The future for the treatment of genotype 4 chronic hepatitis C

Hepatitis C virus genotype 4 (HCV-4) is the most common type of hepatitis C virus (HCV) in the Middle East and Africa, in particular Egypt. Since the development of new protease inhibitors, the response of HCV-4 to the standard regimen of treatment (pegylated interferon/ribavirin) lags behind other genotypes and has become the most resistant type to treat. The development of therapeutic strategies for all patients with HCV-4 whether they are na?ve, have experienced a virological breakthrough, are relapsers or non-responders is still a considerable challenge. New types of interferon (Consensus Interferon, Y-shaped, Albinterferon...) and new direct action antiviral drugs (Nitazoxanide, Vit.D, other) may improve the treatment of patients with HCV-4. The IL28B CC polymorphism may be associated with sustained virological response.     

Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study

BACKGROUND AND AIMS: Hepatitis C virus (HCV) reinfection after liver transplantation is frequent and leads to chronic hepatitis and cirrhosis. The use of antiviral therapy in this situation remains controversial. This study aimed to assess the safety and efficacy of interferon alfa-2b plus ribavirin for recurrent hepatitis C following liver transplantation. METHODS: Transplant recipients with recurrent chronic hepatitis C were randomized to receive either no treatment or therapy with interferon alfa-2b (3 MU 3 times a week) plus 1000-1200 mg/day ribavirin for 1 year. Patients were followed up for 6 months after the end of treatment. The primary end point was loss of HCV RNA 6 months after the end of treatment. RESULTS: Fifty-two patients were randomized (treatment, 28; placebo, 24). Sixteen patients were withdrawn from the study; 12 (43%) were from the treated group (mainly for anemia [7 patients]) and 4 (17%) from the control group. In the treated group, serum HCV RNA was undetectable in 9 patients (32%) at the end of treatment and 6 (21.4%) at the end of the follow-up period, whereas no patient in the control group lost HCV RNA at any point (P = 0.036 at the end of follow-up). However, there was no significant histologic improvement. CONCLUSIONS: The combination of interferon alfa-2b plus ribavirin induced a sustained virologic response in 21% of transplant recipients with recurrent hepatitis C. However, 43% discontinued therapy due to adverse events (primarily severe anemia). Strategies to enable treatment with lower doses of ribavirin need to be explored.     

Management of chronic hepatitis C patients who have relapsed or not responded to pegylated interferon alfa plus ribavirin

Summary.  Development of therapeutic strategies for patients with chronic hepatitis C who experience virological breakthrough, relapse or nonresponse lag behind those for treatment-naïve patients. The probability of a previously treated patient responding to re-treatment depends on the nature of the previous regimen, the magnitude of the response to previous treatment and the patient's characteristics. Relapsers have higher sustained virological response rates than nonresponders when re-treated with pegylated interferon plus ribavirin. Re-treatment of nonresponders to pegylated interferon plus ribavirin with the standard 48-week regimen resulted in an approximate 6% sustained response rate in the EPIC-3 program. In the REPEAT trial, the sustained response rate was significantly higher in nonresponders to pegylated interferon alfa-2b (12 kD) plus ribavirin randomized to 72 weeks of peginterferon alfa-2a (40 kD) plus ribavirin, compared with a 48-week regimen (16% vs 8%, P  = 0.0006). Based on available data, extended treatment is the best option for these individuals. Undetectable viral RNA at week 12 is an important criterion for re-treatment in the REPEAT and EPIC studies. Maintenance therapy with pegylated interferon is generally ineffective in nonresponders and cannot be recommended. Directly acting antivirals may increase response rates and the burden of adverse events when combined with the standard of care, but will not be available for some years. In conclusion, after careful evaluation of an individual's benefit–risk ratio, a 72-week regimen is the preferred strategy for optimizing sustained response rates in patients who have not responded to the standard of care, provided that viral RNA is undetectable at week 12 of re-treatment.     

