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Background and Aims: The influence of direct-acting antivirals (DAAs) on chronic hepatitis C (CHC)-related hepatocellular carcinoma (HCC) remains controversial. We investigated the effect of eradicating CHC using DAAs on treatment outcomes in patients with CHC-related HCC treated with transarterial chemoembolization (TACE)., Methods: This nationwide, multi-center, retrospective study recruited patients with CHC-related HCC treated with TACE as the first-line anti-cancer treatment, and who achieved a sustained virological response (SVR) using DAAs (DAA group) between 2006 and 2017. Patients achieving an SVR following interferon-based treatment (IFN group) and those without treatment (control group) were also recruited for comparison., Results: A total of 425 patients were eligible for the study. Of these, 356 (83.8%), 26 (6.1%), and 43 (10.1%) were allocated to the control, IFN, and DAA groups, respectively. A multivariate analysis showed that liver cirrhosis, segmental portal vein thrombosis, and larger maximal tumor size independently predicted an increased risk of progression (all p < 0.05), whereas, the DAA group (vs. IFN and control groups) independently predicted a reduced risk of progression (hazard ratio (HR) = 0.630, 95% confidence interval 0.411-0.966, p = 0.034). The cumulative incidence rate of HCC progression in the DAA group was significantly lower than that in the IFN and control groups (p = 0.033, log-rank test). In addition, the DAA group (vs. IFN and control groups) was independently associated with a reduced risk of mortality (p = 0.042)., Conclusions: DAA treatment provided significantly prolonged progression-free survival in patients with CHC-related HCC treated with TACE compared to that in patients administered IFN or no treatment.

We evaluated whether nucleos(t)ide analog (NA) influences the risk of non-hepatocellular carcinoma (non-HCC) malignancies in patients with chronic hepatitis B (CHB). A total of 9867 patients with CHB were followed up for ≥12 months for the occurrence of any type of malignancy between 1998 and 2013. Patients who received NA for ≥180 days were defined as the NA group. Propensity score matching produced the control (n = 2220) and NA groups (n = 2220) after adjustment for age, sex, and the presence of diabetes mellitus and liver cirrhosis. The National Health Insurance Service sample cohort dataset was used for external validation. Regarding non-HCC malignancies, only old age was an independent risk factor (>50 years; hazard ratio 3.17, 95% confidence interval 1.71-5.88, P < .001) in multivariate analysis. With regard to specific cancers such as thyroid, breast, lung, stomach, colorectal, pancreatobiliary, and hematologic malignancy, there was no difference of the incidence of each malignancy between the NA and control groups in both the hospital-based and external validation cohorts. NA treatment neither raises nor lowers the incidence of non-HCC malignancies in patients with CHB. Patients >50 years old are encouraged to undergo surveillance for malignancies similar to the general population.

Studies about long-term entecavir (ETV) therapy for partial virological response (PVR) are lacking. This study aimed to assess the clinical course of PVR patients receiving ETV therapy and analyze the efficacy of tenofovir (TDF). We retrospectively evaluated 130 patients who showed a PVR to ETV. Among these patients, 102 were nucleot(s)ide analogue (NUC)-naïve and 28 were lamivudine (LAM)-experienced. The cumulative rates of VR were 54.1%, 70.8%, and 83.7% for the NUC-naïve group and 37.0%, 42.8%, and 42.8% for the LAM-experienced group after 24, 36, and 48 months of ETV therapy, respectively (P  = 0.008). Low HBV DNA level at 12 months (P < 0.001) and absence of a LAM treatment history (P  = 0.031) were significant associated factors for VR. In VR prediction at 36 months of ETV therapy in NUC-naïve patients, HBV DNA level <95 IU/ml at 12 months showed a 92.9% sensitivity and a 78.3% specificity (AUROC, 0.909; P < 0.001). ETV resistance did not develop in NUC-naïve patients with HBV DNA levels <95 IU/ml at 12 months. The cumulative probability of VR in patients who switched to or additionally received TDF was 91.3% at 15 months. Prolonged ETV therapy induced a VR without the risk of ETV resistance in NUC-naïve patients with HBV DNA levels <95 IU/ml at 12 months. All patients with LAM-experienced or NUC-naïve with HBV DNA levels ≥95 IU/ml at 12 months should be switched to TDF rescue therapy., (© 2015 Wiley Periodicals, Inc.)

