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Dr. Sterne: School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol BS8 2PS, United Kingdom.
Dr. Sabin and Ms. Bansi: Research Department of Infection and Population Health, University College London Medical School, Rowland Hill Street, London NW3 2PF, United Kingdom.
Drs. Justice and Goulet: Veterans Affairs Connecticut Healthcare System and Yale University School of Medicine, Department of Internal Medicine, 950 Campbell Avenue, 11-ACSLG, Building 35A, 2nd Floor, Room 212, New Haven, CT 06516.
Drs. van Sighem and de Wolf: Stichting HIV Monitoring, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
Dr. Bucher: Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel, CH-4031 Basel, Switzerland.
Dr. von Wyl: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Räemistrasse 100, 8091 Zurich, Switzerland.
Drs. Esteve and Casabona: CEEISCAT, Hospital Universitari Germans Trias i Pujol, Carretera Canyet s/n, 08916 Badalona, Spain. Dr. del Amo: National Center of Epidemiology, Instituto de Salud Carlos III, Sinesio Delgado 6, 28029 Madrid, Spain.
Dr. Moreno: Servicio de Enfermedades Infecciosas, Hospital Ramón y Cajal, Carretera de Colmenar Km 9.100, 28034 Madrid, Spain.
Drs. Seng and Meyer: INSERM U1018, Hôpital de Bicêtre, 82 rue du Général Leclerc, 94276 Le Kremlin-Bicêtre Cedex, France.
Dr. Pérez-Hoyos: Methodological Support Unit on Biomedical Research (USMIB), Vall d'Hebron Hospital Research Institute (VHIR), Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain.
Dr. Muga: Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain.
Dr. Lodi: Clinical Trials Unit, Medical Research Council, 222 Euston Road, London NW1 2DA, United Kingdom.
Dr. Lanoy: INSERM U943 and Université Pierre et Marie Curie, 56 boulevard V Auriol, BP 335, 75625 Paris Cedex 13, France.
Dr. Costagliola: INSERM U943, Université Pierre et Marie Curie and Hôpital Pitié-Salpétrière, 56 boulevard V Auriol, BP 335, 75625 Paris Cedex 13, France.
Most clinical guidelines recommend that AIDS-free, HIV-infected persons with CD4 cell counts below 0.350 × 109 cells/L initiate combined antiretroviral therapy (cART), but the optimal CD4 cell count at which cART should be initiated remains a matter of debate.
To identify the optimal CD4 cell count at which cART should be initiated.
Prospective observational data from the HIV-CAUSAL Collaboration and dynamic marginal structural models were used to compare cART initiation strategies for CD4 thresholds between 0.200 and 0.500 × 109 cells/L.
HIV clinics in Europe and the Veterans Health Administration system in the United States.
20 971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 109 cells/L and no previous AIDS-defining illnesses, of whom 8392 had a CD4 cell count that decreased into the range of 0.200 to 0.499 × 109 cells/L and were included in the analysis.
Hazard ratios and survival proportions for all-cause mortality and a combined end point of AIDS-defining illness or death.
Compared with initiating cART at the CD4 cell count threshold of 0.500 × 109 cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death.
CD4 cell count at cART initiation was not randomized. Residual confounding may exist.
Initiation of cART at a threshold CD4 count of 0.500 × 109 cells/L increases AIDS-free survival. However, mortality did not vary substantially with the use of CD4 thresholds between 0.300 and 0.500 ×109 cells/L.
National Institutes of Health.
The protective effect of combined antiretroviral therapy (cART) on the risk for AIDS or death in HIV-1– infected persons has been documented in both randomized clinical trials (1, 2) and observational studies (3, 4). However, the optimal time to initiate cART remains under debate. Although early cART initiation may preserve immune function, reduce chronic inflammation associated with uncontrolled viral replication, prevent HIV transmission, and prolong survival, it may also result in adverse effects and the development of drug resistance, which may decrease survival (5–7). Available evidence strongly supports the initiation of cART in asymptomatic persons with CD4 cell counts less than 0.200 × 109 cells/L (1, 3, 4, 8–10) but is more limited for persons with counts greater than 0.200 × 109 cells/L (11–17).
Clinical guidelines from the European AIDS Clinical Society (18) and World Health Organization (19) recommend initiating cART in asymptomatic persons whose CD4 cell count has decreased to less than 0.350 × 109 cells/L. However, U.S. guidelines (20, 21) are consistent with a recommendation to initiate cART when the CD4 cell count decreases below 0.500 × 109 cells/L. The variation in clinical recommendations, as well as the disagreement among members of the guidelines committee (20), reflects the uncertainty in the published estimates. The available randomized clinical trials (22, 23) do not provide enough information to decide between these strategies, because most patients were not antiretroviral therapy–naive or initiation was not evaluated at CD4 cell counts greater than 0.350 × 109 cells/L. The results of 2 large observational studies of therapy-naive persons (24, 25) have received conflicting interpretations.
Randomized clinical trials comparing initiation strategies (26, 27) will require several years to complete. Mean-while, clinical decisions will necessarily be based partly on observational data. We used observational data from an international collaboration of prospective studies to compare strategies for initiating cART in HIV-infected persons.
The HIV-CAUSAL Collaboration has been described elsewhere (28). In brief, the collaboration includes 12 prospective cohort studies from 5 European countries and the United States: UK CHIC (United Kingdom Collaborative HIV Cohort), ATHENA (AIDS Therapy Evaluation in the Netherlands), FHDH-ANRS CO4 (French Hospital Database on HIV—Agence Nationale de Recherches sur le SIDA), SHCS (Swiss HIV Cohort Study), PISCIS (Proyecto para la Informatización del Seguimiento Clinico- epidemiológico de la Infección por HIV y SIDA [Spain]), CoRIS (Cohorte de la Red de Investigación en SIDA [Spain]), VACS-VC (Veterans Aging Cohort Study–Virtual Cohort [United States]), UK Register of HIV Se-roconverters, ANRS PRIMO and ANRS SEROCO (Agence Nationale de Recherches sur le SIDA [France]), and GEMES (Grupo Español Multicéntrico para el Estudio de Seroconvertores-Haemophilia [Spain]). The last 4 studies include persons for whom the time of HIV seroconversion could be estimated (29–32). Participants in both FHDH-ANRS CO4 and ANRS PRIMO or SEROCO were removed from FHDH-ANRS CO4, those in both CoRIS and PISCIS were removed from CoRIS, and those in both UK CHIC and the UK Register of HIV Seroconverters were removed from UK CHIC.
All cohorts included in the HIV-CAUSAL Collaboration were assembled prospectively and are based on data collected for clinical purposes from national health care systems that offer universal access to care. Each cohort in the collaboration collected data prospectively, including all CD4 cell counts, HIV RNA measurements, treatment initiations, AIDS-defining illnesses, and deaths.
Our analysis was restricted to HIV-infected persons who met the following eligibility criteria between 1996 and 2009: age 18 years or older, antiretroviral therapy-naive (as defined elsewhere ), no history of an AIDS-defining illness (33), no pregnancy (when information was available), no history of a CD4 cell count less than 0.500 × 109 cells/L, and CD4 cell count and HIV RNA measurements within 6 months of each other. A person's baseline was defined as the first time that all of these criteria were met.
We defined “cART initiation” as the date on which a person initiated treatment with 3 or more antiretroviral drugs, 2 ritonavir-boosted protease inhibitors, or a non-nucleoside reverse-transcriptase inhibitor and a boosted protease inhibitor. Alternate definitions of cART (4, 34) did not materially affect the results (data not shown).
We considered 2 outcomes: all-cause mortality and a combined end point of AIDS-defining illness (33) or death. The date of death was identified by using a combination of national and local death registries and clinical records, as described elsewhere (28), and AIDS-defining illnesses were ascertained by the treating physicians. For each person,follow-up started the first time that the CD4 cell count decreased below 0.500 × 109 cells/L and ended when the outcome occurred, 12 months after the most recent laboratory measurement (35), when the person became pregnant (if known), at the cohort-specific administrative end of follow-up (ranging from December 2003 to September 2009), or at censoring, whichever occurred earlier.
