We also estimated the 5-year survival curves under cART initiation at baseline and under no cART initiation during the follow-up period. Overall, the estimated probability of surviving 5 years if cART had been initiated at baseline was 96%, compared with 92% if cART had not been initiated (Fig. 1). These estimates, however, varied by CD4 cell count at baseline (Fig. 2) and transmission group (Fig. 3). The 5-year survival for cART vs. no cART was 89 vs. 43% for CD4 cell count less than 100 cells/μl, 94 vs. 76% for 100 to less than 200 cells/μl, 97 vs. 91% for 200 to less than 350 cells/μl, 97 vs. 94% for 350 to less than 500 cells/μl, and 97 vs. 96% for 500 cells/μl or more. The 5-year survival for cART vs. no cART was 97 vs. 92% for heterosexuals, 97 vs. 95% for homo/bisexuals, 92 vs. 83% for injection drug users, and 95 vs. 94% for others.
The sensitivity analyses described in the previous section did not materially change or suggest a weaker effect of cART (data not shown). For comparison purposes, we also fit unweighted models that did not include any covariates except cART initiation, included only baseline covariates, and included baseline and time-varying covariates. As expected, conventional adjustment via unweighted models led to hazard ratios closer to the null value (Fig. 4). The mortality hazard ratio for cART initiation vs. no initiation was 0.79 when no adjustment for time-varying confounding was attempted and 0.83 when conventional adjustment was used, versus 0.48 when inverse probability weighting was used.
We estimated that initiation of cART reduced the overall incidence of mortality of HIV-infected individuals by 50%. In absolute terms, this mortality reduction was translated into a 5% increase in 5-year survival for cART initiation compared with no initiation. However, the absolute benefit depended on the baseline CD4 cell count: the survival increase ranged from about 46% in individuals with less than 100 cells/μl to about 1% in those with more than 500 cells/μl. Similarly, the absolute benefit was greatest in injection drug users compared with other transmission groups.
Because our collaboration includes a wide range of HIV-infected individuals living in Europe and the United States – including representative clinical cohorts, seroconverters, and US veterans – we could confirm that cART initiation was followed by 40–60% mortality reduction in all of these groups, with perhaps an even greater relative reduction among seroconverters. The survival benefit was clear even among US veterans, who experienced a higher mortality rate (40 deaths per 1000 person-years) than the other cohorts (6–13 deaths per 1000 person-years). The high mortality rate among US veterans – partly explained by their older age, predominantly male sex, and different death ascertainment procedures – is in line with those reported in similar populations [16,37,38].
Previous studies reported mortality hazard ratios for cART vs. no cART in the range 0.1–0.5. However, most previous studies on cART and mortality have been based on ecological comparisons and/or did not appropriately adjust for time-dependent confounders [12–18], which makes the estimates hard to interpret. Lack of appropriate adjustment for time-varying CD4 cell count and HIV RNA levels may result in either underestimation or overestimation of the effect of cART. In contrast to previous studies, we used a prospective cohort design and inverse probability weighting to appropriately adjust for measured confounders. It has been previously shown that effect estimates obtained from observational HIV cohorts via inverse probability weighting, but not those obtained via conventional adjustment methods, can replicate the findings of randomized clinical trials on cART and time to AIDS [3,20]. In the current analysis, we found empirical proof of the bias of conventional methods in that further adjustment for the strong time-varying confounding by indication resulted in a weaker (from 0.79 to 0.83), rather than stronger, effect estimate.
The validity of our effect estimates, however, relies on the untestable assumption that the measured covariates were sufficient to adjust for confounding by indication. We believe this assumption may approximately hold here because the most important clinical information used by physicians as indications for cART initiation (i.e., CD4 cell count and HIV RNA) was collected and used in the analysis. An incomplete or imperfect measurement of confounders would result in attenuation of the effect because the bias due to confounding by indication is upward in this setting. As a further protection against unmeasured confounding, we estimated the effect of cART initiation rather than the effect of continued cART use. This strategy makes it unnecessary to adjust for joint determinants of treatment discontinuation and death, which are less well measured in most observational studies. The price to pay for this strategy is again an attenuation of the effect estimate toward the null (as it would happen in the intention-to-treat analysis of a placebo-controlled randomized clinical trial) if a substantial proportion of individuals stopped taking cART during the follow-up. Thus, our effect estimates could be viewed as conservative estimates of the effect of continuous cART. Note, however, that the effect of continuous cART use would not be clinically interesting if most subjects who discontinue cART do so for toxicity-related reasons.
Other studies have used surrogate biological markers, like HIV RNA and CD4 cell count, in hopes of rapidly inferring the effect of cART on death. Several randomized studies, however, suggest that surrogate markers may not be good proxies for clinical endpoints like death [6–9]. In the MRC Delta Trial, CD4 cell count and HIV RNA changes overestimated clinical benefit (defined as survival or no disease progression) . HIV RNA may be an inadequate surrogate for death because death may be caused mainly by immune system damage or unintended harmful effects via other mechanisms ; CD4 cell count may be inadequate due to biological and assay-based variability, differences between peripheral blood and lymphatic levels, and the existence of other important markers of immune function that are affected by treatment, like CD8 cells . Even if surrogate biological markers provide some indication of short-term clinical endpoints, it is debatable whether these surrogate effects translate into long-term clinical effects, which depend on the interplay among immune factors, drug resistance, and toxicities that may not be evident in the short-term. For example, a regime might be perceived to be favorable in the short-term because its potency allows patients to maintain higher CD4 cell count and lower viral load, but over the long-term, this same potency might cause toxicities that lead to death more quickly. It is best to directly evaluate the effect of cART on mortality in large follow-up studies as we did here. An alternative would be to evaluate the effects of cART on cause-specific morbidity and mortality, but this information is not available in all HIV cohorts.
In summary, in the absence of data from long-term randomized clinical trials, appropriate adjustment for time-varying confounding in observational cohorts provide the best available evidence on the effects of cART on the overall mortality of HIV-infected individuals. We estimated that cART initiation halved the mortality rate of HIV-infected individuals in developed countries, and that the absolute reduction in mortality was stronger in those with worse prognosis at the start of follow-up. Thus, the 46% survival increase estimated for individuals who start cART at CD4 cell count less than 100 cells/μl demonstrates the benefits of being treated even at the most advanced stages of immunosupression. This finding, however, does not imply one should delay cART initiation until the CD4 cell count drops below 100 cells/μl because, besides the possibility of dying during the waiting period, the 5-year mortality risk of treated individuals with less than 100 cells/μl at baseline (11%) was almost four times greater than that of treated individuals with more than 500 cells/μl (3%).
Writing Committee: Maile Ray, Roger Logan, Jonathan A. C. Sterne, Sonia Hernández-Díaz, James M Robins (Coordinating Center), Caroline Sabin, Loveleen Bansi (UK CHIC), Ard van Sighem, Frank de Wolf (ATHENA), Dominique Costagliola, Emilie Lanoy (FHDH-ANRS CO4), Heiner C. Bucher, Viktor von Wyl (SHCS), Anna Esteve, Jordi Casabona (PISCIS), Julia del Amo, Santiago Moreno (CoRIS/CoRIS-MD), Amy Justice, Joseph Goulet (VACS), Sara Lodi, Andrew Phillips (UKRHS), Rémonie Seng, Laurence Meyer (PRIMO/SEROCO), Santiago Pérez-Hoyos, Patricia García de Olalla (GEMES), and Miguel A. Hernán (Coordinating Center).
