The introduction of highly active antiretroviral therapy (HAART) for the treatment of HIV-1 infection has resulted in a major decrease in HIV-1-related morbidity and mortality [1,2]. Initial HAART consisted of a protease inhibitor (PI) and two nucleoside analogue reverse transcriptase inhibitors (NRTI) [3–5]. This combination is known as divergent therapy since it targets two separate viral enzymes for HIV-1 replication: protease and reverse transcriptase [6,7]. Convergent therapy, targeting only the enzyme reverse transcriptase, might be an equally valid approach to the treatment of HIV-1 infection, with the advantage of preserving drugs from the PI class for additional treatment options [8,9]. It can be achieved by combinations of nucleoside analogues resulting in DNA chain termination, or with non-nucleoside drugs (NNRTI), which bind directly to and inhibit the action of reverse transcriptase .
In general, convergent therapy constitutes a simpler drug regimen in terms of number of tablets compared with divergent therapy and it can, therefore, contribute to therapy compliance . Adherence to therapy is an important determinant of durable virological success [12,13].
The objective of the Atlantic study is to compare the efficacy with respect to suppression of HIV-1 virus replication and the safety of two convergent treatment regimens with that of a divergent regimen. The need for such a comparison became more apparent while the study was ongoing as a result of reports of the emergence of an atherogenic lipoprotein profile, particularly in PI-containing treatment regimens, as well as other metabolic changes related to antiretroviral therapy use [14–18].
Interim results from the study were reported during international conferences . Because of the long follow-up period of the trial participants, it is possible to present long-term efficacy data up to 96 weeks after the start of treatment.
Antiretroviral drug-naive patients infected with HIV-1 who were at least 18 years of age, asymptomatic [Centers for Disease Control and Prevention (CDC) class A], had a plasma HIV-1 RNA concentration (pVL) of ≥ 500 copies/ml and a CD4 T lymphocyte count of at least 200 × 106 cells/l, were eligible to be enrolled in the study. In addition, they needed to have at least two pVL samples prior to the start of treatment and, for females, a negative pregnancy test within 1 month prior to the start of treatment. They were excluded if one of the following applied: breastfeeding; abnormal laboratory results at screening, defined as a hemoglobin concentration < 7 mmol/l (men) or < 6.5 mmol/l (women), a neutrophil count < 0.75 × 109 cells/l, a platelet count < 25 × 109 cells/l, an aspartate aminotransferase or alanine aminotransferase measurement ≥ 5 upper limit of normal, or a serum creatinine concentration ≥ 1.5 upper limit of normal; a history of neuropathy, nephrolithiasis or pancreatitis; having received radiotherapy or chemotherapy in the month prior to the start of treatment or the anticipated need to receive such a treatment; having a severe non-HIV-related disease that is assumed to be incompatible with the study treatment as judged by the investigator; alcohol or drug abuse (methadone not included) that is expected to lead to non-compliance or loss to follow-up; or being co-infected with HIV-2.
Recruitment and evaluation of participants took place amongst the HIV-infected patients presenting for regular care at 17 international participating institutions. The study was approved by the ethical committees of these institutions. All participants gave written informed consent.
Treatment allocation and sample size
A computer program at the study coordination centre (IATEC, the Netherlands) generated the treatment allocation sequence through a minimization procedure (`biased coin’ based on disbalance P = 0.2-0.8). Minimization variables were pVL (≤ 20 000 versus > 20 000 copies/ml), CD4 cell count (≤ 350 versus > 350 × 106 cells/l) and study site. The random element consisted of simple randomization. Treatment allocation was concealed from the investigator prior to enrollment of the patient. The allocation sequence was implemented by sending a fax message with treatment details to the study site enrolling the patient, after checking eligibility criteria. Since no patients were enrolled at the study coordination centre itself, generation and implementation of the allocation sequence were fully separated. No blinding existed after treatment allocation.
