Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia

Journal of Hepatology 44 (2006) 97–103 www.elsevier.com/locate/jhep

Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia* Stefan Zeuzem1,*, Maria Buti2, Peter Ferenci3, Jan Sperl4, Yves Horsmans5, Janusz Cianciara6, Endre Ibranyi7, Ola Weiland8, Stephanie Noviello9, Clifford Brass9, Janice Albrecht9 1

Department of Medicine, Saarland University Hospital, Homburg/Saar, Germany 2 S. Hepatologia-Planta 9, Hospital Valle d’Hebron, Barcelona, Spain 3 University Clinic of Vienna, Department of Internal Medicine IV, Vienna, Austria 4 Institute for Clinical and Experimental Medicine, Department of Hepatogastroenterology, Videnska 1958/9, Prague, Czech Republic 5 Hospital Saint Luc-UCL, Bruxelles, Belgium 6 Warsaw Medical University, Warsaw, Poland 7 St Lazlo Hospital, Budapest, Hungary 8 Karolinska University Hospital Huddinge, Department of Infectious Diseases, Stockholm, Sweden 9 Schering-Plough Research Institute, Kenilworth, NJ, USA

See Editorial, pages 4–7 Background/Aims: Previous studies using standard interferon and ribavirin combination therapy suggested that patients infected with HCV-1 and a low pretreatment HCV-RNA level can be treated for 24 weeks without compromising sustained virologic response rates. The aim of the present study was to investigate this schedule in the era of pegylated interferon-a plus ribavirin. Methods: Patients chronically infected with HCV-1 (nZ235) and a screening viremia %600,000 IU/mL (real-time PCR) were treated with peginterferon alfa-2b 1.5 mg/kg subcutaneously once weekly plus ribavirin 800–1400 mg/day based on body weight for 24 weeks. Results: End-of-treatment and sustained virologic response rates were 80 and 50%, respectively. The 48-week historical control (Manns et al., Lancet 2001;358:958–65) had similar end-of-treatment (74%) but higher sustained virologic response rates (71%). This difference was due to a high virologic relapse rate after 24 weeks of therapy (37%) compared with the historical control (4%). A subset of patients who had undetectable serum HCV-RNA at treatment week 4, however, achieved similar sustained virologic response rate (89%) as in the control group (85%). Conclusions: HCV-1 infected patients with a low baseline HCV-RNA concentration who become HCV-RNA negative at week 4 may be treated for 24 weeks without compromising sustained virologic response rates. q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Hepatitis C; Treatment duration; HCV genotype; Pretreatment viremia; Peginterferon; Ribavirin; Early virologic response

Received 20 July 2005; received in revised form 17 October 2005; accepted 18 October 2005; available online 7 November 2005 * The authors who have taken part in this study have declared a relationship with the manufacturers of the drugs involved and they received funding from the drug companies involved to carry out their research. Data of the present study were presented in part at the 40th Annual Meeting of the European Association for the Study of the Liver (EASL), April 13–17, 2005, Paris, France and at the Digestive Disease Week, May 14–19, 2005, Chicago, IL, USA. * Corresponding author. Address: Klinik fu¨r Innere Medizin II, Saarland University Hospital, Kirrbergerstr., 66421 Homburg/Saar, Germany. Tel.: C49 6841 16 23201; fax: C49 6841 16 23267. E-mail address: [email protected] (S. Zeuzem). Abbreviations: ALT, alanine aminotransferase; HCV, hepatitis C virus; PEG, polyethylenglycol; ULN, upper limit of normal. 0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2005.10.003

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1. Introduction

2.2. Study design

Hepatitis C virus (HCV) infection may progress to chronic hepatitis, cirrhosis, and its sequelae [1–3]. Treatment of HCV-infected patients with interferon-a can achieve viral clearance and improve histology and prognosis [4,5]. In the era of standard interferon alfa plus ribavirin, the duration of treatment in patients with chronic hepatitis C was tailored according to HCV genotype and baseline viremia; patients infected with HCV genotype 1 (HCV-1) and high baseline viremia were treated for 48 weeks, while patients infected with HCV-1 and low baseline viremia as well as all patients infected with HCV-2 or HCV3 were treated for 24 weeks [6–8]. More recently, standard interferons have been chemically modified using polyethylenglycol (PEG) to improve antiviral efficacy. Higher sustained virologic response rates in patients with chronic hepatitis C have been reported for the pegylated forms of interferons compared with standard interferons both in monotherapy as well as in combination therapy with ribavirin [9–12]. In these trials patients were treated for 48 weeks. Additional prospective trials in patients chronically infected with genotypes HCV-2 or HCV-3 showed that the treatment duration can be reduced from 48 to 24 weeks without compromising antiviral efficacy [13,14]. Data regarding optimal duration of treatment for patients infected with HCV-1, however, are sparse. The aim of the present study was to investigate efficacy and safety of peginterferon alfa-2b plus ribavirin administered for 24 weeks in patients chronically infected with HCV-1 and a low baseline serum HCV RNA concentration.