This research was supported by NIH grants R01-AI073127 and T32-AI007358. Miguel Hernán, Principal Investigator of the HIV-CAUSAL Collaboration, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Jonathan Sterne has received travel grants from GlaxoSmithKline and honoraria from Gilead Sciences. Sonia Hernández-Díaz has received unrestricted training and research grants, or has consulted for Pfizer, Lilly, Wyeth, Novartis, and AstraZeneca. Caroline Sabin has received travel grants, fees for speaking and honoraria from various pharmaceutical companies including Bristol Myers Squibb, Gilead Sciences, Boehringer-Ingelheim, Janssen Pharmaceutica, and Tibotec. Dominique Costagliola has received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies including Abbott, Boehringer-Ingelheim, Bristol-Myers-Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Merck and Roche. Andrew Phillips has received reimbursement for either/or: attending a symposium; a fee for speaking; a fee for organising education; funds for research; funds for a member of staff; fees for consulting from various pharmaceutical companies including: Roche, BMS, GlaxoSmithKline, Abbott, Boehringer-Ingelheim, Gilead, Tibotec, Oxxon Therapeutics. Heiner C. Bucher has received travel grants, honoraria and unrestricted research grants from various pharmaceutical companies including, GlaxoSmithKline, Bristol-Myers-Squibb, Gilead, Roche, Abbott, Tibotec and Boehringer-Ingelheim. Laurence Meyer has received honoraria from GlaxoSmithKline.
Contributors to the HIV-CAUSAL Collaboration:
UK CHIC: Steering committee: AN Phillips, R Gilson, P Easterbrook, M Fisher, B Gazzard, M Johnson, J Walsh, C Leen, C Orkin, J Anderson, D Pillay, V Delpech, A Schwenk, D Dunn, M Gompels, T Hill, K Porter, A Babiker, C Sabin. Central co-ordination: Royal Free and University College, London (L Bansi, T Hill, A Phillips, C Sabin); Medical Research Council Clinical Trials Unit (MRC CTU), London (A Babiker, D Dunn, K Porter, S Sheehan).
Participating centres: King's College Hospital, London (P Easterbrook, A Waters, D Crates, S Mohamed-Saad); Brighton and Sussex University Hospitals NHS Trust (M Fisher, N Perry, A Pullin, D Churchill, W Harris); Chelsea and Westminster NHS Trust, London (B Gazzard, M Nelson, D Asboe, S Bulbeck, S Mandalia, J Clarke); Mortimer Market Centre, Royal Free and University College Medical School (RFUCMS), London (R Gilson, J Dodds, A Rider, I Williams); Health Protection Agency –Centre for Infections, London (V Delpech); Royal Free NHS Trust and RFUCMS, London (M Johnson, M Youle, F Lampe, C Smith, H Gumley, C Chaloner, D Ismajani Puradiredja); St. Mary's Hospital, London (J Walsh, J Weber, S Cashin, C Kemble, N Mackie, A Winston); Barts and The London NHS Trust, London (C Orkin, R Thomas, K Jones); Homerton Hospital, London (J Anderson, S Gann, K Jones); Edinburgh (C Leen, A Wilson); North Middlesex (A Schwenk, J Ainsworth); North Bristol NHS Trust (M Gompels).
ATHENA. Director: F de Wolf, HIV Monitoring Foundation, Amsterdam. Data analysis group: DO Bezemer, LAJ Gras, A.M. Kesselring, A.I. van Sighem, C. Smit, S. Zhang. Data collection: S. Zaheri. Participating centres (*site coordinating physicians): Academic Medical Centre of the University of Amsterdam, Amsterdam (JM Prins*, JC Bos, JKM Eeftinck-Schattenkerk, SE Geerlings, MH Godfried, JMA Lange, JTM van der Meer, FJB Nellen, DP Olszyna, T van der Poll, P Reiss, SUC Sankatsing, R Steingrover, M van der Valk, JN Vermeulen, SME Vrouenraets, M van Vugt, FWMN Wit), Academic Hospital Maastricht, Maastricht (G Schreij*, S van der Geest, A Oude Lashof, S Lowe, A Verbon), Catharina Hospital, Eindhoven (B Bravenboer*, MJH Pronk), Emma Children's Hospital, Amsterdam (TW Kuijpers, D Pajkrt, HJ Scherpbier), Erasmus Medical Centre, Rotterdam (ME van der Ende*, H Bax, M van der Feltz, LBS Gelinck, JL Nouwen, BJA Rijnders, ED de Ruiter, L Slobbe, CAM Schurink, TEMS de Vries), Erasmus Medical Centre Sophia, Rotterdam (G Driessen, M van der Flier, NG Hartwig), Flevo Hospital, Almere (J Branger), Haga Hospital, location Leyenburg, Den Haag (RH Kauffmann*, EF Schippers), Kennemer Gasthuis, Haarlem (PHP Groeneveld*, MA Alleman, Isala Clinics, Zwolle; RW ten Kate*, R Soetekouw), Leiden University Medical Centre, Leiden (FP Kroon*, SM Arend, MGJ de Boer, PJ van den Broek, JT van Dissel, C van Nieuwkoop), Maasstadziekenhuis, location Clara, Rotterdam (JG den Hollander*), Medical Centre Alkmaar, Alkmaar (W Bronsveld*), Medical Centre Haaglanden, location Westeinde, Den Haag (R Vriesendorp*, FJF Jeurissen, EMS Leyten), Medical Centre Leeuwarden, Leeuwarden (D van Houte*, MB Polée), Medisch Spectrum Twente, Enschede (CHH ten Napel*, GJ Kootstra), Onze Lieve Vrouwe Gasthuis, Amsterdam (K Brinkman*, GEL van den Berk, WL Blok, PHJ Frissen, WEM Schouten), Medical Centre Jan van Goyen, Amsterdam (A van Eeden*, DWM Verhagen), Slotervaart Hospital, Amsterdam (JW Mulder*, ECM van Gorp, ATA Mairuhu, R Steingrover, J Wagenaar), St Elisabeth Hospital, Tilburg (JR Juttmann*, MEE van Kasteren), St Lucas Andreas Hospital, Amsterdam (J Veenstra*, WLE Vasmel), Radboud University Nijmegen Medical Centre, Nijmegen (PP Koopmans*, AM Brouwer, ASM Dofferhoff, R de Groot, HJM ter Hofstede, M Keuter, AJAM van der Ven), University Medical Centre Groningen, Groningen (HG Sprenger*, S van Assen, JTM van Leeuwen, CJ Stek), University Medical Centre Beatrix kliniek, Groningen (R Doedens, EH Scholvinck), University Medical Centre Utrecht, Utrecht (IM Hoepelman*, MME Schneider, MJM Bonten, PM Ellerbroek, CAJJ Jaspers, LJ Maarschalk-Ellerbroek, JJ Oosterheert, EJG Peters, T Mudrikova, MWM Wassenberg, S Weijer), Wilhelmina Children's Hospital, Utrecht (SPM Geelen, TFW Wolfs), Free University Medical Centre, Amsterdam (SA Danner*, MA van Agtmael, WFW Bierman, FAP Claessen, ME Hillebrand, EV de Jong, W Kortmann, RM Perenboom, EA bij de Vaate), Hospital Rijnstate, Arnhem (C Richter*, J van der Berg, EH Gisolf), Hospital Walcheren, Vlissingen (AA Tanis*), Hospitaal/Stichting Rode Kruis Bloedbank, Willemstad, Curaçao (AJ Duits, K Winkel, St Elisabeth).
