Efficacy of a second cycle of interferon therapy in patients with chronic hepatitis C

Chemello, Liliana; Cavalletto, Luisa; Donada, Carlo; Bonetti, Paola; Casarin, P.; Urban, F; Bernardinello, Elisabetta; Pontisso, Patrizia; Alberti, Alfredo

doi:10.1053/gast.1997.v113.pm9352869

Cited by 46 publications

(31 citation statements)

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“…These included age, higher ALT levels, lower ␥-glutamyltransferase levels, negative HCV RNA at the end of the first cycle, low levels of HCV RNA before retreatment, and increased IFN dose in the second course. 2,4,[6][7][8][9]14 Finally, Chow et al 3 failed to identify any predictive item significantly associated with an SR. The drawing of firm conclusions based on the results of these studies is hampered by the small sample size and by the imbalance between the high number of variables included in multivariate models and the small number of events observed, potentially leading to false-negative or false-positive results.…”

Section: Discussionmentioning

confidence: 99%

Chronic hepatitis C: Interferon retreatment of relapsers. A meta-analysis of individual patient data

et al. 1999

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Relapse after interferon (IFN) therapy for chronic hepatitis C virus (HCV) infection occurs in 50% of patients after the initial response. The benefit of retreatment with IFN alone has not been assessed in large controlled studies. To assess the effectiveness and the tolerability of IFN retreatment and to identify the optimal second course regimen, we performed a meta-analysis of individual patient's data on a set of 549 patients (mean age 43.8 years; 12.2 SD, men: 65%) who had an end-of-treatment biochemical response to a first IFN course and then relapsed. Retreatment was started within 24 months after the end of the first course. In chronic hepatitis C, the goal of treatment, defined as complete sustained response (SR) (normal alanine transaminase levels and undetectable serum hepatitis C virus-RNA (HCV-RNA) levels 6 to 12 months after therapy) is achieved in less than 20% of patients with standard interferon (IFN)-alfa schedule. 1 Although a complete end-of-treatment response (ETR) is obtained in about 50% of patients, half of them will relapse with a reappearance of viremia and liver necroinflammation soon after stopping therapy. Therefore, relapse remains a major issue in the long-term management of the disease. Several studies of retreatment with IFN alone in patients who had an ETR but subsequently relapsed after stopping IFN have been published. The results of these studies are inconclusive or conflicting because of the relatively small samples and the difficulty of generalizing patients owing to the differences in patient characteristics, study design, regimens, and types of IFN administered. Although the conclusions of the National Institutes of Health Consensus Development Conference for the retreatment of relapse of chronic hepatitis C have recently been published, 22 important questions still remain unanswered. Is monotherapy retreatment useful in relapsers? Are there any differences in the effectiveness of IFN retreatment between cirrhotic and noncirrhotic patients, between different HCV genotypes and, finally, between different second course regimens?To increase the statistical power and to resolve uncertainty we propose a meta-analysis of the individual patient' s data (MIPD), drawing from 1 Japanese center and 15 European centers. The aims of this MIPD were (1) to assess the efficacy and tolerability of IFN retreatment in obtaining a complete SR in relapsers; (2) to evaluate which retreatment schedule should be used and, finally, (3) to identify possible predictors of complete SR. Our aims seem particularly important at a time when combination therapy (IFN plus ribavirin) is being confirmed as an effective treatment for relapsers. MATERIALS AND METHODSThe study was planned within the European Concerted Action on Viral Hepatitis (EUROHEP). Twenty-four centers throughout the world, all with reported experience in this field, were invited to participate: 15 centers in Europe and 1 center in Japan agreed to make data available. Individual patient data from previously published and unpublished stud...

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confidence: 99%

Chronic hepatitis C: Interferon retreatment of relapsers. A meta-analysis of individual patient data

et al. 1999

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“…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][8][9][10][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.…”

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A Randomized 4–Arm Multicenter Study of Interferon Alfa-2B Plus Ribavirin in the Treatment of Patients With Chronic Hepatitis C Not Responding to Interferon Alone

et al. 2001

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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...

