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Updates in HPV

Updates in HPV. Grand Rounds, May 1, 2019 Robyn Moxley MD CCFP Assistant Professor, Department of Family Medicine Victoria Family Medical Centre. Faculty/ Presenter Disclosure. Faculty: Robyn Moxley Relationships with commercial interests: Grants/Research Support: None

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Updates in HPV

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  1. Updates in HPV Grand Rounds, May 1, 2019 Robyn Moxley MD CCFP Assistant Professor, Department of Family Medicine Victoria Family Medical Centre

  2. Faculty/ Presenter Disclosure • Faculty: Robyn Moxley • Relationships with commercial interests: • Grants/Research Support: None • Speakers Bureau/Honoraria: None • Consulting Fees: None • Other: None

  3. Disclosure of Commercial Support • This program has received no in-kind support. • Potential for conflict(s) of interest: • None • This program has received no commercial financial support.

  4. Mitigating Potential Bias • N/A

  5. Learning objectives • Discuss currently available HPV vaccines, indications, and funding • Describe the role of HPV testing in screening for cervical cancer – current and future recommendations • Review recommendations for follow up in primary care after discharge from colposcopy • Discuss recommendations for screening for anal intraepithelial neoplasia and anal cancer, including anal pap tests and high resolution anoscopy

  6. Human Papilloma Virus • In the absence of vaccination, an estimated 75% of sexually active Canadians will be infected with HPV • Persistent infection with high-risk HPV types can lead to the development of pre-cancerous lesions • These can progress to cancers of the cervix, vulva, and vagina in females, penile cancer in males, and anal and oropharyngeal cancer in both females and males • The total burden of HPV-associated cancers among both genders is estimated at 5.2% of all cancers worldwide Updated Recommendations on Human Papillomavirus (HPV) Vaccines: 9-valent HPV vaccine 2-dose immunization schedule and the use of HPV vaccines in immunocompromised populations An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI

  7. HPV Vaccination

  8. HPV Vaccination • In Canada, immunization against HPV types 16 and 18 can prevent approximately 70% of anogenital cancers and 60% of high-risk precancerous cervical lesions • HPV9 can prevent up to an additional 14% of anogenital cancers and up to 30% of high-risk precancerous cervical lesions caused by the additional five HPV types (31, 33, 45, 52 and 58)

  9. Available Vaccines Against HPV • Gardasil 4 – authorized for use in Canada since 2006 for prevention of HPV types 6, 11, 16, 18 • Cervarix – authorized in 2010, for prevention of HPV 16, 18 • Gardasil 9 –3 dose schedule authorized in 2015, to prevent HPV 6, 11, 16, 18, 31, 33, 45, 52 and 58, • For prevention of anogenital cancers, related pre-cancerous lesions, and AGWs Updated Recommendations on Human Papillomavirus (HPV) Vaccines: 9-valent HPV vaccine 2-dose immunization schedule and the use of HPV vaccines in immunocompromised populations An Advisory Committee Statement (ACS) National Advisory Committee on Immunization (NACI)

  10. Who should be vaccinated • Cervarix, Gardasil 4, and Gardasil 9 are all indicated for girls and women age 9-46 • Gardasil 4 and 9 are indicated for boys and men age 9-26 • No evidence of immunogenicity before age 9

  11. Dose Schedule • 2 dose schedule - if age younger than 15 at time of first dose and immunocompetent • Cervarix – 0, 6 months • Gardasil 4 – 0 and 6-12 months • Gardasil 9 – 0 and 5-13 months • 3 dose schedule – if age 15 or older at time of first dose or immune compromised or HIV infected • Cervarix – 0, 1, 6 months • Gardasil 4 and 9 – 0, 2, 6 months

