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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 cancer1993 Non AIDS-defining malignancies (NADM) is increasing

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HIV and Malignancies

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Hiv and malignancies

HIV and Malignancies

S. De Wit

St Pierre Hospital


Hiv and cancer

HIV and cancer

  • AIDS-definingmalignancies:

    • Kaposi’ssarcoma

    • Non Hodgkin lymphoma1985

    • Cervical cancer1993

    • Non AIDS-defining malignancies (NADM) is increasing

      • Linked with virus HPV (Anal), HBV and HCV (Liver), EBV (HL)

      • Linked with previous immunodeficiency






  • 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.

Hiv and malignancies

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–

    Hiv and malignancies

    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

    Hiv and malignancies

    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

    Hiv and malignancies

    The Natural History of HPV Infection and Cervical Cancer


    Persistent HPV5-10% 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

    Hiv and malignancies

    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


    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 . 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 M3615% 5% p=.0006

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

      Screen VIA0.51 (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)


    AIDS 2008

    132 cases of invasive anal cancer among 86322 HIV-patients

    Median survival 5 years



    Median CD4 188227288

    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

    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





    Repeat in 12 months

    Anoscopy with biopsy



    No lesion seen


    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.

    Hiv and malignancies

    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.

    Lung cancer


    Excess of risk of lung cancer in hiv



















    Dal Maso




















    Excess of risk of lung cancer in HIV

    • Pre-HAART epidemiological studies


    n HIV






    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



    Non HIV


    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



    SIR = 6.5



    LC observed in HIV

    Number of LC

    Number of LC



    LC expected in HIV





    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






    Excess of risk, which mechanisms


    + 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

    Hiv and malignancies

    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

    Hiv and malignancies

    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 . 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



    • 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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