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Epidemiology and Prevention

Serious Fatal and Nonfatal Non-AIDS-Defining Illnesses in Europe

Mocroft, Amanda PhD*; Reiss, Peter MD; Gasiorowski, Jacek MD; Ledergerber, Bruno PhD§; Kowalska, Justyna MD; Chiesi, Antonio MD; Gatell, Jose MD#; Rakhmanova, Aza MD**; Johnson, Margaret MD††; Kirk, Ole MD, DMSc; Lundgren, Jens MD, DMSc‖‡‡for the EuroSIDA Study Group

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: October 1st, 2010 - Volume 55 - Issue 2 - p 262-270
doi: 10.1097/QAI.0b013e3181e9be6b

INTRODUCTION

Observational studies in HIV infection have tracked the incidence rates of AIDS and deaths, detailing the change in clinical event rates associated with the combination antiretroviral therapy (cART),1 how clinical event rates have varied over time according to the current (or latest) CD4 count,2 and demonstrating a decline in AIDS and death rates after cART.3 However, as patients with HIV live longer, there is an increasing focus on so-called non-AIDS events.4,5 Patients may have an increased risk of non-AIDS comorbidity (non-HIV-associated or non-AIDS comorbidity), many of which are associated with aging.4 Comparatively little is known about the incidence of fatal and nonfatal serious non-AIDS events in HIV-infected persons, which have a significant impact on mortality, and how this has changed over time with the widespread use of cART. Observational studies have looked at pancreatitis, cardiovascular (CV) disease, or non-AIDS malignancies6-8 as separate disease entities, but to our knowledge, there are few studies that have considered the overall incidence of serious non-AIDS events and the risk factors for these events. AIDS continues to be described as a composite endpoint, and although the diseases included as non-AIDS events could be debated, a comparison for non-AIDS events as a composite endpoint would provide a useful epidemiological comparison. Although some studies have suggested a role of immunodeficiency for non-AIDS events,7-10 this neither has been widely investigated nor has the role of modifiable risk factors in HIV, such as smoking, diabetes and hypertension. Clinical trials in HIV infection which utilize clinical endpoints, such as the Strategies for Management of Antiretroviral Therapy (SMART), Evaluation of Subcutaneous Proleukin (R) in a Randomized International Trial and Subcutaneous Interleukin-2 in patients with Low CD4 counts under Active Antiretroviral Therapy studies,11,12 and the more recently initiated Strategic Timing of Antiretroviral Therapy study, increasingly use a composite endpoint of nonopportunistic disease as part of the trial endpoint in recognition of the fact of the increasing proportion of deaths which occur in patients without AIDS13 and the role of immunodeficiency in increasing the risk of such events.8,10

The aims of this study were therefore to describe the incidence of fatal and nonfatal non-AIDS events over time across Europe and to determine the predictors of non-AIDS events as compared with the predictors of AIDS events and to investigate the relative impact on mortality of both AIDS and non-AIDS events.

PATIENTS AND METHODS

EuroSIDA was initiated in 1994 and is a prospective study of 16,599 HIV-1-infected patients at 102 centres across Europe, Israel, and Argentina; further details have been reported elsewhere.3 To date, 8 cohorts of patients have been recruited. Data are collected prospectively at clinical sites and is extracted and sent to the coordinating centre at 6 monthly intervals. For cohorts 1-3, eligible patients were those who had had a CD4 count below 500 cells per cubic millimeter at recruitment or during the previous 4 months. The CD4 count restriction was removed for cohorts 4-8. At recruitment, in addition to demographic and clinical information, a complete antiretroviral treatment history is obtained, together with the most recent CD4 count and plasma HIV RNA measurements. At each follow-up visit, details on all CD4 counts and plasma HIV RNA values measured since the last follow-up visit are extracted, as are the dates of starting and stopping each antiretroviral drug received and the use of drugs for prophylaxis against opportunistic infections. The present analysis includes follow-up to a median date of April 2009.