We evaluated the efficacy of tenofovir (TDF)-based rescue therapy and compared the outcomes of TDF monotherapy and TDF-based nucleoside analog (NA) combination therapy in patients with suboptimal response (SOR) to adefovir (ADV) with or without NAs in lamivudine (LAM)-resistant chronic hepatitis B. All study subjects received ADV with or without NAs due to prior LAM resistance, and were then switched to TDF-based rescue therapy due to SOR (hepatitis B virus DNA >20 IU/ml after at least 6 months of therapy). A total of 125 patients were eligible. The overall cumulative proportion of complete virologic response (CVR) was 64 of 74 patients (86.5%) at 48 weeks of treatment. During the follow-up period of 48 weeks, there was no significant difference in CVR rate (P = 0.750) between the TDF monotherapy (n = 18) and the TDF with NA groups (n = 107). Patients with ADV genotypic mutations showed inferior antiviral responses to TDF compared with the patients without ADV genotypic mutations, but this was not statistically significant (P = 0.069). Partial virological response to prior ADV therapy showed higher CVR rates compared to patients with non-response at 12 weeks (P = 0.013), but there was no significant difference after 24 (P = 0.076) and 48 weeks (P = 0.198) of treatment. TDF monotherapy is as effective as TDF plus NA combination therapy in patients with SOR to ADV-based rescue therapy and LAM resistance. TDF, with or without NAs, was effective even in cases of ADV resistance., (© 2015 Wiley Periodicals, Inc.)

Background/aims: To determine the efficacies of entecavir (ETV) in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B (CHB) patients and in those with prior lamivudine (LAM) use who did not develop resistance., Methods: We retrospectively enrolled 337 patients with CHB who were treated with ETV (0.5 mg daily) for at least 30 months. The study included 270 (80.1%) NA-naïve patients and 67 (19.9%) LAM-use patients. Ten of the LAM-use patients were refractory to LAM therapy without developing resistance., Results: Genotypic resistance to ETV developed more frequently in the LAM-use group (13.1%) than in the NA-naïve group (2.6%) at 60 months (P=0.009). In subgroup analysis, after excluding the 10 patients who were refractory to LAM therapy, the cumulative probability of ETV resistance did not differ significantly between the two groups (P=0.149). Prior LAM refractoriness and a higher hepatitis B virus DNA level at month 12 were independent predictive factors for the development of ETV resistance., Conclusions: ETV resistance developed more frequently in LAM-use patients with CHB. However, prior LAM use without refractoriness did not affect the development of ETV resistance. The serum hepatitis B virus DNA level at month 12 was a major predictor for the development of ETV resistance.

Objectives: This study aimed to evaluate the risk of development of hepatocellular carcinoma (HCC) according to underlying liver status and virological response (VR) to entecavir (ETV) in chronic hepatitis B patients with cirrhosis. Procollagen III N-terminal peptide (PIIINP) concentration during ETV treatment and its association with HCC development were also evaluated., Methods: A total of 306 patients with clinically diagnosed liver cirrhosis were treated with ETV for ≥12 months and were subsequently followed up for the occurrence of HCC (median follow-up duration: 37.0 months). Patients who developed HCC within 12 months were excluded. VR was defined as a hepatitis B virus DNA level <20 IU/ml at 12 months after ETV treatment., Results: A total of 209 patients (68.3%) had compensated cirrhosis, and the remaining patients (31.7%) had decompensated cirrhosis. The 5-year cumulative incidence of HCC was 26.8%. A multivariate Cox regression analysis identified the following independent risk factors for developing HCC in all the patients: age >50 years (hazard ratio (HR)=8.41; 95% confidence interval (CI)=3.86-18.28; P=0.000), male sex (HR=4.24; 95% CI=1.83-9.81; P=0.001), high serum PIIINP level at 12 months (HR=1.07; 95% CI=1.02-1.13; P=0.007), and no VR at 12 months (HR=2.10; 95% CI=1.02-4.33; P=0.043). The subgroup analyses showed that no VR at 12 months is a significant risk factor for developing HCC in the patients with decompensated cirrhosis (HR=7.74; 95% CI=1.34-44.78; P=0.022) but not in those with compensated cirrhosis (P=0.749)., Conclusions: The antiviral treatment with ETV did not completely eliminate the risk of developing HCC in our patients with cirrhosis. However, VR to ETV was associated with a low probability that the patients with decompensated cirrhosis would develop HCC.