The study was powered (α = 0.05, β = 0.2) to detect a difference of at least 15% between study arms in the percentage of patients reaching a pVL < 500 copies/ml at 48 weeks after the start of treatment. The null hypothesis was formulated as there being no difference between the study arms in the percentage of patients reaching such a pVL.
All patients enrolled in the study received didanosine (Videx chewable tablets) and stavudine as the ‘antiretroviral backbone'. In addition, the patients were allocated to the use of indinavir (IDV), nevirapine (NVP) or lamivudine (3TC). All drugs were taken orally. Didanosine was dosed as 400 mg once daily (250 mg once daily when body weight < 60 kg), stavudine as 40 mg twice daily (30 mg twice daily when body weight < 60 kg), IDV as 800 mg three times a day, NVP as 400 mg once daily after an initial dosing scheme of 200 mg once daily for the first 2 weeks, and 3TC as 150 mg twice daily. Patients were encouraged to adhere to the prescribed treatment regimen.
The use of didanosine and stavudine as the antiretroviral backbone has proved to be effective in other studies [20,21]. Once daily dosing of didanosine in this study was used prior to the approval of the once daily capsule formulation, but pharmacokinetic and clinical data supported this dosing scheme [22,23].
Follow-up and assessment
Evaluation took place at 4 weeks (screening) and 2 weeks before start of treatment (week 0) and then 2, 6, 12 and every 12 weeks thereafter. Follow-up of patients is intended to last up to 264 weeks.
At each study visit, a complete blood count and analysis of serum chemistry and urine was performed, as well as measurement of pVL and CD4 cell count. All laboratory examinations, with the exception of pVL and blood lipids, were carried out at the participating institutions. Measurement of pVL was carried out at a central laboratory (LabCorp, Research Triangle Park, North Carolina, USA) using the Roche Amplicor assay version 1.5 (Roche Molecular Systems, Pleasanton, California, USA). Two different input volumes were used, yielding a lower limit of quantification of 500 copies/ml and 50 copies/ml, respectively. When the pVL was > 50 000 copies/ml, the assay was repeated with the sample diluted 1 : 100.
Measurement of total cholesterol (TC), high density lipoprotein cholesterol (HDL-c), and triglycerides was also performed centrally at Labcorp using enzymatic assays. The low density lipoprotein cholesterol (LDL-c) concentration was calculated using the Friedewald formula, but only if the plasma concentration of triglycerides was < 4.5 mmol/l.
Safety was assessed by reporting of adverse events and laboratory toxicities, which were classified and graded according to the Aids Clinical Trial Group toxicity scale.
The primary analysis with respect to efficacy of the treatment compared the percentage of patients with a pVL < 500 copies/ml at week 48 in the intention-to-treat (ITT) population (all enrolled patients). Patients were considered to have a treatment failure when either they had a pVL ≥ 500 copies/ml at any point after 24 weeks of follow-up that was confirmed by analysing an additional sample or they withdrew from the study or changed their allocated treatment. For the additional efficacy analysis at week 96, change of allocated treatment between week 48 and 96 was not regarded as treatment failure. Failure at this time point was, therefore, defined by virological parameters only: a confirmed pVL ≥ 500 copies/ml between week 48 and 96. Missing pVL observations were regarded as being > 500 copies/ml unless the pVL was undetectable directly before and after the date of the missing study visit, in which case the pVL was interpolated to be undetectable.
Additional efficacy analyses compared the percentage of patients with a pVL < 500 copies/ml in an on- treatment (OT) population with the percentage of patients with a pVL < 50 copies/ml in both the ITT and the OT population. Furthermore, the change of CD4 cell count over time was analyzed. Only patients that used their allocated treatment at the time point of analysis were included in the OT analyses. All efficacy analyses were repeated after 96 weeks of follow-up.
The safety analysis compared the occurrence of grade III/IV adverse events that were associated with the use of study medication at week 96 in the ITT population, excluding those patients that never started allocated treatment. Laboratory toxicities were identified directly from the laboratory results. When the same event was present more than once in the same patient, the event with the highest toxicity grade was included in the analysis.
