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Serum hepatitis B core-related antigen (HBcrAg) and surface antigen (HBsAg) are surrogate markers of intrahepatic covalently closed circular DNA. The measurement range of the current HBcrAg assay is relatively narrow. Thus, we examined the potential of HBcrAg and HBsAg measured by ultrasensitive assays for predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B treated with entecavir (ETV). We conducted a retrospective cohort study of 180 patients who received ETV for >1 year. All patients had hepatitis B e-antigen negativity at baseline. Serum HBcrAg and HBsAg levels at baseline and year 1 were measured in all patients by ultrasensitive assays using immunoassay for total antigen including complex by pretreatment (iTACT) technology. During the median follow-up of 11.0 years, 22 patients developed HCC (11.8/1,000 person-years). Baseline HBsAg levels were not associated with HCC development during ETV treatment. However, high HBcrAg levels at baseline and at year 1 were significantly associated with HCC development (log-rank test; P < 0.001). In 110 patients (61.1%) with ≥4.0 log U/mL at baseline (high HBcrAg cohort), HBcrAg declined to ≤2.9 log U/mL at year 1 in 25 patients (22.7%). The adjusted hazard ratio for HCC incidence was significantly lower in patients with HBcrAg ≤2.9 log U/mL at year 1 than in those in the high HBcrAg cohort. Conclusion: Measurement of HBcrAg by ultrasensitive assay has better potential for predicting HCC during antiviral treatment than the current HBcrAg assay.

AIMS Hepatitis B surface antigen (HBsAg) seroclearance indicates a "functional cure" in chronic hepatitis B (CHB) virus infection. However, several cases of hepatocellular carcinoma (HCC) development have been reported after HBsAg seroclearance. We evaluated the potential of HBsAg and hepatitis B core-related antigen (HBcrAg), measured by the ultra-highly sensitive assays, in cases with HCC development after HBsAg seroclearance. METHODS We enrolled 17 patients with CHB who achieved HBsAg seroclearance, defined by the conventional assay using Architect HBsAg QT kit (five HCC patients and 12 non-HCC patients). HBsAg and HBcrAg were measured in their stored serum samples using ultra-highly sensitive assays featuring "immunoassay for total antigen including complex via pretreatment (iTACT)" technology. RESULTS All five patients who developed HCC were positive for HBsAg or HBcrAg by iTACT-HBsAg or iTACT-HBcrAg at all follow-up points. HBcrAg levels in the HCC group, using iTACT-HBcrAg, were significantly higher than those in the non-HCC group at HBsAg seroclearance (3.6 LogU/ml (2.8-4.2) versus 2.6 (

Tenofovir disoproxil fumarate (TDF) is widely used to treat hepatitis B virus (HBV) patients worldwide. We previously reported a patient with CHB and cirrhosis in whom viral breakthrough occurred during combination therapy with TDF and entecavir (ETV) against ETV-resistant virus. A recent Korean report showed that two patients with viral breakthrough during treatment with TDF-containing regimens were found to carry five reverse transcriptase (rt) mutations ([rt]S106C[C], rtH126Y[Y], rtD134E[E], rtM204I/V, and rtL269I [I]), with the C, Y, E, and I mutations being associated with tenofovir resistance. We report the clinical course up to September 2019 in our patient, and compare the HBV mutations to those of the two Korean patients. Four mutations (rtS106C, rtD134N/S[N/S], rtM204V, and rtL269I) plus ETV resistance (rtL180M and rtS202G) existed when she developed viral breakthrough during ETV and TDF combination therapy in April 2013. Moreover, three mutations (rtS106C, rtD134N, and rtL269I) existed at baseline. Our patient's father is Korean. Considering these factors, patients with these three or four mutations (CYEI or CN/SI) at baseline could experience tenofovir resistance in addition to lamivudine (LAM) or ETV resistance. In addition, HBV DNA levels fluctuated during tenofovir alafenamide (TAF) and LAM therapy in our patient, although treatment was switched from LAM, TDF, and ETV to LAM and TAF combination therapy in April 2018. In conclusion, three mutations (CN/SI) plus ETV resistance (rtL180M, rtM204V, and rtS202G) can cause tenofovir resistance. Long-term therapy with tenofovir against ETV-resistant virus has the potential to induce viral breakthrough and resistance, necessitating careful follow-up.

