A potent antiviral effect on hepatitis C viral dynamics in serum and peripheral blood mononuclear cells during combination therapy with high-dose daily interferon alfa plus ribavirin and intravenous twice-daily treatment with interferon beta

Hepatitis C virus (HCV) is known to infect and replicate within peripheral blood mononuclear cells (PBMC), thereby enabling the direct evaluation of antiviral mechanisms by analyzing HCV dynamics in PBMC. To address potential molecular differences associated with distinct antiviral regimens, we studied HCV dynamics in both serum and PBMC in 44 patients with HCV genotype 1b and high viral load who were randomly assigned to the following 4 different treatment groups: 1) combination therapy with 6 MU daily of interferon alfa 2b (IFN-alpha2b) plus 800 mg of ribavirin; 2) monotherapy with 6 MU daily of IFN-alpha2b; 3) monotherapy with twice-daily intravenous administration with 3MU of IFN-beta; and 4) monotherapy with daily intravenous administration with 6 MU of IFN-beta. HCV-RNA levels were measured serially using highly sensitive real-time detection polymerase chain reaction (PCR). HCV dynamics in both the serum and PBMC showed a "biphasic" pattern. The exponential decay slopes of the second phase were significantly higher in the combination or twice-daily dosing regimen groups compared with groups 2 or 4 (0.10 +/- 0.08 vs. 0.02 +/- 0.09 or 0.16 +/- 0.09 vs. 0.02 +/- 0.04 day(-1); P <.05 or P <.0005, respectively). Moreover, the viral half-lives in the second phase were significantly shorter in these groups (73.2 +/- 42.5 vs. 240.1 +/- 120.7 or 56.0 +/- 44.6 vs. 361.6 +/- 293.5 hours; P <.05 or P <.05, respectively). Additionally, the slope of HCV decline in PBMC tended to be higher in the combination regimens, as compared with monotherapy. Taken together, our data on HCV dynamics provide molecular insight into utilization of combination or twice-daily dosing regimens to increase rates of sustained viral eradication of HCV.     

Viral kinetics of hepatitis C virus RNA in patients with chronic hepatitis C treated with 18 MU of interferon alpha daily

BACKGROUND: A rapid decrease of hepatitis C virus (HCV) RNA is interferon (IFN) dose-dependent, and a 3-log decline of HCV-RNA is a strong predictor of sustained virological response. In this study, viral kinetics of HCV RNA in patients treated with 18 MU interferon alpha (IFN-alpha) daily for 2 weeks are presented. METHODS: Thirteen treatment-naive patients with chronic hepatitis C received 6 MU of IFN-alpha2a every 8 h for 2 weeks. Samples were obtained daily during the treatment period. HCV-RNA levels were determined using the quantitative VERSANT 3.0 bDNA assay (detection limit 520 IU/ml). When results were below the detection limit, HCV-RNA was measured by qualitative polymerase chain reaction (PCR) using the COBAS AMPLICOR HCV test, version 2.0 (detection limit of 50 IU/ml). RESULTS: In patients infected with genotype non-1, a 3-log decline of viral load was found 2.4 days after the start of induction therapy. Only one of three patients infected with genotype 1 had a 3-log decline in viral load within 14 days of the start of therapy. In four patients, a third phase of viral decline was observed. At the end of treatment, 10/13 (77%) and 7/13 (54%) patients were HCV-RNA-negative in quantitative assay and qualitative PCR, respectively. Only one of 13 patients achieved a sustained virological response (SVR). CONCLUSION: Daily administration of 18 MU IFN-alpha to patients infected with genotype non-1 induces a 3-log decline of viral load within 2.4 days of the start of treatment. In patients infected with genotype 1, only one-third of patients have a 3-log decline at 11 days.     

