CD4 cell count and viral load-specific rates of AIDS, non-AIDS and deaths according to current antiretroviral use
Mocroft, Amandaa; Phillips, Andrew N.a; Gatell, Joseb; Horban, Andrejc; Ledergerber, Brunod; Zilmer, Kaie; Jevtovic, Djordjef; Maltez, Fernandog; Podlekareva, Dariah; Lundgren, Jens D.h,i; for The EuroSIDA study in EuroCOORD
aHIV Epidemiology and Biostatistics group, Research Department of Infection and Population Health, University College London, London, UK
bHospital Clinic i Provincial, Barcelona, Spain
cCentrum Diagnostyki i Terapii AIDS, Warsaw, Poland
dUniversity Hospital Zürich, University of Zurich, Zurich, Switzerland
eWest-Tallinn Central Hospital, Tallinn, Estonia
fThe Belgrade University School of Medicine Hospital for Infectious and Tropical Diseases, Belgrade, Serbia
gHospital Curry Cabral, Lisbon, Portugal
hCopenhagen HIV Program, University of Copenhagen
iDepartment of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Denmark.
*Members of the steering committee are shown in appendix.
Correspondence to Professor Amanda Mocroft, Department of Infection and Population Health, University College London, Rowland Hill St., London, NW3 2PF, UK. Tel: +44 0 2078302239; fax: +44 0 2077941224; e-mail: firstname.lastname@example.org
Received 28 August, 2012
Revised 30 October, 2012
Accepted 16 November, 2012
Background: CD4 cell count and viral loads are used in clinical trials as surrogate endpoints for assessing efficacy of newly available antiretrovirals. If antiretrovirals act through other pathways or increase the risk of disease this would not be identified prior to licensing. The aim of this study was to investigate the CD4 cell count and viral load-specific rates of fatal and nonfatal AIDS and non-AIDS events according to current antiretrovirals.
Methods: Poisson regression was used to compare overall events (fatal or nonfatal AIDS, non-AIDS or death), AIDS events (fatal and nonfatal) or non-AIDS events (fatal or nonfatal) for specific nucleoside pairs and third drugs used with more than 1000 person-years of follow-up (PYFU) after 1 January 2001.
Results: Nine thousand, eight hundred and one patients contributed 42372.5 PYFU, during which 1203 (437 AIDS and 766 non-AIDS) events occurred. After adjustment, there was weak evidence of a difference in the overall events rates between nucleoside pairs (global P-value = 0.084), and third drugs (global P-value = 0.031). As compared to zidovudine/lamivudine, patients taking abacavir/lamivudine [adjusted incidence rate ratio (aIRR) 1.22; 95% CI 0.99–1.49] and abacavir and one other nucleoside [aIRR 1.51; 95% CI 1.14–2.02] had an increased incidence of overall events. Comparing the third drugs, those taking unboosted atazanavir had an increased incidence of overall events compared with those taking efavirenz (aIRR 1.46; 95% CI 1.09–1.95).
Conclusion: There was little evidence of substantial differences between antiretrovirals in the incidence of clinical disease for a given CD4 cell count or viral load, suggesting there are unlikely to be major unidentified adverse effects of specific antiretrovirals.
All antiretrovirals approved for marketing since 1997 have been licensed for use on the basis of changes in CD4 cell counts and HIV-RNA viral load . There are no clinical trials demonstrating the clinical superiority of one regimen over another, instead, licensing bodies rely on the assumption that antiretrovirals act through CD4 cell count and viral load and no other pathways, and that changes in these surrogate markers will ultimately translate into clinical benefits [2–4]. Differences in other factors, such as longer term toxicities, an effect on comorbidities, or differences in drug resistance could lead to a clinical benefit of one antiretroviral compared with another [5–7]. In 2005, a EuroSIDA study considered the risk of AIDS and death for given CD4 cell counts and viral loads related to specific antiretroviral regimens . The study found that the AIDS/death rates were similar regardless of the combination antiretroviral therapy (cART) regimen being taken, and focused both on AIDS and death and on older antiretrovirals, such as indinavir and efavirenz, together with the older nucleoside combinations, such as zidovudine and lamivudine. Over the last 5 years, the use of antiretrovirals, such as lopinavir, atazanavir, tenofovir, and emtricitabine has exponentially increased, but there is no evidence to date regarding a comparison of the clinical event rates for a given CD4 cell count or viral load in people taking these antiretrovirals. The assumption from regulatory authorities is that changes in surrogate markers, evidence on which the drugs are licensed, will translate into a similar clinical benefit regardless of which regimen is in use. In addition, the risk of non-AIDS events have been shown to increase with decreasing CD4 cell count and increasing viral load [9–12], albeit not as markedly as seen for AIDS, and they form an increasing burden of mortality and morbidity [13,14]. The relationship between specific antiretrovirals and non-AIDS events for given CD4 cell counts and viral loads has not yet been reported.