FHDH-ANRS CO4: Scientific committee: S Abgrall, F Barin, M Bentata, E Billaud, F Boué, C Burty, A Cabié, D Costagliola, L Cotte, P De Truchis, X Duval, C Duvivier, P Enel, L Fredouille-Heripret, J Gasnault, C Gaud, J Gilquin, S Grabar, C. Katlama, MA Khuong, JM Lang, AS Lascaux, O Launay, A Mahamat, M Mary-Krause, S Matheron, JL Meynard, J Pavie, G Pialoux, F Pilorgé, I Poizot-Martin, C Pradier, J Reynes, E Rouveix, A Simon, P Tattevin, H Tissot-Dupont, JP Viard, N Viget. DMI2 coordinating center: French Ministry of Health (Valérie Salomon), Technical Hospitalization Information Agency, ATIH (N Jacquemet). Statistical analysis center: U943 INSERM et UPMC (S Abgrall, D Costagliola, S Grabar, M Guiguet, E Lanoy, L Lièvre, M Mary-Krause, H Selinger-Leneman), INSERM Transfert (JM Lacombe, V Potard). COREVIH: Paris area: Corevih Ile de France Centre (GH Pitié-Salpétrière: F Bricaire, S Herson, C Katlama, A Simon; Hôpital Saint-Antoine: N Desplanque, PM Girard, JL Meynard, MC Meyohas, O Picard; Hôpital Tenon: J Cadranel, C Mayaud, G Pialoux), Corevih Ile de France Est (Hôpital Saint-Louis: JP Clauvel, JM Decazes, L Gerard, JM Molina; GH Lariboisière-Fernand Widal: M Diemer, P Sellier; Hôpital Avicenne: M Bentata, P Honoré; Hôpital Jean Verdier: V Jeantils, S Tassi; Hôpital Delafontaine: D Mechali, B Taverne), Corevih Ile de France Nord (Hôpital Bichat-Claude Bernard: E Bouvet, B Crickx, JL Ecobichon, S Matheron, C Picard-Dahan, P Yeni), Corevih Ile de France Ouest (Hôpital Ambroise Paré: H Berthé, C Dupont; Hôpital Louis Mourier: C Chandemerle, E Mortier; Hôpital Raymond Poincaré: P de Truchis), Corevih Ile de France Sud (Hôpital Européen Georges Pompidou: D Tisne-Dessus, L Weiss; GH Tarnier-Cochin: D Salmon; Hôpital Saint-Joseph: I Auperin, J Gilquin; Hôpital Necker adultes: L Roudière, JP Viard; Hôpital Antoine Béclère: F Boué, R Fior; Hôpital de Bicêtre: JF Delfraissy, C Goujard; Hôpital Henri Mondor: C Jung, Ph Lesprit; Hôpital Paul Brousse: D Vittecoq). Outside Paris area: Corevih Alsace (CHRU de Strasbourg: P Fraisse, JM Lang, D Rey; CH de Mulhouse: G Beck-Wirth), Corevih de l'Arc Alpin (CHU de Grenoble: JP Stahl, P Lecercq), Corevih Auvergne-Loire (CHU de Clermont-Ferrand: F Gourdon, H Laurichesse; CHRU de Saint-Etienne: A Fresard, F Lucht); Corevih Basse-Normandie (CHRU de Caen: C Bazin, R Verdon), Corevih Bourgogne (CHRU de Dijon: P Chavanet), Corevih Bretagne (CHU de Rennes: C Arvieux, C Michelet), Corevih Centre (CHRU de Tours: P Choutet, A Goudeau, MF Maître), Corevih Franche-Comté (CHRU de Besançon: B Hoen; CH de Belfort: P Eglinger, JP Faller); Corevih Haute-Normandie (CHRU de Rouen: F Borsa-Lebas, F Caron), Corevih Languedoc-Roussillon (CHU de Montpellier: J Reynes; CHG de Nîmes: JP Daures), Corevih Lorraine (Nancy Hôpital de Brabois: T May, C Rabaud; CHRU de Reims: JL Berger, G Rémy), Corevih de Midi-Pyrénées (Toulouse CHU Purpan: E Arlet-Suau, L Cuzin, P Massip, MF Thiercelin Legrand; Toulouse Hôpital la Grave: G Pontonnier; Toulouse CHU Rangueil), Corevih Nord-Pas de Calais (CH de Tourcoing: N Viget, Y Yasdanpanah), Corevih PACA Est (Nice Hôpital Archet 1: P Dellamonica, C Pradier, P Pugliese; CHG Antibes-Juan les Pins: K Aleksandrowicz, D Quinsat), Corevih PACA Ouest (Marseille Hôpital de la Conception: I Ravaux, H Tissot-Dupont; Marseille Hôpital Nord: JP Delmont, J Moreau; Marseille Institut Paoli Calmettes: JA Gastaut; Marseille Hôpital Sainte-Marguerite: I Poizot-Martin, F Retornaz, J Soubeyrand; Marseille Centre pénitentiaire des Baumettes: A Galinier, JM Ruiz; CHG d'Aix-En-Provence: T Allegre, PA Blanc; CH d'Arles: D Bonnet-Montchardon; CH d'Avignon: G Lepeu; CH de Digne Les Bains: P Granet-Brunello; CH de Gap: JP Esterni, L Pelissier; CH de Martigues: R Cohen-Valensi, M Nezri; CHI de Toulon: S Chadapaud, A Laffeuillade), Corevih Pays de la Loire (CHRU de Nantes: E Billaud, F Raffi), Corevih de la Vallée du Rhône (Lyon Hôpital de la Croix-Rousse: A Boibieux, D Peyramond; Lyon Hôpital Edouard Herriot: JM Livrozet, JL Touraine; Lyon Hôtel-Dieu: L Cotte, C Trepo). Overseas: Corevih Guadeloupe (CHRU de Pointe-à-Pitre: M Strobel; CH Saint-Martin: F Bissuel), Corevih Guyane (CHG de Cayenne: R Pradinaud, M Sobesky), Corevih Martinique (CHRU de Fort-de-France: A Cabié), Corevih de La Réunion (CHD Félix Guyon: C Gaud, M Contant).
Swiss HIV Cohort Study (SHCS): C Aebi, M Battegay, E Bernasconi, J Böni, P Brazzola, HC Bucher, Ph Bürgisser, A Calmy, S Cattacin, M Cavassini, J-J Cheseaux, G Drack, R Dubs, M Egger, L Elzi, M Fischer, M Flepp, A Fontana, P Francioli (President of the SHCS, Centre Hospitalier Universitaire Vaudois, CH-1011- Lausanne), HJ Furrer, C Fux, A Gayet-Ageron, S Gerber, M Gorgievski, H Günthard, Th Gyr, H Hirsch, B Hirschel, I Hösli, M Hüsler, L Kaiser, Ch Kahlert, U Karrer, C Kind, Th Klimkait, B Ledergerber, G Martinetti, B Martinez, N Müller, D Nadal, F Paccaud, G Pantaleo, L Raio, A Rauch, S Regenass, M Rickenbach, C Rudin (Chairman of the MoChiV Substudy, Basel UKBB, Römergasse 8, CH-4058 Basel), P Schmid, D Schultze, J Schüpbach, R Speck, P Taffé, A Telenti, A Trkola, P Vernazza, R Weber, C-A Wyler, S. Yerly.
