Next. And no financial disclosures. Next. And, of course, we know that cervical cancer is sort of the prime example of inequity in cancer incidence and cancer mortality, with Sub-Saharan Africa having the highest numbers for incidence and mortality. Those in the darker colors have much higher cases. And we know it's a preventable disease, yet more than 600,000 women are diagnosed every year, and there are more than 300,000 deaths annually worldwide. Ninety percent of cervical cancer deaths occur in low and middle-income countries. Next. And, in fact, it used to be the most common cancer in the U.S., but with the introduction of widespread screening and then treatment of women who tested positive, it's now, I think, about number 10 in the list for common cancers in the U.S. However, it is still the most common cancer among women in more than 30 countries around the world, and the first, second, or third most common cancer among women in over 100 countries. Next. A big breakthrough, obviously, was the introduction of pap testing to identify three malignant changes on the cervix and then provide treatment before it progressed to cancer. And the next big breakthrough, really, was to discover by Dr. Harold Zurhausen that cervical cancer was a virally-mediated, virally-caused cancer, human papillomavirus, and this allowed us to have further tools in our toolbox in terms of prevention. Primary prevention includes the HPV vaccine, and we'll talk about that a little later. And secondary prevention now allows us to use HPV DNA testing as a method of identifying women who are at risk to develop invasive disease. It has a very long pre-invasive phase, can take more than 10 years for dysplasia to progress to cancer, and so we have many, many opportunities to prevent cancer. No woman should die of cervical cancer, yet many, many women do. Next. The HPV virus is a small, double-stranded DNA virus. There are 13 or 14 genotypes that are considered to be high-risk, and there are lower-risk HPV types that also cause significant but benign disease. Next. It is the second most common of the infection-attributable cancers. Helicobacter pylori has the most cases of cancer attributed to infection, and HPV is next on the list, then followed by hepatitis B and hepatitis C and others. But almost 700,000 cancers are believed to be attributed to HPV around the world. Next. And cervical cancer is not the only HPV-attributed cancer. There are actually six cancers on the list of those caused by HPV. Oropharyngeal carcinoma is growing in prevalence, as well as other genital cancers, anal, penile, vulvar, and vaginal cancers. But the predominant cancer that is an HPV-related cancer is cervix cancer. Next. And in terms of just numbers, the highest number of HPV-associated cancers are in Asia, and if you look at the bottom, it's in less-developed countries. So, the dark blue is cervix, and the other colors are the other HPV-attributed cancers. Next slide. But if you look at the incidence rates, the highest incidence rates are in sub-Saharan Africa, primarily eastern sub-Saharan Africa, with the highest rates in Malawi and Mozambique and other countries in sub-Saharan Africa. It is international prevalence, global prevalence is about 13 per 100,000 women, but you can see in some of the countries in sub-Saharan Africa, the incidence rates are much higher, 40, 50, even 60 per 100,000 women. Next. And if you look in terms of the global burden in terms of percentages in sub-Saharan Africa, almost 30% of cancers are HPV-associated. Obviously, cervix cancer is the one that is more prevalent and more predominant. Next. And HPV is a virus that is sort of endemic. It is everywhere. In the US, 79 or 80 million people are currently infected. It is estimated that more than 80% of people will have HPV at some time in their life. However, fewer than 5% will develop precancerous lesions and less than 1% will develop invasive cervical cancer. But we're talking about very big numbers here, obviously. So, if it infects 80% of the population of the world, even 1% is a lot of people. Next. It is highly transmissible. We estimate the global prevalence to be about 12%. The prevalence will vary with age and geography. It's much more prevalent in younger women that's following sexual debut, usually one to two or three years after that. So, in the 15 to 25 or 30-year-old age group, the prevalence is much higher than in the 40 to 50-year-old age group. But persistence, it's what's required for development of high-grade lesions and cancers. So, while most people will be infected at some time in their life, unless you develop a persistent infection, you will clear the virus naturally and not develop any premalignant lesions. It is considered persistent if a person is positive for more than 12 months. And persistence is particularly common in people who are infected with HPV type 16, the most aggressive of the HPV types, and those with host immunity challenges such as HIV. Next. HPV accounts for about 30% of infection-related cancers. And you can see on this list here, it is responsible for more than 99% of cervical cancers, a very high percentage of anal and vaginal