In order to assess whether the link between surrogate markers and clinical events holds for different regimens and outcomes, this study aimed to investigate the incidence of fatal and nonfatal AIDS and non-AIDS events across current CD4 cell count and viral load strata in patients taking specific nucleoside pairs together with a third drug.
Patients and methods
The EuroSIDA study is a prospective, observational cohort of 16 597 HIV-1 infected patients in 102 centres across 33 European countries, Israel and Argentina. The study has been described in detail previously . In brief, patients were enrolled into eight cohorts from May 1994 onwards. Information is collected on a standardized data collection form every 6 months, including all CD4 cell counts and viral loads measured since the last follow-up and starting and stopping dates of all antiretrovirals. Dates of diagnosis of all clinical AIDS-defining illnesses are recorded using the 1993 clinical definition of AIDS from the Centers for Disease Control , as well as all deaths, with cause of death determined by the Coding Causes of Death in HIV (CoDe) protocol and by applying a standardized algorithm [17,18]. Non-AIDS events were selected for inclusion in this study based on previous research, and included non-AIDS defining malignancies, grade III/IV hepatic encephalopathy, pancreatitis, cardiovascular events (including myocardial infarction, stroke, angioplasty, coronary artery bypass and carotid endarterectomy) and renal disease . To ensure correct patient selection and to verify that accurate data is supplied, members of the coordinating office visit all centres to check the information provided against case-notes for all patients with clinical events and 10% randomly selected patients per year.
Patients contributed to the analyses during periods of time in which they were on a specific cART regimen containing exactly two nucleosides (categorized as zidovudine/lamivudine, stavudine/lamivudine, tenofovir/emtricitabine, tenofovir plus one other (excluding emtricitibine), abacavir/lamivudine or abacavir and one other (excluding lamivudine) together with a ‘third’ drug [abacavir (i.e. a triple nucleoside containing regimen in which the patient was not taking a nucleoside pair including abacavir], nevirapine, efavirenz, indinavir, nelfinavir, atazanavir, or (ritonavir boosted) lopinavir, amprenavir, atazanavir or saquinavir. These antiretrovirals were included according to the a priori decision to only include nucleoside pairs or third drugs with more than 1000 person-years of follow-up (PYFU); older regimens, such as triple nucleoside regimens or indinavir were included for comparative purposes. PYFU were excluded wherein patients were not on one of these specific combinations, or according to the additional criteria below.
PYFU, fatal and nonfatal AIDS, non-AIDS and deaths were calculated for specific categories of the current (most recently measured) CD4 cell count and viral load, stratified according to the antiretrovirals currently used. Recurrences of the same events were excluded (e.g. Kaposi's sarcoma followed by Kaposi's sarcoma) but patients could contribute multiple AIDS or non-AIDS events. Events and PYFU were allocated according to the current CD4 cell count, viral load and cART regimen; thus in those with events the CD4 cell count, viral load and cART regimen immediately before the event were used to categorize patients. Baseline was defined as the first time after 1 January 2001, when patients were on an eligible regimen; this date was used as non-AIDS events have been routinely collected and monitored since this time in EuroSIDA. The median date of last follow-up was April 2011.
Poisson regression, using generalized estimating equations was used to ensure robust standard errors accounting for the clustering of multiple events within patients to compare overall events (AIDS, non-AIDS or death), AIDS events (fatal and nonfatal) or non-AIDS events (fatal or nonfatal) for specific nucleoside pairs and third drugs. The reference categories were chosen a priori as the category with the greatest PYFU, and global P-values were used to compare overall differences between nucleoside pairs or third drugs. Multivariate models were adjusted for age, sex, race, HIV-exposure group, region of Europe, prior AIDS or non-AIDS events, baseline date, time since first starting cART, and CD4 cell count nadir. Hepatitis B and C status, time since starting current third drug (stratified as less than 6 months or more, after examination of the data), CD4 cell count, viral load, anaemia (≤12/≤14 mg/dl for men/women, respectively), diabetes (insulin-dependent diabetes or use of oral antidiabetic medication or insulin), hypertension (treatment with angiotensin-converting-enzyme inhibitors, antihypertensive medication, DBP/SBP ≥90/≥140 mm/Hg, respectively), smoking status and the development of chronic kidney disease [confirmed (>3 months apart) estimated glomerular filtration rate <60 ml/min per 1.73 m2) were all defined in line with previous EuroSIDA work  and included as time-updated covariates.
