Utility of hepatitis C virus serotypes in predicting response to treatment of chronic hepatitis C. Consensus Interferon Study Group

Hepatitis C virus (HCV) genotyping has been shown to predict response to interferon, but is expensive. HCV serotyping is less expensive and simpler, and may be similarly useful. Using data from a large, randomized trial comparing consensus interferon (CIFN) and interferon alfa-2b (IFN alfa-2b) in patients with chronic HCV, we evaluated response rates based on HCV serotypes versus genotypes. Patients included in this analysis received subcutaneous injection of 9 microg CIFN (n = 232) or 3 MU IFN alfa-2b (n = 240) three times weekly for 24 weeks followed by 24 weeks of observation. Serum HCV RNA concentrations were measured regularly during treatment and at the end of both the treatment and post-treatment periods. Response to interferon was similar for HCV antibody types and their corresponding genotypes. The end-of-treatment HCV RNA rate of response (defined as undetectable serum on two consecutive assessments) was 29% for serotype 1 versus 24% for genotype 1 after CIFN; and 14% versus 15%, respectively, after IFN alfa-2b. Independently of treatment, patients infected with serotype or genotype 2 or 3 had a better therapeutic response than those infected with serotype or genotype 1. Similar results were obtained based on HCV antibody typing and genotyping, suggesting the potential of the former for predicting response to interferon.     

Viral dynamics and pharmacokinetics in combined interferon alfa-2b and ribavirin therapy for patients infected with hepatitis C virus of genotype 1b and high pretreatment viral load

OBJECTIVE: The aim of this study was to clarify the viral dynamics and single- and multiple-dose pharmacokinetics of ribavirin and interferon (IFN) alfa-2b in the virologic response to combination therapy with both compounds in patients infected with hepatitis C virus (HCV) genotype 1b and high viral load. METHODS: Fourteen patients received high-dose daily induction therapy followed by intermittent maintenance therapy with IFN alfa-2b and daily oral ribavirin for 24 weeks, and followed up for 24 weeks after treatment. Single- and multiple-dose pharmacokinetic studies and viral dynamics were assessed by serial measurements of serum concentrations of both compounds and HCV RNA, respectively, at weeks 1 and 24. RESULTS: During treatment, all 14 patients showed biochemical response (i.e., normalization of serum alanine transaminase activity), while 11 showed virologic response (i.e., undetectable serum HCV RNA level by qualitative polymerase chain reaction assay). Sustained biochemical and virologic response after cessation of treatment was noted in 8 and 2 patients, respectively. Serum ribavirin concentrations asymptoted by 4 weeks of treatment. Serum ribavirin concentrations in steady state, and maximum concentration and accumulation rate of ribavirin after multiple dosing were significantly higher in the presence of sustained virologic response. HCV-related parameters were not significantly associated with sustained virologic response. CONCLUSIONS: Continuous exposure and tissue accumulation of ribavirin may be necessary for sustained virologic response to combination therapy in chronic hepatitis C with genotype 1b and high viral load. Pharmacokinetic analysis of ribavirin provides information on its mechanism of action and for developing more rational treatment for IFN-resistant HCV.     

Dose-dependent and genotype-independent sustained virological response of a 12 week pegylated interferon alpha-2b treatment for acute hepatitis C

