Download HIV and cancers - Portail VIH/sida du Québec

Cancers et VIH:
Style de vie ou nouvel effet du VIH ?
Jean-Pierre Routy M.D.
McGill University
Le 2 mars 2010
Centre Saint Pierre
Montréal
Liens entre VIH et Cancers
• First case report on Kaposi sarcoma (KS) in gay
men in New-York City and San Francisco (1981)
• AIDS defining cancers:
– KS
– Non-Hodgkin lymphoma (NHL):
• Diffuse type
• CNS
– Cervical cancer (HPV)
• Non-AIDS defining cancers:
– Some type of tumors have been found in greater
frequency in HIV infected persons
Cancers associés au VIH
• Two possible explanations:
– Confounding by shared lifestyle cancer
risk factors
– A direct effect of HIV, likely through an
effect of immune deficiency
• Importance:
– If immune deficiency is responsible, then
reversing immune deficiency might decrease
cancer risk
Récente augmentation de la fréquence des
cancers chez les personnes infectées
• Increasing survival of patients with HIV
might be associated with an increase of
traditional cancer
• Aging of the HIV population
• Life style
• Long-term toxicity of ART ?
• CD4 recovery:
– Opportunist cancers
– Traditional cancers ?
Cancers et VIH:
Rôle du manque d’immunité
Cancer rate should also be increased in
other immunosuppressive disorders
Infection-related cancers
Cohort
Number Observed number Heterogeneity
of studies
of cases
p-value
Meta-analysis SIR (95% CI)
EBV related cancers
Hodgkin lymphoma HIV / AIDS
Transplant
11.03 (8.43 - 14.44)
3.89 (2.42 - 6.26)
7
4
802
21
0.00
0.65
76.67 (39.37 - 149.29)
8.07 (6.40 - 10.17)
6
4
5295
333
0.00
0.02
HHV-8 related cancer
HIV / AIDS*
Kaposi sarcoma
Transplant
3640 (3326 - 3976)
208.0 (113.7 - 349.0)
1
1
494
14
-
HBV/HCV related cancer
HIV / AIDS
Liver
Transplant
5.22 (3.32 - 8.20)
2.13 (1.16 - 3.91)
7
3
133
19
0.01
0.25
Helicobacter pylori related cancer
Stomach
HIV / AIDS
1.90 (1.53 - 2.36)
Transplant
2.04 (1.49 - 2.79)
7
3
89
44
0.49
0.85
Non-Hodgkin
lymphoma
HIV / AIDS*
Transplant
1
10
100
1000
SIR
Figure 2: Standardised incidence ratios for cancers related to infection with Epstein-Barr virus, human herpesvirus 8, hepatitis B and C virus, and
Helicobacter pylori in people with HIV/AIDS and in transplant recipients
EBV=Epstein-Barr virus. HBV=hepatitis B virus. HCV=hepatitis C virus. HHV8=human herpesvirus8. *For AIDS-defining cancers, data from cohorts defined by an AIDS
diagnosis included only those individuals who did not have that type of cancer at the time of AIDS.
Grulich et al. Lancet, 2007, 370, 59–
Cohort
Number Observed number Heterogeneity
of studies
of cases
p-value
Meta-analysis SIR (95% CI)
HPV related cancers
Cervix uteri
HIV / AIDS* 5.82 (2.98 – 11.3)
Transplant 2.13 (1.37 – 3.30)
6
3
104
22
0.00
0.67
Vulva and
vagina
HIV / AIDS
Transplant
6.45 (4.07 – 10.2)
22.76 (15.79 – 32.70)
2
2
21
33
0.55
0.85
Penis
HIV / AIDS
Transplant
4.42 (2.77 – 7.07)
15.79 (5.79 – 34.37)
3
1
21
6
0.52
-
Anus
HIV / AIDS
Transplant
28.75 (21.60 – 38.27)
4.85 (1.36 – 17.29)
6
2
303
18
0.03
0.04
Oral cavity and
Pharynx †
HIV / AIDS
Transplant
2.32 (1.65 – 3.25)
3.23 (2.40 – 4.35)
4
3
238
49
0.07
0.37
Possibly HPV related cancers
Non-melanoma
HIV / AIDS
Skin ‡
Transplant
4.11 (1.08 – 16.62)
28.62 (9.39 – 87.20)
4
3
121
448
0.00
0.00
Lip
2.80 (1.91 – 4.11)
30.00 (16.27 – 55.30)
2
5
30
506
0.45
0.00
HIV / AIDS
Transplant
Oesophagus
HIV / AIDS
Transplant
1.62 (1.20 – 2.19)
3.05 (1.87 – 4.98)
4
3
48
28
0.53
0.28
Larynx
HIV / AIDS
Transplant
2.72 (2.29 – 3.22)
1.99 (1.23 – 3.23)
5
3
142
20
0.55
0.88
Eye
HIV / AIDS
Transplant
1.98 (1.03 – 3.81)
6.94 (3.49 – 13.81)
2
2
11
10
0.92
0.35
.1
1
10
100
1000
SIR
