Erin G. Reid, MD, of UC San Diego Moores Cancer Center, presents "Update on Malignancies in HIV"

1. The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease clinicians, physicians and
researchers. The goal of these presentations is to provide the most
current research, clinical practices and trends in HIV, HBV, HCV, TB
and other infectious diseases of global significance.
The slides from the AIDS Clinical Rounds presentation that you are
about to view are intended for the educational purposes of our
audience. They may not be used for other purposes without the
presenter’s express permission.
AIDS CLINICAL ROUNDS

2. E R I N G O U R L E Y R E I D , M . D .
A S S O C I A T E C L I N I C A L P R O F E S S O R , H E M A T O L O G Y
M O O R E S U C S D C A N C E R C E N T E R
U C S D O W E N C L I N I C
Update on AIDS-related
Malignancies

3. Objectives
 Why is this important?
 What types of cancers are HIV patients getting
now?
 Does early HAART prevent cancer?
 Options for Kaposi’s sarcoma?
 What is different about Hodgkin Lymphoma in the
HIV patient population?
 New treatment options for lymphomas

4. Non-AIDS-related deaths on the rise
Information from Southern Alberta
clinic 12/84 through 12/03
560 deaths in HIV-infected
individuals
 124 in the HAART era
 67% AIDS-related
 Of these 14% cancer related
 7% Kaposi’s sarcoma
 7% NHL
 32% Non-AIDS Related
 19% of these non-HIV
malignancies
 20% of total deaths of HIV
infected patients were
cancer related
Krentz et al HIV Medicine 2005

5. Objectives
 Why is this important?
 What types of cancers are HIV patients
getting now?
 Does early HAART prevent cancer?
 New treatment options for Kaposi’s sarcoma
 What is different about Hodgkin Lymphoma in the
HIV patient population?
 Should we use rituximab in HIV-related
lymphomas?

6. In the year 2000:
International Collaboration on HIV and Cancer
 Cancer incidence data from 23 prospective studies
 47,936 HIV-seropositive individuals
 North America, Europe, and Australia
 Calculated adjusted incidence rates (expressed as number
of cancers per 1000 person-years) for:
 Kaposi's sarcoma
 non-Hodgkin's lymphoma
 Hodgkin's disease
 cervical cancer
 20 other cancer types or sites
 Rate ratios were estimated
 comparing incidence rates from 1997 - 1999 with rates from 1992 -
1996
 Adjusted for study, age, sex, and HIV transmission group.
Highly Active Antiretroviral Therapy and Incidence of Cancer in Human Immunodeficiency Virus-Infected
Adults. International Collaboration on HIV and Cancer. JNCI, Vol. 92, No. 22, 1823-1830, November 15, 2000

7. International Collaboration on HIV and Cancer:
Conclusions
 AIDS-defining cancers contribute more than 90% of
malignancies in HIV.
 NHL
 KS
 Heterogeneity between AIDS-defining cancers in the
relative decline in incidenceover time
 Kaposi's sarcoma shows the greatest decline (rate ratio = 0.32)
 Also decreased:
 Cerebral lymphoma (rate ratio = 0.42)
 Immunoblastic lymphoma (rate ratio = 0.57).
 Stable rates:
 Burkitt's lymphoma (rate ratio = 1.18)
 cervical cancer (rate ratio = 1.87)
Highly Active Antiretroviral Therapy and Incidence of Cancer in Human Immunodeficiency Virus-Infected Adults.
International Collaboration on HIV and Cancer. JNCI, Vol. 92, No. 22, 1823-1830, November 15, 2000

8. Trends in cancer risk among people with AIDS in the
United States 1980–2002
 AIDS Cancer Match Study
 HIV/AIDS and cancer registries in six US states and five
metropolitan areas were linked using a probabilistic
matching algorithm, utilizing registry data on name,
social security number, sex, dates of birth and death, and
race
 the analysis focused on the subsequent 2-year ‘post-
AIDS-onset period’ (from 4 to 27 months after
registration)
HIV/AIDS Cancer Match Study Engels et. al. AIDS 2006, 20:1645–1654

9. Cancer Risk in AIDS patients
HIV/AIDS registries 407,740 people with AIDS
diagnosed in 1977–2004
 Excluded
 Those with AIDS diagnosed before 1980 (18)
 not complete overlap of two registries (26 635)
 children aged 0–14 years (5154)
 375,933 adult and adolescent individuals for
inclusion in the study.
HIV/AIDS Cancer Match Study Engels et. al. AIDS 2006, 20:1645–1654

10. Cancer Risk in AIDS patients
1996-2002
HIV/AIDS Cancer Match Study Engels et. al. AIDS 2006, 20:1645–1654
AIDS Defining Cancers No. cases (%) standardized
incidence
ratio (SIR)
Kaposi sarcoma 494 (30.0) 3640 (3330–
3980)
Non-Hodgkin lymphoma 560 (34.0) 22.6 (20.8–
24.6)
Diffuse large B-cell NHL 266 (16.2) 29.6 (26.1-
33.3)
CNS NHL 115 (7.0) 1020 (838-
1220)
Cervical cancer 30 (1.8) 5.3 (3.6-7.6)

11. Cancer Risk in AIDS patients
1996-2002
HIV/AIDS Cancer Match Study Engels et. al. AIDS 2006, 20:1645–1654
Non- AIDS Defining Cancers No. cases
(%)
standardized
incidence ratio
(SIR)
Anal cancer 43 (2.6) 19.6 (14.2-26.4)
Larynx 16 (1.0) 2.7 (1.6-4.4)
Lung 111 (6.7) 2.6 (2.1-3.1)
Liver 20 (1.2) 3.3 (2.0-5.1)
Myeloid and monocytic
leukemia
11 (0.7) 2.2 (1.1-4.0)
Hodgkin Lymphoma 72 (4.4) 13.6 (10.6-17.1)
Total Non-AIDS defining ca 563 (34.2) 1.7 (1.6-1.9)

12. HIV/AIDS Cancer Match Study
2004-2007
 During 2004–2007,
 15,884 cancers occurred among HIV-infected people
in 34 US states
 7869 (49.5%) were AIDS-defining cancers
 7563 (47.6%) were non-AIDS-defining cancers.
 2191 (29.0%) occurred in the non-AIDS HIV-only population.
 Lung cancer comprised 19.7% of the cancer burden (n = 454)
 Other common cancers in people with HIV-only:
 female breast cancer (n = 166 cancers)
 prostate cancer (n = 147 cancers)
 anal cancer (n = 154 cancers),
 Hodgkin lymphoma (n = 150 cancers)
Shields 2011

13. AIDS-Defining Cancers by Age

14. AIDS NHL Cases & Incidence 1991-2005

15. AIDS KS Cases & Incidence 1991-2005

16. AIDS Cervical Cancer Cases & Incidence 1991-2005

17. Non-AIDS
defining
Cancers
A. Anal B. Lung
C. Liver D. Hodgkins
E. Prostate F. Colorectal

18. The BIG 4 NADC
 In the US 1991–2005
 50% of NADC were comprised of
 Lung cancer (3x)
 Anal cancer (29x)
 Liver cancer (5x)
 Hodgkin (11x)
 These accounted for only 16% of cancers in the
general population
 The cancer burden attributed to each of these four
malignancies has increased over time.
SEER*Stat Database

19. Objectives
 Why is this important?
 What types of cancers are HIV patients getting
now?
 Does early HAART prevent cancers?
 New treatment options for Kaposi’s sarcoma
 What is different about Hodgkin Lymphoma in
the HIV patient population?
 New treatment options for lymphomas

20. Copyright © 209 Wolters Kluwer.
Risk of cancers during interrupted
antiretroviral therapy in the SMART study.
Silverberg, Michael; Neuhaus, Jacqueline; Bower, Mark; Gey, Daniela;
Hatzakis, Angelos; Henry, Keith; Hidalgo, Jose; Lourtau, Leonardo; Neaton,
James; Tambussi, Giuseppe; Abrams, Donald
AIDS. 21(14):1957-1963, September 2007.

21. Copyright © 2009 Wolters Kluwer. 3
SMART baseline characteristics

22. Copyright © 2009 Wolters Kluwer. 4
SMART STUDY
Cancer endpoints for drug conservation and viral suppression arms

23. Objectives
 Why is this important?
 What types of cancers are HIV patients getting
now?
 Does early HAART prevent cancers?
 New treatment options for Kaposi’s
sarcoma
 What is different about Hodgkin Lymphoma in
the HIV patient population?
 New treatment options for lymphomas

24. Kaposi’s sarcoma

25. Kaposi’s sarcoma
“look-alikes”
 Bacillary angiomatosis
 Bartonella species
 Pyogenic granuloma
 Extrapulmonary Pneumocystis carinii
 Occurs even in absence of lung infection
 Chronic venous stasis mimicking plaque KS

26. AIDS Kaposi’s Sarcoma
25
 U.S. 95%+ in homosexual/bisexual men
 Africa M:F=1:1
 Pre-HAART 26% of HIV+ homosexual men
developed KS
 3% HIV+ IV drug users develop KS
 HAART decreased KS >90%
 Sites: cutaneous, mucosa, lymph nodes, viscera
 Variable course: indolent to fulminent

27. Kaposi’s sarcoma
Pathogenesis
 Caused by HHV8 = KSHV
 Gamma herpes virus
 infects human B-cells and
endothelial cells
 Predominately latent infection
state in KS
 HIV’s role in AIDS KS
 Tat induces growth of KS spindle
cells
 expression of adhesion
molecules, cytokines
 VEGF, IL-6

28. Evaluation
 Thorough exam
 Labs
 CD4, HIV viral load
 Chem/LFTs --> if abnl, consider imaging
 CXR
 If abnl --> CT chest
 Fecal occult blood
 If abnl --> endoscopy

29. KS Staging
Kaposi’s Sarcoma
 Criteria evolving: pre vs post HAART
 Pre-HAART
 Localized/disseminated, CD4 count, systemic illness
 Post-HAART
 Stebbing et al Lancet 367:1495 (2006)
 Score 0-15, starting at 10
 Negative points: AIDS-defining KS, CD4
 Positive points: age >50, 2nd AIDS-assoc illness
 Stebbing et al JCO 25:2230 (2007)
 CD8 count: 5% improvement/100 cells

30. KS Staging
Stebbing score and Probability of Survival
Kaposi’s Sarcoma
SCORE 6 months 1 year 2 years 5 years
0 1.0 0.99 0.99 0.98
5 0.99 0.97 0.95 0.918
10 0.93 0.83 0.74 0.63
15 0.69 0.38 0.20 0.08

31. Prognosis: Stebbing score

32. Role of KSHV vGPCR
 vGPCR (lytic gene)
 1st KSHV gene identified with transforming capacity in KS
 Homologue of CXC α-chemokine receptor
 Related to IL-8R
 HIV Tat induces expression of vGPCR
 Functions
 Endothelial cell transformation
 Auto- and paracrine Akt activation in infected endothelial cells
 Akt = kinase, activates mTOR via inactivation of TSC 1/2 (a break on
mTOR signalling)
 Induces VEGF expression via MAPK/SAPK pathway
 Induces EphrinB2 through multiple pathways - establishing arterial
vascular phenotype
 Required for KS cell viability
Sodhi et al. Cancer Cell. 2006 Aug;10(2):133-43.

