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Background and Aim: Direct-acting antivirals (DAAs) have contributed to the improvement of outcomes for all patients with chronic hepatitis C. The aim of this study was to evaluate the long-term hepatic benefits of hepatitis C virus (HCV) cure by DAAs in patients with compensated cirrhosis., Methods: This multicenter cohort study consisted of consecutive patients with compensated cirrhosis who initiated interferon-free DAA treatment before September 2016. The impact of treatment on long-term hepatic function was followed for at least 4 years after the end of treatment, and the progression to decompensation was evaluated., Results: The data of 394 patients were available for study. The median age was 70, and 41% had modified albumin-bilirubin (ALBI) grade 2b. During a short-term follow-up 1 year after the end of treatment, FIB-4 index and ALBI score significantly improved. The achievement rates of FIB-4 < 3.25 (40%) and ALBI grade 1 (70%) reached their plateau in the first year; however, there were significant further improvements in platelet count and α-fetoprotein level after the first year. The annual incidence of decompensation was 1.30 (95% confidence interval 0.83-2.02) per 100 person-years. In multivariable analysis, male sex and modified ALBI grade 2b at baseline were associated with decompensation., Conclusions: In a large real-world cohort of patients with compensated cirrhosis treated with a DAA, remarkable improvement in hepatic function was seen after HCV cure, especially during the first year after the end of treatment. Treatment in the early stage of cirrhosis would be of great benefit for preventing liver deterioration to decompensation., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objectives: A number of publications have demonstrated the cost-effectiveness of sofosbuvir plus ribavirin (SOF+RBV) compared with the former standard therapy with interferon (IFN)-containing regimens. Unlike these cost-effective analyses, where efficacy parameters were obtained from registration trials for drug approval, this analysis is a cost-effectiveness analysis of SOF+RBV for genotype (GT) 2 non-cirrhosis (NC) and compensated cirrhosis (CC) patients using efficacy parameters obtained from a multicentre cohort study (Kyushu University Liver Disease Study; KULDS) in Kyushu area in Japan in order to reflect real-world clinical practice in Japan., Method: A Markov model followed 10 000 patients (62 years old) over their lifetime. Four populations were followed: treatment-naïve (TN)-NC, treatment-experienced (TE)-NC, TN-CC and TE-CC. Comparators were Peg-IFNα2b+RBV for TN-NC and CC patients and telaprevir (TVR)+Peg-IFNα2b+RBV for TE-NC patients. The sustained virological response (SVR) rates of SOF+RBV were taken from KULDS and those of comparators were obtained from systematic literature reviews. There were nine states (NC, CC, decompensated cirrhosis [DC], hepatocellular carcinoma [HCC], SVR [NC], SVR [CC], liver transplantation [LT], post-LT and death) in this model, and an increase in the progression rate to HCC due to ageing was also considered. The analysis was conducted from the perspective of a public healthcare payer, and a discount rate of 2% was set for both cost and effectiveness., Results: Incremental cost-effectiveness ratios (ICERs) of SOF+RBV versus Peg-IFNα2b+RBV were ¥323 928 /quality-adjusted life year (QALY) for TN-NC patients, ¥92 256/QALY for TN-CC patients and ¥1 519 202/QALY for TE-CC patients. The ICER of SOF+RBV versus TVR+Peg-IFNα2b+RBV was ¥849 138/QALY for TE-NC patients. The robustness of the results was determined by sensitivity analysis., Conclusions: The results of this analysis strongly demonstrate the robustness of our previous findings that SOF+RBV regimens are cost-effective in the real world and clinical trial settings for Japanese GT2 NC and CC patients., Competing Interests: Competing interests: AI received the research grants from Gilead Sciences K.K., for this