Clinical Education Initiative TITLE: AN UPDATE ON HPV. Speaker: William Bonnez, MD

Transcription

1 Clinical Education Initiative TITLE: AN UPDATE ON HPV Speaker: William Bonnez, MD 2/8/2017

2 An Update on HPV [video transcript] 00:00:07 - [Tara] Hi, everyone, this is Tara Babu, I'm on faculty at the Monroe County STD Clinic Center of Excellence, and it is with great pleasure that I introduce our speaker today, Dr. William Bonnez. Before I get started with our presentation and introducing him, I would like to mention that if you are not registered currently, to go ahead and register for the Lunch and Learn. And you will receive an about how to get CE credit for this presentation. If you've already been registered, then you will receive the in order to get the CE credit. I'd also like to make a plug for ECHO. Our next ECHO is at the end of this month. It's the fourth Wednesday of every month, and if you're participating, please send cases. We like to do the teleconference, and we like to hear from you. So please send cases to us. If you have never done ECHO before, there's instructions on the CEI website if you'd like to participate in ECHO. So, without further ado, I'm here to introduce Dr. William Bonnez. He is a Professor Emeritus here at the University of Rochester School of Medicine and Dentistry. He actually hails from France. He obtained his medical degree from the University of Bordeaux, after residency in general medicine at the New Britain General Hospital, which is part of the University of Connecticut Affiliated Hospitals Program. He then moved to Rochester, and has been here with us ever since. He participated in Infectious Diseases Clinical Fellowship, followed by a Research Fellowship. It's during the Research Fellowship that he initiated, with his colleagues, Robert Rose and Richard Reichman, the work which led to the development of the present human papillomavirus vaccine. In addition to his interest in HPV vaccine and immunology, he has also studied new treatments and drugs for genital HPV infections. 00:02:09 Also, he is an Infectious Diseases Attending here at Strong Memorial Hospital, and he's been one of my mentors. So, without further ado, here is Dr. Bonnez. - [William] Thank you, Tara, and good afternoon. 00:02:22 My purpose is to give you an update on the Human papillomavirus and this is the outline of my talk where I will present to you data on the epidemiology of those infections, I will discuss the connection between HPV and cancer, and I, finally, will conclude by delving into the prevention of those infections and diseases. 00:02:49 So, let's start with the overview, and those viruses, human papillomaviruses, are nonenveloped viruses enclosing a double-stranded circular DNA genome. And you see to the right a capsid of all the viral follicle. These viruses are species specific, they only infect humans, and they're also tissue specific. They infect the stratified squamous epithelium and the cervical glandular epithelium. Today, there are 201 fully characterized types of HPV, and characterization is based on the sequencing of the L1 gene, the gene that codes for most of the proteins that are incorporated in the viral capsid. These viruses can cause latent, subclinical and clinical infection. And among those clinical infections, they range from benign, they go by names of warts, papillomas or condylomas. And they can involve up to malignant 1

3 lesions, which are preceded by potentially malignant lesion or precancers. The most common term is intraepithelial neoplasias, but in the case of the cervix, people also use the term dysplasias. 00:04:09 This table shows you the three main groups of this disease, with each their own association of HPV Types. The first groups are the cutaneous warts, warts that you get on your hands or feet. The second group is represented by epidermodysplasia verruciformis, a rare disease which is a genodermatosis. This is conditioned by the presence of mutated genes and it has its own assortment of HPV types. Those HPV types in red actually are associated with the development in those subjects of squamous cell carcinomas early in their lives, particularly in the sun-exposed areas. And this was the first model of a connection between HPV and cancer. And finally, the group of this disease that is the objective of my talk are the genital or mucosal infections, represented first by the genital warts or condylomata acuminata, which are mostly caused by HPV six and 11. The same HPV type causes laryngeal papillomas, and at the extreme, one has cancer, or in this instance cervical cancer with HPV 16 and 18 being the leading representants of viruses causing these types of cancers. And all those viruses with malignant potentials are indicated in red here. These are the high-risk papilloma viruses. And because those cancers are preceded by intraepithelial neoplasias, it's not surprising that we find in those lesions an assortment of low-risk and high-risk HPVs. 00:05:57 These diagrams will detail where one finds those mucosal or genital HPVs, obviously in the genital area, including the penis, the vagina and the cervix, but also in the anal canal. They are also present in the upper aerodigestive airways, which is an important fact to keep in mind. 00:06:24 Once an HPV infects the target epithelium, which is the epidermis, in the case of a benign infection it will induce the proliferation of the various layers of the epidermis, except for the most basal, or the deeper layer, the basal layer. So this proliferation, when it affects the stratum spinosum, which is just above the stratum basal, is called acanthosis. When it affects the stratum granulosum, just above, it's called parakeratosis, and when it causes a proliferation of the stratum corneum, it's called hyperkeratosis. In addition, when there is the formation of the wart or papilloma, there is a deepening of the rete ridges, which are the undulation of the basal membrane that gives the fingerprints. Finally, a feature of HPV infection is the presence in the stratum corneum of cells called koilocyte, which are large cells with a shrunken nucleus surrounded by a halo. These cells are seen on the Pap smear and are the hallmark of an HPV infection. 00:07:39 So, when a pathologist reports presence of HPV it's because he has seen those koilocytes on the cytology. 00:07:50 A point to also keep in mind about those infections is that they all occur close to where the squamocolumnar epithelium, sorry, they are close to where the stratified squamous epithelium meets the glandular epithelium, and this is called the squamocolumnar junction. You have a squamocolumnar junction in the larynx. You have one in the anal canal, and one in the cervix. 2