  12. Publicly Funded HPV vaccines In Ontario • Female students in grade 8 were offered Gardasil 4 starting in 2007 • Since 2017, Gardasil 9 has been offered to male and female students in grade 7 (born in 2004 or after) • If a student misses the grade 7 immunization clinic, they may receive the vaccine the next time the public health nurse is at the school, in the Immunization Clinic at the MLHU, or in their family doctor’s office (if they stock the vaccine)

  13. Publicly Funded HPV vaccines In Ontario • Students who miss the vaccine are eligible for catch up at the health unit until the end of grade 12 • Cost at health unit is $175 per dose • Not required for school attendance

  14. High risk HPV immunization Program • Gardasil 9 is offered to men who have sex with men (MSM) age 26 or younger • Available at the MLHU immunization clinic • Among MSM, the risk of persistent HPV infection and genital warts are about 3 times higher than heterosexual males • Risk of anal cancer is 20 times higher in MSM compared to heterosexual males Nine-valent Human Papillomavirus (HPV9) Vaccine for Ontario’s High-Risk HPV Immunization Program: Information for Patients. MOHLTC. http://health.gov.on.ca/en/pro/programs/immunization/docs/hpv9_patient_fact_sheet.pdf

  15. Which one should I prescribe? • Gardasil 9 – can prevent up to an additional 14% of anogenital cancers and up to 30% of high-risk precancerous cervical lesions caused by the additional five HPV types (31, 33, 45, 52 and 58) • NACI has no current recommendations to re-vaccinate people who have previously had Gardasil 4 or Cervarix

  16. Should mid-adult women receive the vaccine? • Risk of high risk HPV (hrHPV) decreases with age • There is a significant portion of mid-adult women (>25) with hrHPV infection, with a second peak of HPV infection in the 4th and 5th decades of life • Risk increases with lifetime number of sexual partners, number of male sexual partners, and number of male partners the met online • Immunosenescence - the natural physiological process in which the ability of the immune system declines with aging Meghan Plotnick, MSc1; Catherine Craig, MD. Should HPV Vaccination Be Offered to Mid-adult Women? J ObstetGynaecol Can 2017;39(5):361e365 https://doi.org/10.1016/j.jogc.2017.01.015

  17. Should mid-adult women receive the vaccine? • Four phase III clinical trials examined seroconversion for HPV-16 and HPV-18 in women >25. Seropositivity appears to last longer for HPV-16 than HPV-18, and longer if divalent vs quadrivalent vaccine is given. • Two clinical trials examined the efficacy of the HPV vaccine in preventing persistent HPV infection with HPV- 16 or HPV-18 in women older than 25 years • More research is needed for women >45 Meghan Plotnick, MSc1; Catherine Craig, MD. Should HPV Vaccination Be Offered to Mid-adult Women? J Obstet Gynaecol Can 2017;39(5):361e365 https://doi.org/10.1016/j.jogc.2017.01.015

  18. Effectiveness of HPV4 in Canada • Systematic review of studies published between 2006 and 2016 (publicly funded HPV4 immunization for girls was introduced in 2007-2009) • Prevalence of HPV types 6, 11, 16, and 18 was lower in qHPV-vaccinated than unvaccinated individuals (1.5% vs. 11.0%) • Risk of AGW incidence decreased by up to 45% • Incidence of CIN 2 + was reduced by up to 86% Steben M, et al. A Review of the Impact and Effectiveness of the Quadrivalent Human Papillomavirus Vaccine: 10 Years of Clinical Experience in Canada Obstet Gynaecol Can 2018;40(12):1635–1645

  19. HPV and cervical cancer screening

  20. Papanicolaou smears • George N. Papanicolaou, “father of cytology” • Also a PhD in zoology, studied cells from vaginal walls of guinea pigs • Discovered cancer cells from a vaginal sample of a hospital volunteer; presented findings at a meeting in 1928 • In 1939, worked with gynecologist and pathologist Herbert F Traut and gynecologist Andrew Marchetti to further develop the Pap test • All women admitted to the obs/gyne service at the New York Hospital routinely had a Pap test • Cancer could be diagnosed in asymptomatic women The History of Cervical Screening I: The Pap. Test. Patricia A. Shaw, JSocObstetGynaecol Can 2000;22(2): I I0-14

  21. Papanicolaou Smears • Initially the test consisted of collecting fluid from the vagina using a glass pipelle • Canadian J Ernest Ayre developed technique of taking a scraping of the cervix, with “Ayre’s spatula” • Paps were gradually adopted across Canada, started as a pilot project in BC in 1949, program was developed in Ontario in 1957 • Gradually incidence and mortality of cervical cancer decreased • Limitations: inadequate screening, false negatives, poor cervical sampling, and inappropriate follow up of abnormal smears The History of Cervical Screening I: The Pap. Test. Patricia A. Shaw, JSoc Obstet Gynaecol Can 2000;22(2): I I0-14

  22. When Pap Testing Fails to Prevent Cervix Cancer • Study recruited women <50 with locally advanced cervical cancer (LACC) • One-third of women presenting with LACC had appropriate Pap screening prior to diagnosis (13 out of 38) – invited for interview • Patients believe delays in their diagnosis resulted in detrimental quality of life • There is a need to educate physicians and the public about the symptoms of cervix cancer and to consider this diagnosis even when Pap screening has occurred Corkum M T, Shaddick H, Jewlal E, et al. (January 24, 2019) When Pap Testing Fails to Prevent Cervix Cancer: A Qualitative Study of the Experience of Screened Women Under 50 with Advanced Cervix Cancer in Canada. Cureus 11(1): e3950. DOI 10.7759/cureus.3950

  23. HPV testing in Screening Programs • For HPV to be considered for organized screening programs, it should have • Greater sensitivity than cytology for detecting existing high-grade cervical lesions • Reduced rates of high-grade lesions in subsequent screening rounds, because of detection and treatment of lesions that would have persisted in the absence of HPV testing • Demonstrated safety of extended screening intervals for HPV-negative patients Murphy, et al. HPV Testing in Primary Cervial Screening: A Systematic Review and Meta-Analysis. J ObstetGynaecol Can 2012;34(5):443–452

  24. HPV testing in screening programs • A systematic review and meta-analysis concluded that there is evidence from good quality RCTs supporting cervical cancer screening with HPV testing starting at age 30 or 35 • HPV testing provides a means of detecting clinically significant lesions earlier • CIN3+ rates are lower in the second screening round • 2 studies showed that the intervention groups (HPV testing) had lower rates of cervical cancer incidence and mortality over time • Lengthening of the screening interval in HPV negative women may be safe and feasible Murphy, et al. HPV Testing in Primary Cervial Screening: A Systematic Review and Meta-Analysis. J Obstet Gynaecol Can 2012;34(5):443–452

  25. HPV FOCAL trial • A publicly funded clinical trial conducted in BC • Comparing primary HPV testing with liquid-based cytology for cervical cancer screening • From 2008-2012, 19 009 women were randomized to the intervention (n = 9552) and control (n = 9457) groups • Intervention group: HPV testing; if results negative returned at 48 months • Control group: liquid-based cytology (LBC) testing; if negative returned at 24 months for LBC, if still negative then returned at 48 months • At 48-month exit, both groups received HPV and LBC co-testing Ogilvie, GS et al. Effect of Screening With Primary Cervical HPV Testing vs Cytology Testing on High-grade Cervical Intraepithelial Neoplasia at 48 Months: The HPV FOCAL Randomized Clinical Trial. JAMA. 2018 Jul 3;320(1):43-52. doi: 10.1001/jama.2018.7464.