For each outcome, we estimated the hazard ratio for initiation within 6 months of the time point at which the CD4 cell count first decreased below thresholds between 0.200 and 0.500 × 109 cells/L. Persons were assigned to CD4 cell count initiation thresholds that were consistent with their observed data, and then a pooled logistic model, which included CD4 threshold as a continuous variable, was fitted for the outcome. The model included a flexible functional form of CD4 threshold (restricted cubic spline), as well as a flexible function of time and the following covariates, measured at the start of follow-up: sex, age (<35, 35 to 49, or ≥50 years), race (white, black, or other or unknown), geographic origin (Western developed countries or other or unknown), method of transmission (heterosexual, homosexual or bisexual, injection drug use, or other or unknown), CD4 cell count (restricted cubic spline with 3 knots), HIV-1 RNA level (<10 000, 10 000 to 100 000, or >100 000 copies/ mL), calendar year (1996 to 1998, 1999 to 2000, 2001 to 2003, or ≥2004), years since HIV diagnosis (<1, 1 to 4, or ≥5 years, or unknown), cohort, and months from baseline to first CD4 cell count below 0.500 × 109 cells/L. We calculated robust SEs to compute 95% CIs for the hazard ratio estimates.
Most persons had data consistent with several CD4 thresholds. For example, a patient whose first recorded CD4 cell count below 0.500 × 109 cells/L was 0.340 × 109 cells/L and who immediately initiated cART would have done so within 6 months of the first time that the CD4 cell count decreased below both 0.350 and 0.500 × 109 cells/L, yielding data consistent with both the 0.350 and 0.500 thresholds (among others). Rather than randomly assigning this patient to a single CD4 threshold (a valid but statistically inefficient approach), we created an exact copy of the data for each CD4 threshold with which those data were consistent. The described model was fit to the expanded data set that resulted from applying this approach to the entire study population.
We censored copies in the expanded data set if their data stopped being consistent with their assigned CD4 threshold. The expansion and censoring procedures are detailed in Appendix 2 (available at www.annals.org) and elsewhere (36). To adjust for the potential bias due to censoring (35, 37), we applied inverse probability weights (informally, the inverse of the probability of having one's own treatment history) to our model. To estimate these weights, we used the original study population to fit pooled logistic models for treatment initiation. The models included the previously listed covariates, time-varying CD4 cell count (restricted cubic spline with 5 knots) and HIV-1 RNA level (<10 000, 10 000 to 100 000, or >100 000 copies/mL), diagnosis of an AIDS-defining illness (when the outcome was death alone), and time since last laboratory measurement (0, 1 to 2, 3 to 4, 5 to 6, or ≥7 months). Our weighted model estimates the parameters of a dynamic marginal structural model (38, 39) when these covariates include all joint determinants of therapy initiation and the outcome. As with previous applications of inverse probability weighting (28, 40), the weights were truncated at a maximum value of 10 for statistical efficiency; however, truncation had little effect on the estimates (data not shown).
We also estimated absolute risks for several CD4 thresholds. To do so, we fit a weighted model like the one described that also included product (interaction) terms between CD4 threshold for initiation and follow-up time (≤6, 7 to 12, 13 to 24, and >24 months). The model's predicted values were then used to estimate the 5-year survival and 5-year AIDS-free survival curves from the first time the CD4 count decreased below 0.500 ×109 cells/L. A nonparametric bootstrap with 500 samples was used to compute 95% CIs for the survival estimates.
All analyses were conducted with SAS, version 9.1.3 (SAS Institute, Cary, North Carolina). The institutional review board at Harvard School of Public Health approved our research.
This research was supported by the National Institutes of Health and the Medical Research Council. The funders had no role in the study design, data collection and analysis, or decision to publish or preparation of the manuscript.
We identified 20 971 therapy-naive persons with baseline CD4 cell counts of 0.500 × 109 cells/L or greater. The median CD4 cell count at baseline was 0.660 × 109 cells/L (interquartile range [IQR], 0.570 to 0.802 × 109 cells/L). Of these 20 971 persons, 390 developed an AIDS-defining illness or died before their CD4 cell count decreased below 0.500 × 109 cells/L (134 died), 2893 initiated cART before their CD4 cell count decreased below 0.500 × 109 cells/L, and 9296 never had a recorded CD4 cell count in the range of 0.200 to 0.499 × 109 cells/L. The remaining 8392 persons did have a CD4 cell count in this range and were included in our analysis. Table 1 shows the characteristics of the study population.
The median time from baseline to first CD4 cell count below 0.500 × 109 cells/L was 9 months. At that time, 89% of CD4 cell counts were in the range of 0.350 to 0.499 × 109 cells/L, with a median CD4 cell count of 0.441 × 109 cells/L (IQR, 0.397 to 0.473 × 109 cells/L). During a median follow-up of 12 months (IQR, 5 to 26 months), 460 persons developed an AIDS-defining illness or died (165 died). The median interval between laboratory measurements was 2 months (IQR, 1 to 4 months) before cART initiation.
Table 2 shows the hazard ratios for progression to either death or the combined end point of AIDS-defining illness or death for cART initiation at CD4 cell count thresholds between 0.200 and 0.500 × 109 cells/L, in increments of 0.050 × 109 cells/L. The mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold, compared with initiating cART at the 0.500 threshold. The estimates showed little evidence of changes in mortality as the CD4 threshold increased from 0.300 to 0.500 × 109 cells/L.
In contrast, the rates of the combined end point of AIDS-defining illness or death were higher for CD4 count thresholds below 0.450 × 109 cells/L than for the 0.500 threshold. The hazard ratios for the 0.350 and 0.200 thresholds, compared with the 0.500 threshold, were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively. If we had not adjusted for time-varying confounding, these estimates would have been closer to the null. The unadjusted hazard ratios for the 0.350 and 0.200 thresholds were 1.00 (CI, 0.86 to 1.17) and 1.05 (CI, 0.89 to 1.24), respectively, for death alone and 1.22 (CI, 1.11 to 1.34) and 1.38 (CI, 1.25 to 1.53), respectively, for the combined end point of AIDS-defining illness or death.
The Figure (top) plots 5-year survival, by CD4 threshold, from the first time the CD4 cell count decreased below 0.500 × 109 cells/L. The proportion was 0.98 (CI, 0.96 to 0.99) for the 0.500 threshold, 0.98 (CI, 0.97 to 0.98) for the 0.350 threshold, and 0.97 (CI, 0.96 to 0.98) for the 0.200 threshold. The 5-year survival difference was 0.5% (CI, −0.8% to 1.8%) for the 0.200 threshold and −0.02% (CI, −1.2% to 1.2%) for the 0.350 threshold compared with the 0.500 threshold.
The Figure (bottom) plots 5-year AIDS-free survival by CD4 threshold. The proportion was 0.94 (CI, 0.92 to 0.96) for the 0.500 threshold, 0.92 (CI, 0.91 to 0.93) for the 0.350 threshold, and 0.88 (CI, 0.87 to 0.90) for the 0.200 threshold. The 5-year AIDS-free survival difference was 5.8% (CI, 3.6% to 7.9%) for the 0.200 threshold and 2.1% (CI, 0.1% to 4.0%) for the 0.350 threshold compared with the 0.500 threshold.
Different analytic decisions had little effect on our estimates. These decisions included restriction to 1999 and later, restriction to men, exclusion of persons with injection drug use as their method of transmission, choice of flexible functional form for CD4 threshold, inclusion of additional covariates in the weight models (such as 3-month change in CD4 cell count), use of inverse probability weights to adjust for censoring at 12 months without a laboratory measurement in addition to the previously described weights, and censoring of persons who had no laboratory measurement at 18 months (results not shown).
We estimated that delaying cART initiation until the CD4 cell count decreased below 0.350 × 109 cells/L would result in a 38% increase in the incidence of AIDS-defining illness or death compared with a threshold of 0.500 × 109 cells/L, which means approximately 48 patients would need to initiate cART when their CD4 cell count decreased below 0.500 × 109 cells/L rather than 0.350 × 109 cells/L to prevent 1 new case of an AIDS-defining illness or death during the first 5 years. However, we estimated little change in all-cause mortality rates between the 0.500 and 0.350 thresholds. This finding is expected because of the low risk for death between the points at which a patient's CD4 cell count decreases below 0.500 and 0.350 × 109 cells/L.