Figure 3: Standardised incidence ratios for cancers related to, or possibly related to, human papillomavirus infection, in people with HIV/AIDS and in
transplant recipients
HPV=human papillomavirus. *For the AIDS-defining cancer (cervical cancer), data from cohorts defined by an AIDS diagnosis included only those individuals who did
not have cervical cancer at the time of AIDS. †Excluding lip and nasopharynx. ‡Any measure of non-melanoma skin.
Grulich et al. Lancet, 2007, 370, 59–
Common epithelial cancers
Number Observed number Heterogeneity
of studies
of cases
p-value
Cohort
Meta-analysis SIR (95% CI)
Breast
HIV / AIDS
Transplant
1.03 (0.89 – 1.20)
1.15 (0.98 – 1.36)
6
5
194
156
0.60
0.66
Prostate
HIV / AIDS
Transplant
0.70 (0.55 – 0.89)
0.97 (0.78 – 1.19)
6
3
202
98
0.22
0.82
Colon and rectum
HIV / AIDS
Transplant
0.92 (0.78 – 1.08)
1.69 (1.34 – 2.13)
5
3
224
185
0.34
0.11
Ovary
HIV / AIDS
Transplant
1.63 (0.95 – 2.80)
1.55 (0.99 – 2.43)
5
3
30
23
0.34
0.61
Trachea, bronchus, HIV / AIDS
and lung
Transplant
2.72 (1.91 – 3.87)
2.18 (1.85 – 2.57)
7
3
1016
234
0.00
0.25
.1
1
10
100
1000
SIR
Figure 4: Standardised incidence ratios for common epithelial cancers in people with HIV/AIDS and in transplant recipients
Grulich et al. Lancet, 2007, 370, 59–
Cancers chez les personnes VIH et
ayant une transplantation d’organes
• The range of cancers occurring at increased
rates is strikingly similar in the two groups
• Mostly those known or suspected to be caused
by infective agents
• Impact of immunodeficiency of these cancers
Baisse de l’immunité et à
risque de cancer
– NHL
– Burkitt
median CD4 350-500 (25% EBV)
– Immunoblastic
median CD4 50-150 (60% EBV)
– Primary CNS median CD4 10-50 (100% EBV)
– KS
–
Median CD4 100-200 (relatively wide interquartile range)
– Hodgkin’s disease
• median CD4 200-350
– HPV-related cancers
• any CD4 count
195
le
meilleur
Non-AIDS cancers and CD4 :
cohorte EuroSIDA
…de CROI 2009
•
•
12 865 patients suivis jusqu’à décès ou dernière visite
Cancers non sida, à l’exclusion des cancers de la peau
Incidence des cancers non sida,
IC 95 % (pour 1 000 années-patient)
10
8
Incidence des cancers non sida
p
CD4 (par valeur doublée)
0,01
Transmission Homo.
UDIV
Hétéro.
Autre
0,98
0,02
0,04
Race
6
ATCD sida
4
2
0
< 50
51 à
200
201 à 351 à > 500
350
500
Dernier taux de CD4 (/mm3)
Blanc
Autre
0,01
Non
Oui
0,002
ATCD Cancer Non
Oui
Négatif
Hépatite B
Positif
Âge
Par 10 ans
Durée ARV
Par 6 mois
0,1
0,001
< 0,001
< 0,001
< 0,001
1
Ratio d’incidence
10
Reekie J, CROI 2009, Abs. 860a
Risk of Hodgkin lymphoma by CD4 count
Clifford and Franceschi, 2009
CD4 and risk of liver cancer
Clifford and Franceschi, Future Oncology 2009
Immunodeficiency or viremia as a risk
factor for non-AIDS cancers
Patient characteristics at start cART
N: Amsterdam cohort
Gender, N (%)
11459
Male
Age, Median (IQR)
8816
(77 %)
38
(32-45)
Region of origin, N (%)
W-Europe
7250
(63 %)
Exposure Group, N (%)
MSM
6003
(52 %)
Hetero
3958
(35 %)
IDU
541
(5 %)
Prior ART, N (%)
2240
(20 %)
Prior AIDS, N (%)
3079
(27 %)
Nadir CD4, Median (IQR)
cells/mm³
150
(55-240)
HIV RNA, Median (IQR)
log10cps/ml
4.9
(4.3-5.3)
HCV, N (%)
Antibody
561
(5 %)
HBV, N (%)
Surface antigen 531
(5 %)
797
(7 %)
Alcohol Abuse, N (%)
Smoking status, N (%)
Ever
4745 / 6701
(71 %)
Kesselring et al IAS 2009
Missing
4758
(42 %)
Variables
Time dependent
• Age
• Exposure to cART
• Latest CD4
– 6 months lagged
• Cumulative exposure to CD4
– Below 200/350/500 cells/mm³
• Latest VL
– 6 months lagged
• Cumulative exposure to VL
– More than 400 cps/ml
Fixed
•
•
•
•
•
•
•
•
•
•
Nadir CD4
CD4 at start cART
Duration of HIV infection
Gender
Region of origin
Mode of transmission
Prior NADM
Prior AIDS
