Treatment of hepatitis C virus with peg-interferon and ribavirin combination therapy significantly affects lipid metabolism

Aim:  We investigated lipid metabolism in patients with chronic hepatitis C virus (HCV), serotype 1, undergoing combination therapy with PEG-IFN α-2b (PEG-IFN) and ribavirin (RBV).
Methods:  A total of 185 patients with chronic HCV (HCV serotype 1; HCV RNA levels ≥ 100 KIU/mL) who received a combination of PEG-IFN and RBV were enrolled.
Results:  Sustained virological response (SVR) was obtained in 82 cases (44.3%). The median age, red blood cell and platelet counts differed significantly between the SVR and non-SVR groups before treatment. However there was no significant difference between total cholesterol (TC), LDL-cholesterol (LDL-C) and triglyceride (TG) levels before treatment. TC and LDL-C levels decreased during the treatment in both groups. In the SVR group, TC and LDL-C levels increased quickly after the end of the treatment and were higher than those before treatment. On the other hand, TC and LDL-C levels returned to pretreatment levels in the non-SVR group and were significantly lower than in the SVR group. TG levels were elevated in both groups after the beginning of treatment. After the end of treatment, this elevation persisted in the SVR group, while TG levels returned to pre-treatment levels in the non-SVR group. There was a significant difference in TG levels at 24 weeks after the end of the treatment between the 2 groups. In the non-SVR group some patients achieved normalization of ALT (alanine aminotransferase) but persistence of normal ALT levels did not contribute to the increase of TC and TG.
Conclusion:  TC, LDL-C and TG levels increase only in patients with HCV, serotype 1, undergoing combination therapy when a SVR is achieved.     

IL28B polymorphism may guide pegylated interferon plus ribavirin therapy even after curative treatment for hepatitis C virus-related hepatocellular carcinoma

The present study was designed to determine the predictive factors for the viral response to pegylated interferon-alpha plus ribavirin combination therapy (PEGIFN/RBV) administered after curative treatment for hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). The study group was 78 patients treated between January 2005 and January 2009. The sustained viral response (SVR) rate was 25.8% (15/58) in patients infected with HCV-genotype 1 and 55.0% (11/20) in those with genotype 2. Among the 78 patients, 32 (41.0%) could not complete the treatment protocol, and this was because of HCC recurrence in 17 (53%) of them. Multivariate analysis identified partial early viral response (pEVR) as the only independent determinant of SVR [odds ratio (OR) 14.73, P = 0.013] for patients with genotype 1. Multivariate analysis identified male gender (OR 8.72, P = 0.001) and interleukin-28B (IL-28B) genotype (rs8099917) TT (OR 7.93, P = 0.007) as independent predictors of pEVR. Multivariate analysis also identified IL-28B genotype GG+TG (OR 14.1, P = 0.021) and α-fetoprotein >30 (OR 5.4, P = 0.031) as independent predictors of null response. Patients with SVR showed a better survival rate than those without SVR (P = 0.034). The second HCC recurrence rate tended to be lower in patients with SVR than in those without SVR (P = 0.054). With regard to the prognosis of patients with SVR, it is desirable to achieve SVR with interferon therapy even when administered after HCC treatment. IL-28B genotype is a potentially useful marker for the response to PEGIFN/RBV therapy administered after curative treatment of HCV-related HCC.     

Suppressor of cytokine signal 3 and IL28 genetic variation predict the viral response to peginterferon and ribavirin

