To determine whether a higher dosage of interferon (IFN) associated with ribavirin and/or prolonged time of administration may improve therapeutic efficacy, we conducted a 4-arm randomized trial on patients with chronic hepatitis C not responding to one or more previous treatment courses with IFN monotherapy. Group 1 (n ؍ 139) received 3 million units (MU) IFN-␣2b 3 times a week (t.i.w.) plus ribavirin 1,000 mg/d for 12 months; group 2 (n ؍ 162) received 5 MU t.i.w. plus ribavirin for 12 months; group 3 (n ؍ 142) received 3 MU t.i.w. plus ribavirin for 6 months; and group 4 (n ؍ 151) received 5 MU t.i.w. plus ribavirin for 6 months. The primary end point was hepatitis C virus (HCV)-RNA clearance at the end of 6-month follow-up. HCV-RNA was negative in 15% of group 1, 23% of group 2, 11% of group 3, 16% of group 4 (group 2 vs. group 3, P ؍ .04). Among patients with genotypes 1 and 4, sustained response was significantly higher in group 2 vs. group 3 (18% vs. 7%, P ؍ .03; group 1 ؍ 9%, group 4 ؍ 12%, P ؍ not significant [NS]). In patients with genotypes 2 and 3, sustained virologic response was not affected by the different regimens (group 1 ؍ 32%, group 2 ؍ 30%, group 3 ؍ 30%, group 4 ؍ 35%, P ؍ NS). In conclusion, about 23% of nonresponders to IFN monotherapy may achieve a sustained response if Combination therapy (interferon [IFN] plus ribavirin) is the first-line therapy for naive patients with chronic hepatitis C 1,2 ; patients who have relapsed after an initial treatment with IFN alone can also be re-treated with good results. 3 Unfortunately, there is no therapeutic option for patients who have not responded to IFN and to date consensus conferences 4,5 have not recommended any therapeutic schedule for IFN nonresponders; these patients nevertheless represent a high percentage of patients.Re-treatment of nonresponders with higher dosages of IFN and/or more aggressive approaches is ineffective 5 or induces a low rate of sustained responders 6 ; recent trials with IFN plus ribavirin combination protocols 7-11 have given disappointing results, but the small number of patients recruited into the studies and the low dosage of IFN used have made the results questionable.To address the question of whether higher than standard IFN dosages associated with ribavirin and/or prolonged time of administration may improve the rate of sustained responses, we conducted a 4-arm randomized trial on patients with chronic hepatitis C not responding to one or more previous treatment courses with IFN alone. The study was designed to compare the efficacy and safety of IFN given at 3 million units (MU) and 5 MU 3 times a week (t.i.w.) plus ribavirin 1,000 mg given daily over treatment durations of 6 and 12 months. PATIENTS AND METHODSDefinition of Nonresponse. According to the Consensus Conference held in Paris, February 26 to 27,1999, nonresponse to IFN monotherapy is defined by abnormal alanine transaminase (ALT) levels or by the presence of hepatitis C virus (HCV)-RNA during therapy; breakthroughs durin...
The evolving role of liver biopsy has induced the formulation of several guidelines on its appropriateness. However, the great divergence among hepatologists is still unresolved. We report the 4-year activity of a day hospital of gastrohepatology in northern Italy. Between January 2001 and July 2004, 835 subjects (mean age, 43+/-12 years) underwent this procedure in our facility. Etiologically, in 465 (56%) and 157 (19%) patients, chronic hepatitis C and nonspecific elevated liver biochemical tests were the first and second indications, followed by chronic hepatitis B and suspected nonalcoholic steatohepatitis. On a purpose basis, procedures requested for staging (n = 578) and/or for diagnosis (n = 217) were identified. Among the former, 80% had the scope of staging chronic hepatitis C, and in 15% of these unsuspected superimposed cirrhosis was detected. Among diagnostic procedures, nonspecific raised liver enzyme level ranked first. Twenty-two percent of patients reported unwanted effects following the procedure. In conclusion, these data accord with indications expressed by international guidelines. The impact of liver biopsy on therapeutic decision-making needs to be studied further.
Combination therapy (Interferon plus ribavirin) is the current therapeutic gold standard for naive Hepatitis C Virus (HCV)-positive patients and with the recent advent of pegylated (PEG) IFN the rate of the sustained virological response (HCV-RNA clearance 6 months after the end of treatment) is about 54%-56% with a therapeutical gain mainly among patients with unfavourable HCV genotype (1a, 1b); in this subset of patients, a 42%-46% sustained response rate is achieved compared with 33%-36% found among genotype 1 patients treated with the standard therapy. Patients who respond to IFN monotherapy but relapse during the follow-up should be re-treated with combination therapy given for at least 6 months at the minimum dose of 3 MU thrice weekly plus ribavirin 1000 mg/daily. Recent data suggest that prolonging the time of treatment (12 months) may induce a significantly higher rate of sustained response among patients with genotype 1. The efficacy of the combination of IFN and ribavirin in retreating patients with chronic hepatitis C not responding to IFN monotherapy is controversial as it ranges between 0% and 40%. Recent data show an overall rate of sustained response of 23% when an aggressive approach is adopted but increasing the dosage and the time of treatment induces a significant therapeutic benefit only in patients with genotype 1. In conclusion, a therapeutic progress for chronic hepatitis C has been achieved during the last 10 years (56% vs 20% of sustained response rate obtained with IFN monotherapy) but several unresolved issues are yet to be addressed.
To determine whether a higher dosage of interferon (IFN) and/or a prolonged time of administration may improve the efficacy of combination therapy, we conducted a 4-arm randomized trial on patients with chronic hepatitis C relapsing after 1 or more previous treatment courses with IFN monotherapy. Group A (n = 70) received 3 MU IFN alfa-2b 3 times per week plus ribavirin 1,000 mg/d for 12 months; group B (n = 70) received 5 MU 3 times per week plus ribavirin for 12 months; group C (n = 82) received 3 MU 3 times per week plus ribavirin for 6 months, and group D (n = 73) received 5 MU 3 times per week plus ribavirin for 6 months. The primary end point was the clearance of viremia at the end of 6-month follow-up: test results for hepatitis C virus (HCV)-RNA were negative in 54% of group A, 56% of group B, 40% of group C, and 49% of group D patients (P = NS). Among patients with genotype 1 and 4, the sustained response was significantly higher in groups A and B than in group C (45%, 49% vs. 22%, P =.03; group D = 33%, P = NS). In patients with genotype 2 and 3, the sustained virologic response was not affected by the different regimens (group A = 69%, group B = 68%, group C = 62%, group D = 71%, P = NS). In conclusion, duration of therapy rather than IFN dosage is more important in increasing the sustained virologic rate among HCV-positive patients with genotype 1 and 4 relapsing after IFN monotherapy; patients with genotypes 2 and 3 can be effectively retreated with a 6-month course of combination therapy, avoiding unnecessary side effects and waste of resources.
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