Advances in the Diagnosis, Management and Epidemiology of

Cancers Associated with HIV Infection

Corey Casper, MD, MPHVaccine and Infectious Disease, Public Health Sciences and Clinical

Research Divisions, Fred Hutchinson Cancer Research Center

Departments of Medicine, Epidemiology and Global Health, University of Washington

Outline

• History of Cancer in the HIV Epidemic• Epidemiology of Cancer in Persons with HIV

– Resource-rich regions– Resource-poor regions

• Factors associated with increased risk of cancer in persons with HIV

• Diagnostic and Therapeutic Strategies for cancer prevention and treatment in persons with HIV

The History of Cancer and HIV in the United States

•In 1981, the description of 8 young men in New York City with a previously rare cancer, Kaposi Sarcoma (KS), heralded the beginning of the HIV epidemic•By 1983, one of every 3 persons with HIV in the United States had KS•Within one year of widespread availability of HAART in US, incidence dropped 10-fold

Hymes KB, et. al. Lancet 1981 ; Eltom MA, J Natl Cancer Inst 2002; IARC Sci Publ 2002

The History of Cancer and HIV in Resource-Poor Settings•Now that persons in resource-poor settings are living longer with HIV, second epidemics of cancer are now being realized

•KS is now the most common cancer in the entire population of many countries in Sub-Saharan Africa•Epidemics of lymphoma are being described in India and South America

Original AIDS-Defining Malignancies

•Cervical Cancer

•Kaposi’s Sarcoma

•Burkitt’s Lymphoma

•Immunoblastic Lymphoma•Primary Brain Lymphoma

Original AIDS-Defining Malignancies

Malignancy Viral Etiology

•Cervical Cancer HPV•Kaposi’s Sarcoma HHV-8•Burkitt’s Lymphoma

EBV•Immunoblastic Lymphoma•Primary Brain Lymphoma

Viral OncogensVirus Cancer

Epstein Barr Virus (EBV) •Burkitt’s Lymphoma•Nasopharyngeal Carcinoma•B-cell Lymphoma

Hepatitis B Virus (HBV) Hepatocelluar Carcinoma

Hepatitis C Virus (HCV)

Human Papillomavirus (HPV) •Cervical Cancer•Anal Cancer

Human T-Cell Leukemia Virus (HTLV) T-cell Leukemia

Human Herpesvirus 8 (HHV-8) •Kaposi’s Sarcoma•Primary Effusion Lymphoma

Simian Virus 40 (SV40) •Mesothelioma?•Non-Hodgkin’s Lymphoma?

Merkel Cell Polyoma Virus •Merkel cell carcinoma

Murine Endogenous Retrovirus •Prostate Cancer

Risk of AIDS-Defining Cancers in HIV Patients vs. General Population

• Meta-analysis of over 444,000 persons with HIV in resource-rich regions consistently found standardized incidence ratio (SIR) of AIDS-defining cancers up to 3600 times that of the general population– KS: 3640 (95% CI 3226-3975)– Cervical Cancer: 5.3 (3.58-7.57)– NHL: 22.60 (20.77-24.55)

Grulich A, Lancet 2007

Risk of “Non AIDS-Defining Cancers” in US / European HIV Patients

Grulich A, Lancet 2007

Cancer Range in SIR in 5 studies of over 440,000 People

Anus 19.63-50.00

Liver 2.73-7.70

Respiratory 1.44-4.50

All Non-AIDS Defining Cancers

1.63-2.79

Risk of AIDS-Defining Cancers in Persons with HIV Compared to General US Population

Patel P, Ann Int Med 2008

Risk of Non-AIDS-Defining Cancers in Persons with HIV Compared to General US Population

Patel P, Ann Int Med 2008

Incidence of AIDS-Associated Cancers in Africa

• Case-control study of cancer in 3 major tertiary care centers in South Africa reviewed odds of HIV infection in 8,487 cancers since 1999 (Stein, et. al. Intl. J Cancer 2008)

Incidence of Cancer In Persons with HIV - India

Dihr Cancer Causes Control 2008

Cancer Diagnoses Increasingly Account for Deaths Among Persons with HIV

• In 2000, nearly 1/3rd of deaths among French patients with HIV were attributable to cancer– 15% due to “AIDS-malignancies”– 13% due to “non-AIDS malignancies”

• Bonnet F, et. al. Cancer. 2004; Jul 15;101(2):317-24

KS, muc

ocut

aneo

us

Anal

KS, visc

eral

Kidne

y

Non-C

NS NHL

Lung

Primar

y CNS N

HL

Live

r

Infe

ction

-unr

elat

ed N

ADCs

AIDS-D

efin

ing

Caner

s

Infe

ction

-rela

ted

NADCs

Overa

ll 0

10

20

30

40

50

60

70

80

90

HIVAM 2-year overall survival - United States CFAR Cohorts

Achenbach AIDS 2011

Epidemiology of Cancer in Persons with HIV: Conclusions

• Data from a wide variety of clinical cohorts in more than 5 continents confirms that persons with HIV are at increased risk of both “AIDS-defining” and “non-AIDS defining” malignancies

• Common Non-AIDS Defining Cancers– Head / Neck Cancers– Anal Cancer– Lung Cancer– Hodgkin’s Lymphoma– Liver Cancer

Factors Which May Impact Risk of Cancer in Setting of HIV

• Immunosuppression• HIV Replication• Antiretroviral Therapy• Environmental / Demographic Factors

Immunosuppression and Oncogenesis

• Long appreciated that immune surveillance plays a role in cancer prevention– Higher incidence of cancer in organ transplant

recipients– Immunotherapy for melanoma– Reduction of immunosuppresion leads to regression

of cancers after transplant• KS after kidney transplant• Recurrent leukemia / lymphoma after HSCT

HIV-Related Immunosuppression and Cancer Risk

Biggar R, JNCI 2007

Not All Immunosuppression is the Same…

Grulich A, Lancet 2007

Both CD4 and HIV RNA Contribute to Cancer Risk

Bruyand M, CID 2009

The Effect of HAART on Cancer Incidence: The Hope

• The reduced incidence of KS is one of the most dramatic effects of HAART

• Not attributable to decreased HHV-8 prevalenceOsmond DH, et al. Jama 2002; 287:221-5.

SEER Cancer Registry and JNCI 2000; 92:1827

The Effect of HAART on Cancer Incidence: The Reality (US)?

• More than 50,000 people living with HIV in the US have been diagnosed with cancer since widespread use of HAART

• ADCs have plateaued while NADCs continue to increase

Shiels JNCI 2011

The Effect of HAART on Cancer Incidence: The Reality (Africa)?

05

10

15

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e in

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nce

ra

te/1

000

peop

le

01

02

03

04

0A

RT

cov

era

ge

%

1998 2000 2002 2004 2006 2008Year

ART coverage KSICC NHL

Secular trends in cancer cummulative rates and ART coverage

Incidence of AIDS-Defining Cancers vs. ART Coverage, Kampala

Mutyaba I, et. al. Lancet 2010

Protease Inhibitors May Have Direct Effect on Oncogenic Virus Replication:

Data from Clinical Cohorts

CD4 <= 200 CD4 > 200

RNA > 10KRNA <=10KRNA > 10KRNA <=10K

Perc

ent

HHV-

8 po

sitive

day

s

100

90

80

70

60

50

40

30

20

10

0

no HAART

HAART

Casper C, CROI 2004

Protease Inhibitors May Have Direct Effect on Oncogenic Virus Replication

Clinical Data in Support of Protease Inhibitors for HIVAM: Kaposi Sarcoma in Uganda

Ngyuen HQ, ICMAOI 2009

Improvement ResolutionUnivariate Multivariate Univariate Multivariate

HR (95% CI) p HR (95% CI) p HR (95% CI) p HR (95% CI) pInitiated antiretroviral therapy prior to diagnosis of KS

2.05 (1.16, 3.61) 0.01 4.70

(1.93, 11.4) <0.001

Antiretroviral therapy

Aantiretroviral therapy vs no antiretroviral therapy

2.18 (1.41, 3.35) <0.001 3.67

(1.11, 12.17) 0.03

Triomune vs no antiretroviral therapy

3.75 (2.31, 6.09)

<0.001

1.31 (0.22, 7.73) 0.8

EFV containing regimens vs Triomune

0.61 (0.29, 1.27) 0.2 7.33

(1.83, 29.3) 0.005

PI containing regimens vs Triomune

2.49 (1.06, 5.88) 0.04 16.0

(1.37, 186) 0.03

Factors Associated With Development of Cancer in HIV+ Patients: Conclusions

• Immunosuppresion clearly contributes to risk of many HIV-associated malignancies– Depth or Duration of low CD4 Count?– What is different about the exceptions (NHL, Cervical Ca, KS?)