Non-AIDS events were selected for inclusion in this analysis based on the data collected as part of the study, which has been developed based on expert opinion from the steering committee as non-AIDS events likely to have a significant impact on morbidity and mortality. Data have routinely been collected on a number of non-AIDS events since January 2001 (forms at: www.cphiv.dk) and includes non-AIDS-defining malignancies, pancreatitis, grade 3 or 4 hepatic encephalopathy or liver-related death, myocardial infarction, stroke, coronary artery bypass graft, coronary angioplasty, carotid endarterectomy (grouped together as serious CV events), and end-stage renal disease. AIDS events were diagnosed using the clinical definition from the Centers for Disease Control.14

EuroSIDA has an extensive quality assurance process. All participating sites are monitored at least once per year. All clinical events (AIDS and non-AIDS) are verified by the monitoring team and a random selection of all patients without clinical events.

Statistical Analyses

All patients with prospective follow-up after January 2001 were included in analyses; prospective follow-up began at January 1, 2001, for patients under follow-up at that date and at the date of recruitment to the study for patients subsequently recruited to the study. Follow-up for the analysis of non-AIDS events accrued until the date of last visit, death, or the development of a non-AIDS event, and for AIDS until the date of last visit, death, or the development of a new AIDS event. Descriptive analyses were used to summarize the incidence rate of each of the non-AIDS or AIDS events and the characteristics of the patients developing them. Only AIDS and non-AIDS events which developed during prospective follow-up were included in analyses and recurrences of the same event were not included as events. Incidence rates of non-AIDS and AIDS events were stratified by calendar time and by current (ie, latest) CD4 count. Poisson regression was used to determine the factors associated with either development of a new non-AIDS or AIDS event; multivariable models were adjusted for the effect of demographic, laboratory markers, and antiretroviral treatment on event rates. Anemia was defined as previously within the EuroSIDA study,15 ≤12 mg/dL or ≤14 mg/dL for females and males, respectively. Diabetes was defined as diagnosis of insulin-dependent diabetes or the use of oral antidiabetic medication or insulin and arterial hypertension was defined as treatment with ACE inhibitors, antihypertensive medication, diastolic blood pressure ≥90 mm/Hg, or systolic blood pressure ≥140 mm/Hg. cART was defined as treatment with a minimum of 3 antiretrovirals.

Cox proportional hazards models, stratified by centre, were used to estimate the RH of death after an AIDS or non-AIDS event compared with the hazard in patients who had not experienced these events. Patient follow-up began at baseline and ended at death or last visit. AIDS and non-AIDS events were included in the model simultaneously as time-updated covariates, and a second model was constructed where the AIDS events were stratified into mild, moderate, and severe,16 and the individual components of the non-AIDS events, again all events were included in the model simultaneously and as time-dependant covariates. In addition, Kaplan-Meier survival analysis was used to estimate survival after diagnosis of either and AIDS or non-AIDS event; patients without a diagnosis of non-AIDS or AIDS were excluded from this analysis, and patient follow-up was measured from the date of diagnosis until death or last visit.

Statistical analyses were performed using SAS (Statistical Analysis Software, Cary, NC, Version 9.1).

RESULTS

Twelve thousand eight hundred fourty-four patients were included in analyses (Table 1). One thousand twenty-five (8.0%) developed an AIDS-defining event during prospective follow-up and 1058 patients (8.2%) developed a non-AIDS event. Patients developing either AIDS or non-AIDS events were more likely to have a diagnosis of AIDS at baseline and have lower CD4 counts and CD4 count nadirs. Patients developing a non-AIDS event tended to be older, whereas those developing an AIDS event had higher viral loads at baseline. Among the non-AIDS events, there were 380 patients diagnosed with a non-AIDS-defining malignancy, 384 with CV events, 183 with hepatic encephalopathy or liver related death, 81 patients with pancreatitis, and 35 patients with end-stage renal disease. The most commonly occurring AIDS events were oesophageal candidiasis (n = 239), pulmonary tuberculosis (n = 85), non-Hodgkins lymphoma (n = 77), pneumocystis jiroveci pneumonia (n = 61), and HIV wasting syndrome (n = 51).