AIM The risk of development of hepatocellular carcinoma (HCC) persisted in patients with advanced fibrosis, even after achieving sustained virologic response (SVR). This study aimed to show the advantage of liver stiffness measurement (LSM) at baseline and after SVR to predict HCC occurrence and esophageal varices (EV) exacerbation. METHODS These risks were evaluated in 398 chronic hepatitis C patients without a history of HCC who achieved SVR after direct-acting antiviral agent and evaluated LSM at least twice during follow up. We defined liver cirrhosis and chronic hepatitis as LSM of ≥12 kPa and

Telomerase reverse transcriptase (TERT) promoter mutation is the most frequent genetic alteration in hepatocellular carcinoma (HCC). However, there is currently no suitable highly sensitive method that can detect such mutation using serum cell-free DNA (cfDNA). We analyzed somatic point mutations that substitute cytosine for thymidine at position 228 (C228T), as one of the hotspots of TERT promoter mutations, in serum cfDNA using a highly sensitive detection method of wild-type blocking polymerase chain reaction (WTB-PCR) combined with Sanger sequencing. In TERT promoter mutation sensitivity study, synthetic oligonucleotides were prepared to determine the lowest detection limit of the WTB-PCR, using serial dilutions of mutant-type (MT) DNA in the background of wild-type (WT) DNA. Using this technique, we conducted a longitudinal study in one patient who developed HCC during the follow-up and determined the relationship between HCC and TERT C228T in serum cfDNA. In the sensitivity study, the mutant peak at position 228 was detected at 0.7% or higher but was not detected at 0.6%. Thus, sequencing analysis of WTB-PCR product demonstrated the limit of detection in excess of 0.7% MT DNA in the background of WT DNA. One male patient with HCV-related cirrhosis developed HCC during the follow-up. TERT C228T was negative before the diagnosis of HCC, positive at the diagnosis of HCC and did not increase with advancement of malignancy. We developed a highly sensitive method for detection of TERT promoter mutation using WTB-PCR combined with Sanger sequencing and demonstrated its clinical usefulness in the measurement of TERT C228T in serum cfDNA. Larger studies are needed to confirm these results and establish the clinical utility of this new method.

Background Chronic hepatitis B virus (HBV) infection is an aetiologic factor for hepatocellular carcinoma (HCC). Baseline HBV DNA is a known independent predictor of HCC, and the serum hepatitis B core-related antigen (HBcrAg) level corresponds to intrahepatic covalently closed circular DNA. Aim To investigate whether the baseline and on-treatment serum HBcrAg levels can predict HCC incidence in patients with chronic hepatitis B following nucleos(t)ide analogue (NA) therapy. Methods This retrospective cohort study included 1268 patients treated with NAs for >1 year. In all patients, serum HBcrAg and hepatitis B surface antigen levels were measured at baseline and 1 year. Results During a median follow-up of 8.9 years, 113 patients (8.9%) developed HCC (10.3/1000 person-years). These patients were stratified by baseline hepatitis B e-antigen (HBeAg) status into HBeAg+ and HBeAg- cohorts. High on-treatment HBcrAg levels at 1 year were found to associate significantly with HCC (HBeAg+ cohort: P = 0.017; HBeAg- cohort: P = 4.30 × 10-5 ; cut-off values: 4.9 log U/mL and 4.4 log U/mL, respectively). In a multivariate Cox regression analysis, patients with persistently high on-treatment HBcrAg levels had a higher risk of HCC than those with low HBcrAg levels (HBeAg+: hazard ratio [HR], 6.15, 95% confidence interval [CI]: 1.89-20.0, P = 0.003; HBeAg- cohort: HR, 2.54, 95% CI: 1.40-4.60; P = 0.002). A sub-analysis of patients without alcoholism yielded similar findings. Conclusions Patients with persistently high on-treatment HBcrAg levels were more likely to develop HCC despite sustained viral suppression via long-term NA treatment.

Primary liver carcinoma with sarcomatous change is a rare malignancy associated with high aggressiveness and poor prognosis. However, the characteristics of these types of tumors are still unknown. The aim of this study was to assess the imaging features, prognostic significance, and clinicopathological characteristics of patients with these tumors. Of 1070 patients who underwent surgical resection of primary liver carcinoma at Toranomon Hospital (Tokyo, Japan) from 2003 to 2017, 10 patients were diagnosed with primary liver carcinoma containing sarcomatous component. This study included all 10 patients. We evaluated the percentage of the sarcomatous component in each tumor. Patients were classified into two groups: the low percentage group (area of sarcomatous changes ≤30%) and high percentage group (area sarcomatous component ≥70%). We also divided patients into two groups based on the combination of the percentage of sarcomatous tissue and tumor size (≥40 mm or

