1. IAS–USA From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Slide 1 of 31 Non-AIDS-Defining Cancers in HIV Ronald T. Mitsuyasu, MD Professor of Medicine University of California Los Angeles Director, UCLA Center for Clinical AIDS Research and Education

2. Slide 2 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Age distribution of HIV-infected individuals living in the United States High K P et al. Clin Infect Dis. 2008;47:542-553 © 2008 by the Infectious Diseases Society of America

3. Slide 3 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Shiels M S et al. JNCI J Natl Cancer Inst 2011;103:753-762 Cancer Incidences in HIV in USA

4. Slide 4 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Non-AIDS-defining Cancers Emerging Epidemiologic Features 1991-19951996-2002 Proportion of Cancers in HIV NADC31%58% Standardized Incidence Ratio HIV: non-HIV Lung2.62.6 Hodgkin lymphoma 2.86.7 Larynx1.82.7 Anus109.1 Liver03.7 Engels EA, Int J Cancer. 2008;123:187-194

5. Slide 5 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Categorizing Cancers in PWHA AIDS-defining Cancer (decreasing)AIDS-defining Cancer (decreasing) –KS –NHL (BL, CNS, DLCBL) –Cervical Cancer (added in 1993) Non-AIDS-defining Cancers (increasing)Non-AIDS-defining Cancers (increasing) –Anal Cancer –Lung Cancer –Hodgkin Lymphoma –Liver Cancer Elevated but rareElevated but rare –Merkel Carcinoma –Leiomyosarcoma –Salivary gland LEC Unchanged IncidenceUnchanged Incidence –Breast –Colorectal –Prostate –Follicular lymphoma

6. Slide 6 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Shiels M S et al. JNCI J Natl Cancer Inst 2011;103:753-762 Published by Oxford University Press 2011. ADC number and incidence in AIDS in USA 1991-2005 Kaposi’s sarcoma NHL Cervical Cancer

7. Slide 7 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Selected NADC Number and Incidence in AIDS in USA 1991–2005 Shiels M S et al. JNCI J Natl Cancer Inst 2011;103:753-762 Anal Liver Prostate Lung Hodgkin’s Colorectal

8. Slide 8 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Factors Contributing to the Increase in Cancer Cases in HIV 4-fold increase in HIV/AIDS population Greater and earlier start to smoking in HIV Rising proportion of HIV pts > 50 yo Cancer incidence increases with age Increase in some CA incidence rate among HIV – –Lung (3X), anal (29X), liver (3X), HL (11X)

9. Slide 9 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Polesel et al, Infect Agents and Cancer 2010 5(Suppl 1):A78.

10. Slide 10 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Does HIV Cause Cancer to Occur at an Earlier Age? Is the Higher Incidence of Cancer in HIV a Reflection of Accelerated Aging?

11. Slide 11 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Shiels M S et al. Ann Intern Med 2010;153:452-460 Hypothetical Cancer Distribution in AIDS and General Population Cancer Risk higher, But same age distribution Cancer Risk higher, But younger age distribution

12. Slide 12 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Shiels M S et al. Ann Intern Med 2010;153:452-460 Prostate Breast Anal Hodgkin’s Colon Liver Lung Observed and Expected Cancer in HIV and General Population, 1996-2007

13. Slide 13 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. NADC Incidence and Mortality Retrospective survey of Kaiser Permanente, N. and S. California; 22,081 HIV+, 230,069 HIV- matched by age, sex, clinic and initial yr of F/U 5-yr survival for incident prostate, anal, lung, colorectal cancers or Hodgkin lymphoma. All cause mortality rates and mortality hazard ratios Earlier mean age at dx in HIV+ for anal, lung and colorectal, but not for prostate or HL HIV+ dx at higher stage for lung and HL HIV+ reduced survival for HL, lung and prostate, but not for anal and colorectal Silverberg M et al. 19 th CROI, Seattle, 2012, abs 903.

14. Slide 14 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. NADC Mortality HIV+ vs HIV- Hodgkin Lymphoma HR 3.0 (1.3-10.8) Lung 1.7 (1.3-2.2) Prostate 2.2 (1.2-4.3) Anal 1.7 (0.6-5.4) Colorectal 1.6 (0.8-3.1) Silverberg M et al. 19 th CROI, Seattle, 2012, abs 903.

