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Update on HPV: Beyond cervical cancer

Thomas Cox, MD
University of California Santa Barbarba
Santa Barbara, California

Epidemiology and natural history of HPV in benign and malignant disease: Primary prevention of CIN 3 and AIS with HPV vaccination

My name is Tom Cox. I’m Director of the Women’s Clinic at University of California Santa Barbara and for the next two years President of the American Society for Colposcopy and Cervical Pathology. And I have the honor of having with me for this session Dr. Hope Haefner, who is Professor of OB/GYN at the University of Michigan and really one of the world’s foremost experts on vulvar disease, was actually the key author in the Vulvodynia Guidelines. And to her left is Dr. Joel Palefsky, Professor of Medicine at UCSF. Joel is one of the foremost HPV experts in the world. He, in fact, was the head of the International HPV Conference in 2005. So we have a couple of very distinguished people here on the podium with me today. And I hope that we can give you a lot of information in our update on HPV will be useful to you in your clinical practice. I’d also like to thank the sponsor of this particular symposium, Merck, for providing the access for all of you to have lunch here today.

At the conclusion of the symposium participants should be able to describe the mechanism of HPV-induced oncogenesis and the data to date on the prevention of cervical precancer through HPV vaccination. And too in the next two sessions after me, discuss the burden of HPV disease related to the vulva and vagina, discuss the burden of HPV disease related to the penis and anus. So we want you to have a clear understanding when you leave that this virus is not just responsible for cervical disease, it has many other issues that are important to prevent.

There also may be a discussion of off-label or otherwise non-approved uses of the vaccine and the reason for that is there’s going to be at least some discussion on males here and so that is not an FDA approved use at this point in time. So just to let you understand that ahead of time.

You have in your syllabus the disclosures. There’s one glaring miss on that and so I added it into the slide here. I’m on the Merck Data and Safety Monitoring Board for the vaccine trials. These boards are independent of the company and that’s probably why they didn’t include it on there for me but I think it’s important you know that.

So I’m going to start out talking about this virus in our everyday practice. I’d like for you to understand by the end of this session what it causes and how it causes it, particularly how it causes cancer and then I’ll talk about the primary information on the vaccine in the vaccine trials.

This is just a drawing of the viral genome itself. Many of you have seen this in the past. The important thing that I want to just present to you in this is that these two genes on the virus are responsible for it’s oncogenic potential. And I’ll talk a bit more about that in a minute but this is something that produces, the proteins produced from these two genes can actually highjack our anticancer genes and allow mutations to start to accumulate and can cause cancer. It doesn’t happen to most people but it can happen and that’s going to be what we’re going to be talking about here today. The L1 gene is important because it produces the protein capsid that surrounds the DNA and this protein capsid is what is injected without the DNA in an individual getting the vaccine. So it’s antibodies to this protein capsid that protect the individual from getting HPV for the four types in the vaccine.

This is just a representation of the phylogenetic tree of the two major groups of genital HPV types. Those that are called low-risk, which do not have the capability of producing these proteins that we just discussed. They don’t produce them in large enough amounts to cause cancer and are responsible primarily for genital warts and other low-grade disease. And the high-risk types, which do have the capability of producing enough of these proteins, which we’ll discuss in a bit.

I first wanted to start out talking about the life cycle of an HPV infection because an infected partner will shed cells from the surface epithelia infected with HPV DNA. And if those cells get access to the basal epithelium or the basal cells in the epithelium the protein capsid comes into contact with that basal cell and the HPV DNA can enter the cell and leaves the capsid behind. So if you could have antibodies present here to this protein capsid you could prevent the virus from ever attaining access to the basal epithelium in the first place. And that’s how the vaccine works. If that individual doesn’t already have spontaneous immunity to these viral types or to vaccine immunity, than the person will get infected with this virus and at some point after a period of short or long-term latency will start to replicate virus in the upper layers of cells in the epithelium and as it gets into the upper layer of epithelium as the cells mature and begin to die it puts its protein capsid back on. So there is never HPV DNA infected without a protein capsid on it and that’s why the virus works so well. And these can be shed from the surface to infect a new partner that had not already been exposed.

This is a very common virus and this was from Rutgers University almost ten years ago now but it showed that just women coming in for routine birth control and tested with a sensitive HPV DNA test over a quarter of them were positive at any one time. And they followed these women for three years, every six months with HPV DNA tests and there were 46% of these women got new or first infections during that three-year period of time. So overall about 60% of college women in this university got HPV. And this is not just an East Coast phenomenon. We’ve had similar studies on the West Coast, in fact, one by the group up at the University of Washington recently showed that if they followed women from a virginal state when they’re HPV DNA negative, and had only one partner, by the end of one year with only one partner about 26% were HPV DNA positive. By the end of three years with only one partner, almost 50%. This is a very common virus, very transmittable.