TABLE 1
TABLE 1:
Baseline* Characteristics of Included Patients

The incidence of non-AIDS events was 1.77 per 100 person-years of follow-up [95% confidence interval (CI): 1.66 to 1.87] and of AIDS events was 1.72 (95% CI: 1.61 to 1.83). There were few changes over calendar time in either the incidence of non-AIDS or AIDS events, as shown in Figure 1A. Figure 1B shows the incidence of both events stratified by current CD4 count; as expected, there was a strong relationship between current CD4 count and AIDS events; the incidence of AIDS at a current CD4 count ≤50 cells per cubic millimeter was 29.5 per 100 person-years of follow-up (95% CI: 25.4 to 33.5), decreasing to 0.5 per 100 person-years of follow-up (95% CI: 0.3 to 0.6) at a current CD4 count >700 cells per cubic millimeter. There was also a strong, but less marked, gradient for non-AIDS events; the incidence at a current CD4 count ≤50 cells per cubic millimeter was 7.1 per 100 person-years of follow-up (95% CI: 5.3 to 8.9), decreasing to 1.1 per 100 person-years of follow-up (95% CI: 0.9 to 1.3) at a current CD4 count >700 cells per cubic millimeter. The incidence of non-AIDS events exceeded, or was similar to, the incidence of AIDS events at all current CD4 counts above 200 cells per cubic millimeter.

FIGURE 1
FIGURE 1:
Incidence of AIDS and non-AIDS events. A, Calender year of follow-up; B, Current CD4 cell count.

The multivariate (adjusted) incidence rate ratios (IRR) for AIDS and non-AIDS events are shown in Table 2. Factors strongly related to the development of a new non-AIDS event included coinfection with hepatitis B or C and age. There was a 71% increased incidence of non-AIDS events associated with a 10-year age increase (IRR: 1.71, 95% CI: 1.60 to 1.83, P < 0.0001). Patients with diabetes had a 49% increased incidence of a non-AIDS event (IRR: 1.49, 95% CI: 1.22 to 1.82, P < 0.0001), those with hypertension had a 63% increased incidence (IRR: 1.63, 95% CI: 1.43 to 1.87, P < 0.0001), and those with anemia had 82% increased incidence (IRR: 1.82; 95% CI: 1.56 to 2.13, P < 0.0001). There was a significantly increased incidence of non-AIDS events at lower CD4 counts compared with patients with a current CD4 of 351-500 cells per cubic millimeter, with the highest incidence in those with current a CD4 ≤50 cells per cubic millimeter. However, there was not a significantly decreased incidence of non-AIDS events at current CD4 counts of 500-700 cells per cubic millimeter or >700 cells per cubic millimeter compared with current CD4 counts between 351-500 cells per cubic millimeter. There was no evidence of a change in the incidence of non-AIDS events over time (P = 0.11). In contrast, the strongest factors associated with the development of a new AIDS event were current viral load and current CD4 count. Compared with patients with a current CD4 count of 351-500 cells per cubic millimeter, the incidence of new AIDS events continued to decrease at higher CD4 counts; patients with a current CD4 count of >700 cells per cubic millimeter had approximately half the incidence of new AIDS events (IRR: 0.62; 95% CI: 0.44 to 0.87, P = 0.0054). Being anemic was associated with over a 65% increased incidence of an AIDS event (IRR: 1.65; 95% CI: 1.39 to 1.96, P < 0.0001).

