HIV and Malignancies S. De Wit St Pierre Hospital Brussels.
Transcript of HIV and Malignancies S. De Wit St Pierre Hospital Brussels.
HIV and Malignancies
S. De WitSt Pierre HospitalBrussels
HIV and cancerHIV and cancer
• AIDS-defining malignancies:– Kaposi’s sarcoma– Non Hodgkin lymphoma 1985– Cervical cancer 1993
• Non AIDS-defining malignancies (NADM) is increasing
• Linked with virus HPVHPV (Anal), HBVHBV and HCVHCV (Liver), EBVEBV (HL)• Linked with previous immunodeficiency
HPVHPVEBVEBVHHV8HHV8
Background
• Before introduction of HAART, ADCs common, including Kaposi’s sarcoma, NHL, and invasive cervical carcinoma
• Rate of ADCs significantly increased from early to late pre-HAART era and then significantly decreased following introduction of HAART
• Rates of nADCs stable during pre-HAART eras and then significantly increased following introduction of HAART
Crum-Cianflone N, et al. AIDS. 2009;23:41-50.
SIR = Standardised Incidence RatioSIR = Standardised Incidence RatioNb cases of cancer in the HIV population
Expected nb of cases in the general population, calculated with local cancer registry incidence
=
Cancer Incidence in AIDS Patients
• Study of cancer risk in AIDS patients from 1980-2006 (N=372,364)
• Predominantly male (79%), non-hispanic black (42%), MSM (42%)
• Median age of 36 years at the onset of AIDS
Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.
Cancer type No. cases SIR 95% CI
AIDS-defining cancers
Kaposi sarcoma 3136 5321 5137 - 5511
Non-Hodgkin lymphoma
3345 32 31 - 33
Cervical cancer 101 5.6 5.5 - 6.8
Non-AIDS-defining cancers
Anal cancer 219 27 24 - 31
Liver cancer 86 3.7 3.0 - 4.6
Lung cancer 531 3.0 2.8 - 3.3
Hodgkin lymphoma 184 9.1 7.7 - 11
All non-AIDS related cancers
2155 1.7 1.5 - 1.8
SIR=Standardized Incidence Ratios
Cancer Mortality in AIDS Patients
Population attributable risk among people with AIDS in the US
Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.
Cum
ulati
ve In
cide
nce
(%)
Increased rates of nADCs. Why ?
• 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 ?
HIV associated cancers
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
Pathogenesis of NADC• Some are virally-induced cancers, but not all• HIV-tat may transactivate cellular genes or proto-
oncogenes, inhibit tumor suppressor genes• Microsatellite alterations (MA) due to genetic
instability in HIV (e.g 6 fold higher number of MA in HIV lung CA over non-HIV)1
• Increase susceptibility to effects of carcinogens (tobacco)
• Population differences based on genetics and exposure to carcinogens
• Decreased immune surveillance11Wistuba, AIDS 1999;13:415-26Wistuba, AIDS 1999;13:415-26
HIV & Cancers Role of immune deficiency ?
Cancer rate should also be increased in other immunosuppressive disorders
Infection-related cancers
EBV related cancers
Hodgkin lymphoma
Non-Hodgkin lymphoma
HHV-8 related cancer Kaposi sarcoma
HBV/HCV related cancer Liver
HIV / AIDS Transplant
HIV / AIDS*
Transplant
HIV / AIDS*
Transplant
0.00 0.65
0.00
0.02
-
-
HIV / AIDS
0.01
Transplant
0.25
Cohort Meta-analysis SIR (95% CI) Heterogeneity
p-value Number
of studies
Stomach Transplant 0.85 HIV / AIDS
802 21
5295
333
494
14
133
19
44 89
11.03 (8.43 - 14.44) 3.89 (2.42 - 6.26)
76.67 (39.37 - 149.29)
8.07 (6.40 - 10.17)
3640 (3326 - 3976)
208.0 (113.7 - 349.0)
5.22 (3.32 - 8.20)
2.13 (1.16 - 3.91)
2.04 (1.49 - 2.79) 1.90 (1.53 - 2.36)
7 4
6
4
1
1
7
3
3 7 0.49
1 10 100 1000
Helicobacter pylori related cancer
Observed number of cases
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–
HPV related cancers Cervix uteri
Vulva and vagina
Penis
Anus
Oral cavity and Pharynx †
Possibly HPV related cancers Non-melanoma Skin ‡
Lip
Oesophagus
Larynx
Eye
HIV / AIDS* Transplant
HIV / AIDS Transplant HIV / AIDS Transplant HIV / AIDS Transplant HIV / AIDS Transplant
HIV / AIDS Transplant HIV / AIDS Transplant HIV / AIDS Transplant HIV / AIDS Transplant HIV / AIDS Transplant
6 3
2 2 3 1 6 2 4 3
4 3 2 5 4 3 5 3 2 2
0.00 0.67
0.55 0.85 0.52 -
0.03 0.04 0.07 0.37
0.00 0.00 0.45 0.00 0.53 0.28 0.55 0.88 0.92 0.35
104 22
21 33
21 6 303 18 238 49
121 448
30 506
48 28 142 20
11 10
5.82 (2.98 – 11.3) 2.13 (1.37 – 3.30)
6.45 (4.07 – 10.2) 22.76 (15.79 – 32.70)
4.42 (2.77 – 7.07) 15.79 (5.79 – 34.37)
28.75 (21.60 – 38.27) 4.85 (1.36 – 17.29)
2.32 (1.65 – 3.25)
3.23 (2.40 – 4.35)
4.11 (1.08 – 16.62) 28.62 (9.39 – 87.20)
2.80 (1.91 – 4.11) 30.00 (16.27 – 55.30)
1.62 (1.20 – 2.19)
3.05 (1.87 – 4.98)
2.72 (2.29 – 3.22) 1.99 (1.23 – 3.23)
1.98 (1.03 – 3.81) 6.94 (3.49 – 13.81)
.1 1 10 100 1000
Cohort Meta-analysis SIR (95% CI) Heterogeneity
p-value Number
of studies Observed number
of cases
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
Ovary
Trachea, bronchus, and lung
HIV / AIDS Transplant
HIV / AIDS Transplant
1.63 (0.95 – 2.80) 1.55 (0.99 – 2.43)
2.72 (1.91 – 3.87) 2.18 (1.85 – 2.57)
5 3
7 3
Breast HIV / AIDS Transplant
1.03 (0.89 – 1.20) 1.15 (0.98 – 1.36)
6 5
0.60 0.66
Prostate HIV / AIDS Transplant
0.70 (0.55 – 0.89) 0.97 (0.78 – 1.19)
6 3
0.22 0.82
Colon and rectum HIV / AIDS Transplant
30
23
1016 234
194 156
202 98
224 185
0.92 (0.78 – 1.08) 1.69 (1.34 – 2.13)
5 3
0.34 0.11
0.34 0.61
0.00 0.25
.1 1 10 100 1000
Cohort Meta-analysis SIR (95% CI) Heterogeneity
p-value Number
of studies Observed number
of cases
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 in HIV and transplant patients
• 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 on these cancers
Clifford and Franceschi, Future Oncology 2009
CD4 and risk of liver cancer
Current CD4 count and death from cancer
D:A:D study group AIDS 2008, 22:2143–
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
Cancer Incidence in AIDS Patients
Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.
Cancer type No. cases SIR 95% CI
AIDS-defining cancers
Kaposi sarcoma 3136 5321 5137 - 5511
Non-Hodgkin lymphoma
3345 32 31 - 33
Cervical cancer 101 5.6 5.5 - 6.8
Non-AIDS-defining cancers
Anal cancer 219 27 24 - 31
Liver cancer 86 3.7 3.0 - 4.6
Lung cancer 531 3.0 2.8 - 3.3
Hodgkin lymphoma 184 9.1 7.7 - 11
All non-AIDS related cancers
2155 1.7 1.5 - 1.8
SIR=Standardized Incidence Ratios
Anogenital Cancers
• Invasive cervical carcinoma– Considered an AIDS-defining condition
• Anal cancer1
– Not AIDS defining but very common
• HPV involvement1-2
– Both derive from premalignant dysplastic lesions due to HPV– Most oncogenic strains: 16, 18, 31, 33, 35, 45– Repeated infections and infection with multiple HPV strains increase
the risk of developing neoplasia
1Phelps RM, et al. Int J Cancer. 2001;94:753-757.2Martin F, et al. Sex Transm Infect. 2001;77:327-331.
HPV-induced cancerHPV-induced cancer
• Cervix• Vulva• Vagina• Anal• Oro-pharyngal
• Penis
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 82
Schiffman, M. et al. N Engl J Med 2005;353:2101-2104
The Natural History of HPV Infection and Cervical Cancer
HIV- HIV+HIV+
Persistent HPVPersistent HPV 5-10% 20-40%20-40%
Cervical cancer Cervical cancer x 3-11x 3-11
Vulva & vagina cancer Vulva & vagina cancer x 4-10x 4-10
Infection with oncogenic HPV Infection with oncogenic HPV in HIV womenin HIV women
• Prevalence is higher :20-40% (vs.5-10%)
• Multiple genotypes: 40 % (vs. 12% )
• New infection? Reactivation of latent infection
• Linked with younger age, lower CD4 and higher HIV VL
Paleksky. J Natl Cancer Inst 1999
Strickler. Journal of the National Cancer 2005
D Konopnicki, Y Manigart, C Gilles, de Marchin J*, M Delforge, F Feoli*, P Barlow, S De Wit and N Clumeck. ECCMID 2011
Saint-Pierre CohortN=592
Prevalence of HR-HPV infection according to both age and CD4 cell strata (count/µL). (p=0.03, logistic regression)
EACS guidelines 2011. Available at http://www.europeanaidsclinicalsociety.org/guidelinespdf/EACS-EuroGuidelines_FullVersion.pdf . Accessed March 2011.
Problem Patients Procedure Evidence of benefits
Screening interval Additional Comments
Breast cancer
Women 50–70 yrs Mammography ↓breast cancer
mortality 1–3 years
Cervical cancer
Sexually active women
Papanicolau test,HPV DNA test
↓cervical cancer mortality 1–3 years
Target age group should include at least the age range 30 to 59 years. Longer screening interval if prior screening tests repeatedly negative
Colorectal cancer
Persons 50–75 yrs
Fecal Occult Blood test
↓colorectal cancer mortality 1–3 years Benefit is marginal
Cancer screening – EACSCancer screening – EACS
Screening in developing countriesScreening in developing countries• Screen-and-treat approach• Randomised , n=6555 with 956 HIV-positive women in South Africa,
35-65 years first screen. Excluded macroscopic lesions (6%)
• 3 arm– HPV test and cryotherapy– Visual inspection+ acetowhite detection and cryotherapy– Control : delayed at 6 months
• Women had colposcopy and biopsy at Month 6 (all), 12, 24 and 36 (subset)
HIV pos HIV neg ≥CIN2 at M36 15% 5% p=.0006Screen HPV RR M36 0.2 (0.06-0.07) 0.3 (0.02-.005) ps for
bothScreen VIA 0.51 (0.29-0.89) p=ns
Kuhn and al. AIDS 2010
Anal CancerAnal CancerInvasive cancerSIR 6-8 (in USA, St-Pierre Cohort)
PikettyAIDS 2008132 cases of invasive anal cancer among 86322 HIV-patientsMedian survival 5 years
RecentRecent PrePre EarlyEarly
Median CD4Median CD4 188 188 227227 288288Death due to ACDeath due to AC 50% 50% 40%40% 68.8%68.8%
http://clinicaloptions.com/hiv
Anal Cancer Incidence
• Incidence and risk of invasive anal cancer – Higher in HIV-infected vs age- and gender-matched general population (P
< .001)
• 60/100,000 PYs (95% CI, 40-89) vs 0.52/100,000 PYs (95% CI, 0.27-0.78)
– Nonsignificant difference in pre-HAART and post-HAART era for HIV-positive individuals (P > .05)
• 35/100,000 PYs (95% CI, 15-72) vs 92/100,000 PYs (95% CI, 52-149)
– Higher relative risk of anal cancer vs general population in post-HAART era
• Pre-HAART era, 67
• Post-HAART era, 176
Bower M, et al. J Acquir Immune Defic Syndr. 2004;37:1563-1565.
Anal Cytology Screening for AIN in HIV-positives
Screening Pap
Normal ASCUS
LSIL HSIL
Repeat in 12 months
Anoscopy with biopsy
Treat or follow Treat
No lesion seen
Chin-Hong PV et al. J Infect Dis. 2004;90:2070-2076.
LSIL HSIL
In summaryIn summary
• HPV-induced cancers are not reduced after cART introduction
• Screening should be improved for cervical cancer and for anal cancer
• Preventive vaccination against HPV should be more extensively studied and applied in HIV patients
Cancer Incidence in AIDS Patients
Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.
Cancer type No. cases SIR 95% CI
AIDS-defining cancers
Kaposi sarcoma 3136 5321 5137 - 5511
Non-Hodgkin lymphoma
3345 32 31 - 33
Cervical cancer 101 5.6 5.5 - 6.8
Non-AIDS-defining cancers
Anal cancer 219 27 24 - 31
Liver cancer 86 3.7 3.0 - 4.6
Lung cancer 531 3.0 2.8 - 3.3
Hodgkin lymphoma 184 9.1 7.7 - 11
All non-AIDS related cancers
2155 1.7 1.5 - 1.8
SIR=Standardized Incidence Ratios
Hodgkin’s Disease• Association with HIV-infection
– Hodgkin’s disease: RR: 5 to 30– Non-Hodgkin’s disease: RR: 24 to 165
• Patients with HIV present with:– B symptoms (70% to 96%), worse histology, higher-
stage tumor (74% to 92% are III or IV), bone marrow involvement (40% to 50%), pancytopenia
• Good response to MOPP/ABV– Complete response: 74.5%– 2-year disease-free survival: 62% – Early better results with Stanford V and BEACOPP
Gerard L, et al. AIDS. 2003;17:81-87.
Clifford and Franceschi, 2009
Risk of Hodgkin lymphoma by CD4 count
Cancer Incidence in AIDS Patients
Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.
Cancer type No. cases SIR 95% CI
AIDS-defining cancers
Kaposi sarcoma 3136 5321 5137 - 5511
Non-Hodgkin lymphoma
3345 32 31 - 33
Cervical cancer 101 5.6 5.5 - 6.8
Non-AIDS-defining cancers
Anal cancer 219 27 24 - 31
Liver cancer 86 3.7 3.0 - 4.6
Lung cancer 531 3.0 2.8 - 3.3
Hodgkin lymphoma 184 9.1 7.7 - 11
All non-AIDS related cancers
2155 1.7 1.5 - 1.8
SIR=Standardized Incidence Ratios
LUNG CANCER
SIR*Post-HAART
SIR*Pre-HAART
Studyn HIV Author
Reviewed in Lavolé, Lung Cancer 2005. *SIR is defined by the number of LC observed in the HIV-population/number of LC expected in the general population matched for age
Excess of risk of lung cancer in HIVExcess of risk of lung cancer in HIV
• Pre-HAART epidemiological studies
Savès, CID 2003
57
33
HIVNon HIV
% of smokers
– risk factors for cardiovascular disease
– age 35 to 44 years old– HIV patients, n=274 (APROCO cohort)– non HIV-persons, n=1038
(WHO-MONICA project)
Excess of risk of lung cancer in HIVExcess of risk of lung cancer in HIV
• Bias due to difference of smoking habits in HIV ?
• Bias due to difference of smoking habits in HIV ?
Parker, Chest 1998
SIR = 6.5
0
10
20
30
40
0
10
20
30
40
100 % of smokersunknown % of smokers
LC observed in HIVLC expected in HIV
• Bias due to difference of smoking habits in HIVexpected number of LC in the general population if 100 % of the
persons were smokers
• Bias due to difference of smoking habits in HIVexpected number of LC in the general population if 100 % of the
persons were smokers
Excess of risk of lung cancer in HIVExcess of risk of lung cancer in HIV
Num
ber o
f LC
Num
ber o
f LC
SIR = 2.5
Cadranel, Respiration 1999; Bower, AIDS 2004
• Hypothesies for causal factors…– increased frequency of smoking in HIV population,
but intensity and duration not different– HIV status seems probable, but the mechanisms
remain unknown :• degree of immune deficiency• duration of immune deficiency• oncogenic role of HIV per se• other oncogenic virus• role of HAART
Excess of risk of lung cancer in HIVExcess of risk of lung cancer in HIV
3p LOH, microsatellite alterations 9p21 LOH telomerase upregulation, MYC over expression 8p21-23 LOH neoangiogenesis, loss of FHIT, P53 mutations, aneuploidy, methylation 5q21 APC-MCC LOH, K-ras 12 mutation
Wistuba, JAMA 1997
Excess of risk, which mechanisms
Smoking
Increase of genomic instability ?
