Pegylated interferons: What role will they play in the treatment of chronic hepatitis C?

The primary therapy for patients with chronic hepatitis C virus (HCV) infection is interferon. Unfortunately, standard interferon, because of its very short half-life and side-effect profile, has limited efficacy in most patients with this disease. Pegylated interferons are produced by attaching the inert polymer, polyethylene glycol, to the standard interferon alpha protein. This process enhances the biological activity of interferon, primarily by prolonging the half-life, when compared with the native protein. To date, two types of pegylated interferon alpha have been developed. Both of these products have been shown to be superior to standard interferon, at both eradicating HCV RNA during therapy and at achieving a sustained virologic response. When combined with ribavirin, treatment with pegylated interferon can achieve sustained virologic response in approximately 42% of patients infected with HCV genotype 1 and 80% of patients with HCV genotypes 2 or 3.     

Treatment of chronic hepatitis C virus in African Americans with genotypes 2 and 3

Previous studies have documented that sustained virologic response (SVR) is significantly reduced in African Americans with chronic HCV genotype 1 following treatment with interferon and ribavirin when compared with Caucasians. The specific aim of the present retrospective study was to assess virologic response to interferon and ribavirin in African Americans with HCV genotypes 2 and 3. A review of our database identified 42 African Americans and 334 Caucasians with HCV genotypes 2 and 3. Patients coinfected with hepatitis B or human immunodeficiency virus, chronic renal failure, and recipients of an organ transplant were excluded. Thirty of the African Americans were treated with either standard interferon or peginterferon and ribavirin as initial treatment for chronic HCV. Ninety of the 334 Caucasians were matched to the African Americans with regards to genotype, cirrhosis, treatment regimen, sex, age, and body weight for comparison of virologic response. The proportion of patients with HCV genotype 2 was significantly greater (P < 0.001) in African Americans compared with Caucasians (81%vs 52%). End-of-treatment virologic response was observed in 94% of Caucasians compared with 80% in African Americans (P= 0.036). SVR was observed in 82% and 57% of Caucasians and African Americans, respectively (P= 0.012). Similar results were observed when patients who had been treated with only peginterferon and ribavirin were assessed. These results suggest that African Americans have a global defect in their ability to eradicate HCV infection following treatment with interferon and ribavirin which transcends across all genotypes.     

A randomized, controlled trial to determine whether continued ribavirin monotherapy in hepatitis C virus-infected patients who responded to interferon-ribavirin combination therapy will enhance sustained virologic response

This study assessed the use of ribavirin monotherapy to enhance sustained virologic response in hepatitis C virus (HCV)-infected patients who achieved virologic response to interferon (IFN)-ribavirin combination therapy. Patients who had chronic HCV infection and prior relapse were retreated with IFN-ribavirin for 6 months. Patients with an end-of-treatment virologic response were assigned randomly to either stop use of both IFN and ribavirin or to continue use of ribavirin as monotherapy for an additional 6 months. HCV RNA became undetectable during treatment in 46 patients, who then entered the randomized trial. Sustained virologic response was observed in 13 of 26 patients who continued ribavirin monotherapy and in 15 of 20 patients who stopped use of both IFN and ribavirin (P, not significant). Sustained virologic response was significantly more common in patients with HCV genotype non-1 (75% vs. 56%) and in patients with a virus titer < 2 x 10(6) copies/mL (93% vs. 43%). The results indicate that continuing ribavirin monotherapy after achieving a virologic response does not improve sustained virologic response.     

