Combination therapy with interferon-alpha and ribavirin in patients with dual hepatitis B and hepatitis C virus infection

BACKGROUND: Patients with dual hepatitis B virus (HBV) and hepatitis C virus (HCV) infection have responded poorly to interferon (IFN) monotherapy. The purpose of the present paper was to assess the effect of combined IFN-alpha and ribavirin therapy in patients infected with both hepatitis B and C. METHODS: Thirty-six patients received 3 or 5 MU IFN-alpha-2b thrice weekly and oral ribavirin (800-1200 mg/day) for 24 weeks. All patients had positive hepatitis B surface antigen, antibody to HCV, and HCV-RNA. Before treatment, one patient had positive hepatitis B e antigen. Eighteen patients had positive HBV-DNA tested by Amplicor (Cobas Amplicor Monitor, Roche Diagnostics, Branchburg, NJ, USA), with a mean HBV-DNA level of 3.1 +/- 0.9 log copies/mL. Another 72 patients with HCV infection alone served as controls. RESULTS: Adverse events led to withdrawal in three patients receiving 5 MU IFN. Based on an intent-to-treat analysis, the biochemical response and serum HCV clearance rate at the end of 48 weeks follow up was similar in patients with dual infection and HCV infection alone (56% vs 72%; and 69% vs 71%, respectively). There was no significant difference in sustained HCV clearance rate between the 3-MU group (n = 13) and the 5-MU group (n = 23; 85% vs 61%). At the end of 48 weeks follow up, two (11%) of 18 pretreatment viremic patients had negative serum HBV-DNA (<200 copies/mL), while eight of those without pretreatment viremia had re-occurrence of HBV-DNA. CONCLUSIONS: Combination therapy with IFN-alpha and ribavirin was effective in achieving sustained HCV clearance in patients with dual HBV and HCV infection, comparable to those with hepatitis C infection alone. Combination therapy using 3 MU IFN-alpha seemed as effective as 5 MU, and was well tolerated in the study population. However, large-scale control trials are necessary to clarify these findings.     

Dual chronic hepatitis B virus and hepatitis C virus infection

Dual hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are common in HBV or HCV endemic areas. However, several clinical and pathogenetic issues remain unresolved. First, clinical and in vitro studies suggest the interactions between two viruses. The dynamics of the interaction in untreated setting versus treated setting and its influence on the long-term outcomes await further studies. A key issue regarding viral interactions is whether modulation of infection occurs in the same dually infected individual hepatocyte of the liver. Clarifying this issue may help to understand the reciprocal interference between HCV and HBV and provide clues for future immunopathogenetic studies. Second, the prevalence and clinical significance of coexisting occult HBV infection in patients with chronic HCV infection need further investigations. Third, combination therapy of peginterferon alfa-2a and ribavirin appears to be just as effective and safe for the treatment of hepatitis B surface antigen (HBsAg)-positive patients chronically infected with active chronic hepatitis C as it is in patients with HCV monoinfection. Nevertheless, one-third of dually infected patients with nondetectable serum HBV DNA-level pretreatment developed HBV reactivation posttreatment. How to prevent and treat this reactivation should be clarified. Furthermore, about 10% of the dually infected patients lost HBsAg. Underlying mechanisms await further investigations. Finally, the optimal treatment strategies for dually infected patients with hepatitis B e antigen-positive chronic hepatitis B should be identified in future clinical trials.     

Treatment of patients with dual hepatitis C virus and hepatitis B virus infection: Resolved and unresolved issues

