1. HIV and Malignancies
S. De Wit St Pierre Hospital Brussels

2. HIV 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 HPV (Anal), HBV and HCV (Liver), EBV (HL)
Linked with previous immunodeficiency
HHV8
EBV
HPV

3. 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.

4. SIR = Standardised Incidence Ratio
Nb cases of cancer in the HIV population
Expected nb of cases in the general population,
calculated with local cancer registry incidence =

5. Cancer Incidence in AIDS Patients
Cancer type
No. cases
SIR
95% CI
AIDS-defining cancers
Kaposi sarcoma
3136
5321
Non-Hodgkin lymphoma
3345 32
Cervical cancer
101
5.6
Non-AIDS-defining cancers
Anal cancer
219 27
Liver cancer 86
3.7
Lung cancer
531
3.0
Hodgkin lymphoma
184
9.1
All non-AIDS related cancers
2155
1.7
Study of cancer risk in AIDS patients from (N=372,364)
Predominantly male (79%), non-hispanic black (42%), MSM (42%)
Median age of 36 years at the onset of AIDS
Aims: To address the question what impact the decline on AIDS-related mortality had on cancer rates. Overall 3 questions were asked: 1) Cancer risk during year 3-5 after AIDS onset relative to the general population. 2) 5. year cumulative incidence of AIDSdefining cancer (ADC) and non-AIDS-defining cancer (NADC). 3) Fraction of deaths among people with AIDS attributable to cancer
Methods: Records of n= people with AIDS ( ) were linked to corresponding cancer registry records. The observation for outcomes (cancer or death) began at month 4 after AIDS among those who were alive and cancer-free.
Conclusions: Elevated risks for ADCs and some NADCs relative to the general population. Particularly cancers of the anus, liver (but cave no adjustment for smoking which is found more frequent in HIV-serpositive cohorts), lung and Hodgkin lyphoma are found more often in the HIV-positive population.
SIR=Standardized Incidence Ratios
Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 27.

6. Cancer Mortality in AIDS Patients
Population attributable risk among people with AIDS in the US
Cumulative Incidence (%)
Cumulative incidence of ADCs has declined, consistent with improvements in immune status. Cumulative incidence of some NADCs increasing in the HAART era particularly cancers of the anus, liver, lung and hodgkins lymphomaancers of the anus, liver, lung and Hodgkins lymphoma.
Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 27.

7. 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 ?

8. 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

9. 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 surveillance
1Wistuba, AIDS 1999;13:415-26

10. HIV & Cancers Role of immune deficiency ?
Cancer rate should also be increased in other immunosuppressive disorders

12. Infection-related cancers
Grulich et al. Lancet, 2007, 370, 59–

13. Grulich et al. Lancet, 2007, 370, 59–

14. Common epithelial cancers
Grulich et al. Lancet, 2007, 370, 59–

15. 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

16. CD4 and risk of liver cancer
Clifford and Franceschi, Future Oncology 2009

17. Current CD4 count and death from cancer
D:A:D study group AIDS 2008, 22:2143–

18. 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

19. Cancer Incidence in AIDS Patients
Cancer type
No. cases
SIR
95% CI
AIDS-defining cancers
Kaposi sarcoma
3136
5321
Non-Hodgkin lymphoma
3345 32
Cervical cancer
101
5.6
Non-AIDS-defining cancers
Anal cancer
219 27
Liver cancer 86
3.7
Lung cancer
531
3.0
Hodgkin lymphoma
184
9.1
All non-AIDS related cancers
2155
1.7
Aims: To address the question what impact the decline on AIDS-related mortality had on cancer rates. Overall 3 questions were asked: 1) Cancer risk during year 3-5 after AIDS onset relative to the general population. 2) 5. year cumulative incidence of AIDSdefining cancer (ADC) and non-AIDS-defining cancer (NADC). 3) Fraction of deaths among people with AIDS attributable to cancer
Methods: Records of n= people with AIDS ( ) were linked to corresponding cancer registry records. The observation for outcomes (cancer or death) began at month 4 after AIDS among those who were alive and cancer-free.
Conclusions: Elevated risks for ADCs and some NADCs relative to the general population. Particularly cancers of the anus, liver (but cave no adjustment for smoking which is found more frequent in HIV-serpositive cohorts), lung and Hodgkin lyphoma are found more often in the HIV-positive population.
SIR=Standardized Incidence Ratios
Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 27.