Background/aims: Relapse has been reported after stopping nucleos(t)ide (NUC) therapy in the majority of chronic HBeAg negative hepatitis patients. However, the ideal treatment duration of HBeAg negative chronic hepatitis B (CHB) is not well known. We investigated the frequency of relapse in HBeAg negative CHB patients receiving NUC therapy., Methods: The NUC therapy was discontinued at least 3 times undetectable level of HBV DNA leave 6 months space in 45 patients. Clinical relapse was defined as HBV DNA >2,000 IU/mL and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times of upper limit of normal range. Virological relapse was defined as HBV DNA >2,000 IU/mL., Results: Clinical relapse developed in 16 (35.6%) and 24 (53.3%) patients after stopping therapy at 6 months and 12 months off therapy, respectively. Virological relapse developed 22 (48.9%) and 33 (73.3%) patients at 6 months and 12 months off therapy. The factors such as age, gender, cirrhosis, baseline AST, ALT, HBV DNA levels, treatment duration, and consolidation duration were analyzed to investigate the predictive factors associated with 1 year sustained response. Of these factors, cirrhosis (86.1% in CHB, 22.2% in LC) was significantly associated with 1 year virological relapse rate. Baseline HBV DNA and total treatment duration tended to be associated with virological relapse., Conclusions: Virological relapse developed in the majority (73.3%) of HBeAg negative CHB patients and clinical relapse developed in the half (53.3%) of patients at 1 year off therapy. Cirrhosis may be associated with the low rate of virological relapse.

Whether multidrug-resistant (MDR) hepatitis B virus (HBV) harbors mutations co-located in the same HBV clones that confer reduced sensitivity to antiviral therapy remains uncertain. This study investigated the evolution of MDR HBV strains developed from sequential monotherapy with lamivudine (LAM), adefovir (ADV), and entecavir (ETV) during LAM plus ADV salvage therapy. Sera were obtained from six patients who had developed sequential resistance to LAM, ADV, and ETV before and during LAM plus ADV therapy. The HBV genomes from each patient were amplified, cloned, and sequenced. Among 6 sets of 20 clones obtained before salvage therapy, all clones harbored the rtM204V mutation, and ETV-resistant mutations were detected with the rtM204V in 108 clones. The rtA181 mutation was not detected at baseline, but emerged in five patients during therapy. Among 9 sets of 20 clones obtained during salvage therapy, 39 clones harbored rtA181T/V ± rtN236T mutations, which were detected in the absence of rtM204 and ETV-resistant mutations in 37 clones (94.9%). Only two clones (5.1%) harbored both rtA181T/V and ETV-resistant mutations. The rtA181T/V mutation emerged after reversion from ETV-resistant mutants to wild-type HBV. Five patients achieved a partial virologic response to LAM plus ADV therapy. In conclusion, the majority of MDR mutations existed in different genomes. Suboptimal response to LAM plus ADV therapy may not result from the co-localization of MDR HBV mutations in the same genome, but instead the low antiviral potency of these drugs. Thus, more potent antiviral drug combinations may be an effective salvage therapy for patients infected with MDR HBV., (Copyright © 2012 Wiley Periodicals, Inc.)

This study evaluated the efficacy of adefovir (ADV) plus lamivudine (LAM) or ADV add-on therapy for patients with entecavir (ETV)-refractory hepatitis B infection. Twenty-nine ETV-resistant and 8 patients with suboptimal response to ETV were enrolled. Twenty-seven patients received ADV + LAM therapy and 10 patients received ADV + ETV therapy for >24 weeks. In 29 patients who were ETV-resistant, the mean reduction in HBV DNA levels at 24 weeks was not different between the ADV + LAM and ADV + ETV groups (-1.98 log(10)  IU/ml vs. -2.16 log(10)  IU/ml; P = 0.792). Primary non-response was observed in 52.2% (12/23) of ADV + LAM group and 33.3% (2/6) of ADV + ETV group (P = 0.651). Initial virologic response (IVR) was observed in 17.4% (4/23) of ADV + LAM group and 33.3% (2/6) of ETV + ADV group (P = 0.362). In eight patients with suboptimal response to ETV, the ADV + ETV group had a greater reduction in HBV DNA at 24 and 48 weeks than the ADV + LAM group (-2.29 log(10)  IU/ml vs. -0.09 log(10)  IU/ml and -2.04 log(10)  IU/ml vs. -0.72 log(10)  IU/ml; P = 0.020 and P = 0.012, respectively). Primary non-response and IVR did not significantly differ between the two groups [100% (4/4) vs. 50% (2/4) and 0% (0/4) vs. 50% (2/4); P = 0.429 and P = 0.429, respectively]. The antiviral efficacies of ADV-based therapy with ETV or LAM for patients with ETV-resistant hepatitis B were limited and did not differ between the two groups. However, adding ADV to ETV may be more effective than ADV + LAM therapy in patients with suboptimal virologic response to ETV., (Copyright © 2011 Wiley Periodicals, Inc.)

