Ronald Mitsuyasu, MD

1
Cancers in HIVA Growing Problem

• Ronald Mitsuyasu, MD
• Professor of Medicine
• Director, UCLA Center for Clinical AIDS Research
  and Education
• Group Chairman,
• AIDS Malignancy Consortium (AMC)

2
AIDS Defining Cancers

• Kaposis sarcoma
• B-cell non-Hodgkins lymphoma
• Primary CNS lymphoma
• Cervical cancer

3
Number of people living with AIDS, AIDS-defining
cancers, non-AIDS-defining cancers, and all
cancers in the USA during 19912005.
Cancer Incidences in HIV in USA
Shiels M S et al. J Natl Cancer Inst
2011103753-762
4
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 risk but rare
• Merkel Carcinoma
• Leiomyosarcoma
• Conjunctival cancer
• Salivary gland LEC

• Unchanged risk
• Breast
• Colorectal
• Prostate
• Follicular lymphoma

5
Cancer is the One of the Most Frequent Causes of
Death in HIV-Infected Patients
Cause of Death 2000 2005
Cancer (all) 29 34
Cancer - AIDS defining 16 13
Cancer - Non-AIDS defining 13 21
Hepatitis (non cancer) 14 12
Other infections 7 4
Mortalité 2000 and 2005 studies Bonnet et al.,
Cancer 101 3172004 and CID 48633 2009.
6
7 Notable Cancers in HIV
Cancer Relative Risk in U.S. people with AIDS vs. general pop (SIR 1990-1995) Estimated cases/yr in US based on 2004-7 HIV/Cancer Match Registry data Etiologic agents Relationship with immune suppression (CD4 or AIDS)
Kaposi sarcoma 22,100 735 KSHV
Non-Hodgkin lymphoma 53 1146 EBV
Cervical cancer 4.2 85 HPV
Lung cancer 3.3 324 Tobacco
Hodgkin lymphoma 13.6 174 EBV
Anal cancer 20.7 226 HPV
Liver cancer 4.0 90 HCV, HBV, alcohol
Refs Engels AIDS 2006, Biggar JNCI 2007, Engels
Int J Cancer 2008, Chaturvedi JNCI 2009,
Guiguet Lancet Oncol 2009
7
Cancers in HIV Disease

• AIDS-Defining Virus
• Kaposis Sarcoma HHV-8
• Non-Hodgkins Lymphoma EBV, HHV-8
• (systemic and CNS)
• Invasive Cervical Carcinoma HPV
• Non-AIDS Defining
• Anal Cancer HPV
• Hodgkins Disease EBV
• Leiomyosarcoma (pediatric) EBV
• Squamous Carcinoma (oral) HPV
• Merkel cell Carcinoma MCV
• Hepatoma HBV, HCV

8
HIV-Cancers Overview

• Non-AIDS defining malignancies
• Anogenital neoplasia
• Lymphomas
• Kaposis Sarcoma
• Cancer Prevention

9
Non-AIDS Defining CancersNADC
10
While ART Reduced the Incidence of ADCs, the Rate
of NADCs Did Not Decrease During the ART Era
NADCs
ADCs
Crude Incidence Rates of Cancer Among 20,775
HIV-Positive Patients Enrolled in Kaiser
Permanente California (1996-2008), by ART Use
Status
11
Non AIDS-defining CancersEmerging Epidemiologic
Features
1991-1995 1996-2002
Proportion of Cancers in HIV Proportion of Cancers in HIV
NADC 31 58
Standardized Incidence Ratio Standardized Incidence Ratio
Lung 2.6 2.6
Hodgkin lymphoma 2.8 6.7
Larynx 1.8 2.7
Pancreas 0.8 2.5
Liver 0 3.7
Engels EA, Int J Cancer. 2008123187-194
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Factors Contributing to the Increasein Cancer
cases in HIV

• 4-fold increase in HIV/AIDS Population
• Patients living longer and not dying of OI
• Rising proportion of HIV pts gt 50 yo
• Cancer incidence increases with age
• Greater and earlier start to smoking in HIV
• Increase in some CA incidence rate among HIV
• Lung (3X), anal (29X), liver (3X), HL (13X)
• Suggests may be additional risk from HIV

13
Pathogenesis of Cancer in HIV

• Many are virally-induced cancers, but not all
• Immune activation, immune dysregulation,
  inflammation 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/epithelial cell abnormalities induced
  or facilitated by HIV may allow for cancer
  development
• Population differences based on genetics and
  exposure to carcinogens

Wistuba Il, Pathogenesis of NADC a review. AIDS
Pt Care 199913415-26
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Outcomes of cancer in HIV