Two large observational studies of therapy-naive persons (24, 25) have addressed this question. The When to Start Consortium (24) combined recent data with data from the pre-cART era and concluded that the mortality rate was 13% higher in persons who deferred therapy until their CD4 cell count was in the range of 0.251 to 0.350 × 109 cells/L than in those who initiated therapy at higher CD4 cell counts. As in our analysis, the effect was stronger for the combined end point of AIDS-defining illness or death (28%) than for death alone. The North American AIDS Cohort Collaboration on Research and Design (41) compared persons followed during the cART era and concluded that persons who deferred initiation until their CD4 cell count was below 0.500 × 109 cells/L had a higher risk for death than those who initiated at higher CD4 cell counts. This analysis (which included 9.2% of the persons in our analysis) reported a 94% increase in mortality rate for delayed versus immediate cART initiation. However, insufficient methodologic detail was provided for us to determine whether what seemed to be a surprisingly strong effect could have been due to bias (42) Other observational studies (43) have been criticized (44) for inadequate handling of deaths that occurred between study entry and the time when the CD4 threshold is crossed. Our analytic approach eliminates this bias by design.
Two previous randomized clinical trials (22, 23) have also provided some evidence on the effects of the timing of cART initiation. However, the SMART (Strategies for Management of Antiretroviral Therapy) trial (22) was neither designed nor powered to answer this question (and the relevant results were based primarily on persons with previous exposure to cART), and the CIPRA (Comprehensive International Program of Research on AIDS) HT-001 trial (23) evaluated only CD4 thresholds at or below 0.350 × 109 cells/L in a resource-limited setting with a high incidence of tuberculosis. Future and ongoing trials may need large sample sizes to find differences between cART initiation strategies, because many persons may never reach their assigned CD4 threshold during follow-up, and thus will remain untreated throughout the study. In our analysis, we estimated that 47% and 82% of eligible persons spent their entire follow-up AIDS-free and above the 0.350 and 0.200 thresholds, respectively.
Our study has limitations. First, the validity of our effect estimates rests on the assumption that we appropriately adjusted for confounding. Adjustment for the most important clinical information used by physicians as indications for cART initiation (such as CD4 cell count and HIV RNA level) increased the differences between cART initiation strategies. However, we could not adjust for health-seeking behaviors or other variables that may be associated with both early initiation of cART and better prognosis. As always, the possibility of confounding can be ruled out only by a well-designed and well-conducted randomized clinical trial.
Second, our analysis (like previous observational analyses of cART initiation) did not include information on the incidence of serious nonfatal events other than AIDS-defining illnesses, because this information was not collected in all participating cohorts. Serious nonfatal events other than AIDS-defining illnesses have been found to occur more frequently in people who interrupted antivetroviral therapy than in those who did not (45). The incidence of such events may be lower in those who initiate antivetroviral therapy at higher CD4 cell counts, but evidence for this is limited (22).
Third, our results may not be generalizable to health care systems with less frequent measurements of CD4 cell counts or to resource-limited settings. Given that all of the cohorts used in this analysis are from developed countries, it would not be appropriate to apply these estimates to populations in the developing world. Finally, like other studies, the average duration of the follow-up in our study was less than 2 years. Future studies will be needed to investigate the effect of earlier cART initiation on long-term toxicity and the prevention of non–AIDS-related deaths.
In summary, if the goal is to prevent AIDS-defining illness or death, our findings support cART initiation once the CD4 cell count decreases below 0.500 × 109 cells/L. However, delaying initiation until the CD4 cell count decreased below 0.350 × 109 cells/L did not seem to substantially affect overall mortality. The benefits of early initiation cannot be fully realized if most persons present for medical care with CD4 cell counts below 0.500 × 109 cells/L; thus, early HIV testing would be beneficial.
The optimal time to initiate combined antiretroviral therapy in HIV infection continues to be debated.
In models that used pooled data from 12 large observational cohorts, initiating combined antiretroviral therapy when the CD4 cell count decreased below 0.500 × 109 cells/L resulted in longer AIDS-free survival than delaying treatment until CD4 cell counts decreased below 0.350 or 0.200 × 109 cells/L. However, mortality did not differ substantially among these strategies.
The study design could not eliminate residual confounding. Results may not be generalizable to resource-constrained countries.
Randomized, controlled trials are needed to better define the optimal time of initiation of combined antiretroviral therapy in HIV infection.
Grand Support: By the National Institutes of Health (grants R01- AI073127 and U10-AA013566) and the Medical Research Council (grant G0700820).
Steering committee: J. Ainsworth, J. Anderson, A. Babiker, V. Delpech, D. Dunn, P. Easterbrook, M. Fisher, B. Gazzard, R. Gilson, M. Gompels, T. Hill, M. Johnson, C. Leen, C. Orkin, A. Phillips, D. Pillay, K. Porter, C. Sabin (principal investigator), A. Schwenk, J. Walsh.
UCL Medical School, London: L. Bansi, T. Hill, A. Phillips, C. Sabin.
Medical Research Council Clinical Trials Unit, London: D. Dunn, K. Porter, A. Glabay.
Barts and The London National Health Service (NHS) Trust, London: C. Orkin, R. Thomas, K. Jones.
Brighton and Sussex University Hospitals NHS Trust: M. Fisher, N. Perry, A. Pullin, D. Churchill.
Chelsea and Westminster NHS Trust, London: B. Gazzard, M. Nelson, D. Asboe, S. Bulbeck, S. Mandalia, J. Clarke.
Health Protection Agency—Centre for Infections, London: V. Delpech.
Homerton University Hospital NHS Trust, London: J. Anderson, S. Munshi.
King's College Hospital, London: F. Post, P. Easterbrook, Y. Khan, P. Patel, F. Karim, S. Duffell.
UCL Medical School and The Mortimer Market Centre, London: R. Gilson, S.L. Man, I. Williams.
North Bristol NHS Trust: M. Gompels, D. Dooley.
North Middlesex University Hospital NHS Trust, London: A. Schwenk, J. Ainsworth.
Royal Free NHS Trust and Department of Infection & Population Health, UCL Medical School, London: M. Johnson, M. Youle, F. Lampe, C. Smith, H. Grabowska, C. Chaloner, D. Ismajani Puradiredja, L. Bansi, T. Hill, A. Phillips, C. Sabin.
Imperial College Healthcare NHS Trust, London: J. Walsh, J. Weber, C. Kemble, N. Mackie, A. Winston.
The Lothian University Hospitals NHS Trust, Edinburgh: C. Leen, A. Wilson.
Director: F. de Wolf, HIV Monitoring Foundation, Amsterdam.
Data analysis group: D.O. Bezemer, L.A.J. Gras, A.M. Kes-selring, A.I. van Sighem, C. Smit, S. Zhang.
Data collection: S. Zaheri.
Academic Medical Centre of the University of Amsterdam, Amsterdam: J.M. Prins†, K. Boer, J.C. Bos, S.E. Geerlings, M.H. Godfried, M.E. Haverkort, T.W. Kuijpers, J.M.A. Lange, J.T.M. van der Meer, F.J.B. Nellen, D. Pajkrt, T. van der Poll, P. Reiss, H.J. Scherpbier, M. van der Valk, S.M.E. Vrouenraets, M. van Vugt, F.W.M.N. Wit.
Academic Hospital Maastricht, Maastricht: G. Schreij†, S. Lowe, A. Oude Lashof.
Catharina Hospital, Eindhoven: B. Bravenboer†, M.J.H. Pronk.
Erasmus Medical Centre, Rotterdam: M.E. van der Ende†, M. van der Feltz, L.B.S. Gelinck, J.L. Nouwen, B.J.A. Rijnders, E.D. de Ruiter, L. Slobbe, C.A.M. Schurink, A. Verbon, T.E.M.S. de Vries-Sluijs.
Erasmus Medical Centre Sophia, Rotterdam: G. Driessen, N.G. Hartwig.
Flevo Hospital, Almere: J. Branger.
Haga Hospital, Location Leyenburg, Den Haag: R.H. Kauff-mann†, E.F. Schippers.