OBJECTIVES: The optimal regimen for acute hepatitis C (AHC) is considered to be a 24 week treatment with interferon (IFN) alpha-2b. A 24 week treatment with pegylated IFN (PEG-IFN) alpha-2b is also effective. This study was designed to assess response rates to a 12 week regimen of PEG-IFN alpha-2b. PATIENTS AND METHODS: Patients with AHC were treated with PEG-IFN alpha-2b for 12 weeks in an open, non-randomized, prospective cohort study. Diagnosis of AHC was made with positive serum HCV RNA and elevated alanine aminotransferase (ALT) levels with a documented seroconversion or a known risk factor in the preceding 6 months. Treatment was administered within a median of 31 days (range 0-116) of the ALT level peak at a dosage varying from 1.06 to 1.66 microg/kg/week. The primary end-point was a sustained virological response (SVR). RESULTS: Nineteen patients were treated, of whom 11 patients (57.9%) had HCV genotype 1. Fourteen patients were asymptomatic. An SVR was achieved in 74% of patients and the SVR rate was 100 and 83.3%, respectively, in genotype 1 and non-1 infected patients treated with a dosage>or=1.33 microg/kg, compared with 40 and 50%, respectively, in those who received a lower dosage. An SVR was significantly associated by multivariate analysis only with PEG-IFN dosage>or=1.33 microg/kg/week. No significant association was found with any viral genotype. CONCLUSIONS: The rate of SVR was independent of the HCV genotype and was significantly associated by multivariate analysis only with the higher PEG-IFN dosage. Early identification and treatment of AHC is likely to decrease the burden of chronic hepatitis, especially when caused by HCV genotype 1.     

Anticarcinogenic impact of interferon on patients with chronic hepatitis C: a large-scale long-term study in a single center

BACKGROUND: The anticarcinogenic capacity of interferon (IFN) was assessed in a cohort of Japanese patients with chronic hepatitis C en masse. PATIENTS AND METHODS: The rate of hepatocarcinogenesis was analyzed in 2,166 patients with chronic hepatitis C, of whom 1,654 had received IFN therapy while 512 had not. RESULTS: Crude rates of hepatocarcinogenesis in treated and untreated patients were 2.6 and 4.6% at the end of the 5th year, 5.8 and 12.7% at the 10th year and 13.9 and 23.9% at the 15th year (after completion of IFN therapy for those treated) (p < 0.001). IFN decreased the hazard ratio of carcinogenesis to 0.42 (p < 0.001) in multivariate analysis with adjustments for significant covariates including fibrotic stage, gamma-glutamyl transpeptidase level, gender, platelet count and age. Among the 1,654 patients treated with IFN, 606 (36.6%) achieved persistent loss of hepatitis C virus (HCV) RNA and an additional 266 (16.1%) gained normal levels of alanine aminotransferase without loss of HCV RNA for 6 months or longer after the completion of IFN therapy. Cumulative rates of hepatocarcinogenesis in sustained virological responders and biochemical responders were 1.4 and 2.0% at the end of the 5th year, 1.9 and 3.6% at the 10th year and 1.9 and 7.5% at the 15th year, respectively. The hazard ratio of sustained virological response was 0.10 (p < 0.001), and that of biochemical response was 0.12 (p < 0.001). Normalization of aminotransferase levels after IFN therapy without loss of serum HCV RNA decreased hepatocarcinogenesis. CONCLUSION: IFN significantly decreased the rate of hepatocarcinogenesis in patients with chronic hepatitis C as a whole in Japan, even in those who fail to clear HCV RNA from serum.     

High sustained virologic response rate after interferon monotherapy in Japanese hepatitis C patients with a low HCV RNA titer and/or HCV genotype 2. A prospective study

OBJECTIVE: Hepatitis C virus (HCV) RNA titer and HCV genotype are considered to be major determinants of the outcome of interferon monotherapy. To clarify whether interferon monotherapy is really effective in patients with the appropriate viral parameters, we prospectively examined these parameters and treated the patients with interferon monotherapy. METHODS: Sixty-four patients with an HCV RNA titer <100 kIU/ml and/or HCV genotype 2 were enrolled in the study. Eighteen patients with an HCV RNA titer >100 kIU/ml and genotype 1 were also enrolled as controls. All patients were treated with 10 megaunits of interferon-alpha2b every day for 2 weeks and then 3 times a week for 24 weeks. RESULTS: Of the 64 patients with either HCV RNA <100 kIU/ml and/or genotype 2, seven dropped out from the study. Of the remaining 57 who completed the treatment, 48 (84%) showed a virologic sustained response. In contrast, only 4 of the 18 patients (22%) with HCV RNA >100 kIU/ml and genotype 1 were virologic sustained responders (p < 0.001). CONCLUSION: Our current study showed that the patients with HCV RNA <100 kIU/ml and/or HCV genotype 2 are good candidates for interferon monotherapy.     