Recent studies have suggested that quantifying the serum HBsAg levels can predict the response to pegylated interferon. We aimed to determine the change in serum HBsAg levels during entecavir (ETV) treatment and the correlation with treatment response in chronic HBeAg-positive and HBeAg-negative hepatitis B patients. Serial HBsAg levels were measured using the Architect assay (Abbott Laboratories, Abbott Park, IL) in sera from 101 treatment-naive chronic hepatitis B (CHB) patients receiving ETV. During treatment, in HBeAg-positive patients, the mean HBsAg level was 3.51, 3.22, 3.34, 3.36, and 3.40 log₁₀  IU/ml at baseline, 3, 6, 12, and 24 months, respectively, and there was no significant change compared with the baseline level, except the decline at 3 months (P = 0.009). In HBeAg-negative patients, the mean level of serum HBsAg showed increase with 3.06, 3.09, 3.20, 3.26, and 3.27 log₁₀  IU/ml at baseline, 3, 6, 12, and 24 months of treatment, respectively. In HBeAg-positive patients, HBV-DNA negativity (<2,000 copies/ml; P = 0.010) and HBsAg level < 3,000 IU/ml (P = 0.026) at 3 months were independent predictors of HBeAg loss/seroconversion at 12 months. After 24 months of treatment, the HBsAg levels at baseline (P = 0.046) was an independent factor of HBeAg loss/seroconversion. In HBeAg-negative patients, undetectable HBV DNA at 6 months was an independent factor predicting undetectable HBV DNA after 12 months of therapy. The level of serum HBsAg before and during therapy was a good predictor of HBeAg loss/seroconversion in naïve HBeAg-positive CHB patients receiving entecavir., (Copyright © 2011 Wiley-Liss, Inc.)

Background/aims: The usefulness of liver stiffness measurement (LSM) for monitoring changes in fibrosis and inflammation in chronic hepatitis B (CHB) patients receiving antiviral therapy is unknown. The aim of this study was to evaluate changes in liver stiffness and correlate them with changes in serological markers and histology in CHB patients receiving entecavir., Methodology: The study included 38 patients with CHB and 24 cirrhotic patients with CHB. All patients received entecavir for over 12 months. Liver stiffness was measured by transient elastography at baseline and after 48wks of therapy. Liver biopsy was performed on 15 patients at baseline and during therapy., Results: Among 62 treated patients, 51 (82.2%) achieved HBV DNA <50 copies/mL and 43 (69%) achieved alanine aminotransferase (ALT) normalization at 48wks. The median liver stiffness value at baseline was 15.1 kPa (5.6-75.0) and decreased significantly to 8.8kPa (3.0-33.8) after 48wks. A decrease in liver stiffness value during therapy correlated significantly with decreases in albumin (r=-0.357, p=0.004), bilirubin (r=0.342, p=0.007), ALT (r=0.319, p=0.012), and aspartate aminotransferase (AST) (r=0.353, p=0.005) concentrations. Decreases in liver stiffness values correlated significantly with improvement in necroinflammatory scores., Conclusion: We suggest that LSM can reflect the changes of necroinflammation in patients with chronic hepatitis B receiving antiviral therapy.

Background/aims: Entecavir is a potent and selective guanosine analogue that has demonstrated a significant antiviral efficacy against hepatitis B virus (HBV). The aim of this study was to characterize the response to entecavir and to examine the factors affecting that response., Methods: We administered 0.5 mg of entecavir once daily for more than 12 months to 114 naive chronic hepatitis B (CHB) patients. We measured the levels of liver enzymes, serological markers, and serum HBV DNA at 3-month interval., Results: Normalization of serum alanine aminotransferase levels was observed in 68.5% (76/114), 74.6% (85/114), and 81.6% (62/76) of patients after 6, 12, and 24 months of therapy, respectively. HBV DNA levels of <50 copies/mL (as evaluated by polymerase chain reaction) were observed in 43.9% (50/114), 71.1% (81/114), and 85.5% (65/76) of patients after 6, 12, and 24 months, respectively. Viral breakthrough was not observed. The rates of HBeAg loss and seroconversion were 43.5% (27/62) and 14.5% (9/62), respectively, after 12 months of therapy, and 56.4% (22/39) and 15.4% (6/39) after 24 months. The independent factor associated with PCR negativity was early virologic response (EVR; HBV DNA <2,000 copies/mL after 3 months of therapy, P<0.001). The independent factors predicting HBeAg loss were found to be serum albumin levels (P=0.041) and EVR (P=0.005)., Conclusions: Entecavir induced excellent biochemical and virologic responses in naive CHB patients. EVR was an independent factor for predicting HBV PCR negativity and HBeAg loss.