The Clinical Implications of HPV Infection CME/CE
Rachel Caskey, MD, MAPP
Since the first vaccine against human papillomavirus (HPV) was introduced in 2006, its uptake has lagged behind that of other vaccines recommended for the same age group, namely, Tdap and meningococcal MCV4 vaccines.
And although pediatricians, family medicine providers, nurses, and other healthcare providers have learned much about HPV and the diseases that it causes, and that are preventable with the HPV vaccine, emphasis on the vaccine’s importance in adolescent health has not been consistent.
To provide us with perspective on HPV and the current use of HPV vaccines in the United States, we have asked Dr Rachel Caskey of the University of Illinois at Chicago to join us for today’s discussion. Dr Caskey, welcome.
Dr Caskey: Thank you. Glad to be here.
Ms Brill: I would like to begin our discussion with a question about the prevalence of HPV. Most clinicians already know that it is one of the most common sexually transmitted diseases in the United States. Can you give us a bit more background information on how prevalent HPV is, what age groups it primarily infects, and its mode of transmission?
Dr Caskey: Human papillomavirus is the most common sexually transmitted infection in the United States and worldwide. It is estimated that most adults have a lifetime risk of 80% or greater of contracting a genital HPV infection. That means that 80% or more of sexually active adults will have a genital HPV infection at some point during their lives, making this virus essentially ubiquitous.
As with most sexually transmitted infections, adolescents and young adults — those in their mid to late teens through early 20s — have the highest annual prevalence of infection. However, what makes HPV different from all other sexually transmitted infections is that its prevalence remains high throughout the life course. HPV infection is substantially higher than other sexually transmitted infections in adolescence and young adulthood.
Both men and women in their 40s, 50s, and 60s still have a high chance of contracting a genital HPV infection. In contrast, the prevalence of gonorrhea and chlamydia, infections we commonly test for, becomes nearly negligible as men and women age. Research has found that 1 in 4 men over the age of 45 has a high-risk genital HPV infection. 
Ms Brill: What is the relationship between HPV infection and sexual activity?
Dr Caskey: We know that HPV infection tends to occur very soon after the onset of sexual activity. Research has found that approximately 25% of girls will contract a genital HPV infection the first time they have penetrative intercourse. However, it’s important to understand that although sexual intercourse is a very efficient way to transmit HPV, it is not required. HPV can be spread through any skin-to-skin contact involving the genitals, including genital-to-genital contact without sex or fingers touching genitals.
This explains why some early studies have found vaginal HPV infections among adolescent girls who report never having engaged in penetrative sexual activity. Most likely they participated in other types of intimate experimentation that did not involve sex but involved genital touching.
Ms Brill: So for those individuals who have been infected with HPV, how often is the infection cleared by the immune system?
Dr Caskey: The majority of genital HPV infections — approximately 90% — will clear within the first 2 years. The challenge is the 10% that do not clear. Those are the infections that put individuals at risk for HPV-related disease.
Ms Brill: Can you talk a bit more about the different types of HPV-related disease for which this 10% is at risk?
Dr Caskey: The type of disease depends on the HPV serotype. Serotypes 6 and 11 cause over 90% of genital warts: skin lesions in the genital area of both males and females that can vary in size from very small to very large. Types 6 and 11 HPV are what we consider low-risk HPV types. Although genital warts are not pleasant from a cosmetic perspective, the warts typically do not cause long-term complications.
Dr Caskey: What we worry about are the high-risk HPV serotypes, the types of HPV that can go on to cause cancer. These oncogenic serotypes include types 16 and 18, which cause about 62% of HPV-associated cancers, half of which are cervical cancers. Oncogenic serotypes also include types 31, 33, 45, 52, and 58, which account for 14% of HPV-related cancers in women and 5% in men.
Ms Brill: You mentioned cervical cancer, which is the type of cancer most commonly associated with HPV. Can you elaborate on the prevalence of cervical cancer as well as other types of cancers caused by HPV?
Dr Caskey: The association between HPV and cervical cancer was discovered over 30 years ago. There are over 12,000 new cases of cervical cancer per year in the United States, and over 4000 women die annually in the United States from cervical cancer. The good news is that the mortality rate from cervical cancer has been decreasing due to screening with the Pap test. A Pap test can detect abnormal cells before cervical cancer develops, and the cells can be removed before cancer develops. Currently, for women 30 years or older, Pap tests can be paired with DNA testing for high-risk HPV types which helps identify women who may be at greater risk of HPV-related cancer.