PISCIS: Coordinators: J Casabona (Centre d'Estudis Epidemiològics les Infeccions de Transmissió Sexual i Sida de Catalunya: CEEISCAT), JM Miró (Hospital Clínic-Idibaps, Universitat de Barcelona). Field coordinator: A Alquézar, V Isern (CEEISCAT). Steering committee: J Casabona, A Esteve, A Alquézar (CEEISCAT), JM Miró (Hospital Clínic-Idibaps, Universitat de Barcelona), D Podzamczer (Hospital de Bellvitge de Barcelona), J Murillas (Hospital Son Dureta de Mallorca). Scientific committee: JM Gatell, F Agüero (Hospital Clínic-Idibaps, Universitat de Barcelona), C Tural, B Clotet (Hospital Universitari Germans Trias i Pujol, Universitat Autónoma de Barcelona), E Ferrer (Hospital de Bellvitge de Barcelona), M Riera (Hospital Son Dureta de Mallorca) F Segura G Navarro (Corporació Parc Taulí de Sabadell), L Force (Hospital de Mataró), J Vilaró (Hospital de Vic), A Masabeu (Hospital de Palamós), I García (Hospital General d'Hospitalet), M Guadarrama (Hospital Alt Penedès de Vilafranca), A Romero, C Agustí (CEEISCAT). Data Management and statistical analysis: A Esteve, A Montoliu, N Ortega (CEEISCAT), E Lazzari (Hospital Clínic- Idibaps, Universitat de Barcelona). Technical support: E Puchol (CEEISCAT), M Sanchez (Hospital Clínic- Idibaps, Universitat de Barcelona). Participating centres: Hospital Clínic-Idibaps, Barcelona (JL Blanco, F Garcia-Alcaide, E Martínez, J Mallolas M López-Dieguez, JF García-Goez), Hospital Universitari Germans Trias i Pujol, Barcelona (G Sirera, J Romeu, A Jou, E Negredo, C Miranda, MC Capitan), Hospital Universitari de Bellvitge, L'Hospitalet (M Olmo, P Barragan, M Saumoy, F Bolao, C Cabellos, C Peña), Corporació Sanitària Parc Taulí (M Sala, M Cervantes, MJ Amengual, M Navarro, E Penelo), Hospital de Mataró (P Barrufet), Hospital Alt Penedès de Vilafranca (M Guadarrama).
CORIS/CORIS-MD: Steering committee: J Berenguer, J del Amo, F García, F Gutiérrez, P Labarga, S Moreno, MA Muñoz. Field work, data management, and statistical analyses: AM Caro-Murillo, P Sobrino, I Jarrín. Participating centres: Hospital Universitario de Canarias, Santa Cruz de Tenerife (JL Gómez Sirvent, P Rodríguez, MR Alemán, MM Alonso, AM López, MI Hernández), Hospital Carlos III, Madrid (V Soriano, P Labarga, P Barreiro, J Medrano, P Rivas, D Herrero, F Blanco, ME Vispo, L Martín, G Ramírez, M de Diego), Hospital Doce de Octubre, Madrid (R Rubio, F Pulido, V Moreno, C Cepeda, Rl Hervás), Hospital Donostia, San Sebastián (JA Iribarren, J Arrizabalaga, MJ Aramburu, X Camino, F Rodríguez-Arrondo, MA von Wichmann, L Pascual, MA Goenaga), Hospital General Universitario de Elche (F Gutiérrez, M Masiá, JM Ramos, S Padilla, V Sánchez-Hellín, E Bernal, C Escolano, F Montolio, Y Peral), Hospital Gregorio Marañón, Madrid (J Berenguer, JC López, P Miralles, J Cosín, M Sánchez, I Gutiérrez, M Ramírez, B Padilla), Hospital Universitari de Tarragona Joan XXIII (F Vidal, M Sanjuan, J Peraire, S Veloso, C Viladés, M López-Dupla, M Olona, M Vargas), Hospital La Fe, Valencia (JL Aldeguer, M Blanes, J Lacruz, M Salavert, M Montero, S Cuéllar), Hospital de la Princesa, Madrid (I de los Santos, J Sanz), Hospital San Pedro, Logroño (JA Oteo, JR Blanco, V Ibarra, L Metola, M Sanz, L Pérez-Martínez), Hospital de Navarra, Pamplona (J Sola, J Uriz, J Castiello, J Reparaz, MJ Arriaza, C Irigoyen), Hospital Ramón y Cajal, Madrid (S Moreno, A Antela, JL Casado, F Dronda, A Moreno, MJ Pérez, D López, C Gutiérrez, B Hernández, M Pumares, P Martí, L García, C Page), Hospital San Cecilio, Granada (F García, J Hernández, A Peña, L Muñoz, J Parra), Hospital Universitario Virgen del Rocío, Sevilla (P Viciana, M Leal, LF López-Cortés, M Trastoy, R Mata).
Veterans Aging Cohort Study-Virtual Cohort: Principal investigator and co-principal investigator: AC Justice, DA Fiellin. Participating VA centers: Atlanta, GA (D. Rimland, C Jones-Taylor), Baltimore, MD (KA Oursler, R Titanji), Bronx, NY (S Brown, S Garrison), Houston, TX (M Rodriguez-Barradas, N Masozera), Los Angeles, CA (M Goetz, D Leaf), Manhattan-Brooklyn, NY (M Simberkoff, D Blumenthal, J Leung), Pittsburgh, PA (A Butt, E Hoffman), and Washington, DC (C Gibert, R Peck). Core Faculty: K Mattocks (Deputy Director), S Braithwaite, C Brandt, K Bryant, R Cook, J Conigliaro, K Crothers, J Chang, S Crystal, N Day, J Erdos, M Freiberg, M Kozal, N Gandhi, M Gaziano, M Gerschenson, B Good, A Gordon, JL Goulet, MA Hernán, K Kraemer, J Lim, S Maisto, P Miller, L Mole, P O'Connor, R Papas, JM Robins, C Rinaldo, M Roberts, J Samet, B Tierney, J Whittle.
UK Register of HIV Seroconverters: Steering Committee: A Phillips (Chair), University College London (UCL), London; A Babiker, MRC CTU, London; R Brettle, The Lothian University Hospitals NHS Trust, Edinburgh; J Darbyshire, MRC CTU, London; V Delpech, Health Protection Agency, London; P Easterbrook, King's College Hospital, London; S Fidler, St Mary's Hospital, London; M Fisher, Brighton & Sussex University Hospitals NHS Trust, Brighton; R Gilson, West London Centre for Sexual Health, London; D Goldberg, Health Protection Scotland, Glasgow; D Hawkins, Chelsea & Westminster NHS Trust, London; H Jaffe, University of Oxford, Oxford; A Johnson, UCL, London; M Johnson, UCL and Royal Free NHS Trust, London; K McLean, West London Centre for Sexual Health, London; D Pillay, UCL, London. Central co-ordination: Kholoud Porter (PI), Adam Cursley, Fiona Ewings, Keith Fairbrother, Louisa Gnatiuc, Sara Lodi, Brendan Murphy. Clinical centres and collaborators: G Douglas, Aberdeen City Hospital, Aberdeen; N Kennedy, Monklands Hospital, Airdrie; J Pritchard, Ashford Hospital, Ashford; U Andrady, Ysbyty Gwynedd, Bangor; N Rajda, North Hampshire Hospital, Basingstoke; R Maw, S McKernan, Royal Victoria Hospital, Belfast; S Drake, G Gilleran, D White, Birmingham Heartlands Hospital, Birmingham; J Ross, Whittall Street Clinic, Birmingham; S Toomer, Blackpool Victoria Hospital, Blackpool; R Hewart, Royal Bolton Hospital, Bolton; H Wilding, R Woodward, Royal Bournemouth Hospital, Bournemouth; G Dean, L Heald, Royal Sussex County Hospital, Brighton; P Horner, Bristol Royal Infirmary, Bristol; S Glover, Southmead Hospital, Bristol; D Bansaal, Queens Hospital, Burton-upon-Trent; S Eduards, West Suffolk Hospital, Bury St Edmunds; C Carne, Addenbrooke's Hospital, Cambridge; M Browing, R Das, Cardiff Royal Infirmary, Cardiff; B Stanley, North Cumbria Acute Hospitals NHS Trust, Carlisle; S Estreich, A Magdy, St Helier Hospital, Carshalton; C O'Mahony, Countess of Chester Hospital, Chester; P Fraser, Chesterfield & North Derbyshire Royal Hospital, Chesterfield; B Hayman, St Richard's Hospital, Chichester; SPR Jebakumar, Essex County Hospital, Colchester; U Joshi, Castle Hill Hospital, Cottingham; S Ralph, Bishop Auckland General Hospital, County Durham; A Wade, Coventry & Warwickshire Hospital, Coventry; R Mette, Mayday University Hospital, Croydon; J Lalik, Doncaster Royal Infirmary, Doncaster; H Summerfield, Weymouth Community Hospital, Dorset; A El-Dalil, Guest Hospital, Dudley; A J France, Dundee Royal Infirmary, Dundee; C White, University Hospital of North Durham, Durham; R Robertson, Muirhouse Medical Group, Edinburgh; S Gordon, S McMillan, S Morris, Royal Infirmary of Edinburgh, Edinburgh; C Lean, S Morris, Western General Hospital, Edinburgh; K Vithayathil, Leatherhead Hospital, Epsom; L McLean, A Winter, Gartnavel General Hospital & Glasgow Royal Infirmary, Glasgow; D Gale, S Jacobs, Gloucestershire Royal Hospital, Gloucester; Salford Hope Hospital, Greater Manchester; Farnham Road Hospital, Guildford; S Tayal, Hartlepool University Hospital, Hartlepool; L Short, Huddersfield Royal Infirmary, Huddersfield; Ayrshire Central Hospital, Irvine; M Roberts, S Green, Kidderminster General Hospital, Kidderminster; G Williams, Crosshouse Hospital, Kilmarnock; K Sivakumar, The Queen Elizabeth Hospital, King's Lynn; D N Bhattacharyya, Victoria Hospital, Kirkaldy; E Monteiro, Leeds General Infirmary, Leeds; J Minton, St James Hospital, Leeds; J Dhar, Leicester Royal Infirmary, Leicester; F Nye, Royal Liverpool University Hospital, Liverpool; CB DeSouza, A Isaksen, Barts & The London NHS Trust, London; L McDonald, Central Middlesex Hospital, London; K McLean, Charing Cross Hospital, London; A Franca, D Hawkins, Chelsea & Westminster Hospital, London; L William, Ealing Hospital, London; I Jendrulek, B Peters, Guy's & St Thomas NHS Trust, London; S Shaunak, Hammersmith Hospital, London; S El-Gadi, Homerton Hospital, London; PJ Easterbrook, King's College Hospital, London; C Mazhude, Lewisham University Hospital, London; R Gilson, R Johnstone, Mortimer Market Centre, London; A Fakoya, Newham General Hospital, London; J Mchale, A Waters, North Middlesex Hospital, London; S Kegg, S Mitchell, Queen Elizabeth Hospital Woolwich, London; P Byrne, M Johnson, Royal Free Hospital, London; P Rice, St George's Hospital, London; S Fidler, SA Mullaney, St Mary's Hospital, London; S McCormack, Victoria Sexual Health Clinic, London; D David, West Middlesex University Hospital, London; R Melville, Whipps Cross Hospital, London; K Phillip, Whittington Hospital, London; T Balachandran, Luton & Dunstable Hospital, Luton; S Mabey-Puttock, A Sukthankar, Manchester Royal Infirmary, Manchester; C Murphy, E Wilkins, North Manchester General Hospital, Manchester; S Ahmad, Withington Hospital, Manchester; S Tayal, James Cook Hospital, Middlesbrough; J Haynes, Milton Keynes General Hospital, Milton Keynes; E Evans, E Ong, Newcastle General Hospital, Newcastle; R Das, Royal Gwent Hospital, Newport; R Grey, J Meaden, Norfolk & Norwich University Hospital, Norwich; C Bignell, City Hospital, Nottingham; D Loay, K Peacock, George Eliot Hospital, Nunneaton; MR Girgis, Royal Oldham Hospital, Oldham; B Morgan, Radcliffe Infirmary, Oxford; A Palfreeman, Peterborough District Hospital, Peterborough; J Wilcox, Freedom Fields Hospital, Plymouth; J Tobin, L Tucker, St Mary's Hospital, Portsmouth; AM Saeed, Royal Preston Hospital, Preston; F Chen, Royal Berkshire Hospital, Reading; A Deheragada, East Surrey Hospital, Redhill; O Williams, Glan Clwyd District General, Rhyl; H Lacey, Baillie Street Health Centre, Rochdale; S Herman, D Kinghorn, Royal Hallamshire Hospital, Sheffield; S V Devendra, J Wither, Royal Shrewsbury Hospital, Shrewsbury; S Dawson, Upton Hospital, Slough; D Rowen, Royal South Hampshire Hospital, Southampton; J Harvey, Stirling Royal Infirmary, Stirling; E Wilkins, Stepping Hill Hospital, Stockport; A Bridgwood, G Singh, North Staffordshire Hospital, Stoke-on-Trent; M Chauhan, Sunderland Royal Hospital, Sunderland; D Kellock, S Young, King's Mill Centre, Sutton-in-Ashfield; S Dannino, Y Kathir, Singleton Hospital, Swansea; G Rooney, The Great Western Hospital, Swindon; J Currie, M. Fitzgerald, Taunton & Somerset Hospital, Taunton; S Devendra, Princess Royal Hospital, Telford; F Keane, Royal Cornwall Hospital, Truro; G Booth, T Green, Clayton Hospital, Wakefield; J Arumainayyagam, S Chandramani, Manor Hospital, Walsall; S Rajamanoharan, T Robinson, Watford General Hospital, Watford; E Curless, Royal Albert Edward Infirmary, Wigan; R Gokhale, Arrowe Park Hospital, Wirral; A Tariq, New Cross Hospital, Wolverhampton; M Roberts, Worcester Royal Infirmary, Worcester; O Williams, Maelor Hospital, Wrexham; G Luzzi, Wycombe General Hospital, Wycombe; M FitzGerald, Yeovil District Hospital, Yeovil; I Fairley, F Wallis, Monkgate Health Centre, York Hospital NHS Trust, York. Laboratories: E Smit, HPA Birmingham; F Ward, St Bartholomew's and the Royal London NHS Trust.