Isala Clinics, Zwolle: P.H.P. Groeneveld†, M.A. Alleman, J.W. Bouwhuis.
Kennemer Gasthuis, Haarlem: R.W. ten Kate†, R. Soetekouw.
Leiden University Medical Centre, Leiden: F.P. Kroon†, S.M. Arend, M.G.J. de Boer, P.J. van den Broek, J.T. van Dissel, H. Jolink, C. van Nieuwkoop.
Maasstadziekenhuis, Location Clara, Rotterdam: J.G. den Hollander†, K. Pogany.
Medical Centre Alkmaar, Alkmaar: W. Bronsveld†, W. Kort-mann, G. van Twillert.
Medical Centre Haaglanden, Location Westeinde, Den Haag: R. Vriesendorp†, E.M.S. Leyten.
Medical Centre Leeuwarden, Leeuwarden: D. van Houte†, M.B. Polée, M.G.A. van Vonderen.
Medisch Spectrum Twente, Enschede: C.H.H. ten Napel†, G.J. Kootstra.
Onze Lieve Vrouwe Gasthuis, Amsterdam: K. Brinkman†, G.E.L. van den Berk, W.L. Blok, P.H.J. Frissen, W.E.M. Schouten.
Medical Centre Jan van Goyen, Amsterdam: A. van Eeden†, D.W.M.61Verhagen.
Slotervaart Hospital, Amsterdam: J.W. Mulder†, E.C.M. van Gorp, P.M. Smit, S. Weijer.
St. Elisabeth Hospital, Tilburg: J.R. Juttmann†, A.E. Brou- wer, M.E.E. van Kasteren.
St. Lucas Andreas Hospital, Amsterdam: J. Veenstra†, K.D. Lettinga.
Radboud University Nijmegen Medical Centre, Nijmegen: P.P. Koopmans†, A.M. Brouwer, A.S.M. Dofferhoff, M. van der Flier, R. de Groot, H.J.M. ter Hofstede, M. Keuter, A.J.A.M. van der Ven.
University Medical Centre Groningen, Groningen: H.G. Sprenger†, S. van Assen, R. Doedens, E.H. Scholvinck, C.J. Stek.
University Medical Centre Utrecht, Utrecht: A.I.M. Hoepel- man†, J.E. Arends, P.M. Ellerbroek, J.C.H. van der Hilst, C.A.J.J. Jaspers, L.J. Maarschalk-Ellerbroek, J.J. Oosterheert, E.J.G. Peters, T. Mudrikova, M.M.E. Schneider, M.W.M. Wassenberg.
Wilhelmina Children's Hospital, Utrecht: S.P.M. Geelen, T.F.W. Wolfs.
Free University Medical Centre, Amsterdam: S.A. Danner†, M.A. van Agtmael, W.F.W. Bierman, F.A.P. Claessen, E.V. de Jong, W. Kortmann, R.M. Perenboom, E.A. bij de Vaate.
Hospital Rijnstate, Arnhem: C. Richter†, J. van der Berg, E.H. Gisolf.
Hospital Walcheren, Vlissingen: M. van den Berge†, A. Stegeman.
Sint Elisabeth Hospitaal, Willemstad, Cura¸cao: A.J. Duits, K. Winkel.
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, M.A. Khuong, J.M. Lang, A.S. Lascaux, O. Launay, A. Mahamat, M. Mary-Krause, S. Matheron, J.L. Meynard, J. Pavie, G. Pialoux, F. Pilorgé, I. Poizot-Martin, C. Pradier, J. Reynes, E. Rouveix, A. Simon, P. Tattevin, H. Tissot-Dupont, J.P. Viard, N. Viget.
French Ministry of Health: V. Salomon.
Technical Hospitalization Information Agency, ATIH: N. Jacquemet.
U943 INSERM et UPMC: S. Abgrall, D. Costagliola, S. Grabar, M. Guiguet, E. Lanoy, L. Lièvre, M. Mary-Krause, H. Selinger-Leneman.
INSERM Transfert: J.M. Lacombe, V. Potard.
Corevih Ile de France Centre
GH Pitié Salpétrière: F. Bricaire, S. Herson, C. Katlama, A. Simon.
Hôpital Saint-Antoine: N. Desplanque, P.M. Girard, J.L. Meynard, M.C. Meyohas, O. Picard.
Hôpital Tenon: J. Cadranel, C. Mayaud, G. Pialoux.
Corevih Ile de France Est
Hôpital Saint-Louis: J.P. Clauvel, J.M. Decazes, L. Gerard, J.M. Molina.
G.H. Lariboisiére-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, J.L. 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.
G.H. Tarnier-Cochin: D. Salmon.
Hôpital Saint-Joseph: I. Auperin, J. Gilquin.
Hôpital Necker Adultes: L. Roudière, J.P. Viard.
Hôpital Antoine Béclère: F. Boué, R. Fior.
Hôpital de Bicêtre: J.F. Delfraissy, C. Goujard.
Hôpital Henri Mondor: C. Jung, P. Lesprit.
Hôpital Paul Brousse: D. Vittecoq.
CHRU de Strasbourg: P. Fraisse, J.M. Lang, D. Rey.
CH de Mulhouse: G. Beck-Wirth.
Corevih de l'Arc Alpin
CHU de Grenoble: J.P. Stahl, P. Lecercq.
CHU de Clermont-Ferrand: F. Gourdon, H. Laurichesse.
CHRU de Saint-Etienne: A. Fresard, F. Lucht.
CHRU de Caen: C. Bazin, R. Verdon.
CHRU de Dijon: P. Chavanet.
CHU de Rennes: C. Arvieux, C. Michelet.
CHRU de Tours: P. Choutet, A. Goudeau, M.F. Maître.
CHRU de Besançcon: B. Hoen; CH de Belfort: P. Eglinger, J.P. Faller.
CHRU de Rouen: F. Borsa-Lebas, F. Caron.
CHU de Montpellier: J. Reynes.
CHG de Nîmes: J.P. Daures.
Nancy Hôpital de Brabois: T. May, C. Rabaud.
CHRU de Reims: J.L. Berger, G. Rémy.
Corevih de Midi-Pyrénées
Toulouse CHU Purpan: E. Arlet-Suau, L. Cuzin, P. Massip, M.F. Thiercelin Legrand.
Toulouse Hôpital la Grave: G. Pontonnier.
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: J.P. Delmont, J. Moreau.
Marseille Institut Paoli Calmettes: J.A. Gastaut.
Marseille Hôpital Sainte-Marguerite: I. Poizot-Martin, F. Retornaz, J. Soubeyrand.
Marseille Centre pénitentiaire des Baumettes: A. Galinier, J.M. Ruiz.
CHG d'Aix-en-Provence: T. Allegre, P.A. Blanc.
CH d'Arles: D. Bonnet-Montchardon.
CH d'Avignon: G. Lepeu.
CH de Digne Les Bains: P. Granet-Brunello.
CH de Gap: J.P. 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 Valleée du Rhône
Lyon Hôpital de la Croix-Rousse: A. Boibieux, D. PeyRamond.
Lyon Hôpital Edouard Herriot: J.M. Livrozet, J.L. Touraine.
Lyon Hôtel-Dieu: L. Cotte, C. Trepo.
CHRU de Pointe-à-Pitre: M. Strobel.
CH Saint-Martin: F. Bissuel.
CHG de Cayenne: R. Pradinaud, M. Sobesky.
CHRU de Fort-de-France: A. Cabié.
Corevih de La Réunion
CHD Félix Guyon: C. Gaud, M. Contant.
C. Aebi, M. Battegay, E. Bernasconi, J. Böni, P. Brazzola, H.C. Bucher, P. Bürgisser, A. Calmy, S. Cattacin, M. Cavassini, J.J. Cheseaux, G. Drack, R. Dubs, M. Egger, L. Elzi, M. Fischer (deceased), M. Flepp, A. Fontana, P. Francioli (President of the SHCS, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne), H.J. Furrer, C. Fux, A. Gayet-Ageron, S. Gerber, M. Gorgievski, H. Günthard, T. Gyr, H. Hirsch, B. Hirschel, I. Hösli, M. Hüsler, L. Kaiser, C. Kahlert, U. Karrer, C. Kind, T. 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.
