# Presentation: 655929

## Human Papilloma Virus Vaccine2007

**Amy Groom MPH**
**IHS Immunization Program **
**Neil Murphy M.D.**
**Southcentral Foundation**

## Special Thanks

- Tom Hennessey, CDC, Arctic Investigations Program
- Cosette Wheeler, Dept. of Molecular Genetics & Microbiology, UNM
- American Society for Colposcopy and Cervical Pathology (ASCCP)

## Overview

- Historical impact of vaccines
- Natural history of HPV infection
- Vaccines for cancer prevention
- Early HPV vaccine trials
- Screening
- Treatment
- Implementation

## Slide 4

**Notes:**
Diphtheria is an excellent example of the impact that vaccines have on global health.  In 1900 diphtheria actually killed more Americans than did cancer, but today there are an average of only 3 cases of diphtheria each year in the United States.

## Slide 5

**Notes:**
This is a listing of the infectious agents that we now have vaccines for.  How many of us have ever seen a single case of many of the infectious diseases such as tetanus or diphtheria which we now routinely control by vaccination?  In fact medical students graduating today may never see a single cases of measles since less than 100 cases now occur each year in the U.S.

## Slide 6

**Notes:**
One of the next areas where vaccines are expected to have an important impact is in the reduction of cancers that are caused by specific infectious agents.  Globally approximately 18% of all cancers are caused by specific infectious agents and are potentially preventable with vaccines.  Vaccines against hepatitis B have been available for almost twenty years and have reduced the incidence of liver cancer in regions of the world where hepatocellular carcinomas were extremely common before the introduction of the vaccine.  For example, in 1984 Taiwan introduced a nationwide program of universal hepatitis B vaccination.   The incidence of hepatocellular carcinoma in children 6 - 9 years of age declined from 0.52 per 100,000 to 0.13 per 100,000.(Chang et al. NEJM 1997:336;1855)  Although a vaccine against Helicobacter pylori is not yet available, several companies are actively working on developing an H. pylori vaccine.

HPV associated cancers are one of the most common cancers associated with infectious agent and account for 5.2% of all cancers globally.  It is hoped that over the next two decades there will be dramatic reductions in the incidence of HPV-associated  cancers due to the HPV vaccines.  

## Slide 7

**Notes:**
Based on their phylogenetic relationship to other viruses the papillomaviruses now been given their own taxonomic family which is papillomaviridae.  The papillomaviruses are highly diverse and there are papillomaviruses which infect almost all known mammals and birds.  One of the only animals that does not appear to be infected by papillomavirus is the laboratory mouse.  Papillomaviruses are classified based on their species specificity and their degree of DNA relatedness.  Thus there are bovine, equine, canine, cotton-tailed rabbit, canary, and many other types of papillomaviruses.  These viruses rarely cross host-species barriers.  
To date nearly 100 human papillomavirus (HPV) types have been identified and it is widely believed that there are many additional types that have not been fully characterized.  Many of these HPV types have been shown to be ubiquitous and globally distributed.

## Slide 8

**Notes:**
This is a diagram which which is designed to demonstrate the degree of  similarity at the DNA level of one HPV type to another.  HPV types which are close together on the diagram  have a very similar genome whereas those which are further apart are less related.  Based on their genetic sequences the anogenital HPV types can be divided into two general groups.  These are “low-risk” HPV types and “high-risk” types.  The low-risk types include HPV types 6 and 11 which are the viruses that most commonly cause genital warts.  Notice how close together on the diagram HPV 6 and 11 are - this indicates that they are almost identical in DNA sequence.  
The high-risk HPV types include HPV 16 and 18 which are the types most commonly found in cervical cancers.  Notice that the high-risk HPV types fall into three general groups.  On group includes HPV 16 as well as HPV 35, 31, 33, 58, and 52.  This group is called the A9 clade.  Another group includes HPV 18, 45, 39, 68, 34, 26, and 51.  This is the A7 clade.  These groupings are important because it is quite possible that a vaccine directed against HPV 16 may cross-protect against other members of the A9 clade and a vaccine against HPV 18 may cross-protect against the rest of the viruses in the A7 clade.

