24 september, 2009 hiv-associated malignancies in the antiretroviral era corey casper, md, mph

Welcome to I-TECH HIV/AIDS Clinical Seminar Series

24 September, 2009

HIV-Associated Malignancies in the Antiretroviral Era

Corey Casper, MD, MPH

HIV-Associated Malignancies in the Antiretroviral Era

Corey Casper, MD, MPHCorey Casper, MD, MPHVaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center

Division of Infectious Disease, University of Washington

Outline

• The history of cancer in the HIV epidemic• Definition of AIDS-defining and non-AIDS defining cancers• The epidemiology of cancers in persons with HIV• Specific AIDS-associated malignancies

– Cervical Cancer– Anal Cancer– Hepatocellular Carcinoma– Lung Cancer– Kaposi Sarcoma– Lymphoma

• Prevention and Treatment Strategies

Case 1

54 year old man presents with several painless, raised, purple lesions on the chest, back and in the groin

Case 1: Additional History

• History of Hairy Cell Leukemia, in remission for 5 years after treatment with cladaribine and an experimental agent at the National Cancer Institute

• In steady relationship with male partner for 3 years

• Tested HIV-negative one week after starting present relationship

Case 1: KS

• HIV test: positive EIA, confirmed by Western Blot

• CD4 count: 96• HIV viral load: >500,000

copies• Follow-up:

– Improving after starting tenofovir, emtricitabine and Kaletra

KS in the HAART Era

• 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.

• May be due to immune reconstitution, or direct antiviral effect of ART on HHV-8

SEER Cancer Registry and JNCI 2000; 92:1827

Decline in KS Incidence with HAART May Not Be Seen in Endemic Areas

0

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1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Year

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ART HIV KS -- Men KS--Women

No change in KS incidence in Uganda despite over 100,000 persons started on HAART

Current Treatment for KS in Resource-Rich Settings is Inadequate

Nguyen HQ, et. al. AIDS 2008

Current Treatment of KS in Resource-Poor Settings is Inadequate

• 177 patients with HIV-associated KS seen at the Infectious Disease Institute followed for 2 years• Over 1 year, 70% improved with ART and/or chemotherapy, but only 8% resolved• Associated with improvement: male sex, HAART, and chemotherapy• Less likely to improve: low BMI and lesions located on the lower extremities • Among patients on HAART, those receiving efavirenz- and protease inhibitor-containing HAART

were 6.9 (95% CI: 1.7-27, p=0.006) and 15 times (95% CI: 1.3-183, p=0.03) more likely to experience resolution compared to those receiving Triomune (stavudine-lamivudine-nevirapine).

No. at risk H+C

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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

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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

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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

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

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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

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0 90 180 270 360 450 540 630 720

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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

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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

The History of an Epidemic…• 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

• Hymes KB, et. al. Lancet 1981; 2:598-600.

• By 1983, one of every 3 persons with HIV in the United States had KS

• In 1994, KS attributed to infection with human herpesvirus 8

• Chang Y, et. al. Science 1994; 266:1865-9.

• Within one year of widespread availability of HAART in US, incidence dropped 10-fold

• Eltom MA, J Natl Cancer Inst 2002;94:1204-10.

• Today, KS is the most common cancer in the entire population of Uganda, and the most common cancer among persons with HIV worldwide

• IARC Sci Publ 2002;155:1-781• Eltom MA, J Natl Cancer Inst 2002;94:1204-10.

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

Winning the Battle Against HIV…• Mortality has dropped dramatically among persons with

HIV in the highly active antiretroviral era• Persons living with HIV have a nearly normal risk of

death when compared with HIV-negative persons…

Mocroft A, et. al. Lancet 2003

Mocroft A, et al. Lancet 2003;362:22-9

…But Losing the War to Cancer?Resource-Rich Regions

• 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

…Losing the War to Cancer?Africa

UNAIDS 2006

Burden of Cancer in Africa

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

HIV-Related Immunosuppression and Cancer Risk

Biggar R, JNCI 2007

HIV-Associated Malignancies:Change in Incidence Over Epidemic “Eras”

Powles, et. al. JCO 2009

Not All Immunosuppression is the Same…

Incidence of AIDS-Associated Cancers in Resource-Poor Settings

•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)