• HIV replication may lead to permissive environment for tumorigenesis– Increased viral oncogen replication– “Inflammatory / Angiogenic Milieu”

• Not all HAART regimens may be the same in terms of prevention of cancer in those at high risk

Public Health Ramifications of Relationship between HIV and Cancer

• When to start HAART– Adhere to WHO guidelines in areas with high incidence of

HIV-associated cancers?– Heed call for starting HAART at higher CD4 counts to avoid

cancer risk?• What HAART to start

– Given ease of Atripla and cost of Triomune, are there exceptions to when they should be used as first-line therapy

• How to screen for HIV-associated cancers?

From Infection to Cancer:Novel Opportunities for Cancer Prevention and Treatment

Primary Infection

Chronic Infection

Replication

Progression to Cancer

Vaccine against HBV nearly eradicated the most common

cancer in Taiwanese Children

Predictive and Treatment-Selective

Biomarkers

• EBV DNA quantity in blood predicts

development of NPC in China

• Treatment of HBV /

HCV prevents

development of HCC

• Treatment of HHV-8 prevents

development of

lymphoma

• Vaccine against EBV

may prevent cancer in Chinese adults

Antibiotics cure some forms of stomach

cancer associated with H. pylori

Antimicrobial Therapy as the New Chemotherapy?

Virus Cancer Antimicrobial Therapy

Epstein Barr Virus (EBV)

•Lymphoma (PTLD) •Use of ganciclovir may prevent development of and serve as useful adjunctive for therapy

Hepatitis B Virus (HBV) Hepatocelluar Carcinoma •Antiviral therapy has been shown to reduce the progression from chronic infection to HCC

Hepatitis C Virus (HCV)

Human T-Cell Leukemia Virus (HTLV)

T-cell Leukemia •Antiretroviral therapy may prevent development of cancer

Human Herpesvirus 8 (HHV-8)

•Primary Effusion Lymphoma•Multicentric Castleman Disease

•Use of ganciclovir may prevent development of and serve as useful adjunctive for therapy

Helicobacter pylori •Mucosal associated lymphatic tumor

•Antibiotic therapy associated with successful treatment of early (and late?) gastric and intestinal tumors

Antivirals in the Prevention and Treatment of EBV-Associated Lymphomas

• High-dose aciclovir was ineffective in the prevention of lymphoma among HIV-infected persons– OR 0.83, insufficient power due to small number of cases

– Ioannidis JP, et al. J Infect Dis. 1998 Aug;178(2):349-59

• Ganciclovir use is associated with the regression of EBV-associated lymphoma in combination with chemotherapy and antiretroviral therapy

– Raez L, et al. AIDS Res Hum Retroviruses. 1999 May 20;15(8):713-9. – Brockmeyer NH, et al. Eur J Med Res. 1997 Mar 24;2(3):133-5.– Aboulafia DM. Clin Infect Dis. 2002 Jun 15;34(12):1660-2.

