Introduction
Combination antiretroviral therapies (cART) containing two nucleoside reverse transcriptase inhibitors (NRTIs) and either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI) are recommended by current guidelines as first-line regimens due to their frequently observed efficacy and convenience [1,2]. Regimens containing efavirenz (EFV) have become the standard-of-care comparator in clinical trials and consistently prove to be effective [3-6]. Nevirapine (NVP)-based regimens are recommended for pregnant women with low CD4 cell counts and for patients who cannot tolerate the central nervous system toxicity of EFV [1,2].
Virological outcomes of NNRTI-based regimens containing either NVP or EFV were compared in patients mostly experienced in NRTIs and PIs in a previous EuroSIDA analysis [7]. In common with other observational studies, NVP was found to be virologically inferior to EFV, after adjustment for baseline characteristics including CD4 cell count, viral load, previous antiretroviral therapy (ART) and number of drugs in regimen [8-12]. Although this may have reflected differences in the effectiveness of the two drugs in this setting, there may, however, have been unmeasured confounding variables that biased the results. The 2NN large-scale randomized clinical trial making a similar comparison in ART-naive patients found no significant difference between the two groups [13].
Contrary to the patients included in 2NN, most of the patients in the previous EuroSIDA analysis had already virologically failed other antiretroviral drugs, posing the possibility that the differences in outcome could be explained by differences in HIV ART resistance to other drugs used as part of the NNRTI-containing regimen. The subsequent development of the EuroSIDA genotypic resistance database has allowed a re-investigation to assess whether variations in resistance present when the regimen was initiated was a source of bias. Drug resistance is associated with virological failure in patients undergoing treatment [14-16] and NNRTIs have a low genetic barrier for resistance [1,17]. Indeed recent studies have demonstrated a role for mutations in the connection domain (residues 316-427) in conferring resistance to NNRTIs [18,19]. Conversely, there is evidence that some HIV-RNA mutations in the reverse transcriptase (RT) gene may encourage hypersusceptibility to NNRTIs [20,21].
The following analyses aimed to compare virological outcome, taking into account HIV ART resistance detected at initiation of treatment, in patients starting NVP- and EFV-containing regimens and to investigate resistance profiles in patients who virologically failed these drugs.
Methods
Patients
The EuroSIDA study is a prospective, observational cohort of 14 282 HIV-1-infected patients in 93 centres across Europe, Israel and Argentina, described in detail in a previous publication [22]. Patients were enrolled into seven cohorts from May 1994 onwards and follow-up time was to July 2006. Information was collected on a standardized data collection form every 6 months, including all CD4 cell counts and viral loads measured during that period in the clinical centres and details of antiretroviral use. 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 a proportion of patients.
EuroSIDA requests plasma samples from patients to be collected every 6 months and stored in a central repository. This repository currently holds 57 004 plasma samples from 8251 patients. Samples are then selected for retrospective genotypic resistance testing based on patient inclusion criteria. At present, the genotypic resistance database contains 3927 partial or full sequences of the RT and protease (PR) genes from 2423 patients. Sequence analysis of HIV-1 RT and PR reading frames is performed using the Trugene HIV-1 genotyping kit and OpenGene DNA Sequencing System according to the manufacturer's recommendations (Bayer, Barcelona, Spain). Mutations are identified by comparison against a reference sequence of the subtype B isolate, HXB2. The database also holds information on mutations identified in resistance tests performed at the clinical sites. A total of 1724 paper copies of resistance test results from 1151 patients have been collected.
Inclusion criteria for the current analyses were as in the previous EuroSIDA analysis [7]. Patients were required to be under follow-up at or after July 1997, to have started a regimen containing either NVP or EFV (not both) after July 1997 with no previous NNRTI experience, with a viral load and CD4 cell count measured within 6 months before time of treatment initiation (baseline) and with two viral load measurements after.
Statistical methods
Baseline patient characteristics were compared using chi-squared tests and Fisher's exact tests for categorical data, and Kruskal-Wallis tests for continuous data. Genotypic resistance profiles, defined according to IAS-USA (October/November 2006) [23], were described at baseline (using the most recent plasma sample within a year before treatment initiation) and at time of virological failure (most recent plasma sample at least 2 weeks after treatment initiation and up to 1 year after time of virological failure as defined below). At time of failure, patients were required to still be receiving an NNRTI.
Time to virological failure following initiation of a NNRTI-containing regimen was investigated using Cox proportional hazards models, with virological failure defined as two consecutive viral loads > 500 copies/ml after starting the regimen. If the baseline viral load was > 500 copies/ml, these values were required to have been measured at least 6 months after initiation. Time of virological failure was defined as the first of these two measurements. For patients who did not experience virological failure, the follow-up time was right censored at the time of the penultimate available viral load measurement. Analyses were performed according to an intention-to-treat principle ignoring treatment switches over follow-up.
A multivariable model was developed to compare patients starting NVP and EFV, stratified by the clinical centre in which patients were seen and adjusting for factors chosen a priori in the previous EuroSIDA analysis [7]. Additional potential confounders including demographics and use of specific drugs were also investigated and the effect of baseline genotypic resistance was analysed. This was interpreted using both the IAS-USA figures of drug resistance mutations [23], with resistance defined as at least one NRTI, NNRTI or major PI mutation, and three algorithms that produce genotypic sensitivity scores to measure sensitivity to the drugs in the regimen: Rega Algorithm Version 7.1 (available at http://www.kuleuven.be/rega/cev/links/rega_algorithm), ANRS Algorithm July 2006 and Stanford University Genotypic Resistance Algorithm (HIVdb) Version 4.2.9 (both available at http://hivdb.stanford.edu).
Multivariable linear regression models were also used to analyse changes in viral load and CD4 cell count between baseline and the last measurement 6 to 12 months following treatment initiation. Patients with no measurements during this time were excluded and for undetectable viral loads, the value taken was the level of detection minus one.
All tests were two-sided and a P-value of less than 0.05 was taken to be statistically significant. SAS software version 9.1 (SAS Institute, Cary, North Carolina, USA, 2002-2003) was used for all analyses.
Results
Patient characteristics at non-nucleoside reverse transcriptase inhibitor initiation
A total of 5301 patients fulfilled the original inclusion criteria, of whom 2435 (45.9%) started NVP and 2866 (54.1%) started EFV. Baseline genotypic resistance test results were available for 759 (14.3%) patients of which 618 (81.4%) had retrospective genotypic tests performed on plasma samples taken at baseline and 141 (18.6%) had resistance tests carried out at the clinical sites at time of treatment initiation. Figure 1 displays the subsets of patients investigated in these analyses. A comparison between these 759 patients and the 4542 who did not have results available, showed that patients with resistance tests on average started their regimens earlier, had lower baseline CD4 cell counts and higher viral loads, and were less likely to be previously ART-naive.
Table 1 displays the baseline patient characteristics in those with resistance test results according to whether patients started NVP (n = 389, 51.3%) or EFV (n = 370, 48.7%). NVP patients started their regimens earlier than EFV patients (median: August 1998 versus May 2000, P < 0.001). Most patients in both groups were NRTI- and PI- experienced and over half started a PI as part of the regimen.
Baseline genotypic drug resistance
Figure 2 displays IAS-USA viral mutations associated with drug resistance detected at the start of the NNRTI-containing regimens. In general, there were similar proportions of patients showing resistance in those starting NVP and EFV. In total, 569 (75.0%) had at least one NRTI resistance mutation (80.5% NVP, 69.2% EFV, P < 0.001), 26 (3.4%) had NNRTI resistance (3.1% NVP, 3.8% EFV, P = 0.597) and 385 (50.7%) had major PI resistance (48.3% NVP, 53.2% EFV, P = 0.176). NVP patients had a higher prevalence of M184I/V, L210W and T215F/Y mutations and lower prevalence of I84V.