15. Slide 15 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Pathogenesis of NADC Many are virally-induced cancers, but not allMany are virally-induced cancers, but not all Immune activation and decreased immune surveillanceImmune activation and decreased immune surveillance HIV may activate cellular genes or proto- oncogenes or inhibit tumor suppressor genesHIV may activate cellular genes or proto- oncogenes or inhibit tumor suppressor genes HIV induces genetic instability (eg 6 fold higher number of MA in HIV lung CA over non-HIV) 1HIV induces genetic instability (eg 6 fold higher number of MA in HIV lung CA over non-HIV) 1 Increase susceptibility to effects of carcinogensIncrease susceptibility to effects of carcinogens Endothelial abnormalities may allow for cancer developmentEndothelial abnormalities may allow for cancer development Population differences based on genetics and exposure to carcinogensPopulation differences based on genetics and exposure to carcinogens 1 Wistuba, AIDS 1999;13:415-26

16. Slide 16 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Cancers in HIV Disease AIDS-DefiningVirus Kaposi’s SarcomaHHV-8Kaposi’s SarcomaHHV-8 Non-Hodgkin’s Lymphoma EBV, HHV-8Non-Hodgkin’s Lymphoma EBV, HHV-8 (systemic and CNS) Invasive Cervical CarcinomaHPVInvasive Cervical CarcinomaHPV Non-AIDS Defining Anal CancerHPVAnal CancerHPV Hodgkin’s DiseaseEBVHodgkin’s DiseaseEBV Leiomyosarcoma (pediatric)EBVLeiomyosarcoma (pediatric)EBV Squamous Carcinoma(oral)HPVSquamous Carcinoma(oral)HPV Merkel cell CarcinomaMCVMerkel cell CarcinomaMCV Hepatoma HBV, HCVHepatoma HBV, HCV

17. Slide 17 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Incidence and Risk Factors for NADCs Among HIV-Infected Individuals Predictors in the multivariate analyses:Predictors in the multivariate analyses: –Older Age HR 1.99 per 10 yrs (CI 1.67, 2.36), p<0.001HR 1.99 per 10 yrs (CI 1.67, 2.36), p<0.001 –Caucasian/non-Hispanic Compared to AA, HR 1.56 (CI, 1.78, 1.22) p=0.02Compared to AA, HR 1.56 (CI, 1.78, 1.22) p=0.02 –HAART was protective for ADC but not NADC OR 0.21, p<0.001OR 0.21, p<0.001 –Lower most recent CD4 count –Smoking history; other lifestyle behaviors –History of Hepatitis B –Socioeconomic status and access to care Crum-Cianflone AIDS 2009, 23:41-50 Llibfre JM. Curr HIV Res 2009, 7;365-77 Reekie J, Cancer 2010, 116;5306-15

18. Slide 18 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Aging Phenotype Increase CD8+ CD28- cells Increase CD4+ CD28- cells Shorten telomeres Increased CD31- cells (esp on CD45RA+) Increased CD56+ CD57+ cells See this in both HIV+ individuals and elderly HIV- individuals Boucher et al., Exp. Gerontol. 33:267, 1998 Effros R et al., Aging and Infect Dis 47:542-53, 2008 Rickabaugh T et al., PLoS One 6:16459, 2011

19. Slide 19 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. ACS, NCI and USPSTF Cancer Screening Guidelines Cervical CA – begin within 3 yrs of 1 st intercourse or 21 yo and q 1-2 yrs. If 30-70 and 3 normal Paps q3 yrs Prostate CA – discuss with MD at 50. DRE yearly and individualized PSA testing Breast CA – clinical breast exam q 3 yr 20-30, yearly at 40, yearly mammogram start age 50 Colon CA – flex sig q 5yrs or colon q 10 yrs and FOBT yearly Others – periodic health exams after age 20, with health counseling and oral, skin, lymph nodes, testes, ovaries and thyroid exam Other tests based on family history, other known cancer risk exposures or known risk factors

20. Slide 20 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. HIV Patient Screening Routine screening for HIV patients seems to be done LESS frequently than age-appropriate SOC screening for breast (67% vs 79%) and colon (56% vs 77.8%) and prostate biopsies – –Preston-Martin. Prev Med 2002;31:316-92 – –Reinhold JP. Am J Gastroenterol 2005;100:1805-12 – –Hsiao W, Science World J 2009;9:102-8 Concerns about higher false positive rate in HIV (eg, NLST found reduction in lung cancer mortality (20%) in older cigarette smokers) but also high false positive rates, which may be true in HIV as well

21. Slide 21 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Lung Cancer Screening CT imaging for early detection of lung cancer is controversial (N Engl J Med. 2011 Aug 4;365(5):395-409), and HIV+ may be at greater risk of developing lung cancer VA Aging Cohort substudy – prospective Examination of HIV Associated Lung Emphysema (EXHALE) 2009-10, smokers, 145 HIV+ and 125 HIV- convenience sample, 86% smokers, single CT to determine rate of abnormal findings Sigel K et al. 19 th CROI, Seattle, 2012, abst 907