## Slide 9

**Notes:**
Today it is accepted that infection with specific high-risk types of HPV is essential for the development of invasive cervical cancer.  This is based on four separate lines of evidence.  The first is molecular studies of invasive cervical cancers that have shown that essentially all invasive cervical cancers contain the DNA of high-risk types of HPV.  The second line of evidence is case-control studies of women with cancer and age-matched control women without cancer.  These studies have shown extremely high risks for cancer among women infected with high-risk types of HPV.  The third line of evidence is prospective follow-up studies that have clearly shown that infection with HPV precedes the development of cancer.  The demonstration of the correct temporal relationship was quite important in convincing skeptics that infection with specific high-risk HPV types is essential for cervical cancer to develop.  Finally, there is a large amount of experimental evidence that clearly demonstrates that HPV can transform cells in tissue culture systems and that continued expression of the HPV oncoprotoeins are required for maintaining the transformed phenotype.

## Slide 10

**Notes:**
The second line of epidemiological evidence indicating that HPV is essential for invasive cervical cancer comes from case-control studies in which women with cervical cancer and age-matched control women without cervical cancer are tested for specific high-risk HPV types.  These case-control studies have shown extraordinarily high odds ratios for cervical cancer associated with infection with high-risk HPV types.

## Slide 11

**Notes:**
These are the results from one of the largest of the case-control studies conducted by the IARC.  The slide presents the results for just 5 of the 15 high-risk types of HPV but the results for the other HPV types are similar.  Extraordinarily high-risk odds ratios for having invasive cervical cancer are associated with infection with high-risk types of HPV.  For HPV 16 the odds ratio of having cervical cancer if infected are 434.  For HPV 18 the odds ratio of having cancer are 248.

## Slide 12

**Notes:**
To put the risk for having invasive cervical cancer if infected with HPV 16 into perspective it is useful to compare it the risk associated with risk factors for cancers at other sites.  In the study just presented, women who were HPV 16 positive had an odds ratio of having invasive cervical cancer of 434 compared to women who were HPV 16 negative.  Lung cancer is a good example of another cancer caused by a specific agent with which to compare this elevated risk for cervical cancer.  It is widely accepted that smoking is associated with lung cancer however the relative risk of lung cancer in a U.S. white male smoker compared to a non-smoker is only 8 - this is only about 2% of the risk associated for cervical cancer if infected with HPV 16.  

We all know how women reacted to the publication from the Women’s Health Initiative demonstrating an increase in risk of breast cancer for women receiving hormone replacement therapy (HRT).  However the hazards ratio of breast cancer associated with use of HRT was only 1.3 in the Women’s Health Initiative.

## Slide 13

**Notes:**
This diagram was developed several years ago to explain the natural history of HPV infections to clinicians.  The first step in infection is the initial infection with HPV.

## Slide 14

**Notes:**
Recently the Centers for Disease and Control and Prevention of the U.S. (CDC) estimated that 20 million Americans are DNA positive for an anogenital HPV at any time.  This accounts for about 15% of the population when children are excluded.  Of these, 9.2 million are sexually active adolescents or young adults 15 to 24 years of age.  Those figures relate to prevalent infections.  Based on the best available data it is estimated that about 6.2 million individuals become newly infected with HPV yearly in the U.S.