TABLE 2
TABLE 2:
Multivariate Incidence Rate Ratios: Risk of Non AIDS and AIDS Events

Current CD4 count was also included in models as a continuous variable. After adjustment, a doubling of the CD4 count was associated with a 37% reduction in the incidence of AIDS events (IRR: 0.63; 95% CI: 0.60 to 0.66, P < 0.0001) and a 20% reduction in the incidence of non-AIDS events (IRR: 0.80; 95% CI: 0.75 to 0.85, P < 0.0001). A doubling of current CD4 count was associated with non-AIDS-defining malignancies (IRR: 0.78; 95% CI: 0.69 to 0.87, P < 0.0001), end-stage renal disease (IRR: 0.70; 95% CI: 0.57 to 0.80, P = 0.0006), pancreatitis (IRR: 0.79; 0.63 to 0.98, P = 0.036), and liver-related events (IRR: 0.73; 95% CI: 0.65-0.83, P < 0.0001), but not with CV events (IRR: 0.98; 95% CI: 0.85 to 1.12, P = 0.78).

Figure 2 shows the Kaplan-Meier progression to death after diagnosis of either AIDS or non-AIDS events. Three hundred thirty-nine patients with an AIDS event subsequently died (33.1%); at 4 years after diagnosis, 38.4% of patients were estimated to have died (95% CI: 34.9% to 41.9%). In contrast, there were 462 deaths after a non-AIDS event (43.7%), and at 4 years, 47.0% of patients were estimated to have died (95% CI: 43.6% to 50.4%). Compared with patients without an event, there was more than a 4-fold increased risk of death associated with the diagnosis of an AIDS-defining event (RH: 4.14; 95% CI: 3.47 to 4.97, P < 0.0001) and almost a 7-fold increased risk of death associated with a non-AIDS event (RH: 6.72; 95% CI: 5.61 to 8.05; P < 0.0001). These events are further stratified in Figure 3. As would be expected, the diagnosis of a serious AIDS event had the worst prognosis, compared with a moderate or mild AIDS-defining event. For non-AIDS events, a liver-related event was associated with the worst prognosis, over a 22-fold increased risk of death (RH: 22.77; 95% CI: 15.19 to 34.14, P < 0.0001). The risk of death associated with the other non-AIDS events varied from a 1.5-fold increased risk of death after a coronary artery bypass graft, coronary angioplasty, or carotid endarterectomy (RH: 1.54; 95% CI: 0.61 to 3.88, P = 0.36) to over a 8-fold increased risk of death after a diagnosis of end-stage renal disease (RH: 8.52; 95% CI: 6.17 to 11.76, P < 0.0001).

FIGURE 2
FIGURE 2:
Kaplan-Meier progression to death after a new AIDS or non-AIDS event.
FIGURE 3
FIGURE 3:
Adjusted* relative hazard of death associated with non-AIDS and AIDS events. *Stratified by center and adjusted for gender, race, HIV exposure group, hepatitis B and C status (time-updated), prior AIDS diagnosis, age, current CD4 count, current viral load, current anemia status. !Including coronary artery bypass graft, coronary angioplasty, carotid endarterectomy. Two separate models are presented. The first (A) shows the adjusted relative hazard of death after diagnosis of AIDS and non-AIDS (mutually adjusted). B, Shows the adjusted relative hazard of death after diagnosis of the individual non-AIDS event and type of AIDS (mild, moderate, and severe, mutually adjusted).

DISCUSSION

This large study has compared and contrasted the factors associated with developing either an AIDS event or a non-AIDS event in a European population of HIV-infected patients under follow-up from 2001 to 2009. The study identified considerable mortality associated with non-AIDS events, which exceeded that of AIDS events and was particularly high for liver-related events.