Novel alpha interferon (IFN-alpha) variant with improved inhibitory activity against hepatitis C virus genotype 1 replication compared to IFN-alpha2b therapy in a subgenomic replicon system

Hepatitis C virus (HCV) treatment is based on the association of pegylated alpha interferon (IFN-α) and ribavirin. To improve the level of sustained virological response to treatment, especially in patients infected with HCV genotype 1, new IFNs with improved efficacy and toxicity profiles may be developed. In this report, we show that, in the BM4-5 cell line harboring an HCV subgenomic replicon, a novel and naturally occurring human IFN-α17 variant, GEA007.1, which was discovered by using an original population genetics-based drug discovery approach, inhibits HCV genotype 1 RNA replication more efficiently than does IFN-α2b. Moreover, we show that complete viral clearance is obtained in BM4-5 cells after long-term treatment with GEA007.1, while HCV subgenomic RNA is still detected in cells treated with other IFN-α variants or with standard IFN-α2b. Eventually, we demonstrate that the better inhibitory activity of GEA007.1 compared to that of standard IFN-α is likely to be due to stronger and faster activation of the JAK-STAT signaling pathway and to broader expression of IFN-α-responsive genes in cells. Our results demonstrate a superior inhibitory activity of GEA007.1 over that of IFN-α2b in the HCV replicon system. Clinical trials are required to determine whether GEA007.1 could be a potent “next generation” IFN for the treatment of HCV infection, especially in nonresponders or relapsing patients infected with HCV genotype 1 who currently represent a clinical unmet need.     

Overview of the PROVE studies evaluating the use of telaprevir in chronic hepatitis C genotype 1 patients

Current treatment for genotype 1 HCV infection with pegylated interferon (PEG IFN) and ribavirin (RBV) is effective in less than 50% of patients. The advent of direct-acting antiviral agents that target replication of HCV promises to improve therapy for the disease. Telaprevir is a new peptidomimetic serine protease inhibitor that specifically targets the NS3/4a HCV serine protease to cause rapid reduction in HCV RNA levels. Three Phase II Protease Inhibition for Viral Evaluation (PROVE) studies have assessed the efficacy and safety of telaprevir in genotype 1 patients. The studies examined sustained virological response (SVR) rates and also the adverse events related to the use of this drug in different groups. The results of these studies suggested that the addition of this specific protease inhibitor to PEG IFN alfa-2a and RBV can significantly improve the results of treatment in patients affected with chronic HCV infection with genotype 1, when compared with the standard treatment, PEG IFN alfa-2a and RBV alone. The key observations in these Phase II trials of telaprevir were higher rate of SVR above current standard of care (61-69% for T12PR24 treatment-naive patients compared with 46-48% for standard of care in naive patients). Low rates of relapse were observed in T12PR24-treated patients (2-14% vs 22-23%). The studies suggest that the duration of treatment could be reduced for rapidly responsive naive patients from 48 to 24 weeks while maintaining improved SVR rates. RBV remains an essential component of treatment with protease inhibitors combined with PEG IFN. The main adverse reactions of note with its use were rashes, anemia and nausea.     

