Transcript Virus-Mediated Malignancies in the Antiretroviral Era

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, MPH
Vaccine 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 prevalence
Osmond 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
ART
HIV
KS -- Men
KS--Women
60
70000
50
60000
40
50000
40000
30
30000
20
20000
KS cases per 100,000 /
HIV prevalence (%)
No of People Treated with ART
80000
10
10000
0
0
1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
Year
No change in KS incidence in Uganda despite over
100,000 persons started on HAART
Current Treatment for KS in ResourceRich Settings is Inadequate
Nguyen HQ, et. al. AIDS 2008
Current Treatment of KS in ResourcePoor Settings is Inadequate
HAART
Chemo
HAART + Chemo
HAART
Cumulative Incidence
Cumulative Incidence
0.8
0.6
0.4
0.2
Log Rank: p <0.0001
•
•
•
•
0.8
0.6
0.4
0.2
0.0
0.0
•
HAART + Chemo
1.0
1.0
Days since
treatment
Chemo
Days since
treatment
0
90
270
360
450
540
630
720
No. at risk H
78
64
56
49
38
27
19
16
16
12
12
8
8
No. at risk H
78
62
48
37
29
18
12
5
0
No. at risk C
32
15
12
8
8
6
5
3
2
2
2
2
2
No. at risk C
20
17
11
9
9
5
3
3
3
No. at risk H+C
24
23
18
9
8
5
4
4
3
3
1
1
0
No. at risk H+C
46
40
29
28
24
15
13
8
6
0
30
60
90 120 150 180 210 240 270 300 330 360
180
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 inhibitorcontaining HAART were 6.9 (95% CI: 1.7-27, p=0.006) and 15 times (95% CI: 1.3183, p=0.03) more likely to experience resolution compared to those receiving
Triomune (stavudine-lamivudine-nevirapine).
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
•
•
•
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
•
•
Hymes KB, et. al. Lancet 1981; 2:598-600.
Eltom MA, J Natl Cancer Inst 2002;94:120410.
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;94:120410.
Original AIDS-Defining Malignancies
•Cervical Cancer
•Kaposi’s Sarcoma
•Burkitt’s Lymphoma
•Immunoblastic
Lymphoma
•Primary Brain
Lymphoma
Original AIDS-Defining Malignancies
Malignancy
•Cervical Cancer
•Kaposi’s Sarcoma
Viral Etiology
HPV
HHV-8
•Burkitt’s Lymphoma
•Immunoblastic
Lymphoma
•Primary Brain
Lymphoma
EBV
Viral Oncogens
Virus
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 AIDSdefining 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;362:22-9
Mocroft A, et. al. Lancet 2003
…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
Cancer
Anus
Range in SIR in 5 studies of
over 440,000 People
19.63-50.00
Liver
2.73-7.70
Respiratory
1.44-4.50
All Non-AIDS
Defining Cancers
1.63-2.79
Grulich A, Lancet 2007
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)
ul
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Median Annual % Change
Cancer Incidence Trends in Uganda,
1992-2005
Trends in Cancer Incidence, Uganda 1992-2005
40.00
20.00
0.00
20.00
40.00
60.00
80.00
100.00
Cancer
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 HIVPositive 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 women
Mathews WC. Top HIV Med. 2003 Mar-Apr;11(2):45-9
• Effective HAART use may not
be associated with a decline in
anal dysplasia / cancer
Piketty 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
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 (3143)
21.5
(10.547.5)
13 (7-29)
Tumor
Stage n
(%)
n=144
I&II n=11
3
7
1
III&IV
n=133
37
81
15
19.8
(17.722.4)
19.8
(16.722.9)
17.7
(14.7-18.5)
Median (IQR) BMI
(Only for those
≥18years n=109
Bateganya M, IAS 2009
NHL in Uganda:
Impact of ART Survival
Bateganya M, IAS 2009
NHL in Uganda:
Impact of Chemotherapy on Survival
Bateganya M, IAS 2009
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
HBV
HCV
•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
Vaccine eliciting
neutralizing
antibodies
Chronic Infection
Agents to Promote Viral
Latency
Antiviral
Agents
Viral Replication
•Angiogenesis Inhibitors
Transformation to
Malignancy
•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 EBVassociated 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
46,
(10-320)
216,
(80-1280)
302,
(20-1280)
0,
(0-0)
Neutralizing
antibody titers
Geometric Mean
Titer (1:n),
(Range)
•Neutralizing antibodies may be protective against HHV-8
Kimball, 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 T-cell Leukemia
Virus (HTLV)
•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.
–
Percent of People PCR Positive
Antiviral Medications Against HHV-8
100
80
Crossover
Valganciclovir
Crossover
60
40
20
0
1
7
14
7
14
21
28
35
42
49
56
7
14
Day
•
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)
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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