Antiviral therapy for chronic hepatitis C in patients with inherited bleeding disorders: an international, multicenter cohort study

Summary. Background: Hepatitis C is a major co‐morbidity in patients with hemophilia. However, there is little information on the efficacy of antiviral therapy and long‐term follow‐up after treatment.Objectives: To assess the effect of interferon‐based (IFN‐based) therapy on hepatitis C virus (HCV) eradication, to identify determinants associated with treatment response, and to assess the occurrence of end‐stage liver disease (ESLD) after completing antiviral therapy.Patients and methods: In a multicenter cohort study, 295 treatment‐naïve hemophilia patients chronically infected with HCV were included. The effect of therapy was expressed as sustained virological response (SVR). Determinants associated with treatment response were expressed as odds ratios (ORs). Cumulative incidence of ESLD was assessed using a Kaplan–Meier survival table.Results: Among human immunodeficiency virus (HIV) negative patients (n = 235), SVR was 29% (29/101) for IFN monotherapy, 44% (32/72) for IFN with ribavirin, and 63% (39/62) for pegylated IFN (PegIFN) with ribavirin. In patients co‐infected with HIV (n = 60), IFN monotherapy, IFN with ribavirin, and PegIFN with ribavirin eradicated HCV in 7/35 (20%), 1/2 (50%), and 11/23 (48%), respectively. SVR increased with genotype 2 and 3 [OR 11.0, 95% CI: 5.8–20.5], and combination therapy (IFN and ribavirin OR 3.7, 95% CI: 1.7–8.4), PegIFN and ribavirin (OR 4.2, 95% CI: 1.8–9.5). Up to 15 years after antiviral treatment, none of the patients with a SVR relapsed and none developed ESLD. In contrast, among unsuccessfully treated patients the cumulative incidence of ESLD after 15 years was 13.0%.Conclusions: Successful antiviral therapy appears to have a durable effect and reduces the risk of ESLD considerably.     

Treatment options for nonresponders and relapsers to initial therapy for hepatitis C

As treatment for chronic hepatitis C virus (HCV) infection has advanced over the past decade, efforts have evolved to retreat patients who did not achieve a sustained virologic response to previous antiviral regimens. Retreating nonresponders to interferon alfa monotherapy with a combination of interferon and ribavirin yields a sustained virologic response in 9% to 32% of patients, whereas retreatment with peginterferon alfa plus ribavirin yields a sustained virologic response in up to 30% to 40% of patients. Sustained virologic response is more likely in retreated patients with HCV genotype 2 or 3, low serum HCV RNA levels, and lack of response to prior interferon monotherapy. Retreatment of nonresponders to interferon-ribavirin combination therapy is associated with lower response rates (< or = 20%). Despite treatment advances, the efficacy of current antiviral regimens for nonresponders remains inadequate. The next few years will see more-targeted antiviral regimens for these patients and therapies focused on slowing the progression of liver disease rather than viral eradication.     

Treatment with peginterferon plus ribavirin vs. interferon plus ribavirin for 48 weeks in Chinese patients with chronic hepatitis C

Introduction:  Virological responses to interferon (IFN) treatment for chronic hepatitis C (CHC) have been found to be correlated with racial differences. Furthermore, higher sustained virological response (SVR) rates were obtained in many randomised clinical trials (RCT) in Caucasian patients with CHC after treating with peg‐IFN than those with IFN. However, it is not clear whether this conclusion can be adapted to patients of Chinese descent. Methods:  A search of MEDLINE and China National Knowledge Infrastructure between 1966 and 2008 was performed. Trials comparing the use of peg‐IFN plus ribavirin vs. IFN plus ribavirin in treating Chinese patients with CHC were assessed. Results:  Of the 94 studies screened, seven RCTs including 398 patients (peg‐IFN therapy 232, IFN therapy 166) were analysed. The SVRs obtained in patients treated with peg‐IFN plus ribavirin were significantly higher than in patients treated with IFN plus ribavirin [70% vs. 35%, relative risk, 1.76; 95% confidence interval: 1.21–2.56; p (0.01)]. Withdrawal rates were similar between patients treated with peg‐IFN plus ribavirin and IFN plus ribavirin. Conclusion:  Chinese patients with CHC also have a greater likelihood of achieving an SVR with peg‐IFN plus ribavirin.     