+ HIV + ID + HAART…
Lung Cancer
• Most frequent NADC in HAART era• Incidence 2-4 fold higher than general population
– SIRS between 2 and 3 and stable over time• Diagnosed at younger age with advanced disease
and primarily in smokers• Adenocarcinoma is most frequent sub-type• No clear screening strategy• No argument to treat differently than non-HIV
infected patients
Cancer Incidence in AIDS Patients
Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.
Cancer type No. cases SIR 95% CI
AIDS-defining cancers
Kaposi sarcoma 3136 5321 5137 - 5511
Non-Hodgkin lymphoma
3345 32 31 - 33
Cervical cancer 101 5.6 5.5 - 6.8
Non-AIDS-defining cancers
Anal cancer 219 27 24 - 31
Liver cancer 86 3.7 3.0 - 4.6
Lung cancer 531 3.0 2.8 - 3.3
Hodgkin lymphoma 184 9.1 7.7 - 11
All non-AIDS related cancers
2155 1.7 1.5 - 1.8
SIR=Standardized Incidence Ratios
Hepatocellular Carcinoma
• Linked to coinfection by hepatitis B and C viruses
• No clear difference between HAART users and non-users
• Estimated to be 7 times more frequent than in general population
• Optimal treatment similar to general population
Breast cancerBreast cancer
• No higher incidence in HIV-positive women
• There might even be a lower incidencelower incidence:– Significant decrease was recorded in Tanzania
following HIV epidemics. Amir. J Natl Med Assoc 2000
– Significant decrease in relative risk (observed cases/expected cases based incidence in general population ). Frisch. JAMA 2001
Why breast cancer could be less Why breast cancer could be less frequent in HIV women?frequent in HIV women?
• Reduced incidence is also found in other immunosuppressed patients
Steward. Lancet 1995
• Suggesting that physiological immune response is a facilitating factor in breast carcinogenesis
• Hormone production is reduced in HIV: oestradiol or testosterone
• Body composition change with HAART (waist gain)…and the USA obesity epidemics
Why breast cancer could be less Why breast cancer could be less frequent in HIV women?frequent in HIV women?
• CXCR4-tropic HIV is protective against breast cancer because – In vitro: this receptor is highly expressed by tumor
cells and CXCR4 HIV induces tumor cells apoptosisEndo M. Curr HIV Res 2008
– In vivo : decreased incidence of breast cancer when compared to CCR5 HIV-infected patients
Hessol N . PloS ONE Dec 2010. vol 5;12:e14349.
• Ritonavir has been studied in preclinical trials for its activity against breast cancer growth
Why breast cancer could be less Why breast cancer could be less frequent in HIV women?frequent in HIV women?
EACS guidelines 2011. Available at http://www.europeanaidsclinicalsociety.org/guidelinespdf/EACS-EuroGuidelines_FullVersion.pdf . Accessed March 2011.
Problem Patients Procedure Evidence of benefits
Screening interval Additional Comments
Breast cancer
Women 50–70 yrs Mammography ↓breast cancer
mortality 1–3 years
Cervical cancer
Sexually active women
Papanicolau test,HPV DNA test
↓cervical cancer mortality 1–3 years
Target age group should include at least the age range 30 to 59 years. Longer screening interval if prior screening tests repeatedly negative
Colorectal cancer
Persons 50–75 yrs
Fecal Occult Blood test
↓colorectal cancer mortality 1–3 years Benefit is marginal
Cancer screening – EACSCancer screening – EACS
Other Malignancies
• Non-melanomatous skin cancer• Conjunctival cancer• Sarcoma• Melanoma• Germ cell tumors• Other hematopoietic neoplasms including
myeloma and leukemia• Many present with advanced disease at diagnosis
HAART and chemotherapy• Many patients will receive HAART and
chemotherapy concurrently with high likelihood of drug interactions
• Protease inhibitors and non-nucleoside reverse transcriptase inhibitors are substrates and potent inhibitors or inducers of cytochrome P450 system (CYP)– Many anti-neoplastic drugs also metabolized by CYP
system leading to either drug accumulation and possible toxicity or decreased efficacy
• Paclitaxel and docetaxel• Vinca alkaloids
Summary
• Since introduction of HAART, NHL and KS incidence has decreased
• Incidence of other cancers has increased related to other risk factors – immunosuppression, viral coinfections, smoking
• Prevention via risk factor control and screening• Optimization of antiretroviral treatment• Treatment strategies similar for non-HIV infected
individuals