A prospective study of interferon therapy modified by pre-treatment viral load in cirrhotic patients. Tokyo-Chiba Hepatitis Research Group

BACKGROUND/AIMS: The relative role of hepatitis C virus (HCV) load and subtype as predictors of the efficacy of interferon therapy has been clarified in patients with chronic hepatitis C, but the effectiveness of interferon therapy in cirrhotic patients is still unclear. METHODS: To resolve this issue, we undertook a multicenter, randomized, and prospective study of 114 cirrhotic patients with hepatitis C virus infection. The patients were selected to undergo two different periods (6 or 12 months) of IFN therapy according to viral load. Patients with "low" viral load (< or = 10(5.8) copies/ml serum) were randomly divided into three groups, receiving 6 or 9 million units (MU) interferon three times a week for 6 months (total dose: 468 or 702 MU), or of a modified regimen using 6MU of IFN over 6 months (total dose 564 MU), while patients with "high" viral load (< or = 10(6.3) copies/ml serum) were also randomly divided into two groups of 6 or 9 MU of IFN three times a week for 12 months (total dose: 936 or 1,404 MU). RESULTS: HCV-RNA negativity rate at the completion of treatment with 6 or 9 MU IFN was 65% in patients with "low" viral load, in contrast to 14% in patients with "high" viral load. Sustained virological response was found in 40% of patients with "low" viral load irrespective of the three different regimens, in contrast to only 1 out of 35 patients (3%) with "high" viral load. Viral eradication was found in approximately 50% of patients having a low virus load (< or = 10(4.3) copies/ml) and with HCV subtype 2a. Univariate and multivariate analysis revealed that pretreatment viral load was a significant factor contributing to efficacy of IFN therapy. CONCLUSIONS: Sustained response was scarcely achieved in cirrhotic patients with high viral loads even after a 12-month course of intensive IFN therapy. This result indicates that there is a certain cut-off level of HCV RNA load which can not be eradicated.     

A prospective study of interferon therapy modified by pre‐treatment viral load in cirrhotic patients

Abstract: Background/Aims: The relative role of hepatitis C virus (HCV) load and subtype as predictors of the efficacy of interferon therapy has been clarified in patients with chronic hepatitis C, but the effectiveness of interferon therapy in cirrhotic patients is still unclear. Methods: To resolve this issue, we undertook a multicenter, randomized, and prospective study of 114 cirrhotic patients with hepatitis C virus infection. The patients were selected to undergo two different periods (6 or 12 months) of IFN therapy according to viral load. Patients with “low” viral load (≤10^5.8 copies/ml serum) were randomly divided into three groups, receiving 6 or 9 million units (MU) interferon three times a week for 6 months (total dose: 468 or 702 MU), or of a modified regimen using 6MU of IFN over 6 months (total dose 564 MU), while patients with “high” viral load (≤10^6.3 copies/ml serum) were also randomly divided into two groups of 6 or 9 MU of IFN three times a week for 12 months (total dose: 936 or 1404 MU). Results: HCV‐RNA negativity rate at the completion of treatment with 6 or 9 MU IFN was 65% in patients with “low” viral load, in contrast to 14% in patients with “high” viral load. Sustained virological response was found in 40% of patients with “low” viral load irrespective of the three different regimens, in contrast to only 1 out of 35 patients (3%) with “high” viral load. Viral eradication was found in approximately 50% of patients having a low virus load (≤10^4.3 copies/ml) and with HCV subtype 2a. Univariate and multivariate analysis revealed that pretreatment viral load was a significant factor contributing to efficacy of IFN therapy. Conclusions: Sustained response was scarcely achieved in cirrhotic patients with high viral loads even after a 12‐month course of intensive IFN therapy. This result indicates that there is a certain cut‐off level of HCV RNA load which can not be eradicated.     