Another type of cancer caused by human papillomavirus is anal cancer. The rate of anal cancer has been increasing in both men and women by about 2.7% per year over the past decade. This cancer occurs at equal rates in both men and women.
Head and neck cancers, also called oropharyngeal cancers, have more recently been associated with human papillomavirus. Currently, an estimated 70% to 80% of head and neck cancers are believed to be caused by HPV type 16.
The prevalence of head and neck cancers has been increasing annually in both men and women, yet we are seeing the most rapid increase among men younger than 50. Notably, many of the HPV-related head and neck cancers among younger men are in men who report having never smoked and who have no other discernible risk factors.
Ms Brill: That’s interesting. Smoking is considered to be a major risk factor for oropharyngeal cancer, right?
Dr Caskey: Yes, tobacco use and heavy alcohol use remain mediators in the development of oropharyngeal cancers. However, because of HPV, there has been an increase in oropharyngeal cancer over the past decade despite a decrease in tobacco use. If this trend continues, it is estimated that in the next 5 years we will have more US men with HPV-related cancer than women.
Ms Brill: So there’s been a real shift in the demographics of HPV-related cancer?
Dr Caskey: Yes, and this demographic shift is important because much of the messaging the public received when the HPV vaccines first came out was focused on prevention of cervical cancer among females with no mention of prevention of disease in males. As a result, what remains in the memory of a lot of parents is that HPV vaccine is only for females. So the message we need to spread is that HPV is equally important for both males and females and perhaps, in the near future, will be a predominantly male disease in the United States.
Ms Brill: Can you provide some background information on how HPV vaccines work and how they differ from other vaccines?
Dr Caskey: What is interesting about the HPV vaccines is that the technology used in these vaccines had to elicit a stronger immune response than natural infection. This is because unlike most infections, genital HPV infection does not elicit a strong natural immune response against the virus. In contrast, if one of us is infected with other vaccine-preventable infections, such as pertussis, we know we are ill. We feel it. Our immune system reacts, and we have symptoms such as fever, cough, and fatigue. HPV does not cause this type of strong immune response.
So the manufacturers had to create a vaccine that produces a much stronger immune response than natural infection, which is the opposite approach used for most other vaccines. To achieve this effect, the HPV vaccine incorporates a new vaccine technology that uses noninfectious viral-like proteins (VLPs). These proteins elicit a strong B-cell-mediated immune response, which should provide long-term, if not lifelong, immunity. The vaccines are designed to produce a virus-neutralizing antibody response to prevent initial infection by the HPV types in the vaccine.
Ms Brill: One of the questions most commonly asked by parents whose children are eligible for the vaccine is, “How well does it work?” In other words, how well does this strong B-cell-mediated immune response translate into effectiveness in preventing infection by HPV and the occurrence of HPV-related cancers down the road?
Dr Caskey: I have been involved in vaccine research for years, and I have looked at efficacy data from the HPV vaccines as well as from many other routinely used vaccines. The HPV vaccines appear to be some of the most effective vaccines based on available data. The manufacturer trial data show that over 90% of participants developed antibodies against the vaccine’s HPV types. Although the development of antibodies is important, what we really want to know is whether the vaccine prevents disease. The manufacturer trials show nearly 100% prevention of cervical, vaginal, and anal intraepithelial neoplasms in individuals who were vaccinated prior to contracting any HPV infection. The trials followed females for 5 years after vaccination.
Ms Brill: That certainly answers the question about effectiveness. The other question parents most often ask is whether or not the HPV vaccine is safe. Are there any adverse effects associated with the vaccine?
Dr Caskey: HPV vaccines are safe. The most common adverse side effect associated with the HPV vaccine is the same adverse side effect associated with any vaccine, which is mild pain at the injection site — a stinging sensation when the needle enters the muscles of the arm and mild muscle pain, or myalgia, at the site of injection. These adverse side effects are considered minor.
There have been reports of adolescent boys and girls fainting after HPV vaccination, but an Institutes of Medicine report found that this effect is related to adolescents receiving vaccines in general, not specifically HPV. It is reasonable to have an adolescent sit for 10 to 15 minutes after any vaccination.
Ms Brill: HPV vaccines have been shown to be both effective and safe in the prevention of HPV infection and HPV-related cancers. There are currently 3 HPV vaccines on the market: a bivalent, a quadrivalent, and a 9-valent. Although all 3 vaccines have the same dosage schedule — a 3-dose series at time points 0, 2, and 6 months — they differ in the HPV serotypes they target and their indications with regard to age and gender. Can you elaborate on the differences among the 3 vaccines in terms of their targeted serotypes and indications?
