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CLINICAL SCIENCE

Where is the greatest impact of uncontrolled HIV infection on AIDS and non-AIDS events in HIV?

Mocroft, Amandaa; Laut, Kamillab; Reiss, Peterc,d; Gatell, Josee; Ormaasen, Vidarf; Cavassini, Matthiasg; Hadziosmanovic, Vesnah; Mansinho, Kamali; Pradier, Christianj; Vasylyev, Martak; Mitsura, Victorl; Vandekerckhove, Linosm; Ostergaard, Larsn; Clarke, Amandao; Degen, Olafp; Mulcahy, Fionaq; Castagna, Antonellar,s; Sthoeger, Zedt; Flamholc, Leou; Sedláček, Daliborv; Mozer-Lisewska, Iwonaw; Lundgren, Jens D.b for the EuroSIDA Study

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doi: 10.1097/QAD.0000000000001684
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Abstract

Introduction

The relative frequency of AIDS, non-AIDS and deaths of persons with HIV has changed significantly since the advent of combination antiretroviral therapy (cART), with the proportion of AIDS and AIDS-related mortality decreasing and the proportion of non-AIDS events increasing [1–3]. The role of immune deficiency and uncontrolled HIV viraemia in both AIDS and non-AIDS events is now well established [4–7], with a near-normal life expectancy in those with well controlled HIV-infection [8–10] and evidence to show that HIV positive (HIV+) persons no longer experience an increased risk of AIDS or death when the CD4+ cell count increases above 500–750 cells/μl [11–13].

As persons with HIV live longer, the role of ageing plays an increasingly important role. Older persons have less ability to reconstitute CD4+ cells [14], possibly due to a decline in thymus function associated with ageing [15,16]. Long-term management of comorbidities in HIV-positive persons, as well as their HIV infection, becomes increasingly important and is now included alongside recommendations for antiretroviral treatment in both United States and European HIV treatment and management guidelines [17,18]. Importantly, there is little known about whether the relative contribution to morbidity and mortality within age groups differs for those with controlled or uncontrolled HIV, which might provide an insight into ageing and HIV pathogenesis.

The underlying incidence of AIDS and non-AIDS events varies considerably across regions of Europe [19], likely due to regional differences in pathogens as well as clinical management and access to care, but whether there are important differences across regions comparing those with controlled or uncontrolled HIV infection is unknown. Equally, the difference in risk of AIDS and non-AIDS for those with controlled or uncontrolled HIV might have widened or narrowed over calendar time, given the significant improvements in cART and management of HIV seen over the past decades.

We hypothesized that there would be differences in AIDS and non-AIDS events between those at low and high risk according to age, region of Europe and calendar year of follow-up. This would address the relative importance of biological ageing versus controlled HIV when considering the differences within age groups, and the role of controlled HIV and clinical management when considering differences within regions of Europe or changes over calendar time. To our knowledge, this is a novel way of looking at AIDS and non-AIDS events. The aims of this study were therefore to identify whether risk of HIV disease progression comparing controlled and uncontrolled HIV was different across age groups, year of follow-up or European regions of care between 2001 and 2016.

Method

Patients

EuroSIDA was initiated in 1994 and is a prospective study of 23 071 HIV-1-infected persons at 116 centres across Europe, Israel and Argentina; further details are available at http://www.cphiv.dk/Ongoing-Studies/EuroSIDA/About. To date, 10 cohorts of HIV+ individuals have been recruited. Data are collected prospectively at clinical sites and is extracted and sent to the coordinating centre at 12 monthly intervals. For cohorts I–III, eligible persons were those who had had a CD4+ cell count below 500 cells/μl at recruitment or during the previous 4 months. The CD4+ cell count restriction was removed for cohorts IV onwards. Cohort 10 only includes persons coinfected with hepatitis C and HIV. At recruitment, in addition to demographic and clinical information, a complete antiretroviral treatment history is obtained, together with the most recent CD4+ cell count and plasma HIV-RNA measurements. At each follow-up visit, details on all CD4+ cell 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. AIDS events were diagnosed using the clinical definition from the Centers for Disease Control [20]. Cardiovascular events, non-AIDS malignancies, end-stage liver disease and end-stage renal disease were included as non-AIDS events [21] and fatal events were classified as AIDS or non-AIDS [22]. Participating countries were grouped into Southern Europe (Greece, Israel, Italy, Portugal, Spain and Argentina), Western Europe (Austria, Belgium, France, Germany, Luxembourg and Switzerland), Northern Europe (Denmark, Finland, Iceland, Ireland, The Netherlands, Norway, Sweden and United Kingdom), Central Eastern Europe (Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Hungary, Poland, Romania, Serbia, Slovakia and Slovenia) and Eastern Europe (Belarus, Estonia, Georgia, Latvia, Lithuania, Russian Federation and Ukraine).