study. He received grants from AbbVie GK., grants from Abbott Japan Inc., grants from Beckton Dickinson and Company, personal fees from Chugai Pharmaceuticals Inc., personal fees from Astellas Pharma Inc., grants from Eli Lilly Japan K.K., personal fees from CSL Behring Japan Inc., personal fees from Fuji film Inc., personal fees from Takeda Pharmaceutical Inc., grants from Milliman Inc., grants from Creativ-Ceuticals Inc., grants from PFIZER INC., grants from Intuitive Surgical G.K., personal fees from Sanofi Japan Inc., grants from Terumo corporation, outside the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The real-world effectiveness and safety of all-oral direct-acting antivirals (DAAs) for chronic hepatitis C (HCV) infection and chronic kidney disease (CKD) have not been fully elucidated. This study assesses elbasvir (EBR) plus grazoprevir (GZR) for patients with HCV genotype 1 infection in the clinical setting, focusing on CKD stage 3-5D. This multicenter, real-world cohort study consisted of 282 Japanese patients who were treated with EBR (50 mg) plus GZR (100 mg) for a fixed 12-week duration. We evaluated the sustained viral response rate 12 weeks after the end of treatment (SVR12), longitudinal liver and renal parameters, and adverse effects according to the cirrhosis and CKD status. Of those enrolled, 89 (31.6%) were CKD stage 3-5 and 21 (7.4%) were CKD stage 5D (hemodialysis-dependent). The overall and CKD stage 3-5D SVR12 rates in the per protocol populations were 98.6% (272/276) and 98.1% (101/103). High SVR12 rates were observed in almost all groups, except for prior all-oral DAA failure with NS5A resistance-associated substitutions. There was no significant change during treatment or follow-up period in estimated glomerular filtration rate, irrespective of CKD status. In contrast, the serum complement level (C3 and C4) increased, with significance for C3. Serious adverse effects were very rare, both in the groups with normal eGFR and CKD, and discontinuation was required for only six (2.1%) patients. EBR plus GZR for HCV genotype 1 was highly effective with a low rate of adverse effects, regardless of CKD status. In addition, liver parameters and complement levels improved longitudinally., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective Interferon-free regimens of direct-acting antiviral agents have improved the treatment response for chronic hepatitis C virus (HCV) infection, and improvement in the serum albumin level during interferon-free therapy has been reported. The aim of this study was to identify the factors that influence the improvement in the serum albumin level in patients receiving interferon-free antiviral therapy. Methods This retrospective, multicenter study consisted of 471 Japanese patients with chronic hepatitis and compensated liver cirrhosis infected with HCV who completed 12-week interferon-free sofosbuvir (SOF)-based therapy [SOF plus ledipasvir for genotype 1 (n=276) and SOF with ribavirin for genotype 2 (n=195)]. We evaluated the changes in the serum albumin level from baseline to the end of treatment (ΔAlb). Results When compared with the normal-albumin group (baseline serum albumin >35 g/L, n=406), the low-albumin group (baseline serum albumin ≤35 g/L, n=65) showed a significant increase in the mean ΔAlb (5.5 g/L vs. 1.0 g/L, p<0.001). In the low-albumin group, a multivariate logistic regression analysis extracted diabetes mellitus as a negative predictive factor of median ΔAlb >5.0 g/L (odds ratio: 0.19, 95% confidence interval: 0.048-0.79, p=0.020). In the low-albumin group, the mean ΔAlb was significantly lower in the diabetic patients (n=14) than in the non-diabetic patients (n=51) (3.9 g/L and 5.7 g/L, p=0.049). Conclusion Interferon-free SOF-based therapy significantly improved the serum albumin in the low-albumin group patients with chronic HCV infection. However, the improvement in the serum albumin level was significantly lower in the diabetic patients than in the non-diabetic patients.