4 00:08:22 In the cervix the squamocolumnar junction has the characteristic of, and here we are looking at the cervix head on, so the squamocolumnar junction when the baby is born is very external to the opening of the cervix. But under the influence of acidification of the vagina hormonal factor, the squamocolumnar junction will start receding towards the os. And the area that is covered from where it was at birth, and where it is at the time of examination is called the transformation zone. This is in this transformation zone that cervical cancer develops. There's no transformation zone in the other areas where we find other squamocolumnar junctions. 00:09:11 So here, the diagram represents what happens when HPV infects the cervix. We start with normal epithelium. Because it's a mucosal surface the stratum corneum is not developed. And when the infection begins, causing a benign infection, it will make the koilocytes appear and for the pathologist it will be diagnosed as a flat condyloma, right here. Now, a stage further, is the development, the proliferation, of the stratum basale where when it occupies the lower third of the epithelium with those large cells with large nucleus and somewhat normal mitosis. This is called cervical intraepithelial neoplasia stage 1 or CIN 1. When this process, called dyskaryosis, occurs and involves more than one third but less than two thirds of the epithelium is called cervical intraepithelial grade 2, or CIN 2. Finally, when this process involves more than two thirds of the epithelium, it's called cervical intraepithelial neoplasia grade 3, or CIN 3. Carcinoma in situ is when this process occupies the full thickness of the epithelium. And once the process breeches the basal membrane, one has invasive cancer. The CIN classification is rooted in histology. But there is another classification that parallels that one, which is based on cytology. And it re-groups the flat condylomas and CIN 1 under the name of low-grade squamous intraepithelial lesion or LSIL. And it re-groups CIN 2 and 3 under the term of high-grade squamous intraepithelial lesion or HSIL. At the bottom of the diagram, you can see that as the lesions become more and more high-grade, there is a greater prevalence of high-risk HPVs. So that by the time one has invasive cervical cancer, for instance, literally all those lesions will contain HPV that is oncogenic. 00:11:46 These are illustrations showing different diseases associated with those viruses. To the left is the introitus of a female bearing multiple condylar acuminata. In the middle, this is an anal, perianal wart. And to the left, there is a cervical condyloma made visible by the application of acetic acid. 00:12:13 One stage further, the lesions called CINs. CIN 2 and 3 are on the left, and invasive cancer to the right. The characteristics: There are several characteristics allowing the distinction of those lesions with some reliability, and one of those characteristics is the presence of blood vessels. 00:12:39 Now let's go into the epidemiology of those cervical infections. 00:12:44 And this represents the age-specific prevalence of HPV infection and it's quite clear that they are most prevalent in the young adults, late adolescent. And then the prevalence decreases with advancing age. 3

5 Within some countries a second peak towards the 60's of the individual, but this profile is not seen in every country. 00:13:10 Now the old vision of HPV infection was that the bulk of patients were infected at some point by HPV. It was felt that about 60% of the population had a past infection that they noted by the presence of antibodies. And that if one looked at the cervix of the patients, 10% would have the presence of HPV DNA. Only 4% would have an abnormal cytology or colposcopy, and finally 1% would be represented by genital warts. 00:13:52 In fact, these numbers are likely an underestimation. There are two large surveys that were conducted, one based on urine samples which is not as sensitive as sampling the cervix, and it was felt in the largest and most recent that was involving patient age of 14 to 59 that about 40% of the population had an HPV, a cervical HPV infection. And it can be appreciated that the highest prevalence was in the age group 20 to 24 that started at a fairly young age, as soon as age of 14. It can be also appreciated that having only one lifetime sexual partners was associated with a fairly significant prevalence of 18%.The last point I will make is that the types that I included in the vaccines are not very common infections in cervical infections. That is not to say that the vaccine targets the wrong types. It's because those types are the ones that are present in cervical cancer. 00:15:14 Now how do you acquire HPV? 00:15:17 Sexual contact is essential in the acquisition of HPV. But it doesn't necessarily mean intromissive intercourse. There are all different sexual plays that can lead to the transmission of the virus. And because very often the person who gives the virus has a subclinical infection it is not easy to trace where the infection comes in a given subject. And that can lead to a lot of difficulties for the patient who is found to have an HPV infection. The incubation period ranges from three weeks to several months, which adds another difficulty in tracing the origin of the infection. Fomite transmission: Fomite, inert objects, like for instance sex toys may occur, but it's presumably rare. And finally, the last mode of transmission is through perinatal transmission probably in the case of disease affecting the upper airways, recurrent respiratory papillomatosis. 00:16:28 Now this diagram represents the cumulative incidence of HPV infection in a group of college-age women who when they arrived in college were virgins and didn't have any HPV DNA. In the four years of college some of them became sexually active and it shows that by the end of the fourth year, about half of the women had acquired the HPV infection in their cervix. And even if the sexual contact was limited to a first male sexual partners, the rate of acquisition was still quite high. So one doesn't need to be promiscuous to acquire HPV. 4