PRIMO: JM Molina, B Loze (St Louis - Paris), P Morlat, M Bonarek, F Bonnet, C Nouts, I Louis (St André - Bordeaux), F Raffi, V Reliquet, F Sauser, C Biron, O Mounoury, H Hue, D Brosseau (Hotel Dieu - Nantes), JF Delfraissy, C Goujard, J Ghosn, MT Rannou (Bicêtre – Le Kremlin Bicêtre), JF Bergmann, E Badsi, A Rami, M Diemer, MParrinello (Lariboisière - Paris), PM Girard, D Samanon-Bollens, P Campa, M Tourneur, N Desplanques (St Antoine - Paris), JM Livrozet, F Jeanblanc, P Chiarello, D Makhloufi (E Herriot - Lyon), AP Blanc, T Allègre (CHG - Aix en Provence), J Reynes, V Baillat, V Lemoing, C Merle de Boever, C Tramoni (Gui de Chauliac - Montpellier), A Cabié, G Sobesky, S Abel, V Beaujolais (CHU - Fort de France), G Pialoux, L Slama, C Chakvetadze, V Berrebi (Tenon - Paris), P Yeni, E Bouvet, I Fournier, J Gerbe (Bichat - Paris), C Trepo, K Koffi, C Augustin-Normand, P Miailhes, V Thoirain, C Brochier (Hotel Dieu - Lyon), R Thomas, F Souala, M Ratajczak (Pontchaillou - Rennes), J Beytoux, C Jacomet, F Gourdon (G Montpied - Clermont-Ferrand), E Rouveix, S Morelon, C Dupont, C Olivier (A Paré - Boulogne), O Lortholary, B Dupont, JP Viard, A Maignan (Necker - Paris), JM Ragnaud, I Raymond (Pellegrin - Bordeaux), C Leport, C Jadand, C Jestin, P Longuet, S Boucherit (Bichat - Paris), D Sereni, C Lascoux, F Prevoteau (St Louis - Paris), A Sobel, Y Levy, JD Lelièvre, AS Lascaux, S Dominguez, C Dumont (H Mondor - Créteil), H Aumaître, B Delmas, M Saada, M Medus (St Jean - Perpignan), L Guillevin, D Salmon, T Tahi (Cochin - Paris), Y Yazdanpanah, S Pavel, MC Marien (CH Dron - Tourcoing), B Drenou, G Beck-Wirth, C Beck, M Benomar (E Muller - Mulhouse), C Katlama, R Tubiana, H Ait Mohand, A Chermak, S Ben Abdallah (Pitié-Salpétrière - Paris), M Bentata, F Touam, (Avicenne - Bobigny), B Hoen, C Drobacheff, A Folzer (St Jacques - Besançon), P Massip, M Obadia, L Prudhomme, E Bonnet, F Balzarin (Purpan - Toulouse), E Pichard, JM Chennebault, P Fialaire, J Loison (CHR - Angers), P Galanaud, F Boué, D Bornarel (Béclère - Clamart), R Verdon, C Bazin, M Six, P Ferret (CHR Côte de Nacre - Caen), L Weiss, D Batisse, G Gonzales-Canali, D Tisne-Dessus (HEGP - Paris), A Devidas, P Chevojon, I Turpault (Corbeil Essonnes), A Lafeuillade, A Cheret, G Philip (Chalucet - Toulon), P Morel, J Timsit (St Louis - Paris), S Herson, N Amirat, A Simon, C Brancion (Pitié-Salpétrière - Paris), J Cabane, O Picard, J Tredup, N Desplanques (St Antoine - Paris), A Stein, I Ravault (La Conception - Marseille), C Chavanet, M Buisson, S Treuvetot (Bocage - Dijon), P Choutet, P Nau, F Bastides (Bretonneau - Tours), T May, L Boyer, S Wassoumbou (CHU - Nancy), E Oksenhendeler, L Gérard (St Louis - Paris), L Bernard, P De Truchis, H Berthé (R Poincaré - Garches), Y Domart, D Merrien (CH - Compiègne), A Greder Belan, (A Mignot - Le Chesnay), M Gayraud, L Bodard, A Meudec (IMM Jourdan - Paris), C Beuscart, C Daniel, E Pape (La Beauchée - St Brieuc), P Vinceneux, AM Simonpoli, A Zeng (L Mourier - Colombes), L Fournier (M Jacquet - Melun), JG Fuzibet, C Sohn, E Rosenthal, M Quaranta (L'Archet - Nice), P Dellamonica, S Chaillou, M Sabah (L'Archet - Nice), B Audhuy, A Schieber (L Pasteur - Colmar), P Moreau, M Niault, O Vaillant (Bretagne Sud - Lorient), G Huchon, A Compagnucci (Hotel-Dieu - Paris), I De Lacroix Szmania, L Richier (Intercommunal - Créteil), I Lamaury (Abymes - Pointe à Pitre), F Saint-Dizier, D Garipuy (Ducuing – Toulouse), JA Gastaut, MP Drogoul, I Poizot Martin, G Fabre (St Marguerite – Marseille), G Lambert de Cursay, B Abraham, C Perino (CH - Brives), P Lagarde, F David (CH - Lagny), J Roche-Sicot, JL Saraux, A Leprêtre (S Veil - Eaubonne), B Fampin, A Uludag, AS Morin (Beaujon – Clichy), O Bletry, D Zucman (Foch - Suresnes), A Regnier (CH - Vichy), JJ Girard (CH - Loches), DT Quinsat, L Heripret (CH - Antibes), F Grihon (Haute Vallée de l'Oise - Noyon), D Houlbert (CH - Alençon), M Ruel, K Chemlal (CH - Nanterre), F Caron, Y Debab (C Nicolle - Rouen), F Tremollieres, V Perronne (F Quesnay - Mantes La Jolie), G Lepeu, B Slama (H Duffaut - Avignon), P Perré (Les Oudairies - La Roche sur Yon), C Miodovski (Paris), G Guermonprez, A Dulioust (CMC Bligny - Briis s/Forges), P Boudon, D Malbec (R Ballanger - Aulnay s/bois), O Patey, C Semaille (CH - Villeneuve St Georges), J Deville, G Remy, I Béguinot (CH - Reims).
SEROCO: Hopital Antoine Beclere, Clamart (P Galanaud, F Boue, V Chambrin, C Pignon, GA Estocq, A Levy), Hopital de Bicetre, Le Kremlin Bicetre (JF Delfraissy, C Goujard, M Duracinsky, P Le Bras, MS Ngussan, D Peretti, N Medintzeff, T Lambert, O Segeral, P Lezeau, Y Laurian), Hopital Europeen Georges Pompidou, Paris (L Weiss, M Buisson, C Piketty, M Karmochkine, D Batisse, M Eliaszewitch, D Jayle, D Tisne- Dessus, M Kazatchkine), Hopital Bichat Claude Bernard, Paris (C Leport, U Colasante, C Jadand, C Jestin, X Duval, W Nouaouia, S Boucherit, JL Vilde), Hopital Saint Antoine, Paris (PM Girard, D Bollens, D Binet, B Diallo, MC Meyohas, L Fonquernie, JL Lagneau), Hopital Cochin, Paris (D Salmon, LGuillevin, T Tahi, O Launay, MP Pietrie, D Sicard, N Stieltjes, J Michot), Hopital Henri Mondor, Creteil (A Sobel, Y Levy, F Bourdillon, AS Lascaux, JD Lelievre, C Dumont), Hopital Necker, Paris (B Dupont, G Obenga, JP Viard, A Maignan), Hopital Paul Brousse, Villjuif (D Vittecoq, L Escaut, C Bolliot), Hopital Pitie Salpetriere, Paris (F Bricaire, C Katlama, L Schneider, S Herson, A Simon, M Iguertsira), Hopital de la Conception, Marseille (A Stein, C Tomei, I Ravaux, C Dhiver, H Tissot Dupont, A Vallon, J Gallais, H Gallais), Hopital Sainte Marguerite, Marseille (JA Gastaut, MP Drogoul, G Fabre), Hopital de L'Archet, Nice (P Dellamonica, J Durant, V Mondain, I Perbost, JP Cassuto, JM Karsenti, H Venti, JG Fuzibet, E Rosenthal, C Ceppi, M Quaranta), Hopital Avicenne, Bobigny (JA Krivitsky, M Bentata, O Bouchaud, P Honore), Hopital Saint Louis, Paris (D Sereni, C Lascoux, J Delgado), ACCTES / Hopital Necker, Paris (C Rouzioux, M Burgard, L Boufassa), Hopital Mignot, Le Chesnay (J Peynet).