Background: Little real-world cohort data has been reported for Asians who have received interferon-free regimens with sofosbuvir (SOF) for chronic hepatitis C virus (HCV) infection. We evaluated the effectiveness and safety in clinical practice of ledipasvir (LDV) plus SOF for Japanese patients infected with HCV genotype 1., Methods: This large, multicenter, real-world cohort study consisted of 772 patients treatment-naive or -experienced, with or without compensated cirrhosis, who were treated with LDV (90 mg)/SOF (400 mg) for a fixed 12-week duration. Direct sequence analysis of the NS5A genes (L31 and Y93) was performed at baseline., Results: Almost all (99.6%) were infected with HCV genotype 1b. The overall sustained virological response 12 weeks after the end of treatment (SVR12) rate was 98.8% (763/772). Multivariable logistic regression analysis extracted male (odds ratio [OR] 6.62, p = 0.024), cirrhosis (OR 20.1, p = 0.0054), and baseline NS5A resistance-associated variants (RAVs) (OR 29.3, p = 0.0018) as independently associated with treatment failure. Notably, the SVR12 rate for cirrhosis patients with baseline NS5A RAVs (87.5%, 49/56) was statistically lower than for the other groups. This tendency was found except for patients with prior daclatasvir/asunaprevir failure. All patients with treatment failure had NS5A Y93H at relapse, whether or not they had NS5A RAVs at baseline. Serious adverse effects were very rare, and discontinuation was required for only five (0.6%) patients., Conclusions: LDV/SOF for HCV genotype 1b was exceptionally effective, however, NS5A RAVs undermined the virological effect for cirrhosis patients. Moreover, LDV/SOF was shown to be safe, irrespective of age or fibrosis status.

Older patients with chronic hepatitis C virus (HCV) infection have historically been designated difficult-to-treat. We evaluated the efficacy and safety of sofosbuvir (nucleotide NS5B polymerase inhibitor) plus ribavirin for patients with HCV genotype 2 infection in a real-world clinical setting, with the focus on elderly patients aged ≥ 65. This large, multicenter study consisted of 446 Japanese HCV genotype 2 patients (303 treatment-naïve and 143 treatment-experienced), including 190 (42.6%) aged ≥ 65 and 90 (20.2%) with compensated cirrhosis. Efficacy was assessed by the sustained virological response 12 weeks post-treatment (SVR12). The overall SVR12 rate was 95.7% (427/446), and the SVR12 rate of patients aged ≥ 65 was 95.3% (181/190). For treatment-naïve patients, almost all with compensated cirrhosis (95.6%, 43/45) achieved SVR12, irrespective of age. For treatment-experienced patients, cirrhosis undermined the treatment outcome, both for the aged ≥65 (SVR12: 80.0%, 20/25) and <65 (85.0%, 17/20) patient groups when compared to non-cirrhosis patients (≥65: 95.7%, 45/47 and < 65: 96.2%, 50/52). The most common adverse effect was anemia (hemoglobin <10 g/dL), especially for patients aged ≥ 65 with the inosine triphosphate pyrophosphatase CC genotype at rs1127354 (26.2%, 33/126). Notably, ribavirin reduction was not related to treatment failure. Only three (0.7%) patients, all aged ≥ 65, discontinued treatment, but all achieved SVR12. Sofosbuvir plus ribavirin for HCV genotype 2 was effective for patients aged ≥65, especially those who were treatment-naïve or treatment-experienced/non-cirrhosis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background and Aim: The addition of hepatitis C virus (HCV) NS3/4A protease inhibitors to pegylated-interferon alpha (PEG-IFNα) and ribavirin (triple therapy) has greatly improved treatment outcome. The aim of this study was to compare the effectiveness and safety of simeprevir-based or telaprevir-based triple therapy for non-cirrhotic patients in real-world clinical practice., Methods: This multicenter study consisted of 835 consecutive Japanese HCV genotype 1b patients treated in a clinical setting, 716 of whom were enrolled (simeprevir = 256 and telaprevir = 460). Logistic regression was carried out after propensity score matching to assess