Cancer Incidence Trends in Uganda, 1992-2005

Case 2

• 45 year old Kenyan woman with B3 HIV (CD4 375, HIV RNA 51,000, not on ART) presents for routine annual PAP

• Found to have high-grade squamous epithelial lesion (HSIL)

• Referred for colposcopy, where biopsy reveals CIN III

• Treated with surgical ablation, topical flurouricil, and intiation of HAART

Cervical Cancer in the HAART Era

• In the Women’s Interagency HIV Study (WIHS), both increasing HIV plasma RNA levels and decreasing CD4 counts were associated with an increased risk of abnormal cervical cytology

– Massad LS, et al. J Acquir Immune Defic Syndr. 1999 May 1;21(1):33-41

• The use of HAART was associated with an increased rate of “regression” over six months (two normal Pap smears)

– Ahdieh-Grant L, et al J Natl Cancer Inst. 2004 Jul 21;96(14):1070-6

Cervical Cancer Screening in HIV-Positive Patients

• Cervical cancer screening twice in the first year after diagnosis of HIV infection and then annually, provided the test results are normal.

• HPV testing?– Increased frequency of testing (q6 months?) if

positive for high-risk strain

• Some recommend a screening colposcopy at initial evaluation

Case 3

• 51 year old Caucasian male with history of C3 HIV (current CD4 405, HIV RNA undetectable) presents with rectal bleeding– Presented with AIDS-dementia with CD4 count of 7 in

2000, treated successfully with AZT / lamivudine / Kaletra

• On rectal exam, large verrucous lesion originating from the posterior half of the anus or from 9 o'clock to 3 o'clock position, originating from multiple narrow pedicles.

Anal Cancer in the HAART Era• Risk of anal cancer among HIV-

positive men who have sex with men is 60-fold higher than the general population

Frisch M, et al. J Natl Cancer Inst. 2000; 92:1500-10

• Grade of squamous intraepithelial lesions may be correlated with degree of immunosuppression in both men and womenMathews WC. Top HIV Med. 2003 Mar-Apr;11(2):45-9

• Effective HAART use may not be associated with a decline in anal dysplasia / cancerPiketty C, et. al. Sex Transm Dis. 2004 Feb;31(2):96-9

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

Case 4

• 41 year old man with B2 HIV (last CD4 311, HIV RNA undetectable on Atripla) presents with 20 pound weight loss over the last 3 months

• History of untreated hepatitis C virus infection and cirrhosis on liver biopsy

• Non-compliant with annual ultrasound and alpha-fetoprotein screening

HCC in the HAART Era

• Co-infection with HIV and viral hepatitis (B and C) could result in an epidemic of hepatocellular carcinoma in long term survivors of HIV

• Suppression of HBV or HCV replication is associated with reduced risk of cancer

• Patients with HIV may be between 2-8 times more likely to develop hepatocellular carcinoma when compared with the general population

Chiao E, et al. Curr Opin Oncol 2003:15; 389

Case 5

• 43 year old Cambodian man with A3 HIV (last CD4 621, HIV RNA undetectable on Atripla) presents with fevers of 3 weeks duration but no other symptoms

• Solitary pulmonary nodule detected on chest x-ray and confirmed on CT scan

Case 5: CT Scan

Lung Cancer in the HAART Era

• HIV-infected patients may be at 1.5-4.5 times increased risk of lung cancer compared with the general population

• May be attributable to:– High rates of tobacco use?

• Two studies have found risk to be independent of tobacco use

– Permissive cytokine milieu by HIV (Tat, etc.)– Differences in DNA methylation patterns

Chiao E, et al. Curr Opin Oncol 2003:15; 389

Prostate Cancer in the HAART Era

• Large series have found conflicting evidence for an increased rate of prostate cancer among persons with HIV

– Chiao E, et al. Curr Opin Oncol 2003:15; 389

• One study found a relationship between duration of HIV infection and prostate cancer, suggesting that prostate cancer may become an issue among long-term survivors of HIV

– Crum NF, et. al. Cancer 2004: 101; 294-9

Case 6

• 31 year old Ethiopian woman with C3 HIV (AIDS-defining illness = KS, current CD4 981 HIV RNA undetectable on Atripla) presents with fevers of 6 months duration, weight loss of 15 kg, fatigue