Using the Rega algorithm to interpret resistance, 460 (64.3%) patients had resistance (full or intermediate) to at least one drug in the regimens they were starting: 256 (68.6%) NVP patients and 204 (59.5%) EFV patients, P = 0.011. A total of 27 (3.6%) patients had NNRTI resistance: 13 (3.3%) NVP patients (11 with full resistance, two with intermediate) versus 14 (3.8%) EFV patients (10 with full, four with intermediate), P = 0.743.
Virological response to non-nucleoside reverse transcriptase inhibitor-containing regimen
Virological response was first analysed in the 5301 patients who fulfilled the original inclusion criteria to confirm previous findings in EuroSIDA. Using a Cox proportional hazards model stratified by clinical centre and adjusted for number of previous NRTIs and PIs, previous AIDS, year started NNRTI, CD4 cell count (baseline and nadir), viral load (baseline and maximum ever) and number of NRTIs and PIs in the regimen, it was found that patients starting EFV were significantly less likely to virologically fail their regimen than those starting NVP [relative hazards (RH), 0.65; 95% confidence interval (CI), 0.59-0.72; P < 0.001].
This analysis was then repeated in the subset of 759 patients with baseline resistance test results available (either from retrospective analysis of samples or resistance tests performed at clinical sites). A total of 287 (73.8%; 95% CI, 69.7-78.4%) of the 389 NVP patients and 168 (45.4%; 95% CI, 40.6-50.7%) of the 370 EFV patients experienced virological failure, P < 0.001. Of these 455 virological failures, 24 (5.3%) started the regimen with a baseline viral load of ≤ 500 copies/ml (6.6% NVP, 3.0% EFV, P = 0.093). The median times between viral load measurements after starting the regimen were similar for NVP and EFV (P = 0.601) making it unlikely that frequency of measurements was a source of bias explaining these differences. In particular, in those who experienced virological failure, the median time between the two consecutive measurements > 500 copies/ml was 2 months (95% CI, 1-4 months) in the NVP group and 2 months (95% CI, 2-4 months) in the EFV group, P = 0.748. NNRTI discontinuation was similar in the two groups with 234 (60.1%) of the NVP group and 246 (66.5%) of the EFV group stopping their original drug within a year, P = 0.071. Of the 234 patients discontinuing NVP during the first year, 5.1% switched to EFV and 11.5% switched to a PI-based regimen within a month of stopping. Of the 246 patients discontinuing EFV, 8.1% switched to NVP and 7.3% switched to a PI within a month.
A univariable Cox proportional hazards model showed that patients starting EFV were 51% less likely to virologically fail their regimen than those starting NVP (RH, 0.49; 95% CI, 0.39-0.62; P < 0.001). After adjustment for the same variables as mentioned above, the result remained similar (RH, 0.52; 95% CI, 0.40-0.67; P < 0.001; Fig. 3).
Patients with baseline NNRTI resistance were twice as likely to experience virological failure than those without NNRTI mutations (P = 0.009) and patients with NRTI resistance were 49% more likely (P = 0.014). Adjustment of the multivariable model for this information did not, however, explain the difference in virological failure between EFV and NVP [RH, 0.51; 95% CI, 0.39-0.66; P < 0.001 (Fig. 3)].
An alternative model adjusting for the Rega genotypic sensitivity score, i.e. number of active drugs in the regimen excluding the NNRTI, as well as for NNRTI resistance, was also developed. It was found that for each increase of one active drug (NRTI or PI) in the regimen, there was a 24% decreased chance of virological failure (adjusted RH, 0.76; 95% CI, 0.68-0.86; P < 0.001). There was no significant difference between patients with NNRTI resistance and those without (P = 0.283). This model also did not result in a change in the RH of virological failure in patients starting EFV compared to NVP [RH, 0.50; 95% CI, 0.39-0.65; P < 0.001 (Fig. 3)]. Using the ANRS and Stanford algorithms instead of Rega gave similar findings.
Sensitivity analyses using the multivariable model adjusting for the Rega score and NNRTI resistance were carried out. Left censoring at the date of enrolment into EuroSIDA, right censoring at the time of NNRTI discontinuation and including only the 618 patients whose resistance test results came from retrospective analysis of stored plasma samples all gave consistent results. A subset of 98 patients who were previously ART-naive provided an adjusted RH of 0.2 (95% CI, 0.04-1.18; P = 0.215).
Finally, linear regression was used to analyse change in viral load and CD4 cell count from baseline to the last measurement 6 to 12 months after starting the regimen. A total of 711 (93.7%) patients had viral loads measured during this time and those on EFV-containing regimens had a viral load reduction on average 0.65 log10copies/ml greater than those on NVP-containing regimens, P < 0.001, after adjustment for the same variables as in the main analysis. CD4 cell counts were also measured in 711 (93.7%) patients during this 6-month period and after adjustment, those in the EFV group had a CD4 cell count increase of on average 26 cells/μl higher than those in the NVP group, P = 0.042. After adjustment for the change in viral load, changes in CD4 cell count were similar between the two groups: 9 cells/μl higher in the EFV group compared to the NVP group, P = 0.474.
Genotypic drug resistance at time of virological failure
In total 131 (28.8%) of the 455 patients who experienced virological failure (among the 759 with a baseline resistance test) were still taking an NNRTI and had resistance test results available at the time of failure. Prevalence of resistance was found to be similar between the NVP and EFV groups. Overall, 89.3% had NRTI resistance, 85.5% had NNRTI resistance and 67.9% had major PI resistance (Fig. 4).
A comparison with baseline results showed that between baseline and virological failure times, 55 (42.0%) patients developed a new NRTI resistance mutation (39.1% NVP, 47.7% EFV, P = 0.344), 111 (84.7%) developed a new NNRTI resistance mutation (83.9% NVP, 86.4% EFV, P = 0.712) and 36 (27.5%) developed a new PI resistance mutation (28.7% NVP, 25.0% EFV, P = 0.651). The most common new NNRTI resistance mutations that developed were K103N (34.5% NVP, 65.9% EFV), V108I (10.3% NVP, 20.5% EFV), Y181C (46.0% NVP, 4.6% EFV) and G190A (35.7% NVP, 9.1% EFV). Logistic regression models adjusting for factors in the main analysis including Rega score and NNRTI resistance also showed significant differences in the detection of K103N, Y181C and G190A between the two groups.
Discussion
In this cohort of HIV-1 infected patients from across Europe, Israel and Argentina, it was found that among 759 mostly NRTI/PI-experienced patients starting an NNRTI-containing regimen for the first time, those starting EFV had a 50% reduced risk of virological failure in comparison with those starting NVP. NNRTI-resistant HIV was detected in 3% of patients at baseline with similar levels in both NVP and EFV groups. Out of 131 patients still on an NNRTI and with resistance test results available at time of virological failure, NNRTI resistance was detected in 86% of patients and was similar between the groups; however different resistance profiles emerged. The K103N mutation was more prevalent in those who failed on EFV and the Y181C and G190A mutations were more prevalent in those who failed on NVP.
The main findings in this report match those from the previous EuroSIDA analysis [7]. At the time of that analysis, drug resistance data was not available and therefore it was unknown as to whether baseline resistance profiles could explain the difference in virological outcome observed. The present findings suggest that although patients with at least one IAS-USA NNRTI resistance mutation at baseline or a lower number of fully active drugs in the regimen (as defined by the Rega algorithm or others) were more likely to experience virological failure, adjusting for either of these factors does not confound the association between the risk of virological failure and the use of NVP or EFV. This result was consistent in a number of sensitivity analyses with the exception of a nonsignificant difference found between groups in the subset of 98 ART-naive patients. The results remained in favour of EFV, however, and as the number of patients included was much lower, the power of the analyses to detect true differences was reduced. Conversely, this could also reflect that possible differences in intrinsic virological efficacy between the two NNRTIs are less pronounced in patients harbouring fully susceptible virus.