  26. HPV Focal Trial • The primary outcome was the cumulative incidence of CIN3+ 48 months following randomization; cumulative incidence of CIN2+ was a secondary outcome • The CIN3+ incidence rate was 2.3/1000 (95% CI, 1.5-3.5) in the intervention group and 5.5/1000 (95% CI, 4.2-7.2) in the control group. The CIN3+ risk ratio was 0.42 (95% CI, 0.25-0.69).  • Baseline HPV-negative women had a significantly lower cumulative incidence of CIN3+ at 48 months than cytology-negative women (CIN3+ incidence rate, 1.4/1000 [95% CI, 0.8-2.4]; CIN3+ risk ratio, 0.25 [95% CI, 0.13-0.48]). • Among women undergoing cervical cancer screening, the use of primary HPV testing compared with cytology testing resulted in a significantly lower likelihood of CIN3+ at 48 months Ogilvie, GS et al. Effect of Screening With Primary Cervical HPV Testing vs Cytology Testing on High-grade Cervical Intraepithelial Neoplasia at 48 Months: The HPV FOCAL Randomized Clinical Trial. JAMA. 2018 Jul 3;320(1):43-52. doi: 10.1001/jama.2018.7464.

  27. HPV testing in Ontario • Currently in Ontario, HPV testing should only be considered as a triage following an atypical squamous cells of undetermined significance (ASCUS) result for women who are age 30 years and older  • HPV testing is not funded by OHIP • Cancer Care Ontario’s screening guidelines recommend that Ontario transition to primary HPV screening • Cancer Care Ontario is working with the MOHLTC to implement the HPV test as a primary tool for cervical cancer screening

  28. HPV testing in Ontario • Cervical Screening: Guideline Recommendations were released by Cancer Care Ontario in 2005, revised in 2011 – currently under review • Suggested changing to primary HPV screening in 2013 with interim guidelines which included recommendations for use of cytology • Evidence supports the use of HPV DNA testing of cervical cells as primary screening in women age 30 and over, with cytology only if HPV test is positive J. Murphy, E. Kennedy, S. Dunn, M. Fung Kee Fung, D. Gzik, C.M. McLachlin, M. Shier, and L. Paszat. Cervical Screening: Guideline Recommendations. A Quality Initiative of theProgram in Evidence-Based Care (PEBC), Cancer Care Ontario (CCO). Original Report Date: May 20, 2005 Current Report Date: October 5, 2011

  29. Summary of Screening recommendations from 2005-2013

  30. J. Murphy, E. Kennedy, S. Dunn, M. Fung Kee Fung, D. Gzik, C.M. McLachlin, M. Shier, and L. Paszat. Cervical Screening: Guideline Recommendations. A Quality Initiative of theProgram in Evidence-Based Care (PEBC), Cancer Care Ontario (CCO). Original Report Date: May 20, 2005 Current Report Date: October 5, 2011

  31. HPV testing in primary screening There is insufficient evidence to make a recommendation for the age at which HPV testing should be used as the primary screen HPV testing performs better for women age 30 and over The recommendation for HPV testing is applicable only in the context of an organized screening program with an adequate database infrastructure that allows for an invitation to screening at recommended intervals, and a follow-up of women with abnormal test results J. Murphy, E. Kennedy, S. Dunn, M. Fung Kee Fung, D. Gzik, C.M. McLachlin, M. Shier, and L. Paszat. Cervical Screening: Guideline Recommendations. A Quality Initiative of theProgram in Evidence-Based Care (PEBC), Cancer Care Ontario (CCO). Original Report Date: May 20, 2005 Current Report Date: October 5, 2011

  32. How to order HPV testing • HPV DNA testing of cervical cells, collected in same way as a pap smear • Detects the presence of 14 high risk HPV types, and specifically identifies HPV16 and HPV18 • Options to order HPV with pap, reflex HPV testing if pap result is ASCUS, HPV without pap • Not recommended in women less than 30 • Cost is $90