Pegylated interferons for the treatment of chronic hepatitis C infection

BACKGROUND: Interferon (IFN) alfa is a clinically effective therapy used in a wide range of viral infections and cell-proliferative disorders. Combination therapy with IFN alfa-2b and ribavirin is the current standard of care for the treatment of chronic hepatitis C (CHC) infection. However, standard IFN alfa has the drawbacks of a short serum half-life and rapid clearance. To overcome this problem, 2 pegylated forms of IFN have been developed and tested clinically. OBJECTIVE: This article reviews the development and properties of pegylated IFN alfa-2b and pegylated IFN alfa-2a, and presents safety and efficacy data from recent clinical trials. METHODS: Relevant clinical studies were identified through a MEDLINE search from 1966 through the present using the key words hepatitis C and interferon. Studies of the pegylated IFNs in humans were then selected. RESULTS: Pegylated IFN alfa-2b is formed by covalent conjugation of a 12-kd mono-methoxy polyethylene glycol (PEG) molecule to IFN alfa-2b, and pegylated IFN alfa-2a by covalent conjugation of a 40-kd branched mono-methoxy PEG molecule to IFN alfa-2a. The 2 pegylated IFNs differ in the mixture of pegylation isomers resulting from their conjugation chemistry. Pegylated IFN alfa-2b has a prolonged serum half-life (40 hours) relative to standard IFN alfa-2b (7-9 hours). The greater polymer size of pegylated IFN alfa-2a acts to reduce glomerular filtration, markedly prolonging its serum half-life (72-96 hours) compared with standard IFN alfa-2a (6-9 hours). In clinical studies, once-weekly dosing of the pegylated IFNs was associated with a sustained virologic response in patients infected with hepatitis C virus (HCV). Once-weekly dosing with either of the pegylated IFNs was more effective than the respective thrice-weekly regimen of IFN alfa, with a comparable safety profile. The combination of once-weekly pegylated IFN and ribavirin effectively reduced HCV viral load and sustained viral suppression. CONCLUSIONS: Once-weekly dosing with either pegylated IFN alfa-2b or pegylated IFN alfa-2a has been shown to produce significantly higher rates of viral eradication than standard thrice-weekly IFN alfa therapy without compromising safety. With respect to the treatment of CHC, the greatest anti-HCV efficacy has been achieved with the combination of once-weekly pegylated IFN and ribavirin.     

A sustained virological response to interferon or interferon/ribavirin reduces hepatocellular carcinoma and improves survival in chronic hepatitis C: a nationwide, multicentre study in Taiwan

BACKGROUND: The long-term benefit for chronic hepatitis C (CHC) patients treated with interferon (IFN)/ribavirin (RBV) combination therapy remains unclear. We aimed to evaluate the long-term effects of IFN monotherapy and IFN/RBV combination therapy on reducing hepatocellular carcinoma (HCC) and mortality in patients with chronic hepatitis C virus (HCV) infection, adjusting for risk factors. METHODS: A total of 1,619 patients with biopsy-proven CHC, including 1,057 receiving IFN-based therapy (760 on IFN/RBV combination therapy) and 562 untreated controls from three medical centres and one regional core hospital in Taiwan were enrolled in this retrospective-prospective cohort study. RESULTS: The incidence of HCC and survival during a follow-up period of 1.0-15.3 (mean 5.18) and 1-16 (mean 5.15) years in treated and untreated patients, respectively, was analysed using Cox proportional hazards regression. The cumulative incidence of HCC was 35.2% and 12.2% for untreated and treated groups, respectively (P=0.0013). The cumulative survival rate was 93.1% and 96.2% for untreated and treated groups, respectively (P=0.3928). Significantly lower incidences of HCC and mortality were observed in sustained virological responders (both for IFN monotherapy and IFN/RBV combination) but not in nonresponders when compared with untreated patients. HCV genotype 1 patients had significantly higher incidences of HCC than genotype non-1 patients. In multivariate analysis, pre-existing cirrhosis, non-response, HCV genotype-1 and age were associated with HCC; pre-existing cirrhosis and non-response correlated to mortality. CONCLUSION: A sustained virological response secondary to IFN monotherapy or IFN/RBV combination therapy could reduce the risk for HCC and improve survival of CHC patients.     

Response to combined interferon and ribavirin is better in patients infected with hepatitis C virus genotype 6 than genotype 1 in Hong Kong

Data on the treatment efficacy of interferon (IFN)-alpha and ribavirin in patients with chronic hepatitis infected with hepatitis C virus (HCV) of genotype 6 are lacking. A study has been reported from Hong Kong which compared the treatment efficacy of IFN-alpha and ribavirin in the treatment of chronic HCV infection with genotypes 1 and 6. Twenty-four patients with HCV genotype 1 and 16 patients with HCV genotype 6 were studied. The baseline demographic data including median age, gender ratio, alanine aminotransferase levels, bilirubin levels, HCV RNA levels and histological scores were comparable between the two groups of patients. All patients received IFN-alpha 5 million units three times per week and ribavirin (1,000 mg for those weighing 75 kg) for 1 year. Patients infected with HCV genotype 6 achieved virological response significantly higher than those with HCV genotype 1 (67 vs. 33% at week 24, p = 0.02; 75 vs. 42% at the end of treatment, p = 0.05; 63 vs. 29% at 6 months after completion of treatment, p = 0.04). Histological improvement in inflammatory activity and fibrosis in the liver were observed in 25% and 25% of patients infected with HCV genotype 6 in contrast to only 13 and 8% in patients infected with HCV genotype 1; however, the differences were not statistically significant. In conclusion, patients with HCV genotype 6 gain a better response to combined treatment with IFN-alpha and ribavirin than those with HCV genotype 1 and achieve a significantly higher rate of sustained virological response.     

Efficacy of daclatasvir in hepatitis C virus

Daclatasvir is a novel NS5A inhibitor of hepatitis C virus (HCV). Daclatasvir combined with peginterferon α-2a and ribavirin in Japanese patients infected with genotype 1b HCV achieved sustained virological response (SVR) in 100% of treatment-naïve patients, due to high rates of favorable IL28B allele and genotype 1b. SVR 24 was achieved by asunaprevir and daclatasvir in 87.4% of intolerant and 80.5% of nonresponder patients. Baseline NS5A-resistant variants were detected and they failed to achieve SVR. Most patients with genotype 1a experienced virological breakthrough by dual oral treatment, and should be treated QUAD or replaced by all oral regimens that are more potent and have fewer side effects. IFN-free regimens including daclatasvir and asunaprevir for genotype 1 null responders should be tailored to subtype, and preexisting NS5A-resistant variants should be evaluated carefully before choosing the drugs. This regimen alone is unlikely to move forward without additional agents.     

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

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

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

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

Impaired response to interferon-alpha2b plus ribavirin in cirrhotic patients with genotype 3a hepatitis C virus infection

Patients with chronic infection with the 3a genotype of hepatitis C virus (HCV) are considered as 'easy-to-treat' with interferon/ribavirin (IFN/RBV), independent of liver disease severity. However, patients with extensive fibrosis or cirrhosis were under-represented in all the registration Phase III trials performed so far. To assess the influence of liver fibrosis on the outcome of anti-HCV therapy, all patients with genotype 3a hepatitis C who were naive to IFN-based therapies, and received RBV combined with standard IFN or pegylated IFN-(alpha2b (peg-IFN-alpha2b) as standard of care for their disease, were investigated at our centre. A sustained virological response (SVR) was achieved in 68 of 91 patients (75%) independent of IFN type, pretreatment viraemia, clearance of HCV RNA at week 4 and relevant co-morbidities. A SVR was less common in cirrhotics (6 of 17) than in non-cirrhotics (62 of 74; 35% vs 84%; P<0.0005). Compared to non-cirrhotics, the age and sex adjusted odds ratio (OR) of treatment failure for cirrhotics was 10.1 (95% confidence interval: 2.4-41.7). By multivariate analysis, cirrhosis was the only predictor of non-SVR. In conclusion, cirrhosis is an independent predictor of IFN/RBV treatment failure in patients chronically infected with HCV 3a and is associated with an increased risk of post-treatment hepatitis relapse. Evaluation of liver fibrosis is important in the management of patients with genotype 3a hepatitis C, since it helps to predict response to IFN/RBV therapy.     

Genetic variation in BCL-2 and response to interferon in hepatitis C virus type 4 patients

The prevalence of hepatitis C virus (HCV) infection varies across the world, with the highest number of infections reported in Egypt. BCL-2 gene polymorphism at codon 43 (127G/A) has been found to be a reliable and sensitive marker for the prediction of response to interferon therapy during viral infections. This study examined the correlation of BCL-2 gene polymorphism with the response to treatment with pegylated-IFN-alfa2b and ribavirin. Eighty patients with type 4 HCV and 40 healthy volunteers as controls were enrolled in a prospective study. Quantification of HCV-RNA by real-time PCR was performed for every patient, and gene polymorphism of BCL-2 (ala 43 Thr) was performed for all patients and controls. There was a statistically significant difference between non-responder patients and control group as regards the 43Thr genotype and allele (P<0.05). Also, there was a statistically significant difference between responders and non-responders (P<0.05) as regards 43Thr genotype and alleles. We conclude that BCL-2 gene polymorphism at codon 43 (127G/A) is a new biological marker to potentially identify responders and non-responders of HCV genotype 4 patients to achieving a sustained virological response to treatment with IFN in combination with ribavirin.     

Sustained suppression of hepatitis C virus by high doses of interferon and ribavirin in adult hemophilic patients

BACKGROUND: In a recent randomized controlled study, only a minority (15%) of adult hemophiliacs with chronic HCV achieved a sustained virologic response to treatment with interferon (IFN) and ribavirin given at standard doses. STUDY DESIGN AND METHODS: Whether the therapeutic response might be improved in these patients by increasing the doses of IFN was evaluated. Thirty-four previously untreated, adult hemophiliacs with chronic HCV but negative for HIV were investigated. There were 33 men and 1 woman, aged 21 to 60 years (mean, 36). Twenty-three patients (68%) had genotype 1, and median serum HCV-RNA was 473 x 10(3) IU per L (range, 3.6-2145). Patients were treated with IFN at 5 million units (MU) thrice weekly for 6 months, followed by 3 mol/L for 6 additional months in combination with daily oral doses of 1 or 1.2 g of ribavirin. RESULTS: A total of 33 patients (97%) completed the study; one patient withdrew because of treatment-related symptoms. Treatment dosage had to be reduced in 20 patients (59%). By intention-to-treat analysis, 14 patients (41%) had a sustained virologic response, particularly those infected by HCV genotype 2 or 3 (70% vs. 29% with genotype 1 or 4, p < 0.05). Sustained response rates were similar in the 13 compliant patients and the 20 patients who had to reduce IFN and/or ribavirin doses (54% vs. 35%). CONCLUSIONS: High-dose IFN therapy plus ribavirin provided high rates of sustained virologic responses in adult hemophiliacs with chronic HCV, even if side-effects led to dose reduction in half of these patients.     

Combined interferon and ribavirin therapy for chronic hepatitis C in Taiwan

Chronic hepatitis C virus (HCV) infection, including its sequelae, is an important healthcare problem in Taiwan. The seroprevalence of HCV infection in first-time blood donors in Taiwan is 1.2% and an estimated 2-5% in the general population, with a great geographic variation. Genotype 1b is the most prevalent HCV genotype in Taiwan, with a prevalence rate of 50-70%. An increasing incidence of hepatocellular carcinoma (HCC) is mainly attributed to HCV infection, while the declining role of HBV is observed in Taiwan. The seroprevalence of hepatitis B surface antigen among patients with HCC was 90% three decades ago, while recently, chronic HCV infection accounts for more than 30% of HCC patients in the National Taiwan University Hospital. With the advent of a combined conventional interferon (IFN)-alpha and ribavirin therapy, to which Taiwan has contributed in the early study phase, the sustained virological response rate has been greatly improved compared with IFN monotherapy. The sustained virological response rate in Taiwanese patients treated with the combination therapy for 6 months has reached up to 50-60%, which is higher than that reported in patients from the Western countries receiving a 12-month regimen. It is necessary to search for the underlying mechanisms for the better treatment outcome with IFN plus ribavirin combination therapy in Taiwanese patients. Whether long-term effects of IFN plus ribavirin therapy can reduce the incidence of HCC needs to be established.     

Viral etiology of hepatocellular carcinoma and HCV genotypes in Taiwan

Etiologic variations of hepatocellular carcinoma (HCC) exist in different geographic areas of the world. Hepatitis B virus infection is associated with HCC. However, hepatitis C virus (HCV) infection plays an increasingly more important role in the development of HCC and is associated with more than 30% of HCC in Taiwan. The prevalence of HCV infection and HCV genotypes vary in different geographic areas. The prevalence of HCV genotype 1b (HCV-1b) was around 50-70% in Taiwan and even varied in different townships. In addition to host factors, HCV genotypes may be associated with the development of HCC. In our study, the prevalence of HCV-1b in patients with HCC was significantly higher than in those with liver cirrhosis and chronic hepatitis; multivariate analysis revealed that the disease severity was significantly correlated with age and HCV-1b. Furthermore, HCV-1b was associated with a lower response rate to interferon (IFN) therapy than HCV-2. Our study has demonstrated that mutations in the IFN sensitivity-determining region, spanning nucleotides 2,209-2,248 in the NS5A region, correlate with the sustained virological response to combination therapy with IFN and ribavirin in patients with chronic HCV-1b infection in Taiwan. A third-generation enzyme immunoassay for antibody to HCV can be used to predict viremia and monitor the virological response.     

Interferon-alpha therapy exerts selective pressure on hepatitis C virus quasispecies equilibrium

Two patients with chronic hepatitis C virus (HCV) genotype 2b infection were studied. They responded biochemically to interferon (IFN) but had early virological and later biochemical relapse. The HCV quasispecies equilibrium in these patients was studied by a combination of cloning, sequencing and construction of phylogenetic trees. Another patient with chronic HCV genotype 2b infection was followed every 6 months for 30 months (including one episode of biochemical exacerbation) to serve as the control. Quasispecies equilibrium drifted during IFN therapy but moved back in the direction of the original equilibrium during biochemical relapse. In the control patient, there was no significant drifting throughout the follow-up period. These data suggest that IFN therapy exerts selective pressure on HCV quasispecies equilibrium.     

Peginterferon alfa-2a (40KD) (Pegasys) for the treatment of patients with chronic hepatitis C

Compared with conventional interferon alfa, peginterferon alfa-2a (40KD) has improved pharmacokinetics, provides sustained therapeutic plasma levels, and can be administered once weekly. In randomised, multinational trials, peginterferon alfa-2a (40KD) 180 microg once weekly was significantly more effective than three times weekly interferon alfa-2a in patients with chronic hepatitis C, including patients with cirrhosis. Peginterferon alfa-2a (40KD) and ribavirin 1000/1200 mg/day for 48 weeks produced significantly higher sustained responses than three times weekly interferon alfa-2b and ribavirin 1000/1200 mg/day in patients with chronic hepatitis C including those with HCV genotype 1, genotypes 2/3 and those with high or low viral loads at baseline. The drug is well tolerated when given alone or in combination with ribavirin. Health-related quality of life was significantly less impaired during treatment with peginterferon alfa-2a (40KD) than interferon alfa-2a in randomised trials. Peginterferon alfa-2a (40KD) is widely approved for use in patients with chronic hepatitis C.