Low CD4 counts have long been established as a risk factor for the development of AIDS events, and there is now emerging evidence that lower CD4 counts are also associated with diagnoses which are typically thought to be non-AIDS related.17-21 Consistent with other studies, we found that a lower CD4 count was associated with each of the non-AIDS events we included in the composite endpoint,9,10,22-25 with the exception of CV disease. There is, to date, no strong evidence linking CV disease with immunodeficiency6,26; risk of CV disease is thought to depend more on lipid changes, lifestyle, and inflammation.27-31 One of the ways in which cART reduces morbidity and mortality is by increasing the CD4 count, so it is possible that patients starting cART would also have lower rates of non-AIDS events, as recently demonstrated by the SMART study.11 It was interesting to note that there continued to be a decreasing incidence of AIDS events as the CD4 count increased from 351 to 500, 501 to 700, and >700 cells per cubic millimeter, confirming the results of previous studies32,33 and suggesting that there is a continuum of decreasing risk of new AIDS events as the CD4 count approaches levels seen in uninfected persons.34 The same relationship was not seen for non-AIDS events, and there were no further decreases at CD4 counts above 350 cells per cubic millimeter. However, the incidence of non-AIDS events was similar to, or exceeded, the incidence of AIDS events at CD4 counts of ≥200 cells per cubic millimeter.

Development of anemia was a very strong risk factor for both AIDS and non-AIDS events and probably reflects a general deterioration in health and increasing morbidity; anemia has previously been demonstrated to be a strong predictor of AIDS35-37 and is also frequently described in non-HIV-infected patients who develop CV disease, diabetes, and malignancies.38-40 As would be expected, the development of diabetes and hypertension were all associated with non-AIDS events, are known to be associated with a higher risk of CV disease41-43 and together with smoking, are potentially associated with less healthy lifestyle choices which may increase the risk for other non-AIDS events, such as malignancies and liver disease. Smoking, diabetes, and hypertension are all potentially modifiable risk factors and it would be of interest to determine if stopping smoking, an increase in exercise, or improvement in diet would impact on the incidence of these events in the same way as in non-HIV-infected persons.

One third of patients were estimated to have died within 12 months of a non-AIDS diagnosis, although developing a non-AIDS event during follow-up was associated with almost a 7-fold increased risk of death, consistent with results from the SMART study44 and suggesting that non-AIDS events are a significant contributor to hospitalizations and deaths.45 This study does not include any patients without HIV, so we cannot comment whether our death rates are higher than those seen in HIV-negative persons with the same comorbidites. There are some early markers of comorbidities, which may be useful to identify patients at risk and potentially decrease morbidity and mortality associated with these events. For example, estimated glomerular filtration rate is used to identify patients with chronic kidney disease,46 although the relationship between chronic kidney disease and end-stage renal disease is yet to be fully explored in HIV.47 We found a similar gradient of risk of death when stratifying the AIDS events into mild, moderate, and severe as recently published from the Antiretroviral Cohort Collaboration,16 to which EuroSIDA contributes data. There was also a gradient of risk of death when comparing different non-AIDS events; development of a liver-related event was associated with a 14-fold increased risk of mortality, whereas patients developing a stroke or myocardial infarction had 3-fold to 4-fold increased risk of mortality. EuroSIDA is currently assessing all causes of death to estimate the contribution of AIDS and non-AIDS (and different components of these events) to morbidity, which will help further identify non-AIDS events in HIV-infected persons.48 In addition, reports considering the cause of death of HIV-infected patients have highlighted the reduction in the proportion of patients who die with AIDS and the increasing proportion of patients who die with so called ‘non-HIV’-related illnesses13,49-51 and describing the relative contribution of these events.

There are few studies, which have focused on the predictors of non-AIDS events in HIV-infected patients. The Data on Adverse Events (D:A:D) study recently presented data confined to fatal events looking at the impact of modifiable risk factors for liver-related deaths, deaths from CV disease, and non-AIDS malignancies52 and, consistent with the results presented here, highlighted hypertension and diabetes as potentially modifiable risk factors. Moore et al17 demonstrated a strong relationship between current CD4 cell count and non-AIDS events in a much smaller cohort of patients followed until 2006, but did not look in detail at other predictors of these events, although preliminary results from the SMART study and others illustrate the considerable mortality after a non-AIDS event compared with AIDS events.44,53 Ferry et al54 found CD4 count, age, and also viral load were the strongest predictors for severe non-AIDS clinical events, where a considerably more inclusive definition of non-AIDS events were used.