## Slide 15

**Notes:**
Cervical cancer is not the only cancer which is attributable to HPV.  This slide is developed from data developed by Max Parkin and shows what proportion of cancers of the oropharnyx, anus, oral cavity, vulva, and penis are attributable to HPV.    Estimates are based on the global burden of disease and the "attributable fraction" of a given cancer type is due to HPV (e.g., what proportion of a given cancer is caused by HPV).  Because cervical cancer is both the most common of the cancers and because the attributable fraction due to HPV is 100%, cervical cancer accounts for about 75% of HPV attributable cancers globally.  However there are a number of other cancers which have a considerable proportion attributable to HPV.  For example, the majority (90%) of anal cancers are attributable to infection with HPV as are 40% of cancers of the vulva and penis.  A much smaller proportion of cancers at the other sites such as oropharynx and mouth are attributable to HPV. 

## Slide 16

**Notes:**
According to data from the American Cancer Society, in 2001 there were about 13,000 cases of invasive cervical cancer diagnosed in the United States and only 4,400 women died of this disease.  When viewed from the perspective of overall cancer-related deaths or deaths in women, cervical cancer is no longer a significant problem in the United States.  Cervical cancer accounts for only one out of 50 cancer-related deaths and accounts for less than half a percent of all female deaths in this country.

This reflects the remarkable triumph of cytological screening for cervical cancer in the United States.  Having said this, it should be realized that despite the fact that cervical cancer can, for the most part, be prevented by screening - each day 13 women die of this disease in the U.S.

## Slide 17

**Notes:**
The CDC estimates that annually there are 500,000 to a 1,000,000 new cases of genital warts annually in the U.S.  Genital warts account for approximately 240,000 initial office visits each year in the U.S.  About 1% of the sexually active U.S. population between the ages of 18 and 49 years old have genital warts at any point in time and the treatment of genital warts accounts for about one-third of all STD dollars annually.

## Slide 18

**Notes:**
This diagram summarizes how VLP-based vaccines are made.  The first step is to isolate the DNA of a naturally occurring HPV and then clone the gene or open reading frame (ORF) encoding the L1 capsid protein into a plasmid.  The plasmid containing the L1 gene is then introduced into a eukaryotic cell, the L1 gene is transcribed  into mRNA and the cell then translate the mRNA into L1 capsid proteins.  These capsid proteins then combine together to form a viral like particle.  Since no viral DNA (except for the L1 gene) has been introduced into the eukaryotic cell, there are no viral genomes available to incorporate with the viral like particles so there is no danger of producing infectious virions.  The VLPs are then purified and used to elicit an immune response in the host.  

## Slide 19

**Notes:**
This is the first "proof of principle" trial demonstrating vaccine efficacy for a prophylactic HPV vaccine in humans.  The trial was Phase II trial that looked at a monovalent HPV 16 only VLP vaccine.  It is important to recognize that a monovalent vaccine will not be used clinically.  This trial was a double-blinded placebo controlled trial in which 2,392 women 16 to 23 years of age received either vaccine of placebo.  Three doses of vaccine or placebo were given - at entry into the study and 2 and 6 months later.  Women in this study were followed for a median of 17.4 months.  

## Slide 20

**Notes:**
Recently, 48 months of follow-up have been published from this "proof of principle" trial that utilized a monovalent HPV 16 VLP vaccine.  After protracted follow-up the vaccine efficacy remained 100% for HPV 16 persistent infections which are defined as detecting HPV 16 at two consecutive visits at least 4 months apart.  The extend follow-up also allowed us to evaluate the impact of the monovalent HPV 16 vaccine on development of HPV 16 asociated CIN lesions.  There were 24 HPV 16 associated CIN lesions in the placebo group and none in the group that received all 3 dosages of the vaccine.