Aim: The aim of this study was to investigate the relationship among the expression of suppressor of cytokine signaling 3 (SOCS 3) in the liver, the SNPs in the IL28B locus, and the outcome of interferon therapy. Methods: Prior to interferon treatment, we immunostained 67 liver specimens from chronic hepatitis C (CHC) patients who were receiving peginterferon alpha‐2b/ribavirin therapy for suppressor of cytokine signaling 3 (SOCS3), and compared the expression of SOCS3, IL28 polymorphisms and other clinical factors between the patients and compared their eventual outcomes. Results: Significant differences between the low SOCS3 group and high SOCS3 group were found in age, as well as in the platelet, transaminase, gamma‐glutamyl transpeptidase levels. The incidence of high SOCS3 was not significantly different between subjects with the TT genotype and the TG genotype (TT : TG = 71%:29%, P = 0.250). In a multivariate analysis, age (≥65 years old) (odds ratio 0.221 [0.120–0.966], P = 0.045), IL28B gene (genotype TT) (odds ratio 5.422 [1.254–23.617], P = 0.024) and SOCS3 (high) (odds ratio 0.308 [0.104–0.948], P = 0.040) were significant predictors of the interferon response. In patients with the TT genotype, those with low SOCS3 immunostaining showed a high sustained virological response (69%), while the sustained virological rate was low (27%) in the patients with high SOCS3 immunostaining. Conclusions: Using a combination of the SOCS3 immunostained area in the liver and the expression of IL28B single nucleotide polymorphisms might be a useful predictor of hepatitis C virus clearance by interferon therapy.     

Hepatitis C virus therapy with peg-interferon and ribavirin in Myanmar: A resource-constrained country

AIM To investigate peg-interferon(peg-IFN) and ribavirin(RBV) therapy in Myanmar and to predict sustained virologic response(SVR).METHODS This single-center, open-label, study was conducted in Myanmar between 2009 and 2014. A total of 288 patients infected with HCV genotypes 1, 2, 3 and 6 were treated with peg-IFN alpha-2a(180 μg/wk) or alpha-2b(50 to 100 μg as a weight-based dose) and RBV as a weight-based dose(15 mg/kg/d). Treatment duration was 48 wk for genotypes 1 and 6, 24 wk for genotype 2, and 24 or 48 wk for genotype 3 based on rapid virologic response(RVR). Those co-infected with hepatitis B received 48 wk of therapy.RESULTS Overall, SVR was achieved for 82% of patients and the therapy was well tolerated. All patients achieved SVR at equivalent rates regardless of HCV genotype(P = 0.314). Low fibrosis scores(P 0.001), high baseline albumin levels(P = 0.028) and low baseline viral loads(P = 0.029) all independently predicted SVR. On the other hand, IL-28 B TT and CC genotypes were not found to significantly predict SVR(P = 0.634; P = 0.618). Among those who completed treatment, the occurrence of RVR showed a 96% positive predictive value for achieving SVR. Treatment duration did not significantly impact the likelihood of achieving SVR for patients infected with genotype 3 HCV(P = 0.371). The most common adverse events were fatigue(71%) and poor appetite(60%). Among patients with genotype 3 HCV, more patients in the 48-wk treatment group required erythropoietin than in the 24-wk treatment group(61.1% vs 49.2%).CONCLUSION SVR rates were high with peg-IFN and RBV therapy in Myanmar. Fibrosis scores, baseline albumin, HCV RNA levels and RVR independently predicted SVR.     

干扰素联合利巴韦林治疗对Huh7细胞微RNA122表达的影响

目的 探讨IFNβ联合利巴韦林(RBV)治疗对肝癌细胞株Huh7的微RNA122表达的影响.方法 Huh7细胞分别经过单用不同剂量RBV处理3 d、单用不同剂量IFNβ处理4 h,以及IFNβ联合RBV处理后,采用噻唑蓝(MTT)法检测其生长曲线,RT-PCR法检测IFN诱导基因54(ISG54)的表达,然后分别以小核核糖核酸6(U6)和单位细胞数为内参照,茎环结构实时PCR检测微RNA122表达变化.数据比较采用单因素方差分析,两两比较采用q检验.结果 MTT结果显示,RBV能以剂量依赖方式抑制Huh7细胞增殖,而IFNβ仅能轻微地且不能以剂量依赖方式抑制Huh7细胞增殖.RT-PCR结果显示,IFNβ能以剂量依赖方式诱导Huh7细胞ISG54 mRNA表达,而RBV单用和联合IFNβ均不能以剂量依赖方式诱导ISG54 mRNA表达.以U6为内参照,在RBV终浓度为3.125 mg/L时,联合lFN8 100 U/mL和1000 U/mL,微RNA122相对表达量分别为0.770±0.082和0.720±0.045,与单用IFNβ组相比,差异有统计学意义(q=4.623,q=5.112;均P<0.05).提示存在协同效果,而在RBV终浓度为6.25 mg/L和12.5 mg/L时无协同效果.以细胞数为内参照,RBV单用和联合IFNβ均能下调细胞微RNA122表达,以RBV终浓度为3.125 mg/L明显,联合IFNβ 10 U/mL、100 U/mL和1000 U/mL时,微RNA122相对表达量分别为0.680±0.055、0.560±0.084和0.610±0.030,与单用IFNβ组相比,差异有统计学意义(F=4.121,P<0.05),亦提示存在协同效果.结论 RBV在终浓度为3.125 mg/L时,能协同IFNβ下调Huh7细胞微RNA122表达,这可能为临床上RBV提高IFN抗HCV疗效的一个新的分子机制.     

Erythrocyte ribavirin concentration for assessing hemoglobin reduction in interferon and ribavirin combination therapy

Background

Ribavirin-induced hemolytic anemia is one of the important adverse effects for the premature cessation of interferon and ribavirin combination therapy for hepatitis C virus clearance. To elucidate the mechanism of this matter, we examined the effects of plasma and erythrocyte ribavirin concentration on hemoglobin (Hb) reduction to assess hemolytic anemia in this combination therapy.

Method

Nineteen patients, treated with the interferon alpha-2b and ribavirin combination therapy, were included. Plasma and erythrocyte ribavirin concentrations were monitored for the first 28 days of the combination therapy, in relation to changes in hematological parameters, Hb and hematocrit values. The initial dose of ribavirin was 11.5 ± 1.5 mg/kg/day.

Results

Steady-state plasma and erythrocyte ribavirin concentrations were 8.9 ± 2.6 and 1218 ± 270 μM, respectively. Significant correlation was observed between erythrocyte ribavirin and Hb reduction (r = 0.360, p < 0.05), but not between plasma ribavirin and Hb reduction. The patients with higher levels of erythrocyte ribavirin (≥1000 μM) had greater Hb reduction compared to those with lower levels (<1000 μM) (3.8 ± 1.2 g/dL versus 2.6 ± 0.9 g/dL, p < 0.05). Nine cases out of 12 patients who developed anemia within the first 28 days of the combination therapy had higher levels of erythrocyte ribavirin (≥1000 μM).

Conclusion

We confirmed that erythrocyte ribavirin was strongly associated with Hb reduction in interferon and ribavirin combination therapy.     

Single nucleotide polymorphisms of the IL28B and sustained virologic response of patients with chronic hepatitis C to PEG-interferon/ribavirin therapy: A meta-analysis: Meta-analysis of IL28B

Background

Hepatitis C is a global health problem and represents a major cause of liver disease and socioeconomic burden. Effective antiviral therapy may prevent these complications, but the current treatment for patients with chronic hepatitis C virus (HCV) infection does not produce sustained virologic response. Therefore, identification of the determinants of response to treatment is a high priority. A number of host and viral factors have been associated with treatment outcomes.

Objectives

To assess the associations of single nucleotide polymorphisms (SNP) of the IL28B and sustained virologic response (SVR) of patients with chronic hepatitis C to PEG-interferon/ribavirin therapy.

Materials and Methods

We searched PubMed, Medline and Cochrane Library, and found 7 eligible papers involved in this study. Then we performed a meta-analysis comparing the SVR rate at SNP of the IL28B in individuals with PEG-interferon/ribavirin therapy. Meanwhile, the SVR rate between different races and HCV genotypes was studied.

Results

The sustained virologic response rate was higher in patients with the rs12979860 CC and rs8099917 TT alleles in the IL28B SNP, comparing with the rs12979860 CT, or TT and rs8099917 TG or GG. Furthermore, a higher SVR was observed in the Caucasians than in Afro-Americans (OR = 3.85, 95% CI: 3.06-4.83); the percentage of rs12979860 TT genotype was lower in Caucasians (OR = 0.25, 95% CI: 0.20-0.31) and the percentage of rs12979860 CC genotype was higher in Caucasians than that of Afro-Americans (OR = 3.45, 95% CI = 2.68-4.44). Between different HCV genotypes, the SVR was much lower in those with HCV genotype 1 than those with genotype 2/3 (OR = 0.16, 95% CI: 0.11-0.24).

Conclusions

IL28B is significantly associated with response to PEG-interferon/ribavirin therapy of patients with chronic HCV infection. Both the rs12979860 and rs8099917 alleles could be used as independent predictors of the treatment response. The rs12979860 allele in particular, is more important from our study. The polymorphism even explains part the difference in response rate between different ethnic groups and HCV genotypes.     

IL28B polymorphism genotyping as predictor of rapid virologic response during interferon plus ribavirin treatment in hepatitis C virus genotype 1 patients

AIM: To clarify the association of interleukin-28B (IL28B) single nucleotide polymorphisms (SNPs) with hepatitis C virus (HCV) viremia changes for assessment of interferon (IFN) response.METHODS: A cohort of 118 Caucasian treatment-naïve HCV-G1 infected patients, treated with pegylated-IFN alpha 2a or 2b associated with ribavirin (53 responders, 65 non-responders) during the period 2010-2012, were genotyped for IL28B SNPs rs12979860 C>T and rs8099917 T>G. Genotyping was performed by real-time allelic discrimination assay. Serum HCV RNA levels were assayed at 2, 4, 12, 24 and 48 wk during therapy. Correlation between IL28B genotypes and serum HCV RNA kinetics was investigated. Multivariable logistic regression analysis was performed to identify predictors of null-response.RESULTS: Twenty-six out of 118 patients (22%) had no HCV RNA decline ≥ 1 log IU/mL at therapy week 4 (null-responders). IL28B genotype was rs8099917 (G*)/rs1297860(**) in 21/26 (80%) of null-responder patients. Using multivariate analysis, it was shown that the presence of the rs8099917 G allele was the best predictor of null-response (OR = 7.9, 95%CI: 1.99-31.18). The presence of at least one favorable genotype showed a positive predictive value of above 90% for HCV RNA reduction ≥ log at week 4. Analysis of the HCV RNA kinetics during 12 wk of therapy in patients with IL28B rs12979860 CT heterozygosis (n = 73), according to their rs8099917 status, showed that the viremia reduction was significantly different in patients carrying the rs8099917 G allele compared to those with favorable homozygosis.CONCLUSION: Our findings emphasize the association of the IL28B rs8099917 G allele with HCV. Genotyping for both IL28B SNPs is useful in clinical practice for thorough patient risk stratification based on IFN responsiveness.     

Current therapy for hepatitis C: pegylated interferon and ribavirin

The combinations of peginterferon alfa-2a or peginterferon alfa-2b with ribavirin lead to significant improvement in sustained virological response when compared with standard interferon and ribavirin therapy. These newer agents represent the most effective treatments available for the initial therapy of patients with chronic hepatitis C. A review of the clinical trials to date suggests certain similarities and differences between the two preparations. For both regimens, however, it is apparent that information concerning the predictability of response and the importance of adherence to the treatment regimens will be of great value in the therapeutic management of chronic hepatitis C. Although viral load and genotype, gender, age, and absence of fibrosis have been shown consistently to be important predictors of response, identification of additional host immune and genetic factors involved in determining outcome of antiviral therapy are necessary.     

Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C

BACKGROUND/AIMS: To elucidate whether ribavirin acts as a mutagen in the clinical setting and to clarify the relationship between ribavirin-induced mutations and virological response to combined therapy. METHODS: Thirty-four patients with hepatitis C virus (HCV) genotype 1b received ribavirin monotherapy for 4 weeks, followed by a 24-week course of IFN/ribavirin therapy. HCV mutations during a non-treatment observation period and during subsequent ribavirin monotherapy were determined, and the relationship between mutations and response to subsequent IFN/ribavirin therapy was evaluated. RESULTS: Serum HCV significantly decreased from 6.90 to 6.56 log10copy/ml in response to ribavirin monotherapy (P < 0.0001). Nucleotide mutations in the NS5A and NS5B regions occurred during ribavirin monotherapy at a rate of 2.9 x 10(-2)/site/year and 1.3 x 10(-2)/site/year, respectively, a significantly higher rate than the mutation rates during the prior non-treatment observation period (0.60 x 10(-2)/site/year and 0.24 x 10(-2)/site/year, P = 0.02, respectively). Mutation rates in the NS5A region were significantly higher in sustained viral responders (SVRs, n = 10) than in non-responders (8.8 x 10(-2)/site/year vs. 0.38 x 10(-2)/site/year, P = 0.0005, respectively). In the NS5A region, non-synonymous mutations only occurred in SVRs. CONCLUSIONS: Ribavirin may act as a mutagen, and mutations occurring during ribavirin therapy correlate with the virological response to subsequent IFN/ribavirin combination therapy.     

Combination of interferon induction therapy and ribavirin in chronic hepatitis C.

The initial clearance of hepatitis C virus (HCV) during interferon-alfa therapy is dose-dependent. Therefore, higher initial interferon doses (induction therapy) may improve treatment results. This concept was tested in a prospective, randomized controlled trial. Previously untreated patients with chronic hepatitis C were randomized to receive 3 different interferon doses during the first 14 weeks of therapy (Group A, n = 130: 10 MU IntronA [AESCA-Schering Plough, Traiskirchen, Austria]/day for 2 weeks, followed by 10 MU/2 days for 12 weeks; Group B, n = 124: 5 MU/day for 14 weeks; Group C, n = 119; 5 MU/2 days for 14 weeks) followed in all by 5 MU/2 days for 24 weeks. Throughout the whole study all patients received 1 to 1.2 g ribavirin/day. On treatment, no differences in viral clearance rates were observed. Sustained response rates were also not different among the groups (A: 48.5%, B and C: 41.3%, intent to treat). When data were analyzed according to genotypes, sustained response was almost twice as high in patients with genotype 1 receiving high-dose interferon induction therapy (A: 44.2%, B: 28.6%, C: 27%, P <.05). In contrast, results were not different in genotype 3a patients (A: 61.3%, B: 75.9%, C: 56.3%; P >.1). These data indicate that high-dose interferon induction therapy may improve the outcome of interferon/ribavirin combination therapy in genotype 1 patients.     

Cost-effectiveness of combined interferon and ribavirin versus interferon alone

Several decision analysis, computer-generated models developed to study the cost effectiveness of current treatment for chronic hepatitis C appear to have produced similar results. They indicate that IFN monotherapy and the combination of IFN plus ribavirin treatment have calculated cost-effectiveness ratios that either fall within the bounds of other widely accepted current therapies in medicine or are cost-saving. This cost effectiveness has been shown for the treatment of previously untreated patients, for the re-treatment of patients who experience relapse after an initial course of IFN monotherapy, and for the re-treatment of those patients who did not respond to IFN monotherapy. Although targeting treatment to patients most likely to respond will improve cost effectiveness, the benefits of treatment are such that even empiric IFN monotherapy, without liver biopsy, HCV RNA quantitation, or HCV genotyping, has an acceptable cost effectiveness. Although not studied, empiric combination therapy might result in even further cost efficiencies.