• With prolonged survival of HIV population and
  aging, more people will develop cancer,
  especially NADCs.
• HIV-infected cancer patients may have worse
  outcomes in some cancers
• Late presentation, advanced stage
• Poor access to care
• Medical comorbidity, treatment toxicity
• Unclear if HIV has adverse impact on cancer
  behavior, immune control, cancer-free survival
• Limited data for guiding cancer treatment in
  HIV-infected people

Biggar JAIDS 2005, Little J Clin Oncol 2008,
Rengan Lancet Oncol 2012, Suneja AIDS 2013
15
The Incidence of Lung Cancer Is Higher in
HIV-Positive Patients
Estimated Incidences of Lung Cancer Among 5053
HIV-Positive Patients and 50,530 Population
Controls (Danish HIV Cohort Study 1995-2009)
HIV-Positive Patients
Cumulative Incidence ofLung Cancer,
Population Controls
14
10
12
8
6
4
2
0
Time After Index Date, Years
Engsig FN, et al. BMC Cancer. 2011111-10.
16
HIV-Positive Patients With Lung Cancer Have an
Increased Mortality Rate
Survival After Diagnosis of Lung Cancer Among
5053 HIV-Positive Patients and 50,530 Population
Controls (Danish HIV Cohort Study 1995-2009)
Subjects Surviving After Diagnosis,
Population Controls
HIV-Positive Patients
Years After Diagnosis of Cancer
Engsig FN, et al. BMC Cancer. 2011111-10.
17
Contribution of Smoking to Lung CA

• Prevalence of smoking among people with HIV ---
  estimated to be higher than among the general US
  population
• New England clinics More than 70 of HIV smoke
• Overall US smoking prevalence 20
• Swiss HIV Cohort Study
• 72 are current/former smokers
• 96 among IDUs
• Overall Danish smoking prevalence 30

Niaura R et al. Smoking among HIV-positive
persons. Ann Behav Med 1999 21(Suppl)S116 Cliffo
rd, GM et al. Cancer risk in the Swiss HIV Cohort
Study J Natl Cancer Inst 200597425-432
18
Anogenital Cancers
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Why is anogenital cancer important?

• Cervical cancer is the most common cancer in
  women worldwide
• Anal cancer is as common in MSM (137/100,000) as
  cervical cancer is 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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Cervical cancer in HIV

• Cervical cancer caused by HPV
• Low CD4 count associated with
• ? HPV persistence
• ? HPV clearance
• ? incidence cervical cancer precursor lesions
• No decline with introduction of cART
• Immunosuppression may affect only early steps in
  carcinogenesis.

Sources Strickler JNCI 2005, Engels AIDS 2006,
Biggar JNCI 2007,
21
Relative risk of anal cancer in U.S.A.
AIDS-cancer registry match study(compared to
HIV-)
Frisch et al, JNCI, 2000921500-1510.
22
Prevalence of anal HPV detection among
MSMPopulation-based data
Prevalence,
HIV-seropositiveparticipants
HIV-negativeparticipants
All participants
Chin-Hong et al. Ann Int Med. 2008149300-6.
22
23
Spectrum of HPV disease
24
Anal anatomy
Ryan DP et al. New Engl J Med. 2000342792-800.
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Screening for cervical and anal dysplasia

• Many HIV groups recommend yearly cervical Paps
  with colposcopy 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 (VIA, Pap,
  ?HPV testing)
• No USA national or international guideline for
  anal screening other than NYS DOH anal Pap
  screening guidelines, but no guidance on what to
  do if positive

Chiao EY et al. Clin Infect Dis
200643223-33 Goldie SJ et al. JAMA
19992821822-9
26
Screen gt17,385
Enroll 5,085
Active Monitoring
Treatment
Retain for 5 years
Estimate lt50develop cancer
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Lymphomas
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Pathology of AIDS-RelatedNon-Hodgkins Lymphoma

• Small noncleaved-cell lymphoma
• Burkitts lymphoma and Burkitt-like lymphoma
• Immunoblastic lymphoma (primary CNS)
• Diffuse large-cell lymphoma (90 CD20)
• Large noncleaved-cell lymphoma
• CD30 anaplastic large B-cell lymphoma
• Plasmablastic lymphoma
• Advanced stage (gt75 III or IV)
• Extranodal involvement
• Central nervous system, liver, bone marrow,
  gastrointestinal

Tirelli U, et al. AIDS. 2000141675-1688.
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EBV-positive tumors
Burkitts lymphoma
Nasopharyngeal carcinoma
30
AIDS-related Lymphoma Experience Suggests Cancer
Treatment Outcome Can be Equivalent to General
Population
Besson et al. Blood. 2001 98 2339-2344 Little
et al Blood. 2003 101 4653-4659
31
Hodgkins Disease

