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While the combination therapy of ribavirin (RBV) and sofosbuvir (SOF) is effective in genotype 2 HCV infection, the predictors of treatment efficacy and posttreatment changes in α-fetoprotein (AFP) and liver stiffness (markers of hepatocellular carcinoma), remain unclear. In this study, 302 patients with chronic HCV genotype 2 infection were treated with SOF (400 mg) plus RBV (400-1000 mg; based on body weight) for 12 weeks. We evaluated the efficacy and safety of treatment, as well as measured serum AFP, liver stiffness, and controlled attenuation parameter (CAP, a surrogate marker of steatosis) at baseline and within 48 weeks of treatment completion. The intention-to-treat analysis showed a sustained virological response (SVR) rate of 95.7%. None of the patients discontinued treatment due to side effects. Multivariate analysis identified pretreatment (no treatment with interferon), level of AFP (AFP; <10 μg/L), and RBV/body weight (BW) ratio (≥9.0 mg/kg) as independent predictors of SVR. The SVR rate in patients with two predictors of poor response (AFP ≥10 μg/L and RBV/BW ratio <9.0 mg/kg) was significantly lower than in other patients. In the SVR group, posttreatment AFP level and liver stiffness were significantly lower than at baseline. CAP tended to be higher after treatment than at baseline in all patients. SOF plus RBV combination therapy achieved a high SVR rate and was safe in HCV genotype 2 infected patients. Treatment reduced AFP levels and improved liver stiffness, but increased CAP., (© 2018 Wiley Periodicals, Inc.)

Introduction: In Japan, hepatitis C virus (HCV) genotype (GT) 2 accounts for approximately 32% of HCV infections. Limited treatment options exist in Japan for HCV GT2-infected patients. GIFT-II was a phase 3, randomized, open-label study evaluating the efficacy and safety of 16- and 12-week regimens of co-formulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus ribavirin (RBV) in Japanese adults with HCV GT2 infection., Methods: Patients were randomized in a 1:1 ratio to once-daily, co-formulated OBV/PTV/r (25/150/100 mg) with weight-based RBV for 16 or 12 weeks. The primary efficacy endpoint was the sustained virologic response at 12 weeks post-treatment (SVR12) rate in the primary efficacy population of non-cirrhotic treatment-naive patients., Results: A total of 171 patients were randomized to OBV/PTV/r + RBV. In the primary efficacy population, SVR12 rates were 91.5% (43/47; 95% confidence interval 83.5-99.5%) and 75.0% (36/48; 95% confidence interval 62.8-87.2%) in the 16-week arm and 12-week arm, respectively. No patient in the 16-week arm relapsed by post-treatment week 12. Among non-cirrhotic treatment-experienced patients, the overall SVR rate in the 16-week arm was 75.8% (25/33) and was highest [93.8% (15/16)] among those who had relapsed after previous interferon-based therapy. SVR12 rates were consistently higher in patients with HCV GT2a infection versus HCV GT2b infection [16-week treatment arm: 93.9% (31/33) versus 85.7% (12/14) and 93.8% (15/16) versus 56.3% (9/16) among non-cirrhotic treatment-naive and treatment-experienced patients, respectively]. No patient discontinued treatment because of an adverse event. The most common adverse events were anemia, increased blood bilirubin, and nasopharyngitis., Conclusions: OBV/PTV/r + RBV for 16 weeks resulted in high SVR12 rates in non-cirrhotic Japanese patients infected with HCV GT2 who were treatment-naive or who had relapsed after an interferon-based therapy. Higher SVR12 rates were observed among patients with HCV GT2a infection versus those with GT2b infection. This regimen demonstrated a favorable safety profile., Trial Registration: ClinicalTrials.gov identifier, NCT02023112., Funding: AbbVie.

The study objective was to compare the efficacy and safety of peginterferon lambda-1a combined with ribavirin/daclatasvir (Lambda/RBV/DCV), versus peginterferon alfa-2a combined with ribavirin/telaprevir (Alfa/RBV/TVR), in patients chronically infected with hepatitis C virus (HCV), genotype 1b. This was a prospective, randomized, open-label, phase 3 study (NCT01718158) in adults (aged ≥18 years) who were treatment naïve or prior relapsers to peginterferon alfa/ribavirin therapy. The primary endpoint was sustained virologic response at post-treatment follow-up week 12 (SVR12). Patients were randomized in a 2:1 ratio to receive 24 weeks of Lambda/RBV/DCV or response-guided 24 or 48 weeks of Alfa/RBV/TVR. Overall, 440 patients were treated (294 with Lambda/RBV/DCV; 146 with Alfa/RBV/TVR). The proportion of patients achieving SVR12 was 88.8% in the Lambda/RBV/DCV arm and 70.5% in the Alfa/RBV/TVR arm (difference between arms: 18.3%; 95% confidence interval: 9.9-25.7; P < 0.0001). Patients in the Lambda/RBV/DCV group had fewer rash-related adverse events (AEs), cytopenic abnormalities, flu-like symptoms, serious AEs, and discontinuations due to AEs, but more liver abnormalities than those in the Alfa/RBV/TVR group. In conclusion, treatment with Lambda/RBV/DCV led to higher SVR12 rates and a more favorable safety profile than Alfa/RBV/TVR in patients with chronic HCV, genotype 1b infection.

Background and Aim: Vaniprevir is a macrocyclic hepatitis C virus (HCV) non-structural (NS)3/4A protease inhibitor. The objective of these phase 3 multicenter, open-label trials was to evaluate the safety and efficacy of vaniprevir + peginterferon alfa-2b + ribavirin (PR) in Japanese patients with HCV genotype (GT)1 infection who had previously failed treatment with interferon-based regimens., Methods: Japanese patients with chronic HCV GT1 were enrolled. In PN044, patients with previous relapse or virologic breakthrough were randomized to vaniprevir (300 mg twice daily) + PR for 12 weeks followed by PR for another 12 weeks (12-week arm) or vaniprevir + PR for 24 weeks (24-week arm). In PN045, patients with previous partial/null response received vaniprevir + PR for 24 weeks. The primary endpoint was sustained virologic response at 24 weeks after completing treatment (SVR 24 )., Results: In PN044 (n = 51), SVR 24 was 92.0% and 96.2% in the 12- and 24-week arms, respectively. In PN045 (n = 42), SVR 24 was 61.9% in all patients and 55.2% in previous null responders. In both studies, vaniprevir + PR was generally safe and well tolerated; the majority of adverse events were mild/moderate and included pyrexia, decreased hemoglobin, headache, nausea, pruritus, and decreased platelet count. Polymorphisms in the HCV NS3 gene at baseline (Y56, Q80, and V170) did not impact treatment outcome. Virologic failure was principally associated with the on-treatment emergence of R155 or D168 mutations., Conclusions: Vaniprevir + PR is an effective, well-tolerated treatment for Japanese patients with HCV GT1 infection who failed previous interferon-based treatment. ClinicalTrials.gov Identifier NCT01405937 and NCT01405560 (Protocols PN044 and PN045)., (© 2016 The Authors Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: Daclatasvir combined with asunaprevir is the first all-oral, ribavirin-free treatment of hepatitis C virus genotype 1b infection in Japan. This study compared the efficacy and safety of daclatasvir plus asunaprevir versus telaprevir plus peginterferon/ribavirin in Japanese treatment-naive patients infected with hepatitis C virus genotype 1b., Methods: Treatment-naive patients (20-70 years; baseline viral load, ≥ 100,000 IU/mL) were randomly assigned (stratified by IL28B rs8099917 TT/non-TT status) to receive either daclatasvir 60 mg tablets once daily and asunaprevir 100 mg softgel capsules twice daily for 24 weeks or telaprevir 750 mg (3 × 250 mg tablets) three times daily for 12 weeks and peginterferon/ribavirin per Japanese prescribing information for 24 weeks. A cohort of prior relapsers to peginterferon/ribavirin (20-75 years; baseline viral load, ≥ 100,000 IU/mL) received daclatasvir plus asunaprevir., Results: In treatment-naive patients, sustained virologic response at post-treatment week 12 in daclatasvir plus asunaprevir recipients was non-inferior (treatment difference, +25.8% in favor of daclatasvir plus asunaprevir) and higher (89.1%, 106/119) than telaprevir plus peginterferon/ribavirin recipients (62.2%, 69/111); sustained viral response was achieved in 95.5% (n = 21/22) of relapsers. Numerically, fewer patients receiving daclatasvir plus asunaprevir compared with telaprevir plus peginterferon/ribavirin experienced serious adverse events (4.2% vs. 5.4%), adverse events leading to discontinuation of any drug (5.0% vs. 62.2%), grade 3/4 treatment-related adverse events (14.3% vs. 72.1%), rash-related events (0% vs. 13.5%), or anemia (0% vs. 47.7%)., Conclusion: Marked differences were observed in the efficacy and safety profile of daclatasvir in combination with asunaprevir, compared with telaprevir plus peginterferon/ribavirin., (© 2015 Bristol-Myers Squibb. Journal of Gastroenterology and Hepatology published by Wiley Publishing Asia Pty Ltd. and Journal of Gastroenterology and Hepatology Foundation.)