The CDC shows figures estimates that about 20 million individuals are infected with HPV DNA at any one particular time and about half of these are young individuals in the 15 to 24 year old age group. About 80% of all of us get HPV at some point in our lives. I’m not sure it isn’t even higher than that. But if you have intercourse you’re certainly at risk unless you only have intercourse with somebody who has never had intercourse with anybody else before and you stay that way the rest of your life.

These are the low-risk types. And 6 and 11, which are two of the types in the vaccine are the most important lower risk types. They cause genital warts such as this genital wart near the hymenal ring here and these are called condyloma acuminatum on mucosa such as you see here. You see the blood vessels more clearly, you’ll see a picture of that condyloma on keratinized skin later that shows that they’re usually more white and cauliflower in appearance.

But these two types cause about 90% of genital warts, about 10% of low-grade cervical disease. So most of the cervical changes that we have that we call low-grade are actually due to high-risk viral types. And even with that, most low-grade changes do respond to our immune system and will resolve on their own without any kind of treatment.

I’m going to throw a couple of case studies in just to illustrate why it’s so important for this vaccine to be administered before an individual either has the opportunity to choose to have intercourse or not.

This young woman I saw a few years ago who had no intention of an intercourse and she was date raped and within a month she had genital warts and they were really all over her vulva, all over the perianal area. And this is quite devastating. I think the important thing to just realize is that we don’t always have choices over what happens to us in our life and the best thing to do is to encourage your patients to have their daughters vaccinated before they have any opportunity to have intercourse, whether in this unfortunate manner or one that’s by choice.

Now we’re talking about, in the next section here, the high-risk viral types that cause cervical precancer and cancer and vulvar and penile precancer and cancer and vaginal as well. Sixteen and 18 are by far the most important types that cause any of these precancers. This is a CIN 3, two quadrant CIN 3, of the cervix.

We can just look at large studies of women around the world and see that close to 100% of all women that have cervical squamous and glandular cancer have HPV DNA of a high-risk type present. So basically what we can say at this point in time in history is that more than likely the cervical cancer is a cancer that requires HPV and the International Agency of Research on Cancer said this in 1999 that is may be the first human cancer to have a single necessary cause.

This is a second case that I saw a few years ago. I didn’t actually see her, this is in review of the case after this happened. But she was 29, she had intercourse that started at age 15 with the median age in the U.S. is 16 now, she had a pretty normal number of lifetime partners. A lot of normal Paps but there were some reactive changes on there that were still called normal but unfortunately when re-read later after the fact were read as having a high-grade glandular changes. To make a long story short, she had recent onset of postcoital bleeding and died a year later of cervical adenocarcinoma.

So I think the question that we can ask in women like this, now that we’re in a new kind of decade of prevention of cervical cancer, would she be alive if she could have had the vaccine before she ever got exposed to 16 or 18, which could have occurred as early as age 15.

And I just say statistically there’s a good chance of it. If we look at the percentage of squamous cell carcinoma that is caused by 16, 18, it’s about 70% with 30% caused by all the other high-risk types. If we look at adenocarcinomas of the cervix it’s about 86% are caused by 16 or 18. So she had about and 86% chance that her adenocarcinoma would have been prevented had she been able to get the vaccine ahead of time.

So there are a lot of cervical cancers in the world. They’ve certainly been reduced in this country by about 75% to about 11,000 new cases occurring in 2007 and that reduction has been from Pap smear screening with about 3900 deaths. In the world, it’s still the second most common cancer, worldwide the second most common cause of cancer deaths in women with about a half million new cases and about a quarter of a million deaths.

It also takes away more years of life than other female cancers for women who end up dying of it because it generally occurs at younger ages. And you can see from this study, about 26 years of potential years of life are lost from a woman dying of cervical cancer versus 19 for breast and 17.4 for ovary. And it often occurs when women still have children at home. So it can be a very tragic loss within a family.

So I think just sort of in a summary of this natural history, most people get HPV at some time. Most people will clear high-risk HPV but some do not. And the time to clearance is variable, although for many individuals it’s within a fairly short six to twelve months. But its persistence of high-risk HPV DNA over a period of time that results in high-grade CIN 3 such as you see here. And if the HPV persists with that high-grade lesion, which would be required for the high-grade lesion to persist than cervical cancer can occur. And it occurs because of the accumulation of random mutation.

So what I want to kind of just give you a short synopsis on is how HPV causes cancer. Now every cancer is the result of loss of control over normal cell growth.