There are a number of limitations to this study. It is observational in nature, and information on non-AIDS events were not routinely collected until 2001, hence the exclusion of EuroSIDA patients who died or were lost to follow-up before this date. Complete information on all variables was not available for all patients; however, a sensitivity analysis using multiple imputation55 revealed very similar results (data not shown). The analysis of non-AIDS events was based on information captured on forms, and the incidence depends, on part, on the non-AIDS events included in our composite endpoint. The data collected in EuroSIDA reflects the steering committee expert opinion and focus on the most important contributors to morbidity and mortality. It is possible that reporting of non-AIDS events has improved over time, suggesting an underestimate of the contribution of non-AIDS events. The use of AIDS or non-AIDS as a composite endpoint has advantages and disadvantages. The advantages are that it increases power and provides a powerful overview and epidemiological description, the disadvantages that risk factors may differ for different components of the endpoint. Indeed, many studies continue to use AIDS as a composite endpoint, despite these issues. Combining the different non-AIDS events results in a heterogeneous collection of endpoints, but some of the non-AIDS events have been the subject of individual studies within EuroSIDA or other large cohort studies,6,7,10,21,56 and we therefore chose to combine the events for our primary analysis. The results for the 3 most common components of the endpoint, CV disease, non-AIDS malignancies, and liver-related events, are shown in an online Table (Supplemental Digital Content 1,http://links.lww.com/QAI/A69). Finally, there are likely to be a considerable number of factors associated with non-AIDS events, such as diet, exercise, and alcohol use, which we have not routinely collected and, therefore, we cannot adjust for.

To conclude, non-AIDS events (CV disease, non-AIDS malignancies, end-stage renal disease, liver disease, and pancreatitis) were common in the cART era and were associated with considerable mortality. The increasing burden of other comorbidities highlights the need for both observational studies and clinical trials to collect this information in a standardized way, as has been developed over the years for AIDS, and where necessary, to incorporate such comorbidities into studies considering clinical disease progression and the impact of cART. The risk factor profile for non-AIDS events was diverse with multiple potentially modifiable immunodeficiency and lifestyle-related risk factors. Although there is much evidence in non-HIV-infected persons about the public health impact of modifying such risk factors, evidence on the impact of modifying these factors and the relationship with non-AIDS events in HIV-infected persons is an important but unmet research need.

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APPENDIX I: The EuroSIDA Study Group (National Coordinators)

Argentina: (M. Losso), C. Elias, Hospital JM. Ramos Mejia, Buenos Aires. Austria: (N. Vetter) Pulmologisches Zentrum der Stadt Wien, Vienna; (R. Zangerle) Medical University Innsbruck, Innsbruck. Belarus: (I. Karpov), A. Vassilenko, Belarus State Medical University, Minsk, VM. Mitsura, Gomel State Medical University, Gomel; O. Suetnov, Regional AIDS Centre, Svetlogorsk. Belgium: (N. Clumeck) S. De Wit, B. Poll, Saint-Pierre Hospital, Brussels; R. Colebunders, Institute of Tropical Medicine, Antwerp; (L. Vandekerckhove) University Ziekenhuis Gent, Gent. Bosnia: (V. Hadziosmanovic) Klinicki Centar Univerziteta Sarajevo, Sarajevo. Bulgaria: K. Kostov, Infectious Diseases Hospital, Sofia. Croatia; J. Begovac, University Hospital of Infectious Diseases, Zagreb. Czech Republic: (L. Machala) H. Rozsypal, Faculty Hospital Bulovka, Prague; D. Sedlacek, Charles University Hospital, Plzen. Denmark: (J. Nielsen) G. Kronborg, T. Benfield, M. Larsen, Hvidovre Hospital, Copenhagen; J. Gerstoft, T. Katzenstein, A-B E. Hansen, P. Skinhøj, Rigshospitalet, Copenhagen; C. Pedersen, Odense University Hospital, Odense, L. Oestergaard, Skejby Hospital, Aarhus. Estonia: (K. Zilmer) West-Tallinn Central Hospital, Tallinn, Jelena Smidt, Nakkusosakond Siseklinik, Kohtla-Järve. Finland: (M. Ristola), Helsinki University Central Hospital, Helsinki. France: (C. Katlama) Hôpital de la Pitié-Salpétière, Paris; J-P Viard, Hôpital Necker-Enfants Malades, Paris; P-M Girard, Hospital Saint-Antoine, Paris; JM. Livrozet, Hôpital Edouard Herriot, Lyon; P. Vanhems, University Claude Bernard, Lyon; C. Pradier, Hôpital de l'Archet, Nice; F. Dabis, D. Neau, Unité INSERM, Bordeaux. Germany:(J. Rockstroh) Universitäts Klinik Bonn; R. Schmidt, Medizinische Hochschule Hannover; J. van Lunzen, O. Degen, University Medical Center Hamburg-Eppendorf, Infectious Diseases Unit, Hamburg; HJ. Stellbrink, IPM Study Center, Hamburg; S. Staszewski, JW. Goethe University Hospital, Frankfurt; J. Bogner, Medizinische Poliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne. Greece: (J. Kosmidis) P. Gargalianos, G. Xylomenos, J. Perdios, Athens General Hospital; G. Panos, A. Filandras, E. Karabatsaki, 1st IKA Hospital; H. Sambatakou, Ippokration Genereal Hospital, Athens. Hungary: (D. Banhegyi) Szent Lásló Hospital, Budapest. Ireland: (F. Mulcahy) St. James's Hospital, Dublin. Israel: (I. Yust) D. Turner, M. Burke, Ichilov Hospital, Tel Aviv; S. Pollack, G. Hassoun, Rambam Medical Center, Haifa;S Maayan, Hadassah University Hospital, Jerusalem. Italy: (A. Chiesi) Istituto Superiore di Sanità, Rome; R. Esposito, I. Mazeu, C. Mussini, Università Modena, Modena; C. Arici, Ospedale Riuniti, Bergamo; R. Pristera, Ospedale Generale Regionale, Bolzano; F. Mazzotta, A. Gabbuti, Ospedale S. Maria Annunziata, Firenze; V. Vullo, M. Lichtner, University di Roma la Sapienza, Rome; A. Chirianni, E. Montesarchio, M. Gargiulo, Presidio Ospedaliero AD. Cotugno, Monaldi Hospital, Napoli; G. Antonucci, F. Iacomi, P. Narciso, C. Vlassi, M. Zaccarelli, Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome; A. Lazzarin, R. Finazzi, Ospedale San Raffaele, Milan; M. Galli, A. Ridolfo, Osp. L. Sacco, Milan; A. d'Arminio Monforte, Istituto Di Clinica Malattie Infettive e Tropicale, Milan. Latvia: (B. Rozentale) P. Aldins, Infectology Centre of Latvia, Riga. Lithuania: (S. Chaplinskas) Lithuanian AIDS Centre, Vilnius. Luxembourg: (R. Hemmer), T. Staub, Centre Hospitalier, Luxembourg. Netherlands: (P. Reiss) Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam. Norway: (J. Bruun) A. Maeland, V. Ormaasen, Ullevål Hospital, Oslo. Poland: (B. Knysz) J. Gasiorowski, Medical University, Wroclaw; A. Horban, E. Bakowska, Centrum Diagnostyki i Terapii AIDS, Warsaw; D. Prokopowicz, R. Flisiak, Medical University, Bialystok; A. Boron-Kaczmarska, M. Pynka, Medical Univesity, Szczecin; M. Beniowski, E. Mularska, Osrodek Diagnostyki i Terapii AIDS, Chorzow; H. Trocha, Medical University, Gdansk; (E. Jablonowska) E. Malolepsza, K. Wojcik, Wojewodzki Szpital Specjalistyczny, Lodz. Portugal: (F. Antunes) E. Valadas, Hospital Santa Maria, Lisbon; K. Mansinho, Hospital de Egas Moniz, Lisbon; F. Maltez, Hospital Curry Cabral, Lisbon. Romania: (D. Duiculescu) Spitalul de Boli Infectioase si Tropicale: Dr. Victor Babes, Bucarest. Russia: (A. Rakhmanova), Medical Academy Botkin Hospital, St Petersburg; E. Vinogradova, St Petersburg AIDS Centre, St Peterburg; S. Buzunova, Novgorod Centre for AIDS, Novgorod. Serbia: (D. Jevtovic), The Institute for Infectious and Tropical Diseases, Belgrade. Slovakia: (M. Mokráš) D. Staneková, Dérer Hospital, Bratislava. Slovenia: (J. Tomazic) University Clinical Centre Ljubljana, Ljubljana. Spain: (J. González-Lahoz) V. Soriano, L. Martin-Carbonero, P. Labarga, Hospital Carlos III, Madrid; (S. Moreno) Hospital Ramon y Cajal, Madrid; B. Clotet, A. Jou, R. Paredes, C. Tural, J. Puig, I. Bravo, Hospital Germans Trias i Pujol, Badalona; JM. Gatell, JM. Miró, Hospital Clinic i Provincial, Barcelona; P. Domingo, M. Gutierrez, G. Mateo, MA. Sambeat, Hospital Sant Pau, Barcelona. Sweden: (A. Karlsson), Karolinska University Hospital, Stockholm; PO. Persson, Karolinska University Hospital, Huddinge; L. Flamholc, Malmö University Hospital, Malmö. Switzerland: (B. Ledergerber) R. Weber, University Hospital, Zürich; P. Francioli, M. Cavassini, Centre Hospitalier Universitaire Vaudois, Lausanne; B. Hirschel, E. Boffi, Hospital Cantonal Universitaire de Geneve, Geneve; H. Furrer, Inselspital Bern, Bern; M. Battegay, L. Elzi, University Hospital Basel. Ukraine: (E. Kravchenko) N. Chentsova, Kiev Centre for AIDS, Kiev; (G. Kutsyna) Luhansk AIDS Center, Luhansk; (S. Servitskiy), Odessa Region AIDS Center, Odessa; (S. Antoniak) Kiev; (M. Krasnov) Kharkov State Medical University, Kharkov. United Kingdom: (S. Barton) St. Stephen's Clinic, Chelsea and Westminster Hospital, London; AM. Johnson, D. Mercey, Royal Free and University College London Medical School, London (University College Campus); A. Phillips, MA. Johnson, A. Mocroft, Royal Free and University College Medical School, London (Royal Free Campus); M. Murphy, Medical College of Saint Bartholomew's Hospital, London; J. Weber, G. Scullard, Imperial College School of Medicine at St. Mary's, London; M. Fisher, Royal Sussex County Hospital, Brighton; C. Leen, Western General Hospital, Edinburgh.

Virology group: B. Clotet, R. Paredes(Central Coordinators) plus ad hoc virologists from participating sites in the EuroSIDA Study.

Steering Committee: F. Antunes, B. Clotet, D. Duiculescu, J. Gatell, B. Gazzard, A. Horban, A. Karlsson, C. Katlama, B. Ledergerber (Chair), A. D'Arminio Montforte, A. Phillips, A. Rakhmanova, P. Reiss (Vice-Chair), J. Rockstroh

Coordinating Centre Staff: J. Lundgren (project leader), O. Kirk, A. Mocroft, N. Friis-Møller, A. Cozzi-Lepri, W. Bannister, M. Ellefson, A. Borch, D. Podlekareva, J. Kjær, L. Peters, J. Reekie, J. Kowalska.

Keywords:

AIDS-defining illnesses; CD4; HIV; morbidity; mortality; non-AIDS-defining illnesses

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