Pegylated interferon plus ribavirin combination therapy in postliver transplant recipients with recurrent hepatitis C virus infection

Posttransplant hepatitis C virus (HCV) recurrence is universal in chronic hepatitis C recipients. Antiviral therapy is suggested after liver transplant to halt disease progression. Pegylated interferon plus ribavirin therapy remains the standard of care in many areas where direct antiviral agents are poorly accessible. This study aimed to assess the treatment efficacy and safety of the regimen for Taiwanese patients with post-transplant HCV recurrence. Nine patients with HCV recurrence postliver transplantation were allocated. Patients received either pegylated interferon α-2a 180 μg/wk or pegylated interferon α-2b 1.5 mg/kg/wk plus ribavirin for 24–48 weeks. The primary endpoint was the achievement of sustained virological response (SVR), defined as undetectable HCV RNA throughout 6 months of follow-up after the end of treatment. The safety profiles were also documented. The rates of rapid virological response, early virological response, end-of-treatment virological response, and SVR were 33%, 63%, 75%, and 56% respectively. Of the four patients who failed antiviral treatment, the treatment responses were nonresponse (n = 1), loss of follow-up (n = 1), and relapse (n = 2). Three patients terminated therapy early due to severe adverse events, including severe anemia, intra-abdomen infection, and hepatocellular carcinoma recurrence. One of the three patients who terminated treatment early at Week 6 experienced rapid virological response followed by SVR. Pegylated interferon/ribavirin combination allowed a chance for cure with a fair SVR rate in Taiwanese chronic hepatitis C patients postliver transplantation. Early identification of side effects and careful monitoring during therapy might enhance the treatment efficacy.     

First-line therapy with daily versus thrice-weekly interferon alfa-2b plus ribavirin for chronic hepatitis C

OBJECTIVES: Combination therapy with interferon and ribavirin is the most effective treatment for chronic hepatitis C today. Before pegylated interferons became available, higher and more frequent doses of interferon were expected to be more effective than the standard regimen of three million units thrice weekly. In fact, daily dosing is still proposed for non-pegylated interferon. The aim of this study was to compare the efficacy and safety of daily versus thrice-weekly interferon alfa-2b in combination with ribavirin as first-line treatment of chronic hepatitis C. METHODS: A total of 116 treatment-naive patients were randomised to receive either interferon alfa-2b three million units daily or thrice-weekly in combination with ribavirin for 24 weeks. Patients with hepatitis C virus (HCV) genotype 1 who were HCV-RNA negative at 24 weeks continued treatment with thrice-weekly interferon plus ribavirin for another 24 weeks. Sustained virological response was defined as an undetectable HCV-RNA level 24 weeks after treatment was completed (end of follow-up). RESULTS: In an intention-to-treat analysis, HCV-RNA was undetectable at the end of treatment in 71% and 74% of patients treated with daily and thrice-weekly interferon, respectively. At the end of follow-up, HCV-RNA was undetectable in 47% and 57% of patients treated with daily and thrice-weekly interferon, respectively. Sustained virological response rates were almost twice as high in patients with genotypes 2 and 3 as in patients with genotype 1 but were not different between treatment groups. CONCLUSIONS: This study could not show any difference between daily and thrice-weekly standard interferon plus ribavirin in achieving end-of-treatment and sustained virological responses in chronic hepatitis C.     

Amantadine triple therapy for non-responder hepatitis C patients. Clues for controversies (ANRS HC 03 BITRI)

BACKGROUND/AIMS: To determine whether addition of amantadine to pegylated interferon/ribavirin improved response rates among chronic hepatitis C patients, non-responders to interferon/ribavirin and study the dynamic of response. METHODS: In a double blind, multicenter, randomized trial, 200 non-responder patients received pegylated interferon 1.5 microg/kg per week and ribavirin 800-1200 mg/day, plus either amantadine 200 mg/day or placebo for 48 weeks. Endpoints were virological responses, ALT normalization, and histological benefit overtime. RESULTS: Twenty percent of all patients achieved a sustained virological response (SVR). This rate was 8% higher in the triple therapy group (24%) compared with the double therapy group (16%) (P = 0.22). A better virological response rate at week 24 was observed in the triple regimen group (43 vs 29%; P = 0.06), which was lost at week 48 suggesting viral escape. The biochemical response rate was also significantly higher with triple therapy at week 12 (63 vs 49%; P = 0.05) and week 24 (64 vs 49%; P = 0.03). Fibrosis stabilized or improved in 77% of all patients. CONCLUSIONS: Re-treatment of interferon/ribavirin non-responder patients should be encouraged since a substantial proportion benefits from re-treatment with pegylated interferon/ribavirin +/- amantadine. In triple therapy involving amantadine, a time wise response and an increased SVR rate in subgroups less prone to viral breakthrough suggest clues for existing controversies.     

