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

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Presentation on theme: "HIV and Malignancies S. De Wit St Pierre Hospital Brussels."— Presentation transcript:

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

2 HIV and cancer AIDS-defining malignancies: – Kaposis sarcoma – Non Hodgkin lymphoma1985 – Cervical cancer1993 Non AIDS-defining malignancies (NADM) is increasing HPVHBVHCVEBV Linked with virus HPV (Anal), HBV and HCV (Liver), EBV (HL) Linked with previous immunodeficiency HPV EBV HHV8

3 Background Before introduction of HAART, ADCs common, including Kaposis 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 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 Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 27. Cancer typeNo. casesSIR95% CI AIDS-defining cancers Kaposi sarcoma Non-Hodgkin lymphoma Cervical cancer Non-AIDS-defining cancers Anal cancer Liver cancer Lung cancer Hodgkin lymphoma All non-AIDS related cancers SIR=Standardized Incidence Ratios

6 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, Abst. 27. Cumulative Incidence (%)

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 1 Wistuba, AIDS 1999;13:415-26

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

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

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

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 Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 27. Cancer typeNo. casesSIR95% CI AIDS-defining cancers Kaposi sarcoma Non-Hodgkin lymphoma Cervical cancer Non-AIDS-defining cancers Anal cancer Liver cancer Lung cancer Hodgkin lymphoma All non-AIDS related cancers SIR=Standardized Incidence Ratios

20 Anogenital Cancers Invasive cervical carcinoma – Considered an AIDS-defining condition Anal cancer 1 – Not AIDS defining but very common HPV involvement 1-2 – 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 1 Phelps RM, et al. Int J Cancer. 2001;94: Martin 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 Schiffman, M. et al. N Engl J Med 2005;353: The Natural History of HPV Infection and Cervical Cancer HIV+ HIV-HIV+ Persistent HPV20-40% Persistent HPV5-10% 20-40% Cervical cancer x 3-11 Vulva & vagina cancer x 4-10

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 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)

25 EACS guidelines Available at EuroGuidelines_FullVersion.pdf. Accessed March ProblemPatientsProcedure 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 yearsBenefit is marginal Cancer screening – EACS

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 M3615% 5% p=.0006 Screen HPV RR M ( ) 0.3 ( ) ps for both Screen VIA0.51 ( ) p=ns Kuhn and al. AIDS 2010

27 Anal Cancer Invasive cancer SIR 6-8 (in USA, St- Pierre Cohort) Piketty AIDS cases of invasive anal cancer among HIV-patients Median survival 5 years Recent PreEarly PreEarly 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 NormalASCUSLSILHSIL Repeat in 12 months Anoscopy with biopsy Treat or follow Treat No lesion seen Chin-Hong PV et al. J Infect Dis. 2004;90: LSILHSIL

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 Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 27. Cancer typeNo. casesSIR95% CI AIDS-defining cancers Kaposi sarcoma Non-Hodgkin lymphoma Cervical cancer Non-AIDS-defining cancers Anal cancer Liver cancer Lung cancer Hodgkin lymphoma All non-AIDS related cancers SIR=Standardized Incidence Ratios

32 Hodgkins Disease Association with HIV-infection – Hodgkins disease: RR: 5 to 30 – Non-Hodgkins 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 Clifford and Franceschi, 2009 Risk of Hodgkin lymphoma by CD4 count

34 Cancer Incidence in AIDS Patients Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 27. Cancer typeNo. casesSIR95% CI AIDS-defining cancers Kaposi sarcoma Non-Hodgkin lymphoma Cervical cancer Non-AIDS-defining cancers Anal cancer Liver cancer Lung cancer Hodgkin lymphoma All non-AIDS related cancers SIR=Standardized Incidence Ratios

35 LUNG CANCER

36 SIR*Post- HAART SIR*Pre- HAART Studyn HIVAuthor 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 Excess of risk of lung cancer in HIV Pre-HAART epidemiological studies 8.93yes1 R8640Bower 2yes1 P77,025Herida no3.8yesR31,616Grulich no6.5yesR26,181Parker no4yesR302,834Frish no2.4yesR60,421Dal Maso

37 Savès, CID HIV Non 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 HIV Bias due to difference of smoking habits in HIV ?

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

39 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 HIV

40 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 NormalDysplasiaHyperplasiaMetaplasiaCarcinoma Smoking Increase of genomic instability ? + HIV + ID + HAART…

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

42 Cancer Incidence in AIDS Patients Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 27. Cancer typeNo. casesSIR95% CI AIDS-defining cancers Kaposi sarcoma Non-Hodgkin lymphoma Cervical cancer Non-AIDS-defining cancers Anal cancer Liver cancer Lung cancer Hodgkin lymphoma All non-AIDS related cancers SIR=Standardized Incidence Ratios

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 lower incidence 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 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 frequent in HIV women?

47 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:e Ritonavir has been studied in preclinical trials for its activity against breast cancer growth Why breast cancer could be less frequent in HIV women?

48 EACS guidelines Available at EuroGuidelines_FullVersion.pdf. Accessed March ProblemPatientsProcedure 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 yearsBenefit is marginal Cancer screening – EACS

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

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