Incidence and risk factors of hepatocellular carcinoma change over time in patients with hepatitis C virus infection who achieved sustained virologic response.

AIM: In patients with chronic hepatitis C, hepatocellular carcinoma (HCC) occurs at a certain frequency, even if a sustained virologic response (SVR) is achieved by antiviral treatment. Old age, liver fibrosis, and high post-treatment α-fetoprotein (AFP) level are typical risk factors of post-SVR HCC. We examined whether the frequencies and factors of HCC in patients with an SVR achieved from interferon treatment changed. Methods Among patients prospectively registered for pegylated interferon and ribavirin treatment, 2021 with an SVR without HCC development during the treatment period were followed up. The mean observation period was 49.5 ± 26.2 months. RESULTS: The multivariable Cox regression analysis showed that older age, diabetes mellitus, advanced liver disease, and higher post-treatment AFP level were the independent risk factors throughout the observation period. The annual occurrence rate of HCC was 0.74% in the third year, 0.54% in the fourth year, and 0.40% in the fifth year; it gradually decreased from the third year. Because the time course hazards for HCC changed at 48 months, we separately analyzed its risk factors before and after this change point. The multivariable Cox regression analysis showed that the four above-mentioned factors were significantly related to HCC development within 4 years. Conversely, the univariable Cox regression analysis only identified diabetes mellitus as a significant factor for HCC development after 4 years. CONCLUSION: The frequency of HCC in hepatitis C patients who achieved an SVR from interferon treatment decreased during the observation period, and its risk factors changed between the early and late periods.

Ultra-deep sequencing analysis of resistance-associated variants during retreatment with simeprevir-based triple therapy after failure of telaprevir-based triple therapy in patients with genotype 1 hepatitis C virus infection.

AIM: Simeprevir (SMV)-based triple therapy is an effective retreatment option following failure of telaprevir (TVR)-based triple therapy. However, it is unclear whether the persistence of resistance-associated variants (RAVs) induced by TVR-based therapy may reduce the treatment effect of SMV-based therapy. METHODS: The factors associated with the treatment effect, including RAVs in the NS3 region, were examined in 21 patients with genotype 1b HCV infection who were treated with SMV-based therapy after failure of TVR-based therapy. Ultra-deep sequencing was carried out to detect RAVs. RESULTS: With the exception of one patient who discontinued treatment owing to adverse events, the sustained virologic response (SVR) rate was 50% (10/20). Ultra-deep sequencing at the start of SMV-based therapy revealed that TVR-resistant variants were detected in six patients (29%), and no variants were observed at position 168. Cross-resistance between TVR and SMV with low frequency was detected in only one patient, and this patient achieved SVR. Higher SVRs for SMV-based therapy were attained in patients who discontinued treatment owing to the adverse effects of prior TVR-based therapy (discontinuation 100% vs. non-discontinuation 29%, P = 0.005), and patients who relapsed following prior pegylated interferon plus ribavirin therapy (relapse 100% vs. non-response 20%, P = 0.007). CONCLUSIONS: In this study, ultra-deep sequencing analysis revealed that TVR and/or SMV-resistant variants may have no influence on the effect of SMV-based therapy after failure of TVR-based therapy. Patients who discontinued treatment owing to adverse effects of TVR-based therapy and relapsers to previous pegylated interferon/ribavirin therapy would be good candidates for retreatment with SMV-based therapy.

Impact of ribavirin dosage in chronic hepatitis C patients treated with simeprevir, pegylated interferon plus ribavirin combination therapy.

