Reducing Non-AIDS Malignancy Risk Through Early ART

Starting ART early after HIV acquisition reduces long Starting ART early after HIV acquisition reduces long- -term Non Non- -AIDS AIDS- -Defining Defining Malignancy risk Malignancy risk term Iris van der Wulp, MD NCHIV, November 28, 2023

Disclosure Disclosure Disclosure of speaker s interests Disclosure of speaker s interests (Potential) conflict of interests (Potential) conflict of interests None None

Background Background Non-AIDS-Defining Malignancies (NADM) are currently one of the leading causes of death in people with HIV 1,2 Incidence of NADM is increased compared to individuals without HIV3,4, particularly that of infection-related NADM 5,6,7 Overall, people with HIV who start ART at a higher CD4+-cell count have a reduced malignancy risk (i.e. all malignancies including AIDS-Defining Malignancies) When considering all NADM, infection-related NADM, or infection-unrelated NADM separately results have not been statistically significant thus far 8,9,10 Previous studies have all based their definition of early start of ART on the CD4+-cell count prior to ART start 1. Smith el a. 2014. 2. Vandenhende et al. 2015. 3. Fontela et al. 2020. 4. Frasceschi et al. 2010. 5. Hernandez-Ramirez et al. 2017. 6. van der Zee et al. 2023. 7. Nicolau et al. 2023. 8. Silverberg et al. 2021. 9. Chammartin et al. 2021. 10. Borges et al. 2016.

Aims Aims To assess if starting ART within 12 months of documented evidence of HIV acquisition reduces the risk of: 1) Non-AIDS-Defining Malignancies (NADM) overall & 2) Infection-related NADM and infection-unrelated NADM when considered separately

Methods & definitions Methods & definitions Individuals aged 18 starting ART between Jan 1st2000 and Dec 31st2022 Excluding those with a NADM diagnosed before start of ART Early start of ART Early start of ART: starting ART within 365 days of a documented negative HIV test result or a documented primary HIV infection Late start of ART: Late start of ART: starting ART more than 365 days after a documented negative HIV test result or documented primary HIV infection, or in the absence of a documented prior negative HIV test result Infection Infection- -related penile, vaginal and vulvar cancer, stomach cancer, Hodgkin Lymphoma and non- AIDS defining Non-Hodgkin Lymphoma subtypes related- -NADM NADM: hepatocellular carcinoma, oropharyngeal, laryngeal, anal,

Statistical analysis Statistical analysis Cox proportional hazards models to estimate cause-specific hazard ratios for: 1) All NADM 2) Infection-related NADM 3) Infection-unrelated NADM Baseline: time of ART start Censoring in case of: diagnosis of outcome of interest in the respective analysis; lost to follow-up; death or end of follow-up (December 31, 2022) Models were adjusted for: sex at birth, HIV transmission category and region of origin (fixed at baseline); and age, CD4+-cell count category (lagged by 3 months), CD4/8 ratio, smoking habit, calendar time, and time spent with HIV RNA > 1000 copies/ml while on ART (time-updated)

Characteristics at start ART Characteristics at start ART Early ART start Early ART start (n = 2,035; 8.5%) (n = 2,035; 8.5%) 1,919 (94.3) 34.5 [27.8 - 44.4] 1,273 (62.6) 570 [400 752] 794 (39.0) 638 (31.4) 172 (8.5) 434 (21.2) 1,792 (88.1) 180 (8.9) 3 (0.2) 60 (2.9) 317 (15.6) 696 (34.2) 1,022 (50.2) 2.6 [1.3 - 5.2] 66 Late ART start Late ART start (n = 21,954; 91.5%) (n = 21,954; 91.5%) 17,557 (80.0) 39.2 [31.6 - 47.4] 11,083 (50.5) 330 [200 500] 8,776 (40.0) 7,169 (32.7) 2,714 (12.4) 3,295 (15.1) 12,668 (57.7) 7,182 (32.5) 427 (1.9) 1,731 (7.9) 10,433 (47.5) 6,298 (28.7) 5,223 (23.8) 13.5 [2.8 - 83.1] 115 Male at birth Male at birth Age Age Dutch Dutch CD4 CD4+ +- -cell cell count Smoking habit Smoking habit count - Never Never - Current Current - Former Former - Unknown Unknown - MSM MSM - Heterosexual Heterosexual - IDU IDU - Other/unknown Other/unknown - 2000 2000- -2010 2010 - 2011 2011- -2015 2015 - 2016 2016- -2022 2022 HIV HIV t transmission ransmission category category Calendar time Calendar time Time since HIV diagnosis (months) Time since HIV diagnosis (months) Median Medianfollow follow- -up (months) up (months) Number (%) Median [IQR]