Pegylated interferon-alpha2a/ribavirin treatment of recurrent hepatitis C after liver transplantation

Abstract: Hepatitis C virus (HCV) infection invariably recurs after liver transplantation (LT), leading to significant morbidity and mortality. Although the combination of pegylated interferon-alpha (IFN-α)/ribavirin is the preferred treatment for these patients, the optimal schedule remains undetermined. In an uncontrolled trial, 19 patients with HCV infection recurring after LT received pegylated IFN-α_2a, 180 μg weekly, and ribavirin, 10 mg/kg body weight daily, for 48 weeks. The proportion of patients with undetectable HCV RNA in their serum after 12 weeks of treatment was 53%. Five patients (26%) dropped out of the study due to intolerance (in 2 cases), depression (in 1), or infectious complications (in 2). A sustained virological response (SVR), defined as undetectable serum HCV RNA 24 weeks after the end of treatment, was observed in 9/19 patients (47%). SVR was associated with an early virological response after 12 weeks of therapy ( P <0.001) and a treatment duration >80% ( P =0.02), but not with baseline HCV RNA level or a cumulative dose of pegylated IFN-α_2a or ribavirin >80% of the scheduled dose. All 4 patients with genotype 2 or 3 reached SVR, as compared with 33% of patients with genotype 1 or 4 ( P =0.03). A 48-week course of pegylated IFN-α_2a/ribavirin therapy is effective in patients with recurrent HCV infection after LT.     

The treatment of chronic hepatitis C in HIV-infected patients: a meta-analysis

OBJECTIVE: Hepatitis C virus (HCV) disease progression appears to be accelerated in patients coinfected with HIV. The impact of HCV on coinfected patients is being realized as patients are now living longer. The objective of our study was to further elucidate incremental improvement and safety concerns with combinations of pegylated interferon (peginterferon), interferon and ribavirin based on data obtained from prospective randomized controlled trials. METHODS: A search of MEDLINE and the Cochrane database for material published between 1966 and 29 August 2005 and a hand search of abstracts from national meetings held between 2001 and August 2005 were performed. Trials comparing the use of peginterferon plus ribavirin vs peginterferon or interferon plus ribavirin were assessed. RESULTS: In six randomized controlled trials, 1756 patients were randomized. Sustained virological response was greater for patients treated with peginterferon plus ribavirin compared with patients treated with interferon plus ribavirin [odds ratio (OR) 3.00; 95% confidence interval (CI) 2.27-3.96]. This increased sustained virological response with peginterferon and ribavirin was found for patients with HCV genotype 1 or 4 (OR 4.40; 95% CI 2.75-7.03) and genotype 2 or 3 (OR 2.56; 95% CI 1.71-3.85). Sustained virological responses were also higher with peginterferon and ribavirin as compared with peginterferon monotherapy (OR 2.60; 95% CI 1.84-3.67). Severe adverse effects (OR 1.09; 95% CI 0.74-1.4) and withdrawal rates (OR 0.97; 95% CI 0.75-1.25) were similar between patients treated with peginterferon plus ribavirin and patients treated with interferon plus ribavirin. CONCLUSIONS: Patients with chronic HCV/HIV coinfection have a greater likelihood of achieving a sustained virological response with peginterferon plus ribavirin. The likelihoods of serious adverse effects and study withdrawal were similar.     

Molekulare Diagnostik und zuk��nftige Therapien bei Hepatitis?C

Over 130 million people worldwide are chronically infected with Hepatitis?C virus. Chronic infection can result in liver cirrhosis and hepatocellular carcinoma, the leading causes of liver transplantation in the western world. The current standard of care consists of pegylated interferon alpha plus ribavirin and has several side effects. Moreover, it achieves sustained virological response in only about 50% of patients with genotype 1 infection. Thus, new treatment options are urgently needed. Phase III studies of the first directly acting antiviral drugs have been recently completed and the new compounds will hopefully be licensed in 2011 or 2012. However, the new treatment regimens with only one directly acting antiviral drug will still be in combination with pegylated interferon alpha and ribavirin. Thus, patients with contraindications for an interferon-based treatment have to wait until an all oral treatment regime, which is likely to be a combination of two or more direct acting compounds,-becomes available.     

