aging and cancer in hiv - virology...

Presented at the 2nd Int. workshop on HIV & Aging, 27 – 28 Oct 2011, Baltimore, USA

Ronald Mitsuyasu, MD Professor of Medicine

Director, UCLA Center for Clinical AIDS Research and Education

Group Chairman, AIDS Malignancy Consortium (AMC)

Aging and Cancer in HIV


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


Number of people living with AIDS, AIDS-defining cancers, non-AIDS-defining cancers, and all cancers in the USA

during 1991–2005.

Shiels M S et al. JNCI J Natl Cancer Inst 2011;103:753-762


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;148:728-736


Cancer Incidence Rates by HAART Period

Crum-Cianflone AIDS 2009, 23:41-50.


Breakdown of causes of death: France 2005

Lewden JAIDS 2008, 48:590-9 0 5 10 15 20 25 30 35 40

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

Percent

N = 937 deaths

Hessamfar-Bonarek Int. J. Epid 2010;39:135-146


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


Non AIDS-defining Cancers Emerging Epidemiologic Features

1991-1995 1996-2002 Proportion of Cancers in HIV

NADC 31% 58% Standardized Incidence Ratio HIV:non-HIV

Lung 2.6 2.6 Hodgkin lymphoma 2.8 6.7

Larynx 1.8 2.7 Anus 10 9.1 Liver 0 3.7

Engels EA, Int J Cancer. 2008;123:187-194


Polesel et al, Infect Agents and Cancer 2010 5(Suppl 1):A78.


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

1Wistuba, AIDS 1999;13:415-26


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;365-77 Reekie J, Cancer 2010, 116;5306-15


Incidence and Risk of NADC in a Large Prospective Cohort

• Incidence of NADCs in 11,112 HIV+ patients seen at Chelsea-Westminster Hospital 1983-2007 – Pre-HAART (1983-1995) SIR 0.95 (CI 0.58-1.47) – Early HAART (1996-2001) SIR 2.05 (CI 1.51-2.72) – Established HAART (2002-2007) SIR 2.49 (CI 2.0-3.07)

• Increased risk in multivariate analyses associated with – Use of HAART HR 1.64 (CI 1.13-2.39) – Nadir CD4 <200 HR 1.67 (CI 1.10-2.54) – Use of NNRTI and HD HR 1.45 (CI 1.01-2.08)

Powles T et al. J Clin Onc 2009, 27:884-890


Higher rate of following cancers compared to general US population:

• Caucasians – Skin cancer

• Basal and squamous

– Melanoma

– Hodgkin’s

– Anal

• African Americans – Hodgkin’s

– Anal

– Lung

– Colorectal

Incidence and Risk Factors for NADCs Among HIV-Infected Individuals

Burgi et al, Cancer 2005; 104:1505-11


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 2.7 2.2 Leukaemia 3.2 2.4 Kidney 1.5 6.8 Oesophagus 1.6 3.1 Stomach 1.9 2.0

Meta-analysis: 444,172 people with HIV, 31,977 transplant patients

Grulich et al, Lancet 2007

HIV and risk of non-AIDS malignancies


Cancer burden of Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer among people living with AIDS in the United States during 1991–2005.


Published by Oxford University Press 2011.

ADC number and incidence in AIDS in USA 1991-2005

Kaposi’s sarcoma

NHL

Cervical Cancer


Selected NADC Number and Incidence in AIDS in USA 1991–2005


Anal

Liver

Prostate

Lung

Hodgkin’s

Colorectal


Prevalence of anal squamous intraepithelial lesions (ASIL) by age group.

Chin-Hong P V et al. JNCI J Natl Cancer Inst 2005;97:896-905

Prevalence of anal squamous intraepithelial lesions (ASIL) by age group


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


Does HIV Cause Cancer to Occur at an Earlier Age?

Is the Higher Incidence of Cancer in

HIV a Reflection of Accelerated Aging?


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 distristribution

Cancer Risk higher, But younger age distribution


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).

Shiels M S et al. Ann Intern Med 2010;153:452-460 ©2010 by American College of Physicians

Age Distribution in AIDS and General Populations


Age at cancer diagnosis among persons with AIDS and the general population in the United States, 1996–2007.Points represent cases of cancer observed among persons with AIDS.

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


Immune Responses

HIV And Aging


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


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 (?)


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


http://www3.niaid.nih.gov/


Thank You

• For information on AMC clinical trials see: http://www.aidscancer.org

• For information on NCI programs in HIV cancer see:

http://www.cancer.gov/cancertopics/types/AIDS

• To refer for AMC clinical trials in LA, call UCLA CARE Center 310-557-1891 or page Dr. Mitsuyasu or Dr. Reddy

aging and cancer in hiv - virology...

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