cancers, and a significant portion of oropharyngeal cancers. Next. I said previously, HPV 16 is the most prevalent genotype and most aggressive genotype that will be detected in precancerous anogenital lesions. And next slide. And regardless of the makeup of the HPV types found in a local population, and you can see on this list here, there's many different HPV types still, HPV 16 and 18 are responsible for 70% of cervical cancers. So, if you did a study and you did HPV testing in 100 people, you might see a wide distribution of different HPV types. But when you do a HPV sample in those with cervical cancer and you test the cancer for HPV types, 16 and 18 are responsible for 70% of the cancers. So, while the distribution varies, it's 16 and 18 that are the bad actors for cervical cancer. Sorry. Next. And the natural history is the same in all settings, regardless of geography. Soon after exposure, an HPV infection can be detected. It will generally regress in a large majority of people, more than 90% of people, it will regress over time. In a certain number of people, you can see on the purple line, there might be development of cervical dysplasia, which can also regress. And then over a longer period of time, those with precancerous lesions can progress and develop cancer. It's a bit of a slower slope in the curve, if you will, but progression and regression is sort of the natural history of HPV until you get further along in the precancerous timeline so that those with a higher grade dysplasia are much less likely to regress than those with a lower grade of dysplasia. Next. The life cycle is such that the basal layer of the epithelial layer has to be infected with HPV, and as the dysplasia progresses through CIN2, CIN3, the thicker portion of the epithelial layer is infected, and eventually when the basal membrane is violated, that is cervical cancer. Next. And again, just with a little chart to show what it looks like, you get infected. Most people will clear it. So on the top row, you see it's a transient infection that clears. On the bottom row, over one to two years, some will develop a persistent infection. We don't always understand why, but over time, this can progress to a higher grade cervical lesion and over 10 to 15 to 20 years, if untreated, may develop into invasive cancer. But obviously, not everybody who gets infected with HPV and even those who have higher grade dysplasia, not everybody will develop invasive cancer. However, a higher percentage of women with high grade dysplasia, CIN3, will progress, and all those women need to be treated. Next. We have opportunities, like I said, to prevent, and HPV vaccination is primary prevention, and this should be given before exposure, and children at a younger age are develop a better immunity to the vaccine, a better immunity to HPV after vaccination. So, it is recommended that children get a vaccine between the ages of nine and before the age of 15. And then, keep in mind, the vaccine is not a preventive vaccine. It must be given prior to exposure for it to be effective. And then, we have many opportunities to do screening and then treatment over the course of a woman's life before she ends up in that invasive cancer category at the far end of this. Next. So, like I said, the vaccines are prophylactic. They will not treat someone who's already infected and has a persistent infection. They're designed to prevent the infection, and then, in doing so, prevent subsequent development and progression to cancer. It is not effective against an existing infection and not effective against pre-invasive lesions. Next. So, it's important to know that the vaccine is not infectious. It is non-oncogenic. It's created from what we call virus-like particles. You cannot get an HPV infection from the vaccine. There are three types available commercially, the bivalent cervix, which will protect against 16, 18, and then the two Merck vaccines, Gardasil 4, which prevents genital warts caused by 6 and 11, and then the oncogenic 16 and 18 HPV types, and Gardasil 9, which came out in 2015 and prevents against 7 oncogenic HPV types. Next. There's been a lot of work, particularly in Australia, on the efficacy of the vaccine. If you look at the occurrence of genital warts, you can kind of compress the timeline to see the effectiveness of the vaccine. Genital warts will usually develop in less than a year and sometimes as quickly as eight weeks, and we can see that the vaccines protect very well against cervical cancer and genital warts, all of them, including the quadrivalent, nonivalent, and the bivalent vaccines. Next. And the vaccine came out in 2006, and so there's now been, after 15 years, a fair amount of data on how the vaccine protects against development of high-grade dysplasia, Denmark, Scotland, even in the U.S., and in Australia, which has published a tremendous amount on the reduction in genital warts, but also against cervical cancer. So, the vaccine has been proven over these last 15 years to be very effective in reducing high-grade dysplasia, but also preventing genital warts. Next. And let's go one more. So in Australia, they started the vaccination program in 2007, and if you look at the graph on the left, you can see that following the introduction of the vaccine, particularly in younger women, there was a pretty dramatic drop in the incidence of genital warts. And interestingly, even though the vaccine did not get administered to boys, the drop in women caused a drop in genital warts in men as well. The earlier you get vaccinated, the more protective it is. That is because the risk of exposure is much less for younger women, but also immunogenicity is much greater in the younger population. Next. And this was sort of a landmark article in October of, I think, 2020. 