Triple therapy for HCV genotype 1 infection: telaprevir or boceprevir?

Boceprevir and telaprevir are the first two protease inhibitors available for the treatment of patients infected with hepatitis C virus (HCV) genotype 1. A sustained virological response (SVR) of 70-80% is observed when either of these protease inhibitors is utilized with pegylated interferon (PEG-IFN) and ribavirin (RBV) in treatment na?ve patients. Both agents are also highly effective in patients who failed to achieve a SVR during previous treatment with PEG-IFN/RBV. A rapid virological response (RVR) is observed in 56-60% of treatment na?ve patients. Patients who achieve a RVR can be treated with a shorter course of therapy (24-28 weeks) and still achieve a SVR rate of 90% or higher. Patients who do not achieve a RVR, those with cirrhosis and certain prior non-responders should be treated for 48 weeks. Although the SVR rates observed with boceprevir and telaprevir are quite similar both globally and within sub-populations, the treatment algorithms for the two agents are unique. The decision of which protease inhibitor to use should assess several factors including the treatment scheme, duration of therapy, adverse event profile, cost and the likelihood of achieving a RVR. The latter is highly dependent upon IFN sensitivity and the IL28B genotype.     

Efficacy and tolerability of pegylated interferon alpha 2b and ribavirin in chronic hepatitis C--a report from eastern India.

AIM: To study the efficacy and tolerability of pegylated interferon alpha 2b and ribavirin therapy in a cohort of chronic hepatitis C patients. METHODS: In a prospective, open label, uncontrolled trial pegylated interferon alpha 2b (Viraferon Peg) 1.5 microgram/ kg subcutaneously weekly plus daily ribavirin 800mg for 24 weeks in genotypes 2 & 3 and 1000mg for 48 weeks in genotypes 1 and 4 was administered to 16 patients of chronic hepatitis C. The primary end point was the sustained viral response. Therapy was prolonged by 3 months if the end of therapy response was not attained. Drug dosage was modified or temporarily discontinued if anaemia or bone marrow suppression developed. RESULTS: Both virological end of therapy response and sustained viral response were seen in 75% cases but not every patient who achieved end of therapy response had a sustained viral response. Relapse was seen in 31% cases and a pattern of delayed response was seen in 2 patients who later experienced a sustained viral response. Biochemical and virological responses were similar. A lower baseline viral load, genotype 3, a high ALT and the parenteral mode of viral acquisition were associated with higher sustained viral response rates. A good response was also seen in men, those over 50 years of age and those with normal baseline ALT. Most relapses occurred in genotype 3 patients whose age was less than 50 years; however the relapsing viral load was very low. 66% of previous interferon and ribavirin non-responders achieved sustained viral response. Treatment was well tolerated; temporary dose modification was required in 3 patients. CONCLUSION: In Indian patients, a combination of peginterferon alpha 2b and ribavirin is safe and effective both as initial treatment of chronic hepatitis C and for use in previous non-responders.     

Consensus Interferon Plus Ribavirin for Hepatitis C Genotype 3 Patients Previously Treated With Pegylated Interferon Plus Ribavirin

Background

Not enough data are available about the effectiveness of consensus interferon (CIFN) among HCV genotype 3 patients who failed to respond to pegylated interferon and ribavirin.

Objectives

We aimed to assess the efficacy and safety of CIFN and ribavirin in non-responders and relapsers to pegylated interferon with ribavirin therapy.

Patients and Methods

This open-label investigator-initiated study included 44 patients who received CIFN 15 µg /day plus ribavirin 800-1200 mg daily. In patients with an early virological response (EVR), the dose of CIFN was reduced to 15 µg thrice a week for further 36 weeks. Patients with delayed virological response continued to receive daily CIFN plus ribavirin to complete 48 weeks. The patients were considered “non-responders” if there were less than 2 log reduction in HCV RNA at 12 weeks and detectable HCV RNA at 24 weeks.