the sustained virological response at week 12 after the end of treatment (SVR12)., Results: In the propensity-matched cohort (253 matched pairs), the SVR12 rates of the patients who underwent simeprevir-based or telaprevir-based triple therapy were 85.0% and 84.2%, respectively, by intention-to-treat analysis. Prior treatment response to PEG-IFNα/ribavirin and IL28B genotype was independently associated with SVR12 in both groups. No significant differences in the SVR12 rates stratified by prior treatment response to PEG-IFNα/ribavirin were found between the simeprevir (treatment-naïve 89.1%, prior relapse 94.3%, prior partial response 65.0%, and prior null response 33.3%) and telaprevir (treatment-naïve 87.8%, prior relapse 90.1%, prior partial response 68.4%, and prior null response 50.0%) groups. The incidence of adverse effects, such as anemia, severe rash, and the elevation of serum creatinine, was markedly higher in the telaprevir group., Conclusions: Considering the effectiveness and safety, simeprevir-based triple therapy will continue to be a useful treatment option in Japan for treatment-naïve or prior relapse patients with a favorable IL28B genotype., (© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Objective: There is little information regarding the incidence of bacterial infections as an adverse effect of telaprevir (TVR)-based triple therapy. This study was performed in order to evaluate the baseline and on-treatment predictors of bacterial infections in patients treated with TVR-based triple therapy., Methods: This multicenter study evaluated 430 patients with chronic hepatitis C who received 12 weeks of TVR in combination with 24 weeks of pegylated interferon α2b plus ribavirin. The occurrence of a bacterial infection during anti-viral treatment was defined as the onset of local or systemic inflammation as a result of pathogenic bacteria., Results: Bacterial infections occurred in 21 of the 430 (4.9%) patients during TVR-based triple therapy. Among these subjects, 71.4% (15 of 21) experienced bacterial infections during the initial eight weeks of treatment. Urinary tract infections were the most frequent infection, observed in 2.8% of cases (12 of 430). The rate of urinary tract infection among women (11 of 215, 5.1%) was significantly higher than that observed among men (1 of 215, 0.5%) (p<0.0001). According to a multivariable logistic regression analysis, the only significant independent predictor was the pretreatment serum albumin level (p=0.0008). Of the 21 patients who experienced bacterial infections, only one (4.8%) had to discontinue the treatment; however, the others were able to continue anti-viral treatment in combination with antibiotic treatment., Conclusion: Clinicians should be concerned regarding the incidence of bacterial infections among patients treated with TVR-based triple therapy, especially those with a low serum albumin level.

Background and Aim: Thrombocytopenia (TCP) of chronic hepatitis C patients with cirrhosis has a negative impact on the management of interferon-based treatment. The aim of this study is to evaluate the efficacy and safety of telaprevir-based triple therapy for patients who have undergone splenectomy (Spx)., Methods: This prospective, multicenter study consisted of 80 patients, including 32 Spx and 48 non-Spx/TCP (platelet count: 60-99 × 10(9) /L) patients with advanced fibrosis infected with hepatitis C virus genotype 1b. All received 12 weeks of telaprevir in combination with 24 weeks of pegylated interferon (PEG-IFN) α2b and ribavirin., Results: The sustained virological response (SVR) rate of the Spx group (75.0%) was significantly higher than that of the non-Spx/TCP group (52.1%) (P < 0.05). Under favorable conditions such as treatment-naïve/prior relapse and interleukin-28B (IL28B) TT allele (rs8099917), the SVR rates of the Spx group were significantly higher than those of the non-Spx/moderate TCP (60-79 × 10(9) /L) groups (91.3% vs 50.0% and 93.8% vs 37.5%, respectively; both P < 0.05). Adequate PEG-IFNα2b adherence was associated