## Slide 21

**Notes:**
Women enrolled in this Phase II study have continued to be followed.  This graph presents the immunogenicity results for these women.  The X-axis gives the time in months since enrollment and the Y-axis shows the geometric mean titers of neutralizing antibodies for HPV 16 identified in the serum of the women expressed in arbitrary units per ml of serum.  The red line indicates the antibody titers among recipients of the HPV 16 L1 VLP vaccine and the blue line the titers in women who were found to be serologically positive at enrollment, but who were PCR negative for HPV 16 DNA at enrollment.  After the first dose of vaccine given at enrollment the mean titers begin to increase and the continue to increase over the first six months.  Note women received three dosages of vaccine.  After the third dose of vaccine was administered vaccinated women had antibody levels almost two orders of magnitude greater than what occurs with naturally-occurring exposure.  Over time there has been a minor reduction in mean antibody titers but even 42 months after the last dose of vaccine the titers in the vaccinated women appear to be approximately a log higher than is seen with naturally-occurring immune responses.  This data is extremely encouraging since it suggests that the effects of the vaccine are likely to be highly durable.

## Slide 22

**Notes:**
Two companies are currently quite far along in the development of prophylactic HPV vaccines.  These are GSK and Merck.  Published Phase II studies from both companies show that their respective vaccines are highly effective in preventing persistent infections with the targeted types of HPV.  Merck has now reported the results from their pivotal Phase III study and filed with the Food and Drug Administration (FDA) in December 2005 for approval of their vaccine for clinical use in the United States. 

## Slide 23

**Notes:**
Currently there are three large Phase III trials in progress.  These include the Merck trail that is investigating a quadrivalent vaccine against HPV 6, 11, 16, and 18.  This is a multi-site trial being conducted at sites around the globe.  The GSK Phase III trial is evaluating a bivalent vaccine against HPV 16 and 18.  Again this is a multi-site trial being conducted at sites around the globe.  Finally the National Cancer Institute (NCI) is conducting a Phase III trial in Costa Rica that is using the GSK bivalent HPV 16 and 18 vaccine.  The NCI trial is extremely important because it is being carried out in a region of Costa Rica where in depth HPV prevalence studies have been conducted and therefore this trial will allow us to investigate the impact of vaccination on the distribution of HPV types in the population.  Combined, these Phase III trials will include of 20,000 young women who will be followed for several years.  All of the trials are using not only virological endpoints of persistence of cervical HPV DNA positivity but also clinical endpoints of CIN 2 and CIN 3.

## Slide 24

**Notes:**
The next several slides present the unpublished results from the Phase III trial of the quadrivalent vaccine being conducted by Merck which is referred to as the Future I trial.  This trial investigated a quadrivalent vaccine for HPV 6, 11, 16, and 18.  The  analyses that are being present were conducted at 18 months after the last patient was enrolled.  They only include women who are classified as being “per-protocol”.  This means that the women were naïve to the relevant HPV types at day 1, that they received all three doses of either the vaccine or the placebo, and they did not become infected with vaccine types of HPV during the 6 month vaccination period.

## Slide 25

**Notes:**
In the per-protocol groups there were 2,240 women in the vaccine arm and 2,258 in the placebo arm.  There was 100% efficacy of the vaccine against CIN lesions associated with any of the vaccinated types of HPV.

## Slide 26

**Notes:**
This was true for low-grade lesions including external genital warts (EGW), VIN 1, and VAIN 1 as well as for high-grade lesions including VIN 2,3 and VAIN 2,3.

## Slide 27

**Notes:**
By the time of licensure it is expected that over 50,000 individuals will have been vaccinated with VLP-based vaccines.  There have been very few adverse events associated with the vaccines. Therefore there appear to be no significant safety issues with respect to these vaccines. 

## Slide 28

**Notes:**
This slide shows the unpublished results with respect to safety in the quadrivalent Phase III study.  83% of the vaccine recipients had at least one injection site adverse event (AE) compared to 73.4% of the placebo recipients.  However, these are generally mild pain or swelling at the injections site.  Essentially equivalent numbers of women in the vaccine and placebo group had systemic adverse events, serious adverse events, or discontinued the study due to an adverse event.  This confirms the very good safety profile of the quadrivalent vaccine.   

