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Catching up on HPV-related cancers: diagnostic advances and treatment controversies Nittaya Phanuphak, MD, PhD Thai Red Cross AIDS Research Centre Bangkok, Thailand Outline • HPV – HIV – Cancers • Screening programs to prevent cervical cancer and anal cancer • Facts and challenges when making decision to screen/treat anal pre-cancerous lesions HPV – HIV – Cancers • HAART prolongs survival of PLHIV but may have incomplete immune recovery • Lack of decline or increased incidence of HPV-related cancers among PLHIV in the HAART era Palefsky JM 2011 Cervical cancer in HIV+ women SIR 8.9 for in situ cancer, 5.6 for invasive cancer Incidence per 100,000 PY 500 448.9 400 300 200 100 177.3 70.9 In situ Invasive 89 90.4 0 1980-1989 1990-1995 1996-2004 Chaturvedi AK, et al. J Natl Cancer Inst 2009;101:1120-30. Anal cancer in HIV+ men and women Incidence per 100,000 PY SIR Males - MSM Women 100 In situ 68.6 89.7 33.0 Invasive 34.6 51.8 14.5 100 MEN 80 80 60 60 40 20.7 20 0 10.5 42.3 40 29.5 20 18.3 1.7 1980-1989 1990-1995 1996-2004 Invasive 0 In situ WOMEN 0 5.2 11.2 5.2 0 1.7 1980-1989 1990-1995 1996-2004 Chaturvedi AK, et al. J Natl Cancer Inst 2009;101:1120-30. Oropharyngeal cancer in HIV+ men and women Incidence per 100,000 PY 50 40 SIR 1.6 30 Invasive 20 10 0 6.5 3.9 0 1980-1989 1990-1995 1996-2004 Chaturvedi AK, et al. J Natl Cancer Inst 2009;101:1120-30. HPV infection and dysplastic transformation Normal Low-grade squamous intraepithelial lesion (LSIL) High-grade squamous intraepithelial lesion (HSIL) Cancer Modified from Palefsky JM 2011 Screening program and prevention of cervical cancer • Rates of cervical cancer have declined in settings where screening programs have been implemented successfully – No RCT performed prior to widespread screening program – Observational studies confirmed risk of invasive cancer in women with high-grade cervical dysplasia • Screening programs remain difficult to implement in low and middle-income settings McCredie MR, et al. Lancet Oncol 2008; 9: 425–34. McIndoe WA, et al. Obstet Gynecol 1984;64:451-8. Screening program and prevention of anal cancer YES NO • More clinics now offer screening for anal HSIL among patients at “high risk” for anal cancer, as a strategy to prevent anal cancer, based on the etiological and pathological similarities to cervical cancer • More research is needed to understand the natural history of anal HSIL and to prove the efficacy and acceptability of its treatment Pria AD, et al. AIDS 2013; 27: 1185-6. Grulich AE, et al. Sex Health 2012;9:628-31. Cervical HPV and histologic HSIL among HIV+ women Prevalence (%) 100 80 SUN (US) THAILAND 100 83 Any HPV types 80 70 High-risk HPV types 60 All histologic SIL 40 16 20 Histologic HSIL 6 0 60 40 35 24 20 19 4 0 HPV infection HPV infection Histologic CIN SIL HPV infection HPV infection Cervical cancer rate in HIV+ women = 90 / 100,000 Histologic CIN SIL • Progression of CIN 3 to cervical cancer = 1 in 80 per year Kojic EM, et al. Sex Transm Dis 2011;38:253-9. Ramautarsing R, et al. 27th Int HPV Conf 2011, Berlin, P-32.33. Chaturvedi AK, et al. J Natl Cancer Inst 2009;101:1120-30. McCredie MR, et al. Lancet Oncol 2008;9:425-34. Anal HPV and histologic HSIL among HIV+ women Prevalence (%) 100 SUN (US) 90 85 100 THAILAND Any HPV types 80 80 High-risk HPV types 60 All histologic SIL 40 16 20 9 0 Histologic HSIL 60 40 20 14 9 0 HPV infection HPV infection Histologic AIN SIL HPV infection HPV infection Anal cancer rate in HIV+ women = 11 / 100,000 AIN • Anal SIL is as common as cervical SIL • More common in women with cervical, vulvar, vaginal high-grade diseases Hessol NA, et al. AIDS 2009;23:59-70. Chaithongwongwatthana S, et al. IGCS 2012. Chaturvedi AK, et al. J Natl Cancer Inst 2009;101:1120-30. Anal HPV and histologic HSIL among HIV+ and HIV- MSM Prevalence (%)(%) Prevalence 100 80 60 40 93 82 Meta-analysis CHINA Any HPV types 74 61 64 58 29 40 37 22 100 High-risk HPV types Any HPV types Histologic HSIL High-risk HPV