GEMES: Principal Investigator: S Pérez Hoyos. Data analysis center: I Ferreros, I Hurtado. Centro Nacional de Epidemiología: J del Amo, I Jarrín, C González, AM Caro. Participating centres: Cohorte del Hospital Germans Trias I Pujol, Badalona (R Muga, A Sanvicens, B Clotet, J Tor), Cohorte de Madrid-Sandoval (J del Romero, P Raposo, C Rodríguez, S García), Cohorte de los Centros de Atención y Prevención del SIDA, Barcelona (P Garcia de Olalla, J Cayla), Cohorte de los CIPS de la Comunidad Valenciana (I Alastrue, J Belda, P Trullen, E Fernández, C Santos, T Tasa, T Zafra), Cohorte de las Prisiones de Cataluña (R Guerrero, A Marco), Cohorte de hemofílicos del Hospital La Paz, Madrid (M Quintana), Cohortes de hemofílicos del Hospital Vall d'Hebron, Barcelona (I Ruiz), Cohortes de hemofílicos del Hospital Virgen del Rocío, Sevilla (R Nuñez, R Pérez), Cohorte de Navarra (J Castilla, M Guevara). Laboratory: C de Mendoza, N Zahonero.
1. Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez CC, McMahon D, et al
. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997; 337:734–739.
2. Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, et al
. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 1997; 337:725–733.
3. Cole SR, Hernán MA, Robins JM, Anastos K, Chmiel J, Detels R, et al
. Effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome or death using marginal structural models. Am J Epidemiol 2003; 158:687–694.
4. Egger M, May M, Chene G, Phillips AN, Ledergerber B, Dabis F, et al
. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002; 360:119–129.
5. Cameron DW, Heath-Chiozzi M, Danner S, Cohen C, Kravcik S, Maurath C, et al
. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group. Lancet 1998; 351:543–549.
6. Pozniak A. Surrogacy in HIV-1 clinical trials. Lancet 1998; 351:536–537.
7. Choi S, Lagakos SW, Schooley RT, Volberding PA. CD4+ lymphocytes are an incomplete surrogate marker for clinical progression in persons with asymptomatic HIV infection taking zidovudine. Ann Intern Med 1993; 118:674–680.
8. Lin DY, Fischl MA, Schoenfeld DA. Evaluating the role of CD4-lymphocyte counts as surrogate endpoints in human immunodeficiency virus clinical trials. Stat Med 1993; 12:835–842.
9. An evaluation of HIV RNA and CD4 cell count as surrogates for clinical outcome. Delta Coordinating Committee and Virology Group.AIDS
10. Hughes MD, Daniels MJ, Fischl MA, Kim S, Schooley RT. CD4 cell count as a surrogate endpoint in HIV clinical trials: a meta-analysis of studies of the AIDS Clinical Trials Group. AIDS 1998; 12:1823–1832.
11. Lewden C, Chene G, Morlat P, Raffi F, Dabis F, Leport C. Mortality rate of HIV-infected adults compared with the general population: long-term and CD4-lymphocyte-dependent results. Med Sci (Paris) 2008; 24:804–806.
12. May MT, Sterne JA, Costagliola D, Sabin CA, Phillips AN, Justice AC, et al
. HIV treatment response and prognosis in Europe and North America in the first decade of highly active antiretroviral therapy: a collaborative analysis. Lancet 2006; 368:451–458.
13. Ewings FM, Bhaskaran K, McLean K, Hawkins D, Fisher M, Fidler S, et al
. Survival following HIV infection of a cohort followed up from seroconversion in the UK. AIDS 2008; 22:89–95.
14. Lima VD, Hogg RS, Harrigan PR, Moore D, Yip B, Wood E, Montaner JS, et al
. Continued improvement in survival among HIV-infected individuals with newer forms of highly active antiretroviral therapy. AIDS 2007; 21:685–692.
15. Perez-Hoyos S, Ferreros I, del Amo J, Muga R, del Romero J, Garcia de Olalla P, Hernandez-Aguado I. Survival and progression to AIDS in a seroconverter cohort in the posthighly active antiretroviral therapy era: effectiveness goes on. AIDS 2006; 20:289–291.
16. Lohse N, Hansen AB, Pedersen G, Kronborg G, Gerstoft J, Sorensen HT, et al
. Survival of persons with and without HIV infection in Denmark, 1995–2005. Ann Intern Med 2007; 146:87–95.
17. Porter K, Babiker A, Bhaskaran K, Darbyshire J, Pezzotti P, Porter K, Walker AS, CASCADE Collaboration. Determinants of survival following HIV-1 seroconversion after the introduction of HAART. Lancet 2003; 362:1267–1274.
18. Mocroft A, Phillips AN, Lundgren JD. HIV survival benefit associated with earlier antiviral therapy. Ann Intern Med 2004; 140:578–579, author reply 579.
19. Hernán MA, Brumback B, Robins JM. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. Epidemiology 2000; 11:561–570.
20. Sterne JA, Hernán MA, Ledergerber B, Tilling K, Weber R, Sendi P, et al
. Long-term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study. Lancet 2005; 366:378–384.
21. The creation of a large UK-based multicentre cohort of HIV-infected individuals: The UK Collaborative HIV Cohort (UK CHIC) Study.HIV Med
22. van Sighem AI, van de Wiel MA, Ghani AC, Jambroes M, Reiss P, Gyssens IC, et al
. Mortality and progression to AIDS after starting highly active antiretroviral therapy. AIDS 2003; 17:2227–2236.
23. Piketty C, Selinger-Leneman H, Grabar S, Duvivier C, Bonmarchand M, Abramowitz L, et al
. Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy. AIDS 2008; 22:1203–1211.
24. Ledergerber B, Egger M, Opravil M, Telenti A, Hirschel B, Battegay M, et al
. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Swiss HIV Cohort Study. Lancet 1999; 353:863–868.
25. Jaen A, Esteve A, Miró JM, Tural C, Montoliu A, Ferrer E, et al
. Determinants of HIV progression and assessment of the optimal time to initiate highly active antiretroviral therapy: PISCIS Cohort (Spain). J Acquir Immune Defic Syndr 2008; 47:212–220.
26. Caro-Murillo AM, Castilla J, Pérez-Hoyos S, Miró JM, Podzamczer D, Rubio R, et al
. Spanish cohort of naive HIV-infected patients (CoRIS): rationale, organization and initial results. Enferm Infecc Microbiol Clin 2007; 25:23–31.
27. Moreno S, Jarrin I, Iribarren JA, Perez-Elias MJ, Vician P, Parra-Ruiz J, et al
. Incidence and risk factors for tuberculosis in HIV-positive subjects by HAART status. Int J Tuberc Lung Dis 2008; 12:1393–1400.
28. Justice AC, Dombrowski E, Conigliaro J, Fultz SL, Gibson D, Madenwald T, et al
. Veterans Aging Cohort Study (VACS): overview and description. Med Care 2006; 44(8 Suppl 2):S13–S24.