• Exam reveals diffuse lymphadenopathy, hepatosplenomegaly

• Complete blood count reveals pancytopenia

Case 6 – CT Scan of Abdomen Showing Massive Splenomegaly and Lymphadenopathy

NHL in the HAART Era• Reduction in all types of NHL is not uniform

– Those associated with EBV show the greatest decline

JNCI 2000; 92:1827 and Eltom MA, et al. JNCI 2002; 94:1204-10

NHL in Uganda: Predictors of Survival

• Retrospective study of 228 patients with NHL at UCI from 2004-2007

• Sought to determine the correlates of successful treatment of NHL in Uganda

Bateganya M, IAS 2009

Characteristic HIV+ HIV- HIV Unk

Number N=228 (%) 59 (26) 136 (60) 33 (14)

Sex, n (%) n=228

Male n=151 44 (29) 83 (55) 25 (17)

Female n=77 15 (19) 53 (69) 8 (24)

Median age (yrs) 37 (31-43)

21.5 (10.5-47.5)

13 (7-29)

Tumor Stage n (%) n=144

I&II n=11 3 7 1

III&IV n=133

37 81 15

Median (IQR) BMI (Only for those ≥18years n=109

19.8(17.7-22.4)

19.8 (16.7-22.9)

17.7 (14.7-18.5)

NHL in Uganda: Impact of ART Survival


NHL in Uganda: Impact of Chemotherapy on Survival


Conclusions about NHL in Uganda

• Profound increase in the incidence of NHL since 1992• Large proportion of NHL patients are HIV-infected, and

treatment of HIV is associated with successful treatment of NHL

• Majority of patients with NHL present with late-stage disease

• Chemotherapy and ART afford a reasonable odds of survival for those who can access optimal treatment courses

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?

Prostate HHV-8? •Smoking Cessation•HHV-8 antibody screening?•Regular DRE and PSA for those at high risk?•HAART?

KS HHV-8 •HAART•HHV-8 antibody and peripheral blood PCR?•Antiviral therapy for those at high-risk?

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

From Primary Infection to Malignancy

Primary Infection

Chronic Infection

Viral Replication

Transformation to Malignancy

Vaccine eliciting neutralizing antibodies

Agents to Promote Viral LatencyAntiviral

Agents

•Angiogenesis Inhibitors

•Cell cycle agents

•Cytokines

•Antibody Therapy

Chemotherapy

Vaccines for Prevention of Viral Associated Malignancies: HPV

Vaccines to Prevent Viral Associated Malignancies: EBV

• Antibodies to a glycoprotein on the surface of EBV, gp350, neutralize infection and transformation of lymphoid cells

• Cross-sectional studies have shown that all persons asymptomatically infected with EBV possess neutralizing antibodies.

• Neutralizing antibody levels are reduced in persons with EBV-associated malignancies

– 1/3rd of patients with nasopharyngeal carcinoma (NPC) and 1/5th of those with Hodgkin’s disease lacked EBV neutralizing antibodies

– The geometric mean titer of EBV neutralizing antibodies was over 3-fold higher in asymptomatically infected

• Antibodies raised to gp350 through vaccination were protective against EBV-induced malignant lymphoma in monkeys

Vaccines to Prevent Viral Associated Malignancies: HHV-8

KSHV+/KS+/HIV+ KSHV+/KS-/HIV+ KSHV+/KS-/HIV- Controls

N = 32 N = 16 N = 24 N = 20

Age, Mean (Range) 32 (20-44) 35 (20-50) 42 (24-60) 28.5 (19-38)

CD4 T cell/ml Mean (Range) 181 (0-667) 544 (350-814) 1005 (723-1554) ND

Neutralizing antibody titers

Geometric Mean Titer (1:n), (Range)

46,(10-320)

216,(80-1280)

302,(20-1280)

0,(0-0)

•Neutralizing antibodies may be protective against HHV-8Kimball, et. al. JID 2004

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.

Antiviral Medications Against HHV-8

• In a randomized, placebo-controlled, crossover study of valganciclovir’s effect on HHV-8 oropharyngeal replication, 46% reduction in detection of HHV-8 in oropharynx during valganciclovir administration (p=0.02)

Crossover Valganciclovir Crossover

1 7 14 7 14 21 28 35 42 49 56 7 14

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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

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24 september, 2009 hiv-associated malignancies in the antiretroviral era corey casper, md, mph

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