Dual hepatitis C virus (HCV)/hepatitis B virus (HBV) infection is not uncommon in HCV or HBV endemic areas and among subjects at risk of parenteral transmission. In patients dually infected with hepatitis C and B, the disease manifestations are usually more severe than those with either virus infection. In the past decade, the following issues have been resolved. In dually infected patients with active hepatitis C, combined pegylated interferon alfa plus ribavirin was effective, the treatment outcomes being similar to patients with HCV monoinfection. During long‐term follow‐up, the HCV response was sustained in around 97% of patients; and the long‐term outcomes including the development of hepatocellular carcinoma and liver‐related mortality were improved. However, several clinical issues remain to be resolved. First, host and viral factors influencing the long‐term outcomes and treatment options in patients with dual HCV/HBV infection await further studies. Second, about 60% of dually infected patients with baseline undetectable serum HBV DNA levels develop HBV reactivation after the start of treatment. How to prevent and treat HBV reactivation should be clarified. Third, about 30% of dually infected patients lose hepatitis B surface antigen at 5 years after the end of combination therapy; the mechanisms need further investigations. Fourth, the optimal treatment strategies for dually infected patients with active hepatitis B or established cirrhosis should be explored in future clinical trials. Finally, the role of new direct‐acting antiviral‐based therapy for the treatment of patients with dual HCV/HBV infection also remains to be evaluated.     

Updates on the treatment and outcomes of dual chronic hepatitis C and B virus infection

Dual hepatitis C virus(HCV)/hepatitis B virus(HBV)infection is found in HBV or HCV endemic areas,and in specific populations exhibiting a high risk of parenteral viral transmission.Clinical observations have revealed that HCV/HBV dually infected patients demonstrate a higher risk of liver disease progression compared with HBV or HCV monoinfected patients.The viral activity responsible for liver disease progression can be determined by examining the viral loads of HCV and HBV and by conducting liver biopsy examinations.Recent trials have confirmed that the combination therapy of peginterferon alpha-2a or 2b and ribavirin for dual hepatitis patients with HCV dominance appears to be as effective and safe as it is in patients with HCV monoinfections.Strikingly,approximately 60% of dually infected patients with inactive hepatitis B before treatment develop HBV reactivation after the clearance of the HCV.The clinical significance of this HBV reactivation and the strategy to prevent and treat this event should be determined.Furthermore,approximately 30%of dually infected patients lost hepatitis B surface antigen(HBsAg)within 5 years after the start of peginterferonbased therapy,and 40%of them harbored occult HBV infection.The underlying mechanisms of their accelerating HBsAg seroclearance and the development of occult HBV await further investigations.Moreover,the optimal treatment strategies for dually infected patients who are seropositive for the hepatitis B e antigen must be explored.Finally,the advent of new direct-acting antiviral-based anti-HCV therapy may change the optimal therapies for patients with dual hepatitis in the near future,which warrants further clinical trials.     

Current therapy for hepatitis C or D or immunodeficiency virus concurrent infection with chronic hepatitis B

Concurrent hepatitis C virus (HCV), hepatitis delta virus (HDV), or human immunodeficiency virus (HIV) infection with chronic hepatitis B virus (HBV) appears to increase the risk of progressive liver disease including liver cirrhosis and hepatocellular carcinoma. There is a 10% prevalence of HCV infection in chronic HBV or HDV infection. Serological evidence of previous exposure to HBV is found in more than 80% of HIV-positive patients in the high risk group. Notably, the most recently acquired virus tends to suppress the pre-existing virus. In chronic HBV infection acquired perinatally or in early childhood, usually HCV is dominant and may suppress or even displace HBV and HDV. Less frequently, HBV or HDV suppresses HCV. It is generally agreed that the dominant virus should be identified in order to make appropriate treatment decisions. Studies with standard interferon (IFN) to treat patients with HCV dominantly dual HBV/HCV infection have showed only limited virological response. But high dose of IFN has been demonstrated with better response rate. Combined ribavirin with standard or pegylated IFN therapy could achieve a sustained HCV clearance rate comparable with those infected with HCV alone. On the contrary, patients with HBV dominantly dual viral infection might indicate more appropriate addition of lamivudine to IFN than ribavirin. Additionally, patients with concurrent infection of HBV and HDV, IFN seems to be the only effective agent. However, the efficacy of IFN is related to the dose. High dose of IFN [9 MU tiw (thrice per week)] and longer treatment duration (at least 2 years) have been shown to achieve adequate virological response. In patients with concurrently infected HBV and HIV, anti-HBV therapy should be considered for all patients with evidence of liver disease, irrespective of the CD4 cell count. In patients not requiring antiretroviral therapy, HBV therapy should be preferentially based on IFN, adefovir, or telbivudine. In contrast, in patients with CD4 cell counts <350 cells/μl or those already on antiretroviral therapy, agents with double anti-HBV and anti-HIV activity are preferred. At present, the evidence of therapeutic efficacy is not sufficient to make a recommendation in treating patients with dual HBV/HCV or HBV/HDV or HBV/HIV infection. Further studies of the well-designed, larger scale are needed to elucidate the role of different regimens or combination in the treatment of dual viral infection.     

