Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes

Bruno Ledergerber*, Jens D. Lundgren, A. Sarah Walker, Caroline Sabin, Amy Justice, Peter Reiss, Cristina Mussini, Ferdinand Wit, Antonella d'Arminio Monforte, Rainer Weber, Gregory Fusco, Schlomo Staszewski, Matthew Law, Robert Hogg, Fiona Lampe, M. John Gill, Francesco Castelli, Andrew N. Phillips, P. Rooney, S. TaylorD. Couldwell, D. Austin, M. Block, J. Clemons, R. Finlayson, K. Petoumenos, D. Quan, D. Smith, C. O'Connor, C. Gorton, D. Allen, B. Mulhall, K. Mutimer, N. Keeffe, D. Cooper, A. Carr, J. Miller, C. Pell, D. Ellis, D. Baker, J. Kidd, R. McFarlane, M. T. Liang, Kevin Brown, S. Huffam, J. Savage, S. Morgan, P. Knibbs, D. Sowden, A. Walker, D. Orth, G. Lister, J. Chuah, W. Fankhauser, B. Dickson, D. Bradford, C. Wilson, H. Ree, H. Magon, Jane Anderson, R. Moore, D. Russell, G. McGovern, R. McNair, J. Bal, K. Fairley, N. Roth, B. Eu, S. Strecker, H. Wood, A. Mijch, J. Hoy, A. Pierce, C. McCormack, K. Watson, N. Medland, J. Daye, S. Mallal, M. French, J. Skett, D. Maxwel, A. Cain, M. Montroni, G. Scalise, A. Costantini, A. Giacometti, U. Tirelli, G. Nasti, G. Pastore, N. Ladisa, M. L. Perulli, F. Suter, C. Arici, F. Maggiolo, F. Chiodo, F. M. Gritti, V. Colangeli, C. Fiorini, L. Guerra, G. Carosi, G. P. Cadeo, C. Minardi, D. Vangi, G. Paraninfo, S. Casari, A. Pan, A. Patroni, C. Torti, E. Quiros-Roldan, L. Tomasoni, F. Moretti, P. Nasta, M. C. Uccelli, D. Bertelli, G. Rizzardini, G. Migliorino, M. Migliorino, C. Abeli, P. E. Manconi, P. Piano, T. Ferraro, A. Scerbo, E. Pizzigallo, F. Ricci, D. Santoro, L. Pusterla, G. Carnevale, D. Galloni, P. Viganò, M. Mena, F. Ghinelli, L. Sighinolfi, F. Leoncini, F. Mazzotta, M. Pozzi, S. Lo Caputo, G. Angarano, B. Grisorio, S. Ferrara, P. Grima, P. Tundo, G. Pagano, N. Piersantelli, A. Alessandrini, R. Piscopo, M. Toti, S. Chigiotti, F. Soscia, L. Tacconi, A. Orani, P. Perini, M. Nigro, A. Scasso, A. Vincenti, A. Scalzini, G. Fibbia, M. Moroni, A. Lazzarin, A. Cargnel, G. M. Vigevani, L. Caggese, F. Tordato, R. Novati, A. Galli, S. Merli, C. Pastecchia, C. Moioli, R. Esposito, N. Abrescia, A. Chirianni, C. Izzo, M. Piazza, M. De Marco, V. Montesarchio, E. Manzillo, S. Nappa, A. Colomba, V. Abbadessa, T. Prestileo, S. Mancuso, C. Ferrari, P. Pzzaferri, G. Filice, L. Minoli, R. Bruno, R. Maserati, S. Novati, C. Tinelli, S. Pauluzzi, F. Baldelli, E. Petrelli, A. Cioppi, F. Alberici, A. Ruggieri, F. Menichetti, C. Martinelli, C. De Stefano, A. La Gala, T. Zauli, G. Ballardini, G. Magnani, M. A. Ursitti, M. Arlotti, P. Ortolani, L. Ortona, F. Dianzani, G. Ippolito, A. Antinori, G. Antonucci, S. D'Elia, P. Narciso, N. Petrosillo, V. Vullo, A. De Luca, L. Del Forno, M. Zaccarelli, P. De Longis, M. Ciardi, G. D'Offizi, P. Noto, M. Lichtner, M. R. Capobianchi, E. Girardi, P. Pezzotti, G. Rezza, M. S. Mura, M. Mannazzu, P. Caramello, A. Sinicco, M. L. Soranzo, L. Gennero, M. Sciandra, B. Salassa, P. A. Grossi, C. Basilico, A. Poggio, G. Bottari, E. Raise, S. Pasquinucci, F. De Lalla, G. Tositti, F. Resta, A. Chimienti, A. Lepri Cozzi, S. Bachmann, M. Battegay, E. Bernasconi, H. Bucher, P. Bürgisser, S. Cattacin, M. Egger, P. Erb, W. Fierz, M. Fischer, M. Flepp, A. Fontana, P. Francioli, H. J. Furrer, M. Gorgievski, H. Günthard, B. Hirschel, L. Kaiser, C. Kind, T. Klimkait, U. Lauper, M. Opravil, F. Paccaud, G. Pantaleo, L. Perrin, J. C. Piffaretti, M. Rickenbach, C. Rudin, J. Schüpbach, R. Speck, P. Tarr, A. Telenti, A. Trkola, P. Vernazza, S. Yerly, F. de Wolf, A. I. van Sighem, I. van Valkengoed, L. Gras, W. Bronsveld, A. Veldkamp, J. M. Prins, J. C. Bos, J. K.M. Schattenkerk Eeftinck, M. H. Godfried, J. M.A. Lange, S. H. Lowe, J. T.M. van der Meer, F. J.B. Nellen, K. Pogany, T. van der Poll, T. A. Ruys, S. Sankatsing, M. van der Valk, M. G.A. van Vonderen, F. W.M.N. Wit, A. van Eeden, J. H. ten Veen, P. S. van Dam, M. E. Hillebrand-Haverkort, K. Brinkman, P. H.J. Frissen, H. M. Weigel, J. W. Mulder, E. C.M. van