  33. Atypical squamous cells of undetermined significance  • ASCUS – if age <30, repeat in 6 m. if negative x 2, then back to routine screening. If repeat abnormal, refer to colposcopy • ASCUS – if 30 or older, offer HPV testing (private pay). If not testing for HPV, then same as above • ASCUS in women age 30 and older is the only time CCO recommends HPV testing – why? • 5-10% of women with ASCUS on their pap will have a high grade lesion • 31% to 60% of women with ASCUS are infected with high-risk HPV, DNA testing for these types has about 99% NPV Provencher D, Murphy K. The Role of HPV Testing. JOCG. 2007. www.jogc.com/article/S1701-2163(16)32576-2/fulltext

  34. When to refer to Colposcopy • ASCUS with positive HPV in women age 30 or older • If repeat pap after ASCUS or LSIL shows any abnormality • ASC-H, AGC, Atypical Endocervical Cells, Atypical Endometrial Cells, HSIL, Squamous Carcinoma, Adenocarcinoma, Other Malignant Neoplasms CCO. Cervical Prevention and Screening Map. https://www.cancercareontario.ca/sites/ccocancercare/files/assets/DPMCervicalPreventionandScreening.pdf

  35. Follow up after Colposcopy • Different pathways depending if HPV testing has been done or not • HPV reflex testing is only recommended for women 30 or older who have LSIL, ASCUS, or normal cytology • HPV exit test should only be done for women 30 or older • It is not recommended to continue to test for HPV test after 2 positive repeat tests

  36. Follow up after colposcopy – with HPV testing • Women 25 and older managed conservatively (no treatment) • Cytology normal, ASCUS or LSIL with -ve HPV – low risk, screen triennially • Cytology normal or ASCUS with +ve HPV at exit from colpo – elevated risk, screen annually in primary care Women treated for cervical dysplasia regardless of age • Cytology normal, ASCUS or LSIL with –ve HPV – low risk, screen trienially • Cytology normal, ASCUS or LSIL with +ve HPV – elevated risk, screen annually in primary care Cancer Care Ontario Clinical Guidance: Recommended Best Practices for Delivery of Colposcopy Services in Ontario. June 2016.

  37. Follow up after colposcopy – with HPV testing • Younger women ages 21-24 • Cytology is LSIL, ASCUS or normal – elevated risk, discharge to screen annually in the primary care setting Atypical Glandular Cells (AGC), Adenocarcincoma In Situ (AIS) regardless of age • Post treatment, they should be followed in the colposcopy clinic for at least 5 years • If all results are negative, they can then be discharged back to primary care for annual screening or have long term annual colposcopy follow up • The role of HPV testing in AIS is unclear as hrHPV is a necessary condition for AIS

  38. Follow up after Colposcopy – without HPV testing • Women 25 and older managed conservatively (no treatment) • If 3 consecutive negative colpo and cyto (initialycolpo visit and 2 follow up visits) – low risk, routine screening triennially • If 3 consecutive colpo negative and cyto is ASCUS or LSIL – elevated risk, screen annually in primary care Women treated for cervical dysplasia regardless of age • If 3 consecutive and colpo negative – low risk, routine screening triennially • If 3 consecutive colpo negative and cyto LSIL or ASCUS – elevated risk, screen annually in primary care

  39. HPV and ANAL Cancer

  40. HPV and Anal Cancer • Anal cancer is rare – 508 cases in Canada in 2010 • 80-90% are caused by HPV (strains 16 and 18) • 80% are squamous cell carcinoma of the anus • Most arise in the squamo-collumnar junction • Incidence in Canada is 1.7 per 100,000 person years • In people with HIV, 49-144 per 100,000 person years Medford, R. Salit, I. Anal cancer and intraepithelial neoplasia: epidemiology, screening and prevention of a sexually transmitted disease . CMAJ 2015. DOI:10.1503 /cmaj.140476

  41. HPV and ANAL cancer • More common in women (66.4%), but increasing in people with HIV infection, especially men who have sex with men (MSM) • Men and women with HIV, women with genital dysplasia or cancer, and recipients of solid-organ transplants are also at increased risk • San Francisco Men's Health Study (SFMHS) • Anal HPV DNA was detected in 93% of HIV-positive (regardless of CD4 count) and 61% of HIV-negative MSM • Rates of anal cancer among HIV-positive men are approximately 70 per 100 000 person years - higher than cervical cancer rates among women, even in areas of the world with the highest rates of cervical cancer Palefsky JM, Holly EA, Ralston ML, et al. Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men. J Infect Dis. 1998 02;177(2):361-7.

  42. HPV and ANAL Cancer • Premalignant changes are called anal intraepithelial lesions (AIN), which can be classified as LSIL or HSIL • Studies have suggested the rate of transformation from HSIL to anal cancer is about 5% • Screening for anal cancer and AIN is recommended for some patients, but there are no consensus guidelines in Canada Long, C, et al. Screening, Surveillance, and Treatment of Anal Intraepithelial Neoplasia. Clin Colon Rectal Surg. 2016 Mar; 29(1): 57–64.

  43. Screening for AIN and Anal Cancer • Digital anorectal exams • Anal pap smears • HPV testing • High resolution anoscopy

  44. Anal Cancer Screening Modalities Leeds, I. Fang, S. Anal cancer and intraepithelial neoplasia screening: A review. World J Gastrointest Surg. 2016 Jan 27; 8(1): 41–51.

  45. Screening for AIN and Anal Cancer • There is a lack of evidence that screening reduces rates of anal cancer or mortality, so there are no guidelines in this area • Anal cytology has not been shown to have any correlation with histology • There is lack of consensus on how abnormal results should be managed • The University of California San Francisco screening algorithm is the most widely disseminated • All high risk patients are screened annually with an anal pap smear • All atypical cytology results are referred for HRA Leeds, I. Fang, S. Anal cancer and intraepithelial neoplasia screening: A review. World J Gastrointest Surg. 2016 Jan 27; 8(1): 41–51.

  46. Recommendations – Cancer Care Ontario • CCO does not provide guidelines for screening for anal cancer in Ontario. • “Experts suggest that anal pap testing should be conducted only in areas where there is access to cytopathology expertise for interpretation of results and appropriate follow-up of abnormal results (i.e. high-resolution anoscopy).” E-mail correspondance from Cancer Care Ontario, Jan 30, 2019

  47. recommendations – Canadian Cancer Society • “Some health professionals now recommend routine anal cancer screening for HIV-positive and HIV-negative MSM, using an anal Pap test, similar to the Pap test done to detect cervical cell changes in women and trans men. Others refer MSM clients for High Resolution Anoscopy. • Studies show that annual screening of HIV-positive MSM and screening every 2-3 years for HIV-negative MSM provides benefits in both life expectancy and cost effectiveness.” Colon cancer screening guidelines for gay and bisexual men . Canadian Cancer Society http://convio.cancer.ca/site/PageServer?pagename=SSL_ON_HCP_HCPG_Colon#_Anal_Pap_test

  48. How to perform an Anal Pap • Avoid anal sex, douching, and the use of enemas for 24 hours prior to this procedure • Use a water-moistened Dacron swab to collect cells (prior to anoscopy or anal examination) • With the patient in left lateral position, gently insert the swab until it cannot be advanced further – it will be proximal to the anorectal transformation zone (squamocolumnar junction) • Withdraw the swab with lateral pressure using a spiral motion • Sample may be processed using the ThinPrep liquid cytology technique Colon cancer screening guidelines for gay and bisexual men Canadian Cancer Society http://convio.cancer.ca/site/PageServer?pagename=SSL_ON_HCP_HCPG_Colon#_Anal_Pap_test

  49. What should we do? • HIV positive MSM are recommended to have anal pap smears • HRA is not currently offered in London • Refer to the Immunodeficiency Clinic at Toronto General Hospital • For HSIL, symptoms, abnormal DRE or anoscopy in office – refer to colorectal surgeon

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