It is currently unclear what impact serum microRNA-122 (miR-122) levels have on clearance of hepatitis B virus (HBV) surface antigen (HBsAg) in HBV-infected patients who had not received antiviral therapy. The current study evaluated the impact of serum miR-122 levels on HBsAg seroclearance in 367 consecutive HBV-infected patients who had not received antiviral therapy between their initial and last visit, and investigated the predictive factors of HBsAg seroclearance. Cumulative HBsAg seroclearance rates were 13.5%, 32.0%, and 37.4% after 10, 20, and 30 years, respectively. The yearly incidence of HBsAg seroclearance over the investigated 30-year period was 1.25%. A significant and strong correlation was observed between serum miR-122 and HBsAg levels. Moreover, there was a significant correlation between serum miR-122 levels and the levels of HBV DNA, hepatitis B e-antigen, and HBV core-related antigen. The HBsAg seroclearance rate in patients with a

Aim The recurrence rates of pruritus after stopping nalfurafine hydrochloride are unknown in chronic liver disease. Methods A prospective confirmatory trial was carried out to determine the recurrence rates of pruritus after cessation of nalfurafine hydrochloride in chronic liver disease. After pretreatment with nalfurafine hydrochloride for 4 weeks or more, 15 consecutive Japanese patients, who confirmed the improvement of pruritus (decrease in the visual analogue scale (VAS) of ≥50 mm), were enrolled in the present study. Patients were classified to the continuous group (continuation of nalfurafine hydrochloride for 4 weeks) or the discontinuous group (cessation of nalfurafine hydrochloride) at the time of consent to study protocol, by self-determination. Results The recurrence rates (increase in VAS of ≥25 mm after stopping nalfurafine hydrochloride) were 100% (5 of 5 patients) and 0% (0 of 10) in the discontinuous and continuous groups, respectively. In the discontinuous group, 3 patients selected retreatment with nalfurafine hydrochloride as salvage therapy, and they generally recovered to the levels of VAS at the discontinuation of treatment. Conclusion The present prospective trial showed the high recurrence rates of pruritus after the stop of nalfurafine hydrochloride in chronic liver disease.

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

Little information is available on the impact of direct-acting antiviral (DAA) therapy on changes in liver fibrosis and steatosis. Liver stiffness (LS) and controlled attenuation parameter (CAP) values were evaluated using transient elastography. The study subjects were 214 elderly patients infected with HCV genotype 1b who received 24-week daclatasvir and asunaprevir dual therapy. All patients of this retrospective study had no hepatocellular carcinoma before and during DAA therapy. LS and CAP were assessed before treatment (baseline), at end of treatment (EOT), and at 24, 48, 72 weeks (W) after EOT. The rate of sustained viral response (SVR) by daclatasvir and asunaprevir therapy was 91%. LS values for the entire group correlated with Fib-4 index at baseline (r = 0.565, P

With rapidly aging population in the world, many elderly patients present with hepatitis B virus (HBV) infection. We conducted a retrospective cohort study involving 359 untreated HBV patients aged 60 and older who were free of hepatocellular carcinoma (HCC) and acute hepatitis at the initial visit, and examined the incidence of HCC and liver-related mortality rate. During the follow-up period of 7.9 years (range, 0-25 years), 26 patients (7.2% of patients) developed HCC, 20 patients died from liver-related diseases (61% of total deaths), including HCC, liver failure, and gastrointestinal bleeding. The cumulative rates of HCC at years 5, 10, and 15 were 6.5%, 15.6%, and 15.6%, respectively. The cumulative rates of mortality from liver-related diseases at years 5, 10, 15 were 3.3%, 12.3%, and 15.7%, respectively. Multivariate analysis identified HBV DNA (≥5.0 Log IU/mL), male gender, and FIB4-Index (≥3.6) as significant independent risk factors for HCC, and alpha-fetoprotein (≥10 ng/mL) as significant independent predictors of liver-related mortality. We conclude that high levels of HBV DNA, progression of liver fibrosis, and male gender are independent risk factors of HCC in untreated patients infected with HBV aged 60 and older.

