HPV well recognized as a cause of majority of cervical cancer High Risk HPV: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and 73 Vulvar and Vaginal, Oral and Pharyngeal/Tonsillar, Anal, Penile
HPV Structure
Non-enveloped virus Genome- three major regions Early region (E1-8) genes >>> transcription, plasmid replication, transformation Late region>>> major (L1), minor (L2) capsid proteins Control region >>> regulatory elements for transcription and replication
HPV At Cellular Level
Enters the body through epithelial trauma Needs differentiated cells for replication Replication in the cellular nucleus Early region expressed in basal (replicating cells) but cannot be transmitted Late-region genes expressed in superficial cells > capsid formation > transmission Episomal: extrachromosomal/plasmid > Benign disease- HPV 6 and 11 Integrated into host chromosome in high grade lesions- E6 and E7 genes implicated- HPV 16 and 18
HPV At Cellular Level
From Beutner, KR et al, "Human Papillomavirus and Human Disease." Am J Med 1997; 102(5A):9-15.
HPV Vaccine
June 2006- CDC (Advisory Committee on Immunization Practices-ACIP) recommended vaccination against HPV FDA approves Gardasil- Merck Vaccine Recommendations- Vaccinate girls aged 11-12, recommended age 13-26 but as early as 9!!!! 3 shots- 0,2 and 6 months. Cost $120/shot (x 3), currently $126/shot Cost related to calculated savings/year
How is Gardasil Made
L1 Capsid Protein spontaneously selfassemble into virus-like particles (VLPs) that resemble authentic HPV virions Gardasil contains recombinant VLPs assembled in Saccharomyces sp. from the L1 proteins of HPVs 6, 11, 16 and 18 VLPs lack the viral DNA- cannot induce cancer VLP antibody response protects recipients from becoming infected with the HPV types represented in the vaccine
Expected Impact of HPV Vaccine
Up to 70% reduction in HPVassociated cervical carcinoma Up to 90% reduction in warts Impact on other HPV associated diseases?
What we know of so far…..
The immunity against HPV types 16, 18 (and 6 and 11 for Gardasil ®) remains good at 5 years- no need for a booster Some evidence of cross protection against HPV 31 and 45 for Cervarix ® Improved cervical cancer prevention when boys are inoculated Minimal side effects- mainly local pain (VAERS) Data on women >26 years of age?
HPV Vaccine is Very Effective So What’s The Problem?
Problem #1 >> Cost
$378/course (3 shots) and no administration reimbursement Preventive healthcare capitation Additive to Pap Screening Governments expected to sponsor the indigent/underinsured- For 14,000 women/year- $5.34 Million x 10 years (TN only) Financial chaos, War on Terror
Problem #2 >> First STD Vaccine!
BLOG-WATCH
SATAN’S HPV VACCINE BEING PUSHED HARD BY DOCTORS Posted on March 15, 2008 by WHY
In response to
No-Brainer Syndrome: Using the HPV Vaccine and Male Circumcision to Fight Disease
Wednesday, Jun. 21, 2006
Defusing the War Over the "Promiscuity" Vaccine By Nancy Gibbs
When my 11-year-old got her tetanus shot during her checkup last week, her pediatrician did not tell her that it was now safe to go dance barefoot on rusty nails… The New Scientist in Britain quoted the Family Research Council's Bridget Maher warning that "giving the HPV vaccine to young women could be potentially harmful, because they may see it as a license to engage in premarital sex" More than 100 lawmakers to write to the CDC to warn about playing politics with what should be purely scientific judgments At a time when government data shows 70% of girls having had intercourse by the time they're 18, the need for a vaccine seemed self-evident
Problem #3 >> Aggressive Marketing!
Problem #3 >> Aggressive Marketing!
Quest for mandatory vaccination Rick Perry (Texas Governor) mandates HPV vaccination in middle school girls starting 2008 Mike Toomey, Perry’s formal chief of staff, a lobbyist for Merck Women in Government (WIG) (advocacy group) strongly pushing for GardasilMerck Corporate Donor Diane White Delisis- state director for WIG- Mother-in-law of the current Perry Chief of Staff Perry’s attempt backfires
Problem #3 >> Aggressive Marketing!
Mandatory Vaccination takes liability away from Merck if Gardasil ® proven dangerous in future (experience from Viaoxx debacle) Merck suspends marketing campaign to make Gardasil ® mandatory Cervarix ® coming up for FDA approval- competition
New Vaccines
Richard Schlegel (Georgetown University) and Bob Garcea (University of Colorado) making a new HPV 16 vaccine (later 6 viruses) Football-shaped VLP vs. building blocksequally immunogenic In Bacteria vs. Fungus Un-refrigerated powder- distribution To be manufactured in India (1/10 cost or even $1/shot)- Gardasil ® being provided in the 3rd world without profit
Tennessee Response
Chapter No. 921 PUBLIC ACTS, 2006 1 CHAPTER NO. 921, SENATE BILL NO. 3678 By Bowers, Burks Substituted for: House Bill No. 3549 By Marrero, Sontany, Lois DeBerry, Rowe, Henri Brooks, John Deberry, Sherry Jones, Cooper, Favors, Coleman, Armstrong, Tindell, Langster, Hargrove, Moore, Brown, Ulysses Jones AN ACT to amend Tennessee Code Annotated, Title 68, relative to establishing the..
Tennessee Cervical Cancer Elimination Task Force- Report Due April 1, 2008
Where does Tennessee Stack Up?
Bottom 5 Chlamydia: Memphis #1 amongst metropolitan areas (810.8/100,000 people vs. 366.4 national avg.) Gonorrhea: #1 (370 cases/100,000 people vs. 131.1 national avg.) Syphilis: #2 (48.5 cases/100,000 people vs. 18 national avg.)
Source: CDC
Recommendations
Pilot study- Top 10 TN counties with cervical cancer- in 5 years entire state Vaccination through VFC and support for qualified women 19-26 (appropriation bill) Educational effort Oversight LBC and continued screening
National Legislative Trend
Enactment of cervical cancer “elimination” task force No mandatory screening but robust education effort/campaigns State funding for the indigent/underinsured- New Hampshire- $5 Million for 2008 Mandating insurance companies to pay up for HPV vaccination
Missouri Legislation- 02/26/08
National Legislative Efforts- Status
Acrobat Document
Prevention vs. Elimination
Certain- much improved prevention Elimination- Total elimination not realistic but efficiency of pap as a screening test (funding) would be challenged
Needed Research
Would HPV vaccination make girls and boys more promiscuous? Government’s responsibility if voluntary vaccination is not accepted- should government pay for subsequent care? Vaccine cross-coverage against other high risk types (Cervarix- HPV 31/45) Vaccination in boys- time and cost factors Reduction in Types 16/18- impact on other high risk HPV types- evolutionary trends (there we go again) vs. intelligent creation
Impact on Cytology
Impact on Gynecologic Cytology
Liquid-based cytology Image-guided cytology Vaccination Closure of cytotech schools
Impact on Surgical Pathology
Decreased number of cervical biopsies (including cones) Decreased number of biopsies from oral mucosa/pharynx/tonsil, vulva and vagina, penis and anal area
Since Pap Smear Gave Life to Cytopathology- Would Pap Smear Kill It Too?
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