6 00:17:20 And when we look at men, we can see the same phenomenon. There is an acquisition of HPV here in different sites in the males that parallels the rate of acquisition in females. 00:17:36 It's not clear if the transmission is easier going from the female to the male, or the reverse. It seems based on the three studies, that it would be easier for the female to transmit to the males. But those studies have limitations. 00:17:55 A point that is probably important to appreciate is sexual behavior begins fairly early in the United States. And before age 13, about 6% of males will have had sexual intercourse, as opposed to 2.2% for the females. But by grade 12 almost 60% of either male or female will have been sexually active. And it's also important to realize that in many cases, those sexual contacts are not protected by the use of condoms. Therefore, if one wants to protect the population with a vaccine that is only efficacious before the patient is exposed to HPV, one has to start vaccinating at an early age. 00:18:58 Looking at the etiology of genital warts, and this is a summary of about 20 studies, one can appreciate 20 studies conducted in different places in the world, one can appreciate that the acquisition of genital warts is a little bit later in males. Between the age 25 to 29 one sees the peak. As opposed to 20 to 24 years of age for females. If one surveys individuals and asking them if they ever had genital warts, 5.6% of the population, age 18 to 59 will say yes. And this is more common for women than it is for men to report such a history. 00:19:52 This is a survey that is conducted periodically to look at the initial visits to selected physicians office for genital warts. And one can appreciate that the trend has been increasing over the years. 00:20:09 Recurrent respiratory papillomatosis is a disease associated with the same HPV genotype that cause genital warts. Here is an example of a papilloma on the vocal cord. And the problem with such a disease is that the mass can grow to almost obstructing the airway. Therefore, this disease requires usually a lot of surgical procedures. 00:20:38 The other danger is that this papillomatosis can extend down to the respiratory tree. There's a bimodality to the incidence of this infection with the first group where the disease is more common and it affects children less than 14 years of age. Typically it affects the first born child because the delivery is longer and provides a greater time for the transmission of HPV. Vaginal delivery from a mother who has genital warts is a risk factor. And also it should be recognized that the acquisition of HPV can occur in utero or peripartum. The second group of this disease is when it affects young adolescents and adults, this is the less common form of the disease. And this is related to the number of sexual partners and the frequency of oral sex. So this is an uncommon disease, but it's caused by the same genotypes as genital 5

7 warts, type 6 and 11. The odd finding about this entity is that it's virtually not seen in HIV positive patients, and I'll come back to this point later. 00:22:01 Looking at the epidemiology of cervical disease, not infection but disease, one can measure that by looking at abnormal Pap smears. 2.5% of pap smears are abnormal either because of low-grade squamous intraepithelial lesion, LSIL. HSIL, high-grade lesions are less common, a fourth. And a squamous cell carcinoma is a twentieth of that number, with adenocarcinoma representing about a fifth of the number of cancers. The problem with the Pap smear is that with equal frequency it will reveal the presence of atypical squamous cells that cannot be interpreted as to the rest of the progression. And this is the difficulty of the Pap smears is that there could be false positive. 00:23:0 Cervical cancer is a problem that is disseminated throughout the world, and those two maps show the incidence and the mortality of this cancer. This is the fourth most common cancer in women throughout the world. And most of the burden is in the developing world. Typically affecting the Eastern and Middle Africa. The cancer, of course, can lead to death. And cervical cancer represents 7.5% of all female cancer death. And a nine out of 10 of those deaths occur, again, in the less developed region of the world. And the variation between the regions of the world where the incidence is low and those where it's the highest is about 18-fold. 00:24:10 In the United States, the numbers are quite good because this is a relatively rare disease with an estimated incidence of 6.4 per 100,000 women. And among female cancers, cervical cancer ranks fifteenth in incidence and mortality, not fourth. 00:24:30 And indeed, when one looks at the curves of the incidence and of the mortality one see that throughout the years there's been a steady decrease in those two rates. 00:24:45 And it shouldn't be forgotten though that the numbers I gave are averages and there are disparities throughout the United States, both in incidence and mortality rates associated with cervical cancer. And in the red are the regions of the United States where those rates are higher, rates that are actually similar to some of the rates seen in the developing world. 00:25:13 In order to keep those rates of cervical cancer low, one has to rely on Pap smears to screen for early lesions and prevent their evolution towards cancer. And 65 million Pap smears are performed each year in the United States. 00:25:33 But when we look at where they are performed, the regions where they are performed less frequently are the ones which are shown in here in red, are the ones where we find indeed the highest rates of incidents and mortality associated with cervical cancer. 6

8 00:25:51 So if we now look at the overall burden of HPV, this disease. We can see that genital warts are the biggest burden, followed by cervical cancer and then oropharyngeal cancer is an issue, followed by anal cancer, vulva cancer, respiratory recurrent papillomatosis, vaginal cancer, and penile cancer. Out of those diseases, the only one that can be screened is cancer of the cervix. 00:26:27 Now I want to make a point about anal cancer screening which was recommended in September 2007 by the New York State Department of Health for HIV seropositive persons. And it was recommended then to do a baseline anal cytology for the following groups: Men having sex with men, any patients with a history of anogenital condylomas, and women with abnormal cervical and/or vulvar histology. And it was advised to repeat the test annually. 00:27:00 And there was a rationale behind this recommendation Which was modeled on cervical cancer screening. Given the same percentage HPV genotypes involved in the anus were the same as the ones involved in the cervix leading to cancer. The target epithelium was also the same. It was an epithelium next to a squamocolumnar junction, except that in the case of the anus, there is no transformation zone and no hormonal factor. There was also the same precursor lesions to target for screening which was the high-grade squamous intraepithelial lesion or high-grade anal intraepithelial neoplasia. And finally a similar tools of detection could be a variable cytology high resolution anoscopy/colposcopy, HPV nucleic acid detection, and biopsy. So this made a very attractive rationale for implementing anal cancer screening. There was also a favorable cost effectiveness profile, but in that model there were many assumptions that were made to substitute for data that was totally absent regarding the natural history of HPV anal disease. And there was also a failure to notice the importance of the anatomical location in HPV pathogenesis, cervix is not the anus, or it's not the larynx. For instance, one would have expected in HIV several positive, men having sex with men, a burst of recurrent respiratory papillomatosis. But that never materialized and is still totally unexplained why it does not occur given that they had all the risk factors for this disease. 00:28:55 The problem with the anal cancer screening is that anal cytology in fact is sensitive for HSIL, but it's not specific and that leads to doing high-resolution anoscopy and biopsies quite often. There's also the fact that these lesion high-grade anal intraepithelial lesions do recur in a majority of patients. So patients are treated but the problem comes back and this causes a burden for procedures and a high number of visits that leads to dropouts. The fundamental problem is that the risk of progression from the highgrade anal intraepithelial neoplasia which which is typically a non-lethal lesion to cancer, which is the lethal lesion, is still poorly known. There was a study conducted at UCSF on 72 patients who had developed anal cancer, and retrospectively 45 of them had HSIL, but not at the site of the cancer. So going after HSIL probably wouldn't have been useful. 14 of those patients were biopsied because of symptoms, not because they were picked up through screening. And only 13 of those patients are representing 18% of the total where asymptomatic, and detected prospectively. What the study showed though is that it's very important to do the Digital Ano-Rectal Examination. Now the biggest problem 7

9 with with doing anal cancer screening is that the population impact of screening on the incidence of anal cancer is still totally unknown. And therefore, the true costs are still totally unknown. 00:30:44 And knowing the cost is important because in the case of cervical cancer screening these costs are really the bulk of the expense, which in the U.S. is about eight billion dollars. 82% of that money is devoted to cervical cancer screening. So if one wants to implement screening one needs to be sure that it is efficacious. 00:31:11 Natural history of HPV infection is, in fact, after this gloomy presentation quite reassuring because most of the infections are transients. And it's only in those patients who fail to clear their infection, which usually takes about a year, that one will find the problem and where cancer will develop. 00:31:36 So in those persistent lesions right here, with time some of those lesions will evolve towards invasive cancer or to CIN persistence or in some cases regression of the lesion. So not all persistent lesions, or not all CIN 3 lesions will develop cancer, but it's not possible to figure out in advance which ones will develop cancer. So one ends up treating lesions, some of them which would not have developed cancer. And this is a problem with screening found in the case of breast cancer and prostate cancer for instance. 00:32:24 I already mentioned that HPV can cause cervical cancer, but also other cancers. 00:32:30 And the pathogenesis, the natural history of cervical neoplasia, is depicted here where the subject contracts an initial HPV infection. This infection, in most instances, is clear or develops CIN 1, but that can be cleared fairly easily. And in a small subset, there's a continuing infection which after up to five years will transform into a CIN 2, 3 infection or disease. And over a course that can go up to 20 years there can be progression towards invasive cervical cancer. And if HPV or the oncogenic HPV infection is necessary for the development of cancer there may be also co-factor for the progression and they include the HPV type, HPV 16 is clearly the most oncogenic of all HPVs. Some variance, some more oncogenic than others in their viral nuclear role. It is the parity of the patient having babies, using oral contraceptive, it presents a higher risk of developing cervical cancer, so is smoking, there's also strong genetic factors that are at play, including HLA types. And finally there are factors that are more disputed, that concerns co-infections, with chlamydia and herpes type 2, or the proper diet. 00:34:01 Now for cervical cancers, virtually all of them are caused by HPV infections. So it's necessary to have an HPV infection in order to develop cervical cancer and that's quite important. The other point to appreciate is that 50% of those cancers are caused by HPV 16. And then additional, about 20%, are caused by HPV 18. So together HPV 16 and HPV 18 represent about 70% of all cervical cancers, with the rest being caused by additional genotypes. 00:34:37 And cervical cancer is not the only cancer as I mentioned. But 40% of vulva cancers are attributable to 8