22. Slide 22 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Lung Cancer Screening CharacteristicHIV+ (n=145) % HIV- (n=126) % P- value Age, years (median)54420.1 Male98870.001 White/Black/Hispanic14/70/1720/64/160.41 Smoking: Current/former/never 65/21/1461/21/180.8 Pack Years (median)26230.2 COPD, emphysema or chronic bronchitis 18 0.9 CD4 count (median)425 Siegel K et al 19 th CROI, Seattle, 2012, abstr 907

23. Slide 23 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Lung Cancer Screening FindingsHIV+ (n=145) % HIV- (n=126) % p- value Nodules noted50460.6 Number nodules (median)870.4 Lymphadenopathy1570.06 Suspicious for cancer420.2 Emphysematous changes40300.07 Pleural effusion010.3 Ground glass infiltrates15140.9 Bronchiectasis660.8 Granulomas24180.2 Follow-up recommended*23290.3 Siegel K, et al, 19 th CROI, Seattle, 2012, abst 907. *4 Lung cancer diagnoses, 3 HIV+ and 1 HIV- p=0.4

24. Slide 24 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Why is anogenital cancer important? Cervical cancer is the most common cancer in women worldwide and anal cancer is as common in MSM (75/100,000) as cervical cancer in unscreened populations of women (50-150/100,000 person-yr) Anal cancer particularly common in HIV+ MSM Anal cancer occurs in women as well Anal cancer is one of several cancers whose incidence in the HAART era is increasing, not decreasing

25. Slide 25 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Increasing Incidence of Anal Squamous Cancer in US Nelson RA, et al. J Clin Oncol, March 18 2013 [Epub ahead print]

26. Slide 26 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Screening for cervical and anal dysplasia No national or international guideline for anal screening other than NYS DOH anal Pap screening guidelines, many recommend yearly cervical and anal PAP, with colposcopy or HRA and biopsy of any suspicious lesions and q 6m F/U for those with abnormalities noted Many cervical cancer screen and treat program now operating in resource-limited settings Chiao EY et al. Clin Infect Dis 2006;43:223-33. Goldie SJ et al. JAMA 1999;282:1822-9

27. Slide 27 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. AMC 052 Percentage of participants sero- and HPV DNA- negative to HPV 6/11/16/18 Percent HPV-negative N=104, Median age=44 HPV 660 HPV 1168 HPV 1662 HPV 1878 Wilkin et al. JID 2010, 202: 1246-53.

28. Slide 28 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. HPV 6 Month 7 (95% CI) HPV 11 Month 7 (95% CI) HPV 16 Month 7 (95% CI) HPV 18 Month 7 (95% CI) Merck 020 Men 16-26 yr 447 (447, 503) 624 (621, 684) 2402 (2485, 2767) 402 (416, 464) AMC 052 HIV+ MSM 357 (256, 497) 525 (412, 669) 1139 (849, 1529) 181 (136, 241) Geometric mean titers among participants naïve to HPV 6, 11, 16, 18 Data from VRBPAC Briefing Doc Sept 9, 2009 (Table 8) and from AMC 052, Wilkin JID 2010, 202:1246-53.

29. Slide 29 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Treatment of AIN in HIV+ 16 wk randomized trial of imiquimod (3 X/wk), topical 5FU (2 X/wk) vs electrocautery-EC (monthly X 4) in 148 HIV+ men with AIN (57% with HGAIN) Subjects evaluated by HRA and bx at 4 wk and 6 mos post treatment ITT RR imiquimod 57% (95%CI 27-52), 5FU 29% (95%CI 18-43), EC 48% (95%CI 31-62) ITT CR imiquimod 26% (95%CI 16-39), 5FU 17% (95%CI 8-3-), EC 41% (95%CI 28-56) p=.003 Relapse rate at 6 mos, 25%, 57%, 17% respectively (p=0.002) SAE rates 43%, 27%, 18% respectively (p=0.02) Richel O, et al. 19 th CROI, Seattle, 2012, abst 135LB

30. Slide 30 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Cancer Prevention Smoking Cessation – Highest priority – –Varenicline not hepatic met and no ART drug interaction expected Hepatitis B and HPV vaccination Treat active Hepatitis C Yearly cervical and anal (?) Paps – Gyn and HRA Advise sun screen and avoid overexposure Maintain high index of suspicion for cancer Complete family history for malignancies Breast, prostate and colon screening as per guidelines for general population Treat all HIV patients with HAART

31. Slide 31 of 31 From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Summary As HIV population ages with persistent immune abnormalities, cancers will increase in number The risk of NADC is high with lung, anal, liver and HL accounting for most of this increase. The risk of colon, breast and prostate cancers are lower in HIV. HL incidence is stable overall, but may reflect lack of younger age peak, as all cases in HIV are EBV+ As a minimum, we should conduct age/gender appropriate screening for cancer. Counsel patients on ways to reduce cancer risks Only through prospective clinical trials research can prevention strategies be effectively evaluated