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Boosting HPV vaccination rates: A call to action

Faculty

Nancy R. Berman, MSN, ANP-BC, NCMP, FAANP, is a nurse practitioner at Michigan Healthcare Professionals in Farmington Hills and a Clinical Instructor in the Department of Obstetrics and Gynecology at Wayne State University School of Medicine in Detroit, both in Michigan.

Intended audience

This continuing education (CE) activity has been designed to meet the educational needs of nurse practitioners, certified nurse-midwives, and other advanced practice clinicians who care for women.

CE approval period

Now through May 31, 2017

Estimated time to complete this activity

1 hour

CE approval hours

1.0 contact hour of CE credit, including 1.0 contact hour of pharmacology content

Needs assessment

Most cervical cancers are preventable. The incidence of cancer related to HPV infection has declined significantly since the inauguration of screening programs in the U.S. more than 50 years ago. However, too many women are still developing cervical cancer, and 4,400 are dying of it each year. More cases of cervical cancer could be prevented with increased uptake of HPV vaccination, increased addition of HPV testing in screening, and improved access to cervical cancer screening in under-screened and unscreened populations.

Goal statement

Nurse practitioners and other advanced practice clinicians who care for women will make a strong recommendation that children aged 11 or 12 get fully immunized against HPV so as to prevent HPV-related diseases in the future.

Educational objectives

At the conclusion of this educational activity, participants should be able to:

1. Understand the efficacy, safety, and immunogenicity of the HPV vaccine, including the new 9-valent vaccine.

2. Be familiar with all of the ACIP guidelines for the HPV vaccine.

3. Boost HPV vaccine uptake in their patient population.

Accreditation statement

This activity has been evaluated and approved by the Continuing Education Approval Program of the National Association of Nurse Practitioners in Women’s Health (NPWH), and has been approved for 1.0 contact hour of CE credit, including 1.0 contact hour of pharmacology content.

Faculty disclosures

NPWH policy requires all faculty to disclose any affiliation or relationship with a commercial interest that may cause a potential, real, or apparent conflict of interest with the content of a CE program. NPWH does not imply that the affiliation or relationship will affect the content of the CE program. Disclosure provides participants with information that may be important to their evaluation of an activity. Faculty are also asked to identify any unlabeled/unapproved uses of drugs or devices made in their presentation.

Nancy R. Berman, MSN, ANP-BC, NCMP, FAANP, has disclosed that she has financial relationships with Hologic and Shionogi.

Disclosure of unlabeled use

NPWH policy requires authors to disclose to participants when they are presenting information about unlabeled use of a commercial product or device or an investigational use of a drug or device not yet approved for any use.

Disclaimer

Participating faculty members determine the editorial content of the CE activity; this content does not necessarily represent the views of NPWH or Merck & Co., Inc. This content has undergone a blinded peer review process for validation of clinical content. Although every effort has been made to ensure that the information is accurate, clinicians are responsible for evaluating this information in relation to generally accepted standards in their own communities and integrating the information in this activity with that of established recommendations of other authorities, national guidelines, FDA-approved package inserts, and individual patient characteristics.

Successful completion of this activity

Successful completion of this activity, J-16-02, requires participants to:

1. “Sign In” at the top right-hand corner of the website if you have an NPWH account. You must be signed in to receive credit for this course. If you do not remember your username or password, please follow the “Forgot Password” link and instructions on the sign-in page. If you do not have an account, please click on “Create an Account.”

2.Read the learning objectives, disclosures, and disclaimers on the next page.

3.Check “Agree to Terms” on the next page and then click the “Continue” button.

4. Study the material in the learning activity during the approval period (now through May 31, 2017).

5.Complete the posttest and evaluation. You must earn a score of 70% or better on the posttest to receive CE credit.

6.Print out the CE certificate if successfully completed.

Commercial support

This activity is supported by educational grants from Merck & Co., Inc.

Before reading the article, click here to take the pretest.

Cervical cancer, caused in nearly all cases by human papillomavirus (HPV), is considered a vaccinepreventable disease. Anogenital warts and other forms of cancer can also be caused by HPV, and can be reduced in frequency with HPV vaccination. Despite the proven efficacy and safety of the three available HPV vaccines—one of which targets up to nine different HPV genotypes—only about one-third of girls in the United States have received the three recommended doses. The author reviews information about the HPV vaccines and the guidelines for their use, and offers strategies for healthcare providers to implement in order to improve HPV vaccine uptake in their age-appropriate patients.

Human papillomavirus (HPV) infection is the most common sexually transmitted infection in the United States.Almost all sexually active adults are or will be infected by HPV at some point in their lives, even if they have had sex with only one other person. Although the vast majority of HPV infections are asymptomatic and resolve spontaneously, a few persist and can lead to cancer.2 Persistent infections with oncogenic HPV types can cause cancers of the cervix, vulva, vagina, anus, and penis, as well as the oropharynx. Infection with non-oncogenic HPV types can cause anogenital warts.

About 79 million persons in the U.S. are already infected with HPV, and 14 million persons acquire HPV infection each year.3 An estimated 17,600 women and 9,300 men receive a diagnosis of an HPVrelated cancer each year. For U.S. women, cervical cancer is the most common HPV-related cancer; approximately 11,000 women are diagnosed with it annually and 4,400 women die of it. For U.S. men, oropharyngeal cancer is the most common HPV-related cancer; about 7,200 U.S. men are diagnosed with it each year.

In an Annual Report to the Nation on the Status of Cancer, Jemal et alreported that many types of HPV-related cancers were on the rise, some disproportionately affecting certain racial and ethnic minorities. For example, from 2000 to 2009, oral cancer rates increased 4.9% for Native American men, 3.9% for white men, 1.7% for white women, and 1% for Asian men. Anal cancer rates doubled from 1975 to 2009. Vulvar cancer rates rose for white women and African-American women and penile cancer rates increased among Asian men.

Most cervical cancers are preventable. The incidence of this disease has declined significantly since the inauguration of screening programs in the U.S more than 50 years ago.5 However, too many women are still developing cervical cancer, and 4,400 are dying of it each year. More cases of cervical cancer could be prevented with increased uptake of HPV vaccination, increased addition of HPV testing in screening, and improved access to cervical cancer screening in under-screened and unscreened populations.

HPV vaccines

For decades, the best that healthcare providers (HCPs) could offer patients in terms of lowering their risk for developing HPV-related cancers were screenings for cervical cancer precursors and for anal pre-cancers and cancers (in highrisk populations) and inspection for vulvar pre-cancers and cancers. But in June 2006, the FDA approved the first vaccine to prevent disease caused by any of four HPV genotypes: 6 and 11, which cause anogenital warts; and 16 and 18, which are the most common causes of cervical cancer.6

Three HPV vaccines are on the market in the U.S. (Table).The bivalent HPV (2vHPV), quadrivalent HPV (4vHPV) and 9-valent HPV (9vHPV) vaccines each target HPV 16 and 18, the types that cause about 70% of cervical cancers and most other HPV-linked cancers in women and men.3,7 The 9vHPV vaccine targets five additional cancer-causing types (HPV 31, 33, 45, 52, 58), which account for about 15% of cervical cancers. The 4vHPV and 9vHPV vaccines also protect against HPV 6 and 11, the types that cause 90% of anogenital warts.

Efficacy

Clinical trials have suggested that HPV vaccines, if used optimally, could likely prevent most cervical cancers.2 Of 10,000 young women vaccinated as part of clinical trials before they could have been exposed to oncogenic forms of HPV, none developed HPV 16- or 18-associated cervical lesions, which are precursors to invasive cancer.8,9 HPV vaccines have been shown to prevent other HPV 16- or 18-associated anogenital pre-cancers and HPV 6- or 11-associated genital warts with similar efficacy.9,10 Women who received the 2vHPV vaccine as part of a clinical trial had a much lower prevalence of oral HPV infection than did participants who had not received the HPV vaccine.11

In a study reported in March 2016, Markowitz et al12 analyzed 4vHPV type prevalence (i.e., types 6, 11, 16, and 18) in cervicovaginal specimens from females aged 14- 34 years in NHANES (National Health and Nutrition Education Survey) in the pre-vaccine era (2003-2006) and during 4 years of the vaccine era (2009-2012). Within 6 years of HPV vaccine introduction, there was a 64% decrease in 4vHPV type prevalence among females aged 14-19 and a 34% decrease in 4vHPV type prevalence among those aged 20-24 years. There was no decrease in 4vHPV type prevalence in older age groups.

Because the HPV vaccine has been available for only 10 years, it will take a while to assess its efficacy in preventing invasive cancers that take years or decades to develop following persistent infection.

Safety

Three population-based safety studies of the HPV vaccine have been conducted in the U.S.13-15 These studies have identified no serious safety concerns, although one study showed an increased risk of syncope on the day of vaccination and skin infections in the 2 weeks following vaccination.15 Gee et al12 evaluated the risk for venous thromboembolism (VTE) in persons aged 9-26 years, and found no increased risk of VTE following vaccination with the 4vHPV vaccine. Chao et al14 found no association between 4vHPV vaccine use and 16 autoimmune conditions.

According to ongoing safety monitoring by the CDC, most reports of adverse reactions to the vaccine are non-serious.16 Among the 7.6% of reports classified as serious, the most common side effects are headache, nausea, vomiting, and fever. Syncope is a common non-serious problem in both female and male adolescents who receive the HPV vaccine. Of note, syncope is not specific to the HPV vaccine. It is recommended that after receiving the injection, patients remain seated for 15 minutes before leaving the clinical setting.

Impact

Drolet et al17 conducted a systematic review and meta-analysis of 20 studies in 9 high-income countries to assess population-level consequences and herd effects after female HPV vaccination programs  and to verify whether the high efficacy reported in randomized controlled trials was materializing in real-world situations. The investigators found that in countries with female vaccination coverage >50%, HPV type 16/18 infections decreased significantly, by 68%, and anogenital warts decreased significantly, by 61%, between pre- and post-vaccination periods in girls aged 13-19 years. In addition, significant reductions were recorded in HPV types 31, 33, and 45 in this age group of girls, suggesting cross-protection. Furthermore, the incidence of anogenital warts declined significantly in boys younger than 20 years and in women aged 20-39 years, suggesting herd effects. In countries with female vaccination coverage <50%, significant reductions in HPV types 16/18 infection and in anogenital warts occurred in girls younger than 20, with no indication of cross-protection or herd effects.

Duration of immunity

According to a 2011 review, the HPV vaccine was found to provide protection against persistent cervical HPV 16/18 infections for up to 8 years—the maximum time of research follow-up at that point.18 More will be known about the total duration of protection as research continues. To date, no evidence suggests waning immunity such as that seen with the menin go coccal conjugate vaccine, which now requires a second dose. Multiple cohort studies are in progress to monitor the duration of immunity.

More about the 9-valent vaccine

To gain the recent endorsement of the CDC’s Advisory Committee on Immunization Practices (ACIP), the 9vHPV vaccine had to demonstrate efficacy, immunogenicity, and safety.19 In particular, the newest vaccine had to show efficacy in terms of preventing infection and disease related to HPV 31, 33, 45, 52, and 58 in a susceptible population and of generating an antibody response to HPV 6, 11, 16, and 18 that was non-inferior to that generated by the 4vHPV vaccine. Studies conducted by Joura et al20 and Luxembourg et al21 showed precisely that.

In 7 pre-licensure studies, the 9vHPV vaccine was evaluated in more than 15,000 females and males.22 In some studies, the 9vHPV vaccine was compared with the 4vHPV vaccine. The 9vHPV vaccine caused slightly more reactions— primarily swelling and redness—at the injection site. As with the 4vHPV vaccine, side effects associated with the 9vHPV vaccine were generally mild. A video summarizing information about the 9vHPV vaccine is available here.

ACIP guidelines

Routine immunizations for 11- and 12-year-olds include HPV vaccination. HCPs should recommend the HPV vaccine on the same day and in the same way as the other vaccines for preteens.

Age, gender, and vaccine type

ACIP recommends that routine HPV vaccination be initiated at age 11 or 12, although the vaccination series can be started as early as age 9.19 Vaccination is also recommended for females aged 13-26 and for males aged 13-21 who have not been vaccinated previously or who have not completed the 3-dose series. HPV vaccination is recommended through age 26 years for men who have sex with men and for immunocompromised persons (including those with HIV infection) who have not been vaccinated previously or have not completed the 3-dose series. Females should receive the 2vHPV, 4vHPV, or 9vHPV vaccine and males should receive the 4vHPV or 9vHPV vaccine. The dosing schedule for each vaccine type is shown in the Table. If the vaccine schedule is interrupted, the vaccination series need not be restarted.

Interchangeability

ACIP recommends that, whenever possible, the HPV vaccination series for females be completed with the same HPV vaccine product.16 If vaccination providers do not know or do not have available the HPV vaccine product previously administered to a given patient, or are in settings transitioning to the 9vHPV vaccine, any available HPV vaccine product may be used to continue or complete the series for females for protection against HPV 16/18, and the 4vHPV or 9vHPV vaccine may be used to continue or complete the series for males.19 There are no data on the efficacy of fewer than 3 doses of 9vHPV.

Concomitant administration with other vaccines

HPV vaccine can be administered at the same visit as other ageappropriate vaccines, such as the tetanus/diphtheria/acellular pertussis (Tdap) and quadrivalent meningococcal conjugate vaccines.16 Giving all indicated vaccines togethe at a single visit increases the likelihood that adolescents will receive each vaccine on schedule. Each vaccine should be administered using a separate syringe at a different anatomic site.

History of sexual abuse or assault

The newest vaccination schedule issued by ACIP recommends that the HPV vaccine be given as early as age 9 or 10 if a child has a history of sexual abuse.23 Studies estimate that 1 in 4 girls and 1 in 20 boys will experience sexual abuse before age 18.

HPV vaccine coverage rates

The HPV vaccine has been available for almost 10 years. Despite its proven efficacy and safety, HPV vaccine coverage rates have been low. In 2012, only 53.8% of 13- to 17- year-old girls had received the first HPV vaccine dose and only 33.4% had completed all 3 recommended doses.24 These rates were substantially lower than HPV vaccine coverage rates in other high-income countries such as Australia and the United Kingdom (71.2% and 60.4%, respectively; Figure).2 More recent reports have indicated some improvement in HPV vaccine coverage rates. For example, in 2014, among girls aged 13-17, 60.0% received at least one dose and 39.7% received the 3 recommended doses.25 The improvement was laudable but insufficient: 6 of every 10 girls in this country are not fully vaccinated against HPV.

Strategies to boost vaccination rates

And, thus, a call to action: Concerted efforts are needed to increase HPV vaccine uptake and achieve its potential to prevent cancers.2 These efforts should promote both initiation of the first dose and completion of all 3 doses for age-eligible adolescents, as well as eligible young adults. What can HCPs do to improve vaccination rates?

1. Keep up to date on what you can do to prevent HPV-related cancers

The CDC launched a new website, HPV: You are the key to cancer prevention, for HCPs so that everything about HPV vaccination is found in one place. The website is easy to navigate; it has only 1 page and 3 tabs: Know the Facts, Commit to the Cause, and Lead the Conversation.26 The recommendations described in items 2, 3, 4, and 6 were also derived from this new CDC website.26

2. Make a strong recommendation

The high coverage rates for the Tdap and meningococcal conjugate vaccines suggest that most preteens and teens are not only going to see their HCP, but they are also getting at least one of the recommended adolescent vaccines.25 However, according to the 2013 National Immunization Survey-Teen, one-third of the parents of girls and more than half of the parents of boys said their child’s HCP had not recommended HPV vaccination—the No. 1 reason for failure to vaccinate their children.27,28 Had the HPV vaccine been administered during visits when another vaccine was given, vaccination coverage for ≥1 dose could have reached 91% by age 13 for adolescent girls born in 2000.25 Evidence shows that an HCP recommendation to get vaccinated is the single most influential factor in determining whether parents gets an immunization for their child!24 HCPs should provide clear and strong recommendations that the HPV vaccine series be given to preteens.

3. Seize the day

Timing is everything.26 Making a strong pitch for preteens to be vaccinated is necessary, but not sufficient. HCPs should take advantage of appropriate opportunities to vaccinate their preteen patients against HPV—for example, during school or camp physical exams—when these patients are still coming in for regular office visits. Once these patients go to college or to work, they are less likely to see their HCP for yearly checkups. To make a timely recommendation, HCPs should do it the same way and the same day that they recommend the Tdap and meningococcal vaccines.

4. Use a reminder system

Reminder systems shown to increase HPV vaccination rates include a reminder letter and direct messaging via automated text, prerecorded voice, and/or postcard.29,30

5. Educate mothers during their routine visits

Another useful strategy is to educate mothers when they are being screened for cervical cancer about the role of HPV infection in cervical cancer. HCPs should explain to mothers that they are undergoing an HPV test to determine whether the virus is present on their cervix, and that their preteen daughters or sons can be vaccinated to be protected from being infected by the HPV types in the vaccine. HCPs can simply say: “HPV is the cause of cervical cancer. We are screening you with the HPV test and the Pap test to detect any existing HPV infection or cervical pre-cancers, which we can then treat to keep them from progressing to cancer. But we can vaccinate your daughters and sons to prevent HPV infection and therefore prevent cervical pre-cancer and cervical cancer.”

6. Address parents’ specific concerns

If a parent’s main concern is side effects, HCPs can say: “Vaccines, like any medication, can have side effects. With the HPV vaccine, the most common side effect is pain and redness at the site of the injection. These symptoms should go away quickly. In addition, the HPV vaccine has not been linked to any serious or long-term side effects.”26 If a parent’s main concern is effect on fertility, HCPs can say, “No scientific data suggest that getting the HPV vaccine has any effect on future fertility. In fact, not getting the HPV vaccine can put a woman’s fertility in jeopardy. Persistent HPV infection can cause cervical cancer, and the treatment of cervical cancer can leave a woman unable to have children. Even treatment for cervical pre-cancer can put a woman at risk for problems with her cervix during pregnancy, causing preterm delivery or other problems.”

7. Hand out written materials

Written materials are helpful in supporting patient education. Patients can refer to them later, after they have spoken to you. Many written materials are available in languages other than English. Spanish-language materials are particularly easy to find. Patient factsheets regarding the HPV vaccine are available on the CDC website.

Conclusion

Considering how effective the HPV vaccine will be in preventing cervical cancer, as well as other HPV-related cancers in both females and males, virtually all preteen girls and boys and all eligible young women and men should be immunized. Vaccination uptake rates, although increasing slowly, are still much too low. These rates will rise dramatically only when HCPs across the country heed the call to action and educate parents about the efficacy and safety of this vaccine and take advantage of opportunities to initiate and complete administration of the 3-dose series.

References

1. Centers for Disease Control and Prevention (CDC). Genital HPV Infection – Fact Sheet. Last updated February 3, 2016.

2. President’s Cancer Panel Annual Report 2012-2013. Accelerating HPV Vaccine Uptake: Urgency for Action to Prevent Cancer.

3. CDC. Clinician Factsheets. HPV Vaccination Information for Clinicians. Page last updated December 29, 2015.

4. Jemal A, Simard EP, Dorell C, et al. Annual Report to the Nation on the Status of Cancer, 1975-2009, featuring the burden and trends in human papillomavirus (HPV)-associated cancers and HPV vaccination coverage levels. J Natl Cancer Inst. 2013; 105(3):175-201.

5. National Cancer Institute. A Snapshot of Cervical Cancer: Incidence and Mortality. November 5, 2014.

6. FDA. June 8, 2006 Approval Letter — Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant.

7. CDC. Clinician Factsheets. Supplemental Information and Guidance for Vaccination Providers Regarding Use of 9- Valent HPV Vaccine. Page last updated December 29, 2015.

8. Lehtinen M, Paavonen J, Wheeler CM, et al. Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-ofstudy analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 2012;13(1):89-99.

9. Muñoz N, Kjaer SK, Sigurdsson K, et al. Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPVassociated genital diseases in young women. J Natl Cancer Inst. 2010;102(5):325-339.

10. Palefsky JM, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med. 2011; 365(17):1576-1585.

11. Herrero R, Quint W, Hildesheim A, et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One. 2013;8(7):e68329.

12. Markowitz LE, Liu G, Hariri S, et al. Prevalence of HPV after introduction of the vaccination program in the United States. Pediatrics. 2016;137(3):1-9.

13. Gee J, Naleway A, Shui I, et al. Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine. 2011;29(46):8279-8284.

14. Chao C, Klein NP, Velicer CM, et al. Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. J Intern Med. 2012;271(2):193-203.

15. Klein NP, Hansen J, Chao C, et al. Safety of quadrivalent human papillomavirus vaccine administered routinely to females. Arch Pediatr Adolesc Med. 2012;166(12):1140-1148.

16. Markowitz LE, Dunne EF, Saraiya M, et al; CDC. Human papillomavirus vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP)MMWR. 2014;63(RR-05):1-30.

17. Drolet M, Bénard É, Boily MC, et al. Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and metaanalysis. Lancet Infect Dis. 2015;15(5):565-580.

18. Romanowski B. Long term protection against cervical infection with the human papillomavirus: review of currently available vaccines. Hum Vaccine. 2011;7(2):161-169.

19. Petrosky E, Bocchini JA Jr, Hariri S, et al; CDC. Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the Advisory Committee on Immunization Practices. MMWR. 2015;64(11):300-304.

20. Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015;372(8):711-723.

21. Luxembourg A, Bautista O, Moell er E, et al. Design of a large outcome trial for a multivalent human papillomavirus L1 virus-like particle vaccine. Contemp Clin Trials. 2015;42:18-25.

22. Markowitz L. CDC Expert Commentary. Common Questions About 9-Valent HPV Vaccine. Medscape Pharmacists. June 22, 2015.

23. Advisory Committee on Immunization Practices (ACIP). Recommended Immunization Schedules for Persons Aged 0 Through 18 Years. United States. 2016.

24. CDC. Human papillomavirus vaccination coverage among adolescent girls, 2007-2012, and postlicensure vaccine safety monitoring, 2006-2013—United States. MMWR. 2013; 62(29):591-595.

25. CDC. National, Regional, State, and Selected Local Area Vaccination Coverage Among Adolescents Aged 13–17 Years — United States, 2014. MMWR. 2015;64(29):784- 792.26. CDC.

26. Human Papillomavirus (HPV). For Clinicians. HPV: You Are the Key to Cancer Prevention. Page last updated September 30, 2015.

27. CDC. Human Papillomavirus Vaccination Coverage Among Adolescents, 2007–2013, and Postlicensure Vaccine Safety Monitoring, 2006–2014 — United States. MMWR. 2014;63(29):620-624.

28. Newitt VN. HPV vaccination: Are you doing enough to make sure that your patients are protected? Nurse Pract Perspect. 2015;2(4):32-36.

29. Chao C, Preciado M, Slezak J, Xu L. A randomized intervention of reminder letter for human papillomavirus vaccine series completion. J Adolesc Health. 2015;56(1):85-90.

30. Bar-Shain DS, Stager MM, Runkie AP, et al. Direct messaging to parents/guardians to improve adolescent immunizations. J Adolesc Health. 2015;56(5 suppl):S21-S26.

The cervical cancer screening dilemma: Choosing the optimal screening strategy

Faculty

Kim Choma, DNP, APN, WHNP-BC, is a Part-time Lecturer at Rutgers University School of Nursing in Camden, New Jersey.

Charles F. Dubin, MD, is a Assistant Clinical Professor at the UCLA David Geffen School of Medicine, University of California at Los Angeles in Los Angeles, California.

Intended audience

This continuing education (CE) activity has been designed to meet the educational needs of women’s health nurse practitioners (NPs), adult NPs, family NPs, and certified nurse midwives (CNMs) involved in women’s health.

CE approval period

Now through March 31, 2017

Estimated time to complete this activity

1 hour

CE approval hours

1.0 contact hour of CE credit

Needs assessment

The essence of the cervical cancer screening (CCS) dilemma is which screening test(s) to use and how frequently to screen. Major national health organizations may differ somewhat in terms of their specific recommendations, but their

general objectives are to prevent morbidity and mortality from cervical cancer (Saslow et al, 2012 [this article presents recommendations from the American Cancer Society, the American Society of Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology]; U.S. Preventive Services Task Force, 2012; American College of Obstetrics and Gynecology, 2012) and to prevent overzealous management of precursor lesions that most likely will regress or disappear.

Educational objectives

At the conclusion of this educational activity, participants should be able to:

1.Understand the importance of maximizing the benefits of cervical cancer prevention while minimizing the harms associated with overtreatment.

2. Evaluate current available options for CCS: cervical cytology, primary HPV testing, and co-testing.

3.Determine the optimal interval for CCS for each patient.

Accreditation statement

This activity has been evaluated and approved by the Continuing Education Approval Program of the National Association of Nurse Practitioners in Women’s Health (NPWH), and has been approved for 1.0 contact hour of CE credit.

Faculty disclosures

NPWH policy requires all faculty to disclose any affiliation or relationship with a commercial interest that may cause a potential, real, or apparent conflict of interest with the content of a CE program. NPWH does not imply that the affiliation or relationship will affect the content of the CE program. Disclosure provides participants with information that may be important to their evaluation of an activity. Faculty are also asked to identify any unlabeled/unapproved uses of drugs or devices made in their presentation.

Kim Choma, DNP, APN, WHNP-BC, has disclosed that she serves on the Speakers’ Bureau and advisory board of Hologic.

Charles Dubin, MD, reports that he serves on the Speakers’ Bureau of Hologic, Myriad Genetics, and Phenogen Sciences.

Disclosure of unlabeled use

NPWH policy requires authors to disclose to participants when they are presenting information about unlabeled use of a commercial product or device or an investigational use of a drug or device not yet approved for any use.

Disclaimer

Participating faculty members determine the editorial content of the CE activity; this content does not necessarily represent the views of NPWH or Hologic. This content has undergone a blinded peer review process for validation of clinical content. Although every effort has been made to ensure that the information is accurate, clinicians are responsible for evaluating this information in relation to generally accepted standards in their own communities and integrating the information in this activity with that of established recommendations of other authorities, national guidelines, FDA-approved package inserts, and individual patient characteristics.

Successful completion of this activity

Successful completion of this activity, J-16-01, requires participants to:

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The authors evaluate current available options for cervical cancer screening (CCS), with an emphasis on the importance of maximizing the benefits of cancer prevention while minimizing the harms associated with overtreatment. Two major dilemmas are addressed: Which CCS method is recommended for women aged 30-65? and What is the optimal interval between screenings for women in any age group?

Cervical cancer screening (CCS) has been one of the most successful screening programs in United States history, reducing cervical cancer-related incidence and mortality by 45% and 49%, respectively, since 1980.1 Until fairly recently, yearly cytology testing was recommended to maximize detection of pre-cancerous lesions. The discovery that infection with the human papillomavirus (HPV) underlies the pathophysiology of nearly all cervical cancers led to the incorporation of HPV testing in general screenings of women aged 30 years or older, starting in 2003.2, 3

Unlike few other forms of cancer, cervical cancer is nearly always

preventable.4 Under optimal circumstances, each potential case of cervical cancer can be forestalled by identifying and treating

disease that progresses, at most, to the high-grade cancer precursor stage.5, 6 At the same time, healthcare professionals (HCPs) want to minimize the harms associated with overtreatment of benign

lesions not destined to become cancerous.6

The cervical cancer screening dilemma

The essence of the CCS dilemma is which screening test(s) to use and how frequently to screen. Major national health organizations may differ somewhat in their specific recommendations, but their general objectives are to prevent morbidity and mortality from cervical cancer and to prevent overzealous management of precursor lesions that most likely will regress or disappear.6, 7

Which cervical cancer screening tests are available?

Two tests, cervical cytology and the HPV test, are used to screen for cervical cancer. In essence, though, HCPs have three CCS options: cytology alone, the HPV test alone (known as the primary HPV test), and co-testing with both methods.

Cervical cytology

A sample of cervical cells is examined under a microscope to screen for premalignant cells that could signal the presence of cancer precursors.8 Cervical cells collected by an HCP are smeared on a glass slide (traditional or conventional cytology—that is, the Pap test) or added to a preservative fluid (liquid-based thin-layer test). Liquid-based cytology, because of its greater sensitivity than conventional cytology in detecting disease, enables extension of the screening interval from 1 year to up to 3 years—without significantly diminishing CCS effectiveness.9

HPV testing

The causal role of persistent HPV infection in the development of cervical cancer and its precursors has been well documented.10 A landmark 2010 study showed that, over a 60-year study period, the 8 most common HPV types identified were (in descending order of frequency) 16, 18, 45, 33, 31, 52, 58, and 35.11 Together, these genotypes account for 91% of all cases of cervical cancer. HPV 16, 18, and 45 were found in 75% of the most common type of cervical cancer (squamous cell) and in 94% of the second most common form (adenocarcinoma). A study of more than 20,000 women showed that those infected with HPV types 16 and/or 18, versus those infected with other high-risk types, had a 10 times greater risk of developing cervical cancer.12 Because HPV cannot be cultured, in most cases its accurate identification relies on molecular biology techniques.13 Molecular assays use primers and probes that identify a region of HPV DNA or HPV mRNA. Of note, HPV tests used in clinical practice need to be FDA approved for validity.6

Co-testing

Recent incorporation of HPV DNA testing into CCS strategies offers the benefits of increasing early disease detection (up to 100% sensitivity) 14 and increasing the length of the interval between screenings—thereby lessening harms such as the adverse psychosocial impact of screening positive, the need for additional visits and procedures, and the treatment of lesions that would have resolved on their own.6 Even more recently, HPV infection can be identified by HPV mRNA testing, which, like standard HPV DNA testing, has up to 100% sensitivity15 but also offers improved specificity, with a 24% reduction in false-positive results.16

Which approaches to screening are recommended for women aged 21-29?

According to guidelines issued in 2012 by the American Cancer Society (ACS), the American Society of Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP), CCS should begin at age 21.6 Women aged 21-29 should undergo cervical cytology every 3 years.6 The same year, the U.S. Preventive Services Task Force (USPSTF) and the American Congress of Obstetricians and Gynecologists (ACOG) issued similar recommendations.17, 18 These organizations all advised against HPV co-testing in women younger than 30; although HPV is commonly present in women in this age group, most of them successfully fight off the infection within a few years.19 An updated Practice Bulletin from ACOG published in January 2016 reinforces the recommendations for women aged 21-29 based on level A evidence: Co-testing in these women and annual cytology should not be performed.20 Until more longterm, level A evidence studies are available to support future updates to the 21-29 age group, HCPs are encouraged to follow the consensus guidelines.6 Although primary HPV testing was not recommended at the time of the ACS/ASCCP/ASCP, USPSTF, and ACOG updates in 2012—in fact, its use was specifically discouraged in women in their 20s—the body of evidence supporting this CCS approach has grown. Findings from the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study (2008-2012) supported the safety and effectiveness of primary HPV testing.21, 22 In 2014, the FDA approved the use of the cobas HPV test as a primary screen for cervical cancer in women aged 25 years or older.23 As a result, interim clinical guidance issued by the Society of Gynecologic Oncology (SGO) and the ASCCP in 2015 supported primary HPV testing as a possible alternative to cytology-based screening and co-testing, but starting no sooner than age 25.24

Which approaches to screening are recommended for women aged 30-65?

Again, HCPs have three CCS options: cervical cytology, primary HPV testing, and co-testing. The ACS/ASCCP/ASCP recommends cytology alone every 3 years or cotesting every 5 years.6 The USPSTF endorses cytology every 3 years, with co-testing as an option in women who want to extend their screening interval to 5 years.17 ACOG supports the options of cytology at 3-year intervals and co-testing at 5-year intervals, with the latter preferred.18 None of these organizations advocates the use of primary HPV testing as an alternative to cytology or co-testing.

Co-testing for women aged 30 or older was approved by the FDA in 2006. But how does co-testing compare with primary HPV testing— as advocated in the interim guidance report—and with cervical cytology alone in predicting outcomes in women in the 30- to 65-year age group?

Studies supporting co-testing 

Blatt et al25 conducted a retrospective study to assess the sensitivity of various testing options for biopsy-proven cervical intraepithelial neoplasia grade 3 or worse (CIN3+). The authors evaluated 256,648 cervical biopsies from women aged 30-65 who had undergone a co-test and colposcopy within 1 year of each other (colposcopy was performed a mean of 54 days after the co-testing result). Among the samples, 4,090 (1.6%) exhibited CIN3+. A positive co-test result was 98.8% sensitive for diagnosing CIN3+, compared with the 94% sensitivity of a positive HPV test result and the 91.3% sensitivity of a positive cytology result. Looked at another way, in this group of women, use of cytology alone would have missed 8.7% of the CIN3+ cases and use of the HPV test alone would have failed to catch 6% of the CIN3+ cases, whereas co-testing would have missed only 1.2% of these cases. Therefore, co-testing identified 80% of the CIN3+ cases that would have been missed by screening with the primary HPV test. Of the 526 confirmed cases of cervical cancer in this study, 98 (18.6%) were HPV test negative and 64 (12.2%) were cytology negative, whereas only 29 (5.5%) were cotest negative. Co-testing identified 70% of cervical cancers that would have been missed by screening with the HPV test alone.

Additional studies conducted over the past 11 years showed that primary HPV testing missed a substantial proportion of cervical cancers, and were in concordance with the landmark study by Blatt and colleagues.11, 26-29

Studies supporting primary HPV testing

The aforementioned interim guidance from the SGO/ASCCP was based, in large part, on the results of several large trials demonstrating that a negative HPV test result provides greater reassurance of low CIN3+ risk than does a negative cytology result. For example, Dillner et al30 evaluated primary data from seven HPV screening studies in six European Union countries, each investigating the predictive value of primary HPV testing for future CIN3+. The cumulative incidence rate of CIN3+ after 6 years was considerably lower among women negative for HPV at baseline (0.27%) than among women with negative results on cytology (0.97%). The cumulative incidence rate among women who were cytology-negative/HPV-positive rose continuously over time, reaching 10% at 6 years, whereas the rate among women who were cytologypositive/HPV-negative remained below 3%.

Other recent studies provided evidence that a negative HPV test result, as compared with a negative cytology result, offers greater reassurance that a woman will be free of CIN3+ over time.31-33 In these studies, participants underwent co-testing. In essence, the investigators found that the HPV test results, relative to the cytology results, were more predictive of outcomes over 3-5 years. That is, the cytology portion of the cotest did not add much information to the HPV portion, suggesting, to some at least, that HPV testing could be used by itself.

The first dilemma: Which CCS method is recommended for women aged 30-65?

The findings of the studies supporting primary HPV testing are open to interpretation. For example, Gage et al32 compared the risks of CIN3+ and of cervical cancer alone for HPV testing every 3 years, cytology testing every 3 years, and co-testing every 5 years among more than 1 million women in the Kaiser Permanente population who were aged 30-64 years and who tested HPV-negative and/or cytology-negative in routine screening. Investigators found that 3-year risks following an HPV-negative result were lower than 3-year risks following a cytology-negative result (CIN3+, 0.069% vs. 0.19%; P <.0001; cancer, 0.011% vs. 0.020%; P<.0001) and 5-year risks following an HPV-negative/Pap-negative co-test result (CIN3+, 0.069% vs. 0.11%; P <.0001; cancer, 0.011% vs. 0.014%; P = .21). That is, the 3- year safety (i.e., reassurance against future risk of pre-cancer and cancer) conferred by a negative HPV test result exceeded the 3-year safety conferred by a negative cytology result or the 5-year safety conferred by a negative cotest result. However, a closer look at the data shows that if HPV testing had been compared with cotesting at the 3-year checkpoint instead of the 5-year checkpoint (the recommended interval), negative co-testing results at baseline were slightly more reassuring than negative HPV results at baseline for CIN3+ and for cancer.

In addition, as HPV-infected cervical cells progress toward cervical cancer, HPV DNA levels decline.34 Depending on the age at which CCS begins and the frequency with which it is performed, relying initially, solely, or mainly on the results of HPV DNA screening tests might miss fastgrowing cancers. Although as HPV integrates itself into the human genome and HPV DNA levels decrease, HPV E6/E7 mRNA levels increase, suggesting that the assay that particularly targets this protein, as compared with the HPV DNA assays, is more specific in indicating lesion severity.35 

Furthermore, with cytology alone, adenocarcinoma and its precursors are difficult to identify— simply because of the cervical anatomy and the detection methods used. Cervical adenocarcinoma is usually farther away from the transformation zone, the area targeted most readily with the use of cervical sampling devices. Cytology alone has been relatively ineffective in identifying glandular lesions associated with adenocarcinoma. Addition of HPV testing to cytology—that is, co-testing—should enhance identification of adenocarcinoma and its precursor, adenocarcinoma in situ (ACIS).18

At this point in time, co-testing seems a reasonable option in women aged 30-65 years because it offers optimal sensitivity and specificity in identifying cervical cancer precursors.

What is the optimal screening interval for cervical cancer screening?

The 2012 ACS/ASCCP/ASCP and ACOG guidelines’ recommended screening intervals are 3 years for liquid-based cytology testing and 5 years for co-testing.6, 18 The updated Practice Bulletin from ACOG states that co-testing every 5 years is preferred, but that screening with cytology alone every 3 years is acceptable.20 ACOG recommends against annual testing. The USPSTF recommends cytology every 3 years for women younger than 30.17 For women aged 30-65 who want to extend their screening interval to 5 years, adding HPV testing is advised. The interim guidance provided by the SGO/ASCCP recommends that re-screening after a negative primary HPV test result occur no sooner than every 3 years—but only in women aged 25 years or older.24

For decades in the past, women underwent conventional Pap testing every year—their single best option for identifying cervical cancer precursors in a timely fashion. But there was a distinct downside to this yearly testing, which often yielded results—atypical squamous cells of undetermined significance (ASCUS) or a higher-grade lesion—that would lead to colposcopy and, depending on the results of the cervical biopsies, a loop electrosurgical excision procedure or conization. Most of these cytologic abnormalities, as well as the HPV infections underlying them, resolve on their own. Screening women every year, then, is bound to lead to unnecessary diagnostic and therapeutic procedures. These procedures are, at the very least, unpleasant and worrisome and at worst, harmful.36-41

The second dilemma: What is the optimal interval between screenings for women in any age group? 

Since the CCS guidelines were published in 2012 and the interim guidance was published last year, a different perspective on the CCS interval has been offered. According to a commentary by Kinney et al,42 which was based on a modeling study for the USPSTF that was published in 2013,43 women who comply with the CCS recommendations and increase the co-testing interval from 3 years to 5 years are increasing their risk for unfavorable consequences, with an additional 1/369 diagnosed with cancer in her lifetime and 1/1,639 dying of cancer. Adoption of a 3-year co-testing interval instead of a 5-year co-testing interval between screenings would “cost” 409 additional colposcopies and 14.3 additional women treated for each cancer death prevented. Many women and their HCPs might argue that the extra screenings, tests, treatments, and related harms are worth it to save even a small number of lives. In  addition, as noted in the discussion of the first CCS dilemma, results of the study by Gage et al32 suggest that the optimal interval for co-testing may be 3 years, not 5 years. Finally, there is considerable clinician resistance to the 5-year screening interval recommended for a negative co-test result.42

Based on what is known to date, HCPs should consider the optimal CCS screening interval to be 3 years, both for cytologic testing in women aged 21-29 or older and for co-testing in women aged 30-65. 

At what age can cervical cancer screening safely be stopped?

According to the ACS/ASCCP/ASCP, CCS can safely be stopped in women older than 65 who have had adequate negative prior screening (three consecutive negative cytology results or two negative co-test results within the previous 10 years, with the most recent test performed within the past 5 years) and no history of CIN2+ within the past 20 years.6 The USPSTF and ACOG are in general agreement with these criteria.17, 18 For women older than 65 with a history of CIN2, CIN3, or ACIS, routine screening should continue for at least 20 years.6, 18 According to the USPSTF, women older than 65 who have never been screened, women who do not meet the criteria for adequate prior screening, or women for whom the adequacy of prior screening cannot be accurately accessed or documented should undergo routine CCS.17 Likewise, routine screening should continue for at least 20 years after spontaneous regression or appropriate management of a highgrade pre-cancerous lesion, even if this extends screening past age 65.

Conclusion

The best approach to prevent cervical cancer entails screening and vaccination. The goals of maximizing benefits and minimizing harms for patients are guiding principles at the forefront of CCS. To this end, using the evidence to date, which includes the 2012 guidelines, the interim guidance published last year, and the updated ACOG practice bulletin, cytology screening every 3 years in women aged 21-29 and co-testing every 3 years in women aged 30-65 are reasonable recommendations to balance patient harms and clinician resistance to 5- year screening intervals.

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31. Katki HA, Kinney WK, Fetterman B, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol. 2011;12(7):663-672.

32. Gage JC, Schiffman M, Katki HA, et al. Reassurance against future risk of precancer and cancer conferred by a negative human papillomavirus test. J Natl Cancer Inst. 2014;106(8).

33. Ronco G, Dillner J, Elfström, EM, et al; International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014;383(9916):524-532.

34. Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond). 2006;110(5):525-541.

35. Lie AK, Kristensen G. Human pap illomavirus E6/E7 mRNA testing as a predictive marker for cervical carcinoma. Expert Rev Mol Diagn. 2008; 8(4):405-415.

36. Sawaya G, Kuppermann M. Identifying a “range of reasonable options” for cervical cancer screening. Obstet Gynecol. 2015;125(2):308-310.

37. Sharp L, Cotton S, Cruickshank M, et al; TOMBOLA Group. The unintended consequences of cervical screening: distress in women undergoing cytologic surveillance. J Low Genit Tract Dis. 2014;18(2):142-150.

38. Sutthichon P, Kietpeerakool C. Perioperative complications of an outpatient loop electrosurgical excision procedure: a review of 857 consecutive cases. Asian Pac J Cancer Prev. 2009;10(3):351-354.

39. Kyrgiou M, Koliopoulos G, Martin- Hirsch P, et al. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and metaanalysis. Lancet. 2006;367(9509): 489-498.

40. Ørtoft G, Henriksen TB, Hansen ES, Petersen LK. Preterm birth and previous conisation of the cervix. Br J Obstet Gynaecol. 2010;117(9):1158-1169.

41. Arbyn M, Kyrgiou M, Simoens C, et al. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ. 2008;337:a1284.

42. Kinney W, Wright TC, Dinkelspiel HE, et al. Increased cervical cancer risk associated with screening at longer intervals. Obstet Gynecol. 2015; 125(2):311-315.

43. Kulasingam SL, Havrilesky LJ, Ghebre R, Myers ER. Screening for cervical cancer: a modeling study for the US Preventive Services Task Force. J Low Genit Tract Dis. 2013; 17(2):193-202.