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HIV and Malignancies. S. De Wit St Pierre Hospital Brussels. HIV and cancer. AIDS- defining malignancies : Kaposi’s sarcoma Non Hodgkin lymphoma 1985 Cervical cancer 1993 Non AIDS-defining malignancies (NADM) is increasing

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hiv and malignancies
HIV and Malignancies

S. De Wit

St Pierre Hospital

Brussels

hiv and cancer
HIV and cancer
  • AIDS-definingmalignancies:
    • Kaposi’ssarcoma
    • 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

background
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.

slide4

SIR = Standardised Incidence Ratio

Nb cases of cancer in the HIV population

Expected nb of cases in the general population,

calculatedwith local cancer registry incidence

=

cancer incidence in aids patients
Cancer Incidence in AIDS Patients

SIR=Standardized Incidence Ratios

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 mortality in aids patients
CancerMortality in AIDS Patients

Population attributableriskamongpeoplewith AIDS in the US

Cumulative Incidence (%)

Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

increased rates of nadcs why
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
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
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

hiv cancers role of immune deficiency
HIV & Cancers Role of immune deficiency ?

Cancer rate should also be increased in other immunosuppressive disorders

infection related cancers
Infection-related cancers

Grulich et al. Lancet, 2007, 370, 59–

common epithelial cancers
Common epithelial cancers

Grulich et al. Lancet, 2007, 370, 59–

cancers in hiv and transplant patients
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
slide16

CD4 and risk of liver cancer

Clifford and Franceschi, Future Oncology 2009

current cd4 count and death from cancer
Current CD4 count and death from cancer

D:A:D study group AIDS 2008, 22:2143–

characteristics of cancer immune control
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 patients1
Cancer Incidence in AIDS Patients

SIR=Standardized Incidence Ratios

Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

anogenital cancers
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 cancer
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

slide22

The Natural History of HPV Infection and Cervical Cancer

HIV- HIV+

Persistent HPV 5-10% 20-40%

Cervical cancer x 3-11

Vulva & vagina cancer x 4-10

Schiffman, M. et al. N Engl J Med 2005;353:2101-2104

infection with oncogenic hpv in hiv women
Infection withoncogenic HPV in HIV women
  • Prevalenceishigher :20-40% (vs.5-10%)
  • Multiplegenotypes: 40 % (vs. 12% )
  • New infection? Reactivation of latent infection
  • Linkedwithyoungerage, lower CD4 and higher HIV VL

Paleksky. J Natl Cancer Inst 1999

Strickler. Journal of the National Cancer 2005

slide24
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 Cohort

N=592

Prevalence of HR-HPV infection according to both age and CD4 cell strata (count/µL). (p=0.03, logistic regression)

cancer screening eacs
Cancer screening – EACS

EACS guidelines 2011. Available at http://www.europeanaidsclinicalsociety.org/guidelinespdf/EACS-EuroGuidelines_FullVersion.pdf . Accessed March 2011.

screening in developing countries
Screening 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=.0006

Screen HPV RR M36 0.2 (0.06-0.07) 0.3 (0.02-.005) ps for both

Screen VIA 0.51 (0.29-0.89) p=ns

Kuhn and al. AIDS 2010

anal cancer
Anal Cancer

Invasive cancer

SIR 6-8 (in USA, St-Pierre Cohort)

Piketty

AIDS 2008

132 cases of invasive anal cancer among 86322 HIV-patients

Median survival 5 years

Recent

PreEarly

Median CD4 188 227 288

Death due to AC 50% 40% 68.8%

anal cancer incidence
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 erafor 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

http://clinicaloptions.com/hiv

Bower M, et al. J Acquir Immune Defic Syndr. 2004;37:1563-1565.

anal cytology screening for ain in hiv positives
Anal Cytology Screening for AIN in HIV-positives

Screening Pap

Normal

ASCUS

LSIL

HSIL

Repeat in 12 months

Anoscopy with biopsy

LSIL

HSIL

No lesion seen

Treat

Treat or follow

Chin-Hong PV et al. J Infect Dis. 2004;90:2070-2076.

in summary
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
cancer incidence in aids patients2
Cancer Incidence in AIDS Patients

SIR=Standardized Incidence Ratios

Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

hodgkin s disease
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.

slide33

Risk of Hodgkin lymphoma by CD4 count

Clifford and Franceschi, 2009

cancer incidence in aids patients3
Cancer Incidence in AIDS Patients

SIR=Standardized Incidence Ratios

Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

excess of risk of lung cancer in hiv

Frish

302,834

R

yes

4

no

Parker

26,181

R

yes

6.5

no

Grulich

31,616

R

yes

3.8

no

Dal Maso

60,421

R

yes

2.4

no

Herida

77,025

P

yes

1

yes

2

Bower

8640

R

yes

1

yes

8.93

Excess of risk of lung cancer in HIV
  • Pre-HAART epidemiological studies

Author

n HIV

Study

Pre-HAART

SIR*

Post-HAART

SIR*

Reviewed in Lavolé, Lung Cancer 2005. *SIR isdefined 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 hiv1
Excess of risk of lung cancer in HIV
  • Bias due to difference of smoking habits in HIV ?
  • 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)

% of smokers

57

HIV

Non HIV

33

Savès, CID 2003

excess of risk of lung cancer in hiv2

SIR = 2.5

Excess of risk of lung cancer in HIV
  • Bias due to difference of smoking habits in HIV
    • expectednumber of LC in the general population if 100 % of the personsweresmokers

40

40

SIR = 6.5

30

30

LC observed in HIV

Number of LC

Number of LC

20

20

LC expected in HIV

10

10

0

0

unknown % of smokers

100 % of smokers

Parker, Chest 1998

excess of risk of lung cancer in hiv3
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

excess of risk which mechanisms

Normal

Hyperplasia

Metaplasia

Dysplasia

Carcinoma

Excess of risk, which mechanisms

Smoking

+ HIV + ID + HAART…

3p LOH, microsatellite alterations

9p21 LOH

telomeraseupregulation, 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

lung cancer1
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 patients4
Cancer Incidence in AIDS Patients

SIR=Standardized Incidence Ratios

Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.

hepatocellular carcinoma
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 cancer
Breast cancer
  • No higher incidence in HIV-positive women
  • There mightevenbe a lower incidence:
    • Significantdecreasewasrecorded in Tanzaniafollowing HIV epidemics. Amir. J Natl Med Assoc2000
    • Significantdecrease in relative risk (observed cases/expected cases based incidence in general population ). Frisch. JAMA 2001
why breast cancer could be less frequent in hiv women
Whybreast cancer couldbelessfrequent 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
slide46

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
slide47

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 2010. vol 5;12:e14349.

  • Ritonavir has been studied in preclinical trials for its activity against breast cancer growth
cancer screening eacs1
Cancer screening – EACS

EACS guidelines 2011. Available at http://www.europeanaidsclinicalsociety.org/guidelinespdf/EACS-EuroGuidelines_FullVersion.pdf . Accessed March 2011.

other malignancies
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
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
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
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