Background & Aims: In a Japanese Phase II study, the hepatitis C virus NS3/4A protease inhibitor simeprevir demonstrated potent antiviral activity and significantly improved sustained virologic response rates when added to peginterferon α-2a/ribavirin in treatment-naïve patients infected with hepatitis C virus genotype 1., Methods: CONCERTO-1 was a Phase III, randomized, double-blind, placebo-controlled trial. Treatment-naïve adults (⩽ 70 years) with chronic hepatitis C virus genotype 1 infection (hepatitis C virus RNA ⩾ 5 log10 IU/ml) were randomized (2:1) to simeprevir 100mg once-daily with peginterferon α-2a/ribavirin for 12 weeks then response-guided therapy with peginterferon α-2a/ribavirin for 12 or 36 weeks, or to placebo with peginterferon α-2a/ribavirin for 12 weeks then peginterferon α-2a/ribavirin for 36 weeks., Results: Overall, 183 patients were treated. Sustained virologic response 12 weeks after treatment end (primary efficacy endpoint) was achieved in 88.6% of simeprevir- and 61.7% of placebo-treated patients (p<0.0001 for stratum-adjusted between-group difference). Overall, 91.9% of simeprevir-treated patients met response-guided therapy criteria and completed treatment at week 24; sustained virologic response rate at 12 weeks in these patients was 92.0%. One simeprevir- (0.8%) and two placebo-treated patients (3.3%) experienced viral breakthrough; respective viral relapse rates were 7.6% and 30.6%. Overall adverse event profile in simeprevir-treated patients was comparable to that in patients who received peginterferon α-2a/ribavirin alone., Conclusions: Simeprevir once daily with peginterferon α-2a/ribavirin significantly improved sustained virologic response rate 12 weeks after treatment end in treatment-naïve patients with chronic hepatitis C virus genotype 1 infection, with a shorter 24-week treatment duration in most patients., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Daclatasvir (DCV; BMS-790052) is a picomolar inhibitor of HCV non-structural protein 5A (NS5A) and has demonstrated efficacy in patients chronically infected with HCV., Methods: In the double-blind, randomized studies AI444021 and AI444022, 71 Japanese patients chronically infected with HCV genotype 1 (predominantly genotype 1b) received DCV (10 mg or 60 mg) plus peginterferon alfa-2b or alfa-2a and ribavirin. Virological failure occurred in 14% (5/36) of treatment-naive patients and 54% (19/35) of prior alfa/ribavirin non-responders. Resistance testing was performed on baseline samples and samples with HCV RNA≥1,000 IU/ml at week 1 through post-treatment week 24., Results: Baseline NS5A resistance-associated polymorphisms had less impact on virological response rates than IL28B genotype. All patients with virological failure had NS5A DCV-resistant variants at the time of failure. The predominant NS5A variants were L31V/M/I plus Y93H; this combination was detected in 100% (5/5) of treatment-naive patients and 74% (14/19) of non-responders with failure. Emergent resistance variants in prior non-responders (four viral breakthroughs, one relapse) were more varied with novel combinations such as L31F-ΔP32 and L28M-R30Q-A92K detected. Significant loss in DCV antiviral activity was generally only seen with ≥ two resistance-associated NS5A substitutions. All DCV-resistant variants were still detected at end of study., Conclusions: Virological failure in HCV genotype 1b treatment-naive Japanese patients receiving DCV plus alfa-2a/ribavirin or alfa-2b/ribavirin was associated with enrichment of NS5A resistance variants L31V/M-Y93H. In prior non-responders, emergent variants associated with failure also included NS5A-A92K or NS5A-ΔP32. As with L31-Y93 variants, these variants persisted.

Background: The aim of this study is to explore the efficacy, safety and pharmacokinetics of 750 mg telaprevir (TVR) given at 8 or 12 h intervals during triple therapy with pegylated interferon-α2b (PEG-IFN) and ribavirin (RBV) for patients with chronic HCV infection., Methods: A total of 52 patients with high viral loads of HCV genotype 1b who were expected to respond well to therapy (rs8099917 TT genotype or relapse to previous therapy) were randomly assigned to two groups who were given 750 mg TVR at either 8 h (q8h) or 12 h (q12h) intervals in combination with PEG-IFN and RBV for 12 weeks, followed by 12 additional weeks of treatment with PEG-IFN and RBV alone. The primary end point of the study was undetectable HCV RNA at 12 weeks after the end of treatment (sustained virological response [SVR]12)., Results: SVR12 rates were 92.3% (24/26) for both q8h and q12h. The changes in mean log10 HCV RNA levels and viral response were also similar in q8h compared to q12h, whereas pharmacokinetic properties such as maximum plasma concentration, area under the concentration-time curve at 24 h and trough plasma concentration of TVR were slightly higher in q8h than in q12h (P>0.2). The frequency of TVR discontinuation due to anaemia or renal damage was significantly higher in q12h than in q8h (6/26 [23%] versus 0/20 [0%], respectively; P=0.02)., Conclusions: TVR given at 12 h intervals should be considered for patients with lower body weight, especially patients with prior relapse and with IL28B polymorphisms at rs8099917 TT (interferon-λ 4 ss469415590 polymorphism TT/TT) genotype in patients with genotype 1b HCV infection.

Background: New direct-acting antiviral agents are currently being developed to treat chronic HCV. The efficacy and safety of daclatasvir combined with peginterferon alfa-2a (alfa-2a) and ribavirin were assessed in a randomized, double-blind Phase IIa study of Japanese patients with chronic HCV genotype-1 infection., Methods: Japanese patients who were treatment-naive (n=25) or prior null (n=12) or partial (n=5) responders received once-daily daclatasvir 10 mg or 60 mg or placebo in combination with alfa-2a and ribavirin. Daclatasvir recipients with a protocol-defined response (HCV RNA<15 IU/ml at week 4 and undetectable at week 12) were treated for 24 weeks; placebo recipients and patients without a protocol-defined response were treated for 48 weeks., Results: Sustained virological response at 24 weeks post-treatment (SVR24) was achieved by 89% and 100% of treatment-naive patients receiving daclatasvir 10 mg and 60 mg, respectively, versus 75% in placebo recipients. Virological failure was more frequent in prior non-responder patients, with 50% and 78% achieving SVR24 in daclatasvir 10 mg and 60 mg groups, respectively. Adverse events occurred with similar frequency among treatment groups and were consistent with the adverse event profile of alfa-2a/ribavirin alone. The most commonly reported adverse events included pyrexia, alopecia, anaemia, lymphopenia, neutropenia, pruritus and diarrhoea. Three patients discontinued treatment due to anaemia., Conclusions: Daclatasvir combined with alfa-2a/ribavirin in treatment-naive patients showed greater efficacy than alfa-2a/ribavirin alone and was generally well tolerated. The 60-mg dose of daclatasvir achieved the highest rates of SVR24 in both treatment-naive and non-responder populations and will be evaluated in a Phase III clinical trial.

Background: Daclatasvir-containing regimens have the potential to address limitations of current regimens combining peginterferon alfa and ribavirin with first-generation protease inhibitors for treatment of chronic HCV genotype 1 infection., Methods: In this randomized, double-blind study, 27 Japanese treatment-naive patients received once-daily daclatasvir 10 mg or 60 mg or placebo, each combined with peginterferon alfa-2b/ribavirin; 18 prior null (n=9) or partial (n=9) responders received the same daclatasvir-containing regimens without a placebo arm. Daclatasvir recipients with protocol-defined response (HCV RNA<15 IU/ml at week 4, undetectable at week 12) were treated for 24 weeks; those without protocol-defined response and placebo recipients continued treatment to week 48., Results: Sustained virological response 24 weeks post-treatment (SVR24) was achieved by 66.7%, 90.0% and 62.5% of treatment-naive patients in the daclatasvir 10 mg, 60 mg and placebo groups, respectively. Prior non-responders had more frequent virological failure; 22.2% and 33.3% of daclatasvir 10 mg and 60 mg recipients, respectively, achieved SVR24. Adverse events were similar across groups and were typical of peginterferon alfa-2b/ribavirin. Pyrexia, headache, alopecia, decreased appetite and malaise were the most common adverse events; two daclatasvir recipients discontinued due to adverse events., Conclusions: Daclatasvir 60 mg combined with peginterferon alfa-2b and ribavirin achieved a high rate of SVR24 in treatment-naive patients with HCV genotype 1 infection, with tolerability similar to that of peginterferon alfa-2b/ribavirin alone. However, regimens with greater antiviral potency are needed for prior non-responders.

The prevalence of hepatitis C virus (HCV) infection in elderly patients has been increasing in Japan. However, there are no reports on the safety and efficacy of the triple therapy of telaprevir, peginterferon, and ribavirin for elderly patients with chronic HCV infection. This study evaluated the safety and efficacy of triple therapy [12 weeks of telaprevir 1,500 mg/day, reduction dose, and 24 weeks of peginterferon and ribavirin] in 18 elderly Japanese patients aged >65 years, with chronic infection with HCV genotype 1b. Four patients received triple therapy with telaprevir 2,250 mg/day and the other 14 patients received telaprevir 1,500 mg/day. Sustained virological response-12 (HCV RNA negativity at 12 weeks after completion of therapy) was 50% (9 of 18 patients); while 4 of 18 (22%) patients discontinued triple therapy due to adverse events (skin rashes, anemia, poor appetite). The dose of telaprevir did not affect HCV RNA clearance rates. Regardless of the dose, 50% of the treated patients achieved sustained virological response-12, evaluated by intention-to-treat analysis. Furthermore, the fall in hemoglobin and the rise in serum creatinine were significantly milder in the telaprevir 1,500 mg group than the telaprevir 2,250 mg/day group. Further analysis showed that 67% (6 of 9 elderly patients) with IL28B gene (rs8099917) genotype TT, treated with telaprevir 1,500 mg, achieved sustained virological response-12. These results suggest that 24-week triple therapy with telaprevir 1,500 mg seems safe and efficacious for elderly Japanese patients infected with HCV genotype 1b., (Copyright © 2013 Wiley Periodicals, Inc.)