33. Copyright ©2007 AlphaMed Press Wan, X. et al. Oncologist 2007;12:1007-1018
vGPCR

34. Kaposi’s sarcoma treatment
 Limited
 HAART alone
 Local injection (Vinblastine)
 Radiation
 Visceral or advanced cutaneous: HAART+
 Doxil (pegylated doxorubicin)
 Taxol
 Gemcitabine, navelbine
 ABV
 Treatment philosophy
 Not curable, manage as a chronic disease

35. Kaposi’s sarcoma
HAART +/- pegylated liposomal doxorubicin
Conclusion
Role of HAART in treatment of advanced KS:
helpful but often not sufficient
Response
rates at 48
weeks
Doxil +
HAART
HAART
alone
Total P
Intent to
treat
10 (76%) 3 (20%) 13 (46%) 0.003
On-
treatment
10 (91%) 3 (2%) 0.0001

36. Kaposi’s sarcoma treatment
Addressing oncogenic mechanisms of KSHV LANA
 LANA inhibits tumor suppressors:
 p53
 impaired apoptosis
 von Hippel-Lindau (VHL)
 increased HIF-1alpha levels which in turn activates genes involved in
angiogenesis, cell proliferation and survival
 Mechanism of inhibition: proteasomal degradation
 via LANA’s ubiquitin E3 ligase activity
 (Cai 2006)
 Role for proteasome inhibition (bortezomib) in KS

37. Kaposi’s sarcoma treatment:
Proteasome inhibition
 Bortezomib demonstrated more cytotoxicity against
PEL cell lines than against myeloma lines
 Demonstrated:
 inhibition of classical and alternative NF-kappaB pathways
 upregulation of p53, p21 and p27 and activation of the caspase
cascade
 synergistic or additive cytotoxic effect in combination with other
chemotherapeutic drugs
 Matta 2005

38. Kaposi’s sarcoma treatment: Lytic activation of KSHV
 HDAC inhibition
AMC 038 Valproic acid: modest lytic
replication documented
 Bortezomib most potent inducer of lytic
activation in related gammaherpesvirus, EBV
 Inhibition of NFkappaB disrupts KSHV
latency and induces apoptosis in PEL

39. Oncolytic viral strategies
Lytic activation of viruses
residing with cells causes:
 Direct cell destruction (cell
lysis)
 Promotes expression of
viral proteins that are more
immunogenic

40. Kaposi’s sarcoma treatment:
Summary of strategies addressing KSHV
 mTOR inhibition
 Pilot oral rapamycin trial underway (AMC 051)
 Unblocking tumor suppressors
 Inducing Lytic activation of KSHV
 HDAC inhibition
 AMC 038 valproic acid (Lechowicz ASH 2007)
 Modest lytic activation demonstrated
 Minor clinical responses
 Limitations: weak HDAC inhibitor, short exposure
 Proteasome inhibition
 AMC 053/063: Bortezomib trials in development within AMC for both
KSHV and EBV-related malignancies

41. Kaposi’s sarcoma
Other future directions
 VEGF inhibition
 Thalidomide and lenolidomide
 Inhibit angiogenesis induced by bFGF
 Tyrosine kinase inhibitors
 Gleevec (AMC 042)
 Immune modulation
 Thalidomide and lenolidomide
 Inhibit IL-1b, IL-6 and bFGF
 IL-6, bFGF drive angiogenesis
 Increase IL-2
 Promotes NK cell cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC)
 Increase IL-12
 defective IL-12 responses is felt to play a role in progressive immune deficiency in HIV
 AMC 063: Proteasome inhibition
 Blocking angiogenesis
 AMC 061: PTC299
 AMC 070: lenalidomide
 Concept: EphB2 inhibition

42. Objectives
 Why is this important?
 What types of cancers are HIV patients getting
now?
 Does early HAART prevent cancer?
 New treatment options for Kaposi’s sarcoma
 What is different about Hodgkin
Lymphoma in the HIV patient population?
 New treatment options for lymphomas

43. Population-based HIV-associated
Hodgkin’s disease
in the San Francisco Bay Area,
1988-98
Sally Glaser, Ph.D.
Christina Clarke, Ph.D.
Northern California Cancer Center
Margaret Gulley, M.D.
University of North Carolina at Chapel Hill
Fiona Craig, M.D.
University of Pittsburgh
Richard Ambinder, M.D., Ph.D.
Johns Hopkins University School of Medicine

44. Overall survival of male patients with HIV-related Hodgkin lymphoma
(118) and HIV-unrelated Hodgkin lymphoma (830) who were
diagnosed during 1988–1998 in the Greater Bay Area
Glaser et. al. CANCER July 15, 2003 / Volume 98 / Number 2

45. Clinical Characteristics, Males
HIV-Associated Hodgkin’s Disease
%
HIV-positive HIV-negative
B-symptoms*† 79 43
Extra-nodal*‡ 67 32
Stage III-IV disease* 58 19
Survival
1-year 75 92
5-year 42 80
*Significantly different from all others at p≤0.05
†Missing for n=182
‡Missing for n=47

46. Tumor Characteristics, Males
HIV-Associated Hodgkin’s Disease
%
Histologic subtype HIV-pos HIV-neg
Nodular Sclerosis* 32 61
Mixed Cellularity* 33 19
Nod. Lymph. Predomin. - 3
Lymph. Predomin. <1 5
Lymph. Depletion* 8 2
Unspecified* 27 11
*Significantly different from all others at p≤0.05

47. EBV Association
HIV-Associated Hodgkin’s Disease
%
HIV-pos HIV-neg
EBV-positive*† 90 33
*Significantly different from all others at p≤0.05
† Based on 519 patients

48. Overall survival of male patients with HIV-related Hodgkin
lymphoma who were diagnosed during 1988–1995 (87 patients)
and during 1996–1998 (n 31 patients) in the Greater Bay Area
Glaser et. al. CANCER July 15, 2003 / Volume 98 / Number 2

49. Incidence of HL and NHL by
CD4 count at AIDS onset
•Biggar et al BLOOD 1 December 2006 Vol 108 number 12

50. Studyname Outcome Statisticsfor eachstudy Eventrateand95%CI
Event Lower Upper
rate limit limit Z-Value p-Value Total
Spina 2002 CR 0.814 0.694 0.894 4.407 0.000 48/59
Calza 2002 CR 0.917 0.378 0.995 1.623 0.105 5/5
Gastaldi 2002 CR 0.944 0.495 0.997 1.947 0.052 8/8
Hartmann 2003 CR 0.962 0.597 0.998 2.232 0.026 12/12
Vilchez 2003 CR 0.261 0.122 0.472 -2.193 0.028 6/23
Hentrich 2006HAART CR 0.647 0.476 0.787 1.689 0.091 22/34
Berenguer 2008HAART CR 0.855 0.762 0.916 5.696 0.000 71/83
Spina 2008 CR 0.662 0.545 0.762 2.679 0.007 47/71
0.721 0.661 0.774 6.617 0.000
-1.00 -0.50 0.00 0.50 1.00
CompleteRemissionRates
MetaAnalysis(fixedeffects)
CR rate
Meta-analysis of Hodgkin lymphoma in HIV

51. Studyname Outcome Statisticsfor eachstudy Event rate and95%CI
Event Lower Upper
rate limit limit Z-Value p-Value
Spina 2002 2year OS 0.695 0.567 0.799 2.911 0.004
Calza 2002 2year OS 0.600 0.200 0.900 0.444 0.657
Gastaldi 2002 2year OS 0.944 0.495 0.997 1.947 0.052
Ribera 2002 2year OS 0.822 0.683 0.909 3.928 0.000
Gerard 2003HAART 2year OS 0.638 0.493 0.762 1.871 0.061
Hartmann 2003 2year OS 0.830 0.520 0.957 2.063 0.039
Glaser 2003 2year OS 0.640 0.553 0.718 3.125 0.002
Hentrich 2006HAART 2year OS 0.740 0.569 0.860 2.675 0.007
Tanaka 2007 2year OS 0.710 0.530 0.841 2.259 0.024
Spina 2008 2year OS 0.690 0.574 0.786 3.118 0.002
0.690 0.644 0.732 7.626 0.000
-1.00 -0.50 0.00 0.50 1.00
2year Overall Suvivial
MetaAnalysis(fixedeffects)
2 yr OS
Meta-analysis of Hodgkin lymphoma in HIV