10 HPV. 70% of vaginal cancer, 50% of penile cancer, 85% of anal cancer, and a new, better appreciated cancer is oropharyngeal cancer, with fairly high percentage being attributable to HPV infection. And most of those HPV infections, in fact, are HPV 16 or :35:14 And so I want to discuss a little bit the oral HPV infection and oropharyngeal cancer. 00:35:21 The oropharynx is this area of the head and neck area. This is essentially the uvula, the base of the tongue and the palatine tonsils. This is about half of the head and neck cancers occur in the hypopharynx. 00:35:42 And it was realized several decades ago that there are basically two types of head and neck cancer involving the hypopharynx. There's the HPV negative types of cancer, the classic head and neck cancer that occurs in older males with the predominance of males being involved relative to females. And the risk factors in this cancer is the consumption of alcohol and tobacco. On the other hand, HPV positive cancer of the oropharynx occur in the younger population it's still predominately affects males and it's not related to alcohol or tobacco, but related to sexual behavior. And the relative good news is that it has a better prognosis as the HPV negative head and neck cancer, oropharyngeal cancer. 00:36:54 The thing that started catching the attention of people was that the prevalence of those HPV-related tonsillar or oropharyngeal cancers was increasing. Here is a study done in Sweden where clearly the HPV prevalence in those cancers was multiplied by three over a period of 30 years. 00:37:24 In the United States this diagram shows that rates of oropharyngeal cancers and it breaks it down into those that are not related to HPV, and those that are related to HPV that showed an increase. 00:37:40 And if we break down the data by sex, we can see that for instance, starting with cervical cancer, there's been a decrease in the rates of cervical cancer. But the rates of oropharyngeal cancers, right here, have been increasing. And this increase is due essentially to men. The main contribution is by men, because in female incidence of oropharyngeal cancer has been decreasing. And if we look at number of cases, here on the left, the scale is logarithmic but here is linear. We can see that there's a dramatic increase in the number of cases of oropharyngeal cancer in men. 00:38:23 And in fact, once we look at insurance data we can see that there's a surge in the number of oral cancer, or head and neck cancer globally. 00:38:35 Now these infections are related to infections of the oral cavity. Here's a study that looked at the presence of oral HPV. And it was seen that oral HPVs are more common in men than they are in women. And this is an infection that is bimodal. There's a peak at about age 30, a first peak at age 30. And the 9

11 second, higher peak at around age 60. The diagram focus on the high-risk HPV, the ones that are oncogenic where we see the same profile. There are factors that increase this prevalence of infection, one is age, as already mentioned, the number of sexual partners, and the number of cigarette smoked. 00:39:34 In fact, among the sexual behavior factors one can see that the risk of an oral HPV infection increases with any sex, with here is the number of partners. Oral sex, and vaginal sex are also factors. In a separate study looking at 409 individuals age 18 to 25, it was found that the risk of oral HPV infection was increased with the number of recent oral sexual partners, but only in men. The risk was decreased in women, but not in men, with the number of vaginal sex partners. 00:40:14 What can we do to prevent those infections? 00:40:16 Well condoms have some efficacy as been shown in reviews of different studies. And there was one study where women were, again college-age women that were a virgin, were asked to record their use of condoms and the highest usage, the women who used condoms most regularly, were the ones that were the least likely to contract and HPV infection of the cervix. 00:40:52 The data was not as convincing in terms of HPV lesions. But with lesions it was clearly seen. 00:41:00 Now the effect of condoms was illustrated in a dramatic fashion in a study looking at 125 couples in the Netherlands where, in those couples, the female had CIN and they were randomized to use condoms or not. And in the couples that used condoms there was a greater rate of clearance of CIN and HPV DNA than in the couples not using condoms. And also some of the males had some flat lesions only visible by the use of a colposcope and those males cleared faster while using condoms. And the clearance effect of condoms was seen only in the couples with concordant HPV types. 00:41:54 HPV vaccination has been the major innovation in preventing this infection. The vaccine consists of taking the gene coding for most of the proteins going into the capsid. The gene is called L1 and by expressing these genes in either yeast or insect cells. 00:42:18 The protein is made in spontaneously aggregates itself into a noninfectious HPV particle. 00:42:25 And to the left you have noninfectious virus-like particle called VLP. And to the right you have the infectious HPV particle which is different because it contains HPV DNA. So the HPV VLP, the base of the vaccine is totally noninfectious. 00:42:43 And there are two main vaccines and a third that we'll discuss later. The two main vaccines are Gardasil and Cervarix. Gardasil is a quadrivalent vaccine, protecting on 6, 11, 16, and 18. Cervarix is bivalent, 10

12 protecting on 16 and 18. One is made in the yeast, the other is made in insect cells. One is using aluminum hydroxyphosphate sulfate as an adjuvant, whereas the other is a mixture of aluminum hydroxide and desacetyl monophosphoryl lipid A, a more potent adjuvant. 00:43:24 And the initial studies shows that those vaccines were quite potent. 00:43:30 This is the type of diseases that were the outcomes and the HPV types associated with those diseases. And as you can appreciate, both Gardasil and Cervarix demonstrated great efficacy against the development of either warts or cervical lesions. 00:43:53 It's important to keep in mind that Gardasil, just like Cervarix is a prophylactic vaccine. If you are positive for an HPV, you would not be protected against disease caused by this HPV type. However, you still can be protected against the HPV types that have not infected you. 00:44:17 The pediatric population: The efficacy in the pediatric population was conducted by looking simply at the immunogenicity of the vaccine to see if they were causing antibodies, since the neutralizing antibodies is really what come first protection. And indeed, the rates of the titers of antibodies were higher in younger females than in adolescent or young adult women. 00:44:46 And in fact, the titers were the highest in the youngest patient and the younger patient, and it decreased with time. 00:44:58 The efficacy in males was also demonstrated, both against condylomas with an efficacy of 68%, and in all intraepithelial neoplasias of different grades. You will note that the vaccine efficacy was not as high in males as it was in females. 00:45:17 The safety of the vaccine has been the object of a lot of noise, but in fact this is a very safe vaccine. The most obvious side effects are local in the week that follows the vaccination. Pain, redness, and swelling are the most common side effects, more common with Cervarix, which contains a more potent adjuvant. And the adjuvant is really the source of the side effects. 00:45:45 The other systemic side effects are noted but with less difference typically between Cervarix and Gardasil. 00:45:55 Mainly, studies have looked at the safety of the vaccine and these are some of them. But basically, looking at many patients, looking at different outcomes, including autoimmune conditions and thrombotic complication, there was not any adverse consequences noted to be associated with the vaccine. So despite all the clamor about the danger of the vaccine, that is really not based on facts. 11

13 00:46:27 There was a study that I want to mention that was conducted in France, it's not published but it's remarkable because it was involving a very large number of subjects. There were close to a million females who had been vaccinated and more that had not been vaccinated that were enrolled in the National Insurance Program. And the author of the study looked at 14 different autoimmune disorders, including multiple sclerosis, Guillian-barre syndrome and so forth. And they asked themselves, was there a difference in the incidence of infections between those two groups? 00:47:08 And in fact, overall there was absolutely no difference in terms of the incidence of any of those conditions. 00:47:17 When they looked at the conditions separately, they saw that that there were two, there was a slight excess of chronic inflammatory bowel disease. 00:47:30 But this was a very small risk and probably the study was not adjusting for the multiple comparison so it's probably not significant. The only risk was an excess of Guillain-Barre syndrome that was observed, which is probably rare. But this is equivalent to one or two cases of Gullain-Barre syndrome for 100,000 vaccinated girls and the adverse consequences seem to be limited. 00:48:00 The sexual behavior is not modified by immunization, and this has been really reviewed in 21 studies that looked at various outcomes that could have been affected by immunization and the conclusion is that being vaccinated for HPV, either doesn't change your sexual behavior, or if anything, it may improve actually. 00:48:29 I will review a couple of things. The efficacy of Gardasil in HPV patients that was looked at and reported all year, this year, where they administered the vaccine to individuals that were 27 and older. And this included mostly MSMs, but some women. And the participants of the study obviously had exposure to HPV. In 60% of the cases there was the presence of HPV DNA in the anus of the patients. And at baseline, a third of the patients had anal HSIL and 64% had an abnormal anal cytology. So the patients immunized with three doses of Gardasil, and screened every six months over three years. 00:49:23 But the study was stopped at 2.4 years because there no evidence of efficacy. The vaccine was highly immunogenic. That had been observed in previous studies conducted in HIV positive patients, although the titers are generally less than the ones observed in known HIV infected patients. The vaccine was also safe, but there was no clinical benefit regarding persistent anal infection or anal HSIL. 00:49:55 Gardasil 9 is the vaccine that is really the one on the market now, and mostly used. 12

14 00:50:02 And Gardasil 9 incorporates not only HPV 16 and 18, but five other types. Types 45, 31, 33, 52, and 58, to cover from 70% which was covered by the classic Gardasil to 90% of the strains causing cervical cancer. 00:50:31 And in fact, one sees that the moving from the classic Gardasil which covers 70% of the causes of cervical cancer. By adding those five strains, you add 20% to get contribution coverage of 90% of the strains. The interest is that it covers more of the strains causing CIN 1 which is the bulk of the lesion that are gonna be detected on Pap smears and that can be confusing. 00:51:03 The study evaluating the vaccine was divided in two. One part was to make sure that the new vaccine triggered the same amount of antibodies for 6, 11, 16 and 18, and then also protected against disease caused by the additional types. 00:51:22 And this was seen here that there was the same type of immunoreaction against 6, 11, 16, and :51:31 And that in terms of protecting against the disease caused by the additional five types, the vaccine was very efficacious, protecting against CIN two or more, or all CIN, vulvar intraepithelial neoplasia, or vaginal intraepithelial neoplasia. 00:51:49 So the vaccine was very efficacious. It also reduced the number of biopsies for genital warts of the cervix. And it also alleviated the use of definitive ablative therapies. 00:52:09 In terms of side effects, because of the greater quantity of adjuvants in the Gardasil 9, the side effects were a little bit more common with Gardasil 9 as compared to the old Gardasil. But there was really not any substantial adverse, serious adverse effect. 00:52:37 The local effects were, again, more common with Gardasil 9 than they were with the classic Gardasil. Reflecting again the greater amount of adjuvant. 00:52:51 Now an interesting point is to see if the vaccine has been effective in the general population. 00:52:59 And looking at the cervical infection, Australia, which has had a very successful vaccine deployment, it was shown that in vaccinated women, the rate of cervical infection collapsed and this is the prevalence ratio. There was a 93% reduction. And this protected effect was also seen in unvaccinated women, which is suggestive of a herd immunity. It was also seen that there was a reduction in some protection for HPV types not included in the vaccine. So that suggested some cross-protection against HPV 31, 33 and 45 which were not in the classic Gardasil used in Australia at the time of the immunization. 13

15 00:53:54 The effect of the vaccine we're also seeing in males who were not immunized in this way. Only female up until 2013 were immunized. And you can see here in green the HPV 16 and 18 prevalence in the urine of men attending an STD clinic in Melbourne. And that started disappearing after the initiation of the vaccination in the female, sensing for HPV 6 and 11. And this was seen also in younger patients. So it was quite clear that the vaccine was beneficial in curbing HPV infections. 00:54:37 In the United States, this effect was also demonstrated with a reduction in the prevalence of HPV comparing the pre-vaccine era to the post-vaccine era. And the effect was the greatest in the subjects more likely to have been exposed to vaccination, the age group 14 to 19. But it was also seen in slightly older females. 00:55:02 So the vaccine does have an impact on cervical infection. 00:55:07 It also has an impact on genital warts. 00:55:10 And this is a summary of 20 vaccine studies. And they broke the results into those countries where the vaccine coverage was greater than 50% and those where the vaccine coverage was less than 50%. If the vaccine coverage is high in women, you can see in the groups that are more likely to have received the vaccine, complete collapse in the incidence of the prevalence of the genital warts. And this is an effect that is clearly seen in those women in the age class that is susceptible to have been vaccinated. But you see it also in women who are not likely to have received the vaccine, but only in the countries where the vaccine coverage is greater than 50%. Therefore, in order to see herd immunity, you need to have a high vaccine coverage. 00:56:07 This was seen also in men who were not vaccinated. But herd immunity protected the men, especially in the countries where there was a high coverage of HPV vaccination. You will notice in all those graphs. With time, the efficacy gets greater. 00:56:25 So it's important to keep giving the vaccine. 00:56:29 The cervical diseases are also effected by vaccination. The data is early, because we need more followup to see, to appreciate this effect. But in the studies conducted in different states throughout the United States, where every time a woman had an abnormal Pap smear, it was inquired whether she had been vaccinated or not. There was a reduction of the prevalence of HPV related cervical lesions in the patients who had been vaccinated related to those who had not been vaccinated. 00:57:09 And finally, in Australia, which again is a model because of its high vaccine coverage, in those subjects 14

16 who got vaccinated there was a marked drop in the incidence of abnormal Pap smears. Whereas the abnormal Pap smear, actually the incidence increased in the ages that were not vaccinated. Again, implicating that the vaccine is effective at preventing cervical disease. 00:57:39 But the guidelines have been issued in last month by the CDC that revise guidelines that had been issued about a year and a half ago. Basically, you vaccinate patients, the general population, starting at age 11 to 12, but you can start as young as age nine. For the females, you can go up to age 26 to vaccinate. And for males is age 21, but it's permissible to give up to age 26 in men. For children with a history of sexual abuse, you start as early as possible, starting at age 9. For those who have not completed vaccination, you complete the vaccination with Gardasil 9 and you can go up to age 26 in females and up to age 21 in males. And for the immunocompromised population, you want to start immunizing as early as age 9 and you can go up to age 26. For MSM, you can start of course, as early as age 9, but you don't know those ages if you are dealing with a MSM, but the point is you can go up to age 26 for MSMs. The insurance will provide cover for that later age. 00:59:06 The major point that are in those recommendations is that now for those patients who are immunized before the age of 15, you can limit yourself to a two dose schedule instead of the traditional 3 dose schedule. If you start immunization at age 15 or older, you still are bound to give three dose schedule. So two dose schedule seems to be equivalent to the 3 dose schedule, at least with the data that is presently available. 00:59:39 And the approach to patients who stop their immunization, you don't need to restart, you just complete the series. There are different contraindications to the vaccine having to do with hypersensitivity, latex allergy if you're using Cervarix, and pregnancy of course. You don't want to give the vaccine during pregnancy, although there have been adverse affects observed in the studies, phase three studies, in patients who inadvertently became pregnant. The main point to remember is, to this day the cervical cancer screening with a Pap smear doesn't change, regardless of vaccination status. And that may change in the future especially if vaccine coverages increase. 01:00:32 So just to finish, I will remind that the vaccine is effective in preventing HPV infections, genital warts, cancer precursor lesions. We don't know yet about cancer, but there's no reason to doubt that it won't be demonstrated. The vaccine is safe. And in contrast to other existing preventive measures, such as condoms and cervical cytology, it uniquely protects early in life, those who later will have poor access to screening, those for whom screening performs less well, such as women less than 30 years of age. And it protects against several other cancers in females and males that are not amenable to screening. 01:01:13 Thank you. 01:01:14 - [Tara] Okay. We have opened up the lines for your questions. 15

17 01:01:25 - [Margie] Hi, this is Margie Urban, thank you William for doing that really comprehensive review. It was fantastic. I wondered if you could comment on the age difference that older men in one of the slides higher rates of HPV compared to younger women, which is the opposite of most sexually transmitted infections. 01:01:49 - [William] I don't remember which slide you're referring to, but it was probably anal HPV infection, no? 01:02:01 - [Margie] I'll have to go back and look, I didn't think it was because I took note of it for many years for gonorrhea and chlamydia the highest rates for men were 20 to 24 and 15 to,19 for women. But I can ask you later, that's fine 01:02:21 - [William] I'm sorry, I cannot think of which slide it is. (reviewing slides) 01:02:42 - [Margie] That's fine. 01:02:43 - [William] Oh okay, well what you have to realize is when they looked at the female, it was checking the cervix. For the males, since there's no cervix, so what they did, they sample normally the glans, the shaft, the scrotum, the urine, and under the fingernails. So they really went at it very much more aggressively than in the females. So that's why you have 62%, is because many more sides were sampled. 01:03:11 - [Margie] Okay. 01:03:17 - [Tara] Are there any other questions? 01:03:27 - [Charles ] Hello? 01:03:29 - [Tara] Yes. 01:03:31 - [Charles] Charles Gonzales here. I was wondering, is there any evidence for waning immunity over time with regard to the vaccines? 01:03:40 - [William] Well there are two points to make. First of all, we don't know below which you start losing protection. So that's the first thing. Because the vaccine is so efficacious that it has not been possible to determine below which antibody level you start developing disease. And the data now goes up to 10 to 12 years, where the vaccine has still been protective. Obviously, with time we'll see. And eventually 16

18 maybe there will be a decline and we'll see the appearance of the loss of protection. However, if you can protect individuals during the years where they are the most likely to contract an infection, it may not be necessary to administer a booster shot. If you do administer a booster shot, the antibody levels shoot right back up even higher. So it's possible to really restimulate the immune system. And with the two dose schedule, in fact, you're sparing the third dose which could be reserved for later administration. 01:05:09 - [Tara] Okay, does that answer your question? 01:05:12 - [Charles] Indeed, indeed. 01:05:15 - [Tara] Great, thank you. Are there any other questions for Dr. Bonnez? 01:05:20 - [Man] I have a question. As time goes forward and vaccination becomes much more common, are we expecting other high-risk HPV types to become more prevalent, and may be the cause of cervical cancer as the ones in the vaccine are dropping out? 01:05:43 - [William] Yeah, this has been a concern. But there are different considerations, both theoretical and objective that shows that vaccine strain replacement, which is the name that defines this phenomenon is not occurring. So it's not as if the other HPVs that are not covered by the vaccine would become suddenly more oncogenic or more common. There's not evidence of that. So it doesn't appear to be, again, a risk both on theoretical considerations, but also on the objective data that has been gathered so far. 01:06:32 - [Tara] Okay. Are there any other questions? Okay, if not we will close by saying thank you to you all for attending. And on a final note about claiming CE, if you have registered to attend today's webinar session, STD Lunch and Learn, you will receive an with instructions to claim your CE credit. If you did not register to attend today's webinar, and would like to claim CE credit for attending today, please go to CEItraining.org website and register. And again, thank you for attending. [End Video] 17