This phase 4, single-arm, open-label, historical-control study assessed the safety and efficacy of 24 weeks of treatment with peginterferon alfa-2b plus ribavirin in previously untreated patients with chronic hepatitis C who were infected with HCV-1 with a screening HCV-RNA concentration %600,000 IU/mL. Eligible patients were treated with peginterferon alfa-2b (PegIntronw, Schering Plough Corp., Kenilworth, NJ) 1.5 mg/kg once per week subcutaneously plus ribavirin (Rebetolw, Schering Plough Corp., Kenilworth, NJ) 800–1400 mg/day orally (!65 kg, 800 mg; 65–85 kg, 1000 mg; O85–105 kg, 1200 mg; O 105 kg, 1400 mg). Weight-based dosing of ribavirin (O10.6 mg/kg/day) was selected to provide the standard of care dosing regimen as well as the optimal dosing regimen with regard to safety and efficacy as established in the historical control [11]. The dose of each study medication was based on the patient’s weight at entry. Patients were treated for 24 weeks, then followed for an additional 24 weeks. The study was approved by the ethics committees at the participating centers and conducted according to the Declaration of Helsinki and the ICH/CPMP guidelines ‘Good Clinical Practice‘. All patients gave written informed consent before enrollment. Patients were evaluated as outpatients for safety, tolerance, and efficacy at weeks 4, 8, 12, 18, and 24 during treatment and at weeks 4, 12, and 24 following the end of treatment. HCV-RNA was quantified by real-time polymerase chain reaction technology (lower limit of detection 29 IU/mL). HCV genotyping was performed by direct sequencing of the 5’-noncoding region. Liver biopsy specimens were assessed by an experienced pathologist who was unaware of clinical and biochemical data as well as of treatment regimen and response. Steatosis was graded according to the percentage of hepatocytes containing visible macrovesicular steatosis. Histological results were classified according to internationally standardized criteria [15].

2.3. Study end points

2. Patients and methods

The primary efficacy endpoint for this study was the proportion of patients with a sustained virologic response, defined as undetectable plasma HCV-RNA levels at 24 weeks following the end of treatment. The secondary endpoint was the proportion of patients with a sustained virologic response and normalization of alanine aminotransferase (ALT) at the end of the follow-up period. The safety and efficacy of 24 weeks of treatment in this trial were compared with the historical control that treated patients with combination therapy including O10.6 mg/kg/day of ribavirin for 48 weeks [11]. Safety data were also compared with the initial 24 weeks of therapy in the historical control.

2.1. Patients

2.4. Statistical analysis

Male and female patients aged 18–70 years with compensated chronic HCV-1 infection not previously treated with interferon, ribavirin and/or amantadine were eligible for enrollment. Eligible patients tested positive for HCV-RNA by reverse transcription-polymerase chain reaction with a concentration %600,000 IU/mL, had a liver biopsy taken within 12 months prior to the screening visit showing chronic hepatitis, and had at least one elevated serum alanine aminotransferase (ALT) level at screening or entry into the trial. Entry leucocyte and platelet counts had to be at least 3000 and 80,000/mL, respectively. Hemoglobin values at entry visit had to be at least 12 g/dL for females and at least 13 g/dL for males. Patients with the following criteria were excluded: any other cause of liver disease or other relevant disorders including human immunodeficiency or hepatitis B virus coinfection, clinically significant hematologic, hepatic, metabolic, renal, rheumatologic, anaphylactic reactions, neurological or psychiatric disease, clinically significant cardiac or cardiovascular abnormalities, organ grafts, systemic infection, clinically significant bleeding disorders, evidence of malignant neoplastic disease, average daily intake of alcohol exceeding 80 g of ethanol, or drug abuse within the past two years. Further exclusion criteria were pregnancy and lactation.

