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Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

We compared the efficacy and tolerability of 24 weeks of treatment with ribavirin 800 mg/day (group A) or 400 mg/day (group B) plus peginterferon alfa-2a 180 μg/week in treatment-naive patients infected with hepatitis C virus (HCV) genotype 2 or 3. A total of 97 of 141 patients randomized to group A (68.8%, 95% confidence interval [CI] 60.5%-76.3%) and 90 of 141 patients randomized to group B (63.8; 95% CI 55.3%-71.7%) achieved a sustained virological response, defined as undetectable serum HCV RNA at the end of untreated follow-up (week 48). Among patients infected with genotype 3, the rate of sustained virological response was 67.5% (95% CI 58.4%-75.6%) in group A and 63.9% (95% CI 54.7%-72.4%) in group B, and among patients infected with genotype 2, the rate of sustained virological response was 77.8% (95% CI 54.2%-93.6%) in group A and 55.6% (95% CI 38.4%-83.7%) in group B. Relapse rates in the 2 treatment groups were similar (17% in group A and 20% in group B). The incidence of adverse events, laboratory abnormalities, and dose reductions was similar in the 2 treatment groups. Conclusion: The results suggest that when administered for 24 weeks with peginterferon alfa-2a, ribavirin doses of 400 and 800 mg/day produce equivalent outcomes in patients infected with HCV genotype 3. (HEPATOLOGY 2008.)

The prevalence of chronic infection with hepatitis C virus (HCV) is estimated to range from 1.5% to 15% depending on the region. In Europe, 8 million to 10 million individuals suffer from chronic hepatitis C, and it is expected that over 10 to 20 years, approximately 20% of these individuals will develop cirrhosis and its complications and will be in need of liver transplantation.1, 2

Effective treatment for chronic hepatitis C would reduce morbidity and mortality, improve health-related quality of life, and avoid the huge costs associated with end-stage liver disease. The current standard of care is a combination of pegylated interferon and ribavirin, which produces an overall cure rate of approximately 50% to 60%.3, 4

The most important predictor of successful response to combination therapy is HCV genotype.5 On the basis of a large randomized international study,4 the optimum treatment for patients with HCV genotype 1 infection is considered to be 48 weeks of combination therapy with pegylated interferon plus ribavirin 1000 or 1200 mg/day.5 In contrast, patients infected with HCV genotype 2 or 3 may be treated with a lower dose of ribavirin (800 mg/day) and for just 24 weeks without compromising efficacy.6, 7 These findings are reflected in treatment guidelines for chronic hepatitis C.5

The use of a lower, fixed 800 mg/day dose of ribavirin is better tolerated and as effective as the higher 1000 or 1200 mg/day standard dose of ribavirin in patients infected with HCV genotype 2 or 3. Recent attempts to further simplify treatment for these patients have focused on shortening the duration to 12 to 16 weeks,8-11 but it is now clear that abbreviated regimens result in higher relapse rates when compared with the standard 24-week regimen.10 It remains to be determined whether the tolerability of treatment can be improved and the costs reduced by further decreasing the dose of ribavirin. For this reason, we compared the efficacy and tolerability of 24 weeks of treatment with ribavirin at a dosage of 800 or 400 mg/day in combination with peginterferon alfa-2a in patients infected with HCV genotype 2 or 3.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Patients eligible for the trial were treatment-naive adults aged 18 to 65 years with chronic hepatitis C, HCV genotype 2 or 3 infection, quantifiable HCV RNA in serum (>600 IU/mL by Cobas Amplicor HCV Monitor Test v.2.0) and elevated serum ALT activity (>1.5 times the upper limit of normal [ULN] in the previous 6 months and during screening). Patients were required to have a hemoglobin value ≥ 12 g/dL (women) or 13 g/dL (men), a leukocyte count ≥ 3000/μL, a platelet count ≥ 100,000/μL, and a serum creatinine level < 1.5 times the ULN.

Women of childbearing potential were required to have a negative pregnancy test within 24 hours of the first dose. All fertile male and female participants were required to use two forms of effective contraception during treatment and for 6 months after the end of treatment.