Results

Twenty-four patients (55%) were non-responders and 20 patients were relapsers to the previous treatment with pegylated interferon plus ribavirin (mean age 43.6 ± 9.4 years, males 25 (57%)). Nine patients were clinically cirrhotic (Child A). End of treatment virological response was achieved in 19 (43.1%) patients and sustained virological response (SVR) occurred in 12 (27.3%). Out of these 12 patients, eight were non-responders and four were relapsers to the previous treatment. Advanced fibrosis or clinical cirrhosis was associated with low SVR. Adverse events were fever, myalgia, anorexia, depression, and weight loss. Two patients received granulocyte colony stimulating factor for transient neutropenia. Seven patients were given erythropoietin to improve hemoglobin, and six were treated for mild depression. Two patients developed portosystemic encephalopathy.

Conclusions

More than one-quarter of treatment-experienced patients with HCV genotype 3 achieved SVR after re-treatment with consensus interferon plus ribavirin.     

Pegylated interferon and ribavirin in re-treatment of responder-relapser HCV patients

BACKGROUND: The re-treatment of patients who relapse after a course of standard interferon and ribavirin with pegylated interferon alfa-2b plus ribavirin is an open issue. AIMS: To evaluate efficacy and safety of treatment with pegylated interferon alfa-2b plus ribavirin and the role of early HCV-RNA assessment as a predictor of sustained response. PATIENTS: Between May 2001 and December 2002, 242 consecutive patients with chronic hepatitis C were enrolled in an open, regional, multicentre study. Seventy-eight of them were responder-relapsers to a previous course of combination therapy. METHODS: Patients were treated with pegylated interferon alfa-2b (1 microg/kg/week) plus ribavirin (800-1200 mg daily). Qualitative HCV-RNA was performed at week 2. Genotypes 1-4 were treated for 48 weeks, while genotypes 2 and 3 were treated for 24 weeks. RESULTS: We obtained an overall sustained virological response rate of 41.0% (78.6% for patients with genotypes 2-3). CONCLUSION: This treatment schedule prove to be safe and effective in relapsers with genotype non-1 while genotype 1-4 patients had a low rate of sustained virological response. Qualitative virological assessment after 2 weeks may identify patients who are more likely to reach sustained virological response, but it is not a valid tool for a stopping rule approach.     

Sustained Viral Response to Pegylated Interferon α-2b and Ribavirin in Chronic Hepatitis C Refractory to Prior Treatment

Hepatitis C virus (HCV) infection refractory to previous therapy is common. Treatment of patients with refractory disease is difficult and less studied. Pegylated interferon α-2b plus ribavirin is used for treatment of HCV patients naïve to therapy. We conducted a randomized study for refractory HCV patients using a high- vs. a low-dose pegylated interferon α-2b and ribavirin protocol. Our aim was (1) to determine the efficacy of pegylated interferon α-2b plus ribavirin to eradicate HCV in previously treated individuals and (2) to compare a low-dose to a high-dose regimen. One hundred fifty-two patients were initiated in the study, 112 (74%) were male and 40 (26%) female. Nineteen percent of patients obtained a sustained viral response (SVR) in the high-dose arm. Prior relapsers had the highest SVR rates: 50% in non-genotype 1 and 34% in genotype 1. The odds of achieving a SVR were six times higher in previous relapsers. The rate of SVR in genotype 1 patients who were nonresponders to prior therapy was only 8%. All patients who achieved a SVR had no detectable virus at week 24. However, only half of those who had undetectable viral titers at week 24 achieved a SVR. In conclusion, retreatment of patients with refractory hepatitis C infection with interferon α-2b and ribavirin combination therapy is well tolerated and gives modest response rates. The most important factor in predicting response to therapy is the manner of response to previous treatment. The likelihood of response to treatment can be predicted from the viral titers at 24 weeks.     

Impact of pegylated interferon alpha-2B and ribavirin on hepatic fibrosis in liver transplant patients with recurrent hepatitis C: an open-label series.