Statistical methods

As prospective and quality assured data on non-AIDS events began in 2001, individuals were included from the latest of recruitment to the study or 1 January 2001 (study baseline). Persons were followed to last clinic visit or death (median June 2016 for persons included in these analyses). Individuals without prospective follow-up after baseline were excluded, as were those without a CD4+ cell count or viral load in the 6-month prior to baseline. Each person could experience more than one event, but not repeated events of the same type. For example, a person diagnosed with non-Hodgkin lymphoma on two separate occasions would only contribute one AIDS-defining event to analyses, whereas a person defined with breast cancer and liver cancer would contribute with two events.

cART was defined as at least three antiretrovirals from any class. Risk of clinical progression was stratified into three groups defined a priori; high risk (viral load ≥10 000 copies/ml and CD4+ cell count ≤350 cells/μl), low risk (viral load <50 copies/ml and CD4+ cell count >500 cells/μl) and intermediate risk (all other combinations of CD4+ cell counts and viral loads). Person-years of follow-up (PYFU) and clinical events were allocated to one of these three strata and allowed to vary over time; thus, PYFU were allocated according to the most recent CD4+ cell count and viral load measured, using the last value carried forward. The median time between CD4+ cell counts and viral loads among patients included was 3 months [interquartile range (IQR) 2–5 months], with 97 and 96% of CD4+ cell counts and viral loads, respectively, measured with less than 12 months apart.

The incidence of AIDS and non-AIDS events within these strata were calculated and Poisson regression was used to determine the adjusted incidence rate ratios (aIRRs) of those at high risk compared with those at low risk, after adjustment for confounding variables. Generalized linear models were adjusted for persons experiencing more than one event. A priori our primary hypothesis was that there were important differences between those at high, intermediate and low risk of clinical disease progression within different periods of calendar year of follow-up, age and European region of care; that is, there was a significant interaction between HIV risk group (high, intermediate and low) and age, calendar periods or European region of care. In addition to the primary variables of interest (risk of clinical progression, age, European region of care and calendar year of follow-up), models were adjusted for sex, CD4+ nadir, HIV exposure group, ethnic origin, prior AIDS and non-AIDS events and date of enrolment to EuroSIDA as fixed covariates at baseline. Hepatitis B and C status, AIDS events, non-AIDS events, diabetes*, hypertension*, smoking status* and anaemia* were included as time-updated covariates (*refer to [21] for definitions). Models were additionally adjusted for non-AIDS events when AIDS was the primary endpoint and AIDS events when non-AIDS was the primary endpoint, both as time-updated covariates.

All analyses were performed using SAS version 9.4 (Statistical Analysis Software; SAS Institute, Cary, North Carolina, USA).

Results

Characteristics and crude incidence rates of clinical progression

A total of 16 839 persons were included in analyses, summarized in Table 1. At baseline, which was significantly later for those at low risk, 3990 (23.7%) were at low risk of disease progression, 11 091 (65.9%) at intermediate risk and 1758 (10.4%) at high risk according to the predefined risk strata. Median age at baseline was 40 years (IQR 34–48), and median nadir CD4+ cell count was 250 cells/μl (IQR 123–403 cells/μl). The majority of individuals were men (n = 12 468; 74.0%), infected with HIV through homosexual exposure (n = 6482; 38.5%) and of white ethnic origin (n = 14 587; 86.6%). Each of the European regions of care was well represented, although the number of persons from Eastern Europe at low risk of disease progression was low.