Pregnant or breast-feeding women and male partners of pregnant women were excluded. Patients were also excluded if they had received prior treatment with interferon or ribavirin at any time; were coinfected with hepatitis B virus or human immunodeficiency virus; had decompensated liver disease or chronic liver disease attributable to another cause; coronary heart disease; diabetes mellitus requiring insulin therapy; autoimmune disorders; and/or any other unstable chronic medical condition. Individuals with severe psychiatric disease, especially depression, and those with a history of active alcohol or drug addiction within the previous 6 months were excluded, although patients on opiate substitution therapy were eligible if they were treated by the drug treatment centre in the Department of Psychiatry, Medical University of Vienna.

Study Protocol

Patients entered a 35-day screening phase before randomization in this multicenter study. Eligible patients were randomized to 24 weeks of treatment with subcutaneous peginterferon alfa-2a (Pegasys, Roche, Basel, Switzerland) 180 μg/week in combination with oral ribavirin (Copegus, Roche) at a dosage of either 800 mg/day (group A) or 400 mg/day (group B). Ribavirin was administered twice daily in both treatment groups

Dose reductions were allowed at the investigator's discretion. In the event of laboratory abnormalities or adverse events, the dosage of peginterferon alfa-2a could be reduced, preferably in a stepwise manner from 180 to 135, 90, and 45 μg/week.

For patients randomized to treatment with ribavirin 800 mg/day, the dose of ribavirin was to be decreased by 200 mg/day in the event of a decrease in hemoglobin to <10 and >8.5 g/dL in patients without significant cardiovascular disease or in the event of a >2 g/dL decrease in hemoglobin over any 4-week period in patients with stable cardiovascular disease. The dose of ribavirin could also be reduced in 200 mg/day increments in patients randomized to treatment with ribavirin 400 mg/day (group B).

Treatment with ribavirin was to be discontinued if the hemoglobin level fell below 8.5 g/dL in a patient without significant cardiovascular disease or if the hemoglobin level remained below 10 g/dL despite 4 weeks of treatment at the reduced dosage of 600 mg/day in patients enrolled in group A. The use of erythropoietin-stimulating agents (i.e., Neorecormon, Roche, Basel) was allowed at the discretion of the investigator if the hemoglobin level fell to <10.5 g/dL. In the event that ribavirin was discontinued, monotherapy with peginterferon alfa-2a could be continued; however, monotherapy with ribavirin was not permitted.

Upon resolution of the event that precipitated the dose reduction, investigators were allowed to increase the dose of peginterferon alfa-2a or ribavirin to the originally assigned dose.

Blocked randomization was performed centrally and was stratified according to HCV genotype (2 versus 3) and baseline HCV RNA level (≤2 versus >2 × 106 copies/mL [≤800,000 versus >800,000 IU/mL]). The ethics committees of all participating hospitals approved the protocol, and patients gave written informed consent before enrollment.

The primary efficacy end point was sustained virological response, defined as undetectable HCV RNA (<50 IU/mL) by qualitative PCR assay (Cobas Amplicor HCV Test v.2.0) after 24 weeks of untreated follow-up (week 48). The safety and tolerability of treatment were secondary end points.

Specimen Collection and Virological Tests

Blood was collected in 9-mL tubes (Vacuette, Greiner bio-one GmbH, Kremsmünster, Austria) and centrifuged at 1,500g for 20 minutes at room temperature within 4 hours of venipuncture. Immediately after centrifugation, serum aliquots were frozen at −70°C until tested. Serum HCV RNA assays were performed according to the manufacturer's package inserts.

Statistical and Analytical Methods

Sample Size Calculation.

On the basis of the results of a large, randomized, multinational trial,6 we assumed that the rate of sustained virological response would be 78% in both treatment groups and that the maximum acceptable difference between these rates was 15%. The total sample size of 192 patients with HCV genotype 3 infection was considered sufficient to compare the sustained virological response rates between the two treatment groups with a power of 80% and a significance level of 5% using a one-sided equivalence test of proportions. It was expected that a small proportion of patients with genotype 2 would be recruited. For this reason, sample size calculation was based on patients with HCV genotype 3 infection. After recruitment was initiated, patients with genotype 2 infection were enrolled until the required number of patients with genotype 3 had been enrolled.

Statistical Analysis.