Coordinators: J. Casabona (Centre d'Estudis Epidemiològics les Infeccions de Transmissió Sexual i Sida de Catalunya: CEEISCAT), J.M. Miró (Hospital Clínic-IDIBAPS, Universitat de Barcelona).
Field coordinator: A. Alquézar, V. Isern (CEEISCAT).
Steering committee: J. Casabona, A. Esteve, A. Alquézar (CEEISCAT); J.M. Miró (Hospital Clínic-IDIBAPS, Universitat de Barcelona); D. Podzamczer (Hospital de Bellvitge de Barcelona); J. Murillas (Hospital Son Dureta de Mallorca).
Scientific committee: J.M. 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 (Cor- poració 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).
Hospital Clínic-IDIBAPS, Barcelona: J.L. Blanco, F. Garcia- Alcaide, E. Martínez, J. Mallolas, M. López-Dieguez, J.F. García-Goez.
Hospital Universitari Germans Trias i Pujol, Barcelona: G. Sirera, J. Romeu, A. Jou E. Negredo, C. Miranda, M.C 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, M. Jose Amengual, M. Navarro, E. Penelo.
Hospital de Mataró: P. Barrufet.
Hospital Alt Penedès de Vilafranca: M. Guadarrama.
Steering committee: J. Berenguer, J. del Amo, F. García, F. Gutiérrez, P. Labarga, S. Moreno, MA. Muñoz.
Field work, data management, and statistical analyses: A.M. Caro-Murillo, P. Sobrino, I. Jarrín.
Hospital Universitario de Canarias, Santa Cruz de Tenerife: J.L. Gómez Sirvent, P. Rodríguez, M.R. Alemán, M.M. Alonso, A.M. López, M.I. Hernández.
Hospital Carlos III, Madrid: V. Soriano, P. Labarga, P. Bar- reiro, J. Medrano, P. Rivas, D. Herrero, F. Blanco, M.E. Vispo, L. Martín, G. Ramírez, M. de Diego.
Hospital Doce de Octubre, Madrid: R. Rubio, F. Pulido, V. Moreno, C. Cepeda, R.L. Hervás.
Hospital Donostia, San Sebastián: JA. Iribarren, J. Arrizabalaga, M.J. Aramburu, X. Camino, F. Rodríguez-Arrondo, MA. von Wichmann, L. Pascual, MA. Goenaga.
Hospital General Universitario de Elche: F. Gutiérrez, M. Masiá, J.M. Ramos, S. Padilla, V. Sánchez-Hellín, E. Bernal, C. Escolano, F. Montolio, Y. Peral.
Hospital Gregorio Marañón, Madrid: J. Berenguer, J.C 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: J.L. 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, J.R Blanco, V. Ibarra, L. Metola, M. Sanz, L. Pérez-Martínez.
Hospital de Navarra, Pamplona: J. Sola, J. Uriz, J. Castiello, J. Reparaz, M.J. Arriaza, C. Irigoyen.
Hospital Ramón y Cajal, Madrid: S. Moreno, A. Antela, J.L. Casado, F. Dronda, A. Moreno, M.J. 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, L.F. López-Cortés, M. Trastoy, R. Mata.
Principal and co-principal investigators: A.C Justice, DA. Fiellin.
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, J.L. Goulet, MA. Hernán, K. Kraemer, J. Lim, S. Maisto, P. Miller, L. Mole, P. O'Connor, R Papas, J.M. Robins, C.Rinaldo, M. Roberts, J. Samet, B. Tierney, J. Whittle.
Atlanta, Georgia: D. Rimland, C. Jones-Taylor.
Baltimore, Maryland: KA. Oursler, R Titanji.
Bronx, New York: S. Brown, S. Garrison.
Houston, Texas: M. Rodriguez-Barradas, N. Masozera.
Los Angeles, California: M. Goetz, D. Leaf.
Manhattan and Brooklyn, New York: M. Simberkoff, D. Blumenthal, J. Leung.
Pittsburgh, Pennsylvania: A. Butt, E. Hoffman.
Washington, DC: C. Gibert, R Peck.
Steering committee: A. Phillips (Chair), 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 coordination: K. Porter (principal investigator), A. Cursley, F. Ewings, K. Fairbrother, L. Gnatiuc, S. Lodi, B. Murphy.
HPA, Birmingham: E. Smit.
St. Bartholomew's and the Royal London NHS Trust: F. Ward.
Aberdeen City Hospital, Aberdeen: G. Douglas.
Monklands Hospital, Airdrie: N. Kennedy.
Ashford Hospital, Ashford: J. Pritchard.
Ysbyty Gwynedd, Bangor: U. Andrady.
North Hampshire Hospital, Basingstoke: N. Rajda.
Royal Victoria Hospital, Belfast: R. Maw, S. McKernan.
Birmingham Heartlands Hospital, Birmingham: S. Drake, G. Gilleran, D. White.
Whittall Street Clinic, Birmingham: J. Ross.
Blackpool Victoria Hospital, Blackpool: S. Toomer.
Royal Bolton Hospital, Bolton: R. Hewart.
Royal Bournemouth Hospital, Bournemouth: H. Wilding, R. Woodward.
Royal Sussex County Hospital, Brighton: G. Dean, L. Heald.
Bristol Royal Infirmary, Bristol: P. Horner.
Southmead Hospital, Bristol: S. Glover.
Queens Hospital, Burton-upon-Trent: D. Bansaal.
West Suffolk Hospital, Bury St. Edmunds: S. Eduards.
Addenbrooke's Hospital, Cambridge: C. Carne.
Cardiff Royal Infirmary, Cardiff: M. Browing, R. Das.
North Cumbria Acute Hospitals NHS Trust, Carlisle: B. Stanley.
St. Helier Hospital, Carshalton: S. Estreich, A. Magdy.
Countess of Chester Hospital, Chester: C. O'Mahony.
Chesterfield & North Derbyshire Royal Hospital, Chesterfield: P. Fraser.
St. Richard's Hospital, Chichester: B. Hayman.
Essex County Hospital, Colchester: S.P.R. Jebakumar.
Castle Hill Hospital, Cottingham: U. Joshi.
Bishop Auckland General Hospital, County Durham: S. Ralph.
Coventry & Warwickshire Hospital, Coventry: A. Wade.
Mayday University Hospital, Croydon: R. Mette.
Doncaster Royal Infirmary, Doncaster: J. Lalik.
Weymouth Community Hospital, Dorset: H. Summerfield.
Guest Hospital, Dudley: A. El-Dalil.
Dundee Royal Infirmary, Dundee: A.J. France.
University Hospital of North Durham, Durham: C. White.
Muirhouse Medical Group, Edinburgh: R. Robertson.
Royal Infirmary of Edinburgh, Edinburgh: S. Gordon, S. McMillan, S. Morris.
Western General Hospital, Edinburgh: C. Lean, S. Morris.
Leatherhead Hospital, Epsom: K. Vithayathil.
Gartnavel General Hospital & Glasgow Royal Infirmary, Glasgow: L. McLean, A. Winter.
Gloucestershire Royal Hospital, Gloucester: D. Gale, S. Jacobs.
Salford Hope Hospital, Greater Manchester: B. Goorney.
Farnham Road Hospital, Guildford: L. Howard.
Hartlepool University Hospital, Hartlepool: S. Tayal.
Huddersfield Royal Infirmary, Huddersfield: L. Short.
Kidderminster General Hospital, Kidderminster: M. Roberts, S. Green.
Crosshouse Hospital, Kilmarnock: G. Williams.
The Queen Elizabeth Hospital, King's Lynn: K. Sivakumar.
Victoria Hospital, Kirkcaldy: D.N. Bhattacharyya.
Leeds General Infirmary, Leeds: E. Monteiro.
St. James Hospital, Leeds: J. Minton.
Leicester Royal Infirmary, Leicester: J. Dhar.
Royal Liverpool University Hospital, Liverpool: F. Nye.
Barts & The London NHS Trust, London: C.B. DeSouza, A. Isaksen.
Central Middlesex Hospital, London: L. McDonald.