Randomized trial of three different regimens for 24 weeks for re-treatment of chronic hepatitis C patients who failed to respond to interferon-alpha monotherapy in Taiwan.

With the favorable result of interferon (IFN)-ribavirin combination therapy for 24 weeks among naive Taiwanese chronic hepatitis C (CHC) patients, the optimal regimens of re-treatment for CHC patients who failed initial IFN monotherapy is not well-established. The study evaluated the effectiveness of re-treatment for 24 weeks with 3 different regimens and predictors for sustained virological response (SVR). METHODS: Total 120 Taiwanese CHC patients (81 males, 70 relapsers, mean age: 48.6 years) who failed initial IFN monotherapy were enrolled. They were assigned randomly (with a ratio of 1:1:2) to receive one of the three regimens for re-treatment for 24 weeks; group A: IFN 6 million units (MU) monotherapy (N=30), group B: combination therapy with ribavirin and IFN 3 MU (N=30) or group C: combination therapy with ribavirin and IFN 6 MU (N=60). The intention-to-treat rate of sustained virological response (SVR) was 38.3%. The SVR rate in group C (53.3%) was significantly higher than group A (16.7%, P<0.005) and group B (30%, P<0.05). Drop-out rates were similar between the three groups. Patients achieving SVR had significant improvement histologically. Hepatitis C virus (HCV) genotype non-1b infection, lower pretreatment HCV RNA levels, combined with ribavirin and with higher IFN dose, and relapsers were independent predictors for SVR. CONCLUSION: We concluded that more than one-third Taiwanese CHC patients achieved SVR after 24 weeks re-treatment and combination therapy, especially with higher dose of IFN, yielded higher efficacy.     

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.     

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.     

Pediatric issues in new therapies for hepatitis B and C

Two antiviral treatments have been approved for hepatitis B virus (HBV) infection by the US Food and Drug Administration (FDA) for use in children: interferon (IFN)-α, 6 MU/m² three times a week subcutaneously for 6 months, and lamivudine, 3 mg/kg/d orally for 12 months. Twenty-six percent to 58% of children treated with IFN become HBV DNA negative, and up to 38% become negative to hepatitis B e antigen (HBeAg). Lamivudine, a nucleoside analogue that blocks viral replication by inhibition of the HBV polymerase, has been associated with comparable rates of seroconversion of HBeAg to anti-HBe. Loss of surface antigen occurs in less than 5% of patients treated with lamivudine, compared with 3% to 33% in those treated with IFN-α. Fifty percent to 65% of children treated with lamivudine clear HBV DNA after 12 months of therapy, but relapse rates have not been clarified. Patients treated with lamivudine develop drug-resistant (YMDD) mutants in the HBV polymerase at the rate of 16% to 32% per year. No treatments for children with hepatitis C virus (HCV) have been approved by the FDA. However, published reports describe treatment with IFN monotherapy and combination therapy with IFN and ribavirin. Trials of PEG-IFN alone or in combination with ribavirin are in progress. Given the lack of data regarding treatment of HCV in children, it is generally agreed among pediatric hepatologists that the optimal treatment is within the context of randomized, controlled trials.     

Personalized Therapy of Chronic Hepatitis C and B Dually Infected Patients With Pegylated Interferon Plus Ribavirin: A Randomized Study

We aimed to investigate whether response-guided therapy (RGT) with peginterferon-alpha plus ribavirin by using hepatitis C virus (HCV) genotype, pretreatment HCV RNA levels, and rapid virological response (RVR, undetectable HCV RNA at treatment week 4) could be applied for active HCV/hepatitis B virus (HBV) dually infected patients, without compromised the treatment efficacy.A total of 203 patients, seropositive of HCV antibody, HCV RNA and HBV surface antigen (HBsAg), and seronegative for HBV e antigen for >6 months, were randomized to receive peginterferon-alpha/ribavirin by either genotype-guided therapy (GGT, n = 102: HCV genotype 1 [HCV-1], 48 weeks; HCV-2/3, 24 weeks) or RGT (n = 101: HCV-1, 48 or 24 weeks if patients with baseline VL <400,000 IU/mL and RVR; HCV-2/3, 24 or 16 weeks if patients with RVR). The primary endpoint was HCV-sustained virological response (SVR).The HCV SVR rate was comparable between the GGT (77.5%, 79/102) and RGT groups (70.3%, 71/101, P = 0.267), either among HCV-1/HBV (69.4% [43/62] vs 63.5% [40/63], P = 0.571) or among HCV-2/3/HBV (90.0% [36/40] vs 81.6% [31/38], P = 0.342) dually infected patients based on intention-to-treat analysis. In HCV-1/HBV dually infected patients, RVR (odds ratio [OR]: 6.05; 95% confidence intervals [CI]: 2.148–17.025, P = 0.001) and lower pretreatment blood glucose levels (OR: 0.97; CI: 0.944–0.989, P = 0.003) were independent predictors of HCV SVR. Although RVR (OR: 10.68; CI: 1.948–58.514, P = 0.006) was the only significant factor associated with HCV SVR in HCV-2/3/HBV dually infected patients. HBsAg loss at 1 year posttreatment was observed in 17 of 185 (9.2%) patients. The rates of discontinuation and adverse events were similar between the 2 groups.RGT with peginterferon-alpha/RBV may be considered for HBeAg-negative HBV/HCV dually infected patients.     

Effect of combination therapy with ribavirin and high-dose interferon-α2b for 24 weeks in chronic hepatitis C

Background and Aim: The aim of the present study was to determine whether a 24‐week course of combination therapy with ribavirin and high‐dose interferon‐α2b (IFN‐α2b) could provide an acceptable treatment efficacy in chronic hepatitis C (CHC). Methods: Seventy‐six patients with CHC whose serum hepatitis C virus (HCV) RNA levels were more than 100 kIU/mL on quantitative polymerase chain reaction (PCR) assay were included. The patients were assigned to two different dose groups of IFN‐α2b: group A (n = 39) received 6 MU and group B (n = 37) received 10 MU. Each group received the dose daily for 14 days then three times per week for a total of 24 weeks. In addition, HCV genotype 1b patients in group A and group B were classified into group C (n = 20) and D (n = 29), respectively. All patients received 600 or 800 mg ribavirin per day. Results: Sustained response rates in group A were significantly higher than those in group B (66.7%vs 35.1%, intent‐to‐treat, P = 0.0060). However, sustained response rates in group C were not different from those in group D (45.0%vs 20.7%, intent‐to‐treat, P = 0.0696). The proportion of patients who discontinued the treatment or reduced drug dosage because of adverse events was significantly higher in group B than in group A (27.0%vs 7.69%, P = 0.0224). Conclusion: A 24‐week course of combination therapy with ribavirin and 6 MU IFN‐α2b had an acceptable efficacy with fewer adverse events than that with ribavirin and 10 MU IFN‐α2b in CHC.     

Iron reduction before and during interferon therapy of chronic hepatitis C: results of a multicenter, randomized, controlled trial

Patients with chronic hepatitis C and low serum and hepatic iron stores may have an improved response to interferon (IFN). We tested whether iron reduction before and during IFN therapy would lead to an improved sustained biochemical and virological response compared with IFN alone. Eighty-two previously untreated patients with chronic hepatitis C were randomized to either: group A IFN-alpha2b 3 MU 3 times per week for 6 months, or group B iron reduction before and during IFN-alpha2b 3 MU 3 times per week for 6 months. Group B patients had lower mean serum alanine transaminase (ALT) levels than group A patients during treatment and follow-up. Group B patients had significantly lower mean hepatitis C virus (HCV)-RNA levels at treatment weeks 4 and 12 (P <.05). Serum HCV RNA was undetectable at the end of treatment in 15 group B patients compared with 7 group A patients (P =.03); 7 group B patients and 3 group A patients had persistently undetectable serum HCV RNA 24 weeks after the end of therapy (P =.20). Paired pre- and posttreatment liver biopsies in 18 group B patients demonstrated significant improvements in 2 of the 3 inflammation scores of the Knodell histological activity index (P <. 05). No changes occurred in the paired biopsies from 15 group A patients. We conclude that iron reduction via therapeutic phlebotomy improves the end-of-treatment virological and histological response to short-term IFN therapy. Additional studies are needed to determine if iron reduction in combination with higher doses or longer duration of IFN may be of benefit.     