The results match findings from other observational cohort studies, which all considered many confounding factors but did not take into account baseline NNRTI resistance and so could not rule this out as potentially biasing the results [8-12]. The question was also addressed in a large randomized clinical trial, the 2NN study [13]. A composite measurement of treatment failure, including virological failure, disease progression and therapy change was investigated in ART-naive patients. In the primary analysis, a comparison of NVP twice daily (n = 387) versus EFV (n = 400), found a nonsignificant but slightly lower proportion of treatment failure at week 48 in those starting EFV compared to those starting NVP, P = 0.091. However, sensitivity analysis excluding 28 patients who were randomized to either of these groups but who never started their treatment found a similar but significant difference between them (7.7%; 95% CI, 0.8-14.6%; P = 0.030). A substudy of the FIRST-CPCRA 058 trial randomized 228 ART-naive patients to receiving NVP or EFV and found no significant difference in rate of virological failure (> 50 copies after 8 months or death) but found that virological failure on NVP was associated with more drug resistance [24].
In the present analyses, similar high levels of NNRTI resistance were found in patients treated with NVP and EFV by the time of virological failure suggesting that the drugs emitted selection pressure indicating that patients had actually adhered to their regimens. This is the largest comparison of resistance profiles reported to date. The Y181C mutation was the most frequently observed in plasma samples from patients who failed an NVP-based regimen and the K103N mutation in samples from patients who failed an EFV-based regimen, which supports other research [25-27]. It has implications for future therapy options as the K103N mutation has been linked to high-level cross-resistance to first-line EFV and NVP, but there is evidence that it does not cause cross-resistance to etravirine and that Y181C alone only confers very limited resistance to etravirine when it is not accompanied by any other NNRTI-related mutation [28-30].
Another bias for explaining the differences observed between NVP and EFV that cannot be ruled out, however, is the possible impact of mutations in the connection domain (C-domain, residues 316-427). It has recently been demonstrated that N348I decreases susceptibility to NVP (7.4-fold) and EFV (2.5-fold) and enhances NNRTI resistance in the context of K103N [18]. Mainly N348I confers decreased susceptibility to zidovudine and NVP and is more likely to be selected with zidovudine and NVP treatment. Another mutation in the C-domain, E399G, has also been shown to slightly increase EFV resistance (3.6-fold) and significantly reduce viral replication capacity when associated with other mutations in the NNRTI binding pocket (L100I, V106I, V179D and F227C) [19]. The clinical impact of the C-domain mutations has not been assessed at the clinical level, however, therefore until these results are available, C-domain mutations cannot be ruled out as a possible explanation for the differences observed in this study and the discordances seen between different trials.
EuroSIDA is one of the largest international HIV cohort studies with a dedicated resistance database, providing a heterogeneous population from centres all across Europe with the same high standards of data collection and checking throughout. The limitations of this study to compare NVP and EFV in terms of virological response should, however, be recognized when interpreting the results. Although a large number of known, measured confounding variables were considered for this analysis, including the new information EuroSIDA has collected on genotypic drug resistance, as the data were from an observational study as opposed to a randomized clinical trial, there may still be some unmeasured or unknown variables that may have biased the comparison, including neuropsychological issues that are not collected in routine clinical care [30]. For example, patients suffering from depression may be less adherent to their regimens [31] resulting in a poorer virological response rate [32] and may also be more likely to receive NVP due to the neurological side effects of EFV [1,2].
In summary, it was found that NVP is associated with an inferior virological outcome compared to EFV in NNRTI-naive (but generally NRTI/PI experienced) patients confirming findings previously reported from EuroSIDA. This difference does not appear to be explained by baseline drug resistance or number of active drugs in the regimen but could be linked to the different resistance profiles emerging over the course of treatment in those starting NVP compared to EFV. This is not, however, a randomized comparison and so does not necessarily reflect the true difference in effectiveness between the two drugs. More randomized trials are needed to investigate virological efficacy in NRTI/PI experienced patients, in addition to ART-naive patients.
Acknowledgements
Sponsorship: Primary support for EuroSIDA is provided by the European Commission BIOMED 1 (CT94-1637), BIOMED 2 (CT97-2713), the 5th Framework (QLK2-2000-00773) and the 6th Framework (LSHP-CT-2006-018632) programs. Current support also includes unrestricted grants by Bristol-Myers Squibb, GlaxoSmithKline, Roche, Gilead, Pfizer, Merck and Co., Tibotec and Boehringer-Ingelheim. The participation of centres from Switzerland was supported by a grant from the Swiss Federal Office for Education and Science.
The EuroSIDA Study Group
The names of the national co-ordinators are given in parenthesis.
Argentina: (M. Losso), A. Duran, Hospital JM Ramos Mejia, Buenos Aires.
Austria: (N. Vetter), Pulmologisches Zentrum der Stadt Wien, Vienna.
Belarus: (I. Karpov), A. Vassilenko, Belarus State Medical University, Minsk.
Belgium: (N. Clumeck), S. De Wit, B. Poll, Saint-Pierre Hospital, Brussels; R. Colebunders, Institute of Tropical Medicine, Antwerp.
Bulgaria: K. Kostov, Infectious Diseases Hospital, Sofia.
Croatia: J. Begovac, University Hospital of Infectious Diseases, Zagreb.
Finland: (M. Ristola), Helsinki University Central Hospital, Helsinki.
Czech Republic: (L. Machala), H. Rozsypal, Faculty Hospital Bulovka, Prague; D. Sedlacek, Charles University Hospital, Plzen.
Denmark: (J. Nielsen), J. Lundgren, T. Benfield, O. Kirk, Panum Institute, Copenhagen; J. Gerstoft, T. Katzenstein, A.-B. E. Hansen, P. Skinhøj, Rigshospitalet, Copenhagen; C. Pedersen, Odense University Hospital, Odense; L. Oestergaard, Skejby Hospital, Aarhus.
Estonia: (K. Zilmer), West-Tallinn Central Hospital, Tallinn; J. Smidt, Nakkusosakond Siseklinik, Kohtla-Järve.
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, 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, JW Goethe University Hospital, Frankfurt; J. Bogner, Medizinische Poliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne.
Greece: (J. Kosmidis), P. Gargalianos, G. Xylomenos, J. Perdios, Athens General Hospital; G. Panos, A. Filandras, E. Karabatsaki, 1st IKA Hospital; H. Sambattakou, Ippokration Genereal Hospital, Athens.
Hungary: (D. Banhegyi), Szent Lásló Hospital, Budapest.
Ireland: (F. Mulcahy), St. James's Hospital, Dublin.
Israel: (I. Yust), D. Turner, M. Burke, Ichilov Hospital, Tel Aviv; S. Pollack, G. Hassoun, Rambam Medical Center, Haifa; S. Maayan, Hadassah University Hospital, Jerusalem.
Italy: (A. Chiesi), Istituto Superiore di Sanità, Rome; R. Esposito, I. Mazeu, C. Mussini, Università Modena, Modena; C. Arici, Ospedale Riuniti, Bergamo; R. Pristera, Ospedale Generale Regionale, Bolzano; F. Mazzotta, A. Gabbuti, Ospedale S Maria Annunziata, Firenze; V. Vullo, M. Lichtner, University di Roma la Sapienza, Rome; A. Chirianni, E. Montesarchio, M. Gargiulo, Presidio Ospedaliero AD Cotugno, Monaldi Hospital, Napoli; G. Antonucci, F. Iacomi, P. Narciso, C. Vlassi, M. Zaccarelli, Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome; A. Lazzarin, R. Finazzi, Ospedale San Raffaele, Milan; M. Galli, A. Ridolfo, Ospedale L. Sacco, Milan; A. d'Arminio Monforte, Istituto Di Clinica Malattie Infettive e Tropicale, Milan.
Latvia: (B. Rozentale), P. Aldins, Infectology Centre of Latvia, Riga.
Lithuania: (S. Chaplinskas), Lithuanian AIDS Centre, Vilnius.
Luxembourg: (R. Hemmer), T. Staub, Centre Hospitalier, Luxembourg.
Netherlands: (P. Reiss), Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam.
Norway: (J. Bruun) A. Maeland, V. Ormaasen, Ullevål Hospital, Oslo.
Poland: (B. Knysz), J. Gasiorowski, Medical University, Wroclaw; A. Horban, Centrum Diagnostyki i Terapii AIDS, Warsaw; D. Prokopowicz, A. Wiercinska-Drapalo, Medical University, Bialystok; A. Boron-Kaczmarska, M. Pynka, Medical Univesity, Szczecin; M. Beniowski, E. Mularska, Osrodek Diagnostyki i Terapii AIDS, Chorzow; H. Trocha, Medical University, Gdansk.
Portugal: (F. Antunes), E. Valadas, Hospital Santa Maria, Lisbon; K. Mansinho, Hospital de Egas Moniz, Lisbon; F. Maltez, Hospital Curry Cabral, Lisbon.
Romania: (D. Duiculescu), Spitalul de Boli Infectioase si Tropicale: Dr Victor Babes, Bucarest.
Russia: (A. Rakhmanova), Medical Academy Botkin Hospital, St Petersburg; E. Vinogradova, St Petersburg AIDS Centre, St Peterburg; S. Buzunova, Novgorod Centre for AIDS, Novgorod.
Serbia: (D. Jevtovic), The Institute for Infectious and Tropical Diseases, Belgrade.
Slovakia: (M. Mokráš), D. Staneková, Dérer Hospital, Bratislava.
Spain: (J. González-Lahoz), V. Soriano, L. Martin-Carbonero, P. Labarga, Hospital Carlos III, Madrid; B. Clotet, A. Jou, J. Conejero, C. Tural, Hospital Germans Trias i Pujol, Badalona; J.M. Gatell, J.M. Miró, Hospital Clinic i Provincial, Barcelona; P. Domingo, M. Gutierrez, G. Mateo, M.A. Sambeat, Hospital Sant Pau, Barcelona.
Sweden: (A. Karlsson), Karolinska University Hospital, Stockholm; P.O. Persson, Karolinska University Hospital, Huddinge; L. Flamholc, Malmö University Hospital, Malmö.
Switzerland: (B. Ledergerber), R. Weber, University Hospital, Zürich; P. Francioli, M. Cavassini, Centre Hospitalier Universitaire Vaudois, Lausanne; B. Hirschel, E. Boffi, Hospital Cantonal Universitaire de Geneve, Geneve; H. Furrer, Inselspital Bern, Bern; M. Battegay, L. Elzi, University Hospital Basel.
Ukraine: (E. Kravchenko), N. Chentsova, Kiev Centre for AIDS, Kiev.
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. Phillips, M.A. Johnson, A. Mocroft, Royal Free and University College Medical School, London (Royal Free Campus); M. Murphy, Medical College of Saint Bartholomew's Hospital, London; J. Weber, G. Scullard, Imperial College School of Medicine at St. Mary's, London; M. Fisher, Royal Sussex County Hospital, Brighton; R. Brettle, Western General Hospital, Edinburgh.
Virology group: B. Clotet (central coordinators) plus ad hoc virologists from participating sites in the EuroSIDA Study.
Steering committee: F. Antunes, B. Clotet, D. Duiculescu, J. Gatell, B. Gazzard, A. Horban, A. Karlsson, C. Katlama, B. Ledergerber (chair), A. D'Arminio Montforte, A. Phillips, A. Rakhmanova, P. Reiss (vice-chair), J. Rockstroh.
Coordinating centre staff: J. Lundgren (project leader), O. Kirk, A. Mocroft, N. Friis- Møller, A. Cozzi-Lepri, W. Bannister, M. Ellefson, A. Borch, D. Podlevkareva, C. Holkmann Olsen, J. Kjær, L. Peters, J. Reekie.
Uncited reference
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