Dr Caskey: The first HPV vaccine, the quadrivalent vaccine, was approved by the US Food and Drug Administration (FDA) in 2006 and targets 4 serotypes: types 6, 11, 16 and 18. Types 6 and 11 are responsible for over 90% of genital warts and types 16 and 18 are responsible for many, but not all, anogenital cancers. This vaccine is approved for females and males 9 to 26 years of age. The bivalent HPV vaccine was FDA approved later that same year. It also targets types 16 and 18. The bivalent vaccine is approved only for females.
More recently, a 9-valent vaccine was approved by the FDA in December 2014. This vaccine targets the same serotypes as the quadrivalent vaccine plus 5 additional serotypes that cause anogenital cancers — types 31, 33, 45, 52, and 58. Although the 9-valent vaccine is currently FDA approved for females 9 through 26 years of age and males 9 through 15 years of age, the Advisory Committee on Immunization Practices (ACIP) has recently recommended the 9-valent vaccine for all females 9 through 26 years of age.
At this time, the FDA label for HPV9 includes males only through age 15 because some of the manufacturer trial data have not yet been reviewed. I anticipate that the FDA label will change and be extended to males through age 26 in the next year.
Ms Brill: In light of the licensing of the 9-valent vaccine, the ACIP issued revised recommendations in February 2015 concerning the target ages for vaccination in males and females. Can you go over these recommendations?
Dr Caskey: The ACIP recommends that the 9-valent vaccine be administered to the same target population as the quadrivalent vaccine. The goal is to target adolescents ages 11 to 12, though the vaccine can be given as young as age 9, and we should vaccinate up through age 26 for those who were not vaccinated at younger ages. There is a slight difference in the ACIP recommendations for males and females if they are not vaccinated by age 12. For females not vaccinated by age 12, the ACIP recommends catch-up vaccination through 26 years of age. If males are not vaccinated by age 12, the ACIP recommends routine vaccination of 13- through 21-year-olds; high-risk males can be vaccinated through age 26.
Ms Brill: Who is considered a high-risk male?
Dr Caskey: According to the ACIP, high-risk males are men who have sex with men and/or men who may be immunocompromised based on a medical condition or medications. However, regardless of risk, I take the opportunity to vaccinate anyone who has not received the vaccine through age 26. Insurance plans almost universally cover vaccination up through this age regardless of sex or risk status.
Ms Brill: Given that the dosage schedule for all 3 of the HPV vaccines is a 3-dose series over a period of 6 months, it is possible that situations would arise in which patients would not have access to the same type of HPV vaccine for all 3 doses. How do you approach this situation?
Dr Caskey: I take a very practical approach: Use what you have, and do not delay vaccination. All 3 vaccines — bivalent, quadrivalent, and 9-valent — can be interchanged. The most important thing is not to miss an opportunity to vaccinate. So, if a patient is in your office and you have any of the 3 vaccine types in the fridge, go ahead and vaccinate. Based on the expanded coverage, the 9-valent would be the most logical first choice if you have it available. But if a patient receives a 9-valent vaccine, comes back 2 months later and all you have is a quadrivalent available, use the quadrivalent. At this point, there is no ACIP recommendation for individuals who have completed the 3-dose series with either the bivalent or quadrivalent to get a booster with the 9-valent, and I do not anticipate such a recommendation in the future.
Ms Brill: So if I understand you correctly, priority should be given to administering the 3-dose series of vaccinations on the recommended dosage schedule rather than delaying vaccination because you do not have the right vaccine on hand.
Dr Caskey: Yes, that’s correct. We do not want to miss an opportunity to vaccinate. Use whatever HPV vaccine you have on hand rather than wait for a new vaccine stock to be available and risk losing a vaccination opportunity.
Ms Brill: Thank you so much for sharing your thoughts with us today, Dr Caskey.
Dr Caskey: You’re welcome.
Ms Brill: We hope you found this first episode of HPV TV — The Clinical Implications of HPV Infection — both informative and helpful. The medical community clearly has on hand a safe and effective vaccine for HPV infection that can have profound implications for reducing the occurrence of cervical, anal, and oropharyngeal cancers. The challenge now is to increase the opportunity to vaccinate as many susceptible individuals as possible at the appropriate ages.
We will be discussing such challenges in our next episode, Overcoming Challenges to Adolescent Immunization, where I’ll be joining Dr Ken Alexander of Nemours Children’s Health Clinic in Orlando, Florida, for a discussion on the barriers to immunization in adolescents and how to overcome these barriers.
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