Immunodeficiency, not viremia, is a risk factor for non-AIDS defining malignancies in patients on cART Anouk Kesselring, Luuk Gras, Colette Smit, Frank.

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Presentation transcript:

Immunodeficiency, not viremia, is a risk factor for non-AIDS defining malignancies in patients on cART Anouk Kesselring, Luuk Gras, Colette Smit, Frank de Wolf, Peter Reiss, Ferdinand Wit HIV Monitoring Foundation, Amsterdam Medical Center, Amsterdam, The Netherlands

Aim Explore the role of immunodeficiency and viremia in the treated HIV population as risk factors for non-AIDS defining malignancies (NADM), while adjusting for traditional risk factors

Data collection (1) Netherlands observational ATHENA cohort Selected patients starting cART >1 Jan 1996 Naïve or prior mono/duo NRTI exposure Follow up started at cART initiation until last available CD4 or HIV RNA

Data collection (2) Cases extracted from patient records Vast majority of malignancies in the Netherlands is histologically confirmed Only non-AIDS defining malignancies occurring after initiation of cART were taken into account Definition of cases according to D:A:D protocol. (Not including basal cell carcinoma and squamous cell carcinoma skin)

Statistical Analysis Time to diagnosis of first NADM Time-updated Cox regression models CD4 and VL measurements updated in 3 month periods Missing CD4 / VL count: previous observation carried forward Adjustment for traditional risk factors for malignancies

Variables 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

N11459 Gender, N (%)Male8816(77 %) Age, Median (IQR)38(32-45) Region of origin, N (%)W-Europe7250(63 %) Exposure Group, N (%)MSM6003(52 %) Hetero3958(35 %) IDU541(5 %) Prior ART, N (%)2240(20 %) Prior AIDS, N (%)3079(27 %) Nadir CD4, Median (IQR)cells/mm³150(55-240) HIV RNA, Median (IQR)log 10 cps/ml4.9( ) HCV, N (%)Antibody561(5 %) HBV, N (%)Surface antigen531(5 %) Alcohol Abuse, N (%)797(7 %) Smoking status, N (%)Ever4745 / 6701(71 %) Missing4758(42 %) Patient characteristics at start cART

Follow up Person years Follow-up, total median (IQR) 67, ( ) cART, total median (IQR) 59, ( ) Cumulative exposure of CD4 <200 9, , ,253 >50018,763 HIV RNA >40013,971

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.

N232 Age at diagnosis, Median (IQR)43( ) Prior to start cART Prior mono/duo NRTI, N (%)89(39 %) Prior AIDS, N (%)89(39 %) Prior NADM, N (%)2(0.9 %) 6 months prior to NADM diagnosis CD4 (/mm³), Median (IQR)340( ) cART, N (%)205(89 %) Undetectable VL, N (%)169(75 %) HBV, N (%)17(7 %) HCV, N (%)14(6 %) Smoking, N (%)120(77 %) Alcohol abuse, N (%)23(10 %) Characteristics of patients with NADM

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

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.

Conclusions In the setting of treated HIV infection: Longer exposure to immunodeficiency below 350 CD4 cells/mm³ associated with NADM Effect was driven by NADM with possible infection-related cause Longer exposure to viremia not associated with NADM

Limitations Less power in subgroup analyses Missing data on traditional risk factors (smoking, alcohol)