The primary efficacy analysis was based on 235 enrolled patients. A prediction model for sustained virologic response was developed using data from Manns et al. [11]. This model included the following prognostic factors: genotype, baseline HCV-RNA level, presence or absence of bridging fibrosis (F3) or cirrhosis (F4), age and gender. The model was then used to predict sustained virologic response rates for the HCV-1 infected patients with low baseline viremia in the present study, had they received 48 weeks of treatment. If the estimated sustained virologic response rate for 48 weeks of treatment based on the model fell within the 95% confidence interval of the actually observed sustained virologic response rate of the present study, then it was concluded that 24 weeks of treatment is equivalent to 48 weeks of treatment. Single-variable logistic regression was used to compute p-values and odds ratios for the effect of prognostic factors (those observed at baseline and also treatment duration) upon sustained response. Stepwise regression analysis was performed to determine the significance of the results from the single-variable logistic regression analysis. The classification tree approach (SAS Enterprise Miner, Tree model using the Chi-square splitting criterion) determined the relationship between baseline viral load and sustained virologic response.

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3. Results

3.1. Biochemical and virological response

For this study, which was performed between October 2001 and October 2004 in 43 European centers, 724 patients were screened and 237 patients were enrolled. Two patients did not have adequate information for analysis (Fig. 1), and, therefore, will be presented in demographics and adverse events, but not in the efficacy analyses. Of the remaining 235 patients, two did not receive treatment and are included in the efficacy analysis as nonresponders. The baseline characteristics of the patients are summarized in Table 1.

An overall intent-to-treat virologic response at the end of therapy was achieved by 189 of 235 patients (80%) and a sustained virologic response by 117 of 235 patients (50%). Using the data of the study by Manns et al. [11], a sustained virologic response rate of 69% was predicted if the present study cohort was treated for 48 weeks. This estimated sustained virologic response rate fell outside the 95% confidence interval (43–56%) of the observed virologic response rate after 24 weeks treatment in the study cohort and therefore did not meet the criterion

484 Patients not enrolled 454 did not meet protocol criteria 19 did not wish to continue 4 administrative reasons 3 lost to follow-up 3 adverse events 1 missing reason

724 Patients screened for eligibility

3 Patients with indeterminate genotype

237 Patients enrolled to 1.5 µg / kg / week peginterferon alfa-2b plus 800-1400 mg/day ribavirin for 24 weeks

2 Patients not included in efficacy analysis

235 Patients included in efficacy analysis, 2 patients did not receive treatment (nonresponders) 15 Patients discontinued treatment 7 for adverse events 3 noncompliance with protocol 2 lost to follow-up 2 subjects did not wish to continue 1 administrative reason 220 Patients completed 24 weeks of treatment

6 Patients lost during follow-up

214 Patients completed follow-up period

Fig. 1. Trial profile.

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Table 1 Demographic, biochemical, molecular, and histological profile of patients with chronic hepatitis C at baseline Demographic characteristics No. (M/F) Caucasian Body weight (kg)b Age (years)b Risk factor for transmission Parenteral Transfusion Sporadic/other Missing Time since exposure (years)b,c Biochemistry ALT (!ULN)b Molecular parameters Baseline serum HCV-RNAd %600,000 IU/mL O600,000 IU//mL Mean Knodell score I (periportalGbridging necrosis) II (parenchymal injury) III (portal inflammation) ICIICIII (total inflammation) IV (fibrosis) Steatosis 0 O0–5% O5–32% O32–66% O66% Missing

237 (127/110)a 225 (95%) 71.3 (44–111) 42.2 (18–69) 77 (33%) 67 (28%) 91 (38%) 2 (1%) 17.6 (0.6–52.0) 2.31 (0.4–7.7)

200 (84%) 37 (16%) 2.7 1.9 2.7 7.2 1.2 96 (41%) 84 (35%) 40 (17%) 1 (!1%) 0 (0%) 16 (7%)

ALT, alanine aminotransferase; ULN, upper limit of normal. a 235 patients were treated. b Mean (range). c Sporadic cases not considered. d Pretreatment HCV RNA levels were determined at the screening and entry visits. Protocol eligibility was determined from the screening viral load. However, for purposes of analysis, the pretreatment virologic sample closest (in time) to the enrollment date was used to determine the baseline viral load. All 37 patients who had a baseline viral load of O600,000 IU/ mL had a viral load of %600,000 IU/mL at the screening determination.