Results Results Incidence rates Incidence rates Early ART start (n = 2,035) Early ART start (n = 2,035) Late ART start (n = 21,954) Late ART start (n = 21,954) Number Number Person PersonYears of Follow of Follow- -Up Years Up Incidence rate Incidence rate per 1000 per 1000PYFU Number Number Person PersonYears of Follow of Follow- -Up Years Up Incidence rate Incidence rate per 1000 per 1000 PYFU PYFU PYFU NADM NADM 26 12,067 2.2 1,154 220,222 5.2 Infection Infection- -related NADM NADM related 8 12,128 0.7 375 222,963 1.7 Infection Infection- - unrelated NADM unrelated NADM 18 12,093 1.5 816 221,893 3.7 Hazard ratios Early ART starters vs. Late ART Hazard ratios Early ART starters vs. Late ART starters starters Unadjusted model, HR [95%CI] Unadjusted model, HR [95%CI] Adjusted model*, HR [95%CI] Adjusted model*, HR [95%CI] NADM NADM 0.46 [0,31-0,68] 0.60 0.60 [0.41 [0.41- -0.89] 0.89] Infection Infection- -related NADM related NADM 0.40 [0.20-0.81] 0.65 [0.32-1.33] Infection Infection- -unrelated unrelatedNADM NADM 0.48 [0.30-0.77] 0.59 [0.37 0.59 [0.37- -0.94] 0.94] * Adjusted for sex at birth, age, CD4+-cell count category (lagged by 3 months), smoking habit, HIV transmission category, region of origin, calendar time, CD4/8 ratio and time spent with HIV RNA > 1000 copies/ml while on ART

Survival curves of adjusted analyses Survival curves of adjusted analyses All NADM (aHR 0.60) - - - - - Early ART Late ART

Survival curves of adjusted analyses Survival curves of adjusted analyses Infection-related NADM (aHR 0.65) All NADM (aHR 0.60) - - - - - Early ART Late ART

Survival curves of adjusted analyses Survival curves of adjusted analyses Infection-related NADM (aHR 0.65) Infection-unrelated NADM (aHR 0.59) All NADM (aHR 0.60) - - - - - Early ART Late ART

Strengths & limitations Strengths & limitations Strengths The ATHENA cohort is one of the few cohorts which systematically collects data on prior negative HIV test results and thereby able to document recent HIV acquisition Limitations In 58% of included ATHENA participants time of HIV acquisition could not be determined and these were regarded as Late ART starters We cannot rule out that a proportion may have started ART within 365 days of HIV acquisition If so, this would have resulted in an underestimation of the benefit of starting ART early after HIV acquisition

Conclusion & recommendations Conclusion & recommendations Starting ART within 12 months of acquiring HIV significantly reduces the risk of NADM and infection-unrelated NADM compared to starting ART later after HIV acquisition, independent of CD4+-cell count Our results highlight the importance of initiatives to improve early diagnosis and treatment Other HIV cohorts should invest in collecting data on prior negative HIV test results Larger studies will be required to definitively assess the impact on infection-related NADM as well as individual NADM types