Table 1
Table 1:
Characteristics of population, stratified by HIV progression risk at study baseline.

The median follow-up was 7.9 years (IQR 3.2–13.5 years). During 136 688 PYFU, there were 1693 AIDS events and 3282 non-AIDS events, giving crude incidence rates of 12.4 [95% confidence interval (CI) 11.8–13.0/1000 PYFU] and 24.0 (95% CI 23.2–24.8/1000 PYFU), respectively, as summarized in Table 2. Among the non-AIDS events, deaths from non-AIDS causes was the most frequent event (1323, 40.3%), followed by non-AIDS-defining malignancy (840, 25.6%), cardiovascular disease (814, 24.8%), end stage liver disease (243, 7.4%) and end stage renal disease (62, 1.9%). During 2001–2004, 24.9% of the follow-up was among those at low-risk increasing to over 55.8% during 2013 or later. The proportion of follow-up at high-risk decreased from 9.4% in 2001–2004 to 2.0% during 2013 or later. As expected, there was a strong gradient of increasing incidence as you moved from low to high risk. The incidence of AIDS increased from 2.9/1000 PYFU in those at low risk to 104.7/10 000 PYFU in those at high risk, a 36-fold difference. The incidence of non-AIDS events increased from 16.1/1000 PYFU in those at low risk to 49.5/10 000 PYFU in those at high risk, a three-fold difference. Table 2 also shows the considerable differences in the incidence of AIDS or non-AIDS events between those at high, intermediate and low risk as well as within age groups, calendar year of follow-up or European region of care.

Table 2
Table 2:
Crude incidence rates (per 1000 person-years of follow-up) of AIDS and non-AIDS events within HIV risk strata and age, calendar year of follow-up and European region of care.

Differences between those at high and low risk of HIV disease progression across age groups

Table 2 shows the crude incidence rates of AIDS and non-AIDS events, which suggest there may be important differences within age groups when comparing those at high, intermediate and low risk of both AIDS and non-AIDS events. After adjustment, persons aged 30 years or less and at high risk at had a six-fold increased incidence (aIRR 6.13; 95% CI 1.87–20.08) of a non-AIDS event compared with those at low risk, whereas older persons has a two-to-three-fold increased incidence (Fig. 1a). The difference in risk of a non-AIDS event between those at high, intermediate and low HIV risk significantly decreased as persons aged (Fig. 1a, P < 0.0001, test for interaction), driven largely by the differences in the youngest age group. There were no differences comparing high-risk, intermediate-risk and low-risk groups across age groups for AIDS events (P = 0.57, test for interaction, Fig. 1b). For example, after adjustment, persons aged 30 years or less and at high risk of AIDS had a 20-fold increased incidence of AIDS events (aIRR 20.51; 95% CI 7.10–59.27) compared with those at low risk, whereas those aged more than 50 had a 23-fold increase (aIRR 95% CI 16.87–32.13).

Fig. 1
Fig. 1:
Relationship between age, clinical risk strata and non-AIDS and AIDS events.(a) Relationship between clinical risk strata, age and non-AIDS events. b) Relationship between clinical risk strata, age and AIDS events. In addition to the primary variables of interest (high, intermediate and low risk of clinical progression, age, European region of care and calendar year of follow-up), models were adjusted for sex, CD4 nadir, HIV exposure group, ethnic origin, prior AIDS and non-AIDS events and date of enrolment to EuroSIDA as fixed covariates at baseline. Hepatitis B and C status, AIDS events, non-AIDS events, diabetes*, hypertension*, smoking status* and anaemia* were included as time-updated covariates (*refer to [21] for definitions). Models were additionally adjusted for non-AIDS events when AIDS was the primary endpoint and AIDS events when non-AIDS was the primary endpoint, both as time-updated covariates.