Daily interferon induction regimen using different manufactured interferons (alpha-2A or alpha-2B) in combination with ribavirin for treatment of chronic hepatitis C: a prospective randomized study

BACKGROUND: [corrected] Studies on hepatitis C virus kinetics showed that serum levels of interferon fall 48 h after drug administration, when viral load is increasing again. Previously to the availability of pegylated interferon, daily induction therapy with standard interferon was under evaluation. AIMS: To evaluate the safety and efficacy of interferon alpha daily induction regimen in combination with ribavirin. PATIENTS AND METHODS: A randomized trial including 93 patients with chronic hepatitis C was carried out. On satisfying all eligibility criteria, patients were randomly allocated to two different treatment groups: 44 individuals in treatment arm A: IFN 3 MU thrice weekly + ribavirin 1.0-1.2 g daily for 48 weeks (IFN TIW) and 49 individuals in treatment arm B: IFN 3 MU daily + ribavirin 1.0-1.2 g daily for 12 weeks followed by IFN 3 MU thrice weekly + ribavirin 1.0-1.2 g daily, until completion of 48 weeks of therapy (IFN QD). HCV genotyping was obtained in 85 subjects. A negative HCV-RNA 6 months after cessation of therapy was considered a sustained virological response RESULTS: Eighty three patients completed treatment, five dropped out (one from IFN TIW and four from IFN QD) and in five patients therapy was discontinued due to medical request (two from IFN TIW and three from IFN QD). There was no statistically significant difference between groups with respect to therapy interruption. The frequency of cirrhosis was 29%, similar in both groups. In the "intention to treat" analysis the overall sustained virological response was 39.8%. There was no significant difference in sustained virological response rate between both treatment strategies (36.4% IFN TIW vs 42.9% IFN QD). In the 83 patients who finished the trial, sustained virological response was 44.6%. Among subjects with HCV genotype-1, the sustained virological response was 42% (40.9% IFN TIW vs 42.9% IFN QD) and among patients with HCV genotype 2 or 3, the sustained virological response was 55.6% (50% IFN TIW vs 63.6% IFN QD) CONCLUSIONS: Combination therapy had an overall sustained virological response rate of 39.8% ("intention to treat analysis"). There was no difference with respect to sustained virological response rates between patients who used daily induction schedule compared to standard regimen. Adverse events, even more frequent in the daily induction group, did not interfere with the treatment strategies.     

Twice-daily administration of interferon-beta for chronic hepatitis C is not superior to a once-daily regimen

Purpose. Although interferon (IFN) is commonly used for the treatment of chronic hepatitis C virus (HCV) infection, eradication of the virus occurs in only a small proportion of patients with genotype 1b and a high virus titer. Modified IFN therapies have been tried, with only limited benefit. Recently, the administration of IFN-beta twice per day has been reported to be more effective than the usual once-daily administration regimen. The aim of this study was to evaluate whether twice-daily IFN results in a sustained response in patients with chronic HCV infection with genotype 1b and a high virus titer. Methods. Twenty patients with genotype 1b and high HCV RNA level (more than 1 MEq/ml by branched DNA probe assay) were randomly assigned to receive either twice-daily 3 MU of IFN beta (group A) or once-daily 6 MU of IFN-beta (group B) for 4 weeks. All patients received a further daily dose of 6 MU IFN-beta for 12 weeks, followed by IFN-alfa three times a week for 16 weeks. Results. Although a rapid fall in HCV RNA levels was noted in group A, a sustained response was observed in only one of nine patients in this group, and none of group B. Adverse effects of IFN were more frequent and pronounced in group A than in group B. Conclusions. We conclude that further modification, which combines the early strong anti-viral effects of the twice-daily regimen with long-term sustained response, is necessary for effective therapy of HCV patients with genotype 1b and high HCV RNA levels. Received: June 22, 2000 / Accepted: November 10, 2000     

Viral Kinetics and Treatment Response in Patients with Hepatitis C During Induction and Standard Interferon Therapy in Combination with Ribavirin

Background: The early decline of hepatitis C virus (HCV) RNA levels during therapy may predict the outcome and can be utilized to improve treatment regimens. We studied the HCV RNA levels during induction and standard interferon (IFN) and ribavirin treatment. Methods: Patients received IFN 3 MU daily for 14 days followed by 3 MU three times a week (induction group; n = 10), or IFN 3 MU three times a week from start (standard group; n = 21), in combination with ribavirin 1000-1200 mg/day. HCV RNA was quantified day 0, 1, 2, 3, 7, 14, 28, 56 and 84 during treatment, and tested qualitatively at the end of treatment and at follow-up. Results: The initial viral load decline was more pronounced in the induction group, and in patients infected with genotype non-1. The sustained response rate was not significantly different between the study groups. At day 1, the mean viral load decline from baseline was significantly greater in patients who became sustained responders than in those who became non-responders; 1.4 log (96%) versus 0.3 log (55%) ( P < 0.05). All sustained responders had a viral load decline of at least 0.7 log (79%) after the first IFN dose. Conclusions: Our short-term induction treatment did not improve the long-term treatment outcome significantly, although a trend was seen. An absent or low initial viral load decline can be used to predict non-response in the individual patient.     

