Aging and Cancer in HIV

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1 Aging and Cancer in HIV Ronald Mitsuyasu, MD Professor of Medicine Director, UCLA Center for Clinical AIDS Research and Education Group Chairman, AIDS Malignancy Consortium (AMC)

2 Age distribution of HIV-infected individuals living in the United States 2008 by the Infectious Diseases Society of America High K P et al. Clin Infect Dis. 2008;47:

3 Number of people living with AIDS, AIDS-defining cancers, non-aids-defining cancers, and all cancers in the USA during Shiels M S et al. JNCI J Natl Cancer Inst 2011;103:

4 Change in Incidence of Cancers in HIV in the HAART Era in USA Kaposi s sarcoma CNS Lymphoma Lymphoma (NHL) Lymphoma (HD) Cervical Cancer Anal Cancer Lung Cancer Prostate Breast Colon Patel P et al, Ann Intern Med 2008;148:

5 Cancer Incidence Rates by HAART Period Crum-Cianflone AIDS 2009, 23:41-50.

6 Breakdown of causes of death: France 2005 AIDS Cancer Hepatitis C CVD Suicide Non-AIDS infection Accident Hepatitis B Liver disease OD / drug abuse neurologic renal pulmonary digestive iatrogenic metabolic psychiatric other unknown N = 937 deaths Hessamfar-Bonarek Int. J. Epid 2010;39: Percent Lewden JAIDS 2008, 48:590-9

7 Cancers in HIV Disease AIDS-Defining Virus Kaposi s Sarcoma HHV-8 Non-Hodgkin s Lymphoma EBV, HHV-8 (systemic and CNS) Invasive Cervical Carcinoma HPV Non-AIDS Defining Anal Cancer HPV Hodgkin s Disease EBV Leiomyosarcoma (pediatric) EBV Squamous Carcinoma (oral) HPV Merkel cell Carcinoma MCV Hepatoma HBV, HCV

8 Non AIDS-defining Cancers Emerging Epidemiologic Features Proportion of Cancers in HIV NADC 31% 58% Standardized Incidence Ratio HIV:non-HIV Lung Hodgkin lymphoma Larynx Anus Liver Engels EA, Int J Cancer. 2008;123:

9 Polesel et al, Infect Agents and Cancer (Suppl 1):A78.

10 Pathogenesis of NADC Some are virally-induced cancers, but not all Immune activation and decreased immune surveillance HIV may activate cellular genes or proto-oncogenes or inhibit tumor suppressor genes HIV induces genetic instability (e.g 6 fold higher number of MA in HIV lung CA over non-hiv) 1 Increase susceptibility to effects of carcinogens Endothelial abnormalities may allow for cancer development Population differences based on genetics and exposure to carcinogens 1 Wistuba, AIDS 1999;13:415-26

11 Incidence and Risk Factors for NADCs Among HIV-Infected Individuals Predictors in the multivariate analyses: Older Age HR 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=0.02 HAART was protective for ADC but not NADC OR 0.21, p<0.001 Lower most recent CD4 count Smoking history History of Hepatitis B Crum-Cianflone AIDS 2009, 23:41-50 Llibfre JM. Curr HIV Res 2009, 7; Reekie J, Cancer 2010, 116;

12 Incidence and Risk of NADC in a Large Prospective Cohort Incidence of NADCs in 11,112 HIV+ patients seen at Chelsea-Westminster Hospital Pre-HAART ( ) SIR 0.95 (CI ) Early HAART ( ) SIR 2.05 (CI ) Established HAART ( ) SIR 2.49 (CI ) Increased risk in multivariate analyses associated with Use of HAART HR 1.64 (CI ) Nadir CD4 <200 HR 1.67 (CI ) Use of NNRTI and HD HR 1.45 (CI ) Powles T et al. J Clin Onc 2009, 27:

13 Incidence and Risk Factors for NADCs Among HIV-Infected Individuals Higher rate of following cancers compared to general US population: Caucasians African Americans Skin cancer Hodgkin s Basal and squamous Melanoma Hodgkin s Anal Anal Lung Colorectal Burgi et al, Cancer 2005; 104:

14 HIV and risk of non-aids malignancies Meta-analysis: 444,172 people with HIV, 31,977 transplant patients For 20 / 28 cancers examined there was significantly increased incidence in both groups strongly suggesting a link with immunodeficiency Standardized Incidence Ratio HIV/AIDS Transplant Lung Leukaemia Kidney Oesophagus Stomach Grulich et al, Lancet 2007

15 ADC number and incidence in AIDS in USA Cancer burden of Kaposi sarcoma, non-hodgkin lymphoma, and cervical cancer among people living with AIDS in the United States during Kaposi s sarcoma NHL Cervical Cancer Shiels M S et al. JNCI J Natl Cancer Inst 2011;103: Published by Oxford University Press 2011.

16 Selected NADC Number and Incidence in AIDS in USA Anal Lung Liver Hodgkin s Prostate Colorectal Shiels M S et al. JNCI J Natl Cancer Inst 2011;103:

17 Prevalence of anal squamous intraepithelial lesions (ASIL) by age group. Prevalence of anal squamous intraepithelial lesions (ASIL) by age group Chin-Hong P V et al. JNCI J Natl Cancer Inst 2005;97:

18 Factors Contributing to the Increase in Cancer cases in HIV 4-fold increase in HIV/AIDS Population Rising proportion of HIV pts > 40 yo Cancer incidence increases with age Increase in some CA incidence rate among HIV Lung (3X), anal (29X), liver (3X), HL (11X) Greater and earlier start to smoking in HIV

19 Does HIV Cause Cancer to Occur at an Earlier Age? Is the Higher Incidence of Cancer in HIV a Reflection of Accelerated Aging?

20 Hypothetical Cancer Distribution in AIDS and General Population Cancer Risk higher, But same age distristribution Cancer Risk higher, But younger age distribution Shiels M S et al. Ann Intern Med 2010;153:

21 Age Distribution in AIDS and General Populations Age distribution in the AIDS and general populations.follow-up time at risk for cancer in both the AIDS and general populations, by age, for regions covered by the HIV/AIDS Cancer Match Study (1996 to 2007) by American College of Physicians Shiels M S et al. Ann Intern Med 2010;153:

22 Observed and Expected Cancer in HIV and General Population, Age at cancer diagnosis among persons with AIDS and the general population in the United States, Points represent cases of cancer observed among persons with AIDS. Prostate Colon Breast Liver Anal Lung Hodgkin s Shiels M S et al. Ann Intern Med 2010;153:

23 Immune Responses HIV And Aging

24 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

25 Cancer Prevention Smoking Cessation Highest priority Hepatitis and HPV vaccination Yearly cervical and anal Paps Gyn and HRA Maintain high index of suspicion for cancer Breast, colon, prostate (PSA?) exam as per guidelines Advise sun screen and avoid overexposure Screen and if Hepatitis B or C positive, follow LFTs, VLs and perhaps AFP periodically Treat all HIV patients with HAART (?)

26 Conclusions As HIV population ages with persistent immune abnormalities, cancers will increase in number The risk of cancer remains high for ADC and NADC with lung, anal, liver and HL accounting for most of this increase. Compared to the general population the risk of colon, breast and prostate cancers are lower in HIV (just not old enough yet or HIV protective effect?) HL incidence is stable overall, but may reflected lack of younger age peak as all cases in HIV are EBV+ Suggests that we need to make prevention of cancer and better treatment for cancers in HIV a higher priority

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28 Thank You For information on AMC clinical trials see: For information on NCI programs in HIV cancer see: To refer for AMC clinical trials in LA, call UCLA CARE Center or page Dr. Mitsuyasu or Dr. Reddy