The factors associated with sustained virologic response (SVR) in chronic hepatitis C (CH-C) genotype 1 patients treated with simeprevir (SMV), pegylated interferon (Peg-IFN) plus ribavirin (RBV) triple therapy have not been fully investigated. Two hundred and twenty-nine treatment-naïve CH-C patients treated with SMV triple therapy were enrolled in this study. The overall SVR rate was 87% in per-protocol analysis. In multivariate analysis, the interleukin (IL) 28B genotype (rs8099917, TT vs. non-TT, odds ratio [OR]: 0.044, P = 0.001) and RBV dose (< 10/10-12/ ≥ 12 mg/kg/day, OR: 4.513, P = 0.041) were significant factors associated with SVR. In patients with the IL28B non-TT genotype, RBV dose affected SVR dose-dependently in stratified analysis of RBV dose (P = 0.015); it was 44% (8/18) for patients administered <10 mg/kg/day of RBV, 78% (14/18) for those administered 10-12 mg/kg/day of RBV, and 100% (3/3) for those administered ≥12 mg/kg/day of RBV, whereas in patients with the IL28B TT genotype, a significant correlation between SVR and RBV dose was not observed (P = 0.229). Regarding RBV dose reduction of less than 10 mg/kg/day, the inosine triphosphate pyrophosphatase (ITPA) genotype (rs1127354, CC vs. non-CC, OR: 0.239, P = 0.003) and age (by 1 y.o., OR: 1.084, P = 0.002) were significant independent factors. RBV dosage affected SVR dose-dependently in patients with the IL28B non-TT genotype treated with SMV triple therapy. Special attention to anemia progression and RBV dosage should be paid to aged patients with the ITPA CC genotype. J. Med. Virol. 88:1776-1784, 2016. © 2016 Wiley Periodicals, Inc.

Efficacy of pegylated interferon and ribavirin combination therapy for patients with hepatitis C virus infection after curative resection or ablation for hepatocellular carcinoma--A retrospective multicenter study.

The use of pegylated interferon (Peg-IFN) plus ribavirin combination therapy for chronic hepatitis C patients who received curative treatment for hepatocellular carcinoma is controversial. This study tried to clarify this. Ninety-nine chronic hepatitis C patients who received curative resection or radiofrequency ablation for primary hepatocellular carcinoma, met the Milan criteria and were treated with Peg-IFN plus ribavirin therapy were enrolled (75 males, 24 females; mean age, 65.0 ± 5.9 years; 79 HCV genotype 1, 20 genotype 2). Among them, 40 patients who had received curative treatment for a single carcinoma were analyzed for recurrence (observation period: 27.6 ± 18.1 months). The factors associated with recurrence were examined using a log-rank test and a Cox proportional-hazards model. The discontinuation rate of the Peg-IFN plus ribavirin combination therapy was 25% (25/99). Among the patients who completed the therapy, the sustained virologic response rates were 35% for the genotype 1 patients and 56% for the genotype 2 patients. The cumulative incidence rates of recurrence were 10.0% at 1 year and 40.8% at 3 years. On multivariate analysis, a virologic response and platelet counts served as independent factors of recurrence (sustained virologic response, hazard ratio = 0.190, P = 0.029; platelet counts <12 × 10(4) /mm(3), hazard ratio = 3.19, P = 0.019). It is concluded that patients with chronic hepatitis C virus infection after curative treatment for hepatocellular carcinoma can be candidates for anti-viral therapy to reduce the recurrence of hepatocellular carcinoma, especially patients with low platelet counts.

Suppression of hepatocellular carcinoma development in hepatitis C patients given interferon-based antiviral therapy.

The advance of antiviral treatment for chronic hepatitis C has brought a high sustained virological response (SVR) rate. In this review article, the suppressive effect of interferon (IFN)-based therapy on the development of hepatocellular carcinoma (HCC), risk factors for developing HCC and the characteristics of HCC development after SVR among chronic hepatitis C patients given IFN-based therapy were studied. The HCC incidence has been revealed to decrease with IFN-based antiviral therapy, especially in SVR, and the risk factors for developing HCC were older age, advanced liver fibrosis and male sex. α-Fetoprotein levels at 24 weeks after the end of IFN-based treatment was associated strongly with HCC incidence irrespective of virological response. In patients with SVR, other risk factors were glucose metabolism disorders, lipid metabolism disorders and alcohol intake. Extra attention to the possibility of HCC incidence should be required for these SVR patients. Antiviral therapy with a combination of HCV-specific direct-acting antivirals (DAA) is expected to be utilized in the future. However, it is not known whether DAA-based treatment can suppress HCC to the level of IFN-based treatment. Further research is required to clarify this.

[Pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C].

The antiviral therapy for patients with chronic hepatitis C virus(HCV) infection has changed from interferon(IFN) monotherapy to dual therapy with IFN plus ribavirin(RBV), moreover pegylated IFN(Peg-IFN) plus RBV. The sustained virologic response(SVR), defined as HCV RNA negativiation at 24 weeks after the treatment, were obtained 50% among the patients with genotype 1 (48 weeks treatment) and 80% among those with genotype 2 (24 weeks treatment) in Peg-IFN plus RBV combination therapy. The baseline host factors such as age, the degree of liver fibrosis progression and a genetic polymorphism near the IL28B gene, the viral factors such as HCV genotype, mutant virus at HCV core region and interferon sensitivity determining region, the treatment factors such as drug adherence and treatment duration have been reported to be associated with SVR. The risk for hepatocellular carcinoma (HCC) incidence was significantly lower in SVR patients than non-SVR patients. Especially, alpha-fetoprotein (AFP) levels decreased through therapy, and the patients with < 5 ng/mL had a low potential of HCC incidence regardless of HCV eradication. It is suggested that AFP levels at 24 weeks after the treatment can be a good surrogate marker for HCC incidence irrespective of the virologic response.

Post-treatment levels of α-fetoprotein predict incidence of hepatocellular carcinoma after interferon therapy.

BACKGROUND & AIMS: In patients with chronic hepatitis C virus (HCV) infection, lack of sustained virologic response (SVR) 24 weeks after the end of interferon therapy is a significant risk factor for hepatocellular carcinoma (HCC). Although many pretreatment factors are known to affect HCC incidence, less is known about post-treatment factors-many change during the course of interferon therapy. METHODS: We performed a prospective study, collecting data from 2659 patients with chronic hepatitis C without a history of HCC who had been treated with pegylated interferon (Peg-IFN) plus ribavirin from 2002 through 2008 at hospitals in Japan. Biopsy specimens were collected before treatment; all patients received Peg-IFN plus ribavirin for 48 to 72 weeks (HCV genotype 1) or 24 weeks (HCV genotype 2). Hematologic, biochemical, and virologic data were collected every 4 weeks during treatment and every 6 months after treatment. HCC was diagnosed based on angiography, computed tomography, and/or magnetic resonance imaging findings. RESULTS: HCC developed in 104 patients during a mean observation period of 40 months. Older age, male sex, lower platelet counts and higher levels of α-fetoprotein at baseline, and lack of an SVR were significant risk factors for HCC. The cumulative incidence of HCC was significantly lower in patients without SVRs who relapsed than those with no response to treatment. Levels of α-fetoprotein 24 weeks after the end of treatment (AFP24) were significantly lower than levels of α-fetoprotein at baseline in patients with SVRs and those who relapsed, but not in nonresponders. Post-treatment risk factors for HCC among patients with SVRs included higher AFP24 level and older age; among those without SVRs, risk factors included higher AFP24 level, integrated level of alanine aminotransferase, older age, and male sex. AFP24 (≥10 ng/mL, 10-5 ng/mL, and then <5 ng/mL) was a better predictor of HCC incidence than pretreatment level of AFP among patients with and without SVRs. CONCLUSIONS: In patients with chronic HCV infection, levels of α-fetoprotein decrease during interferon therapy. High post-treatment levels of α-fetoprotein predict HCC, regardless of whether patients achieve an SVR. University Hospital Medical Information Network Clinical Trials Registry: C000000196, C000000197.

Significance of liver stiffness measurement by acoustic radiation force impulse (ARFI) among hepatitis C patients.

The degree of liver fibrosis is strongly associated with the antiviral effect of interferon on chronic hepatitis C patients. In this study, the accuracy of acoustic radiation force impulse (ARFI) in assessing liver fibrosis and the association between liver stiffness using ARFI and antiviral effects were investigated. The 124 patients with chronic hepatitis C enrolled in this study included 94 with HCV genotype 1 and 40 (30%) with moderate fibrosis (METAVIR fibrosis score ≥ F2). Sixty-one patients received pegylated interferon (peg-IFN) plus ribavirin combination therapy and the treatment responses were assessed. The shear wave velocity (Vs value) by ARFI had a strong correlation with the histological fibrosis stage (P < 0.001). The AUROC of the Vs value, aspartate aminotransferase platelet ratio index and FIB4 for the diagnoses of moderate fibrosis (≥F2) were 0.890, 0.779, and 0.737, respectively. HCV genotype 1 patients with the TT allele of IL28B and with a low Vs value (<1.40 m/sec) who were treated with peg-IFN plus ribavirin therapy achieved a sustained virologic response at a rate of 79% (15/19), while all patients with the TG/GG allele of IL28B and a high Vs value (≥1.40 m/sec) experienced a non-virologic response (6/6). The Vs value measured by ARFI could not predict the treatment response for patients with HCV genotype 2. It is concluded that the combination of ARFI at cut off of 1.4 m/sec and IL28B may be useful for patients with chronic hepatitis C with genotype 1 treated with peg-IFN/ribavirin combination therapy.

Renal impairment during the treatment of telaprevir with peginterferon and ribavirin in patients with chronic hepatitis C.

AIM: Renal damage has been reported as an important complication during combination treatment of peginterferon (PEG IFN), ribavirin (RBV) and telaprevir (TVR) for chronic hepatitis C. However, very little is known about this complication. We investigated the role TVR plays in renal damage during this triple therapy. METHODS: Twenty-five chronic hepatitis C patients with genotype 1 and high viral load received TVR in combination with PEG IFN and RBV for 12 weeks followed by treatment with PEG IFN and RBV. Renal function of these patients was prospectively evaluated for 16 weeks. RESULTS: Creatinine clearance decreased significantly during PEG IFN/RBV/TVR treatment. Consequently, serum creatinine and cystatin C significantly rose during PEG IFN/RBV/TVR treatment. Serum creatinine returned to pretreatment levels after the termination of TVR. The increase of serum creatinine and cystatin C from baseline significantly correlated with serum TVR level at day 7, which was determined by starting dose of TVR per bodyweight . When the patients were classified according to the starting dose of TVR per bodyweight, renal impairment was observed only in the high-dose (TVR ≥33 mg/kg per day) group, not in the low-dose (TVR <33 mg/kg per day) group. CONCLUSION: These results suggest that TVR dose per bodyweight is important for the occurrence of renal impairment in PEG IFN/RBV/TVR treatment.

Clinical factors associated with the therapeutic efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma: A multicenter prospective observational study.

The treatment efficiency and predictors of atezolizumab plus bevacizumab therapy for unresectable hepatocellular carcinoma in real-world practice have not been established. This study aimed to assess the efficacy and safety of atezolizumab plus bevacizumab and to investigate predictors of progression-free survival and overall survival. Patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab therapy in 19 hospitals were enrolled before treatment and observed prospectively. The outcomes of 222 patients in this cohort were analyzed. The objective response rate and disease control rate were 22.0% and 70.6%, respectively, whereas the median progression-free survival was 5.7 months. Independent risk factors for shortened progression-free survival were younger age (<75 years; 3.9 months vs. 8.6 months), higher number of intrahepatic tumors (≥5; 4.0 months vs. 7.9 months), macrovascular invasion (2.3 months vs. 6.7 months), and higher neutrophil-to-lymphocyte ratio (≥3.03; 3.0 months vs. 7.8 months). The median overall survival was not reached; however, independent risk factors for shortened overall survival were absence of hyperlipidemia, higher number of intrahepatic tumors (≥5), macrovascular invasion, higher α-fetoprotein level (≥400 ng/mL), worse Child-Pugh score (≥6), and higher neutrophil-to-lymphocyte ratio (≥3.03). Severe adverse events (grade ≥3) were observed in 96 patients (36.0%), with proteinuria being the most frequent. In conclusion, patients with older age, lower number of intrahepatic tumors, absent macrovascular invasion, and lower neutrophil-to-lymphocyte ratio are expected to have better progression-free survival with atezolizumab plus bevacizumab therapy for unresectable hepatocellular carcinoma.

A multicenter survey of re-treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C in Japan.

AIM: This study aimed to clarify the factors associated the efficacy of re-treatment with pegylated interferon (PEG IFN) plus ribavirin combination therapy for patients with chronic hepatitis C who had failed to respond to previous treatment. METHODS: One hundred and forty-three patients who had previously shown relapse (n = 79), non-response (n = 34) or intolerance (n = 30) to PEG IFN plus ribavirin were re-treated with PEG IFN plus ribavirin. RESULTS: Twenty-five patients with intolerance to previous treatment completed re-treatment and the sustained virological response (SVR) rates were 55% and 80% for hepatitis C virus (HCV) genotype 1 and 2, respectively. On re-treatment of the 113 patients who completed the previous treatment, the SVR rates were 48% and 63% for genotype 1 and 2, respectively. Relapse after previous treatment and a low baseline HCV RNA level on re-treatment were associated with SVR in genotype 1 (P < 0.001). Patients with the interleukin-28B major genotype responded significantly better and earlier to re-treatment, but the difference in the SVR rate did not reach a significant level between the major and minor genotypes (P = 0.09). Extended treatment of 72 weeks raised the SVR rate among the patients who attained complete early virological response but not rapid virological response with re-treatment (72 weeks, 73%, 16/22, vs 48 weeks, 38%, 5/13, P < 0.05). CONCLUSION: Relapse after previous treatment and a low baseline HCV RNA level have predictive values for a favorable response of PEG IFN plus ribavirin re-treatment for HCV genotype 1 patients. Re-treatment for 72 weeks may lead to clinical improvement for genotype 1 patients with complete early virological response and without rapid virological response on re-treatment.

Interleukin-1ß enhances the production of soluble MICA in human hepatocellular carcinoma.

The production of soluble major histocompatibility complex class I-related chain A (MICA) is thought to antagonize NKG2D-mediated immunosurveillance. Interleukin-1ß (IL-1ß) is elevated in patients with chronic hepatitis C (CH), and this might contribute to the escape of hepatocellular carcinoma (HCC) cells from innate immunity. In this study, we investigated the immunoregulatory role of IL-1ß in the production of soluble MICA of HCC cells. First, we investigated the correlation between the serum IL-1ß levels and soluble MICA in CH patients. Serum IL-1ß levels were associated with soluble MICA levels in CH patients. The serum IL-1ß levels of CH patients with the HCC occurrence were significantly higher than those of CH patients without HCC. We next examined the MICA production of IL-1ß-treated HCC cells. Addition of IL-1ß resulted in significant increase in the production of soluble MICA in HepG2 and PLC/PRF/5 cells, human HCC cells. But soluble MICA was not detected in both non-treated and IL-1ß-treated normal hepatocytes. Addition of IL-1ß did not increase the expressions of membrane-bound MICA on HCC cells. These were observed similarly in various cancer cells including a gastric cancer (MKN1), two colon cancers (HCT116 and HT29) and a cervical cancer (HeLa). Addition of IL-1ß also increased the expression of a disintegrin and metalloproteinase (ADAM)9 in HCC cells, and the knockdown of ADAM9 in IL-1ß-treated HCC cells resulted in the decrease in the production of soluble MICA of HCC cells. These findings indicate that IL-1ß might enhance the production of soluble MICA by activating ADAM9 in human HCC.

Indications and limitations for aged patients with chronic hepatitis C in pegylated interferon alfa-2b plus ribavirin combination therapy.

BACKGROUND & AIMS: This study investigated the efficacy and adverse effects of pegylated interferon (Peg-IFN) plus ribavirin therapy in aged patients with chronic hepatitis C (CH-C). METHODS: A total of 1040 naïve patients with CH-C (genotype 1, n=759; genotype 2, n=281), of whom 240 (23%) over 65 years old (y.o.), were treated with Peg-IFN alfa-2b plus ribavirin and assessed after being classified into five categories, according to age. RESULTS: The discontinuance rate was higher for patients over 70 y.o. (36%), the most common reason being anemia. In the presence of genotype 1, the SVR rate was similar (42-46%) among patients under 65 y.o. and declined (26-29%) among patients over 65 y.o. For patients over 65 y.o., being male (Odds ratio, OR, 3.5, p=0.035) and EVR (OR, 83.3, p<0.001) were significant factors for SVR, in multivariate analysis. The Peg-IFN dose was related to EVR, and when EVR was attained, 76-86% of patients over 65 y.o. achieved SVR. SVR was not achieved (0/35, 0/38, respectively) if a 1-log decrease and a 2-log decrease were not attained at week 4 and week 8, respectively. In the presence of genotype 2, the SVR rate was similar (70-71%) among patients under 70 y.o. and declined among patients over 70 y.o. (43%). CONCLUSIONS: Aged patients up to 65 y.o. with genotype 1 and 70 y.o. with genotype 2 can be candidates for Peg-IFN plus ribavirin therapy. The response-guided therapy can be applied for aged patients with genotype 1.

Amino acid substitution in the core protein has no impact on relapse in hepatitis C genotype 1 patients treated with peginterferon and ribavirin.

Previous reports demonstrated that amino acid (aa) substitutions in the hepatitis C virus (HCV) core protein are predictors of non-virological responses to pegylated interferon (Peg-IFN) and ribavirin combination therapy. The aim of this study was to investigate the impact of core aa substitutions on viral kinetics during the treatment and relapse after the treatment. The 187 patients with HCV genotype 1 enrolled in this study were categorized into four groups according to core aa substitution patterns: double-wild group (n=92), Arg70/Leu91; 70-mutant group (n=42), Gln70/Leu91; 91-mutant group (n=31), Arg70/Met91; and double-mutant group (n=22), Gln70/Met91. The relationship between the core aa substitutions and the virological response was examined. Multivariate logistic regression analyses showed that substitution at aa 70 was significantly associated with a poor virological response during the first 12 weeks (decline of <1 log from baseline at week 4, <2 log at week 12), and substitution at aa 91 was significantly associated with detectable HCV RNA at week 24. With respect to relapse, only the ribavirin exposure (odds ratio (OR), 0.77; 95% confidence interval (CI), 0.60-0.98) and HCV RNA disappearance between weeks 13 and 24 (OR, 23.69; 95% CI, 5.44-103.08) were associated independently with relapse, with no correlation being found with the core aa substitutions and relapse. In conclusion, the results showed that core aa substitutions can be strong predictive factors at pretreatment of the non-response, but not for relapse, for virological responders with HCV RNA disappearance during treatment.

Two types of drug-resistant hepatitis B viral strains emerging alternately and their susceptibility to combination therapy with entecavir and adefovir.

