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

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

Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3

BACKGROUND/AIMS: Obesity is associated with impaired treatment responses in chronic hepatitis C. The aim of this study was to determine the relationship between the insulin resistance frequently seen in obese subjects and sustained virological response to anti-viral therapy (SVR) in patients with genotype 2 or 3 infection. METHODS: Eighty-two patients were studied; 59 received interferon/ribavirin while 23 received peg-interferon/ribavirin. RESULTS: The overall SVR was (77%). Patients with a SVR had lower mean serum insulin (10.7+/-0.8 microU/ml vs. 22.2+/-4.9; P = 0.03), fibrosis stage (1.9+/-0.1 vs. 2.7+/-0.3; P = 0.007) and insulin resistance measured by the homeostasis model (HOMA-IR) (2.5+/-0.2 vs. 6.1+/-1.5; P = 0.03). Age, gender, ethnicity, alcohol consumption, treatment regimen, viral load, portal activity and steatosis did not influence the SVR. By linear regression, body mass index (P < 0.001) and fibrosis stage (P < 0.001) were independently associated with HOMA-IR. After adjusting for fibrosis stage, patients with HOMA-IR of < 2 were 6.5 times more likely to achieve SVR than those with HOMA-IR > or = 2. CONCLUSIONS: Even in treatment-responsive genotypes 2 and 3, high HOMA-IR is associated with a reduced response. Improving insulin sensitivity may be a useful adjunct to anti-viral therapy in these individuals.     

Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3

BACKGROUND/AIMS: Treatment duration in patients with chronic hepatitis C in the era of standard interferon-alpha plus ribavirin was tailored according to hepatitis C virus (HCV) genotype: patients infected with HCV-1 were treated for 48 weeks, patients infected with HCV-2/3 for 24 weeks. The aim of the present study was to investigate this schedule for HCV-2/3 infected patients in the era of pegylated interferon-alpha plus ribavirin. METHODS: Patients chronically infected with HCV-2 (n=42) or HCV-3 (n=182) were treated with peginterferon alfa-2b 1.5 microg/kg subcutaneously once weekly plus ribavirin 800-1400 mg/day based on body weight for 24 weeks. RESULTS: The end of treatment (EOT) and sustained virologic response (SVR) was higher in patients infected with HCV-2 (100 and 93%, respectively) than in patients infected with HCV-3 (93 and 79%, respectively). Baseline viremia (P=0.020), treatment duration >16 weeks (P<0.001) and steatosis (<5%, P=0.015) were significant independent predictors of SVR. Adverse events resulted in discontinuation in 5% and dose reduction in 22% of patients. CONCLUSIONS: Treatment for 24 weeks with peginterferon alfa-2b and ribavirin is sufficient in HCV 2 or 3 infected patients. The lower SVR in patients infected with HCV-3 compared with HCV-2 infected patients may be related to higher levels of steatosis in this population.     

聚乙二醇干扰素α-2a治疗慢性丙型肝炎病毒／乙型肝炎病毒共感染临床疗效

目的研究慢性丙型肝炎（CHC）与丙型肝炎病毒/乙型肝炎病毒（HCV/HBV）共感染者用聚乙二醇干扰素α-2a（PEG-IFNα-2a）抗病毒治疗疗效的观察。方法治疗前后定期采集31例CHC、30例HCV/HBV共感染者的外周血,检测HCV RNA、HBV DNA和肝脏纤维化指标。结果治疗后CHC患者血清中HCV RNA含量51.6%〈102拷贝/ml,HCV/HBV共感染者HCV、HBV下降均不理想。结论 PEG-IFNα-2a抗病毒治疗HCV/HBV共感染者疗效较单纯丙型肝炎患者差,但对HBV、HCV有抑制作用,并部分改善机体免疫功能及肝功能。     

Racial differences in response rates to consensus interferon in HCV infected patients naive to previous therapy

BACKGROUND: Despite a rapid evolution in the treatment of Hepatitis C (HCV), response to therapy among different racial and ethnic groups is poorly characterized. STUDY: Three hundred and thirty HCV infected patients naive to previous therapy received induction therapy followed by every other day dosing with consensus interferon. Greater than 30% of treated patients were not white, allowing comparison of response among different races/ethnicities and genotypes. RESULTS: An overall sustained virologic response (SVR) was achieved in 24% of white, 12% of Hispanic, and 4% of AA patients (P = 0.003 white vs. non-white). 15% of white and 13% of Hispanic Genotype 1 patients achieved an SVR; 2% of AA patients achieved an SVR (P = 0.001 AA vs. non AA). Surprisingly, an SVR of 50% and 40% was achieved by AA and White Genotype 2 patients, compared with 10% in Hispanic patients (P = 0.001). CONCLUSION: Significant differences in response rates to induction therapy followed by every other day dosing with consensus Interferon was observed when comparing white to non-white patients, particularly when comparing response rates by genotype. These observations reinforce the requirement that prospective studies that enroll a significant percentage of non-whites are needed to adequately characterize response rates to anti-HCV directed therapy.     

Mutations in the NS5A and E2-PePHD region of hepatitis C virus type 1b and correlation with the response to combination therapy with interferon and ribavirin

Nonstructural 5A (NS5A) and the second envelope (E2) proteins of hepatitis C virus (HCV) have the potential to block interferon (IFN)-induced RNA-dependent protein kinase (PKR) and may therefore interfere with the response to IFN therapy, but controversy still exists regarding the relevance of this. This study aimed to assess whether mutations in these regions correlated with the response to combination therapy, IFN and ribavirin. Pretreatment parameters were analysed in 57 HCV-1b patients who had received IFN-alpha2b (3 or 5 MU three times weekly) and ribavirin (800-1200 mg per day) for 24 weeks. The amino acid sequences of the NS5A and PKR-eIF2alpha phosphorylation homology domain (E2-PePHD) were deduced from the corresponding coding sequence, which were determinated by direct sequencing of the HCV genome amplified by the polymerase chain reaction. Twenty (36%) patients achieved a sustained virological response (SVR). The mean number of amino acid substitutions in the NS5A-PKR binding domain (2209-2274), interferon sensitivity-determining region (ISDR) (2209-2248), and E2-PePHD sequence (659-670) in patients with and without SVR were 4.53 +/- 3.31 vs 2.83 +/- 1.78 (P = 0.094), 2.45 +/- 2.74 vs 1.03 +/- 1.32 (P = 0.042) and 0.25 +/- 0.70 vs 0.03 +/- 0.17 (P = 0.109), respectively. Patients with a mutant-type (>/= 4) NS5A-ISDR had a higher rate of SVR (six of nine, 67%) than those with wild-type (five of 22, 23%) (P = 0.038). Stepwise multiple logistic regression analysis of the factors (age, gender, viral load, cirrhosis rate, IFN dosage and amino acid substitutions) revealed that the mutation in NS5A-ISDR (>/= 4 vs < 4) was the only independent variable of treatment outcome. Our study showed that NS5A-ISDR mutations were correlated with the SVR to combination therapy in chronic HCV-1b patients in Taiwan.     

Low cell binding ability of HCV is closely related to interferon treatment especially in patients with HCV genotype 2a/2b. A large series prospective study on Japanese patients with chronic hepatitis C

BACKGROUND/AIMS: We have previously shown that the quantity of antibody-free virion in the pre-treatment sera of the patients with chronic hepatitis C is a good predictive factor for the efficacy of interferon treatment. However, the biological significance of the free virion should be verified by a prospective study. METHODS: We prospectively evaluated 152 consecutive patients with chronic hepatitis C who received a standardized interferon treatment, and analyzed the free virion and the binding titers, the ability of hepatitis C virus (HCV) to bind to the human lymphocytic cell line. RESULTS: Sixty-five patients achieved a long-term sustained remission, 76 patients did not respond to the interferon therapy, and 11 patients dropped out. The sera from the patients with genotype 2a/2b had significantly lower free virion and cell binding titers than those with genotype 1b. A multivariate analysis showed three independent variables associated with the interferon response; cell binding titer <10(0.5)/ml, viral load <10(4.5) copies/50 microl, and genotype 2a/2b with odds ratios of 14.6, 11.8, and 9.8, respectively. CONCLUSIONS: The low level of in vitro cell binding ability of HCV helped to clarify the good responsiveness to interferon observed in patients especially with a high viral load of genotype 2a/2b.     

Efficacy of short-term interferon therapy for patients infected with hepatitis C virus genotype 2a

BACKGROUND AND AIMS: The efficacy of interferon (IFN)-based antiviral therapy for chronic hepatitis C (CHC) varies depending on predictive factors such as hepatitis C virus (HCV) genotype and viral load. For patients with good predictive factors, a low dose and short course of IFN-based therapy may be adequate. However, there is no evidence about the optimal duration of IFN-based therapy for these patients. The aim of this study was to clarify whether the duration of IFN therapy could be shortened to less than the conventional treatment period for patients with good predictive factors. METHODS: A total of 25 treatment-naive CHC patients with genotype 2a were randomized to receive either IFN monotherapy for 24 wks (group A: long-term IFN therapy, n = 13) or for 6 wks (group B: short-term IFN therapy, n = 12). Patients were monitored for HCV RNA and routine liver function tests during and following treatment, and data were examined according to intention-to-treat analysis. RESULTS: Eleven of 13 patients in group A and all patients in group B completed IFN therapy according to the original planned schedule. At the end of the treatment, viral clearance occurred in all patients. However, 4 patients in group A and 5 in group B relapsed within 6 months of follow-up. There was no significant difference of sustained response rate between group A (53.8%) and group B (58.3%). Among patients who had HCV viral load of <100 kIU/ml, the sustained response rate was 83.3% (5/6) in group A and 100% (5/5) in group B. CONCLUSIONS: In this study, our results suggest that the duration of IFN therapy can be shortened to less than 24 wks in patients with good predictive factors. Further studies, however, should examine the optimal regimen of IFN therapy based on the backgrounds of patients.     

Mutations in the NS5A and E2‐PePHD regions of hepatitis C virus genotype 1b and response to combination therapy of interferon plus ribavirin

Background/aims: Combination therapy with interferon (IFN) and ribavirin is the current standard treatment for chronic hepatitis C, but the efficacy is still not satisfactory, especially for genotype 1b. NS5A and E2 proteins of hepatitis C virus (HCV) may repress the IFN‐induced RNA‐dependent protein kinase (PKR), and thus have the potential to influence the response of HCV to IFN therapy; however, this issue remains controversial. Methods: Nucleotide sequences of the PKR‐eIF2α phosphorylation homology domain (E2‐PePHD) and PKR‐binding domain (NS5A‐PKR bd) of the HCV genome were analyzed by amplification and direct sequencing in 30 HCV genotype 1b patients who had been treated with IFN and ribavirin. Results: Nine (30%) patients achieved a sustained virological response (SVR) to combination therapy. Pretreatment variables and amino acid substitutions were compared between responders and non‐responders. The responders were younger than non‐responders (37.2±10.4 vs. 45.4±9.5 years, P=0.017), whereas no significant statistical differences were found in the number of amino acid substitutions in NS5A and E2‐PePHD regions between the two groups. Conclusions: Genetic heterogeneity in NS5A and E2‐PePHD regions of the HCV genome may not serve as a predictor for treatment outcome with combination therapy in Taiwanese patients with chronic HCV genotype 1b infection.     

A preliminary experience with GM-CSF plus interferon in patients with HBV and HCV resistant to interferon therapy

Summary. An open label trial of GM-CSF plus high-dose interferon (IFN) α 2b was performed in eight patients with chronic hepatitis B infection and 16 patients with chronic hepatitis C, who either failed to clear virus with 6 months of daily high-dose IFN (5 MU daily) therapy ( n = 22) or were considered untreatable because of advanced disease and leukopenia ( n = 2). The dose of GM-CSF used was 500 μg subcutaneously twice weekly. The dose of IFN used was 5 MU daily. Both agents were administered for 4 months. Five of the eight hepatitis B patients and five of the 16 hepatitis C virus patients responded to combined therapy having previously failed IFN therapy alone. The hepatitis B virus responders had low entry ALT, AST, and gamma GPT levels as compared to the non-responders. No such differences for responders and non-responders were seen with the hepatitis C virus patients. These data suggest that the combination of GM-CSF and IFN may be more effective at achieving viral clearance than IFN alone.     

丙型肝炎病毒载量与基因型和抗病毒疗效的关系研究

目的探讨丙型肝炎患者血清HCV RNA载量与基因型的关系及其对抗病毒治疗疗效的影响。方法113例慢性丙型肝炎患者接受聚乙二醇干扰素联合利巴韦林抗病毒治疗。采用实时荧光定量PCR法检测血清HCV RNA载量,应用CE1区测序遗传树比对分析法检测HCV基因型。结果 113例患者分别感染1b、2a、3a、3b和6a共5种基因亚型,其HCV RNA载量（lgcopies/ml）分别为6.6973±1.19245、6.0824±1.68603、6.8393±1.03400、6.5533±1.29577和7.1503±1.16115,经单因素方差分析无明显统计学差异（P=0.166）;治疗前高血清HCV RNA载量者（≥107copies/ml）与低HCV RNA载量者（〈107copies/ml）完成治疗后获得SVR的比例,无论在所有患者（76.4%对75.9%,P=0.950）,还是在HCV1型（66.7%对60.0%,P=0.641）或非1型感染者（82.4%对87.9%,P=0.526）中均无统计学差异。结论治疗前血清HCV RNA载量与HCV基因型无关,血清HCV RNA载量对聚乙二醇干扰素联合利巴韦林抗病毒的疗效无明显影响。     

Mutations within the E2 and NS5A protein in patients infected with hepatitis C virus type 3a and correlation with treatment response

Defined regions of hepatitis C virus (HCV) envelope 2 (E2), PePHD, and nonstructural 5A (NS5A) protein (PKR-binding domain) have been shown to interact with interferon alfa (IFN-alpha)-inducible double-stranded RNA-activated protein kinase (PKR) in vitro, suggesting a possible mechanism of HCV to evade antiviral effects of IFN-alpha. The clinical correlation between amino acid mutations within the E2 PePHD or the NS5A PKR-binding domain and response to antiviral treatment in HCV-3a-infected patients is unknown. Thirty-three patients infected with HCV-3a isolates were treated with IFN-alpha with or without ribavirin. The carboxyterminal half of E2 and of the NS5A gene were sequenced. Sixteen patients achieved a sustained virological response (SR), 6 patients an end-of-treatment response with relapse thereafter (ETR), and 11 patients were nonresponders (NR). Within the PePHD of the E2 protein 0.5 (range, 0-2) mutations were observed in SR patients, whereas the number of mutations in ETR or NR patients was 0.2 (0-1). Quasispecies analyses showed almost no heterogeneity. The mean number of mutations within the PKR-binding domain of the NS5A protein was 1.6 (range, 0-4) in SR patients, 1 (0-2) in ETR patients, and 1.6 (0-3) in NR patients. Patients with higher numbers of mutations within the E2 or NS5A region showed a trend towards lower pretreatment viremia. Phylogenetic and conformational analyses of E2 or NS5A sequences allowed no differentiation between sensitive and resistant isolates. However, mutations within the E2 PePHD in SR patients were frequent, and hydrophobic mutations within the hydrophilic area of PePHD at codon 668 and 669 were exclusively observed in sustained virological responders.     

乙型肝炎病毒基因型与干扰素-α2b疗效的关系

目的研究乙型肝炎病毒基因型与干扰素-α2b治疗疗效的关系。方法采用DNA测序法对222例慢性乙型肝炎患者进行HBV基因分型。其中106例接受干扰素-α2b治疗6个月，观察治疗后应答率与基因型的关系。结果在106例接受干扰素-α2b治疗的患者，C基因型患者肝组织学改变明显重于B基因型。在6个月治疗结束时，B型感染者HBVDNA阴转、HBeAg血清转换和ALT复常率分别为41．9％，38．7％和58．1％，均显著高于C型患者（P〈0．05）。结论HBV基因型与肝损害程度及对干扰素-α2b的应答率有一定的关系。