3.2. Predictors of response Single-variable analysis identified baseline HCV-RNA level, duration of treatment, and age as potential predictors of response. After stepwise multivariable logistic regression analysis, baseline HCV-RNA level (P!0.0001) and treatment duration for at least 16 weeks (PZ0.0135) remained significant independent predictors of sustained virologic response (Table 2). Body weight was not a predictor of sustained virologic response by either singlevariable or stepwise analysis. Undetectable serum HCV-RNA after 4 weeks of therapy was an important predictor of sustained virologic response. The sustained virologic response rate was 89% for those who were first HCV-RNA negative at week 4, compared to 25 and 17% in those who had their first undetectable HCVRNA at week 12 or 24, respectively (Table 3). Patients who had undetectable HCV-RNA at weeks 4 and 24 of treatment had a sustained response rate of 92%. The classification tree model demonstrated that a baseline HCV-RNA level of 250,000 IU/mL best discriminated between patients with or without sustained virologic response. Patients with a baseline HCV-RNA %250, 000 IU/mL had a significantly higher sustained virologic response rate of 67% (93/138) compared with 25% (24/97) in patients with a baseline HCV-RNA level O250, 000 IU/mL (P!0.0001). This was due to both a higher end of treatment virologic response rate (89 vs 68%) and a lower confirmed virologic relapse rate (23 vs 63%) in patients with baseline HCV-RNA levels below 250, 000 IU/mL. Initial viral load and early response were linked. In patients with HCV-RNA concentration of %250, 000 IU/mL, 68% (94/138) had their first undetectable serum HCV-RNA after 4 weeks of treatment compared with 16% Table 2 Predictors of response: single and multiple variable analysis Variable

for establishing effectiveness specified for the present study. At the end of follow-up 134 of 235 patients (57%) had ALT levels within the normal reference range and 110 of 235 patients (47%) had both normal ALT and undetectable HCV-RNA. The correlation between sustained biochemical and virologic response was 94%. ALT levels in sustained virologic but not biochemical responders (nZ5) ranged from 1.03 to 1.25 times the upper limit of normal. However, all five patients had lower ALT values at the end of follow-up compared with pretreatment levels. On the pretreatment liver biopsy two of the five patients had grade 2 steatosis (O5–%32% fat), 2 patients had grade 1 steatosis (O0–%5% fat), and one patient did not have a biopsy sample submitted.

Age (years) Sex (female) Race (Caucasian) Body weight (kg) Baseline HCV RNA %600,000 IU/mL Log10 IU/mL Source of exposure Years since exposure Duration of treatment R16 weeks Ribavirin dose (mg/kg) Knodell score Inflammatory activity Fibrosis Metavir score Inflammatory activity Fibrosis Steatosis Steatosis %5%

Single P-value

Multiple P-value

0.0239 0.3985 0.5452 0.1705 0.0036 !0.0001 0.7035 0.0521 0.0115 0.0141 0.6199 0.5217 0.2480 0.3548 0.1377 0.3869 0.9061

!0.0001

0.0135

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Table 3 Sustained virologic response and relapse rates in patients treated with peginterferon alfa-2b plus ribavirin based on time to first negative HCV-RNA Time to first negative HCV-RNA

Proportion of patients (%)

Week 4 Week 12 Week 24 (end of therapy) All

47 26 10 83

a b

48 weeks treatmenta

24 weeks treatment b

Sustained virologic response

Virologic relapse

Sustained virologic response

Virologic relapseb

98/110 (89%) 15/61 (25%) 2/24 (17%) 117/235 (50%)

9/106 (8%) 44/59 (75%) 16/20 (80%) 69/185 (37%)

11/13 (85%) 14/15 (93%) 2/3 (67%) 27/38 (71%)

1/12 (8%) 0/14 (0%) 0/2 (0%) 1/28 (4%)

Data from the study by Manns et al. [11]. Patients with missing follow-up data not included.

