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PegIFN/Ribavirin Therapy for Cirrhotics
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Reported by Jules Levin
Two studies of treatment with Pegasys plus ribavirin for patients with cirrhosis & decompensated cirrhosis were reported at the 40th EASL liver meeting in Paris, April 2005. In the first study, which was the Canadian Open-Label Expanded Access Program, 34% of cirrhotic patients with 48 weeks therapy & genotype 1 achieved an SVR & 44% of patients with genotype 2 achieved an SVR. The study investigators concluded cirrhotic patients with Chilld Pugh A could be treated safely & effectively. Patients received only 800mg of ribavirin per day & investigators said that 1000-1200mg per day should be used. In the second study reported below, patients with decompensated cirrhosis, more advanced liver disease were treated with peginterferon monotherapy, peginterferon/RBV, or interferon/ribavirin. The SVR was lower 21% for genotype 1 & 53% for genotype 2, as would be expected. 85% of patients experienced adverse events, 18% had to withdraw from treatment. These safety issues & high discontinuation rate are expected & have been observed in other studies treating patients with decompensated cirrhosis. 50% of patients used EPO for anemia & 18% of patients experienced depression. Still, the study authors concluded that therapy for patients with decompensated cirrhosis appears to be safe & effective, as 31% achieved an SVR. As well, therapy resulted in improvements in ALT & other liver synthetic functions. The results from this second study confirm findings from other studies that patients with decompensated cirrhosis can be treated although there are safety concerns. These results are important because many medical care providers are unwilling to treat patients with decompensated cirrhosis but this study & others demonstrate treatment can be successful. It is only fair to patients that treatment for this advanced group be considered & not automatically rejected.
"PEGINTERFERON a-2a (40 kDa) PLUS RIBAVIRIN IN CIRRHOTIC PATIENTS WITH CHRONIC HEPATITIS C: RESULTS OF A CANADIAN MULTICENTER OPEN-LABEL EXPANDED ACCESS PROGRAM"
S.S. Lee (University of Calgary, Calgary, AB, Canada) reported these study results at the 40th EASL liver meeting in Paris, April 2005.
In the only prospective randomized study conducted exclusively in patients with bridging fibrosis/cirrhosis, the overall SVR rate after 48 weeks' treatment with peginterferon a-2a (40 kDa) (PEG-IFNa-2a) 180 µg/week was 30% (Heathcote, NEJM 2000; 343: 1673-80). Patients in clinical trials are highly selected and motivated, and whether the same response rates can be achieved in routine clinical practice remains unknown. We evaluated the efficacy and tolerability of PEG-IFNa-2a/ribavirin in treatment-naive patients enrolled in a multicenter, open-label expanded access program in a routine clinical setting.
Methods: Anti-HCV antibody-positive adults with detectable HCV RNA (>600 IU/ml) were eligible.
Patients with a histological diagnosis of fibrosis/cirrhosis (F3/F4) were eligible provided they had compensated liver disease (Child-Pugh A).
At the investigator's discretion patients were assigned to PEG-IFNa-2a 180 µg/week plus ribavirin 800 mg/day for 24 (A) or 48 weeks (B). The program was initiated before the optimal treatment duration and ribavirin dosage for genotype-1 and 2/3 were known. This analysis was conducted by intention-to-treat.
Results
At baseline 29% of patients had HCV RNA >850,000 IU/mL.
100% of patients had Child Pugh A, which is compensated liver disease; A is earlier disease stage than B or C. In the next study I report below most of the patients had more advanced liver disease & decompensated cirrhosis.
174 of 508 (34%) patients had fibrosis/cirrhosis.
These patients were older, had a higher BMI and were more likely to have genotype-1 infection than non-cirrhotic patients. 5% of patients had serious adverse events; 34% had lab abnormalities; and 5.7% discontinued treatment prematurely. The more advanced patients in the second study beloe experienced more therapy discontinuations and a higher rate of lab abnormalities.
Most patients (380/508, 75%) were assigned to group B. The SVR rate in fibrotic/cirrhotic patients was 44% (34% in genotype-1, and 58% in genotypes 2/3 includes groups A & B).