The change in plasma concentrations of TC, HDL-c, LDL-c and triglycerides was assessed by calculating the mean percentage difference between baseline and week 96 for patients still using their allocated treatment. To use as many late time points as possible where plasma lipid estimates were available, the week 96 sample was defined as the sample closest to week 96, but after week 70. Blood for lipid samples was drawn without a mandatory overnight fast of the patients.
All analyses were carried out according to a predefined data analysis plan, using SAS statistical package version 8.0 (SAS Institute, Cary, North Carolina, USA). Differences in proportion were analysed by an chi square test or Fisher's exact test where appropriate. The change of CD4 cell count over time was analyzed using a generalized linear model (`proc mixed’ procedure). Treatment arm, baseline CD4 cell count and time (categorical) were used as covariates and the covariance matrix of the repeated CD4 cell count measurements was left completely free. This method is capable of dealing with missing values and uses all subjects with at least one measurement. It leads to valid statistical inference under the assumption that the missing measurements are ‘missing at random'. This method is preferred over the use of multiple ANOVA tests at different time points, since this last method does not take into account the fact that the CD4 cell count measurements in one patient are correlated, and has the disadvantage of multiple testing. The changes in lipid plasma concentrations were tested for significance using an F-test.
The overall level of statistical significance was set at α = 0.05. Pairwise comparisons were only performed when the overall test statistic was significant. The level of significance for these pairwise comparisons was interpreted using the Bonferroni method.
Between May 1997 and October 1998, a total of 298 patients were enrolled. Fifteen patients (5%) never started their allocated treatment, while 85 patients (29%) discontinued the study before week 48. This left 198 patients at week 48. The patients that changed their allocated treatment before week 48 (n = 27) were considered to have discontinued the study, as per protocol. However, to maintain the study adequately powered, these patients were included in the study and in the analyses again from week 48 onwards. Between week 48 and 96, 47 out of 225 (198 + 27) patients (21%) discontinued the study. At week 96, 139 of the initially enrolled patients (47%) remained on randomized treatment (Fig. 1).
There were 25 patients in the NVP arm that accidentally received an alternative dose of NVP (200 mg twice daily instead of 400 mg once daily as per protocol). These patients remained in the allocated treatment group, since pharmacokinetic studies have shown that the total exposure to NVP is not different for these two separate dosing regimens . The 24 protocol violators with respect to CDC class at entry (B or C instead of A as per protocol) remained in the study and were included in the analyses.
The baseline characteristics of the patients were similar between the three treatment arms (Table 1).
The primary analysis (pVL < 500 copies/ml, ITT, n = 298) showed that after 48 weeks of follow-up 57.0% of the patients [95% confidence interval (CI), 47.3–66.7] in the IDV arm had a treatment success (Table 2). For the NVP and the 3TC arms, these percentages were 58.4 (95% CI, 48.2–68.7) and 58.7 (95% CI, 49.5–68.0), respectively. These differences did not reach statistical significance (P = 0.965). A post hoc analyses tested if this viral suppression was independent from baseline pVL by performing a logistic regression with the variables stratum (baseline pVL ≤ 100 000 copies/ml versus pVL > 100 000 copies/ml) and study arm. The probability of success in the study arms did not differ statistically significantly between the strata (interaction term stratum × arm, P = 0.697). Treatment success (< 500 copies/ml) in the OT population at 48 weeks (n = 198) was 81.8% (95% CI, 70.4–90.2), 89.5% (95% CI, 78.5–96.0), and 81.3% (95% CI, 70.7–89.4) in the IDV, NVP and 3TC arms, respectively (P = 0.390).