BACKGROUND: Patients with recurrent hepatitis C virus (HCV) are often treated with interferon-based therapy in an attempt to eradicate HCV and prevent cirrhosis requiring retransplantation. We describe our experience with pegylated interferon and ribavirin and the impact of this therapy on hepatic fibrosis. METHODS: Patients were treated with pegylated interferon alpha-2b 1.5 mcg/kg/week and ribavirin 800 mg/day for 6-12 months according to genotype. HCV ribonucleic acid (HCV RNA) was repeated at 3 months, end of treatment (EOT) and 6 months after EOT for patients HCV RNA negative at EOT. Liver biopsies were performed prior to treatment and at EOT. RESULTS: Thirty nine patients were eligible. Twenty two completed treatment and 17 (43.6%) were intolerant. Eleven of 22 (50%) patients who completed treatment developed sustained viral response (SVR). Two patients intolerant to treatment also developed SVR. Serial biopsies were performed in 17 patients and refused in five. Improved fibrosis scores were present in four patients (non-responders, n = 2), unchanged in 10 (non-responders, n = 4), and worse in three (all non-responders). CONCLUSIONS: Side effects are an important limiting factor in recurrent HCV treatment with SVR only 33.3% in an intention-to-treat analysis. However, improved or stable fibrosis scores were also demonstrated in 66.7% of non-responders. This suggests failure to eradicate HCV should not necessarily lead to treatment discontinuation as a subgroup of patients may benefit from maintenance therapy.     

Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy

BACKGROUND: The management of patients with chronic hepatitis C who have relapsed or failed to respond to interferon based therapies is an important issue facing hepatologists. AIMS: We evaluated the efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in this population by conducting a multicentre open label study. PATIENTS: Data from adults with detectable serum hepatitis C virus (HCV) RNA who had not responded or had relapsed after previous conventional interferon or conventional interferon/ribavirin combination therapy were analysed. METHODS: Patients were retreated with peginterferon alfa-2a (40KD) 180 microg/week plus ribavirin 800 mg/day for 24 or 48 weeks at the investigators' discretion. The study was conceived before the optimal dose of ribavirin (1000/1200 mg/day) for patients with genotype 1 was known. The primary endpoint was sustained virological response (SVR), defined as undetectable HCV RNA (<50 IU/ml) after 24 weeks of follow up. The analysis was conducted by intention to treat. RESULTS: A total of 312 patients (212 non-responders, 100 relapsers) were included. Of these, 28 patients were treated for 24 weeks and 284 for 48 weeks. Baseline characteristics between non-responders and relapsers were similar although more non-responders had genotype 1 infection (87% v 69%). Overall SVR rates were 23% (48/212) for non-responders and 41% (41/100) for relapsers. When data were analysed by genotype, SVR rates were 24% (61/253) in genotype 1 and 47% (28/59) in genotype 2/3. CONCLUSIONS: These results in a large patient cohort demonstrate that it is possible to cure a proportion of previous non-responders and relapsers by retreating with peginterferon alfa-2a (40KD) plus ribavirin.     

High predictive value of early viral kinetics in retreatment with peginterferon and ribavirin of chronic hepatitis C patients non-responders to standard combination therapy

BACKGROUND/AIMS: To evaluate the efficacy of peginterferon alfa-2b and ribavirin in unselected consecutive patients with chronic hepatitis C, treated outside of trials, who were relapsers or non-responders to interferon and ribavirin combination. METHODS: One hundred and fifty-four patients were evaluated. There were 101 non-responders and 53 relapsers to standard combination therapy. Patients were retreated with peginterferon alfa-2b 1.5 microg/kg/wk plus ribavirin 1000-1200 mg/day during 48 weeks. RESULTS: Forty-four patients (28.6%) achieved sustained virological response (SVR). Rapid (week 4) and early (week 12) virological response had high negative predictive values of SVR (94% and 97%, respectively); however positive predictive values were relatively low (52% and 49%, respectively). Relapsers had higher SVR rates (58.5%) than non-responders (13%) p<0.0001. In non-responders, SVR raised to 50% in patients with genotype non-1 and mild or moderate fibrosis. In multivariate analysis, predictors of SVR were: relapse after interferon plus ribavirin combination, mild or moderate fibrosis, genotype non-1 and baseline viral load <2 million copies/ml. CONCLUSIONS: Relapsers to interferon plus ribavirin therapy, and non-responders with genotype non-1 and mild or moderate fibrosis, achieved a relatively high SVR rate following retreatment with peginterferon plus ribavirin. Early viral kinetics had a high negative predictive value of SVR.     

Retreatment with interferon-alpha and ribavirin in primary interferon-alpha non-responders with chronic hepatitis C

BACKGROUND/AIMS: Combination therapy with interferon-alpha (IFN-alpha) plus ribavirin is more efficacious than IFN-alpha monotherapy in previously untreated patients with chronic hepatitis C and patients with IFN-alpha relapse. Only limited data are available in IFN-alpha non-responders. In a multicenter trial we therefore evaluated the efficacy of combination therapy in IFN-alpha-resistant chronic hepatitis C. METHODS: Eighty-two patients (mean age 46.8 years, 54 males, 28 females) with chronic hepatitis C were treated with IFN-alpha-2a (3 x 6 MIU/week) and ribavirin (14 mg/kg daily) for 12 weeks. Thereafter, treatment was continued only in virological responders (undetectable serum HCV RNA at week 12) with an IFN-alpha dose of 3 x 3 MIU/week and without ribavirin for a further 9 months. The primary study endpoint was an undetectable HCV RNA by RT-PCR at the end of the 24-week follow-up period. RESULTS: After 12 weeks of combination therapy, an initial virological response was observed in 29 of 82 (35.4%) patients. Due to a high breakthrough rate after IFN-alpha dose reduction and ribavirin discontinuation, an end-of-treatment response was only achieved in 12 of 82 (14.6%) patients. After the follow-up period, a sustained virological response was observed in 8 of 82 (9.8%) patients. Infection with HCV genotype 3 was the only pretreatment parameter, which could predict a sustained response (HCV-1, 5%; HCV-3, 57.1%; p < 0.001). CONCLUSIONS: Despite a high initial response rate of 35.4%, sustained viral clearance was achieved only in 9.8% of the retreated primary IFN-alpha non-responders. Higher IFN-alpha induction and maintenance dose, as well as prolonged ribavirin treatment may possibly increase the virological response rates in non-responders, particularly in those infected by HCV-1.     

Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence

BACKGROUND AND AIMS: A proportion of liver transplanted patients with recurrent chronic hepatitis have a sustained virological response to combination therapy with interferon plus ribavirin. However, the long term benefit of antiviral therapy with regard to hepatitis C virus (HCV) RNA clearance remains unknown in patients with HCV recurrence. This study examined the long term biochemical, virological, and histological outcome in transplanted patients with recurrent chronic hepatitis who had a sustained virological response to antiviral therapy. PATIENTS AND METHODS: Fifty four patients with recurrent hepatitis C were treated with antiviral therapy involving induction by combination therapy (interferon (IFN) plus ribavirin) for six months and maintenance ribavirin therapy for 12 months. Fourteen patients who had recurrent chronic hepatitis and sustained virological response to antiviral therapy were followed for three years after the end of antiviral therapy. Serum alanine aminotransferases were assessed every three months during the observation period. Serum hepatitis C RNA detected by polymerase chain reaction was evaluated every six months during follow up, and protocol biopsy procedures were performed routinely every year. Semiquantitative histopathological assessment of allograft hepatitis was performed using the Knodell score and HCV was also detected by polymerase chain reaction on frozen graft tissue samples. RESULTS: At the end of antiviral therapy, the sustained response rate was 26%. A complete response (normal serum alanine aminotransferase level and undetectable serum HCV RNA) was achieved in 13/14 (93%) patients three years after the end of treatment. A comparison of liver histology findings before and after a mean of three years after antiviral therapy showed a clear improvement in 12/14 (86%) patients. In 5/14 (36%) patients, the last biopsy showed normal or near normal histological findings. After three years of follow up, the total Knodell score was 3.2 (range 1-8) versus 8.3 (range 5-12) before treatment (p=0.001). Graft HCV RNA was detectable before treatment in all 14 patients and was undetectable at the end of follow up in 13/14 (93%) patients tested. CONCLUSION: In patients with biochemical and virological responses induced by ribavirin and interferon, a complete response was sustained in 93% for at least three years after cessation of therapy. This long term response was associated with absence of detectable intrahepatic hepatitis C RNA and marked histological improvement.