Using ultra-deep sequencing technology, the present was designed to investigate whether the emergence of telaprevir-resistant variants (amino acid substitutions of aa36, aa54, aa155, aa156, and aa170 positions in HCV NS3 region) after commencement of triple therapy of telaprevir/peginterferon (PEG-IFN)/ribavirin could be predicted at baseline in previous non-responders to dual therapy. Fourteen patients infected with HCV genotype 1 who did not respond to previous PEG-IFN/ribavirin, received a 24-week regimen of triple therapy, and were evaluated for appearance of telaprevir-resistant variants (amino acid substitutions of more than 0.2% among the total coverage) by ultra-deep sequencing. The sustained virological response rate was 28.6% (4 of 14 patients), which was significantly higher in patients with Arg70 (substitution at core aa70) and partial response (type of previous response to PEG-IFN/ribavirin) than in other patients. Telaprevir-resistant variants at baseline were detected in 7.1% (1 of 14 patients) by direct sequencing and in 21.4% (3 of 14 patients) by ultra-deep sequencing. The appearance of telaprevir-resistant variants was examined by ultra-deep sequencing in 10 who did not show sustained virological responders. De novo variants emerged at re-elevation of viral load, regardless of variant frequencies at baseline (one patient with very high frequency variants [T54S: 99.9%], two patients with very low frequency variants [V36A: 0.2%; and V170A: 0.4%], and seven patients of undetectable variants). It is concluded that it is difficult to predict at baseline the emergence of telaprevir-resistant variants after commencement of triple therapy in prior non-responders of HCV genotype 1, even with the use of ultra-deep sequencing., (Copyright © 2013 Wiley Periodicals, Inc.)

Objective: Anticarcinogenic activity of ribavirin combination therapy for hepatitis C virus (HCV)-related compensated cirrhosis is still unclear., Methods: In study 1, in 157 consecutive patients with HCV-related compensated cirrhosis, treatment efficacy with interferon plus ribavirin therapy was evaluated for 48 weeks of HCV genotype 1b (HCV-1b) or 24 weeks of HCV-2a/2b. In study 2, in 185 consecutive patients with HCV-related compensated cirrhosis, who showed no sustained virological response following the first course of interferon monotherapy, hepatocarcinogenesis rates were evaluated according to the additional treatment, and they were classified into three groups: no treatment, interferon monotherapy, and ribavirin combination therapy., Results: In study 1, in HCV-1b, rates of sustained virological response and sustained biochemical response were 21 and 56%, respectively. In HCV-2a/2b, rates of sustained virological response and sustained biochemical response were 70 and 78%, respectively. In HCV-1b, sustained biochemical response rates were significantly higher than those of sustained virological response. In study 2, the hepatocarcinogenesis rates in ribavirin combination therapy were significantly lower than those in interferon monotherapy and no treatment, respectively., Conclusion: Ribavirin combination therapy for HCV-related compensated cirrhosis reduces the risk of hepatocarcinogenesis in comparison with interferon monotherapy, and higher rates of sustained biochemical response might be associated with lower hepatocarcinogenesis rates., (Copyright © 2012 S. Karger AG, Basel.)

The impacts of IL28B genotype to treatment response of hepatitis C virus (HCV) genotype 2 are still not clear. A total of 381 consecutive Japanese patients infected with HCV genotype 2, who could complete combination therapy with interferon (IFN) plus ribavirin for 24 weeks, were evaluated to investigate pretreatment predictors. Patients, who could not achieve sustained virological response at the first course of 24-week IFN plus ribavirin, were recruited into the study protocol of total 48-week IFN plus ribavirin. In 24-week regimen, rates of sustained virological response and rapid virological response were 82% and 50%, respectively. There were no significant differences in rates of sustained virological response and rapid virological response, according to IL28B genotype. Multivariate analysis identified younger age, higher level of albumin, absence of past history of IFN, and lower level of viremia as significant determinants of sustained virological response. As significant or marginal significant determinants of non-sustained virological response regardless of rapid virological response, multivariate analysis identified IL28B rs8099917 genotype TG + GG and lower level of albumin. In 48-week regimen to 10 patients of non-sustained virological response at the first course of 24-week regimen, sustained virological response rates were 70%. All of six patients, with IL28B TT and relapse at the first course of 24-week regimen, could achieve sustained virological response, but two patients with IL28B TG could not achieve sustained virological response. In conclusion, the present results suggest that IL28B genotype might partly affect viral response of HCV genotype 2 to combination therapy., (Copyright © 2012 Wiley Periodicals, Inc.)

Patients who do not achieve sustained virological response to telaprevir/peginterferon (PEG-IFN)/ribavirin need to be identified. Predictive factors of virological response to the triple therapy in non-responders to previous PEG-IFN/ribavirin therapy are not clear. The aims of this study were to determine the predictive factors of virological response to a 24-week regimen of triple therapy in 15 non-responders to previous PEG-IFN/ribavirin therapy among 61 Japanese adults infected with HCV genotype 1. Overall, sustained virological response and end-of-treatment response were achieved by 27% and 60%, respectively. Telaprevir-resistant variants (by direct sequencing) appeared during or after treatment in 82% of patients who did not show sustained virological response, but disappeared at the end of study, except for one patient with resistant variant at baseline. Substitution at aa 70 (Arg70) and type of previous response to PEG-IFN/ribavirin (partial response) were identified as significant determinants of sustained virological response. In addition, alpha-fetoprotein level (<10 µg/L) and type of previous response (partial response) were identified as significant determinants of end-of-treatment response. Prediction of response to therapy based on the combination of these factors had high sensitivity, specificity, positive, and negative predictive values. In conclusion, this study identified amino acid substitution of the core region, alpha-fetoprotein level, and type of previous response as predictors of virological response to telaprevir/PEG-IFN/ribavirin in patients infected with HCV genotype 1b who had not responded to previous PEG-IFN/ribavirin therapy., (Copyright © 2012 Wiley Periodicals, Inc.)

Objective: To evaluate predictive factors of treatment efficacy to interferon (IFN)/ribavirin in patients infected with HCV genotype 1b (HCV-1b)., Methods: This study investigated pretreatment predictors, including viral- (aa substitutions in core aa 70/91 and NS5A-ISDR/IRRDR) and host-related factors (genetic variation near IL28B gene), to 48-week IFN/ribavirin in 490 Japanese adults infected with HCV-1b., Results: The proportion of patients who showed end-of-treatment response (ETR), sustained virological response (SVR), and SVR after ETR was 76, 54, and 76%, respectively. There was a significant positive correlation between the number of aa substitutions in ISDR and those in IRRDR. Concerning the substitution of core aa 91, the number of aa substitutions in ISDR/IRRDR of patients with Leu91 was significantly higher than that of patients with Met91. Furthermore, levels of viremia were influenced by aa substitutions in core aa 91 and ISDR/IRRDR. By multivariate analysis, rs8099917 genotype was an important predictor of ETR and SVR. With regard to viral factors, core aa 70/91 was an important predictor of ETR, and SVR after ETR. ISDR was an important predictor of SVR, and SVR after ETR., Conclusion: aa substitution in core/NS5A region and genetic variation near IL28B were important predictors of treatment efficacy to IFN/ribavirin., (Copyright © 2011 S. Karger AG, Basel.)

Background & Aims: To evaluate the efficacy and safety of telaprevir in combination with peginterferon-α2b (PEG-IFN) and ribavirin (RBV) in patients with chronic hepatitis C., Methods: In a multi-center randomized clinical trial in Japan, on patients infected with HCV of genotype 1, 126 patients were assigned to telaprevir for 12 weeks along with PEG-IFN and RBV for 24 weeks (Group A), while 63 to PEG-IFN and RBV for 48 weeks (Group B)., Results: HCV RNA disappeared more swiftly in patients in Group A than B, and the frequency of patients without detectable HCV RNA at week 4 (rapid virological response (RVR)) was higher in Group A than B (84.0% vs. 4.8%, p <0.0001). Grade 3 and 4 skin disorders, including Stevens-Johnson syndrome and drug rashes with eosinophilia and systemic symptoms, as well as Grade 3 anemia (<8.0 g/dl), occurred more frequently in Group A than B (skin disorders, 11.9% vs. 4.8%; anemia, 11.1% vs. 0.0%). The total RBV dose was smaller in Group A than B (47.0% vs. 77.7% of the target, p <0.0001). Despite these drawbacks, sustained virological response (SVR) was achieved more frequently in Group A than B (73.0% vs. 49.2%, p=0.0020)., Conclusions: Although the triple therapy with telaprevir-based regimen for 24 weeks resulted in more adverse events and less total RBV dose than PEG-IFN and RBV for 48 weeks, it was able to achieve higher SVR within shorter duration by carefully monitoring adverse events and modifying the RBV dose as required., (Copyright © 2011. Published by Elsevier B.V.)