with SVR. However, the percentage of patients who achieved 80% adherence to PEG-IFNα2b in the non-Spx/moderate TCP (42.9%) group was significantly lower than that of the Spx (79.3%) and non-Spx/mild TCP (80-99 × 10(9) /L) (80.0%) groups. Treatment discontinuation due to adverse effects and the development of bacterial infection did not differ between the Spx and non-Spx/TCP groups., Conclusion: The increase of platelet count after Spx contributed to treatment success, especially for moderate to severe TCP patients who are treatment-naïve/prior relapse or IL28B TT allele., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Elevated serum low-density lipoprotein cholesterol (LDL-C) level has been associated with sustained virological response (SVR) by chronic hepatitis C patients treated with pegylated-interferon (PEG-IFN) α and ribavirin (RBV). The aim of this study was to investigate the relation between the baseline LDL-C level and the treatment outcome from telaprevir (TVR)-based triple therapy. This prospective, multicenter study consisted of 241 treatment-experienced patients infected with HCV genotype 1b. All received 12 weeks of TVR in combination with 24 weeks of PEG-IFNα2b and RBV. The SVR rate was 81.3% (196 of 241) by intention-to-treat analysis. Higher LDL-C level was strongly associated with SVR (P=1.3×10⁻⁸). The area under the receiver operating characteristic curve for predicting SVR was 0.78 and the cutoff value for the LDL-C level at baseline was 95 mg/dL. In multivariable logistic regression analysis of predictors of SVR, LDL-C ≥95 mg/dL (odds ratio [OR] 3.60, P=0.0238), α-fetoprotein ≤5.0 ng/mL (OR 5.06, P=0.0060), prior relapse to PEG-IFNα and RBV (OR 5.71, P=0.0008), and rapid virological response (HCV RNA undetectable at week 4) (OR 5.52, P=0.0010) were extracted as independent predictors of SVR. For prior partial and null responders, the SVR rates of the groups with LDL-C ≥95 mg/dL were significantly higher than those of the <95 mg/dL groups with IL28B TG/GG and pretreatment platelet count <150×10⁹/L (both P<0.05). The baseline LDL-C level exerted a potent influence on the SVR of treatment-experienced patients treated with TVR-based triple therapy, especially for prior partial and null responders to PEG-IFNα and RBV., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background/aims: Although the incidence of hepatocellular carcinoma (HCC) has been shown to be reduced after pegylated glycol-interferon plus ribavirin (Peg-IFN/RBV) therapy in patients with chronic hepatitis C, the risk factors for the development of HCC are not fully understood. The aim of this study was to clarify the incidence and the risk factors for the development of HCC after Peg-IFN/RBV therapy in patients with chronic hepatitis C., Methodology: A total of 474 patients with chronic hepatitis C who received Peg-IFN/RBV therapy between December 2004 and August 2010 were enrolled and followed in a multicenter trial. The patients were assessed for HCC by either ultrasound or computed tomography every 6 months. The incidence and risk factors for the development of HCC were identified., Results: Of the 474 patients, 23 developed HCC during a median follow-up of 4 years and 8 months (range 1-6 years and 3 months) after completion of Peg-IFN/RBV therapy. According to a univariate analysis, higher age, low platelet counts, a low level of serum albumin, a high level of alpha-fetoprotein (AFP) and a sustained viral response (SVR) to Peg-IFN/RBV therapy were independent factors associated with the occurrence of HCC. The multivariate analysis using the Cox proportional hazard model revealed the risk factors for HCC were the platelet count, AFP level and the outcome of Peg-IFN/RBV therapy., Conclusions: To reduce the incidence of HCC in chronic hepatitis C, attainment of a sustained response rate is an essential issue. For patients with low platelet counts and/or a high AFP level, strict surveillance should be continued even after eradication of HCV because the risk of HCC was found to be higher for these patients.

Background & Aims: Anemia is a common adverse effect of telaprevir (TVR) in combination with pegylated interferon (PegIFN)α and ribavirin (RBV) therapy. It occurs at a higher incidence with the TVR relative to PegIFNα and RBV alone. We herein evaluate the baseline and on-treatment predictors of the development of severe anemia by chronic hepatitis C virus (HCV) patients receiving TVR-based triple therapy., Methods: This prospective, multicenter study consisted of 292 patients (median age: 62 years) infected with HCV genotype 1. All received 12 weeks of TVR in combination with 24 weeks of PegIFNα2b and RBV. The definition of severe anemia during antiviral treatment is hemoglobin (Hb)<85 g/L., Results: 101 (34.6%) patients developed severe anemia during the treatment period. Multivariable logistic regression analysis of possible pretreatment predictors of the development of severe anemia extracted baseline Hb < 135 g/L (Hazard ratio [HR], 2.53; p = 0.0013), estimated glomerular filtration rate <80 ml/min/1.73 m(2) (HR, 1.83; p = 0.0265), and inosine triphosphatase (ITPA) CC genotype (rs1127354) (HR, 2.91; p = 0.0024). For patients with ITPA CC (n = 227), multivariable logistic regression analysis of possible pretreatment and on-treatment predictors of the development of severe anemia extracted Hb level at week 2 (HR, 0.96; p = 0.0085) and the initial four weeks of weight-adjusted TVR (HR, 1.05; p = 0.0281)., Conclusions: Anemia remains a risk for all patients treated with TVR-based triple therapy. However, ITPA polymorphism (rs1127354) is useful for predicting the development of severe anemia and will be helpful in the management of treatment., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: This study was performed to evaluate the efficacy of a triple therapy in older Japanese patients; telaprevir (TVR) was added to pegylated interferon α2b and ribavirin., Methods: This prospective study enrolled 120 genotype 1b patients with chronic hepatitis C who received 12 weeks of triple therapy followed by a 12-week dual therapy that included pegylated interferon α2b and ribavirin. Patients were categorized according to age: group A, 64 patients aged >60 and group B, 56 patients aged ⩽60. Serum HCV RNA levels were monitored by COBAS TaqMan HCV test., Results: The rates of undetectable HCV RNA at week 4 (rapid virological response, RVR) were 73.4% in group A and 73.2% in group B. No significant difference in sustained virological response (SVR) was found between groups A (76.6%) and B (83.9%) (p=0.314). The SVR rates for patients with interleukin 28B (IL28B) (rs8099917) TT allele (89.4% and 91.9% for groups A and B) were significantly higher than for those with the IL28B TG/GG allele (41.2% and 68.4%, respectively) (both p<0.05). Multivariate analysis extracted IL28B TT and RVR as independent factors associated with SVR. Adverse effects resulted in treatment discontinuation by 12.5% in each group. Hemoglobin decrease significantly differed between groups A and B: the decrease to ≤100 g/L, to 85 - <100g/L, and to <85 g/L, was 9.4%, 40.6%, and 50% in group A patients, respectively, and 41.1%, 25%, and 33.9% in group B patients, respectively (p=0.0006)., Conclusions: TVR-based triple therapy can be successfully used to treat older patients with genotype 1b chronic hepatitis C., (Copyright © 2013. Published by Elsevier B.V.)

Background & Aims: The effects of pegylated interferon (PegIFN) α and ribavirin (RBV) treatment of chronic hepatitis C on the incidence of hepatocellular carcinoma (HCC) have not been well established. This study investigated the impact of treatment outcome on the development of HCC by chronic hepatitis C patients treated with PegIFNα2b and RBV., Methods: This large-scale, prospective, multicenter study consisted of 1013 Japanese chronic hepatitis C patients with no history of HCC (non-cirrhosis, n=863 and cirrhosis, n=150). All patients were treated with PegIFNα2b and RBV and the follow-up period started at the end of the antiviral treatment (median observation period of 3.6 years). The cumulative incidence rate of HCC was estimated using the Kaplan-Meier method, according to treatment outcome., Results: Forty-seven patients (4.6%) developed HCC during the observation period. In the non-cirrhosis group, the 5-year cumulative incidence rates of HCC for the sustained virological response (SVR) (1.7%) and transient virological response (3.2%) (TVR: defined as relapse or breakthrough) groups were significantly lower than those of the non-virological response (NVR) group (7.6%) (p=0.003 and p=0.03, respectively). A significantly low rate of incidence of HCC by TVR patients in comparison with NVR patients was found for patients aged 60 years and over, but not for those under 60 years of age. In the cirrhosis group, the 5-year cumulative incidence rates of HCC for the SVR (18.9%) and TVR groups (20.8%) were also significantly lower than those of the NVR group (39.4%) (p=0.03 and p=0.04, respectively)., Conclusions: SVR and complete viral suppression during treatment with relapse (TVR) were associated with a lower risk of HCC development when compared with NVR., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

The aim of this large-scale analysis was to assess the effect of 48-week pegylated interferon (PEG-IFN) α-2b and ribavirin (RBV) therapy on virological relapse by patients infected with hepatitis C virus (HCV) genotype 1. The relationship between virological relapse and the dose of PEG-IFNα-2b and RBV was investigated in 619 patients who had once cleared HCV RNA during PEG-IFNα-2b and RBV treatment for 48 weeks. The overall virological relapse rate was 34.1% (211 of 619). The relapse rate was 59.5% (22 of 37) for patients who received <6 mg/kg/day of RBV, even if a sufficient dose of PEG-IFNα-2b (≥1.5 μg/kg/day) was received. In contrast, the relapse rate was 28.1% (16 of 57) for patients who received ≥12 mg/kg/day of RBV, irrespective of the PEG-IFNα-2b dose. The relapse rates were significantly increased with the reduction of the RBV dose for both PEG-IFNα-2b doses of ≥1.2 and <1.2 μg/kg/week (P < 0.0001 and P = 0.0006, respectively). Moreover, the relapse rate was 41.2% (35 of 85) for patients with an early virological response (EVR) who received <6 mg/kg/day of RBV. The relapse rates were significantly increased with the reduction of the RBV dose in both those patients with an EVR and those with a late virological response (P = 0.0006 and P = 0.0088, respectively). To summarize, for HCV genotype 1 patients treated with PEG-IFNα-2b and RBV, the virological relapse of HCV was RBV dose-dependent, irrespective of the dose of PEG-IFNα or the effect of early viral kinetics.

Background and Aims: Pegylated interferon (PEG-IFN) α-2b and ribavirin (RBV) treatment of chronic hepatitis C virus (HCV) infection is associated with a substantially elevated risk of discontinuation. The aim of this study is to evaluate the reason for premature discontinuation during PEG-IFN α-2b and RBV treatment due to adverse effects in patients with chronic HCV infection., Methods: A total of 2871 Japanese patients who had chronic HCV infection treated with PEG-IFN α-2b and RBV were screened. We prospectively investigated the reasons for premature discontinuation of treatment classified by sex and age, and analyzed the timing of discontinuation., Results: Of the 2871 patients, 250 (8.7%) discontinued treatment because of adverse effects. The main reasons for premature discontinuation were neurovegetative symptoms (n = 77, 30.8%), depression-related syndrome (n = 46, 18.4%), hematologic effects (n = 41, 16.4%) and dermatologic effects (n = 27, 10.8%). The rate of discontinuation of treatment for patients aged ≥ 65 years was significantly higher than for patients aged < 65 years, for both men (P < 0.0001) and women (P = 0.0121). Moreover, the frequency of discontinuation due to neurovegetative symptoms, depression-related syndrome, and hematologic effects for men aged ≥ 65 years was significantly higher than for those aged < 65 years (P = 0.0001, P = 0.0016, and P = 0.0170, respectively), but not for women., Conclusion: Premature discontinuation due to the adverse effects of PEG-IFN α-2b and RBV treatment by patients with chronic HCV infection is mainly due to neuropsychiatric symptoms and is more common for older than for younger patients., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Background and Aim: Early hepatocellular carcinoma (HCC) recurrence is common, even after achieving hepatitis C virus (HCV) cure. This study was carried out to assess the long‐term trends and predictors of recurrence after HCV cure by direct‐acting antivirals (DAAs). Methods: This retrospective, multicenter cohort study enrolled 365 consecutive patients with chronic hepatitis C who required HCC treatment following sustained viral response (SVR) by DAA administration. Patients with HCC recurrence before SVR were excluded. Late HCC recurrence and its predictors beyond the post‐treatment early phase (24 weeks after SVR) were evaluated. Results: The data of 326 patients were available for the final analysis. The median follow‐up duration from SVR determination was 2.7 years. Median age was 74, and 220 (67.5%) were 70 or over. The corresponding 5‐year cumulative HCC recurrence rates of previous curative and palliative treatment groups were 45.4% and 65.7%, respectively (log‐rank test: P < 0.001). Cox regression multivariable analysis revealed that cirrhosis (hazard ratio [HR] 1.85, P = 0.021), the number of HCC nodules (≥ 2) (HR 1.52, P = 0.031), and previous palliative HCC treatment (HR 1.71, P = 0.012) were independent predictors of late recurrence, in addition to the predictors of early recurrence; AFP > 7 ng/mL at 12 weeks after DAA administration, time from HCC complete response (CR) to DAA initiation (< 1 year), and the number of HCC treatments necessary to achieve CR (≥ 2). Conclusions: The evaluation of fibrosis and characteristics of the previous HCC would allow for better HCC recurrence stratification, which would be helpful for developing long‐term surveillance strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of hepatocellular carcinoma (HCC) has not been well-controlled, even after the elimination of hepatitis C virus (HCV), especially for those with cirrhosis or of high-age. Fibrosis-related biomarkers have been recognized as useful predictors for the development of HCC; however, there are few analyses of the HCC incidence for the various regimens with direct-acting antivirals (DAA). We found that DAA treatment with sofosbuvir, an oral nucleotide analogue inhibitor of HCV NS5B polymerase, was not associated with the development of de novo HCC within five years by propensity score matched analysis. Moreover, the distribution of the early stage of HCC (the Barcelona Clinic Liver Cancer stage 0/A) was similar for all treatment regimens, irrespective of the use of sofosbuvir. Advanced fibrosis/cirrhosis and related biomarkers have been recognized as useful predictors of the development of hepatocellular carcinoma (HCC) by patients with chronic hepatitis C (CHC) following hepatitis C virus (HCV) cure by direct-acting antivirals (DAAs). However, it remains unclear if DAAs themselves have an influence on or facilitate the development of HCC. This multicenter cohort study included CHC patients without a history of HCC who achieved HCV elimination by DAAs. Cohorts of 835 patients treated with a sofosbuvir (SOF)-based regimen and 835 treated with a SOF-free regimen were matched 1:1 by propensity scoring with nine variables to evaluate differences in HCC incidence. The median observation period was 3.5 years. Sixty-nine cases of HCC were found during 5483.9 person-years (PY) over the entire follow-up period. The annual incidence was similar for both groups (SOF-based 1.25 and SOF-free 1.27 per 100 PY, respectively: adjusted hazard ratio (HR) 1.26, 95% confidence interval (CI) 0.75–2.12, p = 0.39). However, the annual incidence within the first two years was higher for patients treated with SOF than for those without, but did not reach significance (1.50 and 0.97 per 100 PY incidence rates, respectively: adjusted HR 2.05, 95% CI 0.98–4.25, p = 0.06). In summary, DAA treatment with SOF was not associated with an increase in the development of de novo HCC. [ABSTRACT FROM AUTHOR]