Non-cirrhotic patients had higher SVRs: 41% in genotype-1; 77% in genotypes 2/3. The incidence of serious adverse events was similar in fibrotic/cirrhotic (5%) and non-cirrhotic patients (5%).
SVR = undetectable HCV RNA (<50 IU/ml) 24 weeks after end of treatment.
There was no difference between cirrhotics & non-cirrhotics in this study regarding adverse events & dose modifications.
Author Conclusions
The efficacy of PEG-IFNa-2a/ribavirin in this study was similar to that in cirrhotic patients treated with the same regimen in a randomized pivotal study in which different treatment durations and ribavirin dosages were compared (Hadziyannis, Ann Intern Med 2004; 140: 346).
Our results demonstrate that this combination is effective and safe in patients with fibrosis/cirrhosis and results obtained in clinical trials can be achieved in routine clinical practice.
Further improvement in SVR may be obtained with optimal ribavirin dose in genotype-1 patients.
Treatment for Patients with Decompensated Cirrhosis
"SAFETY AND EFFICACY OF ANTIVIRAL THERAPY IN PATIENTS WITH DECOMPENSATED CIRRHOSIS ASSOCIATED WITH CHRONIC HEPATITIS C INFECTION"
J.K. Lim and J.C. Imperial reported this study at EASL.
Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, USA; Department of Medicine, San Mateo Medical Center, San Mateo, CA, USA
Background and Aims: Decompensated liver disease associated with chronic hepatitis C virus (HCV) infection is the most common indication for liver transplantation in the U.S.A. Although interferon-based regimens are frequently used in compensated cirrhosis, the role of antiviral therapy in the treatment of patients with decompensated cirrhosis remains poorly defined.
Methods: We evaluated the safety and efficacy of antiviral therapy in 32 patients with decompensated HCV cirrhosis.
At the time of inclusion, 25.0% of patients were Child-Pugh A, 59.4% were Child-Pugh B, and 15.6% were Child-Pugh C, with a mean Child-Pugh score of 8.03±1.75 (95%CI: 7.40-8.66). (More advanced disease than patients in the first study reported above).
Most patients were white (87.5%) and male (74.2%), with a mean age of 54.9±7.2 years (95%CI: 52.28-57.47) and mean weight of 92.2±24.4 kg (95%CI: 83.41-101.0).
Thrombocytopenia (90.6%), fluid retention (62.5%), esophageal varices (46.9%), and hepatic encephalopathy (21.9%) were the most common decompensation events.
All patients underwent an intensive pretreatment regimen to optimize hepatic function prior to antiviral therapy (e.g. eradication of varices, resolution of ascites), and were monitored closely throughout therapy within a major university transplant program.
Patients were treated with pegylated interferon/ribavirin (78.1%), pegylated interferon monotherapy (12.5%), or interferon/ribavirin (9.4%), for a mean of 37.8±17.1 weeks (95%CI: 31.55-44.13).
Results
Sustained virologic response (SVR) was achieved in 10/32 patients (31.3%), including 21.1% in genotype 1 and 53.8% in non-genotype 1 patients.
Normalization of ALT was achieved in 40.6% of patients.
The mean CTP score following end-of-treatment was 6.06±1.22 (95%CI: 5.62-6.50), as opposed to 8 before therapy.
Most patients (84.4%) experienced adverse events; six (18.8%) required withdrawal of antiviral therapy, and one (3.1%) experienced liver decompensation.
Anemia requiring erythropoietin support (50.0%), neutropenia requiring G-CSF support (15.6%), depression (18.8%), and infections (9.4%) were the most common adverse events.
Five patients (15.6%) were removed from transplant listing due to clinical improvement. No patients died during treatment.
Author Conclusion: Antiviral therapy appears to be safe and effective in carefully selected patients with decompensated cirrhosis associated with chronic HCV infection. Treatment may result in SVR in nearly one-third of patients, and lead to improvements in biochemical markers and liver synthetic function.
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