Immuno-virological discordance and the risk of non-AIDS and AIDS events in a large observational cohort of HIV-patients in Europe

Alexander Zoufaly, Alessandro Cozzi-Lepri, Joanne Reekie, Ole Kirk, Jens Lundgren, Peter Reiss, Djordje Jevtovic, Ladislav Machala, Robert Zangerle, Amanda Mocroft, Jan Van Lunzen, EuroSIDA in EuroCoord, M Losso, M Kundro, N Vetter, R Zangerle, I Karpov, A Vassilenko, V M Mitsura, O Suetnov, N Clumeck, S De Wit, M Delforge, R Colebunders, L Vandekerckhove, V Hadziosmanovic, K Kostov, J Begovac, L Machala, D Jilich, D Sedlacek, J Nielsen, G Kronborg, T Benfield, M Larsen, J Gerstoft, T Katzenstein, A-B E Hansen, P Skinhøj, C Pedersen, L Ostergaard, K Zilmer, M Ristola, C Katlama, J-P Viard, P-M Girard, J M Livrozet, P Vanhems, C Pradier, F Dabis, D Neau, J Rockstroh, R Schmidt, J van Lunzen, O Degen, H J Stellbrink, S Staszewski, J W Goethe, J Bogner, G Fätkenheuer, J Kosmidis, P Gargalianos, G Xylomenos, J Perdios, G Panos, A Filandras, E Karabatsaki, H Sambatakou, D Banhegyi, F Mulcahy, I Yust, D Turner, M Burke, S Pollack, G Hassoun, S Maayan, S Vella, R Esposito, I Mazeu, C Mussini, R Pristera, F Mazzotta, A Gabbuti, S Maria, V Vullo, M Lichtner, A Chirianni, E Montesarchio, M Gargiulo, G Antonucci, A Testa, G D'Offizi, C Vlassi, M Zaccarelli, A Antorini, A Lazzarin, A Castagna, M Galli, A Ridolfo, A d'Arminio Monforte, B Rozentale, I Zeltina, S Chaplinskas, T Staub, R Hemmer, P Reiss, V Ormaasen, A Maeland, J Bruun, B Knysz, J Gasiorowski, A Horban, E Bakowska, A Grzeszczuk, R Flisiak, A Boron-Kaczmarska, M Pynka, M Parczewski, M Beniowski, E Mularska, H Trocha, E Jablonowska, E Malolepsza, K Wojcik, F Antunes, M Doroana, L Caldeira, K Mansinho, F Maltez, D Duiculescu, Victor Babes, A Rakhmanova, N Zakharova, S Buzunova, D Jevtovic, M Mokráš, D Staneková, J Tomazic, J González-Lahoz, V Soriano, P Labarga, J Medrano, S Moreno, J M Rodriguez, B Clotet, A Jou, R Paredes, C Tural, J Puig, I Bravo, J M Gatell, J M Miro, P Domingo, M Gutierrez, G Mateo, M A Sambeat, A Blaxhult, L Flamholc, B Ledergerber, R Weber, P Francioli, M Cavassini, B Hirschel, E Boffi, H Furrer, M Battegay, L Elzi, E Kravchenko, N Chentsova, V Frolov, G Kutsyna, S Servitskiy, M Krasnov, S Barton, A M Johnson, D Mercey, A Phillips, M A Johnson, A Mocroft, M Murphy, J Weber, G Scullard, M Fisher, C Leen, J Gatell, B Gazzard, A Horban, I Karpov, B Ledergerber, M Losso, C Pedersen, A Rakhmanova, J Rockstroh, S De, J Lundgren, A Phillips, P Reiss, O Kirk, A Mocroft, A Cozzi-Lepri, D Grint, D Podlekareva, J Kjær, L Peters, J Nielsen, J Tverland, D Raben, A H Fischer, A Schultze, L Shepherd, O Kirk, A Mocroft, J Grarup, P Reiss, A