types 80 Histologic HSIL 60 20 0 0 HIV-negative 85 59 58 37 40 20 HIV-positive THAILAND 19 HIV-positive 11 HIV-negative Anal cancer rate in HIV+ MSM = 78 / 100,000 and in HIV- MSM = 5 / 100,000 • Progression rate of anal HSIL to cancer (per year) – Theoretical: HIV+ MSM = 1 in 600, HIV- MSM = 1 in 4000 – Australia (73% HIV+ MSM): 1 in 80 Phanuphak N, et al. JAIDS 2013 (In press). Phanuphak N, et al. AIDS 2013 (In press). Hu Y, et al. JAIDS 2013 (In press). Tong WWY, et al. AIDS 2013 (In press). Machalek DA, et al. Lancet Oncol. May 2012;13(5):487-500. Anal HSIL screening • No standard screening guidelines • New York State Department of Health AIDS Institute • Screen at baseline and annually for HIV+: MSM, anogenital warts, abnormal vulvar/cervical histology New York State Department of Health AIDS Institute: www.hivguidelines.org Oct 2007. Palefsky JM 2011. Need for better biomarkers for screening • Anal cytology limitation – Low sensitivity and poor correlation with histologic grading • HRA limitation – Expensive and very limited number of trained physicians/nurses • Potential HGAIN biomarkers – – – – p16 and other cell cycle markers: immunocytochemistry E6/E7 mRNA: flow cytometry E6 oncoproteins: rapid test HPV DNA detection: screening test/genotyping assay Panther LA, et al. Clin Infect Dis. 2004;38:1490-1492. Biomarkers for anal HSIL Best for Best for prediction of detection disease of disease In the future at that visit Phanuphak N, et al. (Submitted) Treatment of anal HSIL • Various “in-office” treatment options are available • Side effects are not uncommon but manageable, some concerns about long-term sexual functioning • Treatment causes regression of lesions, although no prove that it will prevent anal cancer • Recurrence rate is substantial but usually is minimal • Better treatment modalities are needed Richel O, et al. Lancet Oncol 2012;14:346-53. Fox PA. Sex Health 2012;9:628-31. Treatment of anal cancer • Combination chemoradiation as the first-line therapy • In very selected cases, local excision may be used as primary treatment, often with chemoradiation • Salvage abdominoperineal resection for persistent or recurrent anal cancers Stage Localised (confined to 1ry site) 5-year survival (%) 79.0 Regional (spread to regional LN) Distant (metastasised) 58.5 29.6 Szmulowicz UM and Wu JS. Sex Health 2012;9:593-609. SEER 2011. Do I want to screen my patient? YES No • What do you want to screen for? • More research is needed on – Anal cancer: Digital ano-rectal exam – Anal HSIL: Cytology+/HSIL biomarkers and high-resolution anoscopy – Natural history of anal HSIL Do I want to treat anal HSIL in my patient? YES No • Use treatment modalities currently available • More research is needed on • Frequent follow-up • More research is needed on – Better treatment of anal HSIL – Natural history of anal HSIL – Anal cancer biomarkers – Better treatment of anal HSIL and its side effects Summary • HAART not reducing HPV-related cancers – Some cancers increasing • HIV+ men and women are more likely to have HSIL than HIV- men and women – High prevalence of anal HSIL in HIV+ MSM and women • Several challenges are there when considering screening programs for anal HSIL – Dependent on clinician’s interpretation of the data and readiness of the local health systems Acknowledgments Thai Red Cross AIDS Research Centre • • • • • • Nipat Teeratakulpisarn Praphan Phanuphak Tippawan Pankam Jiranuwat Barisri TRC Anonymous Clinic staff Our clinic clients & study participants Chulalongkorn University • • • • • HIV-NAT and SEARCH • • • • Jintanat Ananworanich Steve Kerr Cecilia Shikuma Reshmie Ramautarsing Srinakharinwirot University • Piamkamon Vacharotayangkul Somboon Keelawat Surang Triratanachat Surasith Chaithongwongwatthana Preecha Ruangvejvorachai Sarunya Numto UCSF • Joel Palefsky TREAT Asia • Annette Sohn The AIN Biomarker Study is funded by the US NIH, through a grant to amfAR for the International Epidemiologic Databases to Evaluate AIDS (IeDEA); NIAID/NCI/NICHD, UO1AI069907.