Treatment success with pVL < 50 copies/ml in the ITT population after 48 weeks was 55.0% (95% CI, 45.2–64.8), 53.9% (95% CI, 43.6–64.3), and 45.9% (95% CI, 36.5–55.2) in the IDV, NVP, and 3TC arms, respectively (P = 0.353). In the OT population, such treatment success occurred in 80.3% (95% CI, 68.7–89.1), 80.7% (95% CI, 68.1–90.0), and 58.7 (95% CI, 46.7–69.9) in the IDV, NVP, and 3TC arms, respectively (P = 0.004). These differences were statistically significant when comparing IDV and 3TC (P = 0.006), NVP and 3TC (P = 0.007), but not when comparing IDV and NVP (P = 0.956).
Data on efficacy for week 96 (ITT: n = 298; OT: n = 139) are presented in Table 2. Direct comparisons between the efficacy data of week 48 and week 96 is difficult since the definitions used for treatment failure were not identical (see the Methods). Despite this change, the trends present in the week 48 data were also seen in the week 96 data. There was no difference between the treatment arms in virological suppression to < 500 copies/ml, but there was a less effective suppression to < 50 copies/ml in the patients allocated to 3TC. The percentages of patients with ‘undetectable’ viremia over time are summarized in Fig. 2.
The change in CD4 cell counts over time is depicted in Fig. 3. All three study arms showed an increase from baseline during follow-up. Patients using IDV had an estimated mean increase of 238 × 106 cells/l (SE, 32), compared with 139 × 106 cells/l (SE, 30) for patients using NVP and 233 × 106 cells/l (SE, 29) for patients using 3TC. These estimates are adjusted for baseline level. The fixed effect for study arm was not statistically significant (P = 0.103), while that for time and the interaction between study arm and time were (P = 0.004 and P = 0.012, respectively). The modulating effect of time is especially evident after 24 weeks, when the increase in the NVP arm is slower than that for the other study arms.
One patient in the 3TC arm died 2 months after discontinuation of all study medication. At the start of the study, this 48-year-old male patient was asymptomatic, had a pVL of 188 525 copies/ml, and a CD4 cell count of 307 × 106 cells/l. He stopped the medication after 3 months of use because of hospitalization for pancreatitis, which was probably study-drug related. The patient had pre-existing risk factors for developing pancreatitis (suspected alcohol abuse) and an elevated concentration of amylase prior to study entry.
Overall, 26 patients discontinued the study before 96 weeks of follow-up as a consequence of the development of an adverse event of any severity: 11 (12%) in the IDV arm, six (7%) in the NVP arm, and nine (9%) in the 3TC arm (Fig. 1). The number of patients with a grade III/IV adverse event that was probably or certainly related to study medication is reported in Table 3. Eighteen (19%) patients that were allocated to IDV developed at least one of such an event, compared with 11 patients (13%) in the NVP arm, and 11 patients (11%) in the 3TC arm. All reported dermatological adverse events of grade III/IV severity occurred in different patients using NVP, resulting in an incidence of 7%. Urogenital grade III/IV adverse events were only seen in the IDV arm, except for one patient with renal failure in the 3TC arm. Peripheral neuropathy grade III/IV was seen in five patients. Lipodystrophy was also reported in five patients. Lactic acidosis was reported in a single patient. Reporting of lipodystrophy was solely on the basis of its recognition as a potential study-associated adverse event, and this may have resulted in an underestimation of the syndrome's prevalence.
During the 96 weeks of follow-up, four CDC group C events were reported in three patients; one patient with two events in the 3TC arm and one patient each in the IDV and the NVP arm. All these events occurred in patients that were asymptomatic at the time of inclusion and, therefore, constitute HIV disease progression.
Grade III/IV laboratory toxicities are reported in Table 4. Elevated transaminases (aspartate aminotransferase or alanine aminotransferase) occurred in four (4%), eight (9%), and nine (9%) patients, using IDV, NVP, and 3TC, respectively. An elevated level of gamma-glutamyl transaminase was most often seen in the NVP arm (21%) and is most likely reflecting induction of liver metabolism. No grade III/IV elevation of creatinine concentration was reported in any of the patients.
Changes in lipid profile
The baseline values of the lipid concentrations and the mean percentage difference between baseline and week 96 are summarized in Table 5. The concentration of TC increased significantly in all study arms: 22.0% (SE, 3.7), 22.4% (SE, 7.9) and 14.0% (SE, 2.6) for IDV, NVP and 3TC, respectively. The percentage increase in LDL-c was statistically significant in patients using IDV (14.1%; SE, 5.9), but not in patients using NVP (19.1%; SE, 11.4), and 3TC (3.1%, SE, 5.0). The percentage increase in the concentration of triglycerides was statistically significant in patients using IDV (96.4%, SE, 38.6) and 3TC (60.5%, SE, 14.1), but not in those using NVP (46.4%, SE, 25.1). The differences between the study arms for these parameters were not statistically significant.
Between baseline and week 96, the patients using NVP had a mean increase in HDL-c of 39.7% (SE, 6.7) compared with 5.7% (SE, 5.6) and 20.1% (SE, 5.7) for patients using IDV and 3TC, respectively (P = 0.001). For pairwise comparisons, the level of statistical significance was adjusted to P < 0.017. The difference between NVP and IDV was, therefore, statistically significant (P < 0.001), but the differences between NVP and 3TC (P = 0.020), and between IDV and 3TC (P = 0.098) were not. Patients in the IDV arm had a statistically significant increase in TC/HDL-c ratio (24.5%; SE, 9.1). Although patients in the 3TC arm had a decrease of this ratio during the first 48 weeks of follow-up, at 96 weeks the ratio was increased by 1.9% (SE, 4.8). In contrast, patients using NVP were the only ones with a decrease of the TC/HDL-c ratio up to 96 weeks (5.7%; SE, 8.4). The difference between NVP and IDV is statistically significant (P = 0.006), but the differences between NVP and 3TC (P = 0.449), and IDV and 3TC (P = 0.032) are not. The changes in HDL-c and TC/HDL-c ratio over time are depicted in Fig. 4.
The Atlantic study compared the efficacy and safety of one divergent and two convergent antiretroviral treatment regimens during a long follow-up period of 96 weeks.
The primary efficacy analysis did not reveal statistically significant differences between the three study arms. In all study arms, viral suppression to pVL < 500 copies/ml at week 48 occurred in 55–60% of the patients allocated to the regimen. Of all patients that were still using their allocated treatment after 48 weeks, only patients in the 3TC arm were less likely to reach viral suppression to < 50 copies/ml. After 96 weeks of treatment, all patients allocated to 3TC, irrespective of therapy change, were less likely to have viral suppression below this level. The estimated mean increase from baseline of CD4 T lymphocytes over time was slower, and approximately 100 × 106 cells/l less in the NVP arm compared with both other arms. The incidence of reported adverse events and laboratory toxicities was comparable in the study arms. Patients using NVP had a significantly larger increase in HDL-c and decrease in TC/HDL-c ratio, while this ratio increased in patients using IDV. In the IDV arm, triglycerides increased by 96% while no statistically significant rises in triglycerides were observed in the other two treatment arms.
The finding of comparable virological efficacy between the study arms in suppression to a pVL < 500 copies/ml is compatible with the results of a systematic review of triple combination therapies in antiretroviral therapy-naive patients . In this review, the overall percentages of patients achieving a pVL < 400 copies/ml after 48 weeks in ITT analyses were 53% for patients using two NRTI and one PI, 57% for patients using two NRTI and one NNRTI, and 54% for patients using three NRTI. These treatment regimens were reported to be also comparable in viral suppression to pVL < 50 copies/ml (46%, 51% and 47%, respectively). This latter finding could not be reproduced by the present study, which showed the triple nucleoside combination to be significantly less effective than the other two regimens in suppression the pVL to < 50 copies/ml.
Staszewski et al.  compared a regimen of two NRTI (zidovudine and lamivudine) with either one NNRTI (efavirenz) or one PI (IDV) with a follow-up of 48 weeks. The regimen containing efavirenz performed superior in terms of virological suppression, while there was no difference in the increase in CD4 cell count over time. This does not agree with the present findings of no statistically significant difference in efficacy between the PI-based regimen and the NNRTI-based regimen. Direct comparison between the two trials is difficult since the antiretroviral drug backbone is different and the patients in the trial by Staszewski had a much higher median pVL at entry.
The results of the Atlantic study do not support the hypothesis that the probability of treatment success (pVL < 500 copies/ml) is different for the treatment regimens when patients with baseline pVL ≤ 100 000 copies/ml and baseline pVL > 100 000 copies/ml are compared. This is in accordance with the findings of Staszewski et al. , comparing regimens containing zidovudine plus lamivudine with either indinavir or abacavir (CNAAB study), although such a differential effect was found for viral suppression < 50 copies/ml. However, it is unfortunate that in the CNAAB study no information is given on the interaction effect between treatment arm and baseline pVL stratum and consequently interpretation of this finding remains difficult.
In the Atlantic study, it is not known whether the efficacy of NVP may have been compromised by the use of NVP as a once daily regimen. Although once and twice daily dosing of NVP results in a comparable total exposure, the once daily regimen provides somewhat higher peak and lower trough levels compared with twice daily dosing . Several studies have shown a clear correlation between plasma level of NVP and the speed and durability of virological response [26,27]. In a study comparing once daily and twice daily regimens of NVP in combination with stavudine and didanosine, both dosing schemes showed equal efficacy . The direct comparison between NVP once daily and twice daily is being addressed in the ongoing 2NN study.
The effect of treatment arm on the increase in CD4 T lymphocytes over time did not reach statistical significance, although patients in the NVP arm had a mean estimated increase of 100 × 106 cells/l less than patients in the other arms. When the change over time of the absolute lymphocyte count was analyzed, the same effect was seen, but not with the change of CD8 T lymphocytes or the CD4 percentage over time. The observed magnitude of the increase from baseline in CD4 cell count in the NVP arm is comparable with that found in the INCAS trial . In this trial, patients treated with two NRTI and NVP showed a mean increase from baseline in the number of CD4 T lymphocytes of 139 × 106 cells/l up to 52 weeks after start of treatment. In a preliminary analysis of a Dutch cohort of HIV-1 infected patients (Athena-cohort), therapy-naive patients treated with a first-line regimen containing IDV showed a statistically significant larger increase in CD4 cell count after 96 weeks (240 × 106 cells/l) than patients using a NVP-containing regimen as first-line therapy (150 × 106 cells/l). The explanation as well as the clinical relevance for the observed difference between the NVP arm and the other arms remains unclear.
The findings of the Atlantic study are compatible with those of other studies with respect to the incidence of adverse events and laboratory toxicities. The incidence of NVP-associated rash reported in this study is at the lower end of the wide range that has been reported in the literature [27–29]. In a review of 21 adult antiretroviral treatment trials, Reisler et al.  found an incidence of hepatotoxicity of 5% when using two NRTI and one PI, 8% for two NRTI and one NNRTI, and 5% for the use of two or three NRTI.
The significant increase in plasma HDL-c and decrease in TC/HDL-c ratio in patients using NVP has been described by van der Valk et al. , using the same data but only up to 24 weeks of treatment. That the effect is sustained for at least 96 weeks is of importance, since this lipid profile is associated with a marked decrease in coronary artery disease risk in other settings . The mechanism through which this effect occurs remains to be elucidated and is discussed elsewhere . In patients using IDV, TC, LDL-c, triglycerides and the TC/HDL-c ratio increased. This lipoprotein profile is associated with an increased incidence of coronary artery disease in other settings. Whether blood samples from patients had been drawn fasting was not recorded. However, a lack of fasting is known not to influence estimates of TC or HDL-c significantly. Whether the observed differences between the treatment regimens regarding lipid profile will have an effect on the incidence of coronary artery disease morbidity or mortality in HIV-1-infected patients needs to be examined in more detail in large ongoing prospective studies such as the D:A:D study .