The analysis was conducted according to the intention-to-treat principle. Patients with missing results at the end of follow-up were considered not to have a sustained virological response.

For the primary efficacy parameter (sustained virological response), a 95% confidence interval using a Cochran-Mantel-Haenszel (CMH) statistic stratified by genotype and viral load was calculated for the treatment difference in the per-protocol analysis (group B − group A). The two regimens were considered equivalent if the lower limit of this confidence interval was determined to be greater than −15%. The rate of virological response at the end of treatment and at the end of follow-up (that is, sustained virological response) and two-sided 95% confidence intervals were calculated for each treatment group.

The influence of various baseline variables on the rate of sustained virological response in both treatment groups was investigated by multiple logistic regression analysis.

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The flow of patients through the study is shown in Fig. 1. A total of 291 patients were screened and 282 patients were randomized to treatment. The first patient was enrolled in May 2003 and the last patient completed follow-up in December 2006. Baseline characteristics are presented in Table 1.

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Figure 1. Flow of patients in the study. Figures in brackets refer to patients with genotype 3. *Two (1) patients who withdrew from treatment prematurely returned for follow-up and were HCV RNA negative in weeks 24 and 48.

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Table 1. Baseline Characteristics of All Randomized Patients
 Genotype 2Genotype 3All patients
Group A (ribavirin 800 mg/day), n = 18Group B (ribavirin 400 mg/day), n = 19Group A (ribavirin 800 mg/day), n = 123Group B (ribavirin 400 mg/day), n = 122Group A (ribavirin 800 mg/day), n = 141Group B (ribavirin 400 mg/day), n = 141
Age, years46.8 ± 10.843.9 ± 11.335.5 ± 10.634.3 ± 9.436.8 ± 11.136.2 ± 10.7
SEx, male/female8/109/1076/4778/4484/5787/54
Mean baseline HCV RNA (log10 IU/mL)5.9 ± 0.55.8 ± 0.95.7 ± 0.85.6 ± 0.85.9 ± 0.75.7 ± 0.8
Body weight (kg)72.9 ± 17.373.8 ± 19.270.6 ± 13.673.1 ± 14.971.1 ± 14.073.1 ± 15.4
Mean BMI (kg/m2)24.6 ± 4.624.8 ± 3.823.7 ± 4.023.8 ± 3.923.9 ± 4.123.9 ± 4.0
Means by which HCV acquired, n (%)      
 Blood transfusion    12 (9%) 10 (7%) 
 Intravenous drug use    81 (57%)79 (56%)
 Other    17 (12%)12 (9%) 
 Unknown    31 (22%)40 (28%)

Thirty-five patients did not complete 24 weeks of treatment (group A, 13; group B, 22). Eleven patients discontinued treatment because of adverse events: five in group A for sepsis with multiorgan failure (1), cerebellar infarction (1), herpes simplex (1), pneumonia (1), and depression (1); and six in group B because of circulatory collapse (1), hematuria (1), and psychiatric problems (4). Two of these patients who discontinued treatment prematurely for adverse events (in weeks 14 and 18, respectively) were HCV RNA negative in week 48 and thus had a sustained virological response. Treatment of two patients was terminated because of protocol violations (one was HCV RNA negative at baseline, one was randomized to receive ribavirin 400 mg/day but took 800 mg/day by mistake); one patient was jailed; and three patients withdrew consent. The remaining 18 patients who discontinued treatment prematurely were noncompliant. Nine patients who had an end-of-treatment response did not return for the examination at the end of follow-up and were considered not to have achieved a sustained virological response in the efficacy analysis.

Efficacy.

Overall and in the different genotypes, there was no significant difference in the rate of sustained virological response between the two treatment groups (Table 2).

Table 2. Sustained Virological Response Rates
 Group A (ribavirin 800 mg/day)Group B (ribavirin 400 mg/day)
  1. SVR, sustained virological response; 95% CI, 95% confidence interval. Differences between groups A and B were not statistically significant.

