We will now focus on the natural history of HPV. And I will talk about low-risk HPV versus high-risk HPV courses. So what are the diseases most commonly associated with low-risk HPV? Well, these are the genital warts that we see. 1 million new cases of genital warts occur every year in the United States and HPV types 6 and 11 are responsible for over 90% of these genital warts. In the United States an estimated 1.1 million to 1.6 million Pap tests are diagnosed as CIN1 every year. About 10% of these are associated with HPV 6 and 11. HPV 6 and 11 cause about 100% of both juvenile and adult onset recurrent respiratory papillomatosis, which is shown in the right-hand corner of the slides. What are the diseases most commonly associated with high-risk HPV types? Essentially all cervical carcinomas are associated with these high HPV infections. HPV 16 and 18 account for 70% of invasive cervical carcinomas, HPV 16 accounts for most of the anal cancers we see. 70% of oropharyngeal cancers are caused by HPV, and 50% of those caused by HPV 16 specifically. These infections are common, asymptomatic, and most are cleared within months of infection. Here is a diagram of the natural history of HPV infection and questioning how does it progress to cervical cancer or any cancer for that matter? So let's say the individual is initially infected with HPV. Now, many clear the HPV infection. However, within one year, some can go on to cervical interepithelial neoplasias type 1, which are really not invasive, and some of these women or men clear it whereas others have persistent infection. And persistent infection over the next one to five years can develop into CIN 2 or 3, and some, again, clear the infection, but up two decades later some of these CIN 2 and 3 go on to cervical cancer. Hence, we try to screen with Pap smears. Now here's a slide by Patty Gravette illustrating what could potentially happen in HPV infection. And instead of laboriously going through each one of these arrows I will say that, again, some people persist, some people clear and get reactivated and then they clear again or persist, and they end up either with HPV negative or positive tests, and those who have HPV positive test can go on to neoplasm. The question is what triggers this? And here again is a diagram from Dr Gravett showing a working model of cervical carcinogenesis and the risk factors for progression to neoplasia. So let's say a woman's infected, her normal cervix becomes infected with HPV infection, either through sexual behavior, or she has one partner and her partner has many sexual partners in the past, she can be infected. She can clear it and go on to a normal cervix or it can persist, and going from HPV infection to persistence may have to do with her immune system, whether she's HIV-infected, whether she's on immunosuppressive drugs, for example, if she had a renal transplant. It may have to do with her HLA type or it may have to do with how much HPV infection she was infected with, the type or variants of types. Now, persistence, again, can clear or it can go on to high grade neoplasia. And this is definitely associated with the viral type as we just discussed, 16 and 18 being highly causative of high-grade neoplasia. It may have to do with the viral load of HPV, the variance, parity, smoking for sure, inflammation, perhaps hormones. And then the big question now that's being investigated is does the vaginal microbiota have any effect on causing a woman to go from persistence to high-grade cancer and thus invasion? [MUSIC]