Alcohol, Smoking
HBV / HCV coinfections
Types of malignancies
Other epithelial; 33
Anal; 37
Colon; 10
Mamma; 12
Larynx; 20
Prostate; 16
Liver; 16
Haematological; 17
Lung; 44
Hodgkin; 20
Other infectionrelated; 7
All malignancies n=232
Malignancies due to infection related cause, n=100 (43 %),
Malignancies due to other causes, n=132 (57 %)
Other infection-related group includes oesophagal, stomach and vulva carcinoma.
Other epithelial group includes bladder, colon, pancreas, renal, testis, cerebral, bone malignancies and
melanoma.
Multivariate Cox regression model
Duration of HIV
per yr
0.09
Positive
0.02
Negative
ref
Age
per 10 yrs
<0.0001
Aids
Yes
0.03
No
ref
West
ref
Other
0.006
CD4 exposure / yr <200
0.03
200-350
0.09
350-500
0.51
>500
0.14
>400
0.88
Hepatitis B
Region of origin
VL exposure / yr
0.5
1.0
1.5
2.0
2.5
3.0
HR
Adjusted for gender, cumulative exposure to cART, smoking, alcohol abuse.
Effect of immunodeficiency on malignancies
due to infection-related and other causes
<200
CD4 exposure/yr
0.01
0.27
Infection-related
Other
0.13
200-350
0.28
0.99
350-500
0.42
>500
0.46
0.21
VL exposure/yr
0.36
>400
0.16
0.6
0.8
1.0
1.2
1.4
HR
Adjusted for age, prior AIDS, gender, region of origin, cumulative exposure to cART, estimated
duration of HIV infection prior to start cART, coinfections, smoking, alcohol abuse.
Current CD4 count and death from cancer
D:A:D study group AIDS 2008, 22:2143–
Is the increased risk of cancer reversible
with ART and CD4 recovery ?
Incidence rates of
NHL and KS
US Adult spectrum of disease/HOPS studies
Patel et al. Ann Intern Med 2008, 148, 728-
Trends in Hodgkin lymphoma
and anal cancer
US Adult spectrum of disease/HOPS studies
Patel et al. Ann Intern Med 2008, 148, 728-
Hodgkin lymphoma after HIV: Australia
Pre-HAART
Post-HAART
100
80
SIR
60
40
17.3
20
6.7
9.1
p=0.02
6
0
1982-1989
1990-1995
7.4
1996-1999
Period
2000-2004
van Leeuwen et al, submitted
Anal cancer after HIV: Australia
Pre-HAART
Post-HAART
120
100
SIR
80
60
49.1
36.5
40
20
32.1
p=0.78
3
28.7
0
1982-1989
1990-1995
1996-1999
Period
2000-2004
van Leeuwen et al, submitted
Lower Risk for Certain Non-AIDS–Defining
Cancers With Higher Recent CD4+ Cell Count
Silverberg et al abstract 28
• Risk of anal cancer, oral/pharyngeal cancer, and
Hodgkin’s lymphoma:
– More frequent than in non-HIV
– Increased with lower recent CD4+ cell count
• Lung and colorectal cancer:
– increased among HIV vs HIV-uninfected individuals
– Only when recent CD4+ cell count low (no nadir effect)
• Viral load not associated with risk for cancer
• Detect and treat HIV-1 infection at early stages of
infection may reduce cancer burden in this population
Reversibility of cancer risk
• Most marked declines: KS, NHL
– Decline is not absolute and morbidity remains
substantial
– RR around 10 for NHL
• Little or no decline
– Hodgkin lymphoma, HPV-related cancers
• Increasing age of people with HIV is important as
population rates of cancer increase exponentially
ART and anal
cancer incidence
• Anal cancer is uncommon in the general
population
– 1.4 cases per 100,000 person-years
• HIV infected persons have a higher risk of
anal cancer
• ART and HIV infection duration on anal
cancer not well defined
1. SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2006. 2. Melbye M, Rabkin C, Frisch M,
Biggar RJ. Am J Epidemiol. 1994;139:772-80.; 3. D’Souza G, Wiley DJ, Li X, et al. JAIDS. 2008;48:491-9.; 4. Piketty C, Selinger-Leneman H, et al. AIDS.
2008;22:1203-11.; 5. Diamond C, Taylor TH, Aboumrad T, et al. Sex Transm Dis. 2005;32:314-20.; 6. Chiao EY, Krown SE, Stier EA, et al. JAIDS. 2005;40:451-5.
Study population and Methods