Background: Pegylated interferon, ribavirin, and telaprevir triple therapy is a new strategy expected to eradicate the hepatitis C virus (HCV) even in patients infected with difficult-to-treat genotype 1 strains, although adverse effects, such as anemia and rash, are frequent., Methods: We assessed efficacy and predictive factors for sustained virological response (SVR) for triple therapy in 94 Japanese patients with HCV genotype 1. We included recently identified predictive factors, such as IL28B and ITPA polymorphism, and substitutions in the HCV core and NS5A proteins., Results: Patients treated with triple therapy achieved comparatively high SVR rates (73%), especially among treatment-naive patients (80%). Of note, however, patients who experienced relapse during prior pegylated interferon plus ribavirin combination therapy were highly likely to achieve SVR while receiving triple therapy (93%); conversely, prior nonresponders were much less likely to respond to triple therapy (32%). In addition to prior treatment response, IL28B SNP genotype and rapid viral response were significant independent predictors for SVR. Patients with the anemia-susceptible ITPA SNP rs1127354 genotype typically required ribavirin dose reduction earlier than did patients with other genotypes., Conclusions: Analysis of predictive factors identified IL28B SNP, rapid viral response, and transient response to previous therapy as significant independent predictors of SVR after triple therapy.

Background/aims: Anemia is commonly observed as a side effect in a treatment with protease inhibitors combined with peginterferon alpha and ribavirin for hepatitis C virus infection. This study assessed the safety, tolerability, viral kinetics, and selection of variants in telaprevir monotherapy for 24 weeks, and outcomes of the off-study treatment with peginterferon alpha-2b and ribavirin among Japanese female patients at a median age of 54 years who were difficult to treat with the standard therapy (peginterferon alpha-2b and ribavirin) alone in Japan., Methods: Four treatment-naïve patients with chronic hepatitis C virus subtype 1b infection received telaprevir (750 mg every 8 h) alone for 24 weeks. All patients then started the off-study treatment with peginterferon alpha-2b and ribavirin. Safety, tolerability, hepatitis C virus RNA levels, and emergence of telaprevir-resistant variants were monitored., Results: During the 24 weeks of telaprevir monotherapy, there was no discontinuation due to adverse events, but 2 patients stopped the intake at weeks 6 and 15 because of viral breakthrough. Emergence of telaprevir-resistant variants was observed in 3 patients who showed viral breakthrough. These variants were eliminated by the off-study treatment, and sustained virological response was achieved in all patients., Conclusions: Anemia was manageable by carefully adjusting the ribavirin dosage in the standard therapy that followed telaprevir monotherapy. This sequential regimen seems to be safer and more tolerable than the triple combination of telaprevir, peginterferon alpha, and ribavirin, especially among elderly females with low baseline hemoglobin.

Unlabelled: Polymorphisms of the inosine triphosphatase (ITPA) gene influence anemia during pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy, but their effects during triple therapy with PEG-IFN, RBV, and telaprevir are not known. Triple therapy for 12 weeks, followed by PEG-IFN and RBV for 12 weeks, was given to 49 patients with RBV-sensitive (CC at rs1127354) and 12 with RBV-resistant (CA/AA) ITPA genotypes who had been infected with hepatitis C virus (HCV) of genotype 1. Decreases in hemoglobin levels were greater in patients with CC than CA/AA genotypes at week 2 (-1.63 ± 0.92 vs. -0.48 ± 0.75 g/dL, P = 0.001) and week 4 (-3.5 ± 1.1 vs. -2.2 ± 0.96, P = 0.001), as well as at the end of treatment (-2.9 ± 1.1 vs. -2.0 ± 0.86, P = 0.013). Risk factors for hemoglobin <11.0 g/dL at week 4 were female gender, age >50 years, body mass index (BMI) <23, and CC at rs1127354 by multivariate analysis. RBV dose during the first 12 weeks was smaller in patients with CC than CA/AA genotypes (52 ± 14% vs. 65 ± 21% of the target dose, P = 0.039), but the total RBV dose was no different between them (49 ± 17% and 54 ± 18% of the target, P = 0.531). Sustained virological response (SVR) was achieved in 70% and 64% of them, respectively (P = 0.724)., Conclusion: ITPA polymorphism influences hemoglobin levels during triple therapy, particularly during the first 12 weeks while telaprevir is given. With careful monitoring of anemia and prompt adjustment of RBV dose, SVR can be achieved comparably frequently between patients with CC and CA/AA genotypes., (Copyright © 2010 American Association for the Study of Liver Diseases.)

Objective: The aim of this study was to evaluate the efficacy and safety of combination therapy of natural human interferon-beta and ribavirin for patients for whom prior interferon therapy was discontinued due to depression induced by interferon-alpha., Methods: Inclusion criteria were as follows; 1) HCV-genotype 1b, 2) serum HCV RNA level of ≥100 KIU/mL, 3) stopping the prior interferon-alpha monotherapy or combination therapy of interferon-alpha and ribavirin due to the appearance of depression. A total of 14 were enrolled in this prospective cohort study. The treatment period of combination therapy was 48 weeks. Depression states, reflected by Beck depression inventories and Hamilton depression rating scale, were assessed during combination therapy. Nonparametric procedures were employed for the analysis of background features of the patients with sustained virological response (SVR) and without SVR. A p value of <0.05 was considered to indicate a significant difference., Results: Five of 14 patients (37.5%) had SVR by the intention to treat analysis. The SVR rate in patients who showed negative HCV RNA at 12 and 24 weeks after the initiation of combination therapy was 100% (4/4) and 83.3% (5/6), respectively. All of the patients continued the combination therapy owing to disappearance of severely adverse events contained the exacerbation of depression. Combination therapy did not yield a statistical difference in Beck depression inventories and Hamilton depression rating scale., Conclusion: The combination therapy of IFN-beta and ribavirin is a possible therapy selection for the patients for whom interferon therapy was discontinued due to depression induced by interferon-alpha.

Background & Aims: Ribavirin-induced anemia is one of the major causes of discontinuation and dose reduction during anti-hepatitis C virus therapy. Factors influencing this anemia, especially host genetic factors, are poorly understood. In this study we investigated predictive factors in hepatitis C virus patients treated with combination therapy., Methods: We performed a 2-step genome-wide screening followed by replication analysis and fine-mapping using a total of 923 Japanese hepatitis C virus 1b-infected patients treated with pegylated-interferon plus ribavirin. We also applied logistic regression analysis to search for possible independent associations of clinical parameters and genetic variants with treatment-induced hemoglobin (Hb) decline as well as treatment outcomes., Results: We identified a variant, located upstream of the inosine triphosphate pyrophosphatase gene on chromosome 20p13 that is significantly associated with treatment-induced anemia (combined P = 6.0 × 10(-14)). Resequencing and fine-mapping revealed several single nucleotide polymorphisms (SNPs) strongly associated with Hb decline, including the nonsynonymous SNP rs1127354 (P = 3.5 × 10(-44)), which was recently reported for other ethnic groups. Another reported SNP, the splicing variant-related SNP rs7270101, was not polymorphic in the Japanese population. Stratified analysis based on rs1127354 genotype revealed that inosine triphosphate pyrophosphatase expression is not correlated with Hb decline, suggesting that rs1127354 is a direct causal variant in the Japanese population. Multivariate analysis demonstrated that age, baseline Hb, baseline platelet count, and rs1127354 were independently associated with severe anemia (Hb <10 g/dL)., Conclusions: A missense substitution in inosine triphosphate pyrophosphatase gene affects ribavirin-induced anemia in hepatitis C virus-infected Japanese patients., (Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Genetic variation near the IL28B gene and substitution of amino acid (aa) 70 and 91 in the core region of hepatitis C virus (HCV) genotype 1b can predict the response to pegylated interferon (PEG-IFN)/ribavirin combination therapy, but its impact on triple therapy of telaprevir/PEG-IFN/ribavirin is not clear. The aims of this study were to investigate the predictive factors of sustained virological response to a 12-week or 24-week regimen of triple therapy in 72 of 81 Japanese adults infected with HCV genotype 1. Overall, sustained virological response and end-of-treatment response were achieved by 61% and 89%, respectively. Especially, the sustained virological response was achieved by 45% and 67% in the 12- and 24-week regimens, respectively. Multivariate analysis identified rs8099917 near the IL28B gene (genotype TT) and substitution at aa 70 (Arg70) as significant determinants of sustained virological response. Prediction of response to therapy based on a combination of these factors had high sensitivity, specificity, and positive and negative predictive values. The efficacy of triple therapy was high in the patients with genotype TT, who accomplished sustained virological response (84%), irrespective of substitution of core aa 70. In the patients having genotype non-TT, those of Arg70 gained high sustained virological response (50%), and sustained virological response (12%) was the worst in patients who possessed both genotype non-TT and Gln70(His70)., Conclusion: This study identified genetic variation near the IL28B gene and aa substitution of the core region as predictors of sustained virological response to a triple therapy of telaprevir/PEG-IFN/ribavirin in Japanese patients infected with HCV genotype 1b.

Substitution of amino acid (aa) 70 and 91 in the core region of hepatitis C virus (HCV) genotype 1b can predict the response to pegylated interferon (PEG-IFN)/ribavirin combination therapy, but its impact on triple therapy of telaprevir/PEG-IFN/ribavirin is not clear. The aims of this study were to investigate the rate of HCV RNA loss following 12-week triple therapy, and determine the effect of aa substitutions on very early (within 48 hr) viral dynamics. Sixty-seven patients infected with HCV genotype 1b (HCV-1b) and high viral load who received 12-week triple therapy were studied. RNA loss could be achieved in 2%, 34%, 80%, 92%, 95%, 94%, and 90% of the patients after 1, 2, 4, 6, 8, 10, and 12 weeks of triple therapy, respectively. After 24-hr treatment, the proportion of patients with Arg70 and Leu91 substitutions with > or = 3.0 log fall in HCV RNA was significantly higher than those with < 3.0 log fall (P = 0.008). However, the aa substitution patterns in the core region did not influence the fall in HCV RNA after 48-hr treatment. Multivariate analysis identified substitutions of aa 70 and 91 (P = 0.014) and level of viremia at baseline (> or = 7.0 log IU/ml; P = 0.085) as independent parameters that determined the > or = 3.0 log fall in HCV RNA level after 24-hr triple therapy. It is concluded that 12-week triple therapy achieved high rates of loss of HCV RNA in Japanese patients infected with HCV-1b and high viral load, and that the aa substitution pattern in the core region seems to influence very early viral dynamics., (2010 Wiley-Liss, Inc.)

Objective: The aim of this study was to evaluate the efficacy of combination therapy of natural human interferon-beta and ribavirin in patients infected with hepatitis C virus (HCV) genotype 2 and high virus load., Methods: Inclusion criteria were HCV-genotype 2, serum HCV RNA level of >or=100 KIU/mL before combination therapy. A total of 24 were enrolled in this retrospective cohort study. The treatment period of combination therapy was 24 weeks., Results: Of the 24 study patients, no patient stopped the treatment due to treatment-related adverse events. The dose of drugs were reduced in 8 patients. Twenty-one of 24 patients (87.5%) had sustained virological response (SVR) by the intention to treat analysis. The rate of negative HCV RNA at 8 week after the initiation of treatment was 18/21 (86%) in patients with SVR and 1/3 (33%) in patients with non-SVR. Logistic regression analysis showed that SVR occurred when serum HCV RNA at 8 week after the initiation of combination therapy was negative (hazard ratio: 40.0; 95% confidence interval=1.75-914.78; p=0.021), Conclusion: The combination therapy of IFN-beta and ribavirin offers sufficient safety and efficacy in chronic hepatitis C patients with genotype 2 and high virus load.

Objective: The aim of this study was to evaluate the efficacy of combination therapy of natural human interferon-beta and ribavirin in patients infected with hepatitis C virus (HCV) genotype 1b., Methods: Inclusion criteria were HCV-genotype 1b, serum HCV RNA level of >or=100 KIU/ml before the initiation of treatment. A total of 40 patients were enrolled in this retrospective cohort study. The treatment period of combination therapy was 48 weeks. Nonparametric procedures were employed for the analysis of background features of the patients with SVR and without SVR. A p value of <0.05 was considered to indicate a significant difference., Results: Of the 40 study patients, ten had mental disorders before the initiation of combination therapy. One of the patients stopped the treatment due to exacerbation of depression and another patient stopped due to a skin rash. Three patients suspended the therapy due to an insufficient response of positive serum HCV RNA at 24 weeks after the initiation of treatment. Thus, 34 patients completed combination therapy. Fifteen had sustained virological response (SVR). The SVR rate in patients who showed negative HCV RNA 8 weeks after the initiation of combination therapy was 86.7% (13/15). On the other hand, the SVR rate in patients who showed positive HCV RNA at 8 weeks was 8% (2/25) (p<.001). Continuous period of negative serum HCV RNA was 33.1 weeks in SVR groups, and 12.5 weeks in non-SVR groups (p<.001)., Conclusion: The combination therapy of IFN-beta and ribavirin is a possible therapy selection for patients with type C hepatitis of genotype 1b and high virus load.

Objective: In treatment-resistant patients with genotype 2 chronic hepatitis C the suitable treatment duration is still unclear. The aims were to investigate extending combination therapy with peginterferon plus ribavirin for genotype 2., Methods: 7 patients infected with genotype 2 at a high viral load and who did not achieve a sustained virological response (SVR) with the first course of 24-week IFN plus ribavirin were recruited into the study protocol with a total of 48 weeks of peginterferon plus ribavirin therapy., Results: SVR was achieved in 5 of 7 patients (71%). All 4 patients (100%) who were in relapse with the first course achieved SVR. Only 1 of 3 patients (33%) who had a non-virological response (NVR) with the first course achieved SVR. All 4 patients who had an early virological response (EVR) with the first course achieved EVR and SVR. Two of 3 patients who had no EVR with the first course also did not achieve EVR and SVR. One patient who had no EVR or a NVR during the first course achieved EVR and SVR with the second course., Conclusions: Our results suggest that extending combination therapy for genotype 2 chronic hepatitis C might be useful for patients who relapse following 24-week combination therapy., (2010 S. Karger AG, Basel.)

Background: Response to treatment in patients with chronic hepatitis C, with reference to age and gender, has not been examined fully., Aim: The influence of gender and age on treatment with pegylated interferon (PEG-IFN) and ribavirin was evaluated in a retrospective study., Methods: PEG-IFN and ribavirin were given for 48 weeks to 179 men and 121 women infected with hepatitis C virus (HCV) of genotype 1b in high viral loads (>100 kIU/ml)., Results: Sustained virological response at 24 weeks after treatment was poorer in women than men who were aged >or=50 years (22% vs 53%, P < 0.001). Among the patients aged >or=50 years who had received >or=80% of the doses of PEG-IFN, ribavirin, or both, women responded less often than men (26% vs 64%, P < 0.001; 33% vs 61%, P = 0.022; and 32% vs 63%, P = 0.016; respectively). In multivariate analysis, male gender, retention of indocyanine green, ribavirin dose and compliance with therapy increased sustained virological response., Conclusions: Response to combined PEG-IFN and ribavirin is poorer in female than male patients with hepatitis C who are aged >or=50 years, irrespective of compliance with treatment. Low estrogen levels in older women could be responsible for their impaired response to PEG-IFN and ribavirin.

Unlabelled: Diabetes is present in patients with chronic hepatitis C virus infection. The aim of this retrospective cohort study was to assess the cumulative development incidence and predictive factors for type 2 diabetes after the termination of interferon therapy in Japanese patients positive for hepatitis C virus (HCV). A total of 2,842 HCV-positive patients treated with interferon (IFN) monotherapy or combination therapy with IFN and ribavirin were enrolled. The mean observation period was 6.4 years. An overnight (12-hour) fasting blood sample or a casual blood sample was taken for routine analyses during follow-up. The primary goal was the onset of type 2 diabetes. Evaluation was performed by using the Kaplan-Meier method and Cox proportional hazard analysis. Of 2,842 HCV patients, 143 patients developed type 2 diabetes. The cumulative development rate of type 2 diabetes was 3.6% at 5 years, 8.0% at 10 years, and 17.0% at 15 years. Multivariate Cox proportional hazard analysis revealed that type 2 diabetes development after the termination of IFN therapy occurred when histological staging was advanced (hazard ratio 3.30; 95% confidence interval [CI] 2.06-5.28; P < 0.001), sustained virological response was not achieved (hazard ratio 2.73; 95% CI 1.77-4.20; P < 0.001), the patient had pre-diabetes (hazard ratio 2.19; 95% CI 1.43-3.37; P < 0.001), and age was >or=50 years (hazard ratio 2.10; 95% CI 1.38-3.18; P < 0.001)., Conclusion: Our results indicate sustained virological response causes a two-thirds reduction in the risk of type 2 diabetes development in HCV-positive patients treated with IFN.

Substitution of amino acid (aa) 70 and 91 in the core region of HCV genotype 1b is a useful pretreatment predictor of efficacy of 48-week peginterferon (PEG-IFN) plus ribavirin (RBV) therapy. Here, we determined the efficacy of 72-week PEG-IFN/RBV and the predictive factors to such therapy in a case-control study matched for sex, age, and periods from the start of treatment to initial point of HCV RNA-negative. We compared the treatment efficacy of 72-week regimen in 65 patients with that of 48-week in 130 patients, who were infected with HCV genotype 1b and treated with PEG-IFN/RBV. They consisted mainly of late virological responders (LVR) (HCV RNA-positive at 12 weeks and negative at 24 weeks after start of treatment). Sustained virological response (SVR) was achieved by 61.5% and 32.3% of patients of the 72- and 48-week groups, respectively, while non-virological response was noted in 9.2% and 29.2% of the respective groups. Multivariate analysis identified substitution of aa 70 and 91 (Arg70 and/or Leu91) and duration of treatment (72-week) as independent parameters that significantly influenced SVR. For Arg70 and/or Leu91 of core region, SVR rate was significantly higher in 72- (68.0%) than 48-week group (37.8%). For wild-type of ISDR, SVR rate was significantly higher in 72- (61.2%) than in 48-week group (29.3%). We conclude that 72-week PEG-IFN/RBV improves SVR rate for LVR, especially those with Arg70 and/or Leu91 of core region or wild-type of ISDR. Substitution of aa 70 and 91 is also a useful pretreatment predictor of response to 72-week PEG-IFN/RBV., (Copyright 2009 Wiley-Liss, Inc.)

Objective: Response to pegylated (PEG) interferon (IFN) and ribavirin is achieved only in 40-50% of patients infected with hepatitis C virus (HCV) of genotype 1 in high viral loads, which needs to be improved., Methods: In an open-label pilot study, fluvastatin (HMG-CoA reductase inhibitor), 20 mg daily, was given along with PEG-IFN/ribavirin to 21 patients with chronic hepatitis C. They were followed for HCV RNA in serum., Results: During treatment for 48 weeks, HCV RNA was lost from serum in 93% of the patients. In the 15 patients who received 48-week therapy, a sustained virological response (SVR) with loss of HCV RNA 24 weeks after completion was achieved in 10 (67%), including 7 of the 9 (78%) male and 3 of the 6 (50%) female patients. In the remaining 6 patients who received 72-week therapy, SVR was gained in 4 (67%), including 1 of the 2 male and 3 of the 4 female patients aged 56, 58 and 62 years, respectively., Conclusion: Fluvastatin could be used safely to increase the response to PEG-IFN and ribavirin, especially in aged women who respond poorly to combined PEG-IFN/ribavirin., (Copyright 2009 S. Karger AG, Basel.)

Background: Substitution of amino acids (aa) 70 and 91 in the core region of HCV genotype 1b is a useful pretreatment predictor of poor response to interferon + ribavirin combination therapy, but the impacts of aa substitutions in the core region of HCV genotype 2a are still not clear., Methods: 154 consecutive Japanese adults with a high viral load (> or =100 kIU/ml) of genotype 2a who could complete combination therapy for 24 weeks were evaluated. To examine the differences in virological characteristics between non-sustained virological response (non-SVR) and rapid responder (SVR patients who could achieve a HCV-RNA-negative status within 8 weeks), 86 patients could be analyzed by pretreatment substitution patterns of the core region., Results: SVR was achieved in 127 of 154 patients (83%), and rapid response in 113 of 127 (90%). In all 154 patients, multivariate analysis identified younger age, lower level of viremia, and higher level of albumin as significant determinants of SVR. As significant determinants of rapid response in 86 patients, multivariate analysis identified substitution of aa 4 (non-asparagine) in addition to the significant determinants of SVR., Conclusions: Our results suggest that the aa substitution pattern of the core region in patients with a high titer of genotype 2a may partly affect the virological response to combination therapy., (Copyright 2009 S. Karger AG, Basel.)

Objective: The aim of this study was to evaluate the efficacy of combination therapy of peginterferon and ribavirin in patients infected with hepatitis C virus (HCV) genotype 1b and low virus load., Methods: Inclusion criteria were HCV-genotype 1b, serum HCV RNA level of < 100 KIU/mL at the initiation time of treatment. A total of 60 were enrolled in this retrospective cohort study. The treatment period of combination therapy was 39.8+/-16.1 weeks., Results: Of the 60 study patients, 47 had sustained virological response (SVR) by the intention to treat analysis. SVR occurred when serum HCV RNA was negative 8 weeks after the initiation of the treatment (p=0.004) and continuance of negative HCV RNA during treatment was > or = 30 week (p=0.016). In rapid virological response, all of seven patients with continuance of negative HCV RNA 20 to 29 weeks during treatment had SVR. In early virological response nine of 10 patients with continuance of negative HCV RNA of 30 to 39 week during treatment had SVR., Conclusion: The duration of combination therapy for chronic hepatitis C should be determined based on the time of attainment of negative HCV RNA in patients with genotype 1b and low-virus load.

The dominant treatment used currently for hepatitis B is administration of interferon for 6 months or long-term administration of nucleic-acid analogs. However, since the response rate to interferon treatment is approximately only 30%, nucleic acid analogs are used primarily for the treatment of hepatitis B in our country. Among the nucleic-acid analogs, entecavir is associated with the lowest rate of emergence of mutants (approximately 3% for 3 years). On the other hand, combination therapy with interferon plus ribavirin is predominantly used in the treatment of chronic hepatitis C, and the response rate is approximately 50% in cases with genotype 1b infection and high viral loads and 90% in cases with genotype 2a/2b and high viral loads. Moreover, because interferon monotherapy has been shown to be associated with a 70% response rate in subjects with low viral loads regardless of the genotype, combined Peg-IFN plus ribavirin therapy and interferon monotherapy are mainly used for hepatitis C patients with high and low viral loads, respectively. beta-interferon is mainly used for preventing the development of cancer in patients with compensated cirrhosis, in addition to its use in cirrhosis patients with genotype 1b infection and high viral loads.

Objective: The aim of this study was to elucidate efficacy after dose reduction in combination therapy of peginterferon and ribavirin for chronic hepatitis C., Methods: Inclusion criteria were hepatitis C virus (HCV) genotype 1b, serum HCV RNA level of >/=100 KIU/ml, dose reduction of peginterferon and/or ribavirin between the first 4 weeks and 20 weeks after the initiation of treatment. 164 patients were enrolled in this retrospective cohort study. Predictive factors for sustained viral response (SVR) after dose reduction were examined., Results: Out of the 146 patients treated with dose reduction, 57 had SVR. Multivariate analysis showed that SVR occurred when serum HCV RNA at the time of dose reduction was negative (p < 0.001) and total ribavirin dose was >/=100% of the anticipated total dose (p < 0.001). 57% (55/97) of patients with undetectable serum HCV RNA at the time of dose reduction had SVR. In contrast, only 4% (2/49) of patients with detectable serum HCV RNA at the time of dose reduction had SVR., Conclusions: On dose reduction of combination therapy for chronic hepatitis C, undetectable serum HCV RNA at the time of dose reduction and attainment of the total ribavirin dose of >/=100% enhance SVR., (Copyright (c) 2008 S. Karger AG, Basel.)

Objective: The aim of this study was to determine the suitable treatment period in patients who achieve virological response during combination therapy of peginterferon and ribavirin for chronic hepatitis C virus infection., Methods: Inclusion criteria were HCV-genotype 1b, serum HCV RNA level of > or =100 KIU/ml before treatment, and negativity of serum HCV RNA during treatment. The 366 patients were enrolled in this retrospective cohort study. Patients were classified into four groups according to difference of response: rapid-virological response (RVR) at week 4 after the initiation of treatment (n=37), early-virological response (EVR) at week 5-12 (n=161), late-virological response (LVR) at week 13-24 (n=131), and superlate-virological response (SLVR) at week 25-48 (n=37). A non-relapse in patients with undetectable HCV RNA during therapy was defined as clearance of HCV RNA 6 month after the cessation of therapy., Results: Of the 366 patients, 241 had non-relapse and the non-relapse rate in each group was 89% (33/37) in RVR, 79% (127/161) in EVR, 54% (71/131) in LVR, and 27% (10/37) in SLVR. In RVR, 26 of 27 patients with continuance of negative HCV RNA of > or =30 weeks during treatment had non-relapse. In EVR, patients with period of negative HCV RNA of > or =40 weeks had non-relapse rate of 90% (71/79). In LVR and SLVR, all nine patients with continuance of negative HCV RNA of > or =60 weeks had non-relapse., Conclusion: A suitable treatment period of combination therapy for chronic hepatitis C should be determined based on the time of attainment of negative HCV RNA.

Objective: The aim of this pilot study was to determine the safety and efficacy of natural human interferon beta (nIFNbeta) plus ribavirin (RBV) in patients with chronic hepatitis C who did not respond to pegylated interferon alpha (PEG-IFN), with special emphasis on the incidence of mental disorders or refusal for fear of adverse effects., Methods: We studied 19 patients with HCV genotype 1b, 2a or 2b and a high viral load, including 8 patients with mental disorders. They were treated with nIFNbeta-RBV. Eleven patients with HCV genotype 1b of these patients were treated with nIFNbeta-RBV for 48 weeks (group A), and compared with 22 matched controls treated with PEG-IFN plus RBV for 48 weeks (group B). The other 8 patients with HCV genotype 2 were treated with nIFNbeta-RBV for 24 weeks., Results: Six of 8 patients with mental disorders and 9 of 11 patients without mental disorders completed nIFNbeta-RBV therapy; 1 patient with mental disorder dropped out due to exacerbation of depression, and 3 patients suspended the therapy due to insufficient response. The sustained virological response (SVR) was 27% (3/11) in group A and 41% (9/22) in group B (p = 0.70). During treatment, platelet count increased in group A but not in group B. SVR was 88% (7/8) in patients of genotype 2 and high viral load treated with nIFNbeta plus RBV., Conclusion: nIFNbeta-RBV therapy offers sufficient safety and efficacy for patients with mental disorders, and thus could represent an excellent second-line therapy for subpopulations that are not suitable for PEG-IFN-RBV.

For chronic hepatitis C virus (HCV) infection, evaluation of response to peginterferon (PEG-IFN) plus ribavirin (RBV) therapy based on viral kinetics is useful as an early predictor of treatment efficacy, but the underlying mechanisms of the different viral kinetics to treatment are still unclear. The response to 48-week PEG-IFN-RBV combination therapy was evaluated in 160 Japanese adult patients infected with HCV genotype 1b and determined the rapid virological response (at 4 weeks), early virological response (at 12 weeks), end-of treatment response, and sustained virological response (6 months after end of treatment). The proportion of patients who showed rapid, early and sustained virological, and end-of treatment responses were 50%, 73%, 47%, and 71%, respectively. Furthermore, 66% of patients who achieved early virological response also showed sustained virological response. Multivariate analysis identified substitutions of amino acid (aa) 70 and 91 in the HCV core region (double-wild-type) as a predictor of early HCV-RNA negativity, rapid, early, and sustained virological responses and end-of treatment response, and lipid metabolic factors (high levels of LDL cholesterol and total cholesterol) as predictors of early and rapid virological responses and end-of treatment response. Male sex and low levels of alpha-fetoprotein were other predictors of sustained virological response. Furthermore, female sex and severity of liver fibrosis were determinants of lack of sustained virological response in spite of early virological response. This study identified predictors of efficacy of PEG-IFN-RBV therapy based on viral kinetics in Japanese patients infected with HCV genotype 1b., ((c) 2007 Wiley-Liss, Inc.)

The aim of this study was to elucidate the reduction of hepatocarcinogenesis by prolonged interferon (IFN) monotherapy in aged chronic hepatitis C patients. Inclusion criteria were biopsy-proven chronic hepatitis or liver cirrhosis, 60 years and over, elevated serum aminotransferase and positive hepatitis C virus (HCV)-RNA. One hundred and twenty patients satisfied the above criteria were treated with natural IFN-alpha (dose: 3 million unit (MU), two or three times weekly for 0.5-15.5 years, mean 2.47 years) (IFN group). Another 240 patients treated with herbal medicines excluding IFN were selected as control (no-IFN group). The patients not treated with IFN were matched 2:1 with IFN group patients for sex and age. The clinical and biological differences were compared after treatment with the IFN group and the untreated group. Serum alpha-fetoprotein (AFP) level decreased with statistical significance after initiation of treatment with IFN compared to no treatment. The 5- and 10-year cumulative rates of hepatocellular carcinoma (HCC) were 5.9 and 13.7%, and 17.1 and 32.8%, for the IFN and untreated group, respectively. HCC development occurred when histologic staging was advanced, and IFN was not given, the AFP level after treatment was >10 ng/ml. Cox regression analysis indicated that the relative risk of HCC in patients in the IFN group was 0.3 times of that in the untreated patients. The relative risk rate for HCC in severe fibrosis was 3.9 compared with mild or moderate fibrosis. In conclusion, long-term IFN therapy for aged patients with chronic HCV infection is effective in decreasing the serum AFP level and preventing hepatocarcinogenesis.

Background: The efficacy and safety of peginterferon alpha-2a (40 KD) (peg-IFNalpha-2a) plus ribavirin has not been reported for Japanese patients with chronic hepatitis C. The aim of this study was to evaluate this combination in treatment-naïve patients and in non-responders or relapsers to interferon monotherapy., Methods: Overall, 201 treatment-naïve patients with hepatitis C virus (HCV) genotype-1b were randomly assigned to 180 microg peg-IFNalpha-2a once-weekly plus ribavirin 600-1000 mg/day or peg-IFNalpha-2a plus placebo for 48 weeks. Additionally, peg-IFNalpha-2a plus ribavirin was administered for 48 weeks to 100 non-responders or relapsers (85% genotype-1) to previous interferon monotherapy., Results: A sustained virological response (SVR) was attained among significantly more treatment-naïve patients receiving combination therapy than monotherapy (61% vs 26%, P < 0.001). For patients with high baseline HCV RNA, the SVR rate was 59% with peg-IFNalpha-2a plus ribavirin versus 24% with peg-IFNalpha-2a monotherapy. Among non-responders or relapsers to previous interferon monotherapy, 54% attained an SVR. Adverse events were generally mild, and discontinuations rates due to adverse events or laboratory abnormalities were low., Conclusion: In Japanese patients, peg-IFNalpha-2a plus ribavirin provided significant improvement in SVR rates compared with peg-IFNalpha-2a alone in treatment-naïve patients, and was effective as re-treatment for non-responders or relapsers to previous treatment with interferon monotherapy.

Background/aims: We showed previously that amino acid (aa) substitutions in the HCV core region (HCV-CR) are predictors of non-virological response (NVR) to peginterferon (PEG-IFN) plus ribavirin (RBV) therapy. Here, we determined the predictive factors of sustained virological response (SVR) and early virologic response (EVR) to this treatment., Methods: We evaluated the response to 48-week PEG-IFN-RBV therapy in 114 Japanese adults infected with HCV genotype 1b and determined the predictors of EVR and SVR., Results: EVR was achieved by 70% and SVR by 45% of patients. 64% of patients who achieved EVR also showed SVR, while none of non-EVR achieved SVR. Multivariate analysis identified low-density lipoprotein cholesterol (LDL-C) (>or=86 mg/dl), aa substitutions in HCV-CR (double-wild-type; arginine at aa 70/leucine at aa 91), gamma-glutamyl transpeptidase (GGT) (<109 IU/l), RBV dose (>or=11.0mg/kg), and leukocyte count (>or=4500/mm3) as significant determinants of EVR, and aa substitutions in HCV-CR (double-wild-type), LDL-C (>or=86 mg/dl), male gender, ICG R15 (<10%), GGT (<109 IU/l), and RBV dose (>or=11.0 mg/kg) as determinants of SVR. Prediction of response to therapy based on combination of these factors had high sensitivity, specificity, positive, and negative predictive values., Conclusions: Our study identified aa substitutions in the core region and serum LDL-C as predictors of response to PEG-IFN-RBV therapy in Japanese patients infected with HCV genotype 1b.

Objective: To evaluate power of amino acid polymorphisms in core protein of hepatitis C virus (HCV) for predicting sustained virological response (SVR) to pegylated interferon (Peg-IFN)/ribavirin, when they were combined with virological response., Methods: Peg-IFN/ribavirin was given to 118 patients infected with HCV genotype 1b in high viral loads. Amino acid polymorphisms (Arg70 vs. Gln70 and Leu91 vs. Met91) in combination with on-treatment virological responses were correlated with SVR., Results: End-of-treatment response (ETR) was achieved in 71% and SVR in 47% of the 118 patients. In multivariate analysis, Arg70 and Leu91, and higher ribavirin dose were independently associated with ETR. In patients with Gln70 and/or Met91, SVR was more frequent in those with than without prompt virological response (PVR) for a decrease in viral load >or=1.0 log by 48 h. Specificity in predicting patients without ETR and SVR, in combination with core polymorphisms, was not different between PVR and early virological response at 12 weeks., Conclusion: Core polymorphisms combined with PVR would be useful in promptly identifying the patients who will not respond to Peg-IFN/ribavirin, thereby avoiding unrewarding side effects and high costs., ((c) 2007 S. Karger AG, Basel.)

Objective: The aim of this study was to elucidate the side effects after combination therapy of peginterferon and ribavirin for Japanese patients with chronic hepatitis C., Methods: Inclusion criteria were HCV-genotype 1b and serum HCV RNA level of > 100 KIU/ml. Six hundred and twelve patients were received combination therapy and enrolled in this non-randomized prospective cohort study. Patients were monitored until the discontinuation of combination therapy based on treatment-related side effects. The percentage of each medication actually taken during treatment was calculated., Results: Sixty-eight patients were stopped the combination therapy due to side effects. The cumulative discontinuation rate due to side effects of therapy was 8.4% at 0.5 year and 14.9% at one year. Discontinuation rate due to side effects was high with statistically significant in the following cases: 1) patients > or = 65 years, 2) patients who had diabetes. Sustained viral response (SVR) was 17.6% (12/68) in the discontinuation group. In the discontinuation group, when the percentage of both peginterferon and ribavirin actually taken during treatment was > or = 60%, SVR was 31% (9/29). On the other hand, when the percentage of each medication actually taken during treatment was < 60%, SVR was 7.7% (3/39). In the discontinuation group, patients with adherence of > 60% to the total of scheduled dose tended to have a high SVR compared to those with < or = 60% adherence to the total of scheduled dose., Conclusion: In combination therapy, patient age and complications of patient are important factors contributing to the safety. In the discontinuation group, patients with adherence of > 60% to the total of scheduled dose tend to have a high SVR.

Objectives: The aim of this study was to evaluate whether or not combination therapy of pegylated interferon (IFN) and ribavirin for chronic hepatitis (CH) C patients enhances the serum level of KL-6, a sensitive marker for interstitial pneumonia., Methods: CH C patients proven histologically and treated with combination therapy of pegylated IFN-alpha-2b and ribavirin, IFN monotherapy or untreated for 48 weeks were retrospectively selected in chronological order in groups of 25. Serum levels of KL-6 were measured by enzyme-linked immunosorbent assay by use of serum stored at -80 degrees C before and at 12, 24, 36, 48 weeks after the initiation of treatment or follow up., Results: The average serum KL-6 levels in patients treated with combination therapy of pegylated IFN and ribavirin increased by 21% at 12 weeks after the start, 23% at 24 weeks, and 28% at 48 weeks. In patients treated with combination therapy of pegylated IFN and ribavirin, the serum KL-6 level significantly increased during treatment. Patients achieved an elevated serum KL-6 level of more than 450 U/ml with statistical significance when: 1) combination therapy was given (P=0.011), 2) serum KL-6 level pretreatment was high more than 300 U/ml (P=0.014)., Conclusion: The present study suggests that onset of interstitial pneumonia should be carefully checked in the combination therapy of pegylated-IFN and ribavirin.

Patients with high viral load (> or =1.0 x 10(5) IU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve high sustained virological response rates to interferon (IFN)/ribavirin combination therapy. Previous studies suggested that pretreatment amino acid (aa) substitution patterns in the HCV core region could affect virological non-response especially in patients who could not achieve HCV-RNA negativity during treatment. The present study evaluated 167 consecutive Japanese adults with high HCV genotype 1b viral load who received combination therapy for > or =24 weeks. A case-control study matched for age, sex, genotype, and viral load was conducted to investigate the predictive factors for virological non-response, especially absolute virological non-response (patients who could not achieve >2 log decline of HCV RNA from baseline during the initial 24 weeks of therapy). Virological non-response was identified in 26.3% of patients, and 45.5% of these were absolute virological non-responders. Multivariate analysis identified ribavirin dose <11.0 mg/kg, moderate-to-severe hepatocyte steatosis, and substitutions of aa 70 and/or 91 in the core region as significant independent factors associated with virological non-response. The majority of absolute virological non-responders had such substitutions in the core region (95.0%), as well as substitution of glutamine at aa 70 and/or methionine at aa 91 (90.0%). In the present work, such substitutions significantly affected the viral kinetics in virological non-responders. The results suggest that viral, host, and treatment-related factors determine the response to IFN/ribavirin combination therapy in patients with high HCV genotype 1b viral load, and that amino acid substitution patterns in the core region is potentially useful pretreatment predictor of virological non-response.

Objective: Ribavirin and interferon combination therapy is more effective than interferon monotherapy in patients with chronic hepatitis C virus (HCV) infection. To test the hypothesis that ribavirin induces nucleotide substitutions in the viral genome and reduces viral load by forcing it into error catastrophe in the combination therapy, we investigated the molecular evolution of HCV quasispecies in 3 patients who received combination therapy and 2 patients who received interferon monotherapy., Methods: The quasispecies were analyzed before and after therapy by sequencing at least 8 clones in five regions of the HCV genome; 5' untranslated region, EI, E2, NS5A and NS5B., Results: Marked genetic drift was observed in the NS5A and NS5B regions in patients treated with combination therapy. However, genetic distances between clones obtained after therapy were closer than those obtained before therapy., Conclusion: Our results suggest that the combination therapy modified HCV quasispecies, but that this did not reflect the induction of error catastrophe by ribavirin. Modification of quasispecies by this therapy requires further investigation in a larger number of patients to elucidate the possible mechanism of viral resistance against the combination therapy., (Copyright (c) 2006 S. Karger AG, Basel.)

Objective: Patients with high titer (>/=100 kIU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve highly sustained virological response rates to combination therapy with interferon plus ribavirin. Non-virological responders (NVRs, namely ultimate resistant cases) who do not achieve HCV-RNA negativity during treatment are also encountered. We investigated the pretreatment virological features of NVRs., Methods: We evaluated 50 consecutive Japanese adults with high titer of HCV genotype 1b who received combination therapy for 48 weeks. We investigated the pretreatment substitution patterns in amino acids 1-191 of the core region and amino acids 2209-2248 of NS5A, and early viral kinetics., Results: Overall, a non-virological response was noted in 12 (24%) patients. Multivariate analysis identified serum albumin <3.9 g/dl, substitutions of amino acid 70 in the core region, and substitutions of amino acid 91 as independent and significant factors associated with a non-virological response. Especially, substitutions of arginine (R) by glutamine (Q) at amino acid 70, and/or leucine (L) by methionine (M) at amino acid 91 were significantly more common in NVRs. The falls in HCV-RNA levels during treatment in patients with specific substitutions in the core region were significantly less than in those without such substitutions., Conclusions: Our results suggest that serum albumin and amino acid substitution patterns in the core region in patients with high titers of HCV genotype 1b may have an effect on combination therapy in NVRs. Further large-scale studies are required to examine the role of amino acid substitutions specific to a non-virological response to combination therapy., (Copyright (c) 2005 S. Karger AG, Basel.)

Objective: The purpose of this clinical retrospective cohort study was to determine the most suitable ribavirin concentration on combination therapy of interferon (IFN)-ribavirin., Methods: Entry criteria were serum HCV-RNA level >/=100 KIU/ml, HCV-genotype 1b, chronic hepatitis, and initial combination treatment of IFN-alpha-2b (6 million units daily for 2 weeks and then 3 times weekly for 6 weeks) and ribavirin (600-800 mg/day) for 8 weeks without stopping or decreasing the dosage of IFN and/or ribavirin. Sixty-eight consecutive patients who satisfied the above criteria were given maintenance therapy for another 16 weeks., Results: A sustained virological response (SVR) rate of 25.0% (17/68) was seen in all subjects. The SVR rate was 44.0% (11/25) in the high ribavirin group with a serum ribavirin concentration of >/=3,000 ng/ml at 8 weeks after initiation of combination therapy. SVR was significantly dependent at a serum ribavirin level of >/=3,000 ng/ml (p = 0.005). The incidence of discontinuations and dose modifications for combination therapy in patients having a serum ribavirin concentration of >/=3,500 ng/ml 8 weeks after initiation of therapy was 57.1% (4/7). This value was statistically higher than that in patents with <3,500 ng/ml (p = 0.033)., Conclusion: Our results showed that the most suitable serum ribavirin concentrations are from 3,000 to 3,500 ng/ml 8 weeks after initiation of combination therapy., (Copyright (c) 2005 S. Karger AG, Basel.)

An investigation was carried out to determine whether early viral monitoring could predict efficiently the virological response to combination therapy of two different regimens in treatment-naive chronic hepatitis C patients infected with genotype 1b with high baseline viral load. Patients were randomly assigned to receive interferon (IFN) alpha-2b induction (6 MU daily for 2 weeks) followed by 6 MU thrice weekly for 46 weeks (IFN/R group; n = 20), or pegylated IFN alpha-2b (1.5 microg/kg) weekly for 48 weeks (PEG/R group; n = 28), in combination with ribavirin (600-1,000 mg daily). Serum HCV RNA was quantitated at 0, 6, 12, 24, and 48 hr post-dose, weekly during the first 4 weeks, and thereafter viral kinetics were assessed every 4 weeks. The sustained virological response rates in the IFN/R and PEG/R groups were 40% (8/20) and 43% (12/28), respectively. The non-virological response rates were 40% (8/20) and 39% (11/28), respectively. The cumulative virological response rates were similar in both groups. Multivariate analyses identified no independent baseline variables linked to sustained virological or non-virological response. Early log viral load changes from baseline in both groups were significantly greater at all time-points after 24 hr in virological response patients than in non-virological response patients (P < 0.001 for all). On the receiver operating characteristics curves for prediction of non-virological response, the area under the curves (0.951-1.000), sensitivity (90%-100%), and negative predictive value (96%- 100%) were similar at any time-points after 24 hr. For prediction of sustained virological response, sensitivity of 80% with 86% negative predictive value was observed for negative HCV RNA at week 12, with the highest area under the curves value of 0.919. The results suggest that early monitoring of viral kinetics is a useful measure to predict virological response, and might facilitate development of rational and effective therapeutic strategies., (Copyright 2005 Wiley-Liss, Inc.)

Background: Hemolytic anemia is one of the major adverse events of the combination therapy of interferon and ribavirin. Because of ribavirin-related hemolytic anemia, dose reduction is a common event in this therapy. In this clinical retrospective cohort study we have examined the suitable timing of ribavirin reduction in patients with hemolysis during combination therapy., Methods: Thirty-seven of 160 patients who had HCV-genotype 1b, had high virus load, and received 24-week combination therapy developed anemia with hemoglobin level <10 g/dl or anemia-related signs during therapy. After that, these 37 patients were reduced one tablet of ribavirin (200 mg) per day. After reduction of ribavirin, 27 of 37 patients could continue combination therapy for a total of 24 weeks (group A). However, 10 of 37 patients with reduction of ribavirin could not continue combination therapy because their <8.5 g/dl hemoglobin values decreased to or anemia-related severe side effects occurred (group B). We assessed the final efficacy and safety after reduction of ribavirin in groups A and B., Results: A sustained virological response (SVR) was 29.6% (8/27) in group A and 10% (1/10) in group B, respectively. A 34.4% (12/27) of SVR + biological response in group A was higher than 10% (1/10) in group B ( P = 0.051), with slight significance. With respect to hemoglobin level at the time of ribavirin reduction, a rate of continuation of therapy in patients with > or =10 g/dl hemoglobin was higher than that in patients with <10 g/dl ( P = 0.036)., Conclusions: Reduction of ribavirin at hemoglobin level > or =10 g/dl is suitable in terms of efficacy and side effects.