Efficacy of prolonged 5 million units of interferon in combination with ribavirin for relapser patients with chronic hepatitis C

summary.  Retreatment of relapser patients with chronic hepatitis C with the standard dose of interferon (IFN) of 3 million units (MU) thrice weekly (tiw) plus ribavirin for 24 weeks achieves a sustained response in 30 and 73% of patients with genotype 1 and 2 or 3, respectively. The aim of this study was to evaluate the efficacy and safety of IFN α -2b induction therapy, followed by prolonged treatment with a high dose of IFN α -2b plus ribavirin in relapser patients. A total of 119 patients were randomized to receive IFN α -2b 5 MU daily (Group A: 59 patients) or IFN α -2b 5 MU tiw (Group B: 60 patients) for 4 weeks followed by IFN (5 MU tiw) and ribavirin (1000–1200 mg/day) for 48 weeks in both groups. The primary end point was hepatitis C virus (HCV)-RNA clearance at week 24 after the end of treatment. A sustained virological response (SVR) was achieved in 68 and 60% of Group A and B patients, respectively ( P  = 0.37). Logistic regression analysis identified genotype 2 or 3 as the only independent factor associated with response, whereas induction regimen and baseline viraemia levels did not affect the response. The overall SVR was 53 and 72% in patients with genotype 1 or 4 and 2 or 3, respectively. In conclusion, induction IFN therapy does not enhance the SVR to a 48-week combination therapy. Our study suggests that relapsed patients with genotype 1 or 4 may achieve significant response rates of approximately 50%, if retreated with 5 MU tiw IFN plus ribavirin for 48 weeks.     

Reinforced interferon alpha-2b and ribavirin is more effective than standard combination therapy in the retreatment of chronic hepatitis C previously nonresponsive to interferon: a randomized trial

Interferon-alpha (IFN) monotherapy results in sustained virological clearance in a minority of patients with chronic hepatitis C. The aim of this study was to assess the effect of a reinforced regimen combining ribavirin and high-dose IFN for 48 weeks compared with a nonreinforced regimen combining a standard IFN regimen and ribavirin for 24 weeks in nonresponders with chronic hepatitis C. A total of 231 patients with chronic hepatitis C and previous nonresponse to IFN monotherapy were randomized. The reinforced group (n = 114) received IFN-2b 6 million units (MU) thrice weekly (TIW) and ribavirin for 48 weeks, and the nonreinforced group (n = 117) received IFN-2b 3 MU TIW and ribavirin for 24 weeks. The main outcome measure was a sustained virological response, defined as negative serum hepatitis C virus (HCV)-RNA 24 weeks following the end of treatment. This endpoint was determined in 98 patients of the reinforced group and 105 patients of the nonreinforced group. At the end of follow-up, a sustained virological response was observed in 29 of the 98 patients (29.6%) in the reinforced group vs 16 of the 105 patients (15.2%) in the nonreinforced group (P = 0.014). In multivariate analysis, factors associated with a sustained virological response were treated with a reinforced regimen [odds ratio (OR) 2.9; P = 0.06] and genotype 2 or 3 (OR 8.8; P < 0.0002). A total of 160 patients had paired biopsies before and after treatment. Histological activity improvement was observed in 32 of 80 patients (40%) and fibrosis worsening in 26 of 80 patients (33%) in the reinforced group vs 13 of 80 (16%) and 19 of 80 (24%) in the nonreinforced group (P = 0.30 and 0.20, respectively). Hence in nonresponders, a high-dose 48-week regimen of IFN and ribavirin combination was more effective than a regimen with interferon at lower dose and ribavirin for 24 weeks only.     

Daily dose of interferon alpha-2b and ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection: a randomised controlled study

OBJECTIVE: The treatment of patients with hepatitis C virus (HCV) genotype 1 infection remains disappointing. METHODS: In 1999, we started a multicentre study comparing two regimens of recombinant interferon (IFN) alpha-2b plus ribavirin. Group A (90 patients) received ribavirin plus IFN alpha-2b 5 MU/day for 1 month (induction therapy) followed by IFN alpha-2b 5 MU thrice weekly for 5 months. Group B (85 patients) received ribavirin plus IFN alpha-2b 5 MU thrice weekly for 6 months. Responders in both arms received IFN alpha-2b 3 MU thrice weekly for a further 6 months. A follow-up evaluation was performed at 18 months. RESULTS: One hundred and seventy-five consecutive treatment-naive patients with HCV genotype 1 infection were enrolled in the study. A sustained virological response (SVR) was obtained in 51 (29%) patients: 28 in group A (31%) and 23 in group B (27%). HCV-RNA clearance was greater at 3 months among patients who received induction therapy (57 vs 39%; p < 0.02). Age, sex, and initial viral load did not influence the achievement of a SVR. HCV clearance at the end of the study was lower in cirrhotic patients (3/26 vs 48/149; p < 0.05). The only SVR in patients with cirrhosis occurred in those from group A (p < 0.05). Both regimens were well tolerated. CONCLUSIONS: This study confirms the low rate of SVR in treatment-naive patients with HCV genotype 1 infection treated with IFN alpha-2b plus ribavirin. A 4-week induction regimen was slightly superior to standard IFN alpha-2b plus ribavirin. Although the number of patients with cirrhosis was low, induction therapy seemed to be more effective in cirrhotics. Given its safety and tolerability, the induction regimen evaluated here may be a therapeutic option in treatment-naive patients with HCV genotype 1 infection.     

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.     

Daily or three times per week interferon alpha-2b in combination with ribavirin or interferon alone for the treatment of patients with chronic hepatitis C not responding to previous interferon alone

BACKGROUND/AIMS: We compared the efficacy and safety of the combined therapy of daily interferon alpha-2b and ribavirin with those of interferon alpha-2b three times per week alone or in combination with ribavirin in non-responder patients with hepatitis C virus (HCV) infection.METHODS: A total of 376 patients were randomly assigned to receive interferon alpha-2b (6 MU three times per week for 24 weeks followed by 3 MU three times per week for 24 weeks) alone (group A) or in combination with ribavirin for 48 weeks (group B), or daily interferon alpha-2b (3 MU per day for 24 weeks followed by 3 MU three times per week for 24 weeks) and ribavirin (group C).RESULTS: After 24 weeks of therapy, HCV RNA was undetectable in 11.7, 24.0, and 37.8% for groups A, B, and C, respectively. Sustained virological response was more frequent in patients who received combination therapy with three times weekly interferon (20.9%) or daily interferon (26.0%) than in patients who received interferon alone (5.8%) (P<0.001). The predictive HCV parameters for sustained response were a low viral load on day 7 and a negative HCV RNA on week 12.CONCLUSIONS: In conclusion, in non-responder patients with chronic hepatitis C, virological response with daily interferon and ribavirin, compared to interferon monotherapy, was significantly improved during treatment, although sustained virological response was similar for both combination therapies with ribavirin and three times a week or daily interferon.     

High Doses of α-Interferon Are Required in Chronic Hepatitis Due to Coinfection With Hepatitis B virus and hepatitis C virus: long term results of a prospective randomized trial

OBJECTIVE: Coinfection with hepatitis B (HBV) and hepatitis C (HCV) viruses is associated with a more severe liver disease, increased frequency in the development of hepatocellular carcinoma, and resistance to interferon (IFN) therapy when performed with the standard dosages used in single infections. In the attempt to verify whether the outcome of IFN therapy in patients with hepatitis B and hepatitis C coinfection can be improved, we have planned a prospective, randomized trial with medium to high dosages of interferon three times a week for 6 months.
METHODS: Thirty patients with HBV-HCV coinfection, and chronic hepatitis were randomized to receive either 6 or 9 MU α-interferon three times a week for 6 months. Patients were HBsAg positive, anti-HBe positive, HBV DNA negative by dot blot (6/30 positive by polymerase chain reaction), and anti-HCV-positive, HCV RNA positive. Pretreatment and posttreatment liver biopsies were performed.
RESULTS: Five patients treated with 9 MU IFN consistently cleared HCV RNA and HBV DNA, whereas none of those treated with 6 MU reacted in a similar fashion (   p = 0.045  ). Responders showed significant improvement of histological activity index in comparison with nonresponders (mean Ishak score pretreatment versus posttreatment   p = 0.002  ). Long term follow-up showed that none of the patients treated with high doses developed cirrhosis whereas 4/14 treated with low doses did develop cirrhosis.
CONCLUSION: Even though the percentage was not very high, the sustained response, the striking histological improvement, and the lack of development of cirrhosis achieved in these patients, indicate that with HBV-HCV coinfection, a trial with high doses of interferon is strongly recommended.     

High doses of interferon in combination with ribavirin are more effective than the standard regimen in patients with HCV genotype 1 chronic hepatitis

BACKGROUND/AIMS: The aim of the present, open-labelled, controlled study was to determine whether 5 MU of interferon (IFN) alpha 2b combined with a standard dose of ribavirin might increase the rate of viral clearance in all patients with chronic HCV hepatitis or at least in those with an unfavourable genotype. METHODS: A total of 298 previously untreated patients with chronic hepatitis C were randomized to 5 or 3 MU of interferon alpha 2b 3 times per week with 1000-1200 mg of ribavirin daily (148 and 150 patients, respectively). Patients were treated for 12 months and observed for 6 months posttreatment. RESULTS: In patients infected with HCV genotype 1, the sustained virologic response was 37.8% (95% CI 27.3-48.1) with IFN 5 MU and 19.2% (95% CI 10.1-28.2) with IFN 3 MU (P=0.008). Out of 45 sustained responders with genotype 1, 31 (69%) had received 5 MU and 14 (31.1%) the standard 3 MU dose of IFN in combination with ribavirin (P=0.01). Of the 86 responders infected with genotype non-1, 39 (45.3%) were from the 5 MU IFN group and 47 (54.6%) were from the 3 MU IFN group; these figures were not significant. At the multivariate analysis of baseline features for all patients, the variables with an independent effect for a sustained response were genotype non-1 (odds ratio (OR) 3.98, 95% CI 2.36-6.40), and the histological grading (score 0-2) (OR 2.48, 95% CI 1.12-5.51) and staging (score 0-1) (OR 1.73, 95% CI 1.02-2.95). For patients with genotype 1 only the high regimen of IFN entered the model (OR 2.39, 95% CI 1.13-5.05), whereas for patients with genotype non-1 an age of <40 years (OR 2.64, 95% CI 1.23-5.70) and staging (score 0-1) (OR 2.38, 95% CI 1.07-5.28) were independent predictors of a sustained response. CONCLUSIONS: Our study suggests that when treating naive patients with genotype 1, there is a significant increase in the rate of sustained virologic clearance by increasing the dose of IFN given in combination with ribavirin.     

Firstline treatment for hepatitis C: combination interferon/ribavirin versus interferon monotherapy

In the initial treatment of chronic hepatitis C, interferon‐alfa (IFN‐α) monotherapy for 24–48 weeks induces sustained response rates of only 10–20%. Combination therapy with IFN‐α plus ribavirin induces a sustained response in 40–50% of patients, and can be now recommended as the firstline therapy for chronic hepatitis C. Stopping therapy at week 12 because of persistent viraemia is unnecessary with the combination therapy because later clearance of HCV RNA can still occur with a sustained response. Patients with HCV genotype 1 should receive 48 weeks of combination therapy, in contrast to 24 weeks for patients with genotypes 2 or 3. For patients who cannot tolerate the side effects of ribavirin, such as anaemia, IFN‐α at 3 MU three times weekly for 48 weeks is preferred as the initial therapy. The long‐acting pegylated IFN can be expected to enhance the efficacy of combination therapy in the treatment of chronic hepatitis C and appears to be much more potent as monotherapy. Further studies are needed to improve the current ‘half‐full’ status of chronic hepatitis C treatment.