Charing Cross Hospital, London: K. McLean.
Chelsea & Westminster Hospital, London: A. Franca, D. Hawkins.
Ealing Hospital, London: L. William.
Guy's & St Thomas NHS Trust, London: I. Jendrulek, B. Peters.
Hammersmith Hospital, London: S. Shaunak.
Homerton Hospital, London: S. El-Gadi.
King's College Hospital, London: P.J. Easterbrook.
Lewisham University Hospital, London: C. Mazhude.
Mortimer Market Centre, London: R. Gilson, R. Johnstone.
Newham General Hospital, London: A. Fakoya.
North Middlesex Hospital, London: J. Mchale, A. Waters.
Queen Elizabeth Hospital Woolwich, London: S. Kegg, S. Mitchell.
Royal Free Hospital, London: P. Byrne, M. Johnson.
St. George's Hospital, London: P. Rice.
St. Mary's Hospital, London: S. Fidler, S.A. Mullaney.
Victoria Sexual Health Clinic, London: S. McCormack.
West Middlesex University Hospital, London: D. David.
Whipps Cross Hospital, London: R. Melville.
Whittington Hospital, London: K. Phillip.
Luton & Dunstable Hospital, Luton: T. Balachandran.
Manchester Royal Infirmary, Manchester: S. Mabey-Puttock, A. Sukthankar.
North Manchester General Hospital, Manchester: C. Murphy, E. Wilkins.
Withington Hospital, Manchester: S. Ahmad.
James Cook Hospital, Middlesbrough: S. Tayal.
Milton Keynes General Hospital, Milton Keynes: J. Haynes.
Newcastle General Hospital, Newcastle: E. Evans, E. Ong.
Royal Gwent Hospital, Newport: R. Das.
Norfolk & Norwich University Hospital, Norwich: R. Grey, J. Meaden.
City Hospital, Nottingham: C. Bignell.
George Eliot Hospital, Nuneaton: D. Loay, K. Peacock.
Royal Oldham Hospital, Oldham: M.R. Girgis.
Radcliffe Infirmary, Oxford: B. Morgan.
Peterborough District Hospital, Peterborough: A. Palfreeman.
Freedom Fields Hospital, Plymouth: J. Wilcox.
St. Mary's Hospital, Portsmouth: J. Tobin, L. Tucker.
Royal Preston Hospital, Preston: A.M. Saeed.
Royal Berkshire Hospital, Reading: F. Chen.
East Surrey Hospital, Redhill: A. Deheragada.
Glan Clwyd District General, Rhyl: O. Williams.
Baillie Street Health Centre, Rochdale: H. Lacey.
Royal Hallamshire Hospital, Sheffield: S. Herman, D. Kinghorn.
Royal Shrewsbury Hospital, Shrewsbury: S.V. Devendra, J. Wither.
Upton Hospital, Slough: S. Dawson.
Royal South Hampshire Hospital, Southampton: D. Rowen.
Stirling Royal Infirmary, Stirling: J. Harvey.
Stepping Hill Hospital, Stockport: E. Wilkins.
North Staffordshire Hospital, Stoke-on-Trent: A. Bridgwood, G. Singh.
Sunderland Royal Hospital, Sunderland: M. Chauhan.
King's Mill Centre, Sutton-in-Ashfield: D. Kellock, S.
Young. Singleton Hospital, Swansea: S. Dannino, Y. Kathir.
The Great Western Hospital, Swindon: G. Rooney.
Taunton & Somerset Hospital, Taunton: J. Currie, M. Fitzgerald.
Princess Royal Hospital, Telford: S. Devendra.
Royal Cornwall Hospital, Truro: F. Keane.
Clayton Hospital, Wakefield: G. Booth, T. Green.
Manor Hospital, Walsall: J. Arumainayyagam, S. Chandramani.
Watford General Hospital, Watford: S. Rajamanoharan, T.
Robinson. Royal Albert Edward Infirmary, Wigan: E. Curless.
Arrowe Park Hospital, Wirral: R. Gokhale.
New Cross Hospital, Wolverhampton: A. Tariq.
Worcester Royal Infirmary, Worcester: M. Roberts.
Maelor Hospital, Wrexham: O. Williams.
Wycombe General Hospital, Wycombe: G. Luzzi.
Yeovil District Hospital, Yeovil: M. FitzGerald.
Monkgate Health Centre, York Hospital NHS Trust, York: I. Fairley, F. Wallis.
St. Louis Hospital, Paris: J.M. Molina, B. Loze, D. Sereni, C. Lascoux, F. Prevoteau, P. Morel, J. Timsit, E. Oksenhendeler, L. Gérard.
St. André Hospital, Bordeaux: P. Morlat, M. Bonarek, F. Bonnet, C. Nouts, I. Louis.
Hotel Dieu, Nantes: F. Raffi, V. Reliquet, F. Sauser, C. Biron, O. Mounoury, H. Hue, D. Brosseau.
Bicêtre Hospital, Le Kremlin Bicêtre: J.F. Delfraissy, C. Goujard, J. Ghosn, M.T. Rannou.
Lariboisière Hospital, Paris: J.F. Bergmann, E. Badsi, A. Rami, M. Diemer, M. Parrinello.
St. Antoine Hospital, Paris: P.M. Girard, D. Samanon- Bollens, P. Campa, M. Tourneur, N. Desplanques, J. Cabane, O.Picard, J. Tredup, N. Desplanques.
E. Herriot Hospital, Lyon: J.M. Livrozet, F. Jeanblanc, P. Chiarello, D. Makhloufi.
CHG, Aix-en-Provence: A.P. Blanc, T. Allègre.
Gui de Chauliac Hospital, Montpellier: J. Reynes, V. Baillat, V. Lemoing, C. Merle de Boever, C. Tramóni.
CHU, Fort de France: A. Cabiè, G. Sobesky, S. Abel, V. Beaujolais.
Tenon Hospital, Paris: G. Pialoux, L. Slama, C. Chakvetadze, V. Berrebi.
Bichat Hospital, Paris: P. Yeni, E. Bouvet, I. Fournier, J. Gerbe, C. Leport, C. Jadand, C. Jestin, P. Longuet, S. Boucherit.
Hotel Dieu, Lyon: C. Trepo, K. Koffi, C. Augustin-Normand, P. Miailhes, V. Thoirain, C. Brochier.
Pontchaillou Hospital, Rennes: R. Thomas, F. Souala, M. Ratajczak. G.
Montpied Hospital, Clermont-Ferrand: J. Beytoux, C. Jacomet, F. Gourdon.
A. Paré Hospital, Boulogne: E. Rouveix, S. Morelon, C. Dupont, C. Olivier.
Necker Hospital, Paris: O. Lortholary, B. Dupont, J.P. Viard, A. Maignan.
Pellegrin Hospital, Bordeaux: J.M. Ragnaud, I. Raymond.
H. Mondor Hospital, Créteil: A. Sobel, Y. Levy, J.D. Lelièvre, A.S. Lascaux, S. Dominguez, C. Dumont.
St. Jean Hospital, Perpignan: H. Aumaître, B. Delmas, M. Saada, M. Medus.
Cochin Hospital, Paris: L. Guillevin, D. Salmon, T. Tahi.
CH Dron, Tourcoing: Y. Yazdanpanah, S. Pavel, M.C. Marien.
E. Muller Hospital, Mulhouse: B. Drenou, G. Beck-Wirth, C. Beck, M. Benomar.
Pitié-Salpétrière Hospital, Paris: C. Katlama, R. Tubiana, H. Ait Mohand, A. Chermak, S. Ben Abdallah, S. Herson, N. Amirat, A. Simon, C. Brancion.
Avicenne Hospital, Bobigny: M. Bentata, F. Touam.
St. Jacques Hospital, Besançcon: B. Hoen, C. Drobacheff, A. Folzer.
Purpan Hospital, Toulouse: P. Massip, M. Obadia, L. Prudhomme, E. Bonnet, F. Balzarin.
CHR, Angers: E. Pichard, J.M. Chennebault, P. Fialaire, J. Loison. Béclère
Béclère Hospital, Clamart: P. Galanaud, F. Boué, D. Bornarel.