Intention-to-treat analysis
All patients, SVR/N (%,95% CI)97/141(68.8%, 60.5%–76.3%)90/141(63.8%, 55.3%–71.7%)
 Difference: 5.0; −6.8 to 16.70
Genotype 3, SVR/N (%, 95% CL)83/123(67.5%, 58.4%–75.6%)78/122(63.9%, 54.7%–72.4%)
 Difference: 3.6; −9.2 to 16.2
Genotype 2, SVR/N, (%, 95% CI)14/18(77.8%, 54.2%–93.6%)12/19(63.2%, 38.4%–83.7%)
 Difference: 14.6
Per protocol analysis
All patients, SVR/N (%, 95%CI)97/123(78.9%, 70.6%–85.7%)90/117(76.9%, 68.2%–84.2%)
 Difference: 2.0; −9.4 to13.3
Genotype 3, SVR/N (%,95%CI)83/107(77.6%, 68.5%–85.1%)78/102(76.5%, 67.0%–84.3%)
 Difference: 1.1; −11.2 to 13.5
Genotype 2, SVR/N (%, 95%CI)14/16(87.5%, 61.7%–98.4%)12/15(80.0%, 51.9%–95.7%)
 Difference: 7.5

According to the intention-to-treat analysis, 97 of 141 patients (68.8%, 95% confidence interval [95% CI] 60.5%-76.3%) randomized to ribavirin 800 mg/day and 90 of 141 patients (63.8; 95% CI 55.3%-71.7%) randomized to ribavirin 400 mg/day achieved a sustained virological response.

Among patients infected with genotype 3, the rate of sustained virological response was 67.5% (83 of 123, 95% CI 58.4%-75.6%) in those randomized to ribavirin 800 mg/day and 63.9% (78 of 122, 95% CI 54.7%-72.4%) in those randomized to ribavirin 400 mg/day.

Among patients infected with genotype 2, the rate of sustained virological response was 77.8% (14 of 18, 95% CI 54.2%-93.6%) in those randomized to ribavirin 800 mg/day and 63.2% (12 of 19, 95% CI 38.4%-83.7%) in those randomized to ribavirin 400 mg/day.

Relapse rates in the 2 treatment groups were similar. Among patients randomized to ribavirin 800 mg/day, 21 of 123 individuals (17%) with an end-of-treatment virological response relapsed during follow-up, as did 23 of 117 (20%) individuals randomized to ribavirin 400 mg/day. One patient treated with ribavirin 800 mg/day resumed injection drug use and was reinfected with HCV genotype 1a during follow-up. For the purposes of the analysis, this individual was considered to have had a virological relapse.

By univariate analysis, no baseline factors were statistically significant predictors of sustained virological response. Baseline characteristics are presented according to virological response in Table 3.

Table 3. Baseline Characteristics of Patients According to Virological Response
 SVR (n = 187)Relapse (n = 44)NR (n = 9)
  1. Pooled data from both study groups. Patients who withdrew prematurely or were lost to follow-up were excluded from this analysis.

  2. NR, nonresponse; SVR, sustained virological response.

  3. No differences were statistically significant.

Mean log10 HCV-RNA ± SD5.70 ± 0.695.84 ± 0.785.98 ± 0.61
HCV-RNA < 800,000 versus ≥ 800,000, n (%)103/84 (53.9%)15/29 (34.1%)3/6 (33.3%)
Mean body weight (kg) ± SD70.4 ± 13.678.8 ± 15.178.9 ± 15.1
Mean BMI (kg/m2) ± SD23.7 ± 4.124.8 ± 4.125.3 ± 4.8
Mean age (years) ± SD35.0 ± 10.541.7 ± 10.143.4 ± 10.8
Sex (male/female)105/8229/157/2

Safety.

The two regimens were well tolerated with a low but similar frequency of adverse events. The most common adverse events were flu-like syndrome, fatigue, and/or epigastric discomfort, which were reported collectively by 51 patients in group A and 61 patients in group B. Pruritus and/or exanthemas were reported by 48 patients in group A and 50 patients in group B. Psychiatric adverse events, for the most part depression, were reported by 49 patients in group A and 56 patients in group B. A total of 48 patients complained of hair loss (group A, 25; group B, 23).

The incidence of laboratory abnormalities and peginterferon alfa-2a dose reductions was similar in the two treatment groups (Table 4). Hemoglobin was lower in patients receiving ribavirin 800 mg/day than in those receiving 400 mg/day (Fig. 2), and more patients randomized to a dosage of 800 than 400 mg/day had the dose reduced. Among the nine patients in whom the dose of ribavirin was reduced, six achieved a sustained virological response, two were lost to follow-up, and one individual, who discontinued treatment after one 1 week, did not have a sustained virological response. Although permitted, erythropoietin-stimulating agents were not given to any patient.

Table 4. Laboratory Abnormalities and Dose Reductions
 Group A (ribavirin 800 mg/day) n = 141Group B (ribavirin 400 mg/day) n = 141
  • *

    Dose of peginterferon alfa-2a was reduced because of depression in two patients and because of neutropenia or thrombocytopenia in all others. Treatment with the drug was stopped in one patient because of neutropenia.

Hemoglobin > 8.5 < 10 g/dL (%)7 (5.0%)4 (2.8%)
Hemoglobin < 8.5 g/dL, n (%)2 (1.4%)1 (0.7%)
Neutrophils < 1000/mm366 (46.8%)64 (45.4%)
Neutrophils < 500/mm37 (5.0%)7 (5.0%)
Platelets > 20,000 and < 50,000/mm35 (3.5%)6 (4.3%)
Platelets < 20,000/mm31 (0.7%)0 (0.0%)
Dose reductions  
 Peginterferon alfa-2a*23 (16.3%)22 (15.6%)
 Ribavirin, n (%)9 (6.4%)0 (0.0%)
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Figure 2. Mean hemoglobin concentrations during treatment and follow-up in patients who completed treatment with peginterferon alfa-2a plus ribavirin 800 mg/day (group A) or 400 mg/day (group B). The difference between groups A and B was statistically significant (P = 0.048, by repeated-measures ANOVA).

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Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The results of this study indicate that the dose of ribavirin can be reduced from 800 to 400 mg/day without increasing the relapse rate in HCV genotype 3 patients treated for 24 weeks with the standard of care. The overall rate of sustained virological response in genotype 3 patients was similar to that reported in the large randomized international ACCELERATE trial.10 Infection with HCV genotype 2 is rare in Austria; thus, the results in the small group of patients infected with this genotype were inconclusive about whether a ribavirin dose of 400 mg/day produces outcomes equivalent to those achieved with the recommended dose of 800 mg/day. Although the mean hemoglobin level was lower in patients randomized to ribavirin 800 rather than 400 mg/day (see Fig. 2), the incidence of severe anemia requiring ribavirin dose reduction was similar in the two treatment groups; thus, the tolerability of ribavirin treatment cannot generally be improved by reducing the initial dose of ribavirin below 800 mg/day. Nevertheless, the ribavirin dose can be decreased in patients not tolerating the drug without compromising the efficacy of antiviral therapy.

At the time when the study was designed, the impact of rapid virological response on treatment outcomes was unknown; thus, measurement of serum HCV RNA in week 4 was not required in the protocol. However, HCV RNA was measured at the largest center, which recruited 85 of the 282 patients enrolled in the trial and confirmed that rapid virological response was the best predictor of sustained virological response.12

How should the findings of the present study be incorporated into clinical practice? It is not possible to predict whether any given patient will tolerate or comply with 24 weeks of treatment. Thus, initiating treatment with a ribavirin dose of 400 mg/day may place patients at increased risk of treatment failure should they not complete the full 24-week course of therapy. For this reason, it is best to follow current recommendations and initiate ribavirin treatment at a dose of 800 mg/day. This and other studies have shown that some patients will not tolerate this dose of ribavirin and will require dose reductions. However, our results provide reassurance that the probability of a sustained virological response is not diminished in the small number of patients who require dosage reductions; indeed, six of nine patients randomized to ribavirin 800 mg/day achieved a sustained virological response after having the dose of ribavirin reduced. Such a strategy also leaves open the possibility of shortening the planned duration of treatment if ribavirin is well tolerated and a patient achieves a rapid virological response in week 4, although as noted below, this approach increases the probability of relapse, regardless of the dose of ribavirin.

Aside from having implications for clinical practice, the results of the trial add a further twist to the story of ribavirin in the treatment of chronic hepatitis C. The recent trend has been to increase the dose of ribavirin because it was thought that this would minimize the likelihood of relapse. In sharp contrast, we have shown that the dosage required to maximize the probability of a sustained virological response may actually be lowered when treatment is administered for the “optimal” duration. Several theories have been proposed to explain the mechanism by which ribavirin exerts its antiviral effect on HCV.13 These include depletion of guanosine triphosphate pools through inhibition of inosine monophosphate dehydrogenase, inhibition of viral RNA-dependent RNA polymerase, immunomodulatory effects, and induction of viral mutations rendering a fraction of newly produced virions noninfectious.14-17 The probability of eradicating HCV with combination therapy is significantly influenced by the dose of ribavirin and the duration of treatment. Although fixed durations of treatment are recommended in the guidelines, the duration can be modified on the basis of the rapidity of viral clearance from blood.18 In patients infected with HCV genotype 1, ribavirin prevents virological breakthrough during therapy and relapse during follow-up after the end of treatment. Retrospective analysis of data from a large trial in which a fixed 800 mg/day dosage of ribavirin was used showed that higher exposure to ribavirin (on a milligram/kilogram basis) resulted in higher rates of sustained virological response.3 Subsequent randomized trials have confirmed that the sustained virological response rate of patients with genotype 1 infection is significantly higher in those treated with a standard dose of ribavirin (1,000/1,200 mg/day) or higher compared with 800 mg/day.6, 7 Maintenance of the full planned dose of ribavirin throughout treatment is required to achieve this goal.19 Ribavirin also prevents relapse in patients infected with HCV genotype 2 or 3. The rate of sustained virological response after monotherapy with conventional interferon or pegylated interferon is substantially lower than that achieved after combination therapy.4, 20 The duration of treatment for patients with HCV genotype 2 or 3 can be reduced from 48 to 24 weeks without compromising efficacy6, 7; however, further reduction in the treatment duration from 24 to 12 or 16 weeks is associated with an increase in the rate of virological relapse,9, 10 even among those with a rapid virological response at week 4, and cannot be generally recommended.

In summary, the results of our study suggest that when administered for 24 weeks in combination with peginterferon alfa-2a, ribavirin doses of 400 and 800 mg/day produce equivalent outcomes in patients infected with HCV genotype 3. Further research is needed to confirm whether this less intensive regimen is suitable for patients infected with HCV genotype 2.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

This study was made possible by an unrestricted grant by Roche Austria. The Main Association (Hauptverband) of the Austrian Health Insurers paid for the study medication, Dr. A Klingler performed the statistical analysis, and Dr. Harald Kessler performed the virological analysis. We would also thank Blair Jarvis (Health Interactions Ltd., UK), who provided editorial support on behalf of Roche. Members of the Austrian Hepatitis study group: Graz—Bernhard Bauer, Nicole Hueter, Günther J. Krejs, Csilla Putz-Bankuti, Rudolf Stauber, Barbara Sutter, Gernot Zollner; Innsbruck—Wolfgang Jessner, Karin Nachbaur, Bernhard Nilica, Wolfgang Vogel; Krems—Hartwig Bognar; Linz—Franz Hackl, Rainer Hubmann, Andreas Maieron, Susanne Mild, Andreas Raml, Sabine Metz; Ried—Björn Jagdt, Fritz Renner; Oberpullendorf—Felix Stockenhuber, Salzburg—Christian Datz, Hildegard Doppelmayr, Michael Strasser; Vienna—Susanne Bach, Martin Bischof, Harald Brunner, Barbara Bognar, Ulrike Bergholz, Nina Ebner, Daniela Ferenci-Foerster, Peter Ferenci, Gabriele Fischer, Elisabeth Formann, Alfred Gangl, Michael Gschwantler, Calin Gurguta, Gerold Hartmann, Brigitte Hellmich, Harald Hofer, Hermann Laferl, Karin Mittischek, Christian Müller, Parnaz Ordubadi, Ali Reza Pourbyiabani, Markus Peck-Radosavljevic, Marianne Rosenbeiger, Kurt Schütze, Thomas-Matthias Scherzer, Katharina Staufer, Petra Steindl-Munda, Anika Stückler, Christoph Wenisch; Villach—Rudolf Foditsch; Wels—Peter Knoflach, Bernhard Stadler

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References