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.
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
AIDS; combination antiretroviral therapy; CD4 cell count; death; non-AIDS; viral load