## HPV Vaccine

- Merck HPV vaccine, “Gardasil”
- Type-specific Virus Like Particles (VLP)
- L1 protein produced in yeast cells
- Non-infectious
- Alum adjuvant
- Types 16, 18, 6, 11
- Estimated 70% of cervical cancer, 90% genital warts
- 3 shot series
- Day 1, Month 2, Month 6
- Intramuscular
- Induces neutralizing antibodies

## HPV Vaccine

- Efficacy and Safety Studies
- Females, 16 -26 years old
- Brazil, Europe and U.S.
- No history of abnormal pap
- Prior HPV infection not an exclusion
- “Bridging studies”
- Safety and antibody response
- 9 -15 year olds

## Efficacy and Safety Trials: Conclusions

- High Efficacy
- Among 16 - 26 y.o. without preceding infection
- Seroconversion 99%
- 100% protection against dysplasia by vaccine type
- No evidence of therapeutic effect
- Don’t eliminate existing infections
- Genotype-specific protection
- Two exceptions: genotypes 18 and 45, 16 and 31
- Protection through 5 years
- Protective antibody level, need for booster are unknown
- Safe
- Mainly local reactions: pain, swelling, redness
- Post-licensure reports of fainting in 10 -18 year olds

## HPV Vaccine, ACIP Recommendations

- Routine use in 11 - 12 y.o. females
- Can be used in 9 -26 y.o.
- Catch-up 13 -26 y.o. females
- Can be given with other vaccines
- Tested with Hep B vaccine
- Not recommended for use in pregnancy
- Can be given to lactating women
- Observe in clinic for 15 minutes after dose

## HPV Vaccine, ACIP Recommendations

- Pap Smear recommendations not changed
- No need to test for HPV before vaccinating
- Can vaccinate women with
- Abnormal paps, colposcopy
- Genital warts
- Not indicated for men

## Phase III NEJM  and Lancet May 2007EFFICACY Prevention of Cervical Intraepithelial Neoplasia (CIN) and External Genital Lesions (EGL) – FUTURE I Prevention of Cervical Intraepithelial Neoplasia (CIN) 2/3 including Adeno- and Squamous-cell Carcinoma in situ (CIS)-FUTURE II

## Subject Characteristics FUTURE II

|  | Vaccine(N = 6087) | Placebo(N = 6080) |
| --- | --- | --- |
| Mean age (yrs) | 20.0 | 19.9 |
| Age range (yrs) | 15 to 26 | 15 to 26 |
| Region |  |  |
|   North America | 460 (8%) | 456 (7%) |
|   Latin America | 1599 (26%) | 1594 (26%) |
|   Asia-Pacific | 92 (2%) | 89 (2%) |
|   Europe | 3936 (64%) | 3941 (65%) |
| Mean Age 1st intercourse among non-virgins (~93.4%) | 16.6 | 16.6 |
| Median Lifetime # of sex partners | 2 | 2 |
| Using hormonal contraception | 3613 (59.4%) | 3614 (59.5%) |

## Efficacy Results in PP Efficacy  Combined Phase III Trials 

|   | Vaccine
(N=10,291) |  | Placebo
(N=10,292) |  |  |  |  
Efficacy (%) |  
CI |  
 p-Value  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Endpoint | n | Cases | n |  | Cases |  |  |  |  |
| CIN 2/3 or AIS |   |   |   |  |   |  |   |   |   |
|   HPV 16/18-related | 8579 | 1     | 8550 |  | 85    |  | 99 | (93– 100)                  | < 0.001          |
|   CIN 2 | 8579  | 0    | 8550 |  | 56   |  | 100  | (93– 100)                  |   |
|   CIN 3 | 8579   | 1     | 8550  |  | 51     |  | 98               | (89– 100)                  |   |
|  |  |  |  |  |  |  |  |  |  |

