| |
Improved Inflammatory Activity With Peginterferon Alfa-2b Maintenance Therapy in Non-cirrhotic Prior Nonresponders: a Randomized Study
|
| |
| |
Download the PDF here
Journal of Hepatology Jan 2013
Article in Press
".......despite the improvement in SVR rates with approved triple therapy, there will remain a substantial percentage of non-responders with advanced fibrosis who require alternative treatment options. For these patients, the debate regarding maintenance therapy is not closed, and because of the low power of the 3 published trials that used morbidity, mortality, and biopsy as end points, we as yet cannot exclude a beneficial effect of long-term PEG-IFN alfa monotherapy....."
"With no supporting data from EPIC3, HALT-C, and COPILOT, PEG-IFN alfa maintenance therapy has now largely been surpassed by other recent advances in the treatment of CHC. Boceprevir and telaprevir are approved for the treatment of CHC in combination with PEGIFN plus ribavirin, and have shown efficacy in patients previously unresponsive to PEG-IFN alfa-2b plus ribavirin [14, 15]. In the RESPOND-2 study, 68% of previous treatment failures with bridging fibrosis (F3) or cirrhosis (F4) receiving boceprevir and PEG-IFN alfa-2b plus ribavirin attained SVR, compared with 13% of those receiving PEG-IFN alfa-2b plus ribavirin [14]. Among patients with cirrhosis, SVR rates were 0% in patients receiving PEG-IFN alfa-2b plus ribavirin and 77% in those receiving boceprevir and PEG-IFN alfa-2b plus ribavirin. Similarly, in PROVE 3, 49% of patients with bridging fibrosis or cirrhosis receiving telaprevir and PEG-IFN alfa-2a plus ribavirin attained SVR compared with 11% of patients receiving PEG-IFN alfa-2a plus ribavirin [15]. However, despite the improvement in SVR rates with approved triple therapy, there will remain a substantial percentage of non-responders with advanced fibrosis who require alternative treatment options. For these patients, the debate regarding maintenance therapy is not closed, and because of the low power of the 3 published trials that used morbidity, mortality, and biopsy as end points, we as yet cannot exclude a beneficial effect of long-term PEG-IFN alfa monotherapy."
Thierry Poynard, Jordi Bruix, Eugene R. Schiff, Moises Diago, Thomas Berg,
Ricardo Moreno-Otero, Andre C. Lyra, Flair Carrilho, Louis H. Griffel,
Navdeep Boparai, Ruiyun Jiang, Margaret Burroughs, Clifford A. Brass, Janice
K. Albrecht
"In the EPIC3 study, treatment of previous non-responders with PEG-IFN alfa-2b and ribavirin resulted in an SVR rate of 22% [1]. The results of the present study indicate that low-dose PEG-IFN alfa-2b for two years does not significantly improve MFS when assessed by paired biopsies among patients with METAVIR F2 and F3 disease compared with observation. The number of patients who experienced an improvement in MFS did not differ between groups; however, significantly more patients receiving PEG-IFN alfa-2b experienced an improvement in necroinflammatory activity as assessed by paired biopsies. Furthermore, despite relatively small patient numbers, there appeared to be some benefit associated with PEG-IFN alfa-2b therapy, specifically within the population of patients treated for >2.5 years. As liver fibrosis progression is a slow process, a study of longer duration may be required to establish a clear benefit of active therapy versus observation or, alternatively, a more sensitive estimate of fibrosis progression."
"Three studies indicate that maintenance therapy with low-dose PEG-IFN alfa fails to limit or delay the histologic advancement of liver disease when assessed by biopsy, or delay the development of end-stage liver disease and HCC in patients with advanced liver disease related to CHC infection [2-4]. While reports from EPIC3 and COPILOT focused solely on patients with cirrhotic liver disease, the primary publication from HALT-C reported a mixed population consisting of 40% patients with cirrhosis and 60% with bridging fibrosis [3]. Within the cohort of non-cirrhotic patients, progression of fibrosis was similar in observation and PEG-IFN alfa-2a groups (70% vs 64%), and similar numbers of patients reached the primary composite outcome of death, hepatic decompensation, HCC, Child-Turcotte-Pugh score ≥7, or an increase in Ishak fibrosis score ≥2 (29.7% vs 31.7%) [3]. Furthermore, the rate of progression to cirrhosis was also similar in control and active groups (28.2% vs 31.9%, p =0.46). After the randomization phase of the HALT-C trial, patients continued to be followed, with an overall median duration of participation of 6 years [11]. Of the 622 patients with baseline fibrosis, 109 progressed to cirrhosis at 2 years and a further 69 had developed cirrhosis at 4 years, resulting in an annualized rate of progression to cirrhosis of 9.9%. strongly associated with the incidence of cirrhosis was the ALT level. These data are Between-treatment-group comparisons were not reported, but interestingly the factor most compatible with the very slow progression of liver disease in previously treated non-cirrhotic patients, as well as the possible impact of reduced necrosis and inflammation arising from interferon-based treatment. Thus, data from the present study are consistent with those from HALT-C indicating no benefit of low-dose PEG-IFN alfa therapy in non-cirrhotic patients with
other long-term studies emphasizes that large populations of patients are necessary to see a CHC infection when treated for 2 years and using liver biopsy as a reference. A review of benefit of treatment on fibrosis when using paired biopsies, even within patient populations with SVR [12]. The use of validated non-invasive biomarkers such as FibroTest should increase the power with repeated fibrosis estimates [13]."
Abstract
Background and Aims
Therapeutic options for patients failing hepatitis C retreatment are limited. EPIC3 included a prospective trial assessing long-term peginterferon alfa-2b (PEG-IFN alfa-2b) maintenance therapy in patients with METAVIR fibrosis scores (MFS) of F2 or F3 who previously failed hepatitis C retreatment.
Methods
Patients with F2/F3 MFS who failed retreatment were randomized to PEG-IFN alfa-2b (0.5 μg/kg/week, n=270) or observation (n=270) for 36 months. Blinded liver biopsies obtained before retreatment and after maintenance therapy were evaluated using MFS and activity scores, and confirmatory testing was performed using FibroTest and ActiTest.
Results
In total, 348 patients had paired biopsies: 192 patients had missing post-treatment biopsies and were considered as having no change in fibrosis/activity scores. In total, 16% of patients receiving PEG-IFN alfa-2b and 11% of observation patients had improvement in MFS (p=0.32). More PEG-IFN alfa-2b than observation patients had improvement in activity score (20% vs 9%; p<0.001). Among patients treated for >2.5 years, improvement in MFS or activity score was more common with PEG-IFN alfa-2b than observation (21% vs 14%, p=0.08 and 26% vs 10%, p<0.001). FibroTest and ActiTest evaluations indicated significant benefit associated with PEG-IFN alfa-2b in terms of reduced fibrosis progression and improved activity score. The safety profile of PEG-IFN alfa-2b was similar to previous studies.
Conclusions
PEG-IFN alfa-2b did not significantly improve MFS estimated by biopsy compared with observation; however, activity scores were significantly improved and MFS trended toward increased improvement with treatment durations >2.5 years. Both FibroTest and ActiTest were significantly improved during maintenance therapy.
Activity response
Significantly more patients receiving PEG-IFN alfa-2b had improvement in METAVIR activity score compared with patients in the observation group (20%, [54/270] vs 9% [23/270], p<0.001) (Figure 3). Similar numbers of patients had no change in activity score between pre-treatment and end of maintenance (PEG-IFN alfa-2b, 72% [195/270] vs observation, 77% [209/270]), including those with missing end-of-maintenance liver biopsies. Overall, 8% (21/270) of patients in the PEG-IFN alfa-2b group and 14% (38/270) of those in the observation group experienced deterioration in activity scores at end of maintenance compared with baseline. Activity score improved by ≥2 units in 1% of patients receiving PEG-IFN alfa-2b and 0% of the observation group. As seen with MFS, in the subgroup of patients treated for >2.5 years, the proportion of patients with an improvement in activity score was 26% (49/186) in the PEG-IFN alfa-2b group and 10% (20/197) in the observation group (p <0.0001) (Figure 3). When this analysis was restricted to patients with pre- and post-treatment biopsy (excluding patients with missing post-treatment biopsies), ≥1-unitimprovement in activity score was seen in 54 of 182 patients receiving PEG-IFN alfa-2b, and 23 of 166 patients under observation (29.7% vs 13.9%, p <0.0001).
Using FibroTest equivalence to MFS, significantly more observed patients showed a worsening in fibrosis score compared with those receiving PEG-IFN alfa-2b (14% vs 6%; p =0.02) (Figure 4A) Similarly, using ActiTest equivalence, more patients receiving PEG-IFN alfa-2b showed improvement in METAVIR activity grade compared with the observation group (16% vs 5%; p = 0.001). After 3 years of treatment, FibroTest data revealed a statistically significant improvement in fibrosis among patients receiving PEG-IFN alfa-2b compared with observation (Figure 4B). Based on the last FibroTest assessment, fibrosis score was significantly worse in observation patients than in patients receiving PEG-IFN alfa-2b (0.04 vs -0.002; p = 0.01). Similarly, necroinflammatory activity (as measured using ActiTest) was also significantly better in patients receiving PEG-IFN alfa-2b than in the observation group (Figure 4C). ActiTest scores at the last clinic visit were significantly better in patients receiving PEG-IFN alfa-2b than in observation patients (-0.08 vs. 0.01; p<0.0001).
|
|
| |
| |
|
|
|