Treatment predictors of a sustained virologic response in hepatitis B and C

Treatment predictors are important tools for the management of therapy in patients with chronic hepatitis B and C virus (HBV, HCV) infection. In chronic hepatitis B, several pretreatment parameters have been identified for prediction of virologic response to interferon alfa-based antiviral therapies or treatment with polymerase inhibitors. In interferon alfa and pegylated interferon alfa-treated patients, low baseline HBV DNA concentrations, HBV genotype A (B), and high baseline ALT levels are significantly associated with treatment response. In patients treated with nucleos(t)ide analogues, low baseline HBV DNA but not viral genotype is positively associated with virologic response. During treatment the best predictor of response is HBV DNA kinetics. Early viral suppression is associated with favourable virologic response and reduced risk for subsequent resistance mutations. For the current standard treatment with pegylated interferon alfa and ribavirin in patients with chronic hepatitis C, infection with HCV genotypes 2 and 3, baseline viral load below 400,000-800,000IU/ml, Asian and Caucasian ethnicity, younger age, low GGT levels, absence of advanced fibrosis/cirrhosis, and absence of steatosis in the liver have been identified as independent pretreatment predictors of a sustained virologic response. After initiation of treatment, initial viral decline with undetectable HCV-RNA at week 4 of therapy (RVR) is the best predictor of sustained virologic response independent of HCV genotype.     

Customizing treatment to patient populations

Combination treatment with pegylated interferon plus ribavirin is the most effective therapy for patients with chronic hepatitis C virus (HCV); however, responses are less than optimal in some subpopulations of patients. Emerging insights are suggesting that viral kinetics can be used to predict response. The rapidity of response has been shown to be a more important predictor of sustained virologic response than the duration of therapy. In patients with HCV genotype 2 or 3, shorter durations of treatment might be sufficient in rapid responders and could minimize the risk of toxic effects. Weight-based dosing of ribavirin has emerged as another important consideration. This strategy seems to be most important for difficult-to-treat patients with HCV genotype 1 or advanced fibrosis, and for African-Americans, and is possibly important for patients who have genotype 3 and a high viral load. Re-treatment of nonresponders with interferon-based therapy has been associated with low rates of sustained virologic response. Consensus interferon might offer a new option for patients who do not achieve an early treatment response to standard or pegylated interferon plus ribavirin.     

Treatment of HCV infection with pegylated interferons

The past decade has seen advances in the treatment of chronic hepatitis C infection. Therapy with interferon alpha was disappointing, with only 15% of patients achieving longterm viral clearance. Combination therapy with interferon alpha and ribavirin therapy more than doubled sustained virologic response (SVR) rates. The pegylated interferons are a recent development that have improved the outlook for patients with chronic hepatitis C virus (HCV). Pegylated interferons are produced by the binding of polyethylene glycol to interferon alpha, which results in a compound with improved pharmacokinetic properties with increased efficacy. Combination therapy with pegylated interferon alpha and ribavirin is the optimal treatment for chronic HCV infection. Up to 80% of patients with genotype 2/3 infection and up to 50% of patients with genotype 1 infection achieve SVR with treatment. For the first time, the majority of patients with chronic HCV who are treated can anticipate a long-term cure.     

丙型肝炎的致病机制及药物治疗

丙型肝炎（丙肝）病毒（hepatitis C virus,HCV）可以通过几种途径影响宿主免疫功能,使病毒在宿主细胞内持续复制,最终导致HCV慢性感染。目前治疗慢性丙肝的方法主要是聚乙二醇干扰素和利巴韦林联合用法,此种疗法在HCV1型患者中约50％不能产生持续病毒学应答,且有不良反应。近年来,随着对HCV复制以及病毒非结构蛋白功能的深入研究,针对减少HCV载量的特异性药物的研发取得了较大进展。本文就HCV的细胞人侵、复制、逃避宿主的固有和获得性免疫及抗HCV临床试验药物的最新进展进行综述。     

Treatment of hepatitis C virus genotype 4-related cirrhosis: ribavirin and interferon combination compared with interferon alone