Chemotherapy for KS in Seattle: Some Hope, Some Challenges

Ngyuen HQ, AIDS 2008

Chemotherapy for KS in Uganda: Some Hope, Some Challenges

Ngyuen HQ, ICMAOI 2008

No. at risk H+C

0.0

0.2

0.4

0.6

0.8

1.0

0 30 60 90 120 150 180 210 240 270 300 330 360

Cu

mu

lati

ve I

nci

den

ce

HAART Chemo HAART + Chemo

Days since treatment

No. at risk H 64 4956 38 2778 19 16 16 12 12 8 8

No. at risk C 15 812 8 632 5 3 2 2 2 2 2

23 918 8 524 4 4 3 3 1 1 0

Log Rank: p <0.0001

No. at risk H+C

0.0

0.2

0.4

0.6

0.8

1.0

0 30 60 90 120 150 180 210 240 270 300 330 360

Cu

mu

lati

ve I

nci

den

ce

HAART Chemo HAART + Chemo

Days since treatment

No. at risk H 64 4956 38 2778 19 16 16 12 12 8 8

No. at risk C 15 812 8 632 5 3 2 2 2 2 2

23 918 8 524 4 4 3 3 1 1 0No. at risk H+C

0.0

0.2

0.4

0.6

0.8

1.0

0 30 60 90 120 150 180 210 240 270 300 330 360

Cu

mu

lati

ve I

nci

den

ce

HAART Chemo HAART + Chemo

Days since treatment

No. at risk H 64 4956 38 2778 19 16 16 12 12 8 8

No. at risk C 15 812 8 632 5 3 2 2 2 2 2

23 918 8 524 4 4 3 3 1 1 0

0.0

0.2

0.4

0.6

0.8

1.0

0 30 60 90 120 150 180 210 240 270 300 330 360

Cu

mu

lati

ve I

nci

den

ce

HAART Chemo HAART + Chemo

Days since treatment

No. at risk H 64 4956 38 2778 19 16 16 12 12 8 8

No. at risk C 15 812 8 632 5 3 2 2 2 2 2

23 918 8 524 4 4 3 3 1 1 0

Log Rank: p <0.00010.0

0.2

0.4

0.6

0.8

1.0

0 90 180 270 360 450 540 630 720

Cu

mu

lati

ve I

nci

den

ce

HAART Chemo HAART + Chemo

Days since treatment

No. at risk H 4862 3778 29 18 12 5 0

No. at risk C 1117 920 9 5 3 3 3

No. at risk H+C 2940 2846 24 15 13 8 6

0.0

0.2

0.4

0.6

0.8

1.0

0 90 180 270 360 450 540 630 720

Cu

mu

lati

ve I

nci

den

ce

HAART Chemo HAART + Chemo

Days since treatment

No. at risk H 4862 3778 29 18 12 5 0

No. at risk C 1117 920 9 5 3 3 3

No. at risk H+C 2940 2846 24 15 13 8 6

NHL in Uganda: Impact of ART Survival

Access to Chemotherapy is Vital in Resource-Limited Settings

Proportion of “Ideal Dose” of

Chemotherapy Administered

Hazard of Improvement

No chemo 1.0

<14% of ideal dosage 4.72 (2.72, 8.19)

<0.0001

14-39% of ideal dosage 6.41 (3.52, 11.7)

<0.0001

≥40% of ideal dosage 9.57 (3.62, 25.3)

<0.0001

Screening for HPV / Anal Cancer

• Serologic HPV testing is unreliable• 93% of HIV-infected men and 76% of women may have

HPV DNA detected in the anal mucosa (poor positive predictive value), usually type 16

• Matthews WC. Top HIV Med. 2003 Mar-Apr;11(2):45-9• Anal Pap tests have poor reproducibility, but any

abnormal cytology on Pap smear is suggestive of high grade lesions on biopsy

• Panther LR, et. al. Clin Infect Dis. 2004 May 15;38(10):1490-2 • No good evidence that treating high grade lesions

prevents anal cancer, and recurrences are common

Algorithm for Anal Cancer Screening?

Chin-Hong PV, CID 2002

Preventing Malignancies in HIV-Infected Patients

Malignancy Viral Agent

Action

Anal, Cervical

HPV •Annual Pap smears with biopsy of any abnormal cytology?•Treatment of dysplasia with surgery, antivirals, or cryotherapy?•Smoking cessation•HAART?

Lung ? •Smoking cessation•HAART?

Liver HBVHCV

•Screen for HBV / HCV•Antiviral therapy for viral hepatitis•Yearly ultrasound / AFP

–Only in those with cirrhosis?

KS HHV-8 •HAART•Antiviral therapy for those at high-risk?

Lymphoma EBV •HAART•Aggressive work-up for persons with prolonged B-symptoms or lymphadenopathy

Conclusions

• The increasing survival of HIV-infected patients may predispose to an epidemic of malignancies among long-term survivors

– AIDS-Defining: KS, Cervical Cancer, Lymphoma– Non-AIDS-Defining: Anal, lung, prostate, and hepatocellular cancer

• HAART use may be associated with declines in some, but not all, malignancies in persons with HIV

– In addition to AIDS-defining malignancies, may reduce cervical and anal cancer

• Effective screening and prevention measures have yet to be defined for the non-AIDS-defining malignancies in HIV-infected persons, but may be inferred from those in HIV-negative high risk persons

• Vaccines and antiviral therapy may come to play an increasing role in the prevention and treatment of virally-mediated cancers

Funding generously provided by the Doris Duke Charitable Foundation, NIH (NIAID, NCI), Centers for AIDS Research, USAID and the Fred

Hutchinson Cancer Research Center