20. Anogenital Cancers Invasive cervical carcinoma Anal cancer1
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:
2Martin F, et al. Sex Transm Infect. 2001;77:

21. HPV-induced cancer Cervix Vulva Vagina Anal Oro-pharyngal Penis
16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 82

22. The Natural History of HPV Infection and Cervical Cancer
HIV- HIV+
Persistent HPV 5-10% %
Cervical cancer x 3-11
Vulva & vagina cancer x 4-10
The Natural History of HPV Infection and Cervical Cancer. The peak prevalence of transient infections with carcinogenic types of HPV (blue line) occurs among women during their teens and 20s, after the initiation of sexual activity. The peak prevalence of cervical precancerous conditions occurs approximately 10 years later (green line) and the peak prevalence of invasive cancers at 40 to 50 years of age (red line). (The peaks of the curves are not drawn to scale.) The conventional model of cervical-cancer prevention is based on repeated rounds of cytologic examination, including Papanicolaou smears, and colposcopy (small blue arrows). Alternative strategies include HPV vaccination of adolescents (large beige arrow), one or two rounds of HPV screening at the peak ages of treatable precancerous conditions and early cancer (large reddish-brown arrows), or both.
Schiffman, M. et al. N Engl J Med 2005;353:

23. Infection with oncogenic HPV in 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

24. Saint-Pierre Cohort N=592
Prevalence of HR-HPV infection according to both age and CD4 cell strata (count/µL). (p=0.03, logistic regression)
D Konopnicki, Y Manigart, C Gilles, de Marchin J*, M Delforge, F Feoli*, P Barlow, S De Wit and N Clumeck. ECCMID 2011

25. Cancer screening – EACS
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
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
Benefit is marginal
EACS guidelines Available at . Accessed March 2011.

26. Screening in developing countries
Screen-and-treat approach
Randomised , n=6555 with 956 HIV-positive women in South Africa, 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% % p=.0006
Screen HPV RR M ( ) ( ) ps for both
Screen VIA ( ) p=ns
Kuhn and al. AIDS 2010

27. Anal Cancer Invasive cancer SIR 6-8 (in USA, St-Pierre Cohort) Piketty
AIDS 2008
132 cases of invasive anal cancer among HIV-patients
Median survival 5 years
Recent
Pre Early
Median CD
Death due to AC 50% 40% 68.8%

28. 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, )
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, )
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:

29. Anal Cytology Screening for AIN in HIV-positives
Screening Pap
Normal
ASCUS
LSIL
HSIL
Repeat in 12 months
Anoscopy with biopsy
No lesion seen
LSIL
HSIL
Treat or follow
Treat
Chin-Hong PV et al. J Infect Dis. 2004;90:

30. In 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

31. Cancer Incidence in AIDS Patients
Cancer type
No. cases
SIR
95% CI
AIDS-defining cancers
Kaposi sarcoma
3136
5321
Non-Hodgkin lymphoma
3345 32
Cervical cancer
101
5.6
Non-AIDS-defining cancers
Anal cancer
219 27
Liver cancer 86
3.7
Lung cancer
531
3.0
Hodgkin lymphoma
184
9.1
All non-AIDS related cancers
2155
1.7
Aims: To address the question what impact the decline on AIDS-related mortality had on cancer rates. Overall 3 questions were asked: 1) Cancer risk during year 3-5 after AIDS onset relative to the general population. 2) 5. year cumulative incidence of AIDSdefining cancer (ADC) and non-AIDS-defining cancer (NADC). 3) Fraction of deaths among people with AIDS attributable to cancer
Methods: Records of n= people with AIDS ( ) were linked to corresponding cancer registry records. The observation for outcomes (cancer or death) began at month 4 after AIDS among those who were alive and cancer-free.
Conclusions: Elevated risks for ADCs and some NADCs relative to the general population. Particularly cancers of the anus, liver (but cave no adjustment for smoking which is found more frequent in HIV-serpositive cohorts), lung and Hodgkin lyphoma are found more often in the HIV-positive population.
SIR=Standardized Incidence Ratios
Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 27.