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“…[1][2][3] To date, hepatitis C virus (HCV) is classified into at least 9 major genotypes and more than 30 subtypes. 4,5 In Japan, about 70% of the patients with chronic hepatitis C are infected with HCV genotype 1b (HCV-1b), and the rest are infected with HCV genotype 2 (HCV-2) 6 (25% with HCV-2a and 5% with HCV-2b).…”

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Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection

et al. 1999

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An association has been reported between mutations in the amino acid residues 2209-2248 of the nonstructural protein 5A (NS5A) gene (interferon-sensitivity determining region [ISDR]) and interferon efficacy in hepatitis C virus (HCV)-1b infection. This relationship was analyzed in chronic HCV-2 infection. Forty patients with HCV-2a and 35 with HCV-2b were treated with interferon alfa for 6 months with a total dose of 468 to 860 million units. Pretreatment NS5A sequences were determined by direct sequencing. A higher complete and sustained response rate was observed in HCV-2a than in HCV-2b (70% vs. 34%; P ‫؍‬ .003). Serum HCV-RNA levels were lower in complete responders than nonresponders in HCV-2a (P ‫؍‬ .049) and HCV-2b (P ‫؍‬ .02). The number of amino acid mutations was greater in complete responders than nonresponders in NS5A2193- The current primary therapy for chronic hepatitis C is parenteral administration of type 1 interferons (interferon alfa and beta), while the rate of sustained and complete responses with virus eradication is obtained in only up to 30% of the patients. 1-3 To date, hepatitis C virus (HCV) is classified into at least 9 major genotypes and more than 30 subtypes. 4,5 In Japan, about 70% of the patients with chronic hepatitis C are infected with HCV genotype 1b (HCV-1b), and the rest are infected with HCV genotype 2 (HCV-2) 6 (25% with HCV-2a and 5% with HCV-2b). While the complete response is as low as 10% to 20% in HCV-1b infection, it is considered more than 60% in HCV-2 infection in Japan. [7][8][9][10][11][12] Such differences in interferon efficacy among various HCV genotypes suggest that a certain kind of genetic change of the virus could affect the sensitivity to interferon.We recently identified a region that is associated with the response to interferon in HCV-1b genomes in Japan. 13 An increase in the number of amino acid changes in the nonstructural protein 5A gene (NS5A) (NS5A2209-2248, interferon sensitivity determining region [ISDR]) makes HCV more sensitive to interferon. 14 However, the mechanism of the different response to interferon therapy among patients with HCV-2 infection is still unclear. Some studies suggested that a lower viral load is associated with the good response to interferon in HCV-1b or non-1b, 12,15 the mechanism of which is still unknown. In previous studies, interferon effect and pretreatment viral load were also associated with the mutations in ISDR in HCV-1b. 13,16 Thus, the relation between NS5A structure and interferon effect or viral load in HCV genotypes other than HCV-1b is of great interest.Several studies that focused on biological functions of NS5A revealed some aspects of its properties. In particular, Gale et al. 17 suggested that the NS5A protein inhibits an RNA-dependent protein kinase (PKR), which plays a major role in the viral protection by inhibiting viral protein translation. The NS5A protein of HCV-1b and -1a forms a complex with the PKR and inhibits the phosphorylation of eukaryotic translation initiation factor-2 (eIF-2). Mor...

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Efficacy of a second cycle of interferon therapy in patients with chronic hepatitis C

Cited by 46 publications

References 1 publication

Chronic hepatitis C: Interferon retreatment of relapsers. A meta-analysis of individual patient data

Chronic hepatitis C: Interferon retreatment of relapsers. A meta-analysis of individual patient data

A Randomized 4–Arm Multicenter Study of Interferon Alfa-2B Plus Ribavirin in the Treatment of Patients With Chronic Hepatitis C Not Responding to Interferon Alone

Mutations in nonstructural protein 5A gene and response to interferon in hepatitis C virus genotype 2 infection

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