Cozzi-Lepri, R Thiebaut, J Rockstroh, D Burger, R Paredes, L Peters, Alexander Zoufaly, Alessandro Cozzi-Lepri, Joanne Reekie, Ole Kirk, Jens Lundgren, Peter Reiss, Djordje Jevtovic, Ladislav Machala, Robert Zangerle, Amanda Mocroft, Jan Van Lunzen, EuroSIDA in EuroCoord, M Losso, M Kundro, N Vetter, R Zangerle, I Karpov, A Vassilenko, V M Mitsura, O Suetnov, N Clumeck, S De Wit, M Delforge, R Colebunders, L Vandekerckhove, V Hadziosmanovic, K Kostov, J Begovac, L Machala, D Jilich, D Sedlacek, J Nielsen, G Kronborg, T Benfield, M Larsen, J Gerstoft, T Katzenstein, A-B E Hansen, P Skinhøj, C Pedersen, L Ostergaard, K Zilmer, M Ristola, C Katlama, J-P Viard, P-M Girard, J M Livrozet, P Vanhems, C Pradier, F Dabis, D Neau, J Rockstroh, R Schmidt, J van Lunzen, O Degen, H J Stellbrink, S Staszewski, J W Goethe, J Bogner, G Fätkenheuer, J Kosmidis, P Gargalianos, G Xylomenos, J Perdios, G Panos, A Filandras, E Karabatsaki, H Sambatakou, D Banhegyi, F Mulcahy, I Yust, D Turner, M Burke, S Pollack, G Hassoun, S Maayan, S Vella, R Esposito, I Mazeu, C Mussini, R Pristera, F Mazzotta, A Gabbuti, S Maria, V Vullo, M Lichtner, A Chirianni, E Montesarchio, M Gargiulo, G Antonucci, A Testa, G D'Offizi, C Vlassi, M Zaccarelli, A Antorini, A Lazzarin, A Castagna, M Galli, A Ridolfo, A d'Arminio Monforte, B Rozentale, I Zeltina, S Chaplinskas, T Staub, R Hemmer, P Reiss, V Ormaasen, A Maeland, J Bruun, B Knysz, J Gasiorowski, A Horban, E Bakowska, A Grzeszczuk, R Flisiak, A Boron-Kaczmarska, M Pynka, M Parczewski, M Beniowski, E Mularska, H Trocha, E Jablonowska, E Malolepsza, K Wojcik, F Antunes, M Doroana, L Caldeira, K Mansinho, F Maltez, D Duiculescu, Victor Babes, A Rakhmanova, N Zakharova, S Buzunova, D Jevtovic, M Mokráš, D Staneková, J Tomazic, J González-Lahoz, V Soriano, P Labarga, J Medrano, S Moreno, J M Rodriguez, B Clotet, A Jou, R Paredes, C Tural, J Puig, I Bravo, J M Gatell, J M Miro, P Domingo, M Gutierrez, G Mateo, M A Sambeat, A Blaxhult, L Flamholc, B Ledergerber, R Weber, P Francioli, M Cavassini, B Hirschel, E Boffi, H Furrer, M Battegay, L Elzi, E Kravchenko, N Chentsova, V Frolov, G Kutsyna, S Servitskiy, M Krasnov, S Barton, A M Johnson, D Mercey, A Phillips, M A Johnson, A Mocroft, M Murphy, J Weber, G Scullard, M Fisher, C Leen, J Gatell, B Gazzard, A Horban, I Karpov, B Ledergerber, M Losso, C Pedersen, A Rakhmanova, J Rockstroh, S De, J Lundgren, A Phillips, P Reiss, O Kirk, A Mocroft, A Cozzi-Lepri, D Grint, D Podlekareva, J Kjær, L Peters, J Nielsen, J Tverland, D Raben, A H Fischer, A Schultze, L Shepherd, O Kirk, A Mocroft, J Grarup, P Reiss, A Cozzi-Lepri, R Thiebaut, J Rockstroh, D Burger, R Paredes, L Peters

