Human Papillomavirus (HPV) Nursing CE Course

2.0 ANCC Contact Hours AACN Category

Syllabus

Background

The human papillomavirus (HPV) is the most prevalent sexually transmitted infection (STI) in the US. HPV infection can cause genital warts, genital cancers, and oropharyngeal cancers that can lead to consequential illness or death (Hofstetter, Ompad, Stockwell, Rosenthal, & Soren, 2016). The majority of sexually active women and men will contract a genital HPV infection at some point in their lives, but most of these infections will remain clinically silent and will resolve without treatment or complications (Hahn & Spach, 2019). According to the Centers for Disease Control and Prevention (CDC, 2019), by age 50, at least 4 out of 5 females will have experienced an HPV infection, with the highest number of HPV infections within the 20-24-year age group. HPV is equally common in men but often has no symptoms. Infections with at least one type of HPV affect approximately 80 million Americans, with nearly 14 million new infections diagnosed each year (CDC, 2019). Furthermore, each year over 33,000 cases of cancer in both men and women are linked to HPV in the US. The direct annual cost related to genital HPV infection is estimated to be just over 1.7 billion dollars (Hahn & Spach, 2019).

Pathophysiology

There are more than 170 types of HPV that infect humans, and each type has a known “specificity for epithelial cells” (Hahn & Spach, 2019, p. 3). Since epithelial cells line the throat, intestines, blood vessels, and organs, the HPV virus has opportunity to infect and potentially invade tissues during sexual exposure. The HPV in tissues is identified and typed through the detection of HPV DNA or mRNA and can be classified as low- or high-risk. This detection can be completed through laboratory tests, tissue samples, or blood smears. Low-risk HPV subtypes are non-oncogenic and cause warts, whereas the high-risk HPV subtypes are oncogenic, or cancer causing (CDC, 2015; Hahn & Spach, 2019).

Of the 170 HPV subtypes, 40 have a particular affinity for genital skin and mucosa. The most common low-risk types of HPV are types 6 and 11, which make up 90% of the causative viruses associated with genital warts. Warts can cause lesions in oral, upper respiratory, upper gastrointestinal, and ocular tissues. Benign tumors or papillomas can grow throughout the respiratory tract. This is known as recurrent respiratory papillomatosis (RRP) and is caused by types 6 and 11 (Hahn & Spach, 2018).

The most common high-risk types of HPV are 16 and 18, which account for approximately 63% of all HPV-related cancers and about 66% of cervical cancers. These types of HPV cause high-grade cellular changes and cervical dysplasia, and are associated with anogenital cancers, including cervical, penile, anal, vulvar, vaginal, and oropharyngeal. Additional high-risk HPV types include 31, 33, 45, 52, and 58, which are collectively responsible for about 10% of all HPV-associated cancers (Hahn & Spach, 2018).

Infection by all HPV arises at the basal cell layer of the stratified squamous epithelial cells. The infection stimulates the proliferation of cells in the epithelium, and the infected cells present various cellular changes. There is a wide variety of cellular changes that range from benign hyperplasia of the cells due to low-risk types of HPV to invasive carcinoma secondary to high-risk types of HPV (Hahn & Spach, 2018).

HPV is transmitted primarily through sexual activity. Multiple sexual partners can increase the individual's risk of acquiring HPV; however, even a single partner can cause infection. There are a high number of anal HPV infections among men having sex with men (MSM). Transmission of HPV can occur even without the presence of lesions or knowledge of infection. While rare, transmission from mother to newborn during delivery can occur and cause RRP. Cesarean delivery may not prevent the development of RRP and is not recommended to avoid transmission to the newborn (Hahn & Spach, 2018).