Efficacy and Tolerability of Combination Therapy with Interferon-Alfa Plus Ribavirin in Patients with Chronic Hepatitis C Virus Infection: A Single-Center Study in Relapsers and Nonresponders to Previous Treatment with High-Dose Interferon-Alfa Monotherapy

Background: In chronic hepatitis C virus (HCV) infection, interferon (IFN) monotherapy usually is carried out at doses of 3 to 6 million units (MU) 3 times per week, but treatment efficacy is low.Objective: The aim of our study was to assess the efficacy and tolerability of IFN-alfa_2b in combination with ribavirin in relapsers and nonresponders to high-dose IFN treatment (5 to 6 MU 3 times per week). We measured the biochemical and virologic responses to treatment and the risk for relapse during the 24 weeks following the end of treatment.Methods: Patients with chronic HCV infection (relapsers and nonresponders to a previous treatment with high-dose IFN) received IFN-alfa_2b, 3 MU 3 times per week, and ribavirin, 1000 or 1200 mg/d for 24 or 48 weeks. The patients were then followed up for an additional 24 weeks. Sustained response was defined as normal serum alanine aminotransferase (ALT) level and undetectable HCV RNA 24 weeks after treatment was stopped.Results: Forty-three patients (32 men, 11 women; mean [SD] age, 45 [2] years; 10 relapsers, 33 nonresponders) were included in the study. Four patients were withdrawn from the study at week 4 of treatment because of treatment-related adverse events, and 1 dropped out. At the end of the treatment period, normalization of serum ALT levels and undetectable HCV RNA levels were seen in 58.1% and 30.2% of patients, respectively. No significant difference in virologic response at the end of treatment was found between nonresponders (10/33 [30.3%]) to previous IFN therapy and relapsers (3/10 [30.0%]). At the end of follow-up, 3 (7.0%) treated patients had sustained response (2 nonresponders to the first IFN course and 1 relapser). All of the patients with sustained response were treated for 24 weeks.Conclusion: Based on the results of our study, combination therapy with IFN-alfa and ribavirin may be of value in a limited number of patients with chronic HCV infection who do not respond to, or relapse after, a first course of treatment with high-dose IFN monotherapy.     

Hepatitis C virus/human immunodeficiency virus coinfection in hemophiliacs: high rates of sustained virologic response to pegylated interferon and ribavirin therapy

Summary. Background: Progression of chronic hepatitis C virus (HCV) infection to end‐stage liver disease is accelerated in patients coinfected with human immunodeficiency virus (HIV). HCV/HIV‐coinfected hemophiliacs are no exception. Although eradication of HCV with pegylated interferon (Peg‐IFN) plus ribavirin (Rbv) is the only approach to halt the progression of liver disease, the rates of sustained virologic response (SVR) in coinfected patients are attenuated as compared with those in HCV‐monoinfected patients. Nonetheless, in HCV‐infected hemophiliacs, who are considered to constitute a difficult‐to‐treat population, current treatment strategies yielded rates of SVR similar to those obtained in non‐hemophiliacs. Objectives and patients: In this open‐label, prospective, multicenter study, the efficacy and safety of therapy with Peg‐IFNα2a plus Rbv was evaluated in 34 HCV/HIV‐coinfected adult hemophiliacs naive to previous antiviral therapy. Methods: Peg‐IFNα2a was administered at a dose of 180 μg subcutaneously once‐weekly plus oral Rbv 1000–1200 mg day^?1 for 48 weeks, irrespective of HCV genotype. Results: All but one patient (3%) completed the study, 15 (44%) achieved an SVR, and 13 (38%) required dose reduction of either drug. A rapid virologic response (HCV‐RNA clearance at week 4; P = 0.01), a complete early virologic response (HCV RNA clearance at week 12; P = 0.005) and absence of cirrhosis (P = 0.04) were independent predictors of SVR. During a median post‐treatment follow‐up of 3 years, a steady increase in CD4+ cell count and CD4+/CD8+ cell ratio was observed in SVR patients. Conclusions: These results strongly support the use of anti‐HCV therapy in HCV/HIV‐coinfected hemophiliacs.     