Abstract

Background: The impact of immunosuppression despite virological suppression (immuno-virological discordance, ID) on the risk of developing fatal and non-fatal AIDS/non-AIDS events is unclear and remains to be elucidated.

Methods: Patients in EuroSIDA starting at least 1 new antiretroviral drug with CD4<350 cells/µl and viral load (VL)>500 copies/mL were followed-up from the first day of VL< = 50 copies/ml until a new fatal/non-fatal non-AIDS/AIDS event. Considered non-AIDS events included non-AIDS malignancies, pancreatitis, severe liver disease with hepatic encephalopathy (>grade 3), cardio- and cerebrovascular events, and end-stage renal disease. Patients were classified over time according to whether current CD4 count was above (non-ID) or below (ID) baseline level. Relative rates (RR) of events were calculated for ID vs. non-ID using adjusted Poisson regression models.

Results: 2,913 patients contributed 11,491 person-years for the analysis of non-AIDS. 241 pre-specified non-AIDS events (including 84 deaths) and 89 AIDS events (including 10 deaths) occurred. The RR of developing pre-specified non-AIDS events for ID vs. non-ID was 1.96 (95% CI 1.37-2.81, p<0.001) in unadjusted analysis and 1.43 (0.94-2.17, p = 0.095) after controlling for current CD4 count. ID was not associated with the risk of AIDS events (aRR 0.76, 95% CI 0.41-1.38, p = 0.361).

Conclusion: Compared to CD4 responders, patients with immuno-virological discordance may be at increased risk of developing non-AIDS events. Further studies are warranted to establish whether in patients with ID, strategies to directly modify CD4 count response may be needed besides the use of ART.

Conflict of interest statement

Competing Interests: Primary support is provided by the European Commission BIOMED 1 (CT94-1637), BIOMED 2 (CT97-2713), the 5th Framework (QLK2-2000-00773), the 6th Framework (LSHP-CT-2006-018632), and the 7th Framework (FP7/2007–2013, EuroCoord no. 260694) programmes. Current support also includes unrestricted grants by Gilead, Pfizer, and Merck and Co. The participation of centres from Switzerland was supported by The Swiss National Science Foundation (Grant 108787). AZ received a grant from MSD SHARP & DOHME GmbH for the performance of this research. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Flow chart showing selection of…
Figure 1. Flow chart showing selection of patients enrolled in EuroSIDA for the analysis.
Figure 2. Rates (and 95% confidence intervals)…
Figure 2. Rates (and 95% confidence intervals) of fatal and non-fatal non-AIDS and AIDS in patients with and without immuno-virological discordance (ID).

References

    1. Hughes MD, Daniels MJ, Fischl MA, Kim S (1998) Schooley RT (1998) CD4 cell count as a surrogate endpoint in HIV clinical trials: a meta-analysis of studies of the AIDS Clinical Trials Group. AIDS 12: 1823–1832.
    1. Staszewski S, Miller V, Sabin C, Schlecht C, Gute P, et al. (1999) Determinants of sustainable CD4 lymphocyte count increases in response to antiretroviral therapy. AIDS 13: 951–956.
    1. Wolbers M, Bucher HC, Furrer H, Rickenbach M, Cavassini M, et al. (2008) Delayed diagnosis of HIV infection and late initiation of antiretroviral therapy in the Swiss HIV Cohort Study. HIV Med 9: 397–405.
    1. Mocroft A, Phillips AN, Gatell J, Ledergerber B, Fisher M, et al. (2007) Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study. Lancet 370: 407–413.
    1. Kelley CF, Kitchen CM, Hunt PW, Rodriguez B, Hecht FM, et al. (2009) Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis 48: 787–794.
    1. Robbins GK, Spritzler JG, Chan ES, Asmuth DM, Gandhi RT, et al. (2009) Incomplete reconstitution of T cell subsets on combination antiretroviral therapy in the AIDS Clinical Trials Group protocol 384. Clin Infect Dis 48: 350–361.
    1. Miller V, Mocroft A, Reiss P, Katlama C, Papadopoulos AI, et al. (1999) Relations among CD4 lymphocyte count nadir, antiretroviral therapy, and HIV-1 disease progression: results from the EuroSIDA study. Ann Intern Med 130: 570–577.
    1. Tan R, Westfall AO, Willig JH, Mugavero MJ, Saag MS, et al. (2008) Clinical outcome of HIV-infected antiretroviral-naive patients with discordant immunologic and virologic responses to highly active antiretroviral therapy. J Acquir Immune Defic Syndr 47: 553–558.
    1. Moore DM, Hogg RS, Yip B, Wood E, Tyndall M, et al. (2005) Discordant immunologic and virologic responses to highly active antiretroviral therapy are associated with increased mortality and poor adherence to therapy. J Acquir Immune Defic Syndr 40: 288–293.
    1. Zoufaly A, an der Heiden M, Kollan C, Bogner JR, Fatkenheuer G, et al. (2011) Clinical outcome of HIV-infected patients with discordant virological and immunological response to antiretroviral therapy. J Infect Dis 203: 364–371.
    1. Mocroft A, Reiss P, Gasiorowski J, Ledergerber B, Kowalska J, et al. (2010) Serious fatal and nonfatal non-AIDS-defining illnesses in Europe. J Acquir Immune Defic Syndr 55: 262–270.
    1. Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, et al. (1998) Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet 352: 1725–1730.
    1. revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 17: 1–19.
    1. Kowalska JD, Mocroft A, Ledergerber B, Florence E, Ristola M, et al. (2011) A standardized algorithm for determining the underlying cause of death in HIV infection as AIDS or non-AIDS related: results from the EuroSIDA study. HIV Clin Trials 12: 109–117.
    1. Shrier I, Platt RW (2008) Reducing bias through directed acyclic graphs. BMC Med Res Methodol 8: 70.
    1. Babiker A, Darbyshire J, Pezzotti P, Porter K, Rezza G, et al. (2002) Changes over calendar time in the risk of specific first AIDS-defining events following HIV seroconversion, adjusting for competing risks. Int J Epidemiol 31: 951–958.
    1. Moore RD, Gebo KA, Lucas GM, Keruly JC (2008) Rate of comorbidities not related to HIV infection or AIDS among HIV-infected patients, by CD4 cell count and HAART use status. Clin Infect Dis 47: 1102–1104.
    1. Mocroft A, Bannister WP, Kirk O, Kowalska JD, Reiss P, et al. (2012) The clinical benefits of antiretroviral therapy in severely immunocompromised HIV-1-infected patients with and without complete viral suppression. Antivir Ther.
    1. Lapadula G, Cozzi-Lepri A, Marchetti G, Antinori A, Chiodera A, et al. (2013) Risk of clinical progression among patients with immunological nonresponse despite virological suppression after combination antiretroviral treatment AIDS. 27: 769–779.
    1. Gazzola L, Tincati C, Bellistri GM, Monforte A, Marchetti G (2009) The absence of CD4+ T cell count recovery despite receipt of virologically suppressive highly active antiretroviral therapy: clinical risk, immunological gaps, and therapeutic options. Clin Infect Dis 48: 328–337.
    1. Nies-Kraske E, Schacker TW, Condoluci D, Orenstein J, Brenchley J, et al. (2009) Evaluation of the pathogenesis of decreasing CD4(+) T cell counts in human immunodeficiency virus type 1-infected patients receiving successfully suppressive antiretroviral therapy. J Infect Dis 199: 1648–1656.
    1. Helleberg M, Kronborg G, Larsen C, Pedersen G, Pedersen C, et al. (2013) Poor CD4 response despite viral suppression is associated with increased non-AIDS-related mortality among HIV patients and their parents. AIDS 27: 1021–1026.
    1. Hatano H, Jain V, Hunt PW, Lee TH, Sinclair E, et al. (2012) Cell-Based Measures of Viral Persistence Are Associated With Immune Activation and Programmed Cell Death Protein 1 (PD-1)-Expressing CD4+ T cells. J Infect Dis.
    1. Hsue PY, Hunt PW, Schnell A, Kalapus SC, Hoh R, et al. (2009) Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis. AIDS 23: 1059–1067.
    1. Monforte A, Abrams D, Pradier C, Weber R, Reiss P, et al. (2008) HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS 22: 2143–2153.
    1. Kesselring A, Gras L, Smit C, van Twillert G, Verbon A, et al. (2011) Immunodeficiency as a risk factor for non-AIDS-defining malignancies in HIV-1-infected patients receiving combination antiretroviral therapy. Clin Infect Dis 52: 1458–1465.
    1. Abrams D, Levy Y, Losso MH, Babiker A, Collins G, et al. (2009) Interleukin-2 therapy in patients with HIV infection. N Engl J Med 361: 1548–1559.
    1. Lanzafame M, Lattuada E, Vento S (2009) Maraviroc and CD4+ cell count recovery in patients with virologic suppression and blunted CD4+ cell response. AIDS 27: 869.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe