JAIDS Journal of Acquired Immune Deficiency Syndromes:
Epidemiology and Social Science
Transmitted Drug Resistant HIV-1 and Association With Virologic and CD4 Cell Count Response to Combination Antiretroviral Therapy in the EuroSIDA Study
Bannister, Wendy P MSc*; Cozzi-Lepri, Alessandro PhD*; Clotet, Bonaventura MD, PhD†; Mocroft, Amanda PhD*; Kjær, Jesper MSc‡; Reiss, Peter MD, PhD§; Wyl, Viktor von MSc∥; Lazzarin, Adriano MD¶; Katlama, Christine MD#; Phillips, Andrew N PhD*; Ruiz, Lidia PhD†; Lundgren, Jens D MD, DMSc‡**; the EuroSIDA study group
From the *Department of Primary Care and Population Sciences, Royal Free and University College Medical School, London, United Kingdom; †Hospital Germans Trias i Pujol, Badalona, Spain; ‡Copenhagen HIV Program, Panum Institute, Copenhagen, Denmark; §Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam, The Netherlands; ∥University Hospital, Zürich, Switzerland; ¶Ospedale San Raffaele, Milan, Italy; #Hôpital de la Pitié-Salpétière, Paris, France; and the **Centre for Viral Disease/KMA, Rigshospitalet, Copenhagen, Denmark.
Received for publication September 14, 2007; accepted April 3, 2008.
Correspondence to: Wendy P. Bannister, MSc, Department of Primary Care and Population Sciences, Royal Free and University College Medical School, Rowland Hill Street, London, NW3 2PF, United Kingdom (e-mail: firstname.lastname@example.org).
Objectives: To investigate prevalence of transmitted drug-resistant human immunodeficiency virus (TDR) and factors associated with TDR and to compare virological and CD4 count response to combination antiretroviral therapy.
Methods: In this study, 525 mostly chronically infected EuroSIDA patients were included who had genotypic resistance tests performed on plasma samples collected while antiretroviral therapy naive. TDR was defined as at least one resistance mutation from a list proposed for genotypic TDR surveillance. Multivariable logistic regression was used to analyze factors associated with detection of TDR, with virological (viral load <500 copies/mL) and CD4 count response (≥50% increase) to combination antiretroviral therapy at months 6 -12.
Results: The overall prevalence of TDR was 11.4%, which was stable over 1996-2004. There were no significant differences in virological suppression (those resistant to at least one drug prescribed versus susceptible), adjusted odds ratio: 0.68 (95% confidence interval: 0.27 to 1.71; P = 0.408) or CD4 count response, adjusted odds ratio: 1.65 (95% confidence interval: 0.73 to 3.73; P = 0.231).
Conclusions: Prevalence of TDR in antiretroviral-naive patients was found to be in line with other European studies. No significant differences were found in virological and CD4 count response after initiation of first-line combination antiretroviral therapy between resistant and susceptible patients, possibly due to the small number of patients with resistance and consequently low power.
Resistance of HIV-1 to antiretroviral drugs is a major challenge for the continued efficacy of antiretroviral therapy (ART) and emerges when treatment fails to suppress viral replication effectively, either through suboptimal treatment or incomplete adherence. It is associated with virological failure in patients undergoing treatment and limits subsequent therapy options.1-5 Patients may acquire a drug-resistant HIV strain through infection, and if the initial regimen is prescribed without knowledge of the resistance-associated mutations present, then the selection of drugs may not be optimal.6,7 At present, the clinical use of drug resistance testing in Europe is recommended for newly diagnosed ART-naive patients with acute or recent HIV infection (less than one year) and for chronically infected ART-naive patients starting therapy if the suspicion of resistance is high or if the prevalence of resistance in the population exceeds 10%.8,9
The prevalence of transmitted drug-resistant HIV (TDR) has been estimated to range from as little as 2.1% to 51.5% in ART-naive recently and chronically infected patients across Europe in studies with varying time periods of study, populations, designs, methods, and definitions of resistance.10-27 Temporal trends in prevalence of TDR seem to vary across cohorts.25-36 Increases have been observed that may be due to wider access to ART, use of treatment interruptions, or increasing high-risk behavior. Conversely, improved virological control and management of treatment failure may explain decreases in TDR.
An important unresolved issue is whether or not TDR has an effect on the ability of combination antiretroviral therapy (cART) to suppress viral load and to boost immune regeneration. Some evidence has suggested that its presence leads to a suboptimal response.15,16,31-33 The objectives of these analyses were to investigate the prevalence of TDR in the EuroSIDA cohort and the factors associated with its detection and to compare virological and CD4 count response to cART between patients with resistant and susceptible HIV-1.
The EuroSIDA study is a prospective, observational cohort of 14,310 HIV-1- infected patients in 93 centers across Europe, Israel, and Argentina. The study has been described in detail previously.38 In brief, patients were enrolled into 7 cohorts from May 1994 onward and median follow-up time is to January 2007. Information is collected on a standardized data collection form every 6 months, including all CD4 counts and viral loads measured since the last follow-up and starting and stopping dates of all antiretroviral drugs. Centers participating in EuroSIDA seek ethical approval according to their own local and national requirements.
EuroSIDA also requests plasma samples from patients to be collected prospectively every 6 months and stored in a central repository. Samples that were taken from ART-naive patients were subsequently selected for retrospective genotypic resistance testing. The results of these tests were not used to guide treatment nor communicated to clinicians at the time of storing the sample. HIV-1 RNA is isolated from patient blood plasma using QIAamp kit (Qiagen, Barcelona, Spain), and sequence analysis of HIV-1 reverse transcriptase (RT) and protease (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.
Patient characteristics were compared using χ2 tests and Fisher Exact tests for categorical data and Kruskal-Wallis tests for continuous data. The results from genotypic resistance tests performed on plasma samples taken while the patient was ART naive were used to estimate prevalence of TDR. If the patient had more than one sample available before starting ART, results were cumulated. TDR was defined as the detection of at least one HIV-1 mutation from a list proposed for genotypic TDR surveillance by Shafer et al (2007).39 The International AIDS Society- USA (IAS-USA) 2007 figures of HIV-1 drug resistance mutations40 and the Stanford University Algorithm (HIVdb) Version 4.3.441 were also used to obtain estimates of drug resistance prevalence. Date of HIV infection was estimated in patients who had dates for HIV- negative and HIV- positive serostatus as the midpoint of the 2.
Multivariable logistic regression was used to assess the effect of calendar time and HIV-1 subtype on the detection of TDR after adjustment for potentially confounding factors. All resistance test results were included until the first detection of TDR for each patient, and the analysis was adjusted for repeated tests per patient using generalized estimating equations. Potential confounders investigated were gender, HIV exposure group, region of EuroSIDA, ethnicity, patient's country of origin, prior AIDS diagnosis, hepatitis B/C coinfection serostatus, CD4 count and viral load at the date of the plasma taken, date of enrollment, and age. Those found to be significant in univariable analyses with P < 0.1 were included in a multivariable analysis.
Virological and CD4 count response to cART were analyzed in patients who started a cART regimen [defined as at least 3 antiretroviral drugs including a protease inhibitor (PI), a nonnucleoside reverse transcriptase inhibitor (NNRTI), or abacavir] while ART naive with the potential for at least one year's follow-up. Patients were required to have a baseline (time of initiation of cART) viral load measurement of at least 500 copies/mL for the virological response analysis and a baseline CD4 count for the CD4 count analysis, measured within 6 months before starting cART. Multivariable logistic regression was used on the first measurements in the time window 6-12 months after starting cART to compare response between patients with HIV-1 with full/intermediate resistance to at least one drug started according to the Stanford algorithm and those with HIV-1 susceptible to all drugs started after adjustment for potentially confounding factors. A successful virological response was defined as a viral load <500 copies/mL and a CD4 count response as a 50% or more CD4 increase from the start of cART. Patients with missing measurements in this time window were defined as virological/immunological failures to maximize the number of patients included and reduce potential bias due to people with the worse outcome being those more likely to drop out.
A ‘missing = excluded’ approach was used in a sensitivity analysis. Further sensitivity analyses using the ‘missing=failure’ approach were conducted on a subset of patients who were enrolled into EuroSIDA after starting cART (and therefore had treatment data collected retrospectively), using the Rega Algorithm Version 7.142 to calculate genotypic sensitivity scores instead of Stanford and using the definition of TDR by Shafer et al39 to define groups based on whether or not patients had TDR mutations regardless of the drugs they were starting. A virological endpoint of a viral load <50 copies/mL was also analyzed on a subset of patients whose first viral load measurements in the 6- to 12-month period after starting cART were measured using an assay with a level of detection as low as 50 copies/mL, requiring all those with missing values to be excluded. A further immunological endpoint of a 100 CD4 cells/mm3 increase or more from baseline was also analyzed.
All tests were 2 sided and a P value of less than 0.05 was taken to be statistically significant. SAS software version 9.1 (SAS Institute, Cary, NC, 2002-2003) was used for all analyses.
Patient Characteristics at Enrollment
The patient numbers according to the inclusion criteria are displayed in Figure 1. Of 14,310 patients, 525 (3.7%) had plasma samples available while ART naive that were subsequently tested retrospectively for genotypic resistance. These 525 patients were widespread across Europe with a small minority from Israel (n = 12) and Argentina (n = 3). At the time of enrollment, there were some differences between this subset compared with the 13,785 patients who did not have plasma samples available for testing while ART naive. Patients with resistance test results had a higher median CD4 count (370 versus 284 cells/mm3, P < 0.001) and a higher median viral load (4.4 versus 2.7 log10 copies/mL, P < 0.001). They were also less likely to have a previous AIDS diagnosis and were diagnosed with HIV more recently.
Date of infection could be estimated for 118 (22.5%) of the 525 ART-naive patients tested for resistance. The median time between date of infection and earliest resistance test was 51.0 months [interquartile range (IQR): 24.6-83.5 months] for these patients and was less than one year for 13 (11.0%) patients. In the full set of 525 patients, the median time between HIV- positive diagnosis and earliest resistance test was 46.1 months (IQR: 17.0-88.9 months); therefore, the majority of this subpopulation were chronically infected patients.
Prevalence of TDR
TDR (defined according to Shafer et al39) was detected in 60 of the 525 patients [11.4%, 95% confidence interval (CI): 8.9% to 14.3%]. A total of 49 patients (9.3%, 95% CI: 7.0% to 12.0%) had one or more mutations associated with nucleoside reverse transcriptase inhibitor (NRTI) resistance, 5 (1.0%, 95% CI: 0.3% to 2.2%) had NNRTI resistance mutations, and 16 (3.0%, 95% CI: 1.8% to 4.7%) had PI resistance mutations. A total of 9 patients (1.7%, 95% CI: 0.8% to 3.0%) were infected with multiclass drug -resistant HIV-1. In comparison, using the IAS-USA list of HIV-1 mutations, 71 patients (13.5%, 95% CI: 10.8% to 16.6%) had at least one NRTI, NNRTI, or major PI mutation linked to drug resistance. Finally, 84 patients (16.0%, 95% CI: 13.1% to 19.3%) were infected with HIV-1 with full or intermediate drug resistance according to the Stanford algorithm.
Over calendar time, the difference in overall prevalence of detected TDR between 2-year periods between 1994 and 2004 was of borderline significance (P = 0.050). After an initial relatively high TDR prevalence of 20.3% (95% CI: 12.0% to 31.7%) in 64 patients with plasma samples available for genotypic resistance testing in 1994-1995, the prevalence remained fairly stable. TDR prevalence was 10.5% (95% CI: 6.9% to 15.0%) in 219 patients in 1996-1997, 6.8% (95% CI: 3.4% to 11.5%) in 147 patients in 1998-1999, 6.5% (95% CI: 2.5% to 12.5%) in 93 patients in 2000-2001, and 9.1% (95% CI: 4.4% to 15.7%) in 99 patients in 2002-2004. No resistance test results were available from 2005 onward. NRTI resistance ranged from 4.8% to 20.3%, NNRTI resistance from 0.0% to 2.0%, and PI resistance from 1.6% to 3.9%.
A total of 31 (5.9%) patients were infected with HIV-1 subtype A, 432 (82.3%) with subtype B, 14 (2.7%) with subtype C, and 48 (9.1%) were infected with another subtype or circulating recombinant form. TDR was highest in those infected with subtype B, 12.5% (95% CI: 9.6% to 15.8%), followed by 7.1% (95% CI: 0.1% to 33.9%) of those with subtype C, 6.5% (95% CI: 0.8% to 21.4%) of the subtype A group, and 6.3% (95% CI: 1.3% to 17.2%) of patients in the “other subtype” group. However, there was no overall significant difference found in TDR prevalence between B and non-B subtypes, P = 0.096. Figure 2 displays the frequency of TDR mutations according to subtype.
Factors Associated With TDR
A total of 622 genotypic resistance test results for the 525 ART-naive patients were included in a multivariable logistic regression analysis looking at the effect of calendar time and HIV-1 subtype on the detection of TDR. Multivariable odds ratios (ORs) are displayed in Figure 3. After adjustment for viral load at the time of plasma sample taken, hepatitis C status and EuroSIDA region were found to be significantly associated with detection of TDR, no statistically significant differences could be demonstrated in the detection of TDR between any 2-year time periods compared with 1996-1997. There was also no significant difference in the odds of detection of TDR in patients infected with subtype A compared with subtype B (P = 0.243) and a borderline significantly lower odds in patients infected with other subtypes compared with B (P = 0.066). The wide CIs indicate the limited power of these analyses due to small patient numbers.
Patients With a Resistance Test Before Starting cART
Of the 525 patients with resistance test results, 308 (58.7%) then initiated a cART regimen while they were still ART naive with the potential for one year's follow-up. TDR mutations were detected in 29 (9.4%) patients in this subset. Genotypic sensitivity scores calculated using the Stanford algorithm showed that 13 (4.2%) patients had HIV-1 with full resistance and 24 (7.8%) had HIV-1 with intermediate resistance to at least one drug prescribed in their regimens at the time of starting cART (baseline). A total of 23 (7.5%) had NRTI resistance mutations to an NRTI started including M41L, D67G/N/deletion, K70R, F77L, M184I/V, L210W, T215Y/D/E/S/I, and K219Q, 5 (1.6%) had NNRTI resistance including V106M, and 11 (3.6%) had PI resistance including L24I, M46I, and V82A. Patient characteristics were compared between these 37 patients, the “resistant” group, and the 271 patients with HIV-1 susceptible to all drugs started, the “susceptible” group. These are displayed in Table 1, which shows that the 2 groups were mostly very similar. Both groups had a similar median time between their most recent resistance test while ART naive and starting cART: 8 months (IQR: 4-23 months) for the resistant group and 7 months (IQR: 3-19) for the susceptible group, P = 0.482.
Virological Response to cART
Virological response was analyzed in 277 (89.9%) patients who had baseline viral loads measured (≥500 copies/mL) of which 34 (12.3%) patients had HIV with full or intermediate resistance to at least one drug started (using the Stanford algorithm). Of these 277 patients, 22 (7.9%) had no viral load measurement in the period 6- 12 months after starting cART and so were counted as virological failures in the main analysis. A total of 211 (76.2%) patients achieved virological suppression (<500 copies/mL) at the first measurement 6-12 months after starting cART. Response rates between patients in the resistant and the susceptible groups were similar: 25 (73.5%, 95% CI: 61.6% to 91.2%) of 34 patients compared with 186 (76.5%, 95% CI: 71.6% to 82.3%) of 243 patients, respectively, P = 0.699. After adjustment for gender, EuroSIDA region, date started cART, type of cART regimen, baseline CD4 count and viral load, and time from most recent resistance test, the odds of virological suppression were lower but not significantly in the resistant group compared with the susceptible group, OR: 0.68 (95% CI: 0.27 to 1.71; P = 0.408) (Table 2). Results were similar in those starting PI-containing regimens and those starting NNRTI-containing regimens; no interaction was found between type of cART regimen and resistance, P = 0.222. Sensitivity analyses all gave consistent results to the main analysis and are detailed in Table 2.
CD4 Count Response to cART
CD4 count response was analyzed in 299 (97.1%) patients with baseline CD4 counts of which 36 (12.0%) had HIV with full or intermediate resistance to at least one drug started. Of these 299 patients, 22 (7.4%) had no CD4 count measured 6-12 months after starting cART and so were counted as immunological failures in the main analysis. In total, 130 (43.5%) patients had a CD4 count response (of at least 50% increase from baseline) at the first measurement 6-12 months after starting cART. The response rate of patients in the resistant group was higher than patients in the susceptible group but not significantly: 20 (55.6%, 95% CI: 42.0% to 74.5%) of 36 patients compared with 110 (41.8%, 95% CI: 36.2% to 48.2%) of 263 patients, P = 0.119. After adjustment for type of cART regimen, baseline CD4 count and viral load, time from HIV- positive diagnosis, and time from most recent resistance test, the odds of a CD4 count response were higher but not significantly in the resistant compared with the susceptible group, OR: 1.65 (95% CI: 0.73 to 3.73; P = 0.231) (Table 2). This was very similar after adjustment for change in viral load from baseline in patients with viral load measurements available, OR: 1.80 (95% CI: 0.74 to 4.38; P = 0.198). No interaction was found between type of cART regimen and resistance, P = 0.391.
Sensitivity analyses also gave mostly consistent findings detailed in Table 2. However, using an alternative endpoint of a 100 CD4 cells/mm3 increase resulted in significantly higher odds of a CD4 response in the resistant group compared with the susceptible group, adjusted OR: 2.56 (95% CI: 1.11 to 5.86; P = 0.027). To ensure that these results were not due to undisclosed drug exposure, a subset of only patients who had been diagnosed HIV-1 positive for less than a year before enrollment into EuroSIDA were taken, which included 7 (9.9%) with resistant HIV and 64 (90.1%) with susceptible HIV; therefore, this analysis had very limited power. The adjusted OR of CD4 response for resistant versus susceptible was 0.98 (95% CI: 0.11 to 9.05; P = 0.984).
In this cohort of HIV-1- infected patients from across Europe, the overall prevalence of TDR in chronically infected, ART-naive patients was found to be 11.4%. There was no evidence of significant differences in TDR prevalence between 2-year time periods or between HIV-1 B and non-B subtypes.
This overall prevalence of TDR was found to be in line with the majority of studies investigating TDR across Europe.10,13,16-21,24 The Combined Analysis of Resistance Transmission Over Time of Chronically and Acute Infected HIV Patients (CATCH) study, similarly to EuroSIDA, analyzed sequences from recently and chronically infected patients across Europe and found a prevalence of 10.4%.10 NRTI resistance was found in 7.6%, NNRTI resistance in 2.9%, and major PI resistance in 2.5%. Differences in geographical location, study period, study population, study design, sampling methods, definitions of resistance, timing of the sampling, and sequencing methods could be responsible for differences in reported prevalence of TDR.43,44
The prevalence of TDR remained fairly stable over the years 1996-2004 in this analysis, after an initially high prevalence in 1994-1995. In a multivariable analysis there seemed to be no significant differences in any 2-year period compared with 1996-1997. Other research has reported conflicting trends over time. Increases in TDR over calendar time up to 2003 have been observed in a number of studies.26,28-32,36 In one US study, prevalence of NRTI resistance rose from 0% in 1996-1997 to 13.2% in 2000-2001 and PI resistance from 2.5% to 7.7% in recently infected patients.31 In the United Kingdom, an increasing prevalence of resistance in ART-naive patients was reported over the years 1996-2003 ranging from 11.0% to 19.2%.26 These could be explained by an increase in resistant strains in the HIV-infected population following the increasing availability of ART, treatment interruptions, or increasing high-risk behavior. Decreases in prevalence were observed in 57 acute or recent HIV seroconverters from 25.8% in 1997-1999 to 3.8% in 2000-200134 and in UK ART-naive patients from 14% in 2001-2002 to 8% in 2004.35 There is evidence that drug-resistant HIV, especially multidrug-resistant HIV and HIV with the M184IV mutation, has a substantially reduced transmission capacity compared with wild type.18 Therefore, effective treatment in chronically infected patients may be reducing the transmission of resistant HIV in recently infected patients.
A slightly higher prevalence of TDR was observed in patients infected with HIV-1 subtype B compared with non-B subtypes, but this difference was not statistically significant and supports previous findings by Jayaraman et al (2006).36 A larger number of HIV-1 non-B- infected patients is needed to conclude this with certainty.
The main analyses investigating initial virological and CD4 count response to cART were unable to show significant differences in patients with HIV-1 with full or intermediate resistance to at least one drug started compared with those fully susceptible. However, the power of the analyses to detect true differences was limited due to the relatively small number of patients in the resistant group, and so firm conclusions cannot be drawn from these data. Although the finding was not significant, an inferior virological response to cART in patients with resistant HIV was observed, which supported results found in 2 US studies investigating time to virological suppression after initiation of therapy in recently infected patients31,32 and in 3 European studies evaluating virological response in both chronically infected and patients with primary HIV infection.15,16,33 A further European study could not find any difference in mean change in viral load or CD4 count at months 6 and 12 after starting therapy between patients with TDR and those without TDR.45
Various sensitivity analyses also produced similar results with the exception of significantly higher odds of a 100 cells/mm3 CD4 count increase from baseline in the resistant group. Studies in the United Kingdom found that patients with TDR had higher rates of CD4 cell decline in the absence of therapy25,46; however, the CD4 count response after initiation of cART in these patients is unknown. There is some evidence that patients who develop NNRTI and PI resistance on first-line therapy and experience virological failure will have better CD4 cell increases than nonresponders without mutations. This may be due to a reduced viral fitness in resistant strains, which reduces immunological deterioration.47 An analysis of nearly 2000 patients on ART found little evidence of differences in CD4 slope for a given viral load >500 copies/mL according to the presence of resistance, with the exception of certain NNRTI mutations that were found to be associated with greater CD4 count declines but with large CIs around the estimates.48
The observed superior CD4 response in patients with resistant HIV in this analysis may be due to chance as there were few patients in this group. It may also be explained by variability in CD4 counts. Average CD4 cell measurements at baseline and in months 6-12 were analyzed, but as not all patients had additional measurements available, this resulted in similar findings as the main analysis (results not shown). All known, measured factors found to be potentially confounding the response were adjusted for in multivariable analyses. However, as the patients were from an observational study, unmeasured or unknown confounding variables may have biased the findings.49
Further limitations of this analysis should be recognized when interpreting these results. The average time from HIV- positive diagnosis to earliest resistance test was more than 3 years. Although EuroSIDA aims to collect all prior treatment data, when a patient is enrolled, it cannot be ruled out that errors with dates may have occurred, which could potentially mean undisclosed drug exposure. To try and ensure only truly ART-naive patients were included, plasma samples were required to be dated at least a month before starting ART. If the patient had more than one plasma sample available before starting therapy that had been analyzed for genotypic resistance, then results were cumulated to obtain the best estimate of the extent of mutated virus populations present in the individual.50 As routine assays can only detect mutations in the dominant virus, this gives a more conservative estimate of prevalence as mutations found in later tests are likely to have been present at transmission but were just not detected.
As EuroSIDA captures a geographically diverse population, it is in a position to monitor trends in TDR and to study its impact on the short-term outcomes of ART. It provides a heterogeneous population from a large number of centers all across Europe and has the same high standards of data collection and checking methods throughout. The centers involved in EuroSIDA tend to be highly specialized and consequently may have more clinical experience with HIV and earlier access to new treatments than centers not included; therefore, the cohort may not be completely representative of European clinics in general. However, as patients are enrolled consecutively, this should capture a broad representation of patients regularly seen, and because of the large numbers of clinics in the study, this may be more representative than any one clinic cohort.
In summary, the prevalence of TDR was found to be in line with many other studies from across Europe and above 10%, which according to current European guidelines indicates that genotypic resistance testing should be carried out before starting treatment. No significant differences in odds of virological suppression and in CD4 count response after initiation of a first-line cART regimen were found in this data set between patients with HIV-1 with full or intermediate resistance to at least one drug started compared with those fully susceptible, which could be due to the small number of patients with resistance and consequently low power. Further analyses on a larger number of patients are required to draw firm conclusions. Projects such as the ongoing European Coordinating Committee for the Integration of Ongoing Coordination Actions Related to Clinical, Virological and Epidemiological HIV Research (EuroCOORD) collaboration, integrating 5 projects including EuroSIDA, may provide the ideal study population for this.
The EuroSIDA study was supported by grants from the BIOMED 1 (CT94-1637) and BIOMED 2 (CT97-2713) programs and the fifth framework program (QLK2-2000-00773) of the European Commission. Unrestricted grants were also provided by Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Boehringer Ingelheim, and Roche. The participation of Swiss centers was funded by a grant from the Swiss Federal Office for Education and Science.
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Appendix: The EUROSIDA Study Group (national coordinators in parentheses)
Argentina: (M. Losso), A. Duran, Hospital J. M. 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, 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. Sambattakou, Ippokration General 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 Santa Maria Annunziata, Firenze; V. Vullo, M. Lichtner, University di Roma la Sapienza, Rome; A. Chirianni, E. Montesarchio, M. Gargiulo, Presidio Ospedaliero AD Cotugno, Monaldi Hospital, Napoli; G. Antonucci, F. Iacomi, P. Narciso, C. Vlassi, M. Zaccarelli, Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome; A. Lazzarin, R. Finazzi, Ospedale San Raffaele, Milan; M. Galli, A. Ridolfo, Osp. L. Sacco, Milan; A. d'Arminio Monforte, Istituto Di Clinica Malattie Infettive e Tropicale, Milan.
Latvia: (B. Rozentale), P. Aldins, Infectology Center of Latvia, Riga.
Lithuania: (S. Chaplinskas), Lithuanian AIDS Center, Vilnius.
Luxembourg: (R. Hemmer), T. Staub, Centre Hospitalier, Luxembourg.
The 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 University, 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 Center, St. Petersburg; S. Buzunova, Novgorod Center 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 center 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. Cited Here...
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