Differences between those at high and low risk of HIV disease progression across European region of care

After adjustment, there were no significant differences between those at high, intermediate and low risk of AIDS events when comparing across European region of care (P = 0.090, test for interaction), as shown in Table 3. In all regions, compared with those at low risk those at intermediate risk had approximately a three-fold increased incidence of AIDS after adjustment, increasing to around a 15–20-fold increase for those at highest risk. Although the difference between those at high, intermediate and low risk of AIDS events appeared slightly different in Eastern Europe, the CIs were wide and the test for interaction was not statistically significant (P = 0.090).

Table 3
Table 3:
Adjusteda incidence rate ratio of AIDS and non-AIDS events, stratified by European region of care.

In contrast, we found a difference for non-AIDS events (Table 3) between those at high, intermediate and low risk across regions (P = 0.0029, test for interaction). This difference was largely driven by Eastern Europe. The differences between the HIV risk strata (high, intermediate and low) were two-to-four-fold in all regions except Eastern Europe where those at intermediate and highest risk of non-AIDS events had between a five-fold and 13-fold increased incidence of non-AIDS events after adjustment, compared with those at low risk.

Differences between those at high and low risk of HIV disease progression and calendar year of follow-up

The differences between those at high, intermediate and low risk in different calendar periods of follow-up are shown in Fig. 2a (AIDS) and Fig. 2b (non-AIDS). For non-AIDS events, the difference between those at high and low HIV risk of a non-AIDS event increased from a two-to-three-fold difference between 2001 and 2012 to a five-fold difference in 2013 or larger (P < 0.0001, test for interaction). For AIDS events, there was a similar pattern, with the difference between those at low and high risk being 17-fold in 2001–2004 and 25-fold in 2013 or later, although the test for interaction was marginally statistically significant (P = 0.060).

Fig. 2
Fig. 2:
Relationship between calendar year of follow-up, clinical risk strata and non-AIDS and AIDS events.(a) Relationship between clinical risk strata, calendar year of follow-up and non-AIDS events. (b) Relationship between clinical risk strata, calendar year of follow-up and AIDS events. In addition to the primary variables of interest (high, intermediate and low risk of clinical progression, age, European region of care and calendar year of follow-up), models were adjusted for sex, CD4 nadir, HIV exposure group, ethnic origin, prior AIDS and non-AIDS events and date of enrolment to EuroSIDA as fixed covariates at baseline. Hepatitis B and C status, AIDS events, non-AIDS events, diabetes*, hypertension*, smoking status* and anaemia* were included as time-updated covariates (*refer to [21] for definitions). Models were additionally adjusted for non-AIDS events when AIDS was the primary endpoint and AIDS events when non-AIDS was the primary endpoint, both as time-updated covariates.

Sensitivity analyses

We repeated analyses considering fatal and nonfatal clinical events separately, and redefining the risk strata using a viral load detection limit of 500 copies/ml to classify those at lowest risk, that is viral load less than 500 copies/ml and CD4+ cell count more than 500 cells/μl, with consistent results. The results were also similar if the CD4+ cell count and viral load value used to define the HIV risk strata were carried forward for a maximum period of 1 year.

Discussion

Although it is well established that there are differences in clinical events between those at high, intermediate and low risk, to our knowledge, this is one of the first studies to look whether this difference varies within age groups, European region of care or calendar period of follow-up.

Controlled HIV infection, biological ageing and clinical disease

We found a large difference in the incidence of non-AIDS events between those at high, intermediate and low risk those aged 30 years or less, and this difference was consistently lower among older persons. Young persons aged 30 years or less, with or without HIV, are at a generally low risk of comorbidities such as malignancies and cardiovascular disease. HIV infection itself, and specifically whether it is controlled or not, likely plays a greater role in the development of comorbidities. The difference between those at high, intermediate and low risk of non-AIDS events likely changes as persons age primarily due to non-HIV related risk factors associated with ageing itself, such that the normal ageing process is the dominating factor. Infection with HIV may accelerate ageing, and comorbidities occur at an earlier age than seen in HIV-negative persons [23,24]. Contributing factors include immune activation, immune dysfunction and inflammation, as well as exposure to cART [25–27]. Conversely, older persons are at a greater underlying risk of comorbidities, and as a consequence control of HIV infection may have less impact on the risk of developing non-AIDS events and other risk factors such as smoking, alcohol use, lifestyle and diet may have a greater impact.

