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Cancers et VIH: Style de vie ou nouvel effet du VIH ?

Cancers et VIH: Style de vie ou nouvel effet du VIH ?. Jean-Pierre Routy M.D. McGill University Le 2 mars 2010 Centre Saint Pierre Montr éal. Liens entre VIH et Cancers. First case report on Kaposi sarcoma (KS) in gay men in New-York City and San Francisco (1981) AIDS defining cancers: KS

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Cancers et VIH: Style de vie ou nouvel effet du VIH ?

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  1. Cancers et VIH:Style de vie ou nouvel effet du VIH ? Jean-Pierre Routy M.D. McGill University Le 2 mars 2010 Centre Saint Pierre Montréal

  2. Liens entre VIH et Cancers • First case report on Kaposi sarcoma (KS) in gay men in New-York City and San Francisco (1981) • AIDS defining cancers: • KS • Non-Hodgkin lymphoma (NHL): • Diffuse type • CNS • Cervical cancer (HPV) • Non-AIDS defining cancers: • Some type of tumors have been found in greater frequency in HIV infected persons

  3. Cancers associés au VIH • Two 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

  4. Récente augmentation de la fréquence des cancers chez les personnes infectées • 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 ? • CD4 recovery: • Opportunist cancers • Traditional cancers ?

  5. Cancers et VIH: Rôle du manque d’immunité Cancer rate should also be increased in other immunosuppressive disorders

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

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

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

  9. Cancers chez les personnes VIH et ayant une transplantation d’organes • 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 of these cancers

  10. Baisse de l’immunité et àrisque de cancer • NHL • Burkitt median CD4 350-500 (25% EBV) • Immunoblastic median CD4 50-150 (60% EBV) • Primary CNS median CD4 10-50 (100% EBV) • KS • Median CD4 100-200 (relatively wide interquartile range) • Hodgkin’s disease • median CD4 200-350 • HPV-related cancers • any CD4 count

  11. p 0,01 CD4 (par valeur doublée) Transmission Homo. UDIV Hétéro. Autre 10 0,98 0,02 0,04 8 Race Blanc 6 Autre 0,01 ATCD sida Non 0,002 Oui 4 ATCD Cancer Non Oui 0,001 2 Hépatite B Négatif Positif < 0,001 0 Âge Par 10 ans < 0,001 < 50 51 à 200 201 à 350 351 à 500 > 500 Durée ARV Par 6 mois < 0,001 1 0,1 10 Ratio d’incidence Dernier taux de CD4 (/mm3) 195 Non-AIDS cancers and CD4 : cohorte EuroSIDA • 12 865 patients suivis jusqu’à décès ou dernière visite • Cancers non sida, à l’exclusion des cancers de la peau Incidence des cancers non sida, IC 95 % (pour 1 000 années-patient) Incidence des cancers non sida Reekie J, CROI 2009, Abs. 860a

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

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

  14. Immunodeficiency or viremia as a risk factor for non-AIDS cancers

  15. Patient characteristics at start cART Kesselring et al IAS 2009

  16. Time dependent Age Exposure to cART Latest CD4 6 months lagged Cumulative exposure to CD4 Below 200/350/500 cells/mm³ Latest VL 6 months lagged Cumulative exposure to VL More than 400 cps/ml Fixed Nadir CD4 CD4 at start cART Duration of HIV infection Gender Region of origin Mode of transmission Prior NADM Prior AIDS Alcohol, Smoking HBV / HCV coinfections Variables

  17. Types of malignancies All malignancies n=232 Malignancies due to infection related cause, n=100 (43 %), Malignancies due to other causes, n=132 (57 %) Other infection-related group includes oesophagal, stomach and vulva carcinoma. Other epithelial group includes bladder, colon, pancreas, renal, testis, cerebral, bone malignancies and melanoma.

  18. Multivariate Cox regression model Adjusted for gender, cumulative exposure to cART, smoking, alcohol abuse.

  19. Effect of immunodeficiency on malignancies due to infection-related and other causes Adjusted for age, prior AIDS, gender, region of origin, cumulative exposure to cART, estimated duration of HIV infection prior to start cART, coinfections, smoking, alcohol abuse.