Treatment of chronic hepatitis C with interferon alone or combined with ribavirin in Japan

We treated 665 patients with chronic hepatitis C with interferon (IFN) monotherapy and 288 with combined IFN and ribavirin. At the baseline, age (53.8 +/- 11.1 vs. 49.7 +/- 10.5 years, p < 0.0001) and activity (p = 0.0207) as well as fibrosis (p = 0.0270) were higher in patients who received combination therapy than in those receiving monotherapy. Compliance to treatment (64.2 vs. 62.1%, p < 0.0001) and discontinuation were more frequent (18.1 vs. 14.5%, p < 0.0001) in patients with combination therapy than in those with monotherapy. Patients with combination therapy with genotype 2 infection achieved sustained viral response (SVR) at a rate of 77.0%, regardless of viral loads, in contrast to those with genotype 1 infection, of whom only 24.4% gained SVR. Of patients with combination therapy, reduction (42.6 vs. 29.0%, p = 0.0453) and discontinuation (34.0 vs. 21.6%, p = 0.0414) of ribavirin were more frequently required in the 47 patients > or =65 years than in the 241 patients <65 years. Although a trend for higher SVR to combination therapy was observed in patients aged < 65 than in those aged > or =65 years (39.4 vs. 25.2%), the difference was not significant (p = 0.0819). In patients with genotype 1 infection, IFN monotherapy in addition to the 24-week combination therapy increased the SVR rate (18.3 vs. 42.6%, p = 0.0003). A decrease in SVR was observed with an increased body mass index in patients who received combination therapy.     

Response to interferon-based therapies in HIV-infected patients with chronic hepatitis C due to genotype 4

BACKGROUND: The hepatitis C virus (HCV) genotype is the main predictor of response to interferon (IFN)-based therapies. HCV genotype 4 is spreading among European intravenous drug users, who are frequently coinfected with HIV. Information about treatment response in this subset of patients is scarce and conflicting results have been reported. METHODS: All HIV-infected patients treated for chronic hepatitis C at our institution with a minimum follow-up of 6 months after discontinuing therapy were retrospectively analysed. They had received one of three HCV treatment modalities: IFN monotherapy, IFN plus ribavirin (RBV) or pegylated interferon (PEG-IFN) plus RBV. Treatment responses were stratified according to HCV genotype. RESULTS: A total of 390 patients were analysed. Sustained virological response (SVR) to HCV therapy had been reached by 90 (23.1%): 22/119 (18.5%) with IFN monotherapy; 17/106 (16%) with IFN plus RBV; and 51/165 (30.9%) with PEG-IFN plus RBV. SVR was significantly higher among those with HCV genotypes 2 or 3 (40.4%; 61/151) than in patients with either HCV genotype 1 (11.2%; 22/197) or HCV genotype 4 (16.7%; 7/42) (P<0.0001). In contrast, there were no significant differences in the response rate comparing HCV genotypes 1 and 4 (P=0.53). CONCLUSIONS: Response to IFN-based therapies in HIV-positive patients with hepatitis C due to HCV genotype 4 is poor, similar to that obtained for HCV genotype 1 and much lower than for HCV genotypes 2 and 3. Therefore, HIV-infected patients with hepatitis C due to genotype 4 should be considered as a particular subset of difficult-to-treat patients. New treatment strategies and drugs for these patients are eagerly awaited.     

Iron depletion before HCV antiviral therapy: A pilot,randomized, controlled trial

It is not known whether iron depletion before pegylated IFN or combination treatment improves sustained virological response (SVR) rate in patients with chronic hepatitis C, despite its use in clinical practice in this setting. We aimed to investigate whether blood letting improves the efficacy (SVR) and tolerability of PEG‐IFNα2b + Ribavirin in chronic hepatitis C patients. Patients with chronic hepatitis C and ferritin >100 ng/mL were randomized to: (1) repeated phlebotomies to obtain a ferritin level <50 ng/mL followed by pegylated‐Interferon α2b + ribavirin (active arm); or (2) pegylated‐Interferon α2b + ribavirin (control arm). Primary endpoint was SVR rate, secondary endpoint was frequency of clinical and laboratory grade 3–4 adverse events. Thirty‐three patients were enrolled in the study (19 in active arm, 14 in control arm). The 19 patients in the active arm underwent a median of 5 phlebotomies (range: 1–9) to achieve the targeted ferritin (<50 ng/mL). Phlebotomies significantly reduced ferritin, iron, transferrin saturation, aspartate aminotransferase, alanine aminotransferase, and hemoglobin levels. Platelet count significantly increased, whereas HCV‐RNA levels remained unchanged. After antiviral therapy overall SVR was 31.6% in active arm and 21.4% in control arm (P = 0.698). Considering only the 18 patients who were naive to antiviral therapy, SVR was 60% in active arm versus 25% in control arm (P = 0.188). Tolerability, drug dose reduction or withdrawal were similar in the two arms. In conclusion phlebotomies do not increase the overall efficacy of antiviral therapy. However, the strong trend to higher SVR in naive patients undergoing phlebotomies warrants further investigation. J. Clin. Apheresis 2009. © 2009 Wiley‐Liss, Inc.     

Long-term follow-up of HIV-infected patients with chronic hepatitis C virus infection treated with interferon-based therapies

BACKGROUND: Chronic hepatitis C virus (HCV) infection is frequent among HIV-infected patients. Clearance of serum HCV RNA 6 months after discontinuing HCV therapy is generally interpreted as a cure of HCV infection in HIV-negative subjects. However, the occurrence of liver complications (including hepatocellular carcinoma) and/or HCV relapses in coinfected patients when followed for long periods of time after HCV therapy is not well known. METHODS: All HIV-infected patients who had been treated for chronic hepatitis C at our institution and had a minimum follow-up of 6 months after discontinuing therapy were retrospectively analysed. They had received one of three HCV treatment modalities: IFN monotherapy, IFN plus ribavirin (RBV) or pegylated interferon (PEG-IFN) plus RBV. RESULTS: A total of 351 patients were retrospectively analysed. Sustained virological response (SVR) to HCV therapy had been reached by 77 (22%) of them: 22/119 (18.5%) with IFN monotherapy, 17/106 (16%) with IFN plus RBV and 38/126 (30.2%) with PEG-IFN plus RBV. Considering the HCV genotypes, SVR had been reached by 19/184 (10.3%) of patients with genotype 1, 54/138 (39.1%) with genotypes 2 or 3, and 4/29 (13.8%) of those with genotype 4. Within a total of 4466 patient-months follow-up (mean of 58 months), none of the 77 patients with SVR showed HCV-RNA rebounds, elevations in liver enzymes potentially linked to HCV, development of hepatocellular carcinoma or episodes of decompensated cirrhosis. In contrast, all 274 patients who did not reach SVR with HCV therapy showed evidence of persistent serum HCV RNA and 90% of them showed liver enzyme elevations during a total of 15344 patient-months follow-up (mean of 56 months). Moreover, 11 (4%) developed clinical complications of liver cirrhosis and two of them died of end-stage liver disease. CONCLUSIONS: HCV replication and HCV-related liver disease seem to be permanently halted in HIV/HCV-coinfected patients showing HCV-RNA clearance 6 months after completing any kind of IFN-based therapy. In contrast, complications of liver disease due to persistent HCV infection continue to occur in non-responders. The role of maintenance HCV therapy should be explored in HIV/HCV-coinfected patients.     

Persistence with hepatitis C therapy in the Department of Veterans Affairs

Background: Persistence with Hepatitis C therapy has been identified as a key variable for predicting treatment success. The primary purpose of this study was to assess the persistence with therapy for patients undergoing hepatitis C treatment in the VA healthcare system with two forms of combination therapies: peginterferon alfa‐2a with Ribavirin (peg‐IFN alpha‐2a/Rib) and peginterferon alpha‐2b with Ribavirin (peg‐IFN alpha‐2b/Rib). Methods: A retrospective cohort study design was used to analyse persistence in VA patients undergoing hepatitis C therapy during FY 2003–2004 using a large national VA data set. Stringent inclusion and exclusion criteria along with various defining variables were used to identify the inception cohort. Persistence rates were calculated for each of the two treatment groups at 3, 6, 9 and 11 months using the Kaplan–Meier method. Likelihood ratio test of equality between the two treatment groups was performed to detect any differences in persistence rates. Results: A total of 5816 hepatitis C patients formed the inception cohort. Persistence rates for the overall duration showed significantly higher rates for patients on peg‐IFN alpha‐2a/Rib than peg‐IFN alpha‐2b/Rib. Cox regression analysis also showed favourable hazard ratio of persistence (0·88) for peg‐IFN alpha‐2a/Rib over peg‐IFN alpha‐2b/Rib. Conclusion: Peg alfa‐2A/Rib showed slightly higher persistence rates for the overall duration of treatment as compared to Peg alfa‐2B/Rib. However the differences, even though statistically significant, are small and not likely to translate into any substantial clinical advantage. Further research involving other approaches is required to confirm these findings.     

Efficacy and Safety of Danoprevir-Ritonavir plus Peginterferon Alfa-2a–Ribavirin in Hepatitis C Virus Genotype 1 Prior Null Responders

Danoprevir (DNV) is a hepatitis C virus (HCV) protease inhibitor that achieves high sustained virologic response (SVR) rates in combination with peginterferon alfa-2a–ribavirin in treatment-naive HCV genotype 1 (G1)-infected patients. This study explored the efficacy and safety of ritonavir-boosted DNV (DNVr) plus peginterferon alfa-2a–ribavirin in G1-infected prior peginterferon-ribavirin null responders. Null responders (<2-log₁₀ reduction in HCV RNA level at week 12) were given an open-label combination of 100 mg of ritonavir and 100 mg of DNV (100/100 mg DNVr) every 12 h (q12h) plus peginterferon alfa-2a–ribavirin for 12 weeks. All patients achieving an early virologic response (EVR; ≥2-log₁₀ decrease in HCV RNA by week 12) continued treatment with peginterferon alfa-2a–ribavirin; those without an EVR discontinued all study drugs. Twenty-four prior null responders were enrolled; 16 patients (67%) were infected with HCV G1b, and 8 (33%) were infected with G1a. Ninety-six percent of patients had an IL28B non-CC genotype. A sustained virologic response at 24 weeks posttreatment (SVR24) was achieved in 67% of patients, with a higher rate in G1b-infected (88%) than G1a-infected (25%) patients. Resistance-related breakthrough occurred in 4/8 G1a and 1/16 G1b patients through the DNV resistance-associated variant (RAV) NS3 R155K. NS3 R155K was also detected in 2/2 G1a patients who relapsed. Treatment was well tolerated. Two patients withdrew prematurely from study medications due to adverse events. Two serious adverse events were reported; both occurred after completion of DNVr therapy and were considered unrelated to treatment. No grade 3 or 4 alanine aminotransferase (ALT) elevations were observed. DNVr plus peginterferon alfa-2a–ribavirin demonstrated high SVR24 rates in HCV G1b-infected prior null responders and was well tolerated. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01185860","term_id":"NCT01185860"}}NCT01185860.)     

Treatment of chronic hepatitis C in southern Taiwan

Chronic hepatitis C virus (HCV) infection may lead to cirrhosis and hepatocellular carcinoma. Interferon (IFN)-alpha is effective in the treatment of chronic hepatitis C. The rate of response to IFN is enhanced by increasing the IFN dose. Extending the treatment duration can reduce the relapse rate. Addition of ribavirin to IFN increases the sustained virological response (SVR). Thus, combination therapy with IFN and ribavirin was adopted for the treatment of chronic hepatitis C in Kaohsiung Medical University Hospital in 1998. Approximately 60% of patients receiving IFN/ribavirin therapy gained SVR. IFN 6 million units three times per week combined with daily ribavirin for 6 months achieved SVR more frequently than combination therapy with 3 million units. Factors for SVR in these combination regimens were HCV genotype, viral load and early virological response. Long-term follow-up of patients treated with IFN has shown that SVR might reduce the risk of progression to cirrhosis and hepatocellular carcinoma. Pegylated (peg)-IFN has a longer half-life and better efficacy. Combination therapy with peg-IFN and ribavirin accomplished higher SVR than conventional IFN and ribavirin. A multicenter clinical trial was conducted in Taiwan to compare the efficacy of combination therapy between peg-IFN/ribavirin and conventional IFN/ribavirin for 6 months. SVR was higher in patients receiving peg-IFN and ribavirin, especially in those infected with HCV genotype 1b. Based on the results obtained, the national health insurance started to sponsor the combination therapy in October 2003, with a suggested duration for 6 months. Some small-scale studies in Taiwan have postulated higher SVR for treatment duration of 12 than of 6 months in patients with genotype 1b. Further investigation should be conducted in the near future.     

Efficacy of interferon alfa and lamivudine combination therapy versus interferon alfa monotherapy in Turkish patients with chronic hepatitis B: A double-blind, randomized, comparative study

Background: Interferon (IFN) alfa and lamivudine are the most effective agents used in the treatment of chronic hepatitis B virus (HBV). Monotherapy with IFN alfa or lamivudine provides significant benefit, but the combination of these drugs is still under investigation. It has been suggested that combination therapy has some advantages over monotherapy.Objective: The purpose of this study was to evaluate the efficacy of concurrent combination therapy with lamivudine and IFN alfa versus IFN alfa monotherapy in previously untreated patients with chronic HBV.Method: Patients were randomly assigned to 6 months' therapy with IFN alfa 9 million units 3 times weekly alone or in combination with 100 mg/d oral lamivudine. Alanine aminotransferase (ALT) measurements and viral load assessments (HBV DNA level as measured by polymerase chain reaction) were performed at baseline and months 6 and 12. Levels of hepatitis B e antigen (HBeAg) and anti-HBeAg were determined at baseline and at the end of treatment (month 12). Knodell histologic activity index score was determined at baseline.Results: Fifty patients were enrolled in each group. ALT normalization rates in the monotherapy and combination therapy groups, respectively, were 56% and 86% (P < 0.05 between groups) at month 6, and 48% and 64% at month 12 (P < 0.05 between groups). In the monotherapy and combination groups, respectively, there were 21 (42%) and 24 (48%) complete responders (P < 0.05); 5 (10%) and 10 (20%) partial responders (P < 0.05); and 24 (48%) and 16 (32%) nonresponders (P < 0.05). HBeAg seroconversion rates were 22% in the monotherapy group and 30% in the combination therapy group at the end of 12 months (P = NS between groups).Conclusion: Concurrent combination therapy with IFN alfa and lamivudine has a more beneficial effect on biochemical parameters (ie, ALT levels) than on viral parameters (ie, HBV DNA, seroconversion to anti-HBeAg) and this effect is more pronounced after 1 year of treatment than after 6 months. Further studies are needed to determine the long-term effects of combination therapy with lamivudine and IFN alfa.     

Significance of serum ribavirin concentration in combination therapy of interferon and ribavirin for chronic hepatitis C

OBJECTIVE: The purpose of this clinical retrospective cohort study was to determine the most suitable ribavirin concentration on combination therapy of interferon (IFN)-ribavirin. METHODS: Entry criteria were serum HCV-RNA level >/=100 KIU/ml, HCV-genotype 1b, chronic hepatitis, and initial combination treatment of IFN-alpha-2b (6 million units daily for 2 weeks and then 3 times weekly for 6 weeks) and ribavirin (600-800 mg/day) for 8 weeks without stopping or decreasing the dosage of IFN and/or ribavirin. Sixty-eight consecutive patients who satisfied the above criteria were given maintenance therapy for another 16 weeks. RESULTS: A sustained virological response (SVR) rate of 25.0% (17/68) was seen in all subjects. The SVR rate was 44.0% (11/25) in the high ribavirin group with a serum ribavirin concentration of >/=3,000 ng/ml at 8 weeks after initiation of combination therapy. SVR was significantly dependent at a serum ribavirin level of >/=3,000 ng/ml (p = 0.005). The incidence of discontinuations and dose modifications for combination therapy in patients having a serum ribavirin concentration of >/=3,500 ng/ml 8 weeks after initiation of therapy was 57.1% (4/7). This value was statistically higher than that in patents with <3,500 ng/ml (p = 0.033). CONCLUSION: Our results showed that the most suitable serum ribavirin concentrations are from 3,000 to 3,500 ng/ml 8 weeks after initiation of combination therapy.     

Hepatic interferon receptor mRNA expression: clinical relevance and its relationship with effectiveness of interferon plus ribavirin therapy in patients with genotype 1b hepatitis C virus infection

BACKGROUND/AIMS: Hepatic expression of interferon (IFN) receptor mRNA has been shown to correlate with the effectiveness of IFN monotherapy in patients with chronic hepatitis C virus (HCV) infection. We investigated the expression of hepatic IFN receptor alpha/beta (IFNAR2c) mRNA and its association with the effectiveness of IFN plus ribavirin (RBV) therapy and with the clinical features in patients with HCV genotype 1b (HCV-1b) infection. METHODS: A total of 42 naive patients who had chronic HCV-1b infection were treated with IFN alpha-2b 3 MU or 5 MU three times weekly plus RBV for 24 weeks. Hepatic IFNAR2c mRNA was quantified by real-time RT-PCR. RESULTS: There was no significant difference in the mean expression level of IFNAR2c mRNA between patients with sustained virological response (SVR) and non-SVR (0.069 +/-0.042 versus 0.053 +/-0.033, P=0.182). Multiple linear regression analysis showed that lower fibrosis scores (P=0.006) and younger age (P=0.03) were associated with hepatic IFNAR2c mRNA expression with r2=0.34. CONCLUSIONS: Hepatic IFNAR2c mRNA expression may not be useful for predicting the response to IFN plus RBV therapy in patients with HCV-1b infection, but appeared to correlate inversely with the fibrosis stage and age.     

Peginterferon alpha-2b plus ribavirin with or without amantadine [correction of amantidine] for the treatment of non-responders to standard interferon and ribavirin

BACKGROUND: A significant proportion of hepatitis C patients treated with unmodified interferon plus ribavirin fail to respond. The optimal therapy for these patients has not been established yet. The objective of this study was to assess the efficacy and safety of peginterferon plus ribavirin with or without amantidine in such patients. METHODS: In this open-label, prospective controlled trial, a total of 63 patients were randomly divided into groups A and B with a ratio of 1:2. Group A (21 patients) received weekly peginterferon alpha-2b, 1.5 microg/kg concomitantly with ribavirin 1000-1200mg per day. Group B (42 patients) received peginterferon and ribavirin as in group A, plus amantadine [corrected] 200 mg per day. RESULTS: At the completion of treatment, serum levels of hepatitis C virus RNA were undetectable in 14% and 12% of patients in groups A and B, respectively (P=NS). Hepatitis C virus RNA remained undetectable 24 weeks after the end of treatment in one patient (5%) in group A and three patients (7%) in group B (P=NS). Sustained viral clearance was associated with sustained normalization of serum alanine aminotransferase level. Both drug regimens had similar side effect profiles. CONCLUSION: Peginterferon plus ribavirin therapy with or without amantadine [corrected] is associated with a low sustained virological response in patients who failed interferon and ribavirin combination therapy.     

Retreatment of patients with chronic hepatitis C not responding to interferon/ribavirin combination therapy with daily interferon plus ribavirin plus amantadine

There is currently no accepted therapeutic regimen for patients with chronic hepatitis C who failed to respond to standard combination treatment with interferon-alpha plus ribavirin. We investigated triple combination treatment with induction dosing of interferon-alpha plus ribavirin plus amantadine in these difficult-to-treat patients. Nonresponders (n = 67), breakthroughs (n = 16) and relapsers (n = 19) to previous interferon/ribavirin combination treatment of at least 6 months were included. For the first 16 weeks, patients received interferon-alpha2a 6 MU daily, ribavirin 800-1200 mg/d, and amantadine 200 mg/d. In cases of undetectable HCV RNA at week 12, treatment was continued with interferon-alpha2a 6 MU every other day and the same doses of ribavirin and amantadine until week 48. In cases of HCV RNA positivity at week 12, treatment was stopped. A total of 102 patients were enrolled (80%: genotype 1, 19%: cirrhosis). HCV RNA was negative in 35/102 patients (34%) at week 12 and in 27/ 102 patients (26%) at the end of treatment. Virological response was sustained in 15/102 patients (15%). On-treatment virological response was higher in previous relapsers/breakthroughs than in previous nonresponders (week 12: 49% vs. 27%, p < 0.05; week 48: 46% vs. 16%, p < 0.01) but no such difference was found for sustained virological response (20% vs. 12%, NS). In conclusion, triple combination treatment with daily interferon-alpha plus ribavirin plus amantadine for 3 months can induce virological response in a considerable number of nonresponders/relapsers to previous dual combination treatment, but the sustained virological response rate remains low.     

Development of hepatocellular carcinoma after interferon therapy in chronic hepatitis C. Is it possible to reduce the incidence by ribanirin and IFN combination therapy?

OBJECTIVES: Although the incidence of hepatocellular carcinoma (HCC) has been shown to be reduced after interferon (IFN) monotherapy in chronic hepatitis C, the risk factors for the development of HCC have not been fully understood. The aim of this study is to investigate the risk factors for the development of HCC after IFN in chronic hepatitis C as well as whether the incidence of HCC will be reduced by ribavirin and IFN combination therapy or not. METHODS: 495 patients with chronic hepatitis C and which received IFN monotherapy were followed and the incidence and risk factors for the development of HCC were examined. On the other hand, in the patients which received ribavirin and IFN combination therapy, the sustained response rate was assessed and the reduction rate of HCC development was predicted. RESULTS: Multivariate analysis by the Cox proportional hazard model revealed that the risk factors for HCC development were age, male gender, severe fibrosis and outcome of IFN therapy. On ribavirin and IFN combination therapy, the sustained response rate reached 17.3% in genotype 1b and 74% in genotypes 2a and 2b infection, thus reducing 20% of the estimated incidence of HCC. CONCLUSION: To reduce the incidence of HCC in chronic hepatitis C, improvement of the sustained response rate is an essential issue, and ribavirin and IFN combination therapy shows to be promising.     

Prolonged negative HCV-RNA status led to a good outcome in chronic hepatitis C patients with genotype 1b and super-high viral load

OBJECTIVE: We examined whether a sustained negative HCV-RNA status for 48 weeks affects the outcome in patients with genotype 1b and super-high viral load, and also investigated whether the outcome is affected by the induction therapy of twice-daily pre-administrated interferon (IFN)-beta. METHODS: 78 eligible patients were divided into four groups. 40 were patients assigned to the short treatment protocol. 13 patients received 3 MU IFN-beta twice daily for 2 weeks followed by IFN-alpha2b+ribavirin for 22 weeks (beta-induction group: group 1). 27 patients received IFN-alpha2b+ribavirin for 24 weeks (standard combination group: group 2). 38 patients were assigned to the maintenance treatment protocol. All of the 13 in the beta-induction group (group 3) and 21 of 25 patients in the standard combination group (group 4) who were negative HCV-RNA PCR at week 24 had IFN monotherapy to maintain a negative HCV-RNA result for 48 weeks. RESULTS: An HCV-RNA-negative status at week 24 was observed in 96% (25/26) of groups 1 and 3 versus in 79% (41/52) of groups 2 and 4 (p<0.01). The sustained virological response (SVR) was 38% (5/13) in group 1 and 11% (3/27) in group 2 (p<0.05). In the maintenance treatment, SVR was observed in 46% (6/13) of group 3 and 32% (8/25) of group 4 (NS). CONCLUSIONS: A sustained negative HCV-RNA status for 48 weeks might be associated with viral elimination in patients with genotype 1 and super-high viral load.     

Combination therapy with pegylated interferon plus ribavirin in the treatment of hepatitis C virus-related thrombocytopenia

Background:

Isolated thrombocytopenia is a common manifestation of hepatitis C virus (HCV) infection. There is no established treatment modality for this condition. The efficacy of standard interferon (IFN) monotherapy has been reported in some studies. The major disadvantage of this treatment is the high rate of recurrence due to viral breakthrough during the first 12 weeks of treatment. Pegylated IFNs are now the standard regimen for chronic hepatic disease due to HCV infection. However, due to a lack of evidence, pegylated IFNs are not widely used for HCV-related isolated thrombocytopenia.

Objective:

The aim of this report was to present the case of a male patientwith severe symptomatic thrombocytopenia due to HCV infection.

Methods:

Thrombocytopenia was treated with pegylated IFN plus ribavirin.

Results:

Although standard IFN monotherapy failed to achieve virologic and hematologic improvement, therapy with pegylated IFN alfa-2a plus ribavirin was associated with both virologic and hematologic improvement without any significant adverse effects.

Conclusions:

Pegylated IFN plus ribavirin was effective in this patient for thetreatment of HCV-related thrombocytopenia. However, further research is needed to define the response rate in different patient populations.