The difference between those at high, intermediate or low risk of AIDS events was similar in all age groups, with a large increase in incidence moving from uncontrolled to controlled HIV, regardless of age. This demonstrates that AIDS events are closely linked to uncontrolled HIV and exposure to the pathogens causing AIDS-defining events rather than the age of the person. Our findings highlight the importance of appropriate HIV control for reducing the incidence of AIDS and that persons with uncontrolled HIV are at a high risk of an AIDS event, regardless of age.

Controlled HIV infection, European region of follow-up and clinical disease

Any differences between those with uncontrolled and controlled HIV and risk of AIDS or non-AIDS events in different European regions of care can most likely be attributed to quality of care, both for HIV and other comorbidities. We found important regional variations in non-AIDS events, with the biggest difference between those at low, intermediate and high risk in Eastern Europe, although the wide CIs should be noted due to comparatively shorter follow-up, and the smallest differences in Western and Northern Europe, but no significant differences for AIDS events.

These differences in non-AIDS events likely reflect differences in approach to clinical management of HIV [28]. In regions with good clinical management, adequate screening programmes, resources for managing HIV and comorbidities and with a good health infrastructure, you would expect to see smaller differences in the risk of non-AIDS events when comparing those with uncontrolled and controlled HIV. There are well recognized differences in both HIV and non-HIV-associated mortality and morbidity across regions of Europe [19,29], and these differences are likely to impact on the risk of non-AIDS events in those with uncontrolled and controlled HIV differently. Differences in health policies, quality of care and patterns of health in those from different socioeconomic groups vary across regions of Europe. For example, in Western Europe (South, West and North combined in these analyses) smoking, lung cancer and cardiovascular disease is decreasing [30] but changes have been slower in Eastern Europe [29]. There is a high proportion of persons from Eastern Europe infected with HIV through intravenous drug use [31], with a high prevalence of multidrug resistant tuberculosis [32] which may reflect socioeconomic circumstances or access to care which will also impact on the development of non-AIDS events. Management of HIV-positive persons in Eastern Europe requires a multidisciplinary and coordinated approach to retain individuals in care, and to maintain adherence to antiretrovirals in a setting where HIV+ persons may have less engagement with healthcare settings [33].

The fact that differences in AIDS events between those at low, intermediate and high risk was similar in different European regions of care highlights again that the development of AIDS is more strongly linked to uncontrolled HIV and that persons with uncontrolled HIV are at a high risk of AIDS events regardless of which region of Europe they are followed up in.

Controlled HIV infection, calendar time and clinical disease

The difference between those with at high, intermediate and low risk of non-AIDS events was greatest in 2013 or later. A similar pattern was seen for AIDS events, but the test for interaction was marginally statistically significant (P = 0.060). There has been an increase over time in durability of cART, both in terms of sustained virologic suppression and in efficacy and tolerability of newer antiretrovirals [34–36]. This likely means that those under follow-up between 2013 and 2016 at low risk of non-AIDS, with low viraemia and high CD4+ cell count, have a lower viral load and are better monitored for HIV disease and comorbidities, as focus has changed to monitoring for comorbidities and management of HIV as a chronic disease [17,18]. Those at high risk between 2013 and 2016 with high viral loads and lower CD4+ cell counts, likely have quite different characteristics to those at high risk during earlier years. They may be more likely to be individuals with a complex medical history, with adherence problems, and potentially on salvage regimens.