SAS software version 9.2 (SAS Institute, Cary, North Carolina, USA, 2002–2003) was used for all analyses.
A total of 9801 patients contributed 42372.5 PYFU, during which 437 AIDS and 766 non-AIDS events occurred. The patient characteristics at baseline, and the PYFU within strata are shown in Table 1. For example, there were 7760 patients hepatitis B surface antigen negative at baseline, with 35483.8 PYFU in this strata, 364 AIDS and 635 non-AIDS events. The median baseline date was January 2004 [interquartile range (IQR) January 2001–February 2007], and age was 40.4 (IQR 34.6–47.3 years). At baseline, the median nadir CD4 cell count was 162 (IQR 71–257 per μl), baseline CD4 cell count was 390 (IQR 249–571 per μl) and viral load was 1.9 (IQR 1.7–3.3 log10copies/ml), reflecting the fact that the median time since starting cART was 3.3 years (IQR 0.9–5.1 years). Of 2961 (30.2%) with a prior AIDS diagnosis, the most common diagnoses were oesophageal candidiasis (n = 493, 16.7%), Pneumocystis jirovecii pneumonia (n = 487, 16.5%), and pulmonary tuberculosis (n = 311, 10.5%), occurring a median time of 4.0 (IQR 1.6–6.4 years) prior to baseline. The most common previous non-AIDS events were cardiovascular disease (n = 195, 57.0%) and hepatic encephalopathy (n = 53, 15.5%), occurring a median time of 3.0 (IQR 1.0–7.0 years) prior to baseline.
Figure 1 shows the distribution of PYFU, stratified by nucleoside pairs and third drugs. The most common nucleoside pair was zidovudine/lamivudine (14607.3 PYFU), followed by tenofovir/emtricitabine (9300.5 PYFU) and abacavir/lamivudine (6972.8 PYFU), whereas the three most commonly used third drugs were efavirenz (12256.7 PYFU), nevirapine (7759.4 PYFU) and lopinavir/r (7053.8 PYFU). Among the most common AIDS diagnoses were oesophageal candidiasis (n = 76), pulmonary (n = 43) and extrapulmonary tuberculosis (n = 35); there were 53 deaths with AIDS as the cause. There were 259 cardiovascular events (including 37 fatal events) and 237 non-AIDS defining malignancies (including 18 fatal events) contributing to non-AIDS events, with an additional 184 deaths from non-AIDS events (excluding malignancies and cardiovascular events).
The overall event rate was 2.8 per 100 PYFU [95% confidence interval (CI) 2.7–3.0], of AIDS events was 1.0 (95% CI 0.9–1.1) and of non-AIDS events was 1.8 (95% CI 1.7–1.9). The overall incidence rate ranged from 1.7 per 100 PYFU (95% CI 1.5–1.9) in patients with a current CD4 cell count more than 500 per μl to 31.7 per 100 PYFU in those with a current CD4 cell count 50 per μl or less, and from 2.2 per 100 PYFU (95% CI 2.0–2.4) in those with a viral load less than 50 copies/ml to 15.8 per 100 PYFU (95% CI 12.8–18.9) in which the viral load exceeded 100 000 copies/ml. The overall crude event rates, stratified by current CD4 cell count, current viral load, and shown separately for the nucleoside pairs and third drugs, are shown in Tables 2 and 3, together with the number of AIDS and non-AIDS events within each strata. A similar pattern of increasing incidence with lower CD4 cell count or higher viral load is seen for each of the nucleoside pairs and third drugs.
Table 4 shows the univariate and multivariate incidence rate ratios for the overall event. After adjustment, there was some evidence of a difference between nucleoside pairs, although this failed to reach statistical significance (global P-value = 0.084), and between the third drugs (global P-value = 0.031). Of note, compared with zidovudine/lamivudine, after adjustment, patients taking abacavir/lamivudine [adjusted incidence rate ratio (aIRR) 1.22; 95% CI 0.99–1.49] and abacavir and one other nucleoside (aIRR 1.51; 95% CI 1.14–2.02) had an increased incidence of AIDS or non-AIDS events, albeit of marginal statistical significance for abacavir/lamivudine. Comparing the third drugs, after adjustment, those taking unboosted atazanavir had an increased incidence of AIDS or non-AIDS events compared with those taking efavirenz (aIRR 1.46; 95% CI 1.09–1.95). Other factors associated with an increased incidence of the overall event were a prior AIDS or non-AIDS event at baseline, older age, chronic kidney disease, anaemia, diabetes, hypertension, smoking and current CD4 cell count and viral load.
The final model was repeated for AIDS and non-AIDS events separately, and the comparison of the antiretrovirals are shown in Fig 2a (AIDS) and 2b (non-AIDS). There was no strong evidence of a difference in the incidence of AIDS events across nucleoside pairs (P = 0.10) or third drugs (P = 0.32), although the reduced power of this analysis should be noted. After adjustment, all the nucleoside pairs except abacavir and one had an increased incidence of AIDS events compared with zidovudine/lamivudine, which reached statistical significance for tenofovir/emtricitabine and abacavir/lamivudine. Consistent with all events, those taking unboosted atazanavir had an increased incidence of AIDS compared with those taking efavirenz (aIRR 1.79; 95% CI 1.11–2.90), after adjustment. For non-AIDS events, there was some evidence of a difference between nucleoside pairs, although this just failed to reach statistical significance (P = 0.051), and between the third drugs (P = 0.027). In the adjusted analysis, abacavir and one antiretroviral was associated with an increased incidence of non-AIDS events compared with zidovudine/lamivudine (aIRR 1.78; 95% CI 1.26–2.52), as was abacavir when used as a third drug (aIRR 1.38; 95% CI 1.00–1.91) compared with efavirenz. Ritonavir-boosted saquinavir was associated with a lower incidence of non-AIDS events (aIRR 0.59; 95% CI 0.37–0.95).
Various sensitivity analyses were performed. CD4 cell count and viral load were alternatively included as categorical variables, with highly consistent findings. It is possible that antiretrovirals were switched because of the concerns about possible clinical progression, leading to an increased incidence in those recently started third drugs. We excluded the first 6 or 12 months on any third drug to address this potential bias, again with highly consistent results. Analyses limited to PYFU in which the CD4 cell count and viral load had been measured within the most recent 3 or 6 months also showed similar results (data not shown). Analyses were repeated separately for non-AIDS malignancies (237 events), wherein there was no evidence of a difference between nucleoside pairs (global P-value = 0.40) or third drugs (global P-value = 0.97) and for cardiovascular events (259 events), in which there was stronger evidence of a difference between nucleoside pairs (global P-value = 0.0032) and weak evidence of a difference between third drugs (global P-value = 0.030). After adjustment, compared with zidovudine/lamivudine, abacavir and one nucleoside were associated with a significantly increased incidence of cardiovascular events (aIRR 3.21; 95% CI 1.92–5.35, P < 0.0001), with few differences between the other nucleoside pairs. Abacavir as a third drug was also associated with a nonsignificant increased incidence of cardiovascular events compared with efavirenz (aIRR 1.45, 95% CI 0.86–2.45, P = 0.16), as was unboosted atazanavir (aIRR 1.57; 95% CI 0.86–2.88, P = 0.14). There were few differences between the other third drugs.
This study has demonstrated that there are few differences in the incidence of either fatal or nonfatal AIDS or non-AIDS events for a given CD4 cell count and viral load when comparing commonly used nucleoside pairs or third drugs. This provides important evidence that antiretroviral regimens, which are licensed on the basis of changes in surrogate markers have similar risks of both fatal and nonfatal AIDS and non-AIDS events for a given CD4 cell count and viral load, suggesting there are unlikely to be major unidentified adverse effects of specific antiretrovirals.
There is virtually no data from clinical trials regarding the comparative clinical efficacy of antiretroviral regimens, particularly regarding non-AIDS events, which are now the most common cause of death in HIV-infected persons . CD4 cell count and viral load are used as surrogate markers for clinical events, which implies that the effect of the antiretrovirals can be completely captured through changes in the surrogate markers [21,22]. Previous research from EuroSIDA demonstrated a similar clinical benefit for given CD4 cell counts and viral loads and older regimens, but was not able to consider non-AIDS events or some of the more newly available antiretroviral drugs. It is important to note that these results do not suggest that the nucleoside pairs or third drugs included do not have equal clinical efficacy. Instead, they demonstrate that, for a given CD4 cell count and viral load strata, the rate of AIDS and non-AIDS events are similar with few major differences, regardless of the regimen being used.
There was weak evidence of a difference in the overall clinical event rates for given CD4 cell count or viral load strata associated with abacavir, either when used as part of a nucleoside pair or as a third drug, a result not seen in the earlier study . It is possible this is because abacavir was not specifically categorized within a nucleoside pair, or because substantially longer follow-up has been required to identify potential adverse events. The finding was stronger when considering cardiovascular events, although it was only seen for abacavir and one other nucleoside or abacavir used as a third drug. This would suggest that patients with a similar CD4 cell count, viral load, and other factors adjusted for, have a higher rate of overall events when abacavir is used in the regimen, potentially explained by a higher rate of cardiovascular events specifically. The use of abacavir has been associated with an increased risk of cardiovascular disease in some studies [23,24], and has been shown to inhibit guanylyl cyclase, leading to platelet hyper-reactivity and increased clotting . In addition, there are differences in non-HIV specific cardiovascular disease risks, which may play a role, such as diabetes and lipid abnormalities [26,27]. The majority of the patients taking abacavir and one other nucleoside were taking abacavir with stavudine (60% of the PYFU), demonstrated to be associated with lipoatrophy, hyperlipidaemia and diabetes [28,29]. In addition, recent data suggested that abacavir use was more common in those with chronic kidney disease , in turn associated with cardiovascular disease. Analyses excluding all patients with chronic kidney disease showed consistent results for all endpoints, including cardiovascular disease (data not shown). Clearly, further evidence is required from other studies with greater power to confirm our findings.
There was also weak evidence that unboosted atazanavir was associated with an increased rate of overall events, AIDS and non-AIDS events, cardiovascular events but not non-AIDS defining malignancies for a given CD4 cell count and viral load strata, and the reasons for this are not clear. Unboosted atazanavir is known to have a large variability in pharmacokinetic levels . Ritonavir-boosted and unboosted atazanavir have been shown to have comparable virological efficacy and a similar, or lower rate in unboosted atazanavir, of toxicities and adverse events [32,33]. In terms of cardiovascular risk, the small cardiovascular risks associated with atazanavir are likely to be higher when the drug is ritonavir-boosted , and although there is some evidence that PR intervals from ECG measures are longer in both ritonavir-boosted and nonboosted protease inhibitor regimens, there is no evidence that this differs by specific protease-containing regimens . Sension et al. reported an improvement in lipid profiles in patients on unboosted atazanavir compared with boosted protease inhibitors, and it is possible that clinicians preferentially choose unboosted atazanavir in those with worse lipid profiles. Additional analyses adjusting for lipids (HDL, triglycerides or total cholesterol) in the subset of patients with data on lipids available did not change our findings. Confounding by indication cannot be ruled out, and it is worth remembering that the results are of borderline significance, although consistent for the different analyses performed. Data from further cohorts are needed to clarify this finding and explore the potential reasons.
The limitations of this study should be noted. Although EuroSIDA is one of the larger observational studies, we could not include the most recently available antiretrovirals, such as tipranavir, maraviroc or raltegravir, as we decided a priori to include only antiretrovirals where there was in excess of 1000 PYFU. Even with this limitation, some of the CIs for the comparison of specific antiretrovirals for AIDS or non-AIDS (or specifically non-AIDS malignancies or cardiovascular disease) were wide and further evidence from larger collaborations is required to support our preliminary data and provide more precise estimates of the differences between antiretrovirals. Although our group of non-AIDS events contains most key diseases it is nevertheless arbitrary and based on expert opinion and the data we have available to us, and it is possible that we have not included non-AIDS events in which greater differences between antiretrovirals exist. There is likely to be some heterogeneity between diagnoses in terms of risk factors, as there are for AIDS and different causes of death. In addition, there is a very wide range of antiretroviral regimens used as cART across Europe, and our analysis was limited to those with specific nucleoside pairs or third drugs, excluding nonstandard regimens , in which the risk of AIDS or non-AIDS events may differ overall and within CD4 cell count or viral load strata.
In summary, reassuringly, we found that rates of clinical progression (fatal and nonfatal AIDS or non-AIDS events) for a given CD4 cell count and viral load were similar when comparing common nucleoside pairs or third drugs, which provides evidence that the surrogate markers currently used to approve antiretroviral therapies can be interpreted in the same way, regardless of the regimen in use. There was some evidence that a nucleoside regimen including abacavir, or abacavir or unboosted atazanavir as third drugs, had higher overall event rates, and that abacavir and one other nucleoside or atazanavir or abacavir as third drugs had a higher incidence of non-AIDS events, particularly cardiovascular events. Confounding by indication cannot be ruled out, and larger studies are required to investigate the small differences found.
A.M., A.N.P. and J.L. proposed the concept for analysis and designed the study. A.M. performed all statistical analyses and produced the first draft of the article. J.G., A.H., B.L., K.Z., D.J., F.M. and D.P. contributed with ideas for statistical analysis, interpretation of the data, finalizing the article and national data collection and coordination.
The EuroSIDA Study Group The multicentre study group on EuroSIDA (national coordinators in parenthesis).
Argentina: (M. Losso), M. Kundro, Hospital J.M. 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, V.M. Mitsura, Gomel State Medical University, Gomel; O. Suetnov, Regional AIDS Centre, Svetlogorsk. Belgium: (N. Clumeck), S. De Wit, M. Delforge, Saint-Pierre Hospital, Brussels; R. Colebunders, Institute of Tropical Medicine, Antwerp; L. Vandekerckhove, University Ziekenhuis Gent, Gent. Bosnia-Herzegovina: (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), D. Jilich, 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. Ostergaard, Skejby Hospital, Aarhus. Estonia: (K.Z.), 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; J.M. 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; H.J. Stellbrink, IPM Study Center, Hamburg; S. Staszewski, J.W. 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: (S. Vella), 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 A.D. Cotugno, Monaldi Hospital, Napoli; G. Antonucci, A. Testa, G. D‘Offizi, C. Vlassi, M. Zaccarelli, A. Antorini, 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; A. d’Arminio Monforte, Istituto Di Clinica Malattie Infettive e Tropicale, Milan. Latvia: (B. Rozentale), I. Zeltina, Infectology Centre of Latvia, Riga. Lithuania: (S. Chaplinskas), Lithuanian AIDS Centre, Vilnius. Luxembourg: (T. Staub), R. Hemmer, Centre Hospitalier, Luxembourg. Netherlands: (P. Reiss), Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam. Norway: (V. Ormaasen), A. Maeland, J. Bruun, Ullevål Hospital, Oslo. Poland: (B. Knysz) J. Gasiorowski, Medical University, Wroclaw; A.H., E. Bakowska, Centrum Diagnostyki i Terapii AIDS, Warsaw; A. Grzeszczuk, R. Flisiak, Medical University, Bialystok; A. Boron-Kaczmarska, M. Pynka, M. Parczewski, 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), M. Doroana, L. Caldeira, Hospital Santa Maria, Lisbon; K. Mansinho, Hospital de Egas Moniz, Lisbon; F.M., 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; N. Zakharova, St Petersburg AIDS Centre, St Peterburg; S. Buzunova, Novgorod Centre for AIDS, Novgorod. Serbia: (D.J.), 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, P. Labarga, J. Medrano, Hospital Carlos III, Madrid; 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; J.G., J.M. Miró, Hospital Clinic i Provincial, Barcelona; P. Domingo, M. Gutierrez, G. Mateo, M.A. Sambeat, Hospital Sant Pau, Barcelona. Sweden: (A. Blaxhult), Venhaelsan-Sodersjukhuset, Stockholm; L. Flamholc, Malmö University Hospital, Malmö. Switzerland: (B.L.), 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; V. Frolov, G. Kutsyna, Luhansk State Medical University; Luhansk; S. Servitskiy, Odessa Region AIDS Center, Odessa; M. Krasnov, Kharkov State Medical University, Kharkov. United Kingdom: (S. Barton), St. Stephen's Clinic, Chelsea and Westminster Hospital, London; A.M. Johnson, D. Mercey, Royal Free and University College London Medical School, London (University College Campus); A.P., MA Johnson, A.M., 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..
Steering Committee: J.G., B Gazzard, A.H., I Karpov, B.L., M Losso, A D’Arminio Monforte, C Pedersen, A Rakhmanova, M Ristola, J Rockstroh (Chair), S De Wit (Vice-Chair).
Additional voting members: J Lundgren, A.P., P Reiss.
Coordinating Centre Staff: O Kirk, A.M., A Cozzi-Lepri, D Grint, M Sabin, D.P., J Kjær, L Peters, L Shepherd, A Schultze, J Nielsen, J Tverland, A H Fischer.
EuroSIDA representatives to EuroCoord: O Kirk, A.M., J Grarup, P Reiss, A Cozzi-Lepri, R Thiebaut, J Rockstroh, D Burger, R Paredes, J Kjær, L Peters.
Primary support for EuroSIDA is provided by the European Commission BIOMED 1 (CT94-1637), BIOMED 2 (CT97–2713), the 5th Framework (QLK2–2000–00773), the 6th Framework (LSHP-CT-2006–018632), and the 7th Framework (FP7/2007–2013, EuroCoord no 260694) programmes. Current support also includes unrestricted grants by Gilead, Pfizer, and Merck and Co. The participation of centres from Switzerland was supported by The Swiss National Science Foundation (Grant 108787) and from Serbia by by grant III 41019 from the Ministry of Education and Science of Serbia.
Conflicts of interest
A.M. has received honoraria, lecture fees and/or honoraria from BMS, Gilead, Pfizer, Merck and BI. A.N.P. has received consultancies and/or has grants pending from ViiV, BMS, Giead, Johnson and Johnson, and GSK. J.G. has board membership and/or grants pending from BMS, Gilead, Tobira, Janssen, MSD, BI, and Abbott. B.L. has received consultancy, lecture and/or travel fees from Gilead, Janssen, ViiV, MSD and is a board member of Janssen. D.J. has received travel support and/or lecture fees from GSK, MSD and PharmaSwiss. F.M. nas received consultancy fees and/or lecture fees from Janssen, Gilead, MSD, and Viiv and is a board member of Janssen and Gilead. No other author has reported any conflict of interest.
1. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents 2012. http://AIDSinfo.nih.gov
. [Accessed 19 October 2012].
2. Hughes MD, Daniels MJ, Fischl MA, Kim S, Schooley RT. CD4 cell count as a surrogate endpoint in HIV clinical trials: a meta-analysis of studies of the AIDS Clinical Trials Group
3. Marschner IC, Collier AC, Coombs RW, D’Aquila RT, DeGruttola V, Fischl MA, et al. Use of changes in plasma levels of human immunodeficiency virus type 1 RNA to assess the clinical benefit of antiretroviral therapy
. J Infect Dis
4. O’Brien TR, Blattner WA, Waters D, Eyster E, Hilgartner MW, Cohen AR, et al. Serum HIV-1 RNA levels and time to development of AIDS in the Multicenter Hemophilia Cohort Study
5. Reisler RB, Han C, Burman WJ, Tedaldi EM, Neaton JD. Grade 4 events are as important as AIDS events in the era of HAART
. J Acquir Immune Defic Syndr
6. Ramratnam B, Mittler JE, Zhang L, Boden D, Hurley A, Fang F, et al. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged antiretroviral therapy
. Nat Med
7. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection
8. Olsen CH, Gatell J, Ledergerber B, Katlama C, Friis-Moller N, Weber J, et al. Risk of AIDS and death at given HIV-RNA and CD4 cell count, in relation to specific antiretroviral drugs in the regimen
9. Baker JV, Peng G, Rapkin J, Abrams DI, Silverberg MJ, Macarthur RD, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection
10. Mocroft A, Soriano V, Rockstroh J, Reiss P, Kirk O, de WS, et al. Is there evidence for an increase in the death rate from liver-related disease in patients with HIV?
11. Monforte A, Abrams D, Pradier C, Weber R, Reiss P, Bonnet F, et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies
12. Reekie J, Kosa C, Engsig F, Monforte AD, Wiercinska-Drapalo A, Domingo P, et al. Relationship between current level of immunodeficiency and non-acquired immunodeficiency syndrome-defining malignancies
13. Lewden C, May T, Rosenthal E, Burty C, Bonnet F, Costagliola D, et al. Changes in causes of death among adults infected by HIV between 2000 and 2005: the ‘Mortalite 2000 and 2005’ SURVEYS (ANRS EN19 and Mortavic)
. J Acquir Immune Defic Syndr
14. Mocroft A, Brettle R, Kirk O, Blaxhult A, Parkin JM, Antunes F, et al. Changes in the cause of death among HIV positive subjects across Europe: results from the EuroSIDA study
15. Mocroft A, Ledergerber B, Katlama C, Kirk O, Reiss P, d’Arminio MA, et al. Decline in the AIDS and death rates in the EuroSIDA study: an observational study
16. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults
. MMWR Recomm Rep
17. Kowalska JD, Mocroft A, Ledergerber B, Florence E, Ristola M, Begovac J, et al. A standardized algorithm for determining the underlying cause of death in HIV infection as AIDS or non-AIDS related: results from the EuroSIDA study
. HIV Clin Trials
18. Kowalska JD, Friis-Moller N, Kirk O, Bannister W, Mocroft A, Sabin C, et al. The coding causes of death in HIV (CoDe) project: initial results and evaluation of methodology
19. Mocroft A, Reiss P, Gasiorowski J, Ledergerber B, Kowalska J, Chiesi A, et al. Serious fatal and nonfatal non-AIDS-defining illnesses in Europe
. J Acquir Immune Defic Syndr
20. Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996–2006: collaborative analysis of 13 HIV cohort studies
. Clin Infect Dis
21. Daniels MJ, Hughes MD. Meta-analysis for the evaluation of potential surrogate markers
. Stat Med
22. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled?
. Ann Intern Med
23. Lang S, Mary-Krause M, Cotte L, Gilquin J, Partisani M, Simon A, et al. Impact of individual antiretroviral drugs on the risk of myocardial infarction in human immunodeficiency virus-infected patients: a case-control study nested within the French Hospital Database on HIV ANRS Cohort CO4
. Arch Intern Med
24. Sabin CA, Worm SW, Weber R, Reiss P, El-Sadr W, Dabis F, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multicohort collaboration
25. Baum PD, Sullam PM, Stoddart CA, McCune JM. Abacavir increases platelet reactivity via competitive inhibition of soluble guanylyl cyclase
26. Palella FJ Jr, Phair JP. Cardiovascular disease in HIV infection
. Curr Opin HIV AIDS
27. Carr A, Cooper DA. Adverse effects of antiretroviral therapy
28. Jones R, Sawleshwarkar S, Michailidis C, Jackson A, Mandalia S, Stebbing J, et al. Impact of antiretroviral choice on hypercholesterolaemia events: the role of the nucleoside reverse transcriptase inhibitor backbone
. HIV Med
29. Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere O, Lang JM, et al. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy
30. Bedimo RJ, Westfall AO, Drechsler H, Vidiella G, Tebas P. Abacavir use and risk of acute myocardial infarction and cerebrovascular events in the highly active antiretroviral therapy era
. Clin Infect Dis
31. Regazzi M, Villani P, Gulminetti R, Cusato M, Brandolini M, Tinelli C, et al. Therapeutic monitoring and variability of atazanavir in HIV-infected patients, with and without HCV coinfection, receiving boosted or unboosted regimens
. Ther Drug Monit
32. Ghosn J, Carosi G, Moreno S, Pokrovsky V, Lazzarin A, Pialoux G, et al. Unboosted atazanavir-based therapy maintains control of HIV type-1 replication as effectively as a ritonavir-boosted regimen
. Antivir Ther
33. Squires KE, Young B, Dejesus E, Bellos N, Murphy D, Zhao HH, et al. Similar efficacy and tolerability of atazanavir compared with atazanavir/ritonavir, each with abacavir/lamivudine after initial suppression with abacavir/lamivudine plus ritonavir-boosted atazanavir in HIV-infected patients
34. Soliman EZ, Prineas RJ, Roediger MP, Duprez DA, Boccara F, Boesecke C, et al. Prevalence and prognostic significance of ECG abnormalities in HIV-infected patients: results from the Strategies for Management of Antiretroviral Therapy study
. J Electrocardiol
35. Sension M, Andrade Neto JL, Grinsztejn B, Molina JM, Zavala I, Gonzalez-Garcia J, et al. Improvement in lipid profiles in antiretroviral-experienced HIV-positive patients with hyperlipidemia after a switch to unboosted atazanavir
. J Acquir Immune Defic Syndr
AIDS; combination antiretroviral therapy; CD4 cell count; death; non-AIDS; viral load
© 2013 Lippincott Williams & Wilkins, Inc.
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