Gorp, P. L. Meenhorst, A. T.A. Mairuhu, J. Veenstra, S. A. Danner, M. A. Van Agtmael, F. A.P. Claessen, S. E. Geerlings, R. M. Perenboom, S. Jurriaans, N. K.T. Back, T. Cuijpers, P. J.G.M. Rietra, K. J. Roozendaal, W. Pauw, A. P. van Zanten, P. H.M. Smits, B. M.E. von Blomberg, P. Savelkoul, H. Zaaijer, J. H. Beijnen, K. M.L. Crommentuyn, A. D.R. Huitema, B. Kappelhoff, M. M.R. de Maat, C. Richter, J. van der Berg, R. van Leusen, C. Swanink, R. Vriesendorp, F. J.F. Jeurissen, R. H. Kauffmann, E. L.W. Koger, P. F.H. Franck, A. S. Lampe, B. Bravenboer, C. H.H. ten Napel, T. Mudrikova, R. Hendriks, H. G. Sprenger, W. M.A.J. Miesen, J. Schirm, D. Benne, R. W. ten Kate, D. Veenendaal, D. P.F. van Houte, M. P. Leemhuis, M. Pole, H. Storm, J. H. van Zeijl, F. P. Kroon, E. F. Schippers, A. C.M. Kroes, H. C.J. Claas, G. Schreij, S. van de Geest, A. Verbon, C. A.M.V.A. Bruggeman, V. J. Goossens, P. P. Koopmans, M. Telgt, A. J.A.M. van der Ven, D. M. Burger, P. W.H. Hugen, J. M.D. Galama, Y. A.G.M. Poort, M. E. van der Ende, I. C. Gyssens, S. de Marie, J. L. Nouwen, M. G. Niesters, A. D.M.E. Osterhaus, M. Schutten, J. R. Juttmann, A. G.M. Buiting, C. A.M. Swaans, M. M.E. Schneider, M. J.M. Bonten, J. C.C. Borleffs, I. M. Hoepelman, C. A.J.J. Jaspers, I. Schouten, C. A.M. Schurink, C. A.B. Boucher, R. Schuurman, W. L. Blok, P. H.P. Groeneveld, E. Boel, A. F. Jansz, F. Dabis, R. Thiebaut, G. Chêne, S. Lawson-Ayayi, L. Meyer, F. Boufassa, O. Hamouda, G. Touloumi, A. Hatzakis, A. Karafoulidou, O. Katsarou, R. Brettle, J. Del Amo, J. del Romero, L. van Asten, B. van Benthem, M. Prins, R. Coutinho, O. Kirk, C. Pedersen, I. Hernández Aguado, S. Pérez-Hoyos, A. Eskild, J. N. Bruun, M. Sannes, C. Lee, A. M. Johnson, A. Babiker, J. Darbyshire, N. Gill, K. Porter, P. Vanhems, J. Kaldor, L. Ashton, J. Vizzard, R. Muga, J. Gill, J. Cayla, P. Garcia de Olalla, N. E. Day, Daniela De Angelis, S. Walker, F. Tyrer, V. Beral, S. Raffanti, S. Becker, A. Scarsella, J. Braun, B. Most, R. Balu, L. Gilbert, R. Fleenor, T. Ising, D. Dieterich, J. Fusco, M. Losso, A. Duran, N. Vetter, N. Clumeck, S. De Wit, K. Kabeya, B. Poll, R. Colebunders, L. Machala, H. Rozsypal, J. Nielsen, C. H. Olsen, J. Gerstoft, T. Katzenstein, A. B.E. Hansen, P. Skinhøj, K. Zilmer, M. Rauka, C. Katlama, M. De Sa, J. P. Viard, T. Saint-Marc, C. Pradier, M. Dietrich, C. Manegold, J. van Lunzen, H. J. Stellbrink, V. Miller, F. D. Goebel, B. Salzberger, J. Rockstroh, J. Kosmidis, P. Gargalianos, H. Sambatakou, J. Perdios, G. Panos, A. Filandras, D. Banhegyi, F. Mulcahy, I. Yust, M. Burke, S. Pollack, J. Hassoun, Z. Sthoeger, S. Maayan, S. Vella, A. Chiesi, R. Pristerá, A. Gabbuti, A. Bedini, E. Montesarchio, P. Santopadre, P. Franci, A. Castagna, L. Viksna, B. Rozentale, S. Chaplinskas, R. Hemmer, T. Staub, J. Bruun, A. Maeland, V. Ormaasen, B. Knysz, J. Gasiorowski, A. Horban, D. Prokopowicz, A. Wiercinska-Drapalo, A. Boron-Kaczmarska, M. Pynka, M. Beniowski, H. Trocha, T. Smiatacz, F. Antunes, K. Mansinho, F. Maltez, D. Duiculescu, A. Streinu-Cercel, M. Mokrás, D. Staneková, J. González-Lahoz, B. Diaz, T. García-Benayas, L. Martin-Carbonero, V. Soriano, B. Clotet, A. Jou, J. Conejero, C. Tural, J. M. Gatell, J. M. Miró, L. Zamora, A. Blaxhult, A. Karlsson, P. Pehrson, V. Schiffer, H. Furrer, N. Chentsova, S. Barton, D. Mercey, A. Phillips, M. Youle, M. A. Johnson, A. Mocroft, M. Murphy, J. Weber, G. Scullard, M. Fisher, C. Loveday, L. Ruiz, E. B. Helm, A. Carlebach, M. Mösch, A. Müller, A. Haberl, S. Korn, C. Stephan, M. Bickel, P. Gute, L. Locher, T. Lutz, S. Klauke, H. W. Doerr, M. Stürmer, B. Dauer, B. Jennings, C. Alexander, P. Braitstein, K. Chan, H. Cote, N. Gataric, P. R. Harrigan, M. Harris, S. Bonner, J. Montaner, M. O'Shaughnessy, E. Wood, B. Yip, C. Chaloner, H. Gumley, D. Ransom, M. Lipman, M. Johnson, R. Read, G. Riccio, V. Borghi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

259 Citations (Scopus)

Abstract

Background Treatment strategies for patients in whom HIV replication is not suppressed after exposure to several drug classes remain unclear. We aimed to assess the inter-relations between viral load, CD4-cell count, and clinical outcome in patients who had experienced three-class virological failure. Methods We undertook collaborative joint analysis of 13 HIV cohorts from Europe, North America, and Australia, involving patients who had had three-class virological failure (viral load >1000 copies per mL for >4 months). Regression analyses were used to quantify the associations between CD4-cell-count slope, HIV-1 RNA concentration, treatment information, and demographic characteristics. Predictors of death were analysed by Cox's proportional-hazards models. Findings 2488 patients were included. 2118 (85%) had started antiretroviral therapy with single or dual therapy. During 5015 person-years of follow-up, 276 patients died (mortality rate 5·5 per 100 person-years; 3-year mortality risk 15·3% (95% CI 13·5-17·3). Risk of death was strongly influenced by the latest CD4-cell count with a relative hazard of 15·8 (95% CI 9·28-27·0) for counts below 50 cells per μL versus above 200 cells per μL. The latest viral load did not independently predict death. For any given viral load, patients on treatment had more favourable CD4-cell-count slopes than those off treatment. For patients on treatment and with stable viral load, CD4-cell counts tended to be increasing at times when the current viral load was below 10 000 copies per mL or 1·5 log10copies per mL below off-treatment values. Interpretation In patients for whom viral-load suppression to below the level of detection is not possible, achievement and maintenance of a CD4-cell count above 200 per μL becomes the primary aim. Treatment regimens that maintain the viral load below 10 000 copies per mL or at least provide 1·5 log10copies per mL suppression below the off-treatment value do not seem to be associated with appreciable CD4-cell-count decline.

Original languageEnglish
Pages (from-to)51-62
Number of pages12
JournalThe Lancet
Volume364
Issue number9428
DOIs
Publication statusPublished - 3 Jul 2004

Bibliographical note

Funding Information:
Bruno Ledergerber has received travel grants, grants, or honoraria from Roche, Abbott, Bristol-Myers-Squibb (BMS), GlaxoSmithKline (GSK), MerckSharp&Dohme (MSD), and Aventis. Jens D Lundgren has received grant and travel support and fees from Abbott, BMS, Roche, Boehringer Ingelheim, Pfizer, MSD, and GSK. Sarah Walker has no conflict of interest to declare. Caroline Sabin has received honoraria, consultancy fees, and travel grants from several pharmaceutical companies, including Roche, BMS, Boehringer Ingelheim, Gilead Sciences, and GSK. Fiona Lampe has received grants and travel grants from GSK. Andrew N Phillips has received honoraria, consultancy fees, grants, and travel grants from various pharmaceutical companies, including Roche, DuPont, BMS, Boehringer Ingelheim, and GSK. Amy Justice has received travel grants, unrestricted educational grants, and consultancy fees from various pharmaceutical companies, including GSK, DuPont, MSD, Gilead Sciences, and Roche. Peter Reiss has received honoraria, consultancy fees, grants, and travel grants from various pharmaceutical companies including Roche, BMS, MSD, Boehringer Ingelheim, Gilead Sciences, Tibotec, and GSK. Cristina Mussini has no conflict of interest to declare. Ferdinand Wit has received travel grants or honoraria from Roche, Abbott, BMS, GSK, MSD, Gilead Sciences, and Boehringer Ingelheim. Antonella d'Arminio Monforte has no conflict of interest to declare. Rainer Weber has received travel grants or honoraria from Roche, Abbott, BMS, GSK, and MSD. Gregory Fusco is an employee of GSK. Schlomo Staszewski has received travel grants, unrestricted educational grants, consultancy fees, and honoraria from various pharmaceutical companies including Roche, DuPont, BMS, Boehringer Ingelheim, and GSK. Matthew Law has received consultancy fees from Johnson and Johnson and travel grants from GSK. Robert Hogg has received grant funding and honoraria from Boehringer Ingelheim, BMS, GSK, Merck Frosst, Novartis, and VaxGen. M John Gill has affiliations and competing interests with Glaxo Wellcome, BMS, Roche, DuPont, Abbott, Boehringer Ingelheim, Chiron, Pfizer, Eli Lily, Agouron, and Merck Frosst. Francesco Castelli has received travel grants or honoraria from Gilead Sciences, MSD, Abbott, GSK, Roche, and Vertex.

Funding Information:
We thank all patients, doctors, data managers, and study nurses who were involved in the participating cohort studies. We also thank Jonathan Sterne for statistical advice and Ian Weller for valuable input. The Australian HIV Observational Database received grants from the Clinical Trials and Research Committee of the Australian National Council on AIDS, Hepatitis C and Related Diseases. The Australian National Centre in HIV Epidemiology and Clinical Research was funded by the Commonwealth Department of Health and Ageing. The AIDS Therapy Evaluation Project Netherlands was supported by grant Cure 97-46486 from the Health Insurance Fund Council, Amstelveen, the Netherlands, and the Wellcome Trust, London, UK. The Concerted Action on Seroconversion to AIDS and Death in Europe received a grant from the European Union (QLK2-2000-01431) and additional funding from GlaxoSmithKline. The South Alberta Clinic Cohort was supported by the provincial government of Alberta, Canada. The Collaborations in HIV Outcomes Research – US was funded by GlaxoSmithKline. The EuroSIDA study received funds from the European Commission BIOMED 1 (CT94-1637), BIOMED 2 (CT97-2713), and 5th framework (QLK2-2000-00773) programmes and additional support from GlaxoSmithKline, Roche, Boehringer-Ingelheim, and Bristol-Myers-Squibb. The participation of Swiss sites in EuroSIDA was supported by a grant from the Swiss Federal Office for Education and Science (96.0264). The Swiss HIV Cohort Study was funded by the Swiss National Science Foundation (grant 3345-062041). The Frankfurt HIV Cohort received grants from the Bundesministerium für Bildung und Forschung, GlaxoSmithKline, Roche, and Abbott. The Italian Cohort Naive Antiretrovirals received unrestricted educational grants from GlaxoSmithKline, Italy. The “Management Standardizzato di Terapia Antiretrovirale” (MASTER) data collection has been made possible by a grant from ROCHE Pharmaceuticals Italy. The Modena Cohort received funding from the Istituto Superiore di Sanità, Progetto “Patologia, clinica e terapia dell'AIDS” grant n. 30D.56. The Royal Free Clinic Cohort was funded by the MRC Co-operative Group Grant G0000130. The British Columbia HIV/AIDS Drug Treatment Program was sponsored by the Michael Smith Health Research Foundation, the government of British Columbia, and Canadian Institutes of Health Research. This collaboration was facilitated by an unrestricted grant from GlaxoSmithKline.

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