It is important to note some limitations. EuroSIDA has recruited 10 cohorts of HIV-positive individuals, and it is likely those recruited later are at lower risk of disease progression, partly shown by the later baseline date of those at low risk. Centres participating in EuroSIDA are not necessarily representative of the European region as a whole, and are centres of excellence, and we may be underestimating the differences between those with uncontrolled and controlled HIV for both AIDS and non-AIDS events. Our analyses are based on studying whether the relationship between controlled and uncontrolled HIV and factors of interest (age, region and calendar year of follow-up) differ, that is whether there is a significant interaction, rather than how uncontrolled or controlled HIV affects the risk of AIDS or non-AIDS events. Interaction analyses such as these are typically underpowered, which is why a large study such as EuroSIDA is needed for adequately powered analyses, but should also be planned a priori, before analyses begin, as in the present analysis.

In conclusion, for the first time, our results highlight that as person's age, factors other than optimal control of HIV become more important for predicting non-AIDS events, demonstrating the role of biological ageing, whereas the development of AIDS is much more dependent on uncontrolled HIV in all age groups. The differences in non-AIDS events for those at low, intermediate or high risk in different European regions of care likely reflect differences in clinical management as well as underlying socioeconomic circumstances. The lack of differences between those at high, intermediate and low risk of AIDS in different European regions highlights the essential role of controlling HIV infection and starting and maintaining individuals on an effective treatment regimen. The increasing difference in non-AIDS events between those at high, intermediate and low risk over time likely reflects better care, monitoring and management of both HIV and comorbidities for those with well controlled HIV and that continued improvements in management and HIV control are needed for those at highest risk.

Acknowledgements

EuroSIDA was supported by the European Union's Seventh Framework Programme for research, technological development and demonstration under EuroCoord grant agreement no. 260694. Current support includes unrestricted grants by Bristol-Myers Squibb, Gilead, GlaxoSmithKline LLC, Janssen R&D, Merck and Co. Inc., Pfizer Inc. The participation of centres from Switzerland was supported by The Swiss National Science Foundation (grant no. 108787). The study is also supported by a grant (grant no. DNRF126) from the Danish National Research Foundation.

The EuroSIDA Study Group

The multicentre study group, EuroSIDA (national coordinators in parenthesis).

Argentina: (M. Losso), M. Kundro, Hospital JM Ramos Mejia, Buenos Aires.

Austria: (B. Schmied), 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; D. Paduto, Regional AIDS Centre, Svetlogorsk.

Belgium: (N. Clumeck), S. De Wit, M. Delforge, Saint-Pierre Hospital, Brussels; E. Florence, Institute of Tropical Medicine, Antwerp; L. Vandekerckhove, University Ziekenhuis Gent, Gent.

Bosnia and Herzegovina: (V. Hadziosmanovic), Klinicki Centar Univerziteta Sarajevo, Sarajevo.

Croatia: (J. Begovac), University Hospital of Infectious Diseases, Zagreb.

Czech Republic: (L. Machala), D. Jilich, Faculty Hospital Bulovka, Prague; D. Sedlacek, Charles University Hospital, Plzen.

Denmark: G. Kronborg, T. Benfield, Hvidovre Hospital, Copenhagen; J. Gerstoft, T. Katzenstein, Rigshospitalet, Copenhagen; N.F. Møller, C. Pedersen, Odense University Hospital, Odense; L. Ostergaard, Skejby Hospital, Aarhus, L. Wiese, Roskilde Hospital, Roskilde; L.N. Nielsen, Hillerod Hospital, Hillerod.

Estonia: (K. Zilmer), West-Tallinn Central Hospital, Tallinn; Jelena Smidt, Nakkusosakond Siseklinik, Kohtla-Järve.

Finland: (M. Ristola), I. Aho, Helsinki University Central Hospital, Helsinki.

France: (J.-P. Viard), Hôtel-Dieu, Paris; P.-M. Girard, Hospital Saint-Antoine, Paris; C. Pradier, E. Fontas, Hôpital de l’Archet, Nice; C. Duvivier, Hôpital Necker-Enfants Malades, Paris.

Germany: (J. Rockstroh), Universitäts Klinik Bonn; G. Behrens, Medizinische Hochschule Hannover; O. Degen, University Medical Center Hamburg-Eppendorf, Infectious Diseases Unit, Hamburg; H.J. Stellbrink, IPM Study Center, Hamburg; C. Stefan, J.W. Goethe University Hospital, Frankfurt; J. Bogner, Medizinische Poliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne.