The overall discontinuation rate in the Atlantic study was 40% during 2 years of follow-up, while only 46% of the enrolled patients were still using their allocated treatment at this point in time. The use of the original didanosine formulation in all study arms may have contributed to this, although we did not investigate this. Such a discontinuation rate limits the inferences that can be drawn from the study. However, since the discontinuation rate was comparable in all study arms, it is unlikely that this observation has introduced a significant selection bias. The results of the trial are generalizable since all patients enrolled in the study were selected from those presenting for regular care and the different geographical areas were equally represented in the three study arms. Discontinuation because of an adverse event was similar in all study arms, making the safety analyses a valid estimate of the tolerability of the regimens used.
In conclusion, the results of the Atlantic study demonstrate that a regimen with didanosine and stavudine plus IDV, NVP or 3TC is associated with comparable virological suppression to a pVL of ≤ 500 copies/ml, but that the regimen with 3TC is significantly less likely to achieve additional suppression to ≤ 50 copies/ml. Suppression of the pVL to < 20–50 copies/ml is a better predictor for durable virological success than suppression to < 400–500 copies/ml [34,35]. Therefore, the triple NRTI regimen appears to be inferior with respect to virological suppression than the other two regimens, although this does not result in a less adequate CD4 T lymphocyte response. The rate of discontinuation because of an adverse event and the incidence of grade III/IV adverse events are comparable between the study arms, indicating equal tolerability of the regimens. The use of NVP had a favourable effect on the plasma lipid profile, which in other settings is associated with a decreased cardiovascular risk.
The planned follow-up of 264 weeks will provide the opportunity to study long-term toxicity and lipid profiles for the regimens used.
The Atlantic Study was investigator-initiated by Profs. Sommadossi and Lange. We acknowledge Gerrit-Jan Weverling for statistical support and Engelien Bijleveld for logistic and computer support.
Sponsorship: The sponsor of the study was the International Antiviral Therapy Evaluation Centre, University of Amsterdam, the Netherlands. Funding for the first 48 weeks of the Atlantic Study was provided by Bristol-Myers Squibb, Merck and Boehringer Ingelheim GmbH.
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Study sites and other members of the study AMC Amsterdam, the Netherlands; Germans Trias i Pujol, Badalona, Spain (A. Jou, G. Sirera, J. Romeu, Dra C. Tural); Hospital Clinic, Barcelona, Spain (E. Martinez, L. Luzano); University of Alabama, Birmingham Alabama, USA; CHU Saint-Pierre, Brussels, Belgium; St Laszlo Hospital, Budapest, Hungary (J. Szlavik); Northwestern University Medical School, Chicago Illinois, USA (B. Berzins, J. Drury-Rosen, T. Slom, C. Achenbach); Goethe-University, Frankfurt, Germany (T. Leder, B. Bachmann); Medizinische Hochschule, Hanover, Germany (M. Stoll, G.M. Behrens, D. Meyer-Olsen); Faculdade de Medicina de Lisboa, Lisbon, Portugal (M. Doroana); Institutio de Salut Carlos III, Madrid, Spain (R. Roderiquez-Rosado); University Hospital, Milan, Italy (T. Bini); Cornell University, New York, USA (M. Glesby, D. Pearson, T. Stroberg); Hôpital Pitié-Salpêtriè, Paris, France (M.A. Valantin, M. Bonmarchand); University of Utah, Salt Lake City Utah, USA (S. Bracken); St Paul's Hospital, Vancouver British Columbia, Canada (M. Harris); AIDS Research Centre, Warsaw, Poland (A. Piasek, J. Higersberger, E. Bakowska, P. Pulik, A. Lipniacki, E. Burkacka).