The most serious problem of nucleoside/nucleotide analogue therapy for hepatitis B virus (HBV) infection is the emergence of drug-resistant mutant virus. Here, we describe a patient with chronic hepatitis B infection with a complex drug-resistant mutant virus during sequential therapy with lamivudine (3TC), entecavir (ETV) and adefovir dipivoxil (ADV). The patient was a 52-year-old male with positive hepatitis B e antigen and high HBV DNA (>7.6 log(10) copies/ml). Initial 3TC monotherapy offered little benefit and 3TC resistance was established by the virus with rtA181T and not rtM204V/I. HBV DNA was reduced slightly by replacement with ETV monotherapy and was followed by virological breakthrough. At that time, rtA181T was undetectable and the virus with rtM204V and rtL180M became predominant. ETV resistance was established by an additional rtS202G mutation. Efficacy of subsequent combination therapy with ADV and 3TC was limited because of reappearance of the virus with rtA181T, which might confer cross-resistance to 3TC and ADV. Final combination therapy with ETV and ADV reduced HBV DNA to 3.7 log(10) copies/ml for 5 months, which was the most effective therapy for this patient. Thus, two kinds of mutant viruses (rtM204V-related and rtA181T-related) appeared alternately in this patient. Combination therapy with ETV and ADV might have been effective because these drugs share therapeutic roles, that is, ETV affects the rtA181T-related virus and ADV affects the rtM204V-related virus. This is the first report suggesting clinical significance of combination therapy with ETV and ADV for controlling replication of the complex drug-resistant mutant HBV.

Lamivudine-to-entecavir switching treatment in type B chronic hepatitis patients without evidence of lamivudine resistance.

PURPOSE: A considerable number of chronic hepatitis B (CH-B) patients remain under continuous lamivudine treatment, although switching treatment to entecavir could be beneficial. We investigated the antiviral efficacy of switching treatment to entecavir in CH-B patients without apparent evidence of lamivudine resistance during the preceding lamivudine treatment. METHODS: Forty-four CH-B patients, who underwent lamivudine treatment for more than 6 months and showed no evidence of lamivudine resistance, switched to entecavir. Serial changes in hepatitis B virus (HBV) DNA were correlated with the patients' baseline HBV DNA at the commencement of entecavir administration. The entecavir-resistant substitution was examined by PCR-direct sequencing. The median follow-up period of entecavir treatment was 20 (10-23) months. RESULTS: All 31 patients with baseline HBV DNA <2.6 logcopies/ml maintained HBV DNA-negative status during entecavir treatment. Of seven patients having HBV DNA of 2.6-<4.0 logcopies/ml, all achieved undetectable HBV DNA at the end of follow-up. As for six patients having HBV DNA >or=4.0 logcopies/ml, three patients achieved undetectable HBV DNA, whereas virological breakthrough was observed in one patient at month 15. An entecavir-resistant virus having rtM204V, rtL180M and rtS202G substitutions was detected in this patient. CONCLUSIONS: The lamivudine-to-entecavir switching treatment may be generally recommendable in CH-B patients without evidence of lamivudine resistance during the preceding lamivudine treatment. However, great care should be taken with respect to the emergence of entecavir-resistance, especially in patients who do not respond well to the preceding lamivudine treatment.

Effect of interferon alpha-2b plus ribavirin therapy on incidence of hepatocellular carcinoma in patients with chronic hepatitis.

AIM: The objective of this study was to elucidate the long-term effects of interferon (IFN)alpha-2b plus ribavirin combination therapy and to clarify whether this therapy can reduce the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. METHODS: A total of 403 patients infected with hepatitis C virus (HCV) were enrolled in a multicenter trial. All patients were treated with a combination of IFN-alpha-2b plus ribavirin therapy. We examined the incidence of HCC after combination therapy and analyzed the risk factors for liver carcinogenesis. RESULTS: A sustained virological response (SVR) was achieved by 139 (34%) of the patients. The cumulative rate of incidence of HCC was significantly lower in SVR patients than in non-SVR patients (P = 0.03), while there was no difference in the cumulative incidence of HCC between the transient response (TR) group and the no response (NR) group. Cox's regression analysis indicated the following risk factors as independently significant in relation to the development of HCC: age being > 60 years (P = 0.006), advanced histological staging (P = 0.033), non-SVR to IFN therapy (P = 0.044). The cumulative incidence rate of HCC was significantly lower in patients who had average serum alanine aminotransferase (ALT) levels of < 40 IU/L than in those who showed average serum ALT levels of >== 40 IU/L after the combination therapy (P = 0.021). CONCLUSIONS: These results suggest that the attainment of SVR or continuous normalization of ALT levels after IFN therapy can affect patients apart from HCC development.

Early decline of hemoglobin can predict progression of hemolytic anemia during pegylated interferon and ribavirin combination therapy in patients with chronic hepatitis C.

AIM: Ribavirin, used to treat chronic hepatitis C, can induce hemolytic anemia, forcing the discontinuance of treatment. To establish a predictive measure to help circumvent this, we evaluated the relationship of hemoglobin (Hb) decline with the discontinuance of treatment during the progression of ribavirin-induced anemia. METHODS: One hundred and sixteen patients (71% male) with genotype 1 chronic hepatitis C were treated with pegylated interferon (PegIFN) alpha-2b and ribavirin. The mean age was 50.6 years and 55% were IFN naïve. A decline of Hb concentration by 2 g/dL at two weeks from the start of the treatment ("2 by 2" standard) was adopted as the predictive factor for the progression of anemia. RESULTS: By applying the "2 by 2" standard, with DeltaHb >/= 2 g/dL (34%, n = 39), treatment was discontinued in 12 cases (31%), three of which (8%) because of severe anemia. ForDeltaHb < 2 g/dL (64%, n = 76), treatment was discontinued in 11 (14%) cases; none due to severe anemia. Ten percent (4/39) of patients showed the minimum Hb /= 2 g/dL group, with none in the DeltaHb < 2 g/dL group (P = 0.001). Furthermore, the patients with minimum Hb

Initial viral response is the most powerful predictor of the emergence of YMDD mutant virus in chronic hepatitis B patients treated with lamivudine.

AIM: Lamivudine (LAM) has been widely used to treat chronic hepatitis B (CHB) patients, but the emergence of a LAM-resistant virus greatly limits its therapeutic efficacy. In this study, we tried to identify factors affecting the emergence of a LAM-resistant virus in CHB patients treated with LAM. METHODS: The subjects were 190 CHB patients in continuous LAM therapy (139 males, mean age 50 years, 87 HBeAg-positive). The mean duration of follow-up was 39 months (range 12-104). The initial viral response (IVR) was defined as HBV DNA < 4.0 logcopies/mL, and the initial biochemical response (IBR) as normalization of alanine aminotransferase (ALT) (<40 IU/L) at 6 months. RESULTS: IVR was positive in 86% of the patients. The cumulative emergence rates of LAM-resistant virus were 10% at 1 year, 30% at 2 years and 46% at 3 years. In univariate analysis, factors contributing to the emergence of LAM-resistant virus were baseline HBV DNA > 6.5 logcopies/mL (P = 0.0044), HBeAg-positivity (P = 0.0062), IBR (P = 0.01) and IVR (P < 0.0001). The cumulative emergence rates of LAM-resistant virus in IVR-positive and -negative patients were 4% and 41% at 1 year, and 41% and 79% at 3 years. In multivariate analysis, only IVR was an independent factor affecting the emergence of LAM-resistant virus (P < 0.0001). CONCLUSION: IVR is a useful factor for predicting the emergence of LAM-resistant virus in CHB patients treated with LAM. For IVR-negative patients, therapeutic options other than LAM monotherapy should be used because of the high incidence of the emergence of LAM-resistant virus.