• Association with HIV-infection
• Hodgkins disease RR 5 to 30
• Non-Hodgkins disease RR 24 to 165
• Incidence increasing rapidly in post HAART era
• gt95 are EBV
• Patients with HIV present with
• B symptoms (70 to 96), worse histology,
  higher-stage tumor (74 to 92 are III or IV),
  bone marrow involvement (40 to 50),
  pancytopenia
• Good response to MOPP/ABV
• Complete response 74.5
• 2-year disease-free survival 62 but more
  relapses in HIV
• Early good results with Stanford V, BEACOPP and
  brentuximab vendotin

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Kaposis Sarcoma
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Kaposis Sarcoma

• One of the first recognized AIDS-defining
  illnesses
• Vascular tumor that may involve mucocutaneous,
  lymphatic, gastrointestinal, and pulmonary sites
• Human herpesvirus-8 (HHV8) or KSHV
• HHV8
• DNA virus found in both HIV and HIV- KS.
• Tropism for B cells and endothelial cells, high
  titers in saliva
• Also associated with primary effusion lymphoma,
  Castlemans disease, and angioimmunoblastic
  lymphadenopathy in HIV
• Genome codes for viral homologs of human proteins
  involved in cell cycle regulation and signaling
• HIV- and Kaposis sarcoma-induced angiogenic and
  inflammatory cytokines also stimulate Kaposis
  sarcoma cell growth

34
AIDS-associated Kaposis Sarcoma

• Transmission
• Mostly MSM in US
• IVDU and Heterosexual as well
• Resource limited setting Africa and S. America
• KS still most common cancer in HIV
• Prevalence
• 1300 cases/100,000 persons/yr 1992
• 170 cases/100,000 persons/yr 2006
• Decline of 10 / year
• Cause of considerable morbidity and mortality in
  Africa and Latin America

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Clinical Manifestations

• Mucocutaneous, macular or nodular, dark color
• Lymphadenopathy
• Visceral
• Often asymptomatic
• Mouth, esophagus, stomach, bowel, liver, spleen
• Pulmonary KS
• Rapidly fatal
• Dyspnea without fever, hemoptysis
• Diffuse reticulo-nodular infiltrates, mediastinal
  enlargement, pleural effusions
• Edema, can be extensive and symptomatic

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Kaposis Sarcoma
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Oral Kaposis Sarcoma
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KS in Africa A Different Disease?
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Pulmonary KS on CXR CT Scan
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Treatments for Kaposis Sarcoma
Local1
Systemic1,2

• Radiation therapy
• Photodynamic (laser) therapy
• Cryotherapy
• Alitretinoin gel 9-cis retinoic acid (topical)

• Antiretroviral therapy
• Liposomal anthracyclines
• Paclitaxel
• Bleomycin
• Vinca alkaloids
• Gemcitabine
• Alpha Interferon

1Levine AM, et al. Eur J Cancer.
2001371288-1295. 2Mitsuyasu RT, et al. Cancer
Management. 2008609-632.
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Cancer Prevention

• Smoking Cessation Highest priority
• Hepatitis and HPV vaccination
• Yearly cervical and anal Pap tests Gyn and HRA
• Maintain high index of suspicion for cancer
• Yearly breast, prostate (incl. PSA) exam
• Advise sun screen and avoid overexposure
• Complete family history for malignancies
• If Hepatitis B or C positive, follow LFTs and
• perhaps AFP periodically

44
Cancer Screening in HIV
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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
  after age 50, and FOBT yearly
• Lung CA CT scan for high risk individuals
  (2014)
• 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

46
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 200234386-92
• Reinhold JP. Am J Gastroenterol 20051001805-12
• Hsiao W, Science World J 20099102-8
• Concerns about higher false positive rate in HIV
  (eg, NLST found reduction in lung cancer
  mortality (20) in older cigarette smokers with
  CT) but also high false positive rates, which may
  be true in HIV as well

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Summary

• As patients live longer with HIV, morbidity and
  mortality from cancers are increasing
• The types of cancers in HIV may vary in different
  populations around the world
• Treatment of malignancies in HIV should be
  vigorous and appropriate to the situation
• Side effects of therapy should be
  treated/prevented
• Prevention strategies for virally-associated
  malignancies in HIV need to be investigated
• Through prospective clinical trials research can
  treatment and prevention strategies be
  effectively evaluated

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Thank You

• For information on AMC clinical trials
  seehttp//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 ask for Maricela
  Gonzalez or page/email Dr. Mitsuyasu,
  rmitsuya_at_mednet.ucla.edu