29. The UK register of HIV seroconverters: methods and analytical issues. UK register of HIV seroconverters (UKRHS) Steering Committee.Epidemiol Infect
30. Dalmasso C, Carpentier W, Meyer L, Rouzioux C, Goujard C, Chaix ML, et al
. Distinct genetic loci control plasma HIV-RNA and cellular HIV-DNA levels in HIV-1 infection: the ANRS Genome Wide Association 01 study. PLoS ONE 2008; 3:e3907.
31. Desquilbet L, Goujard C, Rouzioux C, Sinet M, Deveau C, Chaix ML, et al
. Does transient HAART during primary HIV-1 infection lower the virological set-point? AIDS 2004; 18:2361–2369.
32. Perez-Hoyos S, del Amo J, Muga R, del Romero J, García de Olalla P, Guerrero R, et al
. Effectiveness of highly active antiretroviral therapy in Spanish cohorts of HIV seroconverters: differences by transmission category. AIDS 2003; 17:353–359.
33. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults.MMWR Morb Mortal Wkly Rep
34. D'Agostino RB, Lee ML, Belanger AJ, Cupples LA, Anderson K, Kannel WB. Relation of pooled logistic regression to time dependent Cox regression analysis: the Framingham Heart Study. Stat Med 1990; 9:1501–1515.
35. Hernán MA, Hernández-Díaz S, Robins JM. A structural approach to selection bias. Epidemiology 2004; 15:615–625.
36. Robins JM. Marginal structural models.
Paper presented at 1997 Proceedings of the Section on Bayesian Statistical Science. American Statistical Association; 1998; Alexandria, VA.
37. Sackoff JE, Hanna DB, Pfeiffer MR, Torian LV. Causes of death among persons with AIDS in the era of highly active antiretroviral therapy: New York City. Ann Intern Med 2006; 145:397–406.
38. Celentano DD. Mortality among urban drug users and the impact of highly active antiretroviral therapy. Clin Infect Dis 2005; 41:873–874.
Description of cohort studies participating in the HIV-CAUSAL Collaboration.
The UK Collaborative HIV Cohort Study (UK CHIC)  includes HIV-infected individuals from 10 large outpatient HIV clinical centers in the UK. Clinical records data were entered into electronic databases by each center with data prospectively from 1996; these databases were pooled in 2001 and at yearly intervals subsequently. Quality control is conducted through multiple data checks and resolution of discrepancies via queries. Individuals are followed-up at the time of their clinic appointments. Death is ascertained with outpatient medical records and anonymous linkage to UK death registries.
The ATHENA Cohort Study (AIDS Therapy Evaluation National AIDS Therapy Evaluation Centre)  includes HIV-infected individuals presenting at any of 24 hospitals and four pediatric HIV treatment centers in the Netherlands since 1998. Clinical records data are collected by trained staff in each participating hospital, and quality control is performed by source data verification. Individuals are followed-up at the time of their clinic appointments. Mortality is reported by a hospital physician and an HIV Monitoring Foundation data monitor.
The French Hospital Database on HIV (FHDH ANRS CO4)  includes HIV-positive individuals seen at 68 French teaching hospitals belonging to 29 HIV Treatment and Information Centres (COREVIH) in mainland France and French overseas territories. Data have been collected since 1992 through medical records and structured questionnaires with trained research assistants. Quality control is performed via monitored on-site source documentation (AUDIT on randomized individuals). Individuals are followed-up at the time of their clinic appointments, usually every 3 to 4 months, and the study attempts to collect information at least every 6 months. Death is ascertained through medical records review.
The Swiss HIV Cohort Study (SHCS)  includes individuals presenting at any of seven outpatient clinics in Switzerland. Data have been prospectively collected via clinical records with standardized criteria since 1988. Individuals are followed-up at the time of their clinic appointments, usually every 3 to 4 months, and the study attempts to collect information at least every 6 months. Death is ascertained by physician report, and survival status is verified with physicians biannually for patients with no new data in the preceding14 months.
The PISCIS Cohort Study  includes HIV-positive, therapy-naive patients who present at any of 10 participating hospitals in Catalonia and the Balearic Islands, Spain, since 1998. Data are collected via computerized clinical records. Data quality is tested with quality control reports and site visits. The cohort strives for follow-up every 3 to 6 months. Death is ascertained through clinic records, active follow-up, and linkage to vital statistics agencies.
CoRIS  includes HIV-infected, therapy-naive adults from 19 hospitals from nine of the 17 Autonomous Communities of Spain linked to a Biobank. Recruitment started January 1, 2004 and is on-going. Quality control is conducted via internal and external quality controls, with 10% of cohort members submitted to an external audit. Patients are followed-up at the time of their clinic appointments, usually every 3 to 4 months. Mortality records are cross-checked with the National Death Index to validate causes of death. CoRIS-MD  is an open cohort study of HIV-infected subjects with at least 6 months of follow-up in any of 10 hospitals from seven of the 17 Autonomous Communities of the country between 1997 and 2003. The cohort was assembled in 2004. Patients were followed-up at the time of their routine clinical appointments, usually every 3 to 4 months, until December 2003. All patients were crossed-checked with the National Death Index to ascertain mortality and to validate causes of death.
The Veterans Aging Cohort Study Virtual Cohort (VACS-VC)  includes HIV-infected subjects identified through the U.S. Veterans Administration electronic medical records since 1997. To be eligible, patients need at least two outpatient codes or one inpatient code according to an algorithm to identify HIV-infected subjects from clinical records. Patients in VACS-VC are seen according to usual care guidelines, on average once every 4 months. Deaths are ascertained quarterly via searches in the Beneficiary Identification Records Locator Subsystem (BIRLS) and inpatient files in the electronic medical records system. This ascertainment method was found comparable to that obtained from the National Death Index.
Seroconverter Cohorts: The UK Register of Seroconverters  includes HIV-infected individuals presenting at any of 121 clinical centers in the UK whose time of seroconversion is known with reasonable precision. Data have been collected prospectively since 1994 (retrospectively to 1984) through annual clinical report forms. Death is ascertained through clinical records and biannual linkage to national death registries (the Office of National Statistics and the General Register Officer).
The ANRS PRIMO Cohort Study  includes individuals presenting with primary HIV infection in any of 80 French hospitals since 1996. The participants' time of seroconversion is confirmed through laboratory testing with reasonable precision. Data are collected through medical records, laboratory measurement, autoquestionnaires, and frozen serum, plasma, and cells. The cohort attempts to follow up with individuals every 6 months. Death is identified through medical records and cross-checked with city hall records.
The ANRS SEROCO Cohort Study  includes individuals presenting with recent HIV diagnosis (<1 year) or a known date of infection in any of 18 participating clinical sites in France. The cohort was established in 1988, and data are collected from medical records and frozen laboratory samples. The scheduled interval of follow-up is every 6 months. Death is ascertained via medical records and biennial cross-check with the National Register of Deaths.
The Spanish Multicenter Study Group of Seroconverters (GEMES)  includes individuals from 10 seroconverter cohorts in Spain. These cohorts are drawn from hospitals, STI clinics, and counseling and testing centers. For members of all participating cohorts, the time of seroconversion is confirmed via laboratory testing. The study was assembled in 1998 but includes people who seroconverted from 1982 retrospectively. Data from participants are updated yearly from clinical records and cross-checked with AIDS and mortality registries.
39. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, et al
. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008; 5:e203.
Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; HIV infection; inverse probability weighting; marginal structural models; mortality