IAS–USA From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Slide 1 of 31...

IAS–USAFrom 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, MDProfessor of Medicine

University of California Los AngelesDirector, UCLA Center for Clinical AIDS Research

and Education

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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

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

Cancer Incidences in HIV in USA

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Non-AIDS-defining CancersEmerging 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 3.7Engels EA, Int J Cancer. 2008;123:187-194

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Categorizing Cancers in PWHA• AIDS-defining

Cancer (decreasing)– KS– NHL (BL, CNS, DLCBL)– Cervical Cancer

(added in 1993)

• Non-AIDS-defining Cancers (increasing)– Anal Cancer– Lung Cancer– Hodgkin Lymphoma– Liver Cancer

• Elevated but rare– Merkel Carcinoma– Leiomyosarcoma– Salivary gland LEC

• Unchanged Incidence– Breast– Colorectal– Prostate– Follicular lymphoma

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Shiels M S et al. JNCI J Natl Cancer Inst 2011;103:753-762Published by Oxford University Press 2011.

ADC number and incidence in AIDS in USA 1991-2005

Kaposi’s sarcoma

NHL

Cervical Cancer

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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

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Factors Contributing to the Increasein 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)

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Does HIV Cause Cancer to Occur at an Earlier Age?

Is the Higher Incidence of Cancer inHIV a Reflection of Accelerated Aging?

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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

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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

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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 colorectalSilverberg M et al. 19th CROI, Seattle, 2012, abs 903.

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NADC Mortality HIV+ vs HIV-

Hodgkin LymphomaHR 3.0 (1.3-10.8)

Lung1.7 (1.3-2.2)

Prostate2.2 (1.2-4.3)

Anal1.7 (0.6-5.4)

Colorectal1.6 (0.8-3.1)

Silverberg M et al. 19th CROI, Seattle, 2012, abs 903.

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Pathogenesis of NADC• Many 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 (eg 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

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Cancers in HIV DiseaseAIDS-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

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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; other lifestyle behaviors– History of Hepatitis B– Socioeconomic status and access to care

Crum-Cianflone AIDS 2009, 23:41-50Llibfre JM. Curr HIV Res 2009, 7;365-77Reekie J, Cancer 2010, 116;5306-15

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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- individualsBoucher et al., Exp. Gerontol. 33:267, 1998Effros R et al., Aging and Infect Dis 47:542-53, 2008Rickabaugh T et al., PLoS One 6:16459, 2011

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ACS, NCI and USPSTF Cancer Screening Guidelines

• Cervical CA – begin within 3 yrs of 1st 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

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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

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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. 19th CROI, Seattle, 2012, abst 907

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Lung Cancer ScreeningCharacteristic HIV+

(n=145) %HIV-

(n=126) %P-

value

Age, years (median) 54 42 0.1

Male 98 87 0.001

White/Black/Hispanic 14/70/17 20/64/16 0.41

Smoking: Current/former/never

65/21/14 61/21/18 0.8

Pack Years (median) 26 23 0.2

COPD, emphysema or chronic bronchitis

18 18 0.9

CD4 count (median) 425

Siegel K et al 19th CROI, Seattle, 2012, abstr 907

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Lung Cancer ScreeningFindings HIV+

(n=145) %HIV-

(n=126) %p- value

Nodules noted 50 46 0.6

Number nodules (median) 8 7 0.4

Lymphadenopathy 15 7 0.06

Suspicious for cancer 4 2 0.2

Emphysematous changes 40 30 0.07

Pleural effusion 0 1 0.3

Ground glass infiltrates 15 14 0.9

Bronchiectasis 6 6 0.8

Granulomas 24 18 0.2

Follow-up recommended* 23 29 0.3

Siegel K, et al, 19th CROI, Seattle, 2012, abst 907.*4 Lung cancer diagnoses, 3 HIV+ and 1 HIV- p=0.4

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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

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Increasing Incidence of Anal Squamous Cancer in US

Nelson RA, et al. J Clin Oncol, March 18 2013 [Epub ahead print]

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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

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AMC 052Percentage of participants sero- and HPV DNA-

negative to HPV 6/11/16/18

Percent HPV-negative

N=104, Median age=44

HPV 6 60

HPV 11 68

HPV 16 62

HPV 18 78

Wilkin et al. JID 2010, 202: 1246-53.

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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 020Men 16-26 yr

447(447, 503)

624(621, 684)

2402(2485, 2767)

402(416, 464)

AMC 052HIV+ 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.

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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. 19th CROI, Seattle, 2012, abst 135LB

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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

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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

IAS–USA From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA. Slide 1 of 31...

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