CHR Côte de Nacre, Caen: R. Verdon, C. Bazin, M. Six, P. Ferret.
HEGP, Paris: L. Weiss, D. Batisse, G. Gonzales-Canali, D. Tisne-Dessus.
Corbeil Hospital, Essonnes: A. Devidas, P. Chevojon, 1. Turpault.
Chalucet Hospital, Toulon: A. Lafeuillade, A. Cheret, G. Philip.
La Conception Hospital, Marseille: A. Stein, I. Ravault.
Bocage Hospital, Dijon: C. Chavanet, M. Buisson, S. Treuvetot.
Bretonneau Hospital, Tours: P. Choutet, P. Nau, F. Bastides.
CHU, Nancy: T. May, L. Boyer, S. Wassoumbou.
R Poincaré Hospital, Garches: L. Bernard, P. De Truchis, H. Berthé.
CH, Compiègne: Y. Domart, D. Merrien.
A. Mignot Hospital, Le Chesnay: A. Greder Belan.
IMM Jourdan, Paris: M. Gayraud, L. Bodard, A. Meudec.
La Beauchèe Hospital, St. Brieuc: C. Beuscart, C. Daniel, E. Pape.
L. Mourier Hospital, Colombes: P. Vinceneux, A.M. Simon- poli, A. Zeng.
M. Jacquet Hospital, Melun: L. Fournier.
L'Archet Hospital, Nice: J.G. Fuzibet, C. Sohn, E. Rosenthal, M. Quaranta, P. Dellamonica, S. Chaillou, M. Sabah.
L. Pasteur Hospital, Colmar: B. Audhuy, A. Schieber.
Bretagne Sud Hospital, Lorient: P. Moreau, M. Niault, O. Vaillant.
Hotel-Dieu, Paris: G. Huchon, A. Compagnucci.
Intercommunal Hospital, Crèteil: I. De Lacroix Szmania, L. Richier.
Abymes Hospital, Pointe à Pitre: I. Lamaury.
Ducuing Hospital, Toulouse: F. Saint-Dizier, D. Garipuy.
St. Marguerite Hospital, Marseille: J.A. Gastaut, M.P. Drogoul, I. Poizot Martin, G. Fabre.
CH, Brives: G. Lambert de Cursay, B. Abraham, C. Perino.
CH, Lagny: P. Lagarde, F. David.
S. Veil Hospital, Eaubonne: J. Roche-Sicot, J.L. Saraux, A. Leprêtre.
Beaujon Hospital, Clichy: B. Fampin, A. Uludag, A.S. Morin.
Foch Hospital, Suresnes: O. Bletry, D. Zucman.
CH, Vichy: A. Regnier.
CH, Loches: J.J. Girard.
CH, Antibes: D.T. Quinsat, L. Heripret.
Haute Vallée de l'Oise Hospital, Noyon: F. Grihon.
CH, Alençcon: D. Houlbert.
CH, Nanterre: M. Ruel, K. Chemlal.
C. Nicolle Hospital, Rouen: F. Caron, Y. Debab.
F. Quesnay Hospital, Mantes La Jolie: F. Tremollieres, V. Perronne.
H. Duffaut Hospital, Avignon: G. Lepeu, B. Slama.
Les Oudairies Hospital, La Roche-sur-Yon: P. Perré.
Paris: C. Miodovski.
CMC Bligny, Briis-sous-Forges: G. Guermonprez, A. Dulioust.
R. Ballanger Hospital, Aulnay-sous-Bois: P. Boudon, D. Malbec.
CH, Villeneuve St. Georges: O. Patey, C. Semaille.
CH, Reims: J. Deville, G. Remy, I. Béguinot.
Hôpital Antoine Béclère, Clamart: P. Galanaud, F. Boue, V. Chambrin, C. Pignon, G.A. Estocq, A. Levy.
Hôpital de Bicêtre, Le Kremlin-Bicêtre: J.F. Delfraissy, C. Goujard, M. Duracinsky, P. Le Bras, M.S. Ngussan, D. Peretti, N. Medintzeff, T. Lambert, O. Segeral, P. Lezeau, Y. Laurian.
Hôpital Européen Georges Pompidou, Paris: L. Weiss, M. Buisson, C. Piketty, M. Karmochkine, D. Batisse, M. Eliasze- witch, D. Jayle, D. Tisne-Dessus, M. Kazatchkine.
Hôpital Bichât-Claude Bernard, Paris: C. Leport, U. Colas- ante, C. Jadand, C. Jestin, X. Duval, W. Nouaouia, S. Boucherit, J.L. Vilde.
Hôpital Saint-Antoine, Paris: P.M. Girard, D. Bollens, D. Binet, B. Diallo, M.C. Meyohas, L. Fonquernie, J.L. Lagneau.
Hôpital Cochin, Paris: D. Salmon, L. Guillevin, T. Tahi, 0. Launay, M.P. Pietrie, D. Sicard, N. Stieltjes, J. Michot.
Hôpital Henri Mondor, Creteil: A. Sobel, Y. Levy, F. Bour- dillon, A.S. Lascaux, J.D. Lelievre, C. Dumont.
Hôpital Necker, Paris: B. Dupont, G. Obenga, J.P. Viard, A. Maignan.
Hôpital Paul Brousse, Villejuif: D. Vittecoq, L. Escaut, C. Bolliot.
Hôpital Pitié-Salpêtrière, Paris: F. Bricaire, C. Katlama, L. Schneider, S. Herson, A. Simon, M. Iguertsira.
Hôpital de la Conception, Marseille: A. Stein, C. Tomei, 1. Ravaux, C. Dhiver, H. Tissot Dupont, A. Vallon, J. Gallais, H. Gallais.
Hôpital Sainte Marguerite, Marseille: JA. Gastaut, M.P. Drogoul, G. Fabre.
Hôpital de L'Archet, Nice: P. Dellamonica, J. Durant, V. Mondain, I. Perbost, J.P. Cassuto, J.M. Karsenti, H. Venti, J.G. Fuzibet, E. Rosenthal, C. Ceppi, M. Quaranta.
Hôpital Avicenne, Bobigny: J.A. Krivitsky, M. Bentata, O. Bouchaud, P. Honore.
Hôpital Saint Louis, Paris: D. Sereni, C. Lascoux, J. Delgado.
ACCTES/Hôpital Necker, Paris: C. Rouzioux, M. Burgard, L. Boufassa.
Hôpital Mignot, Le Chesnay: J. Peynet.
Principal investigator: S. Pérez-Hoyos.
Data analysis center: I. Ferreros, I. Hurtado.
Centro Nacional de Epidemiología: J. del Amo, I. Jarrín, C. González, A.M. Caro.
Laboratory: C. de Mendoza, N. Zahonero.
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.
Here, we provide additional detail about the procedure for expanding and censoring persons and the weighted analysis.
Consider a nonblinded clinical trial in which therapy-naive persons with CD4 cell counts at or above 0.500 × 109 cells/L are randomly assigned to receive 1 of the following 2 regimens, defined by CD4 cell count threshold: Do not initiate cART when CD4 cell count is at or above 0.500 × 109 cells/L and initiate cART within 6 months after the recorded CD4 cell count first decreases below 0.500 × 109 cells/L (0.500 threshold), or do not initiate cART when CD4 cell count is at or above 0.350 × 109 cells/L and initiate cART within 6 months after the recorded CD4 cell count first decreases below 0.350 × 109 cells/L (0.350 threshold). To emulate such a trial by using observational data, we first determined whether each person's data were consistent with 1 or both thresholds. If the data were consistent with both thresholds, the data set was expanded to include an exact copy of the data for each threshold with which the data were consistent. Finally, copies in the expanded data set were censored if they deviated from the assigned threshold. When the outcome was death alone, the copies in the expanded data set were also censored if cART was not initiated within 6 months of diagnosis of an AIDS-defining illness.