Acknowledgements Treating physicians from the ATHENA national observational cohort study: Academisch Medisch Centrum bij de Universiteit van Amsterdam - Amsterdam: Dr. J.M. Prins*, Drs. J.C. Bos, Dr. J.K.M. Eeftinck-Schattenkerk, Dr. S.E. Geerlings, Dr. M.H. Godfried, Prof. dr. J.M.A. Lange, Dr. J.T.M. van der Meer, Dr. F.J.B. Nellen, Drs. D.P. Olszyna, Dr. T. van der Poll, Prof. dr. P. Reiss, Drs. S.U.C. Sankatsing, Drs. R. Steingrover, Drs. M. van der Valk, Drs. J.N. Vermeulen, Drs. S.M.E. Vrouenraets, Dr. M. van Vugt, Dr. F.W.M.N. Wit. Academisch Ziekenhuis Maastricht - Maastricht: Dr. G. Schreij*, Dr. S. van der Geest, Dr. A. Oude Lashof, Dr. S. Lowe, Dr. A. Verbon. Catharina Ziekenhuis - Eindhoven: Dr. B. Bravenboer*, Drs. M.J.H. Pronk. Emma Kinderziekenhuis - AMC Amsterdam: Prof. dr. T.W. Kuijpers, Drs. D. Pajkrt, Dr. H.J. Scherpbier. Erasmus MC - Rotterdam: Dr. M.E. van der Ende*, Drs. H. Bax, Drs. M. van der Feltz, Dr. L.B.S. Gelinck, Drs. Mendoca de Melo (until September 1, 2008), Dr. J.L. Nouwen, Dr. B.J.A. Rijnders, Dr. E.D. de Ruiter, Dr. L. Slobbe, Drs. C.A.M. Schurink, Dr. T.E.M.S. de Vries. Erasmus MC - Sophia - Rotterdam: Dr. G. Driessen, Dr. M. van der Flier, Dr. N.G. Hartwig. Flevoziekenhuis - Almere: Dr. J. Branger. Haga Ziekenhuis, locatie Leyenburg - Den Haag: Dr. R.H. Kauffmann*, Drs. K. Pogány (until August 1, 2008), Dr. E.F. Schippers (from May 1, 2008). Isala Klinieken - Zwolle: Dr. P.H.P. Groeneveld*, Dr. M.A. Alleman. Kennemer Gasthuis - Haarlem: Prof. dr. R.W. ten Kate*, Dr. R. Soetekouw. Leids Universitair Medisch Centrum - Leiden: Dr. F.P. Kroon*, Dr. S.M. Arend, Drs. M.G.J. de Boer, Prof. dr. P.J. van den Broek, Prof. dr. J.T. van Dissel, Drs. C. van Nieuwkoop. Maasstadziekenhuis - locatie Clara - Rotterdam: Dr. J.G. den Hollander*. Medisch Centrum Alkmaar - Alkmaar: Dr. W. Bronsveld*. Medisch Centrum Haaglanden -locatie Westeinde - Den Haag: Dr. R. Vriesendorp*, Dr. F.J.F. Jeurissen, Dr. E.M.S. Leyten. Medisch Centrum Leeuwarden - Leeuwarden: Dr. D. van Houte*, Dr. M.B. Polée. Medisch Spectrum Twente - Enschede: Dr. C.H.H. ten Napel*, Dr. G.J. Kootstra. Onze Lieve Vrouwe Gasthuis – Amsterdam: Prof. dr. K. Brinkman*, Drs. G.E.L. van den Berk, Dr. W.L. Blok, Dr. P.H.J. Frissen, Drs. W.E.M. Schouten.St. Medisch Centrum Jan van Goyen - Amsterdam: Dr. A. van Eeden*, Dr. D.W.M. Verhagen. Slotervaart Ziekenhuis - Amsterdam: Dr. J.W. Mulder*, Dr. E.C.M. van Gorp, Dr. A.T.A. Mairuhu, Drs. R. Steingrover, Dr. J. Wagenaar. St. Elisabeth Ziekenhuis - Tilburg: Dr. J.R. Juttmann*, Dr. M.E.E. van Kasteren. St. Lucas Andreas Ziekenhuis - Amsterdam: Dr. J. Veenstra*, Dr. W.L.E. Vasmel. Universitair Medisch Centrum St. Radboud - Nijmegen: Dr. P.P. Koopmans*, Drs. A.M. Brouwer, Dr. A.S.M. Dofferhoff, Prof. dr. R. de Groot, Drs. H.J.M. ter Hofstede, Dr. M. Keuter, Dr. A.J.A.M. van der Ven. Universitair Medisch Centrum Groningen - Groningen: Dr. H.G. Sprenger*, Dr. S. van Assen, Dr. J.T.M. van