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

  21. Is the increased risk of cancer reversible with ART and CD4 recovery ?

  22. Incidence rates of NHL and KS US Adult spectrum of disease/HOPS studies • Patel et al. Ann Intern Med 2008, 148, 728-

  23. Trends in Hodgkin lymphoma and anal cancer US Adult spectrum of disease/HOPS studies • Patel et al. Ann Intern Med 2008, 148, 728-

  24. Hodgkin lymphoma after HIV: Australia p=0.026 van Leeuwen et al, submitted

  25. Anal cancer after HIV: Australia p=0.783 van Leeuwen et al, submitted

  26. Lower Risk for Certain Non-AIDS–Defining Cancers With Higher Recent CD4+ Cell CountSilverberg et al abstract 28 Risk of anal cancer, oral/pharyngeal cancer, and Hodgkin’s lymphoma: More frequent than in non-HIV Increased with lower recent CD4+ cell count Lung and colorectal cancer: increased among HIV vs HIV-uninfected individuals Only when recent CD4+ cell count low (no nadir effect) Viral load not associated with risk for cancer Detect and treat HIV-1 infection at early stages of infection may reduce cancer burden in this population

  27. Reversibility of cancer risk • Most marked declines: KS, NHL • Decline is not absolute and morbidity remains substantial • RR around 10 for NHL • Little or no decline • Hodgkin lymphoma, HPV-related cancers • Increasing age of people with HIV is important as population rates of cancer increase exponentially

  28. ART and anal cancer incidence • Anal cancer is uncommon in the general population • 1.4 cases per 100,000 person-years • HIV infected persons have a higher risk of anal cancer • ART and HIV infection duration on anal cancer not well defined 1. SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2006. 2. Melbye M, Rabkin C, Frisch M, Biggar RJ. Am J Epidemiol. 1994;139:772-80.; 3. D’Souza G, Wiley DJ, Li X, et al. JAIDS. 2008;48:491-9.; 4. Piketty C, Selinger-Leneman H, et al. AIDS. 2008;22:1203-11.; 5. Diamond C, Taylor TH, Aboumrad T, et al. Sex Transm Dis. 2005;32:314-20.; 6. Chiao EY, Krown SE, Stier EA, et al. JAIDS. 2005;40:451-5.

  29. Study population and Methods • U.S. Military Natural History Study, following participants from 1985-2008 • 4,901 HIV-infected participants : 40,951 person years (PY) of follow-up • 55% with documented seroconversion dates • Anal cancer cases were histopathologically confirmed squamous cell carcinomas40,951 person years (PY) of follow-up • Characteristics at HIV diagnosis: • Age: 28 years (IQR 24-34) • 92% male • 45% African American and 43% Caucasian • CD4 count: 506 cells/mm3 (IQR 350-676) Nancy Crum-Cianflone, IAS 2009

  30. Demographic Characteristics at Anal Cancer Diagnosis (N=20)

  31. Factors Associated with Anal Cancer 1 Time-updated covariate

  32. Multivariate Analyses of Factors Associated with Anal Cancer 1 Time-updated covariate

  33. Can ART improve survival in cancer patients ?

  34. 1,0 0,75 0,5 Pas d’ARV 0,25 ARV pendant < 90 j ARV pendant ≥ 90 j Années 0 0 1 2 3 4 5 329 96 338 197 49 136 145 34 87 114 22 58 76 18 33 50 10 15 n 196 Lymphome non hodgkinien chez le patient VIH • Étude du Kaiser Permanente (Californie) (1) : comparaison de la survie de LNH diagnostiqués entre 1996 et 2005 chez les patients VIH+ (n = 268) et les patients VIH- (n = 8 203) • Mortalité à 2 ans = 59 % chez VIH+ versus 29 % chez VIH- (OR = 5,93 ; IC 95 % = 4,52-7,78 ; p < 0,01) • La surmortalité chez les patients VIH+ persiste même après ajustement sur chimiothérapie, et au cours de la période la plus récente Probabilité de survie (LNH-COHERE) • Groupe COHERE (2) : 22 cohortes européennes, 56 305 patients • incidence LNH et lymphome cérébral primitif (LCP) pour 100 000 années-patient = 519 si absence HAART versus 229 si HAART • survie à 1 an : • 66 % pour LNH • 54 % pour LCP (1) Chao C, CROI 2009, Abs. 871 ; (2) Bohlius J, CROI 2009, Abs. 872

  35. 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

  36. Conclusions • Meilleur sont les CD4, meilleur pour la santé • Dépend du type de cancers: • Associé à un virus • Style de vie et cancers: • Association très forte • Prévention, dépistage: HPV • VIH et cancers non-SIDA: • En faveur d’une initiation précoce des ART • Dépistage surtout pour les plus de 50

  37. Merci • Bruno Lemay • Info traitement

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