32. Hodgkin’s Disease Hodgkin’s disease: RR: 5 to 30
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.

33. Risk of Hodgkin lymphoma by CD4 count
Clifford and Franceschi, 2009

34. Cancer Incidence in AIDS Patients
Cancer type
No. cases
SIR
95% CI
AIDS-defining cancers
Kaposi sarcoma
3136
5321
Non-Hodgkin lymphoma
3345 32
Cervical cancer
101
5.6
Non-AIDS-defining cancers
Anal cancer
219 27
Liver cancer 86
3.7
Lung cancer
531
3.0
Hodgkin lymphoma
184
9.1
All non-AIDS related cancers
2155
1.7
Aims: To address the question what impact the decline on AIDS-related mortality had on cancer rates. Overall 3 questions were asked: 1) Cancer risk during year 3-5 after AIDS onset relative to the general population. 2) 5. year cumulative incidence of AIDSdefining cancer (ADC) and non-AIDS-defining cancer (NADC). 3) Fraction of deaths among people with AIDS attributable to cancer
Methods: Records of n= people with AIDS ( ) were linked to corresponding cancer registry records. The observation for outcomes (cancer or death) began at month 4 after AIDS among those who were alive and cancer-free.
Conclusions: Elevated risks for ADCs and some NADCs relative to the general population. Particularly cancers of the anus, liver (but cave no adjustment for smoking which is found more frequent in HIV-serpositive cohorts), lung and Hodgkin lyphoma are found more often in the HIV-positive population.
SIR=Standardized Incidence Ratios
Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 27.

35. LUNG CANCER

36. Excess of risk of lung cancer in HIV
Pre-HAART epidemiological studies
Author
n HIV
Study
Pre-HAART
SIR*
Post-HAART
SIR*
8.93
yes 1 R
8640
Bower 2 P
77,025
Herida no
3.8
31,616
Grulich
6.5
26,181
Parker 4
302,834
Frish
2.4
60,421
Dal Maso
Reviewed in Lavolé, Lung Cancer *SIR is defined by the number of LC observed in the HIV-population/number of LC expected in the general population matched for age

37. Excess of risk of lung cancer in HIV
Bias due to difference of smoking habits in HIV ?
% of smokers 57
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)
HIV
Non HIV 33
Savès, CID 2003

38. Excess of risk of lung cancer in HIV
Bias due to difference of smoking habits in HIV
expected number of LC in the general population if 100 % of the persons were smokers 40
SIR = 6.5 40
SIR = 2.5 30 30
LC observed in HIV
Number of LC
Number of LC 20 20
LC expected in HIV 10 10
unknown % of smokers
100 % of smokers
Parker, Chest 1998

39. Excess of risk of lung cancer in HIV
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
Cadranel, Respiration 1999; Bower, AIDS 2004

40. Excess of risk, which mechanisms
Smoking
+ HIV + ID + HAART…
Normal
Dysplasia
Hyperplasia
Metaplasia
Carcinoma
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
Increase of genomic instability ?
Wistuba, JAMA 1997

41. 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
Confounded by role of tobacco consumption as higher in HIV infected individuals

42. Cancer Incidence in AIDS Patients
Cancer type
No. cases
SIR
95% CI
AIDS-defining cancers
Kaposi sarcoma
3136
5321
Non-Hodgkin lymphoma
3345 32
Cervical cancer
101
5.6
Non-AIDS-defining cancers
Anal cancer
219 27
Liver cancer 86
3.7
Lung cancer
531
3.0
Hodgkin lymphoma
184
9.1
All non-AIDS related cancers
2155
1.7
Aims: To address the question what impact the decline on AIDS-related mortality had on cancer rates. Overall 3 questions were asked: 1) Cancer risk during year 3-5 after AIDS onset relative to the general population. 2) 5. year cumulative incidence of AIDSdefining cancer (ADC) and non-AIDS-defining cancer (NADC). 3) Fraction of deaths among people with AIDS attributable to cancer
Methods: Records of n= people with AIDS ( ) were linked to corresponding cancer registry records. The observation for outcomes (cancer or death) began at month 4 after AIDS among those who were alive and cancer-free.
Conclusions: Elevated risks for ADCs and some NADCs relative to the general population. Particularly cancers of the anus, liver (but cave no adjustment for smoking which is found more frequent in HIV-serpositive cohorts), lung and Hodgkin lyphoma are found more often in the HIV-positive population.
SIR=Standardized Incidence Ratios
Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 27.

43. 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

44. Breast cancer No higher incidence in HIV-positive women
There might even be a lower 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

45. Why breast cancer could be less 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

46. Why breast cancer could be less frequent in HIV women?
Hormone production is reduced in HIV: oestradiol or testosterone
Body composition change with HAART (waist gain)…and the USA obesity epidemics

47. Why breast cancer could be less 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 apoptosis
Endo M. Curr HIV Res 2008
In vivo : decreased incidence of breast cancer when compared to CCR5 HIV-infected patients
Hessol N . PloS ONE Dec vol 5;12:e14349.
Ritonavir has been studied in preclinical trials for its activity against breast cancer growth

48. Cancer screening – EACS
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
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
Benefit is marginal
EACS guidelines Available at . Accessed March 2011.

49. 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

50. 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

51. 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