U.S. Military Natural History Study, following participants from 19852008
4,901 HIV-infected participants : 40,951 person years (PY) of follow-up

55% with documented seroconversion dates
Anal cancer cases were histopathologically confirmed squamous cell
carcinomas40,951 person years (PY) of follow-up
Characteristics at HIV diagnosis:

Age: 28 years (IQR 24-34)

92% male

45% African American and 43% Caucasian

CD4 count: 506 cells/mm3 (IQR 350-676)
Nancy Crum-Cianflone, IAS 2009
Demographic Characteristics at Anal
Cancer Diagnosis (N=20)
Age, years
Median (IQR)
41.6 (33.6-46.0)
<20
20-29
30-39
>40
0%
15%
25%
60%
Male gender
95%
Ethnicity
Caucasian
African American
55%
45%
Factors Associated with Anal Cancer
Factor(s)
Hazard Ratio
95% CI
P-value
Age at HIV diagnosis (per 10 years)
0.94
0.52 - 1.73
0.85
Male gender
1.52
0.20 - 11.34
0.69
White ethnicity
1.69
0.70 - 4.08
0.24
Hepatitis B seropositive1
0.77
0.30 - 1.97
0.59
Gonorrhea1
2.33
0.91 - 5.96
0.08
Any STI1
1.22
0.46 - 3.22
0.69
AIDS-defining event1
3.47
1.33 - 9.09
0.01
Nadir CD4 cell count1 (per 50 cells)
0.85
0.73 - 0.98
0.02
CD4 cell count1 (per 50 cells)
0.94
0.87 - 1.03
0.20
HIV RNA1 (per ½ log10)
1.21
0.58 - 2.52
0.62
Antiretroviral therapy use1
2.34
0.62 – 8.87
0.21
Duration of HAART use1
0.92
0.81-1.05
0.22
1 Time-updated
covariate
Multivariate Analyses of Factors
Associated with Anal Cancer
Factor(s)
Hazard Ratio
95% CI
P-value
Model 1:
AIDS-defining event1
Gonorrhea1
3.48
2.34
1.33 – 9.12
0.91 - 6.00
0.01
0.08
Model 2:
Nadir CD4 cell count1 (per 50 cells)
Gonorrhea1
0.85
2.31
0.73 – 0.98
0.90 - 5.95
0.02
0.08
1
Time-updated covariate
Can ART improve survival in
cancer patients ?
196
le
meilleur
…de CROI 2009
Lymphome non hodgkinien chez le patient VIH
• Étude du Kaiser Permanente (Californie) (1) : comparaison de la
survie de LNH diagnostiqués entre 1996 et 2005 chez les patients
VIH+ (n = 268) et les patients VIH- (n = 8 203)
– Mortalité à 2 ans = 59 % chez VIH+ versus 29 % chez VIH(OR = 5,93 ; IC 95 % = 4,52-7,78 ; p < 0,01)
– La surmortalité chez les patients VIH+ persiste même après ajustement
sur chimiothérapie, et au cours de la période la plus récente
Probabilité de survie
(LNH-COHERE)
1,0
•
Groupe COHERE (2) : 22 cohortes
européennes, 56 305 patients
– incidence LNH et lymphome
cérébral primitif (LCP) pour
100 000 années-patient = 519 si
absence HAART versus 229 si
HAART
– survie à 1 an :
– 66 % pour LNH
– 54 % pour LCP
0,75
0,5
Pas d’ARV
0,25
ARV pendant < 90 j
ARV pendant ≥ 90 j
Années
0
n
0
1
2
3
4
5
329
96
338
197
49
136
145
34
87
114
22
58
76
18
33
50
10
15
(1) Chao C, CROI 2009, Abs. 871 ; (2) Bohlius J, CROI 2009, Abs. 872
Characteristics of cancer
immune control
•
•
•
•
•
CD4 cell count
CTL function
NK
Immune memory Central/effector memory
Level of immune activation:
– PD-1, IL-10, Treg
• Immune system on pre-cancerous lesions
Conclusions
• Meilleur sont les CD4, meilleur pour la santé
– Dépend du type de cancers:
• Associé à un virus
• Style de vie et cancers:
– Association très forte
– Prévention, dépistage: HPV
• VIH et cancers non-SIDA:
– En faveur d’une initiation précoce des ART
– Dépistage surtout pour les plus de 50
Merci
• Bruno Lemay
• Info traitement