Human papillomavirus vaccines: Making a difference

Transcription

1 Human papillomavirus vaccines: Making a difference Michele A. Neff-Bulger, DO The first time I met Anna I was struck by her beauty. She had stunning long black hair and sparkly green eyes. Anna had brought her equally beautiful daughter, 2-year-old Jonie, to establish care with me. We quickly formed a connection, and over the next year, Jonie became a very pleasant addition to my practice. SHUTTERSTOCK.COM 10 AOA Health Watch Pediatric and Adolescent Immunizations: We Know Better September 2014

2 After Jonie s routine checkup at age 3, Anna asked me an Oh by the way question on her way out of my office. She asked if I thought her fatigue and multiple bruises, which she showed me, could be Lyme disease. Immediately feeling a sense of doom, I advised Anna to make an appointment with her physician as soon as possible, as my instinct told me that Anna had cancer. Unfortunately, my intuition was correct. Anna had metastatic cervical cancer. This beautiful 41-year-old mother was about to face the most difficult year of her life. Intermittently over the following year, Anna would call or me with a question about Jonie and we would discuss the progress of her cancer treatment. I was still taken aback when I walked into the examination room for Jonie s checkup the following year. Anna s athletic body had withered to a frail skeleton. A silk scarf replaced her once luxurious hair. Her skin was gray and ashen. Her eyes no longer sparkled, but instead had a determination in them to deliver a message that I will never forget. After my visit with Jonie, a very bubbly and curious preschooler, Anna asked to speak alone with me. She sat barely a foot away from me, yet leaned toward me to emphasize the importance of her request. She needed to know that I would make sure that Jonie would get the human papillomavirus (HPV) vaccines when the time was right. She had instructed the same to her husband, but was afraid he might forget given all the stress he was under. She was passing the baton to me to protect her daughter from the very virus that had caused her cancer. Anna died a few months later, leaving behind a motherless child, a widowed husband, countless grieving family and friends, and a pediatrician who feels an even greater obligation to educate my peers and patients of the importance of the HPV vaccines. Human Papillomavirus Human papillomavirus is a doublestranded DNA virus that is among the most commonly transmitted sexually transmitted infections (STIs) in the United States. HPV currently infects approximately 79 million people. Each I feel that the greatest reward for doing is the opportunity to do more. Dr Jonas Salk year, there are 26,000 HPV-related cancers, including 17,000 women, of whom 23% will die of cervical cancer. There are more than 150 types of HPV that are subdivided based on their propensity to infect either cutaneous or mucosal tissue. The HPV genotypes are defined as either high or low risk depending on their association with cancer. Approximately 15 are highrisk oncogenic types that cause many cancers of the cervix, vagina, vulva, penis, anus, and oropharynx. 1 Human papillomavirus types 16 and 18 cause approximately 70% of cervical cancers worldwide. Human papillomavirus types 16 and 18 are also the cause of vaginal (55%), anal (79%), and oropharyngeal cancers (62%). 3 Although HPV infections are very common, not all infections with high-risk types progress to cancer. Persistent infections can cause cellular changes and lead to cancer if not diagnosed and treated. Low-risk types (ie, types 6 and 11) cause anogenital warts and respiratory papillomatosis. 1-3 National Health and Nutrition Examination Survey (NHANES) data estimate prevalence among women between the ages of 15 and 59 years to be 21.6%, with any of the 37 different HPV types transmitted through sexual contact. A prevalence peak is noted among 20 to 24 year olds of 54%. In 2008, an estimated 39.9 million women and 39.2 million men had a prevalent HPV infection. Of those nearly 80 million, 17.9 million were aged years. 4 This is an infection that is contracted very often in youth and often asymptomatic for many years. Risk for disease Cervical cancer is the third-most commonly diagnosed female cancer in the world. It affects over 0.5 million women, accounting for 7% of female cancer deaths in Cervical cancer has a 100% attribution to HPV, meaning that virtually all cases are caused by types of HPV. Human papillomavirus types 16 and 18 cause approximately 70% of cervical cancers and 50% of precancerous cervical intraepithelial neoplasias grade 2 and 3 (CIN 2/3). 3,5 Vaginal and vulvar cancers are less common, but are also highly attributable to HPV, especially HPV16 and HPV18 (Table 1). 6 The incidence of anal cancer is increasing, particularly among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). 7 Human papillomavirus is attributable to 88%, with types 16 and 18 causing approximately 70%. Human papillomavirus is linked to a significant proportion of the increasing squamous cell carcinomas of the head and neck. This rise in oropharyngeal cancers may be linked to the preference Table 1. Global epidemiology of human papillomavirus (HPV)-related cancers in 2012ª and 2008 b INCIDENCE HPV ATTRIBUTABLE FRACTION (%) PERCENT CAUSED BY HPV16 and HPV18 (%) Cervical cancer 530,000ª Vulvar cancer 27,000 b Vaginal cancer 13,000 b Anal cancer 27,000 b Penile cancer 22,000 b Source: Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 2010;19(8): September 2014 Pediatric and Adolescent Immunizations: We Know Better AOA Health Watch 11

3 in oral-genital sex that adolescents are choosing over vaginal-penile intercourse. In the Centers for Disease Control and Prevention National Survey of Family Growth, data show that two-thirds of all youth between the ages of 15 and 24 had participated in oral sex. Of teens between the ages of 15 and 19 years, an average of 44% had received oral sex and 38.5% had given oral sex. 8 Adolescents tend to believe that oral sex is more acceptable than vaginal sex and less risky on health, social, and emotional consequences. Teens who engage in oral sex are also more likely to quickly proceed on to vaginal sex, placing them at further risk for contracting the HPV virus, among other STIs. 8,9 Close skinto-skin contact, digital-anal or vaginal, or fomites can also spread the virus. 10 Vaccines Two prophylactic HPV vaccines are currently available, a bivalent (Cervarix ) and a quadrivalent (Gardasil ) vaccine. Both of these vaccines aim to prevent cancers caused by HPV16 and HPV18. The quadrivalent vaccine (HPV4) also prevents from infection with HPV6 and HPV11, which cause most HPV-related anogenital warts. The vaccines cannot stop progression or eliminate the HPV infection if already contracted. Both vaccines are mixtures of noninfectious capsid protein-based, virus-like particles with aluminum as an adjuvant and are thimerosal free. The vaccines are administered in 3 intramuscular doses. The bivalent (HPV2) vaccine is given at time 0, 1, and 6 months. The quadrivalent vaccine (HPV4) is given at time 0, 2, and 6 months. 11,12 Gardasil was licensed by the US Food and Drug Administration (FDA) in June 2006 and was recommended for girls years of age by the Advisory Committee on Immunization Practices (ACIP) in March In 2009, the FDA approved the bivalent vaccine, Cervarix, and HPV4 vaccination for male genital wart prevention. In 2010, the ACIP began recommending either HPV2 or HPV4 vaccine for all females ages years (it may be given starting at age 9), and the quadrivalent vaccine was permitted for all males for wart and anal cancer prevention. The ACIP, in 2011, extended its HPV4 recommendation for males to all males ages and males ages not previously or incompletely vaccinated. Men who have sex with men are at higher risk for infection with HPV types 6, 11, 16, and 18 and associated conditions, including genital warts and anal cancer. The ACIP recommendation for high-risk (MSM or immunocompromised, including HIV positive) males is to extend vaccination up to age 26 for those who have not been vaccinated previously or who have not completed the 3-dose series. For men aged years who are not high risk, the ACIP supports permissive use of HPV4, but has not included it on the routine vaccination schedule. 13,14 The ACIP recommends HPV vaccination beginning at age 9 years for children and youth with any history of sexual abuse or assault who have not initiated or completed the 3-dose series. Adults through age 26 years who are victims of sexual abuse or assault should receive HPV vaccine if they have not already been vaccinated. 13 Vaccination eligibility and contraindications Previous exposure to HPV or current infection with HPV is not cause for vaccination exclusion, because protection to the other HPV vaccine types can be gained. It is important to educate such individuals with preexisting vaccinetype HPV that their infection will BRUNO BOISSONNET/SCIENCE SOURCE 12 AOA Health Watch Pediatric and Adolescent Immunizations: We Know Better September 2014

4 NIBSC/SCIENCE SOURCE not be treated by the immunization. Vaccination is less beneficial in preventing genital warts and persistent HPV infection for such individuals. Prevaccination screening for existing HPV infection is not recommended. Because the vaccine is prophylactic, it is ideally given before sexual debut, which is often earlier than parents would like to acknowledge. The reality is that nearly half (47.4%) of high school students have ever had sexual intercourse and 33.7% remain currently sexually active. 8 An additional motive to give the vaccine earlier rather than later is data showing a higher antibody response in 11 to 12 year olds than in those over age 16. These studies show a 2- to 3-fold higher geometric mean titer in girls under 16 following the HPV4 vaccine than in girls ages That being said, we do not know the minimum antibody titer required for protection. To date, studies show excellent duration of immunity in women. More information will be known over time, in both men and women, as we progress with the recommended schedule. HPV4 is not a live vaccine and can be administered in those who are immunocompromised as a result of infection (including HIV), disease, or medications. The immune response and vaccine efficacy might be less than in immunocompetent people. The HPV vaccine is not approved for pregnant women; however, no adverse outcomes have been reported in those vaccinated inadvertently during pregnancy. It is advisable to rule out pregnancy in sexually active females before administration of the vaccine. If completion of the series is interrupted by pregnancy, vaccination can simply resume postpartum even if lactating. HPV4 is contraindicated in people with immediate hypersensitivity to baker s yeast because it is produced in Saccharomyces cerevisiae (baker s yeast). The HPV2 vaccine is contraindicated in people with anaphylactic latex allergy because the HPV2 syringes have latex in the rubber stopper. 13 Effectiveness In order for a vaccine to be approved by the FDA, rigorous clinical trials are performed. With the HPV vaccine, these FDA trials showed HPV 16/18-related cervical CIN 2/3 or adenocarcinoma in situ was reduced by 100%. The trials also showed a 97% reduction in female genital warts and an 89% reduction in male genital warts. Since FDA approval, the NHANES has shown a 56% reduction in HPV strains 6, 11, 16, and 18 in US adolescents, where the completion of the series is less than 40%. In Australia, where the completion of the HPV series rate is 70%, the reduction in those same strains is higher at 77%. Similar results are noted with genital warts with a 36% reduction in the United States and an 88% reduction in Australia, where the immunization rates are more than double. 16 Clearly, the higher efficacy observed with a complete series should inspire us to encourage our patients to complete all 3 recommended doses. The 2 currently available vaccines are comparable in efficacy for preventing Clearly, the higher efficacy observed with a complete series should inspire us to encourage our patients to complete all 3 recommended doses. HPV-like particles. Colored transmission electron micrograph (TEM) of particles formed from the outer protein coat (capsid) of the human papillomavirus (HPV). HPV-like particles are used as vaccines against the virus. CIN2 or more severe disease. According to clinical trials including 17,000 females, the HPV4 vaccine was 97%- 100% efficacious versus 93% in the HPV2 vaccine in HPV-naïve patients. Neither vaccine was as effective in a 3-year follow-up (approximately 50%), which underscores the importance of vaccinating before sexual debut. 15,17 We know that HPV16 and HPV18 account for approximately 62% of HPV-related cancers. Another 11% of HPV-related cancers are attributable to another 5 HPV types: HPV 31, 33, 45, 52, and 58. An investigational 9-valent vaccine, which includes these 5 types in addition to the current types in the quadrivalent vaccine, has shown very promising clinical trial data. The data in the 9-valent vaccine trials have shown noninferior HPV 6/11/16/18 immunogenicity versus HPV4 and approximately 97% protection against HPV 31/33/45/52/58-related disease. The 9-valent vaccine may be available, pending licensure, in early Rates of administration Regrettably, since 2007, when the ACIP first recommended routine HPV vaccination for girls, rates of September 2014 Pediatric and Adolescent Immunizations: We Know Better AOA Health Watch 13

5 administration have been poor. In 2012, of girls aged years, only 53.8% received the first of 3 HPV vaccines. Only 33.4% of those girls completed the series. Administration rates for boys are even worse, with only 20.8% receiving the first dose. 13 Opportunities to increase administration Because the HPV vaccination rates are so poor, tactics to increase administration need to be taken. Making the HPV vaccine a school requirement would be a successful strategy in eliminating the perceived stigma associated with vaccine and increasing immunization. The success of this strategy has been proven with higher rates of hepatitis B, tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis, and meningococcal quadrivalent conjugate vaccine vaccine coverage with school requirements. According to the US Department of Health and Human Services, currently only Virginia and the District of Columbia require HPV for sixth-grade entry. 3 Other possible tactics to increase coverage rates could include reminder calls or text messages for second and third doses, standing orders, and the use of alternative locations for vaccination besides the physician s office, such as schools. Seizing any and every opportunity to vaccinate these young men and women is crucial. During a visit for a sport s participation physical or driver s permit may lend an opportunity to increase completion rates. If a patient is overdue for the next injection, the series does not need to be restarted. Ideally, though, the injections will be given on their recommended schedule because it is known that by this schedule excellent efficacy is achieved. Misconceptions of human papillomavirus vaccine Spending a few moments asking vaccinehesitant parents about their fears and counseling them regarding the safety, efficacy, and lack of increased sexual activity or promiscuity postvaccination will likely alleviate apprehension and increase vaccination rates. In a 2012 National Immunization Survey for teens, parents reported their reasons for HPV vaccine refusal. Nearly one-quarter (23%) said that they did not plan on vaccinating their child in the next year. Of those parents, 20% felt that vaccine is not necessary, 10% felt it could be delayed because their child was not yet sexually active, 13% had safety concerns, and, sadly, another 14% reported that their provider did not recommend it. 18 Other studies have shown that parents have concerns for increased promiscuity after receiving the HPV vaccine. There is convincing evidence that sexual activity is not affected by receipt of the HPV vaccine. A study published in Pediatrics in March 2014 looked at 339 women ages years who self-reported SHUTTERSTOCK.COM risk perceptions for STIs other than HPV and need for safer sex behaviors after vaccination in addition to their sexual behaviors. It showed that risk perceptions after HPV vaccination were not associated with riskier sexual behaviors following the 6 months after the initial vaccine, regardless of baseline sexual experience. 19 The safety of a new vaccine is always a concern by both parents and clinicians. Nearly 60 million doses of HPV vaccine have been given in the United States through Both the Vaccine Adverse Event Reporting System and the Vaccine Safety Datalink monitor for adverse events related to the HPV vaccine. From June 2006 through March 2013, 21,194 adverse events were reported in females. The majority of these events (92.1%) were nonserious and consisted of syncope, headache, fever, nausea, dizziness, and urticaria. No deaths have been caused by the vaccine. There is no evidence to support any increased risk of Guillain- Barre syndrome, seizures, deep venous thrombosis, stroke, anaphylaxis, or ovarian failure subsequent to HPV vaccination. As with any immunization, discomfort at injection site is the most common adverse reaction. The HPV vaccine s most common safety concern is syncope experienced the day of administration. 20,21 Keeping your patient seated for observation after getting the vaccine typically prevents this condition. Inform your patients that although the ACIP only started recommended HPV routinely in 2007, it is not new after greater than 60 million doses. It is safe and effective. Although the HPV vaccines are extremely efficacious, they do not eliminate the need for continued cervical cancer screening because the vaccines are only protective against the 2 most common of the cancercausing HPV genotypes. All women, beginning at 21 years, should have cervical cytology (ie, Pap smear) and/or HPV testing performed. 22 The health care provider s role Human papillomavirus contracted in adolescence and young adulthood can 14 AOA Health Watch Pediatric and Adolescent Immunizations: We Know Better September 2014

6 lead to cancer decades later when those individuals are aiming to protect their own children from harm. The largest impact we can have as physicians is to educate and encourage our parents and patients to choose the cancer vaccine. Practice what you preach. Many of my parents who are unsure quickly concede whenever I tell them that I have already vaccinated both of my sons and will vaccinate my daughter when she is old enough. I often tell my families that there are only a few things one can do to prevent cancer: Don t smoke, wear sunscreen, and get the HPV vaccine! When put into these simple terms, it makes the choice obvious. Dr Salk said, I feel that the greatest reward for doing is the opportunity to do more. It may feel inefficient to take time to patiently educate vaccinehesitant parents of the benefits of the HPV vaccine. Consider, though, that for each individual vaccinated, it not only protects them, but it also contributes to the national and global reduction of cancer. Your patience and knowledge are your opportunity to do more. I know that I will forever be inspired by the memory of Anna to do more. References 1. Forman D, de Martel C, Lacey CJ, et al. Global burden of human papillomavirus and related diseases. Vaccine. 2012; 30(suppl 5):F12-F De Sanjose S, Quint WG, Alemany L, et al.; Retrospective International Survey and HPV Time Trends Study Group. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11(11): Dunne E, Markowitz L, Saraiya M, et al.; Centers for Disease Control and Prevention (CDC). CDC grand rounds: reducing the burden of HPV-associated cancer and disease. MMWR Morb Mortal Wkly Rep. 2014;63(4): Satterwhite CL, Torrone E, Meites E, et al. Sexually transmitted infections among US women and men: prevalence and incidence estimates, Sex Transm Dis. 2013;40(3): National Institutes of Health (NIH). Cervical cancer. gov/nihfactsheets/viewfactsheet. aspx?csid=76. Accessed August 15, Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 2010;19(8): 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): Centers for Disease Control and Prevention (CDC). Youth risk behavior surveillance-united States, MMWR Morb Mortal Wkl Rep. June 8, ss/ss6104.pdf. Accessed August 4, Halpem-Felsher BL, Cornell JL, Kropp RY, Tschann JM. Oral versus vaginal sex among adolescents: attitudes, perceptions and behaviors. Pediatrics, 2005;115(4): Palefsky JM. Cutaneous and genital HPVassociated lesions in HIV-infected patients. Clin Dermatol. 1997;15(3): Centers for Disease Control and Prevention (CDC). National and state vaccination coverage among adolescents aged years-united States, MMWR Morb Mortal Wkly Rep. 2013;62: Centers for Disease Control and Prevention (CDC). Advisory Committee on Immunization Practices (ACIP) recommended SHUTTERSTOCK.COM immunization schedules for persons aged 0 through 18 years and adults aged 19 years and older United States, MMWR Surveill Sum. 2013;62(suppl 1): Markowitz L. Updated HPV vaccine ACIP statement; NCHHSTP/CDC. downloads/slides /05-hpv- Markowitz.pdf. Accessed August 4, Centers for Disease Control and Prevention (CDC). Recommendations on the use of quadrivalent human papillomavirus vaccine in males-advisory Committee on Immunization Practices (ACIP), MMWR Morb Mortal Wkly Rep. 2011;60(50); Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital disease. N Engl J Med. 2007;356(19): Markowitz L, Hariri S, Lin C, et al. Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, NHANES, J Infect Dis. 2013;208(3): FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356(19): Dorell C, Yankey D, Kennedy A, Stokley S. Factors that influence parental vaccination decisions for adolescents, 13 to 17 years old: National Immunization Survey-Teen, Clin Pediatr (Phila). 2013;52: Mayhew A, Mullins TL, Ding L, et al. Risk perceptions and subsequent sexual behaviors after HPV vaccination in adolescents. Pediatrics. 2014;113(3): Centers for Disease Control and Prevention (CDC). Human papillomavirus vaccination coverage among adolescent girls, , and postlicensure vaccine safety monitoring, United States. MMWR Morb Mortal Wkly Rep. 2013;62(29): 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): New cervical cancer screening recommendations from the U.S. Preventive Services Task Force and the American Cancer Society/American Society for Colposcopy and Cervical Pathology/American Society for Clinical Pathology. About_ACOG/Announcements/New_Cervical_ Cancer_Screening_Recommendations[n3]. Accessed August 14, Michele A. Neff-Bulger, DO, is affiliated with the Department of Pediatrics, Division of General Pediatrics, at Geisinger Medical Center in Danville, Pennsylvania. She can be reached at jbulger@ptd.net. September 2014 Pediatric and Adolescent Immunizations: We Know Better AOA Health Watch 15