As an example, consider the 6 hypothetical persons in the Appendix Figure. Person 1 met the baseline eligibility criteria and transitioned to a CD4 cell count below 0.500 × 109 cells/L, having not initiated cART at a CD4 cell count of 0.540 × 109 cells/L. When the CD4 cell count first decreased below 0.500 × 109 cells/L, this person's CD4 cell count was 0.450 × 109 cells/L, and cART was not initiated. Thus, person 1′s observed history is consistent with following both the 0.500 threshold (because 6 months remain in which to initiate cART) and the 0.350 threshold (because the CD4 cell count could still decrease below 0.350 × 109 cells/L before cART is initiated). Therefore, 2 copies of person 1 are made. Person 1 initiated cART in the fourth month, when the CD4 cell count was still above 0.350 × 109 cells/L. Therefore, person 1′s data are no longer consistent with the 0.350 threshold, and the copy assigned to the 0.350 threshold is censored at that time. If the outcome develops later, it will count toward only the 0.500 threshold.
Person 2 is like person 1, except that cART is initiated 10 months after the first time the CD4 cell count decreases below 0.500 × 109 cells/L but is still above 0.350 × 109 cells/L. This person is therefore censored from the 0.500 threshold after 6 months and censored from the 0.350 threshold after 10 months. If the outcome develops later, it will count toward neither threshold.
Person 3 is identical to person 2, except that a CD4 cell count measurement of 0.300 × 109 cells/L was obtained in the eighth month. This person is censored from the 0.500 threshold after 6 months but is never censored from the 0.350 threshold. If the outcome develops later, it will count toward only the 0.350 threshold.
Person 4 also met the baseline eligibility criteria and transitioned to a CD4 cell count below 0.500 × 109 cells/L, having not initiated cART at a CD4 cell count of 0.540 × 10 cells/L. This person's first CD4 cell count below 0.500 × 109 cells/L was 0.300 × 10 cells/L. As with person 1, this history is consistent with both thresholds, so the data are copied twice. Person 4 initiated cART in the second month. Then, regardless of CD4 cell count at the time of initiation, person 4 will continue to follow both thresholds for the remainder of follow-up. If the outcome develops later, it will count toward both thresholds.
Person 5 is identical to person 4, except that the outcome developed in the first month before initiating cART. This counts toward both thresholds because the data were consistent with both thresholds when the outcome was developed.
Person 6 met the baseline eligibility criteria but initiated cART before transitioning to a CD4 cell count below 0.500 × 109 cells/L. Because the CD4 cell count was never in the range of 0.200 to 0.499 × 109 cells/L, this person's data were not included in the analysis but did contribute to the estimation of the weights.
We used a generalization of this approach to compare regimens with CD4 thresholds between 0.200 and 0.500 × 109 cells/L in increments of 0.010 × 109 cells/L (36).
The weighted model for the outcome was fitted to the 8392 persons who met the baseline criteria and had a CD4 cell count ranging from 0.200 to 0.499 × 109 cells/L, which would include persons like hypothetical persons 1 to 5 but exclude those like hypothetical person 6. Although we report results only for selected hazard ratios and survival proportions, our method can be used to provide estimates for any CD4 threshold.
The first and last knots for CD4 threshold were placed at 0.250 and 0.450 × 109 cells/L, respectively, and the remaining knots were equally spaced between the first and last knots at 0.317 and 0.383 × 109 cells/L. In both the weighted model for the outcome and the models for the weights, the knots for time were placed at 1,6, 24, and 132 months. Our results were not sensitive to alternate placements of the knots.
The models to estimate the weights were based on all 20 971 persons who met the baseline criteria. Separate weight models were fitted for the person-time before and after the first time that the CD4 cell count decreased below 0.500 × 109 cells/L. All 6 hypothetical persons would therefore be included in the model for the weights before the first time that the CD4 cell count decreased below 0.500 × 109 cells/L, but only hypothetical persons 1 to 5 would be included in the model for the weights after the first time that the CD4 cell count decreased below 0.500 × 10 cells/L. The time-fixed covariates for the model before the CD4 cell count decreased below 0.500 × 109 cells/L were measured at baseline, whereas those for the model after the CD4 cell count decreased below 0.500 × 109 cells/L were measured the first time the CD4 cell count decreased below this threshold.
For all uncensored observations, the probability of having one's own treatment history is equivalent to the probability of remaining uncensored. Therefore, the model for the weights after the first time the CD4 cell count decreased below 0.500 × 109 cells/L was fitted in the unexpanded data set.
Because we defined the clinical regimens of interest in terms of cART initiation only, it was unnecessary to adjust for joint determinants of treatment discontinuation and death, which are less well-measured in most observational studies. However, our strategy may lead to attenuation of the differences between the clinical regimens of interest (as one would expect in an intention- to-treat analysis of a randomized clinical trial with similar rates of discontinuation across clinical regimens). Adjustment for cART discontinuation would be neither appropriate nor clinically interesting if most patients who discontinue cART do so for toxicity-related reasons.
Author Contributions: Conception and design: L.E. Cain, J.A.C. Sterne, C. Sabin, J. Goulet, F. de Wolf, H.C. Bucher, J. Casabona, J. del Amo, D. Costagliola, M.A. Hernán.
Analysis and interpretation of the data: L.E. Cain, R. Logan, J.A.C. Sterne, C. Sabin, A. Justice, J. Goulet, F. de Wolf, J. del Amo, L. Meyer, D. Costagliola, M.A. Hemán,
Drafting of the article: L.E. Cain, J.M. Robins, J.A.C. Sterne, A. Justice, J. Goulet, S. Moreno, S. Lodi, E. Lanoy, D. Costagliola, M.A. Hernán.
Critical revision of the article for important intellectual content: L.E. Cain, J.M. Robins, J.A.C. Sterne, C. Sabin, A. Justice, J. Goulet, F. de Wolf, H.C. Bucher, V. von Wyl, J. Casabona, J. del Amo, S. Moreno, L. Meyer, S. Lodi, E. Lanoy, D. Costagliola, M.A. Hernán.
Final approval of the article: L.E. Cain, J.A.C. Sterne, C. Sabin, L. Bansi, A. Justice, J. Goulet, A. van Sighem, F. de Wolf, H.C. Bucher, V. von Wyl, A. Esteve, J. Casabona, J. del Amo, S. Moreno, R. Seng, L. Meyer, S. Pérez-Hoyos, S. Lodi, E. Lanoy, D. Costagliola, M.A. Hernán.
Provision of study materials or patients: C. Sabin, A. van Sighem, H.C. Bucher, A. Esteve, J. Casabona, J. del Amo, S. Moreno, L. Meyer, S. Pérez-Hoyos, D. Costagliola.
Statistical expertise: L.E. Cain, R. Logan, J.M. Robins, J.A.C. Sterne, J. Goulet, J. Casabona, D. Costagliola, M.A. Hernán.
Obtaining of funding: J.A.C. Sterne, J. del Amo, M.A. Hernán.
Administrative, technical, or logistic support: R. Logan, J. Casabona, M.A. Hernán.
Collection and assembly of data: I.E. Cain, C. Sabin, L. Bansi, A. Justice, J. Goulet, A. van Sighem, F. de Wolf, H.C. Bucher, V. von Wyl, A. Esteve, J. Casabona, J. del Amo, R. Seng, L. Meyer, S. Peírez-Hoyos, S. Lodi, D. Costagliola, M.A. Hernán.
†Coordinating physician for site.
Writing Committee: Lauren E. Cain, PhD; Roger Logan, PhD; James M. Robins, MD; Jonathan A.C Sterne, PhD; Caroline Sabin, PhD; Loveleen Bansi, MSc; Amy Justice, MD, PhD; Joseph Goulet, PhD; Ard van Sighem, PhD; Frank de Wolf, MD; Heiner C Bucher, MD; Viktor von Wyl, PhD; Anna Esteve, PhD; Jordi Casabona, MD, MPH; Julia del Amo, MD, PhD; Santiago Moreno, MD; Rémonie Seng, MD; Laurence Meyer, PhD; Santiago Pérez-Hoyos, PhD; Roberto Muga, MD, PhD; Sara Lodi, PhD; Emilie Lanoy, PhD; Dominique Costagliola, PhD; and Miguel A. Hernán, MD, DrPH.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-2963.
Reproducible Research Statement: Study protocol and data set: Not available. Statistical code: Available from Dr. Cain (e-mail, ude.dravrah. hpsh@niacl).