(16/97) with baseline HCV-RNA concentration of O250, 000 IU/mL. 3.3. Baseline viral load Thirty-seven patients (16%) had a screening viral load of %600,000 IU/mL, followed by a viral load of O600, 000 IU/mL before initiating treatment. This finding is consistent with the known w0.5 log assay variation of real-time PCR testing wherein a proportion of patients with initial viral loads close to the 600,000 IU/mL screening cutoff should retest higher than 600,000 IU/mL. This finding reinforces the concept that one should not attribute clinical significance to small changes (!1 log) in serum viral titers of individual patients with hepatitis C virus infection. 3.4. Adherence Two hundred twenty-one (94%) patients completed at least 80% of the planned treatment duration. Patients were considered adherent to the treatment regimen if they received at least 80% of the assigned dose of both drugs for at least 80% of the treatment duration [16]. Patients who were able to adhere to the assigned treatment regimen were compared with patients who received less than 80% of one or both drugs or completed less than 80% of the treatment duration. The sustained virologic response rate in adherent patients was 52% (102 of 195 patients) compared with 54% (14 of 26 patients) in nonadherent patients. Dose reduction did not seem to affect sustained virologic response rates among HCV-1 infected patients with low baseline HCVRNA levels, but this observation is based on a small sample size, since only 12% (26/221) were considered nonadherent. Therapy for at least 16 weeks, however, was a strong predictor of sustained virologic response. 3.5. Adverse events Serious adverse events (SAE) were reported in 25 patients during the treatment period, representing an SAE rate of 11%. In 19 of the 25 patients the event was considered by the investigator as probably or possibly related to study medication (depression, asthenia,

abdominal pain, fever, anemia, neutropenia, hypocalcemia, pruritus, rash, psoriasis, allergy, thyroiditis, hearing impairment). Seven of 237 patients (3%) discontinued therapy because of adverse events. Two patients discontinued due to depression and one patient each for asthenia, anemia, asthenia plus anemia, breast cancer and psoriasis, respectively. Sixty-one of 237 patients (26%) required dose reduction or interruption due to adverse events (excluding patients who later discontinued due to an adverse event). Anemia (12%) thrombocytopenia (4%), and neutropenia (3%) were the most common adverse events leading to dose modification. Dose modifications were lower in those patients receiving 800 mg/day of ribavirin (9% or 8/87 patients), but similar in patients receiving 1000 mg/day and 1200 mg/day (14% or 16/114 patients and 15% or 5/34 patients, respectively). Treatment-emergent SAEs occurred at similar rates in the present 24-week treatment study and the historical control of patients treated for 48 weeks (11 vs 12%) [11]. However, adverse events leading to discontinuation of therapy (3 vs 14%) or dose modifications due to adverse events (26 vs 49%) were considerably lower in the present study compared with the 48-week historical control study [11]. In addition, adverse events leading to discontinuation or dose modifications in this study were lower than those reported in the initial 24 weeks of therapy in the historical control (11 and 41%, respectively) [11].

4. Discussion This study demonstrates that 24 weeks of therapy with peginterferon alfa-2b 1.5 mg/kg/week plus weight-based ribavirin dosing is insufficient for the treatment of patients infected with HCV-1 and a baseline HCV-RNA level equal or below 600,000 IU/mL. Using the data of the study by Manns et al. [11], a sustained virologic response rate of 69% was predicted if the patients in the present study would have been treated for 48 weeks. This estimated sustained virologic response rate fell outside the 95% confidence interval (43–56%) of the observed virologic response rate after 24 weeks treatment in the study cohort and therefore

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did not satisfy the criterion for establishing effectiveness for the present study. The classification tree model demonstrated that a pretreatment HCV-RNA level of 250,000 IU/mL best discriminated between patients with or without a sustained virologic response after combination therapy with peginterferon alfa-2b and ribavirin for 24 weeks. Future prospective studies should investigate whether only one threshold differentiating between low and high pretreatment viremia is sufficient or whether several ranges of pretreatment HCV-RNA levels could be used to individualize treatment duration. The current definition of low and high viral load originates from the median pretreatment HCVRNA levels in several pivotal trials, i.e. 2,000, 000 copies/mL [6,7]. Unfortunately, the conversion according to the WHO standard is currently inconsistent. According to a real-time quantitative PCR assay developed by Schering Plough Research Institute and other assays the threshold between low and high pretreatment viremia is 600,000 or 800,000 IU/mL, respectively [11–14]. Furthermore, the natural fluctation of HCV-RNA as well as the intra-assay variability of quantitative assays must be kept in mind. Data of the present study show that a subgroup of HCV genotype 1 infected patients who had pretreatment HCV RNA levels below 600,000 IU/mL and became serum HCVRNA negative after 4 weeks of treatment achieved an excellent sustained virologic response rate of almost 90% (compared with 85% in the historical control group treated for 48 weeks [11]). These data are in line with a recent prospective study in which treatment of patients with chronic hepatitis C was individualized according to the early virologic response [17]. In that study, serum HCVRNA was frequently quantified during the initial 6 weeks of peginterferon alfa-2a plus ribavirin combination therapy, and patients were classified as rapid, slow, flat, or null responders. The sustained virologic response rate in HCV-1 infected patients with an initial rapid virologic response who were treated only for 24 weeks was substantial (65%) but was lower than in those patients treated for 48 weeks (83%). This difference was significant in patients with a baseline HCV-RNA O800,000 IU/mL, but not in patients with lower baseline viral load [17]. Beyond the initial virologic response at treatment week 4 only two pretreatment parameters (baseline HCV-RNA level and treatment duration for at least 16 weeks) remained significant independent predictors of sustained virologic response in the present study after stepwise multivariable logistic regression analysis. These predictors as well as the fact that body weight was not a predictor of sustained virologic response are in accordance with a similar study in patients infected with HCV genotypes 2 or 3 [14]. However, in the study with HCV-2 or HCV-3 infected patients hepatic steatosis of less than 5% was an additional independent predictor of sustained virologic response [14]. This can be

explained because infection particularly with HCV-3 leads to hepatic steatosis [18,19]. Overall, the safety profile of the present 24-week treatment regimen was improved compared with patients in the study of Manns et al. [11] who received more than 10.6 mg/kg/day ribavirin for 48 weeks. Adverse events leading to treatment discontinuation or dose reduction occurred at considerably lower rates in the present study compared with the historical control study. Improved adverse event rates in this study were also seen compared with the initial 24 weeks of treatment in the historical control. Over the recent years, investigators may have become more familiar with the medications and the management of their adverse events, leading to this improved safety profile. In general, patients chronically infected with HCV-1 should receive combination therapy with a pegylated interferon plus weight-based ribavirin for 48 weeks. An exception comprises HCV-1 infected patients with a low pretreatment HCV-RNA concentration (below 600, 000 IU/mL) who become undetectable for serum HCVRNA already after 4 weeks of combination therapy. In this subset of patients treatment for 24 weeks does not impair the sustained virologic response rate. Although a baseline HCV-RNA concentration of less than 250,000 IU/mL may predict the need for shorter course therapy, the strongest predictor is virologic response after 4 weeks of therapy. Given the intra-assay variability of PCR testing (w0.5 log), response after 4 weeks of therapy is the most useful predictor of sustained virologic response in clinical practice.

Acknowledgements This study was supported by research grants from Schering-Plough Research Institute, Kenilworth, NJ. In addition to the authors the following investigators were involved in the present study: Austria: W. Vogel, Innsbruck; Belgium: N. Bourgeois, Bruxelles; France: D. Dhumeaux, C. Hezode, Creteil; N. Boyer-Darrigrand, P. Marcellin, Clichy; P. Couzigou, V. de Ledinghen, Bordeaux; V. Leroy, J.-P. Zarski, Grenoble; C. Trepo, M. Maynard-Muet, Lyon; J.-P. Bronowicki, M.-A. Bigard, Nancy; T. Poynard, J. Moussalli, Paris; S. Pol, H. Fontaine, Paris; Germany: M. Huber, Frankfurt; D. Haeussinger, T. Heintges, Duesseldorf; B. Kallinowski, Heidelberg; C. Niederau, Oberhausen; D. Schuppan, Erlangen; M. Manns, H. Wedemeyer, Hannover; H. Porst, Dresden; Greece: E. Manesis, Athens; M. Raptopoulou-Gigi, Thessaloniki; Italy: G. Pastore, Bari; M. Rizzetto, Torino; A. Picciotto, Genova; A. Andriulli, S. Giovanni Rotondo; G. Antonucci, Roma; Norway: O. Dalgard, Oslo; Poland: K. Nazzal, Warsaw; Portugal: A. Carvalho, Coimbra; J. Areias, Setubal; Spain: R. Esteban, Barcelona; R. Sola-Lamoglia, Barcelona; J. SanchezTapias, Barcelona; E. Ortega, Valencia; Gc Ricote, Madrid; J. Garcia-Samaniego, Madrid; J. Salmeron, Granada;

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Sweden: R. Hultcrantz, Stockholm; Switzerland: B. Muellhaupt, E. Renner, Zuerich.

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