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
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
IAS–USA
Slide 2 of 31
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;47:542-553
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 3 of 31
Cancer Incidences in HIV in USA
Shiels M S et al. JNCI J Natl Cancer Inst 2011;103:753-762
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 4 of 31
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
Anus
1.8
10
2.7
9.1
0
3.7
Liver
Engels EA, Int J Cancer. 2008;123:187-194
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 5 of 31
Categorizing Cancers in PWHA
• AIDS-defining
• Non-AIDS-defining
Cancer (decreasing)
Cancers (increasing)
– KS
– NHL (BL, CNS, DLCBL)
– Cervical Cancer
(added in 1993)
• Elevated but rare
– Merkel Carcinoma
– Leiomyosarcoma
– Salivary gland LEC
–
–
–
–
Anal Cancer
Lung Cancer
Hodgkin Lymphoma
Liver Cancer
• Unchanged Incidence
–
–
–
–
Breast
Colorectal
Prostate
Follicular lymphoma
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 6 of 31
ADC number and incidence
in AIDS in USA 1991-2005
Kaposi’s sarcoma
NHL
Cervical Cancer
Published by Oxford University Press 2011.
Shiels M S et al. JNCI J Natl Cancer Inst 2011;103:753-762
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 7 of 31
Selected NADC Number and Incidence in AIDS in USA 1991–2005
Anal
Lung
Liver
Hodgkin’s
Prostate
Colorectal
Shiels M S et al. JNCI J Natl Cancer Inst 2011;103:753-762
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 8 of 31
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)
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 10 of 31
Does HIV Cause Cancer to Occur at an
Earlier Age?
Is the Higher Incidence of Cancer in
HIV a Reflection of Accelerated Aging?
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Hypothetical Cancer Distribution in AIDS
and General Population
Slide 11 of 31
Cancer Risk higher,
But same age distribution
Cancer Risk higher,
But younger age distribution
Shiels M S et al. Ann Intern Med 2010;153:452-460
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Observed and Expected Cancer in HIV and General Population, 1996-2007 Slide 12 of 31
Colon
Prostate
Liver
Breast
Anal
Lung
Hodgkin’s
Shiels M S et al. Ann Intern Med 2010;153:452-460
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 13 of 31
NADC Incidence and Mortality
• Retrospective survey of Kaiser Permanente, N.
and S. California; 22,081 HIV+, 230,069 HIVmatched 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. 19th CROI, Seattle, 2012, abs 903.
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 14 of 31
NADC Mortality HIV+ vs HIV-
Hodgkin Lymphoma
HR 3.0 (1.3-10.8)
Anal
1.7 (0.6-5.4)
Lung
1.7 (1.3-2.2)
Prostate
2.2 (1.2-4.3)
Colorectal
1.6 (0.8-3.1)
Silverberg M et al. 19th CROI, Seattle, 2012, abs 903.
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 15 of 31
Pathogenesis of NADC
• Many are virally-induced cancers, but not all
• Immune activation and decreased immune
surveillance
• HIV may activate cellular genes or protooncogenes 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
Wistuba, AIDS 1999;13:415-26
1
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 16 of 31
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
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 17 of 31
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, 23:41-50
Llibfre JM. Curr HIV Res 2009, 7;365-77
Reekie J, Cancer 2010, 116;5306-15
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 18 of 31
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
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 19 of 31
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
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 20 of 31
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
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 21 of 31
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
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 22 of 31
Lung Cancer Screening
Characteristic
HIV+
HIVP(n=145) % (n=126) % 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
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Lung Cancer Screening
Findings
HIV+
(n=145) %
HIV(n=126) %
Slide 23 of 31
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
*4 Lung cancer diagnoses, 3 HIV+ and 1 HIV- p=0.4
Siegel K, et al, 19th CROI, Seattle, 2012, abst 907.
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 24 of 31
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
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 25 of 31
Increasing Incidence of Anal
Squamous Cancer in US
Nelson RA, et al. J Clin Oncol, March 18 2013 [Epub ahead print]
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 26 of 31
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
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 27 of 31
AMC 052
Percentage of participants sero- and HPV DNAnegative 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.
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 28 of 31
Geometric mean titers among participants
naïve to HPV 6, 11, 16, 18
HPV 6
HPV 11
HPV 16
HPV 18
Month 7
(95% CI)
Month 7
(95% CI)
Month 7
(95% CI)
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)
Data from VRBPAC Briefing Doc Sept 9, 2009 (Table 8) and from AMC 052, Wilkin JID 2010, 202:1246-53.
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 29 of 31
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
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 30 of 31
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
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.
Slide 31 of 31
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
From RT Mitsuyasu, MD, at San Francisco, CA: March 29, 2013, IAS-USA.