This one we know is that loss of control is secondary to a virus. And normally when we have mutations occur in our DNA it results in increased protein levels from particularly our two most important anti-cancer genes or anti-onco genes, these ar p53 and the retinoblastoma gene. And this will usually either fix the cell DNA or destroy the cell. And if it destroys the cell it’s called apoptosis.

So as I already mentioned, the HPV genome, E67 can produce proteins that block this process, this protective apoptotic process and when it does interfere with that process it allows random mutations to accumulate.

And that’s probably why most high-grade lesions persist for many years before they become invasive because it takes quite a while for quite a number of mutations to accumulate that can result in loss of the mortality that cells usually have. And once the cell becomes immortalized it then can become cancer. And this can be promoted by herpes and chlamydia because increased cell turnover in the cervix in the presence of HPV can increase the risk of mutations. And it can be increased by smoking, which causes the accumulation of cotinine and nicotine and nitrosamines in the cervical mucus right where HPV can be destabilizing our apoptotic process.

So with accumulation of thousands of mutations, the cell can become immortalized and cancer such as this adenocarcinoma can occur.

Now let’s talk about the HPV DNA vaccine data. How is the HPV vaccine produced.

I think the most important thing for you to understand is that there is no DNA in this vaccine. It is a pure protein vaccine. The L1 gene is taken out of the HPV DNA and in this situation put in a yeast where it then elaborates the protein capsid without any HPV DNA cause the L1 only produces and L1 capsid. These are then injected into the individual to produce a host immune response that is a B cell antibody response. [16:04]

[30; 16:04] So there have been two major vaccines looked at, the bivalent vaccine 16, 18 is not yet FDA approved but it’s expected to be approved probably in the next year or so. And the quadrivalent vaccine, which is on the market now that has 6 and 11 besides the 16, 18. You can see on here that the study ages were very similar. The schedules were similar, zero, one and six months. And the eligibility criteria were just a little different in that the bivalent vaccine allowed a couples of more partners, lifetime partners, for those individuals entering the trial than the quadrivalent vaccine.

So I’m going to be talking about three groups of data and I don’t want to get you too confused. This first group of data is the perfect world, It’s women that had no HPV DNA present at the time they entered the trial to these four types, no serologic evidence of prior exposure. Got all three vaccines, did everything right in the trial and did not get exposed to these four vaccine types during the seven months that they were getting the vaccine.

And you can see that in this perfect world data there were no cases of CIN 1, 2, 3 or adenocarcinoma in situ in what was called the Future I Trial versus this number in the placebo trial for vaccine efficacy of 100% for each one of these disease points.

For external genital lesions, due to 6, 11, 16 and 18, there were no cases versus the number of cases you see here in the placebo group, again for 100% efficacy.

In the Future II Trial, which was 5300 in each arm of the trial for the vaccine recipients and the placebo recipients. It was 100% efficacious against CIN 2 and adenocarcinoma in situ. There was one case of CIN 3 that was HPV 52 positive throughout the trial from the start before she got the vaccine. And at the end when she was diagnosed with CIN 3 had HPV 52+, also had 16 detected in the vaginal swab. So whether that had anything to do with the disease it’s hard to know or whether it was just a rider. But at any rate, it does have very high efficacy.

Now the bivalent data was looked at in interim analysis before they had enough data to be in a per protocol group. So this group is the same as the last group, what we call a modified intention to treat group except that some of these women might have been exposed to one or more of these four types during the time that they got the vaccine, otherwise everything else was the same.

And that may be one of the reasons why we see a little difference in rates here although, again, with the CIN 2, 3 and the bivalent group you can see there were 6700 vaccine recipients, same number of placebo recipients. You can see the cases of high-grade degree in the placebo group versus the vaccine group for 93% efficacy. And the HPV 18 related CIN 2, 3. There were lesser numbers as is usual for a little lesser efficacy cause there was one case in each of these, and it was the same situation, there was another high-risk type throughout the entire vaccination period and only at the end when the CIN 2, 3 biopsy was obtained was either 16 or 18 detected. So it’s hard to know whether it was the one that caused the disease.

Another important point is that both the quadrivalent and the bivalent vaccine have shown something that we did not expect. And that is that for types that are closely related to the types in the vaccine, there appears to be some cross protection, although it still remains to be shown that there’s cross protection from disease but we can see here that for persistent HPV of these types, HPV 45, which is highly related to HPV 18, the percent decreased in 45 persistent infections was 60%. And then for those other types that are here that are more closely related to 16, there was lesser cross protection but it does give some hope that we may see some efficacy in cross protection.

Now what you have seen in the newspapers at times perhaps is vaccine efficacy not as much as it thought it would be and that is on the basis of what we call intention to treat data. This is everybody in the trial, whether or not they had HPV 6, 11, 16, 18 at the start when they got their first injection or not, whether they had serologic evidence of prior exposure, whether they got all three shots or only one shot, this is kind of what you might see in your normal population of 16 to 26 year old women coming in who want the shot and the kind of efficacy that you might get.

And this just shows you that the reduction in genital lesions, CIN of all grades and CIN 2, 3 are adenocarcinoma in situ is substantial but it is not as substantial as 100%. It’s a 58% reduction in genital lesions of all types, 72% of CIN of all grades and 66% of high-grade CIN or adenocarcinoma in situ.

And so we might ask well why is that the case? The reason is that a lot of these women, at least a quarter of them, already had at least one of these HPV types present or evidence of it being present when they started getting the vaccination. So if you look at the data for the vaccine in terms of accumulation of disease due to these types, these were external lesions due these types, you can see that it sort of paralleled those in the placebo group up until about 9 months and the two started to diverge. As the placebo group was acquiring more new infections and the vaccine group cleared or had manifest all the infections that were going to go ahead and manifest the disease. And so the vaccine group flatlined. So if we follow this out over many years we’d see increasing efficacy I’m sure because of the fact that these lines would continue to diverge. So when you look at efficacy it’s looking at over a shorter period of time where there was already disease manifested due to those already infected.

You see the same for 6, 1, 16, or 18, CIN 1, 2, or 3. Again the vaccine flat lines out as all the previous infections have now manifested themselves.

What about side effects? This is a really safe vaccine. At is says on the CDC FDA site, it has had about half the serious side effects reported as the average vaccine newly coming on the market. We looked at the safety data for the recipients in the trial, sore arms, a little headache for some, a little fever for some, but nothing serious in the nearly 40,000 or so women that have been evaluated around the world in the trials themselves.

This is data from the bivalent trial on chronic and new onset autoimmune diseases and medically significant conditions. And you can see, and by the way, medically significant conditions can include feeling faint after getting the shot. So you can see here that there is really no statistically significant difference between the placebo group and the vaccine group, although no question there’s a sore arm in those that get the vaccine versus placebo.

There has been a lot in the summer in the newspapers about serious side effects of this vaccine. I would like to try to lay that to rest because you’ll be getting questions from you patients and this is not in the syllabus because I just pulled this off the web long after I put the lecture in here. But it’s estimated that 20 million doses have been given and this is a direct report from the CDC/FDA site. In some media reports and on some Websites on the Internet various reports are presented as verified cases of vaccine deaths and injuries. Statements such as these misrepresent the nature of the VAERS surveillance system. VAERS is a vaccine adverse event reporting system. Anybody can pick up the phone and report that their daughter had a sore arm or fainted or you know or had a blood clot that was thrown and there have been some deaths reported within a time span after the vaccine. The CDC and FDA just looked at that data and met this last month and said there was no evidence of any connection in the serious side effects with the vaccine. It just was the background number of those kinds of events you would see in a population whether they got the vaccine or not.

So, the CDC and FDA said that based on ongoing assessments of vaccine safety information, the FDA and CDC continue to find that Gardasil is a safe and effective vaccine.

Now what about duration of protection? A combined analysis of all protocol participants through 36 months in a subset through 60 months shows that there is protection against both persistent infection or disease in the range of 96% and CIN or extended genital lesions 100%. So very, very effective through this little bit longer time look.

So this was approved by the U.S. Food & Drug Administration in June of 2006 for administration. The quadrivalent HPV vaccine that is, not the bivalent yet. And it’s based on the results from these four placebo controlled, double blind, randomized Phase 2 & 3 clinical studies and two immunogenicity bridging studies for younger individuals.

The CDC recommended the following: that routine vaccination of girls 11 to 12 years of age with doses of quadrivalent HPV vaccine that vaccine series could be starting girls as young as 9 years of age at the discretion of the provider and that catch-up vaccination for adolescents and young women 13 to 26 years of age who have not been previously vaccinated is also recommended.

And then the last slide I have here is that, I wanted to give you a little hint of what the CDC recommends in terms of the dosing. The dosing is supposed to be zero, two and six months but we all know that patients don’t come in on an exact schedule like that. And I have many students that go abroad for a while, etc., and so this is what the CDC says about. The minimum intervals for giving the vaccine should not be less than 4 weeks from the first shot, that is the second one and the third one should not be less than 12 weeks between the second and third shots. They say that the maximum interval really hasn’t been defined but they feel that it’s probably okay to give the next shot as soon as possible if it’s longer than the recommended interval, that there would be no maximum interval. If you look on the Merck site, however, they recommended that it be given within the timeframe that the trial had actually studied so they don’t give unlimited timeframes in terms of giving it but certainly the CDC felt comfortable with that. So I’d like to have Dr. Hope Haefner come up here and I thank you for your attention.