BACKGROUND: Response to treatment with interferon alfa, with or without concomitant ribavirin, varies with the viral genotype and the degree of fibrosis in patients with chronic hepatitis C virus (HCV). GOALS: To determine the response of HCV type 4-related cirrhosis to interferon and ribavirin combination treatment compared with interferon alone. STUDY: Patients living in Kuwait were assigned to take either interferon alone at a dosage of 5 million units thrice weekly (26 patients) or interferon 5 million units thrice weekly combined with ribavirin 1,000 mg/d (21 patients) for 24 weeks. Biochemical response was defined as normal alanine aminotransferase (ALT) at end of therapy. Sustained biochemical response was defined as normal ALT 6 months after the end of therapy. Sustained virologic response was defined as negative serum HCV RNA 6 months after the end of therapy. RESULTS: Only 2 (8%) of 26 patients showed biochemical response after interferon alone, whereas 11 (52%) of 21 showed biochemical response after interferon combined with ribavirin (p < 0.01). Only 2 (8%) of 26 patients showed sustained biochemical response after interferon alone, whereas 5 (23%) of 21 showed sustained biochemical response after interferon combined with ribavirin (not significant, p > 0.1). None of the 26 patients showed virologic response after interferon alone, whereas 3 (14%) of 21 showed sustained virologic response after interferon combined with ribavirin (not significant, p > 0.1). CONCLUSION: These results suggest that patients with cirrhosis caused by HCV type 4 show no response to interferon alone and only slightly better response to 24 weeks of interferon combined with ribavirin.     

Therapie der Hepatitis C

The standard treatment for patients with chronic hepatitis C (HCV) is a combination therapy with pegylated interferon and ribavirin. Patients infected with HCV genotype 1 are treated for 48 weeks, and patients infected with HCV genotype 2 or 3 for 24 weeks. Using the HCV genotype together with a baseline viremia and the initial virologic response to therapy enables further individualization of treatment duration. Viramidine could become an alternative to ribavirin with a reduction of ribavirin induced anemia. Many new drugs are currently under investigation in preclinical and clinical studies. The first results of phase I/II studies with specific HCV protease and polymerase inhibitors are promising.     

An urgency to identify and treat chronic hepatitis C

The human and monetary costs of chronic hepatitis C and the complications arising from this disease, including hepatocellular carcinoma and liver transplantation, emphasize the increased urgency to treat hepatitis C virus (HCV)-infected patients earlier in the course of their disease. The current standard of treatment for patients chronically infected with HCV is combination therapy with pegylated interferon plus ribavirin. Among undertreated groups of patients are those with persistently normal alanine aminotransferase levels, those coinfected with human immunodeficiency virus and HCV, and nonresponders to previous treatment with standard interferon. This review summarizes the rationale for earlier treatment of chronic HCV infection, as well as evidence showing that patients who do not achieve a virologic response on treatment may derive benefit from treatment, including improved histologic characteristics and delayed progression of disease.     

Approach to the patient with chronic hepatitis C virus infection

Chronic hepatitis C virus (HCV) infection is common and often asymptomatic. Antibodies against HCV are a highly sensitive marker of infection. Molecular testing for HCV is used to confirm a positive result on antibody testing and to provide prognostic information for treatment; however, quantitative HCV RNA does not correlate with disease severity or risk for progression. Chronic HCV infection is most frequently associated with remote or current intravenous drug use and blood transfusion before 1992, although as many as 20% of infected patients have no identifiable risk factor. In an estimated 15% to 20% of persons infected with HCV, the infection progresses to cirrhosis; alcohol intake is an important cofactor in this progression. Most specialists prefer to include an examination of liver histology in the management of patients with chronic HCV infection to aid prognostic and treatment decisions. The current standard of pharmacologic treatment of chronic HCV is weekly subcutaneous peginterferon in combination with daily oral ribavirin, which results in sustained virologic response in approximately 55% of chronically infected patients. Side effects of interferon therapy include myalgias, fever, nausea, irritability, and depression. The cost-effectiveness of interferon therapy is similar to that of many commonly accepted medical interventions. The primary care physician serves a vital role in identifying patients with chronic HCV infection, educating patients about risk factors for transmission, advising patients about the avoidance of alcohol, and aiding patients in making treatment decisions.     

Daily or three times a week interferon alfa-2b in combination with ribavirin or interferon alone for the treatment of patients with chronic hepatitis C

BACKGROUND/AIMS: Data on hepatitis C virus (HCV) viral dynamics and on the effect of interferon in blocking virion production have suggested a rationale for daily administration of interferon in patients with chronic hepatitis C infection. We compared the efficacy and safety of daily interferon alfa-2b in combination with ribavirin with those of interferon alfa-2b three times a week alone or in combination with ribavirin. METHODS: We randomly assigned 321 patients with chronic hepatitis C to receive standard-dose interferon alfa-2b alone or in combination with ribavirin for 48 weeks or daily interferon alfa-2b (3 million units per day for 12 weeks then 3 million units three times per week for 24 weeks) and ribavirin (36 week treatment). RESULTS: The rate of sustained virologic response (defined as an undetectable serum HCV-RNA level 72 weeks after initiation of treatment) was higher in patients who received combination therapy with three times weekly interferon (51.7%) or daily interferon (46.1%) than in patients who received interferon alone (25%) (P=0.0001 and P=0.002, respectively). Independent predictive factors for sustained virologic response were combination therapy, weight, genotype and viral load. In conclusion, in patients with chronic hepatitis C, combination therapy with induction treatment (daily interferon for 12 weeks) and shorter duration of treatment was not different from combination therapy for 48 weeks without induction treatment. CONCLUSIONS: Induction treatment with interferon for 12 weeks and combination therapy for a total duration of 36 weeks could therefore be cost effective.     

Reversible alopecia universalis secondary to PEG-interferon alpha-2b and ribavirin combination therapy in a patient with chronic hepatitis C virus infection

Combined treatment with pegylated interferon (PEG-IFN) and ribavirin is currently recommended for the treatment of chronic hepatitis C virus (HCV) infection. Many side effects including hair disorders have, however, been reported related to this treatment. Alopecia universalis is a severe form of hair disorder. Three cases of alopecia universalis during PEG-IFN and ribavirin combination therapy have been reported in the literature. Herein is reported a case of reversible alopecia universalis, with complete hair loss extending to the whole body, secondary to PEG-IFN alpha-2b and ribavirin combination therapy for chronic HCV infection. Hair regrowth began within 3 months of the completion of combined therapy. In case the liver disease is advanced, and virologic response occurs, treatment can still be completed, as it appears that these side effects are reversible.     

Maintenance therapy for chronic hepatitis C

Major progress has been made in the treatment of chronic hepatitis C virus (HCV) infection over the 18 years since Hoofnagle et al. initially documented response of non-A non-B hepatitis to interferon alfa. Current optimal therapy with pegylated interferon alfa (PEG-IFN) and ribavirin results in sustained virologic response rates of just over 50%. With an estimated 2.7 million Americans with active HCV infection, we can anticipate a large number of potential treatment failures with the current standard of care. At this time, no therapy is approved by the US Food and Drug Administration for treatment failures of PEG-IFN and ribavirin. Maintenance interferon therapy with the goal of prevention of disease progression rather than viral eradication appears to offer an option for HCV treatment failures with advanced disease. Alternative medical strategies to reduce hepatic fibrosis are also under investigation. With the relatively static number of available organs for transplantation, prevention of disease progression and decompensation is essential for an impact to be made upon the predicted rates of HCV morbidity and mortality in the next 10 to 20 years.     

Effect of ribavirin in genotype 1 patients with hepatitis C responding to pegylated interferon alfa-2a plus ribavirin

BACKGROUND & AIMS: Pegylated interferon alfa-ribavirin combination is the standard treatment for chronic hepatitis C, but the mechanisms by which ribavirin enhances the rate of sustained hepatitis C virus (HCV) eradication remain unknown. We aimed to investigate the role of ribavirin in HCV clearance during therapy and to evaluate the consequences of ribavirin discontinuation in patients infected with genotype 1 hepatitis C who cleared HCV RNA at week 24. METHODS: A total of 516 patients were treated with pegylated interferon alfa-2a, 180 microg/wk, plus ribavirin, 800 mg/day. Seventy percent were RNA negative at week 24. They were randomized to continue with the combination or receive pegylated interferon alone. RESULTS: Responders at week 24 who stopped ribavirin had a significantly higher rate of breakthroughs during, and relapses after, therapy (sustained virologic response, 52.8% vs 68.2%; P = .004), but their side-effect profile and quality of life tended to improve. Multiple logistic regression analysis in the pegylated interferon alfa monotherapy group allowed identification of responders at week 24 who could stop ribavirin without losing their chance of a sustained virologic response, based on baseline viral load and age. Forty-eight weeks of ribavirin may not be needed when HCV RNA is undetectable at week 2. CONCLUSIONS: We made 3 conclusions from this study. First, ribavirin primarily acts by sustaining the virologic response to pegylated interferon alfa; second, ribavirin must be administered for the full treatment duration in most genotype 1-infected patients who respond; third, baseline parameters may help identify patients who could discontinue ribavirin or reduce the dose without losing their chance of success.     

HCV in patients with end-stage renal disease

Chronic hepatitis C virus (HCV) infection remains an important cause of liver disease in patients with end-stage renal disease (ESRD) and conversely, renal failure has a significant impact on morbidity and mortality throughout the natural history of chronic HCV and its treatment. With improved awareness within dialysis units of the potential for spread and the institution of preventative measures, the prevalence of HCV infection in the hemodialysis-dependent population has continued to decline since 1995. Use of HCV (+) donor kidneys is associated with an increase in the prevalence of liver disease, but when compared with continued hemodialysis, transplantation using these kidneys is associated with improved survival. Overall, survival in patients with chronic HCV infection appears to be better after renal transplantation when compared with maintenance hemodialysis, and transplant should be considered for these patients. Data support the use of interferon and the improved efficacy of pegylated interferon formulations for treatment of chronic HCV infection in ESRD patients, although tolerability continues to be troublesome. The newest and most promising data regarding the treatment of HCV in ESRD involve the combination of reduced dose ribavirin with interferon or pegylated interferon suggesting similar enhancements in sustained virologic response (SVR) as seen in non-ESRD patients, but caution is advised, as all studies to date used ribavirin plasma concentration monitoring in patient with ESRD. Finally, with regard to postrenal transplant treatment of HCV infection, there is no evidence to support treatment with interferon-based therapy and pretransplant treatment remains the best option whenever possible.     

Pegylated interferons: What role will they play in the treatment of chronic hepatitis c?

The primary therapy for patients with chronic hepatitis C virus (HCV) infection is interferon alfa. However, use of interferon for treatment of chronic HCV has several shortcomings that limit its effectiveness. Interferon has a very short half-life, must be administered multiple times weekly, and is associated with significant side effects. "PEGylation" is a process whereby the inert polymer, polyethylene glycol (PEG), is attached to a protein pharmaceutical. This process has been shown to alter the properties of PEGylated proteins in a manner that significantly extends half-life, reduces immunogenicity, and enhances biologic activity when compared with the native protein. In recent years, several PEGylated forms of interferon alfa have been developed. Recent studies have demonstrated that PEG-interferons have a significantly prolonged half-life and sustained virologic response when compared with standard interferon. Studies to evaluate the effects of combining PEG-interferons with ribavirin are currently underway. The role PEG-interferons will play in patients who have either relapsed or failed to respond to previous interferon or interferon/ribavirin therapy remains to be defined.     

Improved response to ribavirin interferon combination compared with interferon alone in patients with type 4 chronic hepatitis C without cirrhosis

Response to treatment with alpha interferon with or without concomitant ribavirin varies according to the viral genotype in patients with chronic hepatitis C. AIM: This study was undertaken in order to determine the response of genotype 4 chronic hepatitis C to interferon and ribavirin combination compared to interferon alone in patients without cirrhosis. METHODS: Fifty-two patients were given interferon alone at a dose of 5 million units, 3 times a week and another 60 patients were administered with interferon combined with ribavarin (1,000-1,200 mg/ day) for 24 weeks. Sustained biochemical response was defined as normal ALT, 6 months after end of therapy. Sustained virologic response was defined as negative HCV RNA, 6 months after the end of therapy. RESULTS: Only 10/52 (19%) patients showed sustained biochemical response after interferon alone, while 31/60 (52%) showed sustained biochemical response after interferon combined with ribavirin (p<0.01). Only 4/52 (8%) patients showed sustained virologic response after interferon alone, while 25/60 (42%) showed sustained virologic response after interferon combined with ribavirin (p<0.001). CONCLUSION: These results show that patients with chronic hepatitis due to hepatitis C virus type 4 show a poor response to interferon alone but a better response to interferon combined with ribavirin.     

Efficacy and safety of chronic hepatitis C treatment in hemophilic patients

BACKGROUND/AIMS: Chronic hepatitis C infection is very common among hemophiliacs in the developed World. METHODOLOGY: Retrospective evaluation of the treatment results in hemophiliacs with chronic hepatitis C, all infected with genotype 1b. Twelve patients were treated with interferon-alpha monotherapy, 21 patients with interferon-alpha and ribavirin, and 3 patients with pegylated interferon and ribavirin, all for 48 weeks. RESULTS: Sustained virologic response (defined as an undetectable serum HCV RNA level 24 weeks after treatment was completed) was not achieved in any of 12 patients treated with interferon-alpha alone. Combination therapy with interferon-alpha and ribavirin was associated with better results: 4/10 (40%) patients still untreated with interferon-alpha, 2/4 (50%) relapsers, and 2/7 (29%) non-responders to previous interferon-alpha monotherapy achieved sustained virologic responses. Combination therapy with pegylated interferon and ribavirin has been used in 3 patients. Sustained response was achieved in one patient who had relapsed after treatment with interferon-alpha and ribavirin and in 1 of 2 non-responders to this combination therapy. There were no serious adverse events and it was not necessary to reduce dosages or even cease therapy prematurely. CONCLUSIONS: The efficacy and tolerability of antiviral treatment in hemophiliacs did not differ from other patients with chronic hepatitis C.     

Peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C in Saudi patients commonly infected with genotype 4.

AIM: Comparing the efficacy of peginterferon alpha-2b plus ribavirin with interferon alpha -2b plus ribavirin in Saudi patients with chronic hepatitis C virus (HCV) commonly infected with genotype 4. METHODS: A total of 96 patients with chronic HCV infection were randomly assigned to two treatment groups. Forty-eight patients received once weekly 100 microg of peginterferon alpha-2b plus ribavirin given orally 800 mg/day (peginterferon group). Another 48 patients received thrice weekly 3 million units of interferon alpha-2b plus ribavirin 800 mg/day (interferon group). At the end of treatment (48 weeks) and sustained (72 weeks) biochemical and virologic responses were determined. RESULTS: In the peginterferon group, 70.8% (34/48) patients attained both biochemical and virologic responses at the end of the treatment as against 52.1% (25/48) patients in the interferon group. (P=0.09 for both). Similarly, sustained biochemical and virologic responses in the peginterferon group were attained in 52.1% (25/48) and 43.8% (21/48) patients as against 43.8% (21/48) and 29.2% (14/48) patients in the interferon group, respectively (P=0.54 and 0.20, respectively). The sustained virologic response rates in patients with genotype 4 were 42.9% (12/28) in the peginterferon group and 32.3% (10/31) in the interferon group (P=0.43). Patients in peginterferon group had higher, although statistically not significant adverse reactions. CONCLUSIONS: Saudi patients with chronic HCV attained a higher, although statistically not significant sustained virologic response with pegylated interferon plus ribavirin compared with interferon plus ribavirin.