Aim Pruritus is one of the complications of chronic liver disease, and it is important to investigate the predictors. Methods Six hundred and seventy-three consecutive Japanese patients with chronic liver disease were retrospectively investigated for itch severity. Furthermore, 138 of all 673 patients were introduced to nalfurafine hydrochloride, and the improvement of itch severity was evaluated. The itch severity was self-assessed using the pruritus scores by Kawashima's criteria and visual analog scale. Results Two hundred and twenty-nine of the 673 patients (34.0%) were evaluated as 1 point or more of pruritus severity of Kawashima's criteria, and 46 patients (6.8 %) as 3 points or more. Multivariate analysis established that being negative for hepatitis B surface antigen (HBsAg) and presence of hepatocellular carcinoma (HCC) were significant determinants of pruritus (≥1 point of Kawashima's criteria), and being negative for HBsAg and having lower levels of platelet count were significant determinants of severe pruritus (≥3 points). Ninety-three of the 138 patients (67.4%) with nalfurafine hydrochloride indicated improvement of itch, defined as a decrease in VAS of 50 mm or more. There were no significant differences in treatment efficacy of nalfurafine hydrochloride, regardless of the three predictors of pruritus (HBsAg, HCC and platelet count). Conclusion The present retrospective study indicated the predictors for pruritus, based on the large number of patients with chronic liver disease. Furthermore, this study demonstrated that nalfurafine hydrochloride may be useful for pruritus, regardless of the predictors.

Objective The aim of this study was to clarify the usefulness of a no-touch pincer ablation procedure that uses bipolar electrodes to prevent intrasubsegmental tumor recurrence after radiofrequency ablation (RFA) for patients with hepatocellular carcinoma (HCC). Methods We studied 303 consecutive patients with HCC (single nodule and tumor diameter ≤30 mm) who received RFA between January 2005 and April 2015; 268 patients received touch ablation using a monopolar or bipolar RFA device, and 35 received no-touch ablation using a bipolar RFA device. The pretreatment arterial and portal phase dynamic computed tomography or magnetic resonance images were classified into four enhancement patterns. Type 1 and Type 2 are homogeneous enhancement patterns without or with increased arterial blood flow, respectively. Type 3 is a heterogeneous enhancement pattern with a septum-like structure, and Type 4 is an irregularly shaped ring structure enhancement pattern. Results With regard to intrasubsegmental tumor recurrence, among the 268 patients who underwent the touch ablation procedure, tumors recurred in 52 (19.4%) patients, and among the 35 patients who underwent the no-touch ablation procedure, tumors recurred in one (2.9%) patient. Cumulative intrasubsegmental tumor recurrence rates tended to be higher with touch ablation (P = 0.083). Multivariate Cox proportional hazards analysis revealed that ablation procedure (touch ablation, hazard ratio [HR] 10.32, P = 0.032), type of enhancement pattern (Type 3, HR 3.05, P = 0.006; and Type 4, HR 8.87, P

Aim The effect of transcatheter arterial chemoembolization (TACE) is not necessarily sufficient in patients with multiple hepatocellular carcinoma (HCC). We evaluated the antitumor activity and adverse events of TACE using warmed miriplatin suspension for multiple HCC. Methods Seventy patients with multiple HCC received TACE using warmed miriplatin/lipiodol suspension, including patients who were TACE-naive (group A, n = 5), those undergoing initial TACE after radical therapies (group B, n = 31), and those with a history of repeated TACE (group C, n = 34). Median tumor size was 19.5 mm and a median of four nodules. Results Complete necrosis (TE 4) and partial necrosis (TE 3) of 50% or more were attained in 24 and 19 patients at 3 months after TACE, respectively. Response rates (TE 4 + TE 3) were 60.0% in group A, 83.9% in group B, and 41.2% in group C (P = 0.038). Survival rates of all patients after TACE were 82.6% after 1 year, 65.6% after 2 years, and 47.7% after 3 years. Three-year survival rates of patients in groups A, B, and C were 53.3%, 78.8%, and 29.7%, respectively (P = 0.0029). Conclusion Transcatheter arterial chemoembolization using warmed miriplatin induced high response rate in multiple HCC, and the rate was significantly high in those patients with recurrent multiple HCCs after curative therapies.

The aim of this study was to assess the rate of development of hepatocellular carcinoma (HCC) in patients who achieved sustained virologic response (SVR) by direct antiviral agents (DAA). We retrospectively evaluated patients who achieved SVR by oral DAA interferon-free regimens (n = 77) (daclatasvir/asunaprevir [n = 67], ombitasvir/paritaprevir/ritonavir [n = 9], and telaprevir [n = 1]) and by pegylated-interferon plus ribavirin (Peg-IFN/RBV, n = 528). In all patients, the background was chronic hepatitis or cirrhosis caused by HCV genotype 1b. During a median follow-up period of 4.0 years, two (2.6%) of DAA-treated patients developed HCC. The 3- and 5-year cumulative HCC development rates were 1.30% and 3.03%, respectively, in the DAA group, and 1.02% and 2.19 % in the Peg-IFN/RBV group (P not significant). In patients with Fib-4 score of >3.25, the 3-year HCC development rates were 4.35% and 3.95%, whereas those of the 5 year were 9.66% and 8.37%, in the DAA and Peg-IFN/RBV group, respectively. In patients with Fib-4 score of ≤3.25, none of the DAA group developed HCC, whereas 0.48% at 3-year and 1.05% at 5-year of patients of the Peg-IFN/RBV group did. Propensity score analysis using the inverse probability of treatment weights (IPTW) also showed no significant difference in HCC development rate between the two groups. Serum AFP gradually and similarly decreased after initiation of antiviral therapy in both groups. Our data indicate that the HCC risk rate after SVR is similar regardless of whether the latter was achieved by DAA or IFN-based regimens. J. Med. Virol. 89:476–483, 2017. © 2016 Wiley Periodicals, Inc.

Aim The aim of this study is to clarify the usefulness and limitations of balloon-occluded transcatheter arterial chemoembolization (B-TACE) using miriplatin for patients with four or fewer hepatocellular carcinoma (HCC) nodules. Methods We studied 47 nodules in 30 consecutive patients who received miriplatin by B-TACE to treat HCC with four or fewer nodules per patient. The treatment effect was evaluated using the Response Evaluation Criteria in Cancer of the Liver. Results Nodules were divided according to the presence or absence of portal vein visualization during B-TACE. In the presence group, dynamic computed tomography at 3 months post-therapy showed Response Evaluation Criteria in Cancer of the Liver treatment effect (TE) 4 in 88% (14/16), TE3 in 0% (0/16), TE2 in 0% (0/16), TE1 in 12% (2/16), and objective response in 88% of nodules. In the absence group, the results were TE4 in 35% (11/31), TE3 in 13% (4/31), TE2 in 26% (8/31), TE1 in 26% (8/31), and objective response decreased to 48% of nodules. In addition to typical hypervascular nodules, we treated three nodules with irregular ring enhancement that predicted poorly differentiated HCC and four nodules that included a hypoenhancement area that predicted well to moderately differentiated HCC. All irregular ring enhancement nodules achieved TE4. Other nodules that were predicted to be well to moderately differentiated HCC did not have portal vein visualization during B-TACE and could not achieve TE4. Conclusion Balloon-occluded transcatheter arterial chemoembolization is a useful technique for treatment of classical hypervascular HCC, and portal vein visualization during the B-TACE procedure may provide more favorable local control.

Predictors of treatment efficacy with ledipasvir plus sofosbuvir as direct-acting antiviral (DAA) regimen for HCV infection are still unclear. Retreatment efficacy of ledipasvir plus sofosbuvir for failures to prior DAA regimens, including NS5A inhibitors, are also unknown because resistance-associated variants (RAVs) in NS5A have been shown to persist up to the long-term of post-treatment. One hundred seventy-five patients with chronic HCV genotype 1 infection, without decompensated liver cirrhosis and hepatocellular carcinoma, were evaluated SVR12 by ledipasvir 90 mg plus sofosbuvir 400 mg once-daily for 12 weeks. Overall, SVR12 were 92%, based on intention to treat analysis. In failures to daclatasvir plus asunaprevir, SVR12 were 71%. The study using ultra-deep sequencing showed that ledipasvir plus sofosbuvir was effective to one case of failures to daclatasvir plus asunaprevir with multidrug RAVs (triple mutation in NS3-D168/NS5A-L31/NS5A-Y93). Multivariate analysis identified FIB4 index (

The combination of daclatasvir and asunaprevir is efficacious in the treatment of hepatitis C virus (HCV) infection, but its efficacy and predictors of efficacy in the elderly (≥70 years) remain unclear. In this study, 844 patients with chronic HCV genotype 1b infection, were treated with daclatasvir (60 mg once daily) plus asunaprevir (100 mg twice daily) for 24 weeks. Using the intention-to-treat analysis, the sustained virological response (SVR) rates were 87% and 88% for all 844 patients and 411 elderly (>70 years of age), respectively. In both groups, multivariate analysis identified NS5A-Y93H mutation (

Alanine aminotransferase (ALT) elevations were the most frequent adverse events during all-oral combinations with daclatasvir and asunaprevir for patients with hepatitis C virus (HCV) infection, but the underline mechanisms are unclear. Seventy patients with chronic HCV genotype 1b infection, who were introduced daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily for 24 weeks, were measured serum asunaprevir concentrations at the one point or more of 2, 4, and 8 weeks after the start of treatment. In 4 and 8 weeks after the start of treatment, asunