Battle against Human Papilloma Virus (HPV): Expanded Vaccine Recommendations

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1 Battle against Human Papilloma Virus (HPV): Expanded Vaccine Recommendations Sean W. Clark, Pharm.D. PGY-2 Ambulatory Care Resident Duquesne University and The Center for Pharmacy Care

2 I have no relevant commercial and/or financial relationships to disclose.

3 Learning Objectives 1. Describe HPV Pathology and Epidemiology 2. Summarize previous HPV vaccine recommendations 3. Evaluate the safety and efficacy of available HPV vaccine based on patient specific parameters 4. Apply recent studies to patient specific parameters for recommendations regarding HPV vaccination

4 Pre-Assessment Answer assessment questions using PollEverywhere To participate in poll everywhere: Text seanclark718 to Respond at PollEv.com/seanclark718

12 Case: AG You are a clinical pharmacist practicing at a family medicine clinic. AG is a 14 year old female who presents to the clinic with her parents for a routine visit. AG s past medical history is significant for Asthma and Seasonal Allergies. The provider discussed the risks and benefits of HPV vaccination with the patient and her parents. Based on this conversation, they have decided AG should receive the vaccination. She has not received any doses previously.

15 Case: BH BH is a 24 year old male that presents to your pharmacy. He recently heard about the HPV vaccine and is interested in receiving it. His past medical history is significant for an immunocompromising condition, and he is currently on immunosuppression therapy.

24 What is HPV? Double-stranded circular DNA virus Only infects humans Over 200 types Causes chronic inapparent infections

25 Epidemiology Most common sexually transmitted infection in the United States More than 20 million people are infected with HPV in the U.S. Prevalence of infection with any HPV type was 42.5% among U.S. adults aged during

26 Epidemiology Types 16 and 18 account for approximately 70% of cervical cancers worldwide Types 6 and 11 are responsible for approximately 90% of genital warts worldwide

27 Genotype and Risk High-risk genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 Found in 99% of cervical cancers Low-risk genotypes 6, 11, 40, 42, 43, 44, 53, 54, 61, 72, 73, and 81 Cause genital warts

28 Viral Structure Source: Doorbar J, Egawa N, Griffin H, Kranjec C, Murakami I. Human papillomavirus molecular biology and disease association. Rev Med Virol. 2015;25 Suppl 1(Suppl Suppl 1):2-23.

29 Pathology Two types of infection: Cutaneous Mucosal Transmitted by skin-to-skin or mucosa-tomucosa contact L1 and L2 proteins mediate infectivity Cycle linked to epithelial differentiation

30 Pathology Infection occurs in a microscopic break in epithelium Virons attach to basal stem cell Gene products transcribed at every level of squamous keratinocyte differentiation Infectious virons released after desquamation

31 HPV Binds to Glycoprotein Source: Raff A. B., Woodham A. W., Raff L. M., Skeate J. G., Yan L., Da Silva DM, et al. (2013). The evolving field of human papillomavirus receptor research: a review of binding and entry. J. Virol /JVI

32 HPV Binds to Glycoprotein Source: Raff A. B., Woodham A. W., Raff L. M., Skeate J. G., Yan L., Da Silva DM, et al. (2013). The evolving field of human papillomavirus receptor research: a review of binding and entry. J. Virol /JVI

33 HPV Binds to Glycoprotein Source: Raff A. B., Woodham A. W., Raff L. M., Skeate J. G., Yan L., Da Silva DM, et al. (2013). The evolving field of human papillomavirus receptor research: a review of binding and entry. J. Virol /JVI

34 Growth Factor Receptor Activated Source: Raff A. B., Woodham A. W., Raff L. M., Skeate J. G., Yan L., Da Silva DM, et al. (2013). The evolving field of human papillomavirus receptor research: a review of binding and entry. J. Virol /JVI

35 Growth Factor Receptor Activated Source: Raff A. B., Woodham A. W., Raff L. M., Skeate J. G., Yan L., Da Silva DM, et al. (2013). The evolving field of human papillomavirus receptor research: a review of binding and entry. J. Virol /JVI

36 Signaling Cascade Activated Source: Raff A. B., Woodham A. W., Raff L. M., Skeate J. G., Yan L., Da Silva DM, et al. (2013). The evolving field of human papillomavirus receptor research: a review of binding and entry. J. Virol /JVI

37 Conformational Change Source: Raff A. B., Woodham A. W., Raff L. M., Skeate J. G., Yan L., Da Silva DM, et al. (2013). The evolving field of human papillomavirus receptor research: a review of binding and entry. J. Virol /JVI

38 Binds to Complex Source: Raff A. B., Woodham A. W., Raff L. M., Skeate J. G., Yan L., Da Silva DM, et al. (2013). The evolving field of human papillomavirus receptor research: a review of binding and entry. J. Virol /JVI

39 Binds to Complex Source: Raff A. B., Woodham A. W., Raff L. M., Skeate J. G., Yan L., Da Silva DM, et al. (2013). The evolving field of human papillomavirus receptor research: a review of binding and entry. J. Virol /JVI

40 Endocytosed Source: Raff A. B., Woodham A. W., Raff L. M., Skeate J. G., Yan L., Da Silva DM, et al. (2013). The evolving field of human papillomavirus receptor research: a review of binding and entry. J. Virol /JVI

41 Vesicle is Formed Source: Raff A. B., Woodham A. W., Raff L. M., Skeate J. G., Yan L., Da Silva DM, et al. (2013). The evolving field of human papillomavirus receptor research: a review of binding and entry. J. Virol /JVI

42 After Infection Cytological abnormalities are usually transient Most HPV infections resolve within 12 months Persistent infections increase the likelihood of precancerous or cancerous lesions Possible to enter a latent state

43 Process of Infection CIN= Cervical Intraepithelial Neoplasm Source: Braaten KP, Laufer MR. Human Papillomavirus (HPV), HPV-Related Disease, and the HPV Vaccine. Rev Obstet Gynecol. 2008;1(1):2-10.

44 Cervical Intraepithelial Lesions Source: Braaten KP, Laufer MR. Human Papillomavirus (HPV), HPV-Related Disease, and the HPV Vaccine. Rev Obstet Gynecol. 2008;1(1):2-10.

45 Disease Associations Cancer Nongenital and genital warts Recurrent respiratory papillomatosis Bowen s Disease Epidermodysplasia

46 Link to Cancer HPV Associated Cancers Cervical 96% Anal 93% Vaginal 64% Oropharyngeal 63% Vulvar 51% Penile 36%

47 Detection of HPV 3 Main Categories: HPV DNA testing HPV RNA testing Detection of cellular markers Limited to testing of cervical screenings

48 Defense against HPV FDA approved HPV vaccines Contain synthetically manufactured virus like particles of the L1 epotipe Provide antibodies to protect against infection with most prevalent genotypes

49 HPV Vaccine Timeline 4vHPV vaccine approved (2006)

50 HPV Vaccine Timeline 4vHPV vaccine approved (2006) 2vHPV vaccine approved (2009)

51 HPV Vaccine Timeline 4vHPV vaccine approved (2006) 9vHPV vaccine approved (2014) 2vHPV vaccine approved (2009)

52 Genotype Coverage 4vHPV 6, 11, 16, 18 2vHPV 16, 18 9vHPV 6, 11, 16, 18, 31, 33, 45, 52 and 58

53 Previous Recommendations 4vHPV and 2vHPV vaccines were recommended for routine vaccination 2vHPV vaccine was only approved for females Only given as a 3 dose series prior to 2016

54 Changes to HPV Vaccines 2vHPV and 4vHPV vaccines are no longer available in US 9vHPV vaccine only one currently in use in US Added new dosing schedule for individuals <15

55 HPV Vaccine Recommendations Centers for Disease Control (CDC)/ Advisory Committee on Immunization Practices (ACIP): Routinely vaccinate children age 11 or 12 May start as early as age 9 if at increased risk

56 HPV Vaccine Recommendations CDC/ACIP: If not previously vaccinated: Vaccinate females age 13 to 26 Vaccinate males 13 to 21 Vaccinate males through age 26 at increased risk

57 HPV Vaccine Schedules CDC/ACIP: Age 9-14: 2-dose series Given at 0 and 6-12 months Minimum interval of 5 months

58 HPV Vaccine Schedules CDC/ACIP Age15-26 (or immunocompromised): 3-dose series Given at 0, 1-2, and 6 months Minimum intervals: Dose 1 and 2= 4 weeks Dose 2 and 3= 12 weeks Dose 1 and 3= 20 weeks

59 HPV Vaccine Safety Large volume of evidence to support safety of HPV vaccines Believed to have a favorable risk/benefit profile Some concern by independent researchers that inert placebos were not used during randomized trials

60 HPV Vaccine Safety Meta-analysis by Philips et. Al examined evidence of HPV vaccine safety Update focused on 9vHPV vaccine Identified 109 studies 15 were population-based including over 2.5 million vaccinated individuals

61 HPV Vaccine Safety Injection site reactions determined to be most common adverse event More common in 9vHPV vaccine Headache, fever, nausea, and dizziness were similar between 9vHPV and 4vHPV vaccines

62 HPV Vaccine Safety Meta-analysis by Moreira et al. examined serious adverse effects Studies included >15,000 subjects Occurred in 2.3% of 9vHPV vaccine recipients No deaths were attributed to 9vHPV vaccine administration

63 HPV Vaccine Immunogenicity Immunogenic response has been reported for all HPV vaccines No defined minimum threshold for titer protection Seroconversion from natural infection is much lower and may only provide some protection Vaccines provide titers above natural threshold

64 Efficacy of 9vHPV Vaccine Vaccination is effective in preventing cervical disease in HPV naive individuals Cervical endpoints of protection against genotype 16 and 18 similar to 4vHPV Protection against CIN 2 or more severe disease from 31, 33, 45, 52, and 58 was 97%

65 Efficacy of 9vHPV Vaccine Data for non-cervical endpoints is more limited Better protection for HPV naive Estimated protection: Anal disease- 78% Oral disease- 93% Anogenital warts- 90%

66 Efficacy of 9vHPV Vaccine Duration of protection has been observed up to 10 years Persistent antibody levels and protection against HPV infection Continued protection against highgrade cervical, vaginal, and vulvar neoplasia

67 Recent HPV Update October 5 th, 2018: FDA approved supplemental application for 9vHPV Expanded use to adults age 27-45

68 Data Supporting Expanded Use Based on Phase 3 study of 4vHPV Vaccine Demonstrated: High prophylactic durability Effectiveness 10 years post follow-up Regulatory agencies determined data could be inferred to 9vHPV

69 Data Supporting Expanded Use Study conducted in females years old 3,819 participants randomized Consisted of base study and long-term follow-up phase Mean follow-up of 3.8 years for base study

70 Data Supporting Expanded Use Efficacy based on endpoints: 6-month persistent infection- 89.6% (9 vs 85) CIN (any grade)- 94.1% (1 vs 17) CIN ( 2)- 83.3% (1 vs 6) Condyloma- 100% (0 vs 7)

71 Data Supporting Expanded Use Vaccine related adverse effects: Injection site reaction- 76% vs 64.2% Headache- 21.2% vs 19.9% Pyrexia- 9.4% versus 9% Discontinued due to adverse effect- 0.3% vs 0.1%

72 Data Supporting Expanded Use Long-term data analysis: 600 subjects age Received 3-doses within 1 year in base study HPV naïve Followed up to 10 years

73 Data Supporting Expanded Use Long-term data analysis: No cases of HPV6/11/16/18-related cervical disease or condyloma during the study extension Continued exposure to non-vaccine types Sustained immunogenicity

74 Data Supporting Expanded Use Post-hoc bridging analyses cross-study comparison: Included 5 studies Compared titers of participants age to age16-26 Analyzed males and females

75 Data Supporting Expanded Use Post-hoc bridging analyses cross-study comparison: Women Non-inferiority was demonstrated for HPV types 6, 11, 16, and 18 Men Non-inferiority was demonstrated for HPV types 6, 11, and 16

76 Summary of Expanded Use Data Efficacy of 4vHPV against 6/11/16/18- related disease Demonstrated in women and men Efficacy of 9vHPV against 6/11/16/18-related disease Demonstrated in females Inferred based on non-inferior antibody response regardless of age

77 Cost-Effectiveness Three US models for 9vHPV Current HPV vaccination program offers good value for cost Vaccination of adolescents is cost saving As age increases total cost per QALY increases

78 What Happens Next? ACIP will release 2019 recommendations after February meeting Possible considerations: Harmonization of age recommendations Changing upper age based on health economic analysis Potential recommendation for individual decision making for max catch-up age through 45

79 Final Thoughts Current HPV vaccination rates remain well below Healthy People 2020 goal Resistance must be met with understanding and education May provide additional protection for HPV naive individuals May provide protection against unacquired genotypes May not be cost-effective to recommend catchup schedule for individuals older than 26

80 Post-Assessment Answer assessment questions using PollEverywhere To participate in poll everywhere: Text seanclark718 to Respond at PollEv.com/seanclark718

90 Case: AG You are a clinical pharmacist practicing at a family medicine clinic. AG is a 14 year old female who presents to the clinic with her parents for a routine visit. AG s past medical history is significant for Asthma and Seasonal Allergies. The provider discussed the risks and benefits of HPV vaccination with the patient and her parents. Based on this conversation, they have decided AG should receive the vaccination. She has not received any doses previously.

94 Case: BH BH is a 24 year old male that presents to your pharmacy. He recently heard about the HPV vaccine and is interested in receiving it. His past medical history is significant for an immunocompromising condition, and he is currently on immunosuppression therapy.

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104 References 1. Doorbar J, Egawa N, Griffin H, Kranjec C, Murakami I. Human papillomavirus molecular biology and disease association. Rev Med Virol. 2015;25: Aksoy P, Gottschalk EY, Meneses PI. HPV entry into cells. Mutat Res Rev Mutat Res. 2016;772: Raff A. B., Woodham A. W., Raff L. M., Skeate J. G., Yan L., Da Silva DM, et al. The evolving field of human papillomavirus receptor research: a review of binding and entry. J. Virol /JVI Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance Atlanta: U.S. Department of Health and Human Services; Braaten KP, Laufer MR. Human Papillomavirus (HPV), HPV-Related Disease, and the HPV Vaccine. Rev Obstet Gynecol. 2008;1(1): Brianti P., De Flammineis E., Mercuri S. R. (2017). Review of HPV-related diseases and cancers.new Microbiol HPV Cancer Screening. Centers for Disease Control. December 13, December 12, HPV Vaccine Recommendations. Centers for Disease Control. December 15, December 12, Human Papilloma Virus (HPV). December 1, December 15, Phillips A, Patel C, Pillsbury A, Brotherton J, Macartney K. Safety of human papillomavirus vaccines: an updated review. Drug Saf. 2017;41(4) Martínez-Lavín M, Amezcua-Guerra L. Serious adverse events after HPV vaccination: a critical review of randomized trials and post-marketing case series. Clin Rheumatol. 2017;36(10): Moreira ED, Block SL, Ferris D, Giuliano AR, Iversen OE, Joura EA, et al.. Safety profile of the 9-valent HPV vaccine: a combined analysis of 7 phase III clinical trials. Pediatrics. 2016; 138:e /peds Harper DM, DeMars LR. HPV vaccines - A review of the first decade. Gynecol Oncol. 2017;146: Erratum in: Gynecol Oncol. 2017;147: FDA approves expanded use of Gardasil 9 to include individuals 27 through 45 years. oldhttps:// Newsroom/PressAnnouncements/ucm htm. October 5, December 13, Alain Luxembourg. 9vHPV Vaccine for Mid-Adult Persons (27-45 yo) Results from Clinical Studies. Advisory Committee on Immunization Practices; June 20, 2018; Tom Harkin Global Communications Center. Luxembourg-508.pdf. December 15, 2018.

105 Questions?

9/11/2018. HPV Yoga. Human Papillomavirus. Human Papillomavirus (HPV) Disease. Most common sexually transmitted infection in the U.S.

9/11/2018. HPV Yoga. Human Papillomavirus. Human Papillomavirus (HPV) Disease. Most common sexually transmitted infection in the U.S. Centers for Disease Control and Prevention National Center for Immunization and Respiratory Diseases Human Papillomavirus September 2018 Chapter 11 Photographs and images included in this presentation