**Notes:**
Last week, we unblinded the study, after a total of 4 years of follow-up. The results are shown here, and they are as exciting as the primary results.
The overall efficacy was 94%. For the same endpoint that were used in the first analysis, that is HPV 16 persistent infection or HPV 16-related CIN, the efficacy remained 100%.  26 women developed cervical abnormalities related to HPV 16.  Of these 12 developed high-grade pre-cancer, the last stage of cervical abnormality  prior to frank cancer. Furthermore, these results show the durability of the vaccine’s efficacy. 
Now I want to discuss the final line here. This end-of-study analysis differed from the first analysis because it included the last visits in the study.  So although our endpoints were persistent infection and CIN related to HPV 16, they also included detection of HPV 16 on the last visit on record without a requirement for detection on 2 visits.  Here, there were 19 cases in the placebo group and 7 cases in the vaccine group.  
Now these cases do not necessarily represent true infection –single time detection of HPV 16 in the cervicovaginal tract is a mixed bag of transient infection, deposition of HPV from an infected partner, or contamination from instruments used in GYN offices. However, since women with HPV 16 detection on the very last visit in the study were not followed for another visit, we couldn’t tell whether they had persistent infection or not. One thing we do know is that none of the 7 vaccine cases had evidence of CIN or pap test abnormalities, suggesting contamination. 

## ALL PHASE II and III studies combined

- Average 36 Months After the First Vaccination

|   | Vaccine |  | Placebo |  | Reduction (%) |  95%
CI |  
  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  Endpoint | n | Cases | n | Cases |  |  |  |
| HPV 16/18 |   |   |   |   |   |   |   |
| CIN 2/3 or AIS | 10291  | 142    | 10292 | 255   | 44 | (31– 55)                  |  |
| VIN 2/3 and VaIN 2/3 | 9087 | 9  | 9087 | 31    | 71 | (37– 88)                  |   |
|  |  |  |  |  |  |  |   |

**Notes:**
Last week, we unblinded the study, after a total of 4 years of follow-up. The results are shown here, and they are as exciting as the primary results.
The overall efficacy was 94%. For the same endpoint that were used in the first analysis, that is HPV 16 persistent infection or HPV 16-related CIN, the efficacy remained 100%.  26 women developed cervical abnormalities related to HPV 16.  Of these 12 developed high-grade pre-cancer, the last stage of cervical abnormality  prior to frank cancer. Furthermore, these results show the durability of the vaccine’s efficacy. 
Now I want to discuss the final line here. This end-of-study analysis differed from the first analysis because it included the last visits in the study.  So although our endpoints were persistent infection and CIN related to HPV 16, they also included detection of HPV 16 on the last visit on record without a requirement for detection on 2 visits.  Here, there were 19 cases in the placebo group and 7 cases in the vaccine group.  
Now these cases do not necessarily represent true infection –single time detection of HPV 16 in the cervicovaginal tract is a mixed bag of transient infection, deposition of HPV from an infected partner, or contamination from instruments used in GYN offices. However, since women with HPV 16 detection on the very last visit in the study were not followed for another visit, we couldn’t tell whether they had persistent infection or not. One thing we do know is that none of the 7 vaccine cases had evidence of CIN or pap test abnormalities, suggesting contamination. 

## What happens when ALL women entering the trial are considered for ALL HPV-related precancers REGARDLESS of what HPV type  

**Interim analyses show vaccine effectiveness AFTER ABOUT 3 YEARS OF FOLLOW-UP is ****less than 20%**** ****CIN2/3 disease reduction**
**WHY ? Because women entering the trial were already infected with MANY high risk HPV types ****(<2 lifetime partners)**
**This reduced efficacy occurred EVEN WHEN VIRTUALLY ALL WOMEN (95%) RECEIVE ALL 3 DOSES OF VACCINE **
**This is simply not going to be achieved in the “REAL WORLD”**** **

**Vaccine EFFECTIVENESS IS NOT THAT HIGH – WHY and WHAT NEXT ?**
**Many HPV types other than HPV 16 and 18 cause anogenital disease**
**Many people who will get HPV vaccines under current age licensing  (9-26) will already be infected with  BOTH vaccine and other HPV types **
**The HPV vaccines DO NOT have any clear impact when HPV infections are present at the time of vaccination**

## HPV Vaccine Trial Data Potentially Overlooked

**                        **_**HPV-6, 11-, 16-, or 18-related cervical lesions**_
- 			          _**Vaccine (N = 2,723) Placebo (N= 2,732)**_
**	****	****                     **_**n   Case  Rate**_**        **_**n    Case  Rate**_**   **_**%Reduced**_
- Seroneg and PCR (+) 232   27     4.7         213   31     5.8      19 (<0-54)
- Seropos and PCR (-)   377    0       0           379    2      0.2    100 (<0-100)
- Seropos and PCR (+)  156   41    11.9        137    30    10      -20 (<0-27)

## Slide 41

**Notes:**
This graph shows the incidence per 100,000 women for meningococcal disease by age in the U.S.  The highest incidence of disease occurs during the first year of life.  However > 50% of cases in infants < 1 yrs of age are cause by serogroup B for which there is no vaccine available.   There is another peak of disease in young adults 15 to 19 years of age. Death rates from meningococcal disease are up to 5 times higher in young adults 15 to 24 years of age than they are for younger ages.  The incidence rate is particular high among college freshmen living in dormitories - 5 per 100,000.

## Slide 42

**Notes:**
When we look specifically at college campuses - each year about 100 to 125 college students in the U.S. develop meningococcal disease and 5 to 15 die.  Quadrivalent vaccine for N. Meningitidis are now available and the Advisory Committee for Immunization Practices (ACIP) recommends that 11-12 year olds be vaccinated using the meningococcal conjugate vaccine and that catch-up vaccination be offered to unvaccinated individuals entering high-school or college.   

## Slide 43

**Notes:**
This shows potential reductions in HPV-associated disease that could be achieved using HPV vaccines in the U.S. Tthe X-axis is logarithmic.  Based on data from the College of American Pathologists it appears that each year in the U.S. about one million women are diagnosed with CIN 2,3 and approximately 60% of these would be preventable with a HPV 16 / 18 vaccine.  Using CDC estimates, upwards of 1 million individuals acquire genital warts yearly.  Approximately 90% of these are caused by HPV 6 and 11 and about 5% are associated with HPV 16 and HPV 18.  There are slightly less than 11,000 cervical cancers yearly.  Approximately two-thirds of these are associated with HPV 16/18 and would therefore be preventable.  Similarly, about 4,000 cases of anal cancer occur annually.  About 80% of these are associated with HPV 16/18.  Finally, although the number of cases of recurrent respiratory papillomatosis which occurs annually is unclear, it is likely to be several thousand and over 90% of these would be prevented using a vaccine that included HPV 6 and 11.  To put the potential impact of HPV vaccines into perspective we have provided the number of cases of meningtitis that occurs annually in college-aged students, for which it is recommended that all teenagers and college students be vaccinated against.  This is only 100 to 125 annually!

## Screening and Treatment

- Initially no major changes in American Society for Colposcopy and Cervical Pathology Guidelines
- Screening
- Treatment
- Long term?

## Slide 45

**Notes:**
For those of us who believe that the HPV vaccines will provide a significant benefit to women in the U.S. it is critical that we not forget that approval by the FDA and even a recommendation for use by ACIP does not mean that the vaccine will be utilized.  Funding and advocacy are going to be critical.  Other vaccines such as hepatitis B and varicella had a very slow uptake.  Therefore all of us who are involved with cervical disease are going to need work at the state and local levels to assure that the HPV vaccines are funded and that both clinicians and patients/parents are aware of them.  Some patients / parents have a lot of questions regarding vaccines in general and they are going to be initially unaware of the benefits of the HPV vaccines.  This will require considerable education by clinicians as to the benefits of vaccination.