52. Brentuximab Vedotin
AMC 085
Bortezomib
AMC 053
 Upfront
 Brentuximab Vedotin
substituted for bleomycin
in ABVD
AMC trials for Hodgkins
 Relapsed/Refractory
 Bortezomib + ICE

53. Objectives
 Why is this important?
 What types of cancers are HIV patients getting
now?
 Does early HAART prevent cancer?
 New treatment options for Kaposi’s sarcoma
 What is different about Hodgkin Lymphoma in
the HIV patient population?
 New treatment options for lymphomas

54. AIDS Lymphoma
AIDS
Lymphoma
NHL
DLBCL Burkitt’s Plasmablastic PEL
Hodgkin’s
lymphoma

56. AMC trials for non-Hodgkin lymphoma
 Relapsed/Refractory
 Velcade + ICE +/- rituximab (final cohort enrolling)
 Hematopoietic stem cell transplant
 Auto and allo protocols (enrolling)
 Burkitt’s or Burkitt’s-like
 Modified McGrath Regimen (in follow-up)
 REPOCH (starting enrollment)
 Upfront NHL
 Adding vorinostat (enrolling)
 RCHOP – early stage + favorable prognosis
 REPOCH – advanced stage or unfavorable prognosis

57. AMC S003: Retrospective Plasmablastic NHL
 19/40 cases confirmed on central review
 17/19 patients were HIV positive.
 29% on HAART at the time of lymphoma diagnosis
 First line chemo/immuno therapy given for 17 pts
(89%)
 6 were Primary refractory
 1 relapse

58. Plasmablastic lymphoma Outcome
 At last follow-up, 9 alive, 9 died and 1 lost to follow-
up
 Median follow-up for survivors 49 wks (range, 24-
165) weeks.
 Median Survival 7 years (95% CI, 0.9-9 years)
 1 yr OS 62.7% (SE, 11.2).

59. Plasmablastic lymphoma OS

60.  Why is this important?
 People with HIV are living longer ->more cancer related deaths
 What types of cancers are HIV patients getting now?
 HIV related and Non-HIV related
 Does early HAART prevent cancer?
 AIDS-related lower with early HAART
 New treatment options for Kaposi’s sarcoma?
 no curative therapy
 MULTIPLE strategies under study
 What is different about Hodgkin Lymphoma in the HIV
patient?
 EBV positive, significantly poorer prognosis pre-HAART,
different subtype profile, decreases with lower CD4 count
 HAART era seeing improved response rates and OS
 What is new for HIV-related lymphomas?
 Rituximab shows benefit for remission rates, infection
prophylaxis is important
 EPOCH is likely superior to CHOP for DLBCL
 Use in Burkitts under study
 Outcomes for plasmablastic may be better than previously
reported
 Lytic activation of EBV/HHV8 under study

61. Human defense against retroviruses
APOBEC3G
 cytidine deaminase gene family
 encode proteins that are structurally and functionally
related to the C to U RNA-editing cytidine deaminase
APOBEC1.
 The protein encoded by this gene has been found to be a
specific inhibitor of human immunodeficiency virus-1 (HIV-
1) infectivity.

62. Human defense against retrovirus
infections: ABOBEC3G
APOBEC3G hypermutates viral
cDNA during reverse transcription,
blocking viral replication in newly
infected cell
APOBEC3G incorporated into
virion as it buds from
infected cell
No viral
replication
x

63. Vif protects HIV against APOBEC3G
HIV replicates in
and buds from
newly infected cell
Degradation of ubiquinated
APOBEC3G by proteasome
vif

64. Proposed anti-HIV activity of bortezomib
x
HIV replication blocked
in newly infected cell
Bortezomib inhibits proteasome
degradation of ubiquitinated
APOBEC3G allowing its
accumulation and incorporation into
budding virion
No HIV
replication
vif