Viral kinetics and treatment response in patients with hepatitis C during induction and standard interferon therapy in combination with ribavirin

BACKGROUND: The early decline of hepatitis C virus (HCV) RNA levels during therapy may predict the outcome and can be utilized to improve treatment regimens. We studied the HCV RNA levels during induction and standard interferon (IFN) and ribavirin treatment. METHODS: Patients received IFN 3 MU daily for 14 days followed by 3 MU three times a week (induction group; n = 10), or IFN 3 MU three times a week from start (standard group; n = 21), in combination with ribavirin 1000-1200 mg/day. HCV RNA was quantified day 0, 1, 2, 3, 7, 14, 28, 56 and 84 during treatment, and tested qualitatively at the end of treatment and at follow-up. RESULTS: The initial viral load decline was more pronounced in the induction group, and in patients infected with genotype non-1. The sustained response rate was not significantly different between the study groups. At day 1, the mean viral load decline from baseline was significantly greater in patients who became sustained responders than in those who became non-responders; 1.4 log (96%) versus 0.3 log (55%) (P < 0.05). All sustained responders had a viral load decline of at least 0.7 log (79%) after the first IFN dose. CONCLUSIONS: Our short-term induction treatment did not improve the long-term treatment outcome significantly, although a trend was seen. An absent or low initial viral load decline can be used to predict non-response in the individual patient.     

Potent induction therapy with interferon and ribavirin combination therapy does not achieve a higher sustained virological response rate in chronic hepatitis C with genotype 1b and high hepatitis C virus RNA level

Aims: To compare twice-daily interferon (IFN)-beta administration and once-daily IFN-alpha-2b administration as induction therapy in ribavirin combination therapy in chronic hepatitis C with a high viral load of genotype-1b hepatitis C virus (HCV). Methods: Sixty-one chronic hepatitis patients with a high viral load of genotype-1b HCV were randomly divided into three groups: group A was given IFN-beta 6 MU induction therapy twice daily for 2 weeks; group B was given IFN-alpha-2b 6 MU induction therapy once daily for 2 weeks; and group C was given no induction therapy. All three groups were then given IFN-alpha-2b 6 MU 3 days/week for the rest of the 24-week study period. Ribavirin was given for the entire 24-week study period. Results: Although the cumulative HCV-RNA negative rates tended to be higher in group A than in group B, the differencewas not significant. The HCV-RNA negative rate at week 2 was significantly higher in groups A and B than in group C (P < 0.05). The sustained virological response (SVR) rate was 16% overall, 21% for groups A and B, and 5% for group C; the SVR rate of groups A plus B tended to be higher than that of group C (P = 0.093). Conclusions: There was no difference between the effects of the two induction therapies; potent induction therapy does achieve higher early viral clearance but not a higher SVR rate.     

Rapid Decrease of Plasma HCV RNA in Early Phase of Twice Daily Administration of 3 MU Doses Interferon-β in Patients with Genotype 1b Hepatitis C Infection

Virological response to interferon (IFN) is poor in patients with plasma levels of HCV RNA higher than 1 Meq/ml and genotype 1b hepatitis C viral infection. In 60 patients, a randomized control study was conducted to compare 3 MU of IFN- twice daily for four weeks (group A) and 6 MU once a day for four weeks (group B) followed by a four-week administration of 6 MU once a day. The plasma levels of HCV RNA, determined by an amplicore-monitor method, for patients in group A were significantly lower than those for group B at the fourth and eighth day of IFN administration, and complete virological responses were noted in two patients from group A but none in group B. It is concluded that twice daily administration of 3 MU IFN- is more effective than once a day 6 MU in the early phase of IFN therapy.     

High-dose interferon alpha-2b induction therapy in combination with ribavirin for Japanese patients infected with hepatitis C virus genotype 1b with a high baseline viral load

Background Although pegylated interferon (IFN) is now used in many countries as a standard therapy for chronic hepatitis C, the efficacy and safety of combination therapy of high-dose interferon alpha-2b induction with ribavirin are not fully evaluated, especially in Japanese patients infected with hepatitis C virus (HCV) genotype 1b with a high viral load.Methods Patients (n = 83) received daily, high-dose induction therapy of interferon alpha-2b (6 million units [MU] once daily for 2 weeks), followed by 6MU three times weekly for 22 weeks. Oral ribavirin (800 or 600mg/day) was given daily for 24 weeks, and then the patients were followed up for 24 weeks.Results Of the 83 patients, 67 (81%) had a biochemical response (BR), and 37 (45%) achieved a sustained BR (SBR). Virologic response (VR; undetectable serum HCV RNA level by polymerase chain reaction [PCR]) was noted in 55 (66%) patients, and sustained VR (SVR) in 16 (19%) patients. Baseline viral load did not influence treatment outcome. There was no significant difference in treatment outcome among treatment-naÏve patients, relapsers, and nonresponders to previous IFN monotherapy. Multivariate analyses identified serum ribavirin concentrations at week 8 of therapy (odds ratio [OR], 23.7; 95% confidence interval [CI], 1.84–61.1; P = 0.015) and negativity for serum HCV RNA at week 8 (OR, 22.5; CI, 1.76–57.5; P = 0.017, respectively) as two significant and independent predictors of SVR.Conclusions The efficacy of 24-week combination therapy of high-dose IFN alpha-2b induction and ribavirin deserves attention in HCV genotype 1b patients with a high viral load, especially in nonresponders to previous IFN monotherapy and patients with a very high viral load.     

Kinetics of the hepatitis C virus during interferon therapy as a marker of therapeutic response

BACKGROUND: The viral load and subtype of hepatitis C virus (HCV) are predictors of the efficacy of interferon (IFN) therapy. The kinetics of HCV during IFN therapy have been described recently, suggesting that HCV infection is highly dynamic. These observations have raised the issue as to whether early monitoring of the viral load can help guide IFN therapy. METHODS: We measured HCV-RNA levels at 0, 24 and 48 h after the start of IFN-alpha treatment (10 MU daily for 2 weeks and then three times weekly for 22 weeks) or IFN-beta treatment (6 MU daily for 6 weeks). Then we analyzed the relationship between HCV kinetics and therapeutic response using stepwise multivariate logistic regression analysis. RESULTS: The exponential decay slope of the viral load during the first 24 h, not the first 48 h or the next 24 h, was a predictor of viral eradication at 6 months after completion of the treatment (sustained response; P = 0.0023). This decay slope was not affected by the HCV serotype or the type of IFN used. Initial viral load and HCV serotype were also predictors, as reported previously (P < 0.0001 and P = 0.0347, respectively). We also proposed a model using a prognostic index that predicted a sustained response with more than 80% sensitivity, specificity and efficacy in an independent and external group of patients. CONCLUSION: This study demonstrated that the exponential decay slope of the viral load during the first 24 h was an important predictor of the response to IFN therapy as well as the initial viral load and HCV serotype. The model may also be useful for the clinical management of IFN therapy.     

Interferon-stimulated gene expression and hepatitis C viral dynamics during different interferon regimens

BACKGROUND/AIMS: To address the molecular mechanism for enhanced antiviral efficacy associated with a frequent dosing of interferon (IFN)-beta. METHODS: Serum hepatitis C viral (HCV) dynamics, double-stranded RNA-activated protein kinase (PKR) mRNA and MxA mRNA levels in peripheral blood mononuclear cells (PBMC) were analyzed serially in 140 patients who were randomly assigned to a twice daily (3 MU bid) or once daily (6 MU qd) administration group. RESULTS: In twice daily group, the rate of HCV decline during the second phase was 2-fold greater than in the once daily group (P=0.04). Peak PKR and MxA gene expression levels in the first phase (observed 4 h after a single administration) were 2-fold higher in the once daily group. However, the expression in the second phase was maintained at a significantly higher level in the twice daily group. Initial and peak expression levels were related to initial viral load. Basal expressions in PBMC were significantly correlated with those in the liver tissue (PKR, r=0.81; MxA, r=0.75, respectively, P<0.0001). CONCLUSIONS: Our data suggest that elimination of HCV-infected cells is enhanced by twice daily dosing of IFN-beta, and that this enhanced effect is associated with a higher intracellular expression of PKR and MxA during the second phase.     

Prospective study of interferon therapy for compensated cirrhotic patients with chronic hepatitis C by monitoring serum hepatitis C RNA

Because interferon therapy exhibits low efficacy for cirrhotic patients infected with hepatitis C virus, this prospective study was conducted to determine effective interferon regimens tailored to treatment response by monitoring HCV RNA status. A total of 157 cirrhotic patients were enrolled to receive 9 million units (MU) of interferon three times a week. The HCV RNA values were drawn 8 weeks apart and the patients were randomized to a further 16 or 32 weeks of treatment after two sequential findings of negativity for HCV RNA. A total of 73 out of 157 patients (46%) proceeded to randomization to different durations of treatment, 37 short-course and 36 long-course (duration: 38 +/- 8 and 49 +/- 13 weeks; total amount of interferon: 940 +/- 240 and 1130 +/- 390 MU, respectively). The remaining 84 patients without two sequential negative serum HCV RNA determinations received 44.8 +/- 27.4 weeks of interferon (IFN) therapy with total amount of 993 +/- 633 MU. Of these 157 patients, sustained virological and biochemical response was shown in 32 (20%) and 37 patients (24%), respectively. Sustained virological and biochemical response rate in the randomized patients was significantly higher than in nonrandomized patients (41% vs. 2%, and 38% vs. 11%; each P <.01). Of the 73 randomized patients, the rate of sustained virological response in patients with long-course treatment (50%) was significantly higher than that of patients with short-course treatment (32%) (P =.026: log-rank test), and in patients with early disappearance of HCV RNA especially within 8 weeks, in patients with low virus load (相似文献   

Hepatitis C viral dynamics

It is apparent that the sooner the virus is cleared from the serum following IFN monotherapy, the better the sustained virologic response rates. It is also clear that in patients infected with HCV genotype 1a and 1b, standard dosages of IFN-alpha 2b (3 MU) administered three times a week are inadequate for a substantial and sustained lowering of HCV RNA serum levels. Understanding the kinetics and dynamics of HIV and HBV has greatly improved the understanding of the life cycle of these viruses and their response to therapy. Studies of the kinetics of HCV following initiation of IFN monotherapy have revealed that IFN-alpha 2b causes a rapid dose-dependent (3 < 5 < 10 = 15 MU) reduction in HCV RNA levels within 24 to 48 hours. This rapid exponential decline in RNA levels is best explained by an effect of IFN on viral production or release. The dose of other IFN products that maximally suppresses viral levels needs to be determined. Mathematical calculations reveal that HCV has a serum half-life of 3 hours and a viral production rate of 1.0 x 10(12) virions/d. After this rapid decline, there is a slower phase of viral decline that varies widely among patients and is attributed to the death rate of infected liver cells. The rate of decline of the second phase, which is probably mediated by immune clearance of infected liver cells, is the best viral kinetic predictor of early viral clearance. This kinetic information indicates that in patients infected with HCV genotype 1a or 1b, initial therapy with IFN should be daily and initial doses should be sufficient to reduce viral levels by more than 95% within 48 hours. Whether higher doses of IFN will alter or enhance the second phase of viral decline needs to be investigated. Also, the effect of ribavirin on IFN-mediated changes in HCV RNA levels needs to be investigated in carefully performed kinetics studies to better determine its mechanism of action. Defining the viral kinetics in patients infected with HCV genotype 2 or 3 and in patients who do not respond to IFN therapy will also improve the approach to therapy.     

Different turnover rate of hepatitis C virus clearance by different treatment regimen using interferon-beta

BACKGROUND/AIM: Since patients with high viral load and HCV subtype 1b are known to respond poorly to interferon (IFN) therapy, the viral dynamics of HCV RNA after initiation of interferon therapy were examined in the present study with respect to two different administration regimens, once vs. twice a day. METHODS: Twenty-two patients with chronic hepatitis C confirmed by liver biopsy and with >1 Meq/ml of HCV RNA and HCV subtype 1b were randomly assigned to two different IFN administration regimens (6 million units of IFN once a day or 3 million units of IFN twice a day), and the serum HCV RNA level was serially measured. RESULTS: Graphs of HCV RNA levels vs. treatment time showed an initial rapid fall, followed by a slower clearance phase. Fitting the data to a model for HCV decay proposed by Neumann et al. showed that the treatment efficacy was significantly higher with twice daily administration. Negativity for HCV RNA measured by Amplicor assay in the twice-a-day administration group was 18%, 73% and >89% at 1, 2 and 3 weeks, respectively, in contrast to 0%, 0%, and 18%, respectively, with once-a-day administration. However, a significant reduction of platelet count and albumin level, a marked increase in serum aspartate aminotransferase/alanine aminotransferase, and a high incidence of renal toxicity (proteinuria) were found in patients receiving IFN twice a day in comparison with those receiving it once a day. CONCLUSION: The twice-a-day administration of IFN accelerated the clearance of HCV RNA from serum, leading to a more efficient virological response for patients with chronic hepatitis C, but with a high rate of renal toxicity.     

Efficacy of Daily Induction Dosing vs Standard Thrice Weekly Dosing of Interferon-α2B for Initial Treatment of Chronic Hepatitis C

The aim of this study was to compare the effect on HCV RNA levels of using induction dosing with 5 MU interferon-_2b (IFN) given daily for four weeks followed by 5 MU IFN given three times a week (TIW) for 44 weeks vs standard noninduction TIW dosing of 5 MU IFN for 48 weeks. We randomly assigned 135 patients with chronic hepatitis C to induction therapy or noninduction therapy. After four weeks of therapy 17/65 (26.1%) patients had undetectable HCV viral levels in the induction group compared with 16/64 (25.0%) patients in the noninduction group. The mean HCV viral levels were similar at four weeks in patients who received induction and noninduction therapy. Mean HCV viral titers in the induction group increased from 4 to 16 weeks, whereas the mean viral titers in the noninduction group decreased during this time (P < 0.0001). HCV RNA was undetectable at the end of therapy in 17/66 (25.8%) in the induction group and 21/68 (30.9%) in the noninduction group. The sustained virologic response rate 24 weeks after the end of therapy was 14/67 (20.9%) in the induction group compared with 13/68 (19.1%) in the noninduction group. These results indicate that an initial four week period of daily interferon confers no benefit in the treatment of patients with chronic hepatitis C.     

Evaluation of twice-daily administration of interferon-beta for chronic hepatitis C

To improve the efficacy of interferon (IFN) in the treatment of chronic hepatitis C, administration of IFN-beta twice per day was evaluated. Thirty-eight patients with chronic hepatitis C (26 males and 12 females, aged 25-67 years) were included. Patients were treated with a new protocol that included twice-daily treatment with IFN-beta. Three million units (MU) of IFN-beta was administered twice daily every day for 4 weeks followed by 10 MU of IFN-alpha2b, every day for 2 weeks and then three times a week for 18 weeks (total IFN-beta, 148 MU; IFN-alpha2b, 680 MU). Complete responders (CR) were defined by alanine aminotransferase levels that normalized within 6 months after completion of IFN therapy and remained normal for more than 6 months, and by serum hepatitis C virus (HCV) RNA levels that became negative as determined using the Amplicor assay. Twenty-one of 38 (55.3%) patients were CR. Nine of 21 (42.9%) patients with HCV serotype 1 were responders compared with nine of 12 (75.0%) patients with HCV serotype 2. In patients with an HCV titre greater than 1 million equivalents ml-1 (1 MEq ml-1), nine of 24 (37.5%) responded, and in patients with HCV titres less than 1 MEq ml-1, 12 of 14 (85.7%) responded. In patients with HCV serotype 1 and greater than 1 MEq ml-1 HCV RNA, four of 15 (26.7%) responded to IFN. Two-thirds (66.7%) of the patients who became negative for HCV RNA after 2 weeks of therapy responded, while 72.7% of those with positive HCV RNA after 2 weeks of therapy were non-responders. Proteinuria was frequently observed as an adverse effect of twice-daily administration of IFN-beta. The combination of twice-daily administration of IFN-beta for 4 weeks followed by IFN-alpha showed a high response rate in patients with chronic hepatitis C, but in patients with both serotype 1 and a high titre of HCV RNA, response rates were still low. Thus, the HCV RNA titre 2 weeks after starting therapy with IFN was useful for predicting the eventual response to IFN.     

Biochemical and viral response to consensus interferon (CIFN) therapy in chronic hepatitis C patients: effect of baseline viral concentration. Consensus Interferon Study Group

OBJECTIVE: The effect of baseline viral concentration on response was assessed as part of a multicenter phase 3 trial evaluating the safety and efficacy of CIFN therapy for chronic HCV infection. METHODS: Patients (n = 472) received either CIFN 9 microg or IFN alpha-2b 3 MU subcutaneously t.i.w. for 24 wk, followed by 24 wk of observation. RESULTS: Efficacy was assessed by the percentage of patients who achieved normal ALT values or undetectable HCV RNA values (using RT-PCR with a sensitivity of 100 copies/ml). There was a clear relationship between baseline viral concentration and either ALT or HCV RNA response; patients with lower titer HCV RNA had better response rates. End-of-treatment HCV RNA responses were better for patients with low viral concentrations treated with CIFN (51%) than for patients treated with IFN a-2b (31%) (p = 0.03). ALT responses in patients with low viral concentrations were 60% for CIFN-treated patients and 27% for IFN alpha-2b-treated patients (p < 0.01) at the end of treatment. Patients with high titer HCV RNA were more likely to have a sustained HCV RNA response after treatment with CIFN 9 microg, compared with those treated with IFN alpha-2b (7% vs 0%, p = 0.03). CONCLUSIONS: Both genotype and baseline viral concentration were independent factors that affected response to interferon.     

Twenty-four weeks of interferon alpha-2b in combination with ribavirin for Japanese hepatitis C patients: sufficient treatment period for patients with genotype 2 but not for patients with genotype 1.

BACKGROUND: Hepatitis C virus (HCV) RNA titer and HCV genotype are two major determinants of the outcome of interferon (IFN) monotherapy. To clarify the usefulness of combination therapy with IFN and ribavirin in Japanese hepatitis C patients, we treated patients with a relatively high dose of IFN in combination with ribavirin for 24 weeks and examined the effects in relation to the viral parameters. METHODS: Two hundred and ninety-five patients were enrolled in the study. The patients received either 6 or 10 million units (MU) of interferon alpha-2b every day for 2 weeks and then three times a week for 22 weeks with a daily dose of either 600 or 800 mg of ribavirin. The treatment response and safety of this treatment were examined. RESULTS: The sustained virologic response (SVR) rates were 26.8% in genotype 1 and 76.5% in genotype 2 (P < 0.001), and 36.1% with the 6 MU group and 45.8% with the 10 MU group (P = 0.09). Multivariate analysis indicated that SVR was associated with genotype 2, HCV RNA <500 kilointernational unit/ml (kIU/ml), and HCV RNA undetectability at week 8 of treatment. CONCLUSION: Our current study showed that a 24-week course of IFN plus ribavirin combination therapy was effective with respect to virologic response in Japanese hepatitis C patients, particularly in patients with HCV genotype 2.