| |
Twice Weekly PegIntron Controversy
|
| |
| |
Twice-weekly administration of PegIntron improves viral kinetics in patients with chronic hepatitis C genotype 1
Journal of Viral Hepatitis
Volume 10 Issue 4 - July 2003
E. Formann,1 W. Jessner,1 L. Bennett2 and P. Ferenci1
1Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Vienna, Austria; and 2MDS Pharma Services, Wangen, CH, Switzerland
Summary. The decline in hepatitis C viral load on treatment with peginterferon--2b is not continuous. The aim of this study was to investigate whether twice weekly dosing of peginterferon--2b may improve viral kinetics. Ten interferon-naïve patients with chronic hepatitis C (genotype 1a or b) were randomized to receive either 1.0 g/kg peginterferon--2b once (group A) or twice weekly (group B) for 4 weeks. Viral load and serum concentrations of peginterferon--2b were measured. Peginterferon--2b reached maximal blood concentrations 24 h after the first dose, followed by a linear decline during the subsequent days. On the day before administration of the next dose, peginterferon--2b was undetectable in nine patients in group A (once weekly dosing). The same pattern was observed during the next 3 weeks of therapy. In group B (twice weekly dosing) peginterferon--2b was detectable at any given time point and higher than in group A (P between 0.01 and <0.0001). Viral load decreased in all patients within 2 days after the first dose of peginterferon--2b, but increased again on day 3. In group A, it further increased until day 7. A similar pattern was observed in the second week. In contrast, in group B, viral load decreased again on day 4 and remained lower until the end of the study (P < 0.001). To achieve continuous drug exposure and to improve initial viral clearance, peginterferon--2b has to be given at least two times weekly.
Journal of Viral Hepatitis
Volume 11 Issue 2 Page 187 - March 2004
doi:10.1046/j.1365-2893.2003.00493.x
LETTERS TO THE EDITOR
Does twice-weekly administration of peginterferon alfa-2b really improve viral kinetics in patients with chronic hepatitis C genotype 1?
M. Buti and R. Esteban
Liver Unit, Hospital General Universitari Vall d'Hebron, Paseo Valle de Hebron 119, Barcelona 08035, Spain
Dear Sir,
Formann et al. studied the viral kinetics and pharmacokinetics of two schedules of peginterferon alfa-2b in a small group of patients with chronic hepatitis C infected by genotype 1. They compared 1 ug/kg of peginterferon alfa-2b once a week vs 1 ug/kg of peginterferon alfa-2b two times per week; however, neither of these doses is the recommended dose for therapy of chronic hepatitis C. The study period is very short, only 4 weeks, and then, peginterferon alfa-2b was changed to peginterferon alfa-2a without any clear rationale. Switching to a different type of peginterferon alfa will not allow the evaluation of end-of-treatment or sustained virological response, the latter being the most important therapeutic end point. It is rather difficult to understand why the authors designed the study without having the sustained virological response as the main objective. Furthermore, the two groups of patients studied were not comparable because the baseline demographics were not well balanced and the type of randomization performed is not clear too. The once weekly peginterferon group has a higher number of males, higher body weight and higher baseline viral load, factors associated with poor response. In addition, both groups included patients with normal alanine aminotransferase (ALT) values; these type of patients are not usually included in therapeutic studies of chronic hepatitis C and to our knowledge, viral kinetics studies in patients with normal ALT levels have not been performed; therefore, the inclusion of these patients could modify the results of viral kinetics.
More importantly, there are some interesting anomalies in the design of the study. First, in the abstract published by the authors in 'Hepatology', the twice weekly peginterferon dose was given on days 0, 4, 7, 11, 14, 18, 21 and 24, while in the manuscript published in your journal, it was given on days 0, 3, 7, 10, 14, 17, 21 and 24. What is the real schedule? The second schedule would have been more appropriate taking into account the results of a previous study on viral kinetics with peginterferon alfa-2b in which an HCV-RNA rebound was detected in some cases on day 3, but it seems that the authors really used the first schedule. Secondly, when were the viral kinetics and pharmacokinetics analyses performed, before or after peginterferon administration? It is vital that the authors state this information in order to interpret the results correctly. Thirdly, HCV-RNA values are not given in a log scale as is standard in viral kinetics analyses and the standard deviations are unusually presented. When HCV-RNA results are stated in IU/mL, the variations appear to be higher, but if the results are translated into log values the variations are lower, around one or half a log, and changes of this magnitude can simply be attributed to the variability of the HCV-RNA assay.