Leeuwen, Dr. C.J. Stek. Universitair Medisch Centrum Groningen - Beatrix Kliniek - Groningen: Dr. R. Doedens, Dr. E.H. Scholvinck. Universitair Medisch Centrum Utrecht - Utrecht: Prof. dr. I.M. Hoepelman*, Dr. M.M.E. Schneider, Prof. dr. M.J.M. Bonten, Dr. P.M. Ellerbroek, Drs. C.A.J.J. Jaspers, Drs. L.J. Maarschalk-Ellerbroek, Dr. J.J. Oosterheert, Dr. E.J.G. Peters, Dr. T. Mudrikova, Drs. M.W.M. Wassenberg, Dr. S. Weijer. WilhelminaKinderziekenhuis - UMC Utrecht: Dr. S.P.M. Geelen, Dr. T.F.W. Wolfs. VU Medisch Centrum - Amsterdam: Prof. dr. S.A. Danner*, Dr. M.A. van Agtmael, Drs. W.F.W. Bierman, Drs. F.A.P. Claessen, Drs. M.E. Hillebrand, Drs. E.V. de Jong, Drs. W. Kortmann, Dr. R.M. Perenboom, Drs. E.A. bij de Vaate. Ziekenhuis Rijnstate - Arnhem: Dr. C. Richter*, Drs. J. van der Berg, Dr. E.H. Gisolf. Ziekenhuis Walcheren - Vlissingen: Dr. A.A. Tanis*. St. Elisabeth Hospitaal/Stichting Rode Kruis Bloedbank - Willemstad, Curaçao: Dr. A.J. Duits, Dr. K. Winkel. Virologists: Academisch Medisch Centrum bij de Universiteit van Amsterdam – Amsterdam:Dr. N.K.T. Back, Dr. M.E.G. Bakker, Dr. H.L. Zaaijer.Prof. dr. B. Berkhout, Dr. S. Jurriaans. CLB Stichting Sanquin Bloedvoorziening -Amsterdam: Dr. Th. Cuijpers.Onze Lieve Vrouwe Gasthuis - Amsterdam: Dr. P.J.G.M. Rietra, Dr. K.J. Roozendaal;.Slotervaart Ziekenhuis - Amsterdam: Drs. W. Pauw, Drs. P.H.M. Smits, Dr. A.P. van Zanten.VU Medisch Centrum – Amsterdam: Dr. B.M.E. von Blomberg, Dr. A. Pettersson, Dr. P. Savelkoul; Ziekenhuis Rijnstate – Arnhem:Dr. C.M.A. Swanink.HAGA, ziekenhuis, locatie Leyenburg - Den Haag: Dr. P.F.H. Franck, Dr. A.S. Lampe; Medisch Centrum Haaglanden, locatie Westeinde - Den Haag: Drs. C.L. Jansen.; Streeklaboratorium Twente - Enschede: Dr. R. Hendriks.Streeklaboratorium Groningen - Groningen: Dr. C.A. Benne;.Streeklaboratorium Volksgezondheid Kennemerland - Haarlem: Dr. J. Schirm, Dr. D. Veenendaal.Laboratorium voor de Volksgezondheid in Friesland - Leeuwarden: Dr. H. Storm, Drs. J. Weel, Drs. J.H. van Zeijl; Leids Universitair Medisch Centrum - Leiden: Dr. H.C.J. Claas, Prof. dr. A.C.M. Kroes.Academisch Ziekenhuis Maastricht - Maastricht: Prof. dr. C.A.M.V.A. Bruggeman, Drs. V.J. Goossens.Universitair Medisch Centrum St. Radboud - Nijmegen: Prof. dr. J.M.D. Galama, Dr. W.J.G. Melchers, Dr. Verduyn-Lunel.Erasmus MC - Rotterdam:Dr. G.J.J. van Doornum, Dr. H.G.M. Niesters, Prof. dr. A.D.M.E. Osterhaus, Dr. M. Schutten.St. Elisabeth Ziekenhuis - Tilburg: Dr. A.G.M. Buiting.Universitair Medisch Centrum Utrecht - Utrecht: Dr. C.A.B. Boucher, Dr. E. Boel, Dr. R. Schuurman.Catharina Ziekenhuis - Eindhoven: Dr. A.F. Jansz, drs. M. Wulf; Pharmacologists: Medisch Centrum Alkmaar - Alkmaar: Dr. A. Veldkamp.Slotervaart Ziekenhuis - Amsterdam: Prof. dr. J.H. Beijnen, Dr. A.D.R. Huitema.Universitair Medisch Centrum St. Radboud - Nijmegen: Dr. D.M.Burger.Academisch Medisch Centrum bij de Universiteit van Amsterdam – Amsterdam: Drs. H.J.M. van Kan. *Site coordinating physicians