Individuals infected with HPV are asymptomatic initially, and in the majority of cases, the infection clears spontaneously within two years. The incubation period varies from three to four weeks to several months for anogenital warts and several months to years for cervical cellular changes such as cervical dysplasia. Cervical dysplasia is an abnormal cellular change or precancerous lesion which can transform into cervical cancer, but this usually takes decades to develop. The HPV DNA is typically detected around one year after infection in the cervix and is identified via the Papanicolaou (Pap) test. The infection with HPV has the potential to result in “immune-mediated clearance of HPV from the cervix; progression to a precancerous lesion; regression of precancerous lesions; and progression of precancerous lesions to cervical cancer with invasion of local tissue” (Hahn & Spach, 2018, p. 4). Persistent untreated infection with high-risk HPV increases the risk of precancerous cervical cellular changes and cervical cancer. Further risk factors are older age and immunodeficiency related to other diseases such as HIV (Hahn & Spach, 2018).

Types of anogenital warts include condylomata acuminate, smooth papules, flat papules, and keratotic warts.

  1. Condylomata acuminate are cauliflower-like in appearance. They are typically skin-colored, light pink or hyper-pigmented.
  2. Smooth papules are usually dome-shaped and skin-colored. 
  3. Flat papules are typically skin-colored and have a smooth surface. They may be slightly raised or macular. 
  4. Keratotic warts have a thick keratinized layer and resemble common warts (Hahn & Spach, 2018).

Typical sites for anogenital warts in males include the penis, urethral meatus, scrotum, perineum, and perineal area. In women, warts may develop on the vulva, perineum, vaginal introitus, or perianal area. Women may also have internal warts in the anus, vagina, or cervix. Anal intercourse is not necessary to develop perianal warts, as these can spread by touch, sexual activity other than intercourse, or spread from the vaginal area. Intra-anal warts are primarily found in patients who engage in anal intercourse. External genital warts are more common in women than vaginal or cervical warts. Regardless of the site, anogenital warts generally induce minimal physical symptoms, but pose significant cosmetic and psychological concerns including shame, embarrassment, and anxiety. However, the location of the warts may cause discomfort, in particular those located on the vulva or within the vagina. These locations can lead to dyspareunia (painful intercourse), itching, burning, or bleeding. Warts located on the penis can cause itching and urethral meatal warts can cause hematuria or issues with starting and stopping the urinary stream. Perianal warts may cause pain, itching, or bleeding with defecation (Hahn & Spach, 2018).

Healthcare professionals must remain alert to any preadolescent child who presents with anogenital warts, as this may indicate sexual abuse. While the presence of anogenital warts is not diagnostic for sexual abuse, it is suspicious and warrants further evaluation by a healthcare provider (CDC, 2015; Hahn & Spach, 2018). 

HPV is also responsible for up to 70% of oropharyngeal cancers in the US, which includes all cancers of the oral cavity and oropharynx: the lips, labial and buccal mucosa, tongue, retromolar pad, floor of the mouth, gingiva, hard palate, palatine and lingual tonsils, soft palate, and posterior pharyngeal wall. When HPV is present in a patient with a history of chewing tobacco or smoking, the risk of cancer rises. While some patients may be asymptomatic, the most common symptoms of oropharyngeal cancer include chronic sore throat, earache, hoarseness, swollen lymph nodes, pain with swallowing, or unexplained weight loss (CDC, 2018a).

Prevention

Abstinence remains the only method that is completely effective in avoiding a genital HPV infection. While barrier methods such as condom use or engaging in safe sexual practices such as limiting sexual partners can decrease the likelihood of infection, they do not guarantee protection against HPV (CDC, 2015). HPV vaccination against certain strains of HPV will be discussed later in this activity.

Screening

Routine screening for HPV is cervical cytological testing via the Pap test (CDC, 2018b). The Pap test screens for cervical neoplasia and has specific guidelines for initiation and frequency in testing in females. A primary HPV test will recognize cervical intraepithelial neoplasia and will further direct treatment based on the type of HPV that is found (CDC, 2018b). All women, regardless of sexual orientation or gender identity, should have Pap tests based on the age guidelines established by the American College of Obstetricians and Gynecologists (CDC, 2018b)

Current guidelines suggest the Pap test should begin at age 21. If the test is within normal limits, females between the ages of 21 and 29 can wait three years for their next test. At 30-65 years of age, the woman should discuss the most appropriate pathway for them with their healthcare provider: a Pap test every three years if the test is within normal limits, HPV testing every five years if the test is within normal limits, or an HPV test in combination with a Pap test, called co-testing. If both are within normal limits, the patient can wait five years between screenings. Females over 65 may not need further screening. The healthcare provider will determine the risk based on previous abnormal results on the Pap or HPV test. Additional screening is not required after cervix removal with a hysterectomy or for non-cancerous conditions such as fibroids. Women with a history of CIN2, CIN3, or adenocarcinoma in situ should have routine screening for at least 20 years (CDC, 2018b). Screening among vaccinated females is consistent with screening for their age group and specific healthcare provider guidance based on the current guidelines (American College of Obstetricians and Gynecologists, 2018).

Further CDC STI Treatment Guidelines (2015) for Pap test practices include:

  • Pap tests should be performed 10-20 days after the first day of the last menses. Liquid-based cytology can discern blood from cells and is used for testing during menstruation.
  • If mucopurulent discharge is present, remove the discharge with a saline-soaked cotton swab, and then perform the test.
  • If cervical friability is present, liquid-based cytology should be used.
  • Postpone conventional Pap testing in the presence of heavy bleeding or with cervicitis.
  • Women whose cervix remains after a hysterectomy should continue to have Pap tests.
  • Instruments designed to obtain samples from the cervical transformation zone (i.e., cytobrushes) improve the accuracy of Pap tests.
  • Screening for pregnant women is performed at the same intervals as their non-pregnant counterparts (Hahn & Spach, 2018).

Women with HIV infection have an increased risk of pre-cancer and cervical cancer. Regardless of age, women newly diagnosed with HIV should have a baseline cervical cancer screening within one year of the onset of sexual activity and no later than 21 years of age. For women under 30 years of age and HIV positive, after the initial screening test, a follow-up Pap test should be performed annually. If three consecutive Pap tests are normal, the interval can go to three years. Co-testing (both Pap and HPV tests) is not recommended in this group. For women over 30 years of age and HIV positive, cervical cancer screening should continue throughout their lifetime. Either Pap testing alone or co-testing is acceptable. If Pap testing is utilized, the recommendation mirrors the younger group above: a baseline test and annual testing for three consecutive tests. If all are negative, testing can extend to every three years. If co-testing is utilized, retesting should occur in three years if both tests are negative. If one of the tests is positive for HPV, or if the DNA indicates HPV 16 or 18, a referral for a colposcopy is suggested (Hahn & Spach, 2018). 

Screening for anal cancers is somewhat controversial, with insufficient data available to develop specific guidelines. Anal cytology or an annual digital anorectal examination may be indicated to detect masses that could indicate anal cancer in persons who are HIV positive or MSM with a history of receptive anal intercourse. Anal cytology should be followed by anoscopy if abnormal (Hahn & Spach, 2018).

HPV Vaccination 

There are three HPV vaccines approved by the US Food and Drug Administration (FDA) to prevent against high-risk HPV subtypes that are linked to cancer.  These include Cervarix, Gardasil and Gardasil 9, and all offer protection against types 16 and 18, which cause most cases of cervical cancer. Gardasil also protects against types 6 and 11, while Gardasil 9 further protects against types 31, 33, 45, 52, and 58 (CDC, 2015; National Cancer Institute [NCI], 2019). While the HPV vaccination may be helpful in preventing oropharyngeal cancers, there is insufficient research to demonstrate this protection definitively at this time (CDC, 2018a).

                Gardasil was originally a quadrivalent vaccine with protection against four different types of HPV. A quadrivalent vaccine stimulates an immune response against four different antigens such as viruses. Gardasil was offered for use in 2006 and approved for females age 9 through 26. Initially, it was recommended as a series of three injections for females aged 11 through 26 by the Advisory Committee on Immunization Practices after demonstrating a 98.2% efficacy against HPV 6-, 11-, 16-, and 18-related lesions in the end of study trials. It was later approved for males (Weinstein et al., 2016). In 2018, the FDA approved the expanded use of Gardasil9 in ages 9-45, which is a 9-valent vaccine with increased coverage of additional high-risk HPV types. The recommendations have evolved over the years to now include both males and females. The initial dose of Gardasil9 is recommended for persons aged 11 and 12. The second dose should be given between 6 and 12 months after the first dose (Walker et al., 2018; NCI, 2019). The vaccination series can start as young as nine years of age, but for the most significant impact should be before exposure to HPV (CDC, 2019). Those receiving the initial HPV vaccination before their 15th birthday only need two doses, but children receiving their first dose after their 15th birthday require three doses (CDC, 2018a).

For adults aged 27 through 45 years, public health benefit of HPV vaccination in this age range is minimal; shared clinical decision-making is recommended because some persons who are not adequately vaccinated might benefit (CDC, 2019). Adults who were not vaccinated against HPV should discuss the risk for new HPV infections and the possible benefits of vaccination with their healthcare provider to determine if vaccination is still advised (CDC, 2018a).

                According to the CDC (2019), more than 100,000,000 doses of HPV vaccinations have been administered in the US over the past ten years and the vaccination is considered highly safe. As with any medication, there is the potential for side effects. Some of the most common reported side effects include:

  • Pain, redness or edema near the injection site,
  • Fever,
  • Dizziness or fainting immediately after the injection,
  • Nausea,
  • Headache or tiredness,
  • Joint or muscle pain (CDC, 2019).

Benefits of Vaccination

                The CDC (2019) is in support of the HPV vaccination, declaring the benefits outweigh the potential side-effects or risks. Since the introduction of the HPV vaccine, HPV infections and cervical pre-cancers have dropped significantly. Over the past ten years, females aged 12-19 have experienced a 71% decrease in high-risk HPV infections associated with cancer and anogenital warts. During the same time frame, females aged 30-45 have seen a 61% decrease in high-risk HPV infections. Precancerous cervical lesions caused by HPV types 16 and 18 have dropped by 40% among vaccinated women. The studies further demonstrate that protection remains high after ten years, with no decrease in protection when measuring antibodies from the vaccine in the blood. Approximately 31,200 of the 33,700 HPV-related cancers that are diagnosed each year can be prevented through vaccination. Routine cervical cancer screenings provide early recognition of cellular change and risk, yet there are no recommended screening tests for the other cancers associated with HPV. The vaccination can prevent the development of oropharyngeal, penile, and anal cancers in addition to cervical and vaginal (CDC, 2019).

Barriers to Vaccination

                Since the HPV vaccination is administered to minors, barriers are often premised in parental or legal guardian beliefs, concerns, or opposition to the vaccine. In a study by Johns Hopkins Medicine (2018), parents chose to avoid the HPV vaccination series for their children related to concerns regarding safety of the vaccine, a lack of necessity, a lack of knowledge about HPV, and failure of healthcare providers to properly educate and advocate for the clinical benefits of vaccination. Historically, providers have cited that parents chose to avoid vaccination for HPV over concerns that sexual activity would be encouraged, but this study identified many other barriers to overcome with parents. The same survey showed that the top reason for boys and girls was parent’s perception of a lack of necessity for the HPV vaccine. Healthcare providers are encouraged to educate parents on the safety of the vaccination, along with the increased protection from HPV infection and associated cancers (Johns Hopkins Medicine, 2018). Missed clinical opportunities are also cited by the CDC (2019) as a primary reason for low HPV vaccination rates. Other factors identified include the healthcare provider's knowledge gap of the vaccine and HPV, discomfort discussing sexual behaviors, cost, and concerns for safety (Holman & Roland, 2014). Minority and under-served populations have limited knowledge related to HPV infection and the long-term implications along with the HPV vaccination and its benefits. Insurance coverage, immigration status, and cultural differences can also impact the choice to vaccinate among parents. College students who have not received the HPV vaccination cited barriers as side effects, cost, and an underlying knowledge deficit towards HPV and the vaccination (Holman & Roland, 2014).

Diagnosis

                The Pap test screens for cervical abnormalities and cervical cancer but does not diagnose HPV. However, HPV causes most of the cellular changes in abnormal Pap test results. A pathologist classifies the cellular changes, and the classifications will guide future testing or treatment. For a definitive diagnosis of HPV infection, viral nucleic acid (DNA or mRNA) must be determined. The HPV DNA test detects high-risk HPV from scraped cervical cells. The FDA has approved this test for the triage of women age 21 and above with a Pap test result of atypical squamous cells of undetermined significance (ASCUS) (CDC, 2015; Hahn & Spach, 2018).

The diagnosis of HPV can be validated visible warts, DNA testing, or inspection with a specialized magnifying instrument called a colposcope. The visual manifestation of lesions diagnoses most cases of anogenital warts, but biopsy confirmation may be needed if there is an uncertain diagnosis since herpes simplex virus (HSV) can also cause similar lesions and the treatment regime will be directed according to the diagnosis.  Further indications for biopsy would include an immunocompromised patient; pigmented, indurated, or fixed warts present; persistent ulceration or bleeding; or lesions that do not respond to standard treatment. The CDC also recommends further screening for other STI's, including chlamydia, HIV, syphilis, and gonorrhea when anogenital warts are present (CDC, 2015; Hahn & Spach, 2018).

                 Further use of the HPV DNA testing is in women aged 30 or older in combination with the Pap test. This test is not FDA-approved for men and not typically used for general STI testing. It is not indicated for testing oral or anal specimens or in decision-making for vaccination against HPV (Hahn & Spach, 2018).       

The application of 3% or 5% acetic acid solution may detect genital mucosa infected with HPV. The acid is applied to suspected mucosa to identify difficult to see flat lesions by turning the affected area white. This type of testing will not influence the clinical management of HPV, so current guidelines do not recommend its routine use (CDC, 2015).

Treatment

As noted earlier, asymptomatic or subclinical genital HPV infection will typically clear spontaneously and does not require specific therapy, including antiviral therapy, which would be indicated with HSV. Treatment for all other HPV infections will be dependent upon the diagnosis.

The primary goal of treatment for anogenital warts is the removal of visible warts or precancerous lesions that are caused by HPV. However, the removal of visible warts does not decrease the infectiousness or the risk of cervical or anal cancer. The decision to remove visible warts is based on patient preference, location of the lesions, cost of treatment, or pregnancy status (CDC, 2015; Hahn & Spach, 2018).

Medical management of external anogenital warts may include topical medications, and multiple applications may be needed to eradicate the lesions.  Examples include:

  • Imiquimod (Aldara) 3% or 5% cream is a topical medication that enhances the immune system’s ability to fight HPV. The cream may cause redness and swelling at the application site.
  • Podofilox (Condylox) 0.5% solution or gel is a topical medication that destroys genital wart tissue. It may cause burning and itching at the application site.
  • Sinecatechins (Veregen) 15% ointment contains natural substances found in green tea leaves. This medication is the newest of the FDA-approved patient applied treatments for external genital warts.
  • Trichloracetic acid (Tri-Chlor) is a chemical treatment that burns warts from the genitals and can cause local irritation. It is appropriate for vaginal, cervical, and intra-anal warts but should not be applied on the urethral meatus. (CDC, 2015; Mayo Clinic, 2019).