ATHENA cohort Amsterdam UMC, Amsterdam: M. van der Valk*, M.A. van Agtmael, M. Bomers, S.E. Geerlings, A. Goorhuis, V.C. Harris, J.W. Hovius, B. Lemkes, F.J.B. Nellen, E.J.G. Peters, T. van der Poll, J.M. Prins, K.C.E. Sigaloff, V. Spoorenberg, M. van Vugt, W.J. Wiersinga, F.W.M.N. Wit. H. Berends, C. Bruins, J. van Eden, I.J. Hylkema-van den Bout, L.M. Laan, F.J.J. Pijnappel, S.Y. Smalhout, M.E. Spelbrink, A.M. Weijsenfeld. N.K.T. Back, M.T.E. Cornelissen, R. van Houdt, M. Jonges, S. Jurriaans, C.J. Schinkel, M.R.A. Welkers, K.C. Wolthers. Emma Kinderziekenhuis (Amsterdam UMC, AMC site), Amsterdam: M. van der Kuip, D. Pajkrt. F.M. Hessing, A.M. Weijsenfeld. Admiraal De Ruyter Ziekenhuis, Goes: M. van den Berge*, A. Stegeman. S. Baas, L. Hage de Looff. A. van Arkel, J. Stohr, B. Wintermans. Catharina Ziekenhuis, Eindhoven: M.J.H. Pronk*, H.S.M. Ammerlaan, C. de Bree. E.S. de Munnik, S. Phaf. B. Deiman, A.R. Jansz, V. Scharnhorst, J. Tjhie, M.C.A. Wegdam. DC Klinieken Lairesse Hiv Focus Centrum, Amsterdam: J. Nellen*, A. van Eeden, E. Hoornenborg, S. de Stoppelaar W. Alers, L.J.M. Elsenburg, H. Nobel. C.J. Schinkel. ETZ (Elisabeth-TweeSteden Ziekenhuis), Tilburg: M.E.E. van Kasteren*, M.A.H. Berrevoets, A.E. Brouwer. HIV nurse specialist: B.A.F.M. de Kruijf-van de Wiel. A. Adams, M. Pawels-van Rijkevoorsel. A.G.M. Buiting, J.L. Murck. Erasmus MC, Rotterdam: C. Rokx*, A.A. Anas, H.I. Bax, E.C.M. van Gorp, M. de Mendon a Melo, E. van Nood, J.L. Nouwen, B.J.A. Rijnders, C.A.M. Schurink, L. Slobbe, T.E.M.S. de Vries-Sluijs. N. Bassant, J.E.A. van Beek, E.J.B. de Veer, M. Vriesde, L.M. van Zonneveld. J. de Groot. J.J.A. van Kampen, M.P.G Koopmans, J.C. Rahamat-Langendoen. Erasmus MC Sophia Kinderziekenhuis, Rotterdam: P.L.A. Fraaij, A.M.C. van Rossum, C.L. Vermont. L.C. van der Knaap. Flevoziekenhuis, Almere: J. Branger*, R.A. Douma. HIV nurse consultant: A.S. Cents-Bosma, M.A. Mulder. HagaZiekenhuis, Den Haag: E.F. Schippers*, C. van Nieuwkoop. J. Geilings, E. van de Ven. G. van der Hut. N.D. van Burgel. HMC (Haaglanden Medisch Centrum), Den Haag: E.M.S. Leyten*, L.B.S. Gelinck, F. Mollema. M. Langbein, G.S. Wildenbeest. T. Nguyen. Isala, Zwolle: P.H.P. Groeneveld*, J.W. Bouwhuis, A.J.J. Lammers. A.G.W. van Hulzen, S. Kraan, M.S.M. Kruiper. S.B. Debast, G.H.J. Wagenvoort. Leids Universitair Medisch Centrum, Leiden: A.H.E. Roukens*, M.G.J. de Boer, H. Jolink, M.M.C. Lambregts, H. Scheper. N. van Holten, D. van der Sluis. E.C.J. Claas, E. Wessels. Maasstad Ziekenhuis, Rotterdam: J.G. den Hollander*, R. El Moussaoui, K. Pogany. C.J. Brouwer, D. Heida-Peters, E. Mulder, J.V. Smit, D. Struik-Kalkman. T. van Niekerk. O. Pontesilli, C. van Tienen. Maastricht UMC+, Maastricht: S.H. Lowe*, A.M.L. Oude Lashof, D. Posthouwer, A. Stoop, M.E. van Wolfswinkel. R.P. Ackens, M. Elasri, K. Houben-Pintaric, J. Schippers. T.R.A. Havenith, M. van Loo. Medisch Centrum Leeuwarden, Leeuwarden: M.G.A. van Vonderen*, L.M. Kampschreur, C. Timmer. M.C. van Broekhuizen, S. Faber. A. Al Moujahid. Medisch Spectrum Twente, Enschede: G.J. Kootstra*, C.E. Delsing. M. van der Burg-van de Plas, L. Scheiberlich. Noordwest Ziekenhuisgroep, Alkmaar: W. Kortmann*, G. van Twillert*, R. Renckens, J. Wagenaar. Hiv-consulenten & D. Ruiter-Pronk, B. Stander. J.W.T. Cohen Stuart, M. Hoogewerf, W. Rozemeijer, J.C. Sinnige. OLVG, Amsterdam: K. Brinkman*, G.E.L. van den Berk, K.D. Lettinga, M. de Regt, W.E.M. Schouten, J.E. Stalenhoef, S.M.E. Vrouenraets. H. Blaauw, G.F. Geerders, M.J. Kleene, M. Knapen, M. Kok, I.B. van der Mech , A.J.M. Toonen, S. Wijnands, E. Wttewaal. HIV clinical virologists: D. Kwa, T.J.W. van de Laar. Radboudumc, Nijmegen: R. van Crevel*, K. van Aerde, A.S.M. Dofferhoff, S.S.V. Henriet, H.J.M. ter Hofstede, J. Hoogerwerf, O. Richel. M. Albers, K.J.T. Grintjes-Huisman, M. de Haan, M. Marneef. M. McCall, J. Rahamat-Langendoen, E. Ruizendaal. HIV clinical pharmacology consultant: D. Burger. Rijnstate, Arnhem: E.H. Gisolf*, M. Claassen, R.J. Hassing,. G. ter Beest, P.H.M. van Bentum, Y. Neijland, M. Valette. Haarlem: S.F.L. van Lelyveld*, R. Soetekouw. L.M.M. van der Prijt, J. van der Swaluw. B.L. Herpers, J.S. Kalpoe, A. Vahidnia. Medisch Centrum Jan van Goyen, Amsterdam: F.N. Lauw, D.W.M. Verhagen. M. van Wijk. Universitair Medisch Centrum Groningen, Groningen: Kleinnijenhuis, E. Kloeze, A. Middel, D.F. Postma, H.M. Schenk, Y. Stienstra, M. Wouthuyzen-Bakker. A. Boonstra, M.M.M. Maerman, D.A. de Weerd. K.J. van Eije, M. Knoester, C.C. van Leer-Buter, H.G.M. Niesters. Beatrix Kinderziekenhuis (Universitair Medisch Centrum Groningen), Groningen: B.R. Brandsema, E.H. Sch lvinck, A.R. Verhage. N. van der Woude. M. Knoester, C.C. van Leer-Buter, H.G.M. Niesters. Universitair Medisch Centrum Utrecht, Utrecht: T.Mudrikova*, R.E. Barth, A.H.W. Bruns, P.M. Ellerbroek, M.P.M. Hensgens, J.J. Oosterheert, E.M. Schadd, A. Verbon, B.J. van Welzen. B.M.G. Griffioen-van Santen, I. de Kroon. R. Schuurman, F.M. Verduyn Lunel, A.M.J. Wensing. Wilhelmina Kinderziekenhuis, UMC Utrecht, Utrecht: Y.G.T. Loeffen, T.F.W. Wolfs. M. Kok. F.M. Verduyn Lunel, A.M.J. Wensing. Cura ao Medical Center, Willemstad (Cura ao): E.O.W. Rooijakkers, D. van de Wetering. A. Alberto. I. der Meer. Coordinating centre: M. van der Valk, S. Zaheri. A.C. Boyd, D.O. Bezemer, V.W. Jongen, A.I. van Sighem, C. Smit, F.W.M.N. Wit, M.M.J. Hillebregt, T.J. Woudstra, T. Rutkens, D. Bergsma, N.M. Br tin, L.E. Koster, K.J. Lelivelt, L. van de Sande, M.J.C. Schoorl, K.M. Visser, S.T. van der Vliet, F. Paling, M. van den Akker, O.M. Akpomukai, R. Alexander, Y.M. Bakker, L. Bastos Sales, A. El Berkaoui, M. Bezemer-Goedhart, E.A. Djoechro, J.M. Grolleman, I. El Hammoud, M.R. Khouw, C.R.E. Lodewijk, E.G.A. Lucas, S. van Meerveld- Derks, H.W. Mulder, L. Munjishvili, C.M.J. Ree, R. Regtop, A.F. van Rijk, Y.M.C. Ruijs-Tiggelman, P.P. Schn rr, R. van Veen, W.H.G. van Vliet-Klein Gunnewiek, E.C.M Witte. D. Bergsma, N.M. Br tin, Y.M.C. Ruijs-Tiggelman. C.M.A. Swanink, M. Klein Velderman. Spaarne Gasthuis, W.F.W. Bierman*, M. Bakker, R.A. van Bentum, M.A. van den Boomgaard, J.