The twice a week peginterferon schedule has already been analysed in a pilot study performed by Lurie et al. They compared the effect on HCV-RNA decline at week 12 of peginterferon 1.5 ug/kg administered once weekly or the same dosage divided into two or three times per week in 30 patients infected by the genotype 1. They demonstrated that patients treated with 1.5 g/kg of peginterferon once weekly achieved a higher and more significant reduction in HCV-RNA levels at week 12 (3.5 log10 copies/mL) than those treated with the same dose split two or three times per week with a reduction of 2.1 log10 copies/mL. This shows that administering peginterferon twice or thrice weekly has no additional benefit.
Finally, the authors conclude that 'to achieve a continuous drug exposure and to improve initial viral clearance, peginterferon alfa-2b has to be given at least two times weekly' but they do not find statistically significant differences in the rate of HCV-RNA clearance (3/10 vs 5/10, P = 0.65) between the two groups after 4 weeks of therapy, making this conclusion difficult to support.
[5] Lurie Y, Dusheiko G, Rouzier-Panis R, Glue P. Assesment of optimal dosing frequency of pegylated interferon alfa-2b (Pegintrom) in chronic hepatitis C. Hepatology 2000; 32: 1138A.
LETTERS TO THE EDITOR
Response to Article by Formann et al. (2003)
I. M. Jacobson 1 and J. McHutchison 2
1Weill Medical College of Cornell University New York, New York, USA; 2Duke University Medical Center, Durham, North Carolina, USA
Dear Sir,
Formann et al. showed in a small group of chronic hepatitis C patients that a 1.0 g/kg monotherapy of peginterferon alfa-2b is associated with maximum suppression of HCV-RNA during the first 2 days after each of four weekly doses, followed by an increase in HCV-RNA levels prior to the next dose. This increase was not seen with the administration of peginterferon alfa-2b therapy twice weekly, nor was there a decline in interferon levels to the undetectable range which was noted in many of the once-weekly drug recipients.
Several features of the study design and more general considerations severely limit the clinical applicability of their findings. The authors chose a dose of 1.0 g/kg peginterferon alfa-2b although the 1.5 ug/kg dose is the one widely in use and approved by regulatory authorities internationally. In patients treated with peginterferon alfa-2b monotherapy these two doses had similar rates of sustained virological response (SVR), but the 1.5u g/kg dose was associated with a higher end-of-treatment (ETR) response, which was why the higher dose was subsequently studied in combination with ribavirin. Another potential bias in the Formann study is represented by the mean viral load in the patients treated with interferon once weekly, which was nearly three times the mean levels in those treated twice weekly. Additionally, the mean alanine aminotransferase (ALT) level was over 50% greater.
Most importantly, although viral kinetic studies are a potentially useful means of studying the mechanisms of action of antiviral therapy, they do not represent a viable substitute for studies that evaluate virological response to courses of therapy used in therapeutic trials or clinical practice. This is illustrated by the dichotomy between the kinetic data presented by Formann et al. and a study by Lurie [4], demonstrating a greater degree of viral suppression after 12 weeks of 1.5 ug/kg peginterferon alfa-2b once weekly than twice weekly (3.3 vs 2.7 log). No opportunity to make such a comparison was afforded in the present study, in which all patients were switched to peginterferon alfa-2a and ribavirin after only 28 days of therapy. The authors imply that their findings may explain why 'peginterferon alfa-2b was not different to standard treatment in patients with HCV genotype 1 and high viral load', but in the study referred to (a) ribavirin was given at a low, fixed dose of 800 mg with peginterferon vs 1000-1200 mg with standard interferon, and (b) regression analysis demonstrated superior efficacy when patients in the peginterferon 1.5 ug/kg arm received doses of ribavirin equivalent in body weight-adjusted levels to traditional ribavirin doses, i.e. >10.6 mg/kg daily (37% SVR vs 29% with standard interferon). Notably, in that study also the SVR with peginterferon alfa-2b and ribavirin was the highest yet reported in patients with low viral concentrations (78%).
Perhaps the most important body of work illustrating the limitations of extrapolating data on early viral kinetics to clinical outcomes is the literature on 'induction therapy' with interferon. A number of studies of higher and/or more frequent dosing of interferon at the initiation of treatment failed to show improvement in virologic outcome, culminating in the negative results reported from a large multicentre study.
In light of the existing data on clinical outcomes, even if a repeat study by the authors or others using the dose of 1.5 ug/kg peginterferon alfa-2b currently in clinical use (which was not done here) were to reproduce the present findings, the clinical applicability of such findings would be subject to question.
[4] Lurie Y, Dusheiko G, Rouzier-Panis R, Glue P. Assessement of optimal dosing frequency of pegylated interferon alfa-2b (PegIntron) in chronic hepatitis C. Hepatology 2000; 32: 444A.
|
|
| |
| |
|
|
|