Podophyllin resin (Podocon-25), topical cidofovir (Vistide), intralesional interferon, or photodynamic therapy are alternative therapies that have been occasionally used for the treatment of external anogenital warts. There is little data available to demonstrate efficacy and these interventions may have increased side effects over recommended first-line treatment regimens. Podophyllin resin (Podocon-25) was a previously recommended treatment, but due to the possibility of severe systemic toxicity, it is no longer a frontline treatment. If used, it is advised that this medication is applied sparingly to each wart, then allowed to air dry before coming into contact with clothing. The failure to allow the medication to dry completely increases the opportunity for local irritation and possible systemic toxicity. Podophyllin (Podocon-25) safety in pregnancy has not been established (CDC, 2015).

There is no algorithm to guide the selection of therapy for anogenital warts; however, specific treatment may change due to location, provider experience, availability of treatment modality, or patient preference. In addition to the topical medications listed above, possible treatments for anogenital warts includes surgical removal; freezing with liquid nitrogen (cryotherapy); burning with an electrical current, or laser surgery. Where feasible, cryotherapy and surgical removal are options in all anatomic locations. Warts located in the urethral meatus, vagina, cervix, and intra-anal region can be complicated to treat and may require referral to a specialist for management. Typical treatment for intra-anal warts includes cryotherapy with liquid nitrogen, surgical removal, or trichloroacetic acid (Tri-Chlor) and bichloracetic acid (BCA) (Hahn & Spach, 2018; Mayo Clinic, 2019).  

Several factors, including the age, history of infection, and further testing results, guide the management of patients with cervical cellular abnormalities. Women between 21 and 24 years of age are managed conservatively in comparison to women in older age groups because of a low risk of cancer and high risk for potential harm related to their reproductive health. All patients diagnosed with ASCUS or low grade squamous intraepithelial lesions (LSIL) require repeat cytology in 12 months, regardless of age. Women with ASCUS who are HPV negative should have repeat co-testing in three years. Women who have a normal Pap test but positive HPV test should have further specific HPV 16/18 testing; if positive, the woman should have an immediate colposcopy. If the HPV 16/18 is negative, co-testing is repeated in 12 months. A specialist should manage women with LSIL according to existing guidelines (CDC, 2015; Hahn & Spach, 2018).

For the treatment of an abnormal HPV or Pap test, the healthcare provider may perform a colposcopy. This procedure uses an instrument that gives a magnified view of the cervix and takes biopsies of any abnormal areas. Precancerous lesions can be removed via freezing, surgical removal, laser removal, loop electrosurgical excision procedure (LEEP), or cold knife conization. The conization procedure removes a cone-shaped portion of tissue from the cervix (Mayo Clinic, 2019). If lesions are found on the cervix, treatment options are cryotherapy with liquid nitrogen, surgical removal with the conization procedure, or trichloroacetic acid (Tri-Chlor) or bichloracetic acid (BCA). Management of cervical warts is not initiated until a biopsy is done to exclude high grade squamous intraepithelial lesions (HSIL) has been completed (CDC, 2015). 

Partner Management

                After receiving the diagnosis, most patients are concerned about telling their partner(s). Partner evaluation is not necessary unless visible lesions are present. Sexual partner counseling can decrease anxiety for the patient and their partner, and offer opportunities for questions and education on the risk, potential infection, and counseling on prevention. Anogenital warts are very contagious and the partner should be aware of risk reduction methods such as condoms. The partner should also have screenings such as an HPV or Pap test where appropriate (Hahn & Spach, 2018).

Summary

Significant knowledge and educational gaps continue to exist with HPV and its implications. Mistrust of health care professionals and the health care system decreases opportunities to educate the populations that would benefit from the HPV vaccine. The mistrust drives down the percentage of adolescents and young adults willing to complete the vaccination series. Community-based educational programs that are supported by caregivers and have developed trust offer the highest chance for compliance with vaccination, screening, and overall improved outcomes (Weinstein et al., 2016). With the high number of cancers caused annually by HPV and the morbidity and mortality involved, it is crucial for health care providers to take the time to familiarize themselves with the benefits of HPV vaccinations for adolescent boys and girls as well as adults without a history of vaccination for HPV. Full knowledge of HPV, the benefits of vaccination, and the opportunities to decrease the risk can empower the health care provider to encourage and educate parents on the value of immunization. Being an HPV vaccination champion can improve the lives and futures of patients. For more information on the vaccine and its benefits, the CDC offers educational materials for prospective parents and resources to promote HPV vaccination among boys and girls before exposure (CDC, 2017).

References

The American College of Obstetricians and Gynecologists. (2018). Practice Advisory: Cervical Cancer Screening. Retrieved from https://www.acog.org/Clinical-Guidance-and-Publications/Practice-Advisories/Practice-Advisory-Cervical-Cancer-Screening-Update?IsMobileSet=false

The Center for Disease Control and Prevention. (2015). 2015 Sexually transmitted diseases treatment guidelines: Human papillomavirus (HPV) infection. Retrieved from https://www.cdc.gov/std/tg2015/hpv.htm

The Center for Disease Control and Prevention. (2017). Human papillomavirus (HPV): For Clinicians. Retrieved from https://www.cdc.gov/hpv/hcp/index.html

The Center for Disease Control and Prevention. (2018a). HPV and oropharyngeal cancer. Retrieved from https://www.cdc.gov/cancer/hpv/basic_info/hpv_oropharyngeal.htm

The Center for Disease Control and Prevention. (2018b). What should I know about screening? Retrieved from https://www.cdc.gov/cancer/cervical/basic_info/screening.htm

The Center for Disease Control and Prevention. (2019). Human papillomavirus (HPV). Retrieved from https://www.cdc.gov/hpv/index.html

Hahn, A.W. & Spach, D.H. (2019). National STD curriculum: Human papillomavirus infection. Retrieved from https://cdn.std.uw.edu/pdf/pathogen-based/hpv/core-concept/all

Hofstetter, A., Ompad, D., Stockwell, M., Rosenthal, S., & Soren, K., (2016). Human papillomavirus vaccination and cervical cytology outcomes among urban low-income minority females. JAMA Pediatrics, 170(5) 445-452.. doi:10.1001/jamapediatrics.2015.3926

Holman, D.M. & Roland, K.B. (2014). Barriers to human papillomavirus vaccination among U.S. adolescents: A systematic review of literature, 2014. JAMAPediatric, 158(1), 76-82. doi: 10.1001/jamapediatrics.2013.2752.

Johns Hopkins Medicine. (2018). HPV vaccine: Why parents really choose to refuse. ScienceDaily. Retrieved from www.sciencedaily.com/releases/2018/10/181024112236.htm

Mayo Clinic. (2019). HPV infection. Retrieved from https://www.mayoclinic.org/diseases-conditions/hpv-infection/diagnosis-treatment/drc-20351602

The National Cancer Institute (2019).  Human papillomavirus (HPV) vaccines. Retrieved from https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-vaccine-fact-sheet

Walker, T., Elam-Evans, L., Yankey, D., Markowitz, L., Williams, C., Mbaeyi, S.,… Stokley, S. (2018). National, regional, state and selected local area vaccination coverage among adolescents aged 13-17 year-United States, 2017.  Centers for Disease Control and Prevention: Morbidity and Mortality Weekly Report, 67(33), 718-23. Doi: 10.15585/mmwr.mm6833a2

Weinstein, J., Ananth, A., Brunner, J., Nelson, R., Bateman, M., Carter, J., Buell, J., & Friedlander, P. (2016). Efficacy of a human papillomavirus vaccination educational platform in a diverse urban population. JAMA Otolaryngology-Head & Neck Surgery, 142(6), 590-595. doi: 10.1001/jamaoto.2016.0433