 |
|
|
| |
Pegasys/Ribavirin in African Americans Showed Improved or Stabilized Fibrosis in Nonresponders
|
| |
| |
Reported by Jules Levin
“Peginterferon alfa-2a (40KD) (Pegasys) in Combination With Ribavirin (Copegus) in African American and Caucasian Patients With Chronic Hepatitis C Virus Genotype 1 Infection: Assessment of Histologic Response”
William Cassidy, Louisiana State University Health Sciences Center, Baton Rouge; Lennox Jeffers, Miami VA Medical Center, FLA; Charles Howell, University of Maryland School of Medicine, Baltimore; K. Rajender Reddy, University of Pennsylvania, Philadelphia; Susan Sheridan, Ellen Lentz, George Harb, Sarkis Khouri, Roche, Nutley, NJ
Summary:
Over 90% of the patients in this study, showed either improvement or stabilization in fibrosis. The study authors report that there was modest improvement in mean HAI activity and total HAI scores for both black and white patients. The mean improvement in fibrosis scores was somewhat greater for black patients than for white patients. Many studies in patients with hepatitis C have shown that interferon-based therapy can significantly reduce the rate of fibrosis progression. Our results are in accord with the view that suppression of viral load is the critical factor leading to improvement in fibrosis. Of note, this study found that 14% of blacks who were viral nonresponders and 36% of viral relapsers improved fibrosis; and 68% of blacks and 88% of whites saw a stabilization of fibrosis progression. reducing fibrogenesis. A number of potential underlying mechanisms have been postulated for the antifibrotic effect of interferon, in addition to its antiviral effect. Interferon alfa itself may have a direct impact on reducing fibrogenesis. Although improvement in fibrosis may occasionally occur in patients without eradication of HCV during treatment, the authors suggest that HCV may well be suppressed in these individuals at some time during therapy, and clearly, the prevention of the progression of fibrosis in the absence of HCV eradication may provide a long-term benefit in the treatment of chronic HCV infection. The authors conclude that since a substantial proportion of black patients showed a reduced rate of fibrosis progression in this study, the study data provide evidence of an antifibrotic and antinecroinflammatoru effect of Pegasys/Copegus treatment in this difficult to treat population.
INTRODUCTION
Chronic infection with hepatitis C virus (HCV) is two to three times more common among black Americans than among white Americans. More importantly, the complications of chronic HCV infection, such as cirrhosis, ascites, and hepatocellular carcinoma, are more common among blacks. Pegylated interferons plus ribavirin are now the standard of care for the treatment of patients with chronic hepatitis C. Results of two recent large clinical studies of treatment with pegylated interferons plus ribavirin showed overall sustained virologic response (SVR) rates of 54% and 56%. For patients infected with HCV genotype 1, also more prevalent in blacks than in whites, SVR rates were 42% and 46% in the respective studies.
The value of antiviral therapy in blacks has not been easy to assess because blacks have been underrepresented in prospective clinical trials. In addition to SVR, a virologic measure of efficacy, the effect of treatment on progression of fibrosis is also important in establishing clinical benefit. Many studies in patients with hepatitis C have shown that interferon-based therapy significantly reduces the rate of fibrosis progression. The primary objective of this study was to investigate the efficacy and safety of Pegasys (peginterferon alfa-2a [40KD]) in combination with COPEGUS (RBV) in non-Hispanic black and non-Hispanic white patients with HCV genotype 1. A secondary objective was to investigate the effect of combination therapy with PEGASYS/COPEGUS on liver histology.
METHODS
The primary efficacy variable in the study was the proportion of patients with an SVR at the conclusion of the treatment-free follow-up period (Week 72). SVR was defined as a serum HCV RNA level <50 IU/mL (ie, below the limit of detection) using the COBAS AMPLICOR® HCV Test, v2.0.
Slides of liver biopsy specimens obtained before the study and at the final scheduled visit, or at 24 weeks after completion of treatment, were coded and read by the study pathologist, who was blinded regarding patient identity and the date of biopsy.
A histologic response was defined as a decrease of ≥2 points in the total score on the Histological Activity Index (HAI) scale. With regard to the fibrosis component of the HAI score, “worsening” was defined as an increase by ≥1 point; “stable” was defined as no change; and “improvement” was defined as a decrease of ≥1 point.
RESULTS
VIROLOGIC EFFICACY
A total of 78 black and 28 white patients participated in the study. Using an intention-to-treat (ITT) analysis, 20 black patients (26%, 95% CI, 16%- 35%) and 11 white patients (39%, 95% CI, 21%- 57%) achieved an SVR.
A larger proportion of black patients (45 of 78; 58%) had high viral loads (HVL=HCV RNA >800,000 IU/mL) prior to the initiation of therapy, compared with the white patients (12 of 28; 43%). An SVR was achieved by 9 (20%) and 7 (41%) patients with HVL in each group, respectively.
Mean Baseline HAI Histology Scores: patiets with paired Biopsies (± standard error)
|
| |
| |
| |
Blacks Americans |
White Americans |
| |
N=53 |
n=16 |
| Total HAI score |
9.1 ± 0.42 |
8.8 ± 0.86 |
| HAI activity score |
7.2 ± 0.32 |
6.9 ± 0.69 |
| Fibrosis score |
1.8 ± 0.14 |
1.9 ± 0.3 |
| |
Abbreviated Description |
Attributes as Read to Participants |
|
|
| |
| |
The mean total HAI scores in patients with paired biopsies were comparable to those of the ITT patients in blacks and whites (9.1±0.34 and 9.3±0.57). Only the mean activity scores for white patients with paired biopsies differed somewhat from the score for all white patients (7.5±0.47).
Mean baseline fibrosis scores of patients with paired biopsies were similar to those of the ITT population.
Black patients had slightly greater mean improvement in fibrosis scores than the white patients, but less improvement in activity scores (Figure 1). Mean improvement in Fibrosis Score for black patients was –0.4 vs-0.1 for white patients. The mean improvement in Activity Score was –2.2 for blacks vs –3.3 for whites.
About a quarter of the black patients with paired biopsies showed an improvement in the mean fibrosis score. Over 90% of the patients in both groups showed either improvement or stabilization in fibrosis. 25% of blacks (n=13) and 6% of whites (n=1) showed improvement in fibrosis. 68% of blacks (n=36) and 88% of whites (n=14) showed stabilization of fibrosis. 8% of blacks (n=4) and 6% (n=1) of whites showed worsening of fibrosis. Again, “Improved” was defined as a decrease of ≥1; “stable” was defined as no change; and “worsened” was defined as an increase of ≥1 unit in the Knodell HAI (part IV) score.
Fibrosis responses were also observed in a substantial proportion of black patients who did not achieve an SVR. Of those with an SVR, 5 of 17 (29%) had improvement in fibrosis vs 0/10 whites; of those with a virologic relapse, 5 of 14 (36%) had improvement in fibrosis vs 1/4 whites; and among those who were virologic nonresponders, 3 of 22 (14%) had improvement in fibrosis vs 0/2 whites. biopsies. Fibrosis response was defined as a ≥1-point increase in Knodell (part IV) score. Patients with a virologic relapse had undetectable HCV RNA at some time during the study, but did not achieve an SVR; patients with a nonresponse never had undetectable HCV RNA levels during treatment.
Patients with more advanced fibrosis, particularly in the black group, appeared to benefit most from therapy with PEGASYS/COPEGUS.
Histology Responses for Patients According to Baseline Fibrosis Score |
| |
| |
 |
|
| |
| |
Discussion by Authors
This study is the first well-controlled, prospective clinical study of the efficacy, safety and tolerability of the combination of PEGASYS and COPEGUS in blacks with HCV genotype 1 infection. There was modest improvement in mean HAI activity and total HAI scores for both black and white patients. The mean improvement in fibrosis scores was somewhat greater for black patients than for white patients. Many studies in patients with hepatitis C have shown that interferon-based therapy significantly reduces the rate of fibrosis progression. Our results are in accord with the view that suppression of viral load is the critical factor leading to improvement in fibrosis. Most of the black patients who had improved fibrosis scores cleared HCV while on treatment (5 had SVRs, 5 relapsed). Only 3 black patients who did not clear HCV during treatment had improved fibrosis scores, although viral load may have been suppressed at some point in time. Of 5 patients whose fibrosis worsened, 4 were virologic nonresponders and 1 had a virologic relapse. Fibrosis progression was halted in 7 of 13 black patients who were virologic nonresponders. It is intriguing that only 1 white patient (a virologic relapser) experienced fibrosis improvement 24 weeks after the end of treatment, despite the higher SVR rate in this group. Nonetheless, the majority of both black and white patients had stabilization of fibrosis scores. Thus, our results suggest that black patients may experience more improvement in fibrosis with treatment than white patients.
A number of potential underlying mechanisms have been postulated for the antifibrotic effect of interferon, in addition to its antiviral effect. Interferon alfa itself may have a direct impact on reducing fibrogenesis. Although improvement in fibrosis may occasionally occur in patients without eradication of HCV during treatment, HCV may well be suppressed in these individuals at some time during therapy. Clearly, the prevention of the progression of fibrosis in the absence of HCV eradication may provide a long-term benefit in the treatment of chronic HCV infection.
CONCLUSION
A substantial proportion of black patients showed a reduced rate of fibrosis progression in this study. These data provide evidence of an antifibrotic and antinecroinflammmatory effect of PEGASYS/COPEGUS treatment in this diffi-cult- to-treat population.
|
| |
|
|
|
|
|