1.5 million women, girls in Sweden. And it showed that there was an increase 88, almost 90% reduction in cervical cancer risk if women were vaccinated before the age of 17, and a 50% reduction in risk among those who were vaccinated between the ages of 17 and 30. So a very dramatic decline in the incidence of invasive cervical cancer. And that lower dotted line on this slide in the green there shows the benefit for women vaccinated early, before the age of 17. Next. And then this study came out relatively recently, 2021. And this was in Denmark. I think there were 800,000 women in this study. And again, shows the benefit of vaccination prior to the age of 16. Dramatically reduced the incidence of the development of cervical cancer. Vaccination 17 to 19 years. Yes, a reduction, not as dramatic as if the vaccination was done earlier. And then vaccination in later years, not nearly as compelling. So the real message here is that vaccination needs to be delivered at younger ages and prior to exposure to the virus. Next. I hope there's no questions about the importance and the efficacy and the ability to prevent pain, suffering, morbidity, and mortality with the vaccine. Unfortunately, the vaccine is not easily available in many parts of the world. But even in parts of the world where it is available because of vaccine hesitancy, it is not as universally administered as we would like. Next. It is safe. I don't know what else to say about this. There have been more than 300 million doses delivered worldwide. There's a lot of untruth and misinformation out there on the internet, but it has been studied backwards and forwards and up and down by all the global and national health authorities in the world. It is a safe vaccine. Next. And I don't think I need to go into this. I think most people know about the WHO call to action to eliminate cervical cancer as a public health problem. Next. With the aim of vaccinating 90% of girls by age 15, screening 70% of women with a high quality HPV test at least twice in their life, and then ensuring that women who screen positive or are diagnosed with cervical cancer actually receive treatment. Next. I didn't say, I meant to say about the vaccine. Two doses are recommended prior to the age of 15, three in those who are immunocompromised or over the age of 15. And there are a lot of studies going on now looking at the effectiveness of one dose of the vaccine. And that would be terrific. That would be terrific. It's hard enough to get 10 year olds in for a vaccination, but it's very hard to get them in for their second or their third dose. So it's been quite a challenge, but one dose could be coming and could be approved soon. And I think that would be a great benefit to the population. There have been several studies looking at the fastest way to get to the WHO elimination goal. Many of them involve sort of extrapolation and modeling of a variety of different scenarios. Next slide. But sort of the bottom line for all of them is that with vaccination alone, we can get to the elimination goals, but it will take almost 100 years or 70 or 80 years. The way to get to the elimination goals the fastest is to scale up screening, get to that 90% point and make sure those who screen positive get the treatment that they need. And we could actually get to the elimination goals in the next 30 or 35 years, which would save millions and millions of lives. So the elimination goal is four per 100,000 and we could get there. Actually, maybe it's one per 100,000. So we can get there fairly quickly if we scale up screening and make sure that we follow up those who screen positive with the proper treatment. Next. So again, the summary HPV is associated with six types of cancer, not just cervical cancer. And in fact, in the US, oropharyngeal cancer is more common than cervical cancer now, which is very interesting. HPV-16 is the most oncogenic of all the HPV types. And the incidence of mortality varies with where you are. It varies with socioeconomics and the greatest burden of cervical cancer both dysplasia and mortality from HPV-associated cervical cancer is in lower and middle income countries. These are preventable deaths. And there's a lot of pain and suffering regarding cervical cancer that we can prevent with a good program and good follow-up and good follow-through. Next. Okay. And I don't know if there's any questions, but I'm happy to answer some. I know this is a review for most of you, but thank you for.

HPV

cervical cancer

inequity

Sub-Saharan Africa

prevention

vaccine