Georgia: (N. Chkhartishvili) Infectious Diseases, AIDS & Clinical Immunology Research Center, Tbilisi.

Greece: (P. Gargalianos), G. Xylomenos, K. Armenis, Athens General Hospital ‘G Gennimatas’; H. Sambatakou, Ippokration General Hospital, Athens.

Hungary: (J. Szlávik), Szent Lásló Hospital, Budapest.

Iceland: (M. Gottfredsson), Landspitali University Hospital, Reykjavik.

Ireland: (F. Mulcahy), St. James's Hospital, Dublin.

Israel: (I. Yust), D. Turner, M. Burke, Ichilov Hospital, Tel Aviv; E. Shahar, G. Hassoun, Rambam Medical Center, Haifa; H. Elinav, M. Haouzi, Hadassah University Hospital, Jerusalem; D. Elbirt, Z.M. Sthoeger, AIDS Center (Neve Or), Jerusalem.

Italy: (A. D’Arminio Monforte), Istituto Di Clinica Malattie Infettive e Tropicale, Milan; R. Esposito, I. Mazeu, C. Mussini, Università Modena, Modena; F. Mazzotta, A. Gabbuti, Ospedale S. Maria Annunziata, Firenze; V. Vullo, M. Lichtner, University di Roma la Sapienza, Rome; M. Zaccarelli, A. Antinori, R. Acinapura, M. Plazzi, Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome; A. Lazzarin, A. Castagna, N. Gianotti, Ospedale San Raffaele, Milan; M. Galli, A. Ridolfo, Osp. L. Sacco, Milan.

Latvia: (B. Rozentale), Infectology Centre of Latvia, Riga.

Lithuania: (V. Uzdaviniene) Vilnius University Hospital Santaros Klinikos, Vilnius; R. Matulionyte, Centro poliklinika, Vilnius, Vilnius University Hospital Santaros Klinikos, Vilnius.

Luxembourg: (T. Staub), R. Hemmer, Centre Hospitalier, Luxembourg.

The Netherlands: (P. Reiss), Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam.

Norway: (D.H. Reikvam), A. Maeland, J Bruun, Ullevål Hospital, Oslo.

Poland: (B. Knysz), J. Gasiorowski, M. Inglot, Medical University, Wroclaw; A. Horban, E. Bakowska, Centrum Diagnostyki i Terapii AIDS, Warsaw; R. Flisiak, A. Grzeszczuk, Medical University, Bialystok; M. Parczewski, K. Maciejewska, B. Aksak-Was, Medical Univesity, Szczecin; M. Beniowski, E. Mularska, Osrodek Diagnostyki i Terapii AIDS, Chorzow; T. Smiatacz, M. Gensing, Medical University, Gdansk; E. Jablonowska, E. Malolepsza, K. Wojcik, Wojewodzki Szpital Specjalistyczny, Lodz; I. Mozer-Lisewska, Poznan University of Medical Sciences, Poznan.

Portugal: (L. Caldeira), Hospital Santa Maria, Lisbon; K. Mansinho, Hospital de Egas Moniz, Lisbon; F. Maltez, Hospital Curry Cabral, Lisbon.

Romania: (R. Radoi), C. Oprea, Spitalul Clinic de Boli Infectioase si Tropicale: Dr V. Babes, Bucuresti.

Russia: (A. Panteleev), O. Panteleev, St Petersburg AIDS Centre, St Peterburg; A. Yakovlev, Medical Academy Botkin Hospital, St Petersburg; T. Trofimora, Novgorod Centre for AIDS, Novgorod, I. Khromova, Centre for HIV/AIDS & and Infectious Diseases, Kaliningrad; E. Kuzovatova, Nizhny Novgorod Scientific and Research Institute of Epidemiology and Microbiology named after Academician I.N. Blokhina, Nizhny Novogrod; E. Borodulina, E. Vdoushkina, Samara State Medical University, Samara.

Serbia: (D. Jevtovic), The Institute for Infectious and Tropical Diseases, Belgrade.

Slovenia: (J. Tomazic), University Clinical Centre Ljubljana, Ljubljana.

Spain: (J.M. Gatell), J.M. Miró, Hospital Clinic Universitari de Barcelona, Barcelona; S. Moreno, J.M. Rodriguez, Hospital Ramon y Cajal, Madrid; B. Clotet, A. Jou, R. Paredes, C. Tural, J. Puig, I. Bravo, Hospital Germans Trias i Pujol, Badalona; P. Domingo, M. Gutierrez, G. Mateo, M.A. Sambeat, Hospital Sant Pau, Barcelona; J.M. Laporte, Hospital Universitario de Alava, Vitoria-Gasteiz.

Sweden: (K. Falconer), A. Thalme, A. Sonnerborg, Karolinska University Hospital, Stockholm; A. Blaxhult, Venhälsan-Sodersjukhuset, Stockholm; L. Flamholc, Malmö University Hospital, Malmö.

Switzerland: (A. Scherrer), R. Weber, University Hospital Zurich; M. Cavassini, University Hospital Lausanne; A. Calmy, University Hospital Geneva; H. Furrer, University Hospital Bern; M. Battegay, University Hospital Basel; P. Schmid, Cantonal Hospital St. Gallen.

Ukraine: A. Kuznetsova, Kharkov State Medical University, Kharkov; G. Kyselyova, Crimean Republican AIDS centre, Simferopol; M. Sluzhynska, Lviv Regional HIV/AIDS Prevention and Control CTR, Lviv.

United Kingdom: (B. Gazzard), St. Stephen's Clinic, Chelsea and Westminster Hospital, London; A.M. Johnson, E. Simons, S. Edwards, Mortimer Market Centre, London; A. Phillips, M.A. Johnson, A. Mocroft, Royal Free and University College Medical School, London (Royal Free Campus); C. Orkin, Royal London Hospital, London; J. Weber, G. Scullard, Imperial College School of Medicine at St. Mary's, London; A. Clarke, Royal Sussex County Hospital, Brighton; C. Leen, Western General Hospital, Edinburgh.

The following centres have previously contributed data to EuroSIDA: Infectious Diseases Hospital, Sofia, Bulgaria Hôpital de la Croix Rousse, Lyon, France; Hôpital de la Pitié-Salpétière, Paris, France; Unité INSERM, Bordeaux, France; Hôpital Edouard Herriot, Lyon, France; Bernhard Nocht Institut für Tropenmedizin, Hamburg, Germany; 1st I.K.A Hospital of Athens, Athens, Greece; Ospedale Riuniti, Divisione Malattie Infettive, Bergamo, Italy; Ospedale di Bolzano, Divisione Malattie Infettive, Bolzano, Italy; Ospedale Cotugno, III Divisione Malattie Infettive, Napoli, Italy; Dérer Hospital, Bratislava, Slovakia Hospital Carlos III, Departamento de Enfermedades Infecciosas, Madrid, Spain; Kiev Centre for AIDS, Kiev, Ukraine Luhansk State Medical University, Luhansk, Ukraine; Odessa Region AIDS Center, Odessa, Ukraine.

EuroSIDA Steering Committee

Steering Committee: J. Gatell, B. Gazzard, A. Horban, I. Karpov, M. Losso, A. d’Arminio Monforte, C. Pedersen, M. Ristola, A. Phillips, P. Reiss, J. Lundgren, J. Rockstroh, A. Scherrer, Aho I., Rasmussen L., V.S. Johansson, Wandeler G., Pradier C., Chkhartishvili N., Matulionyte R., Oprea C., Kowalska J., Begovac J., Miro J., Guaraldi G., Paredes R.

Chair: J. Rockstroh

Study Co-leads: A. Mocroft, O. Kirk.

Conflicts of interest

There are no conflicts of interest.

References

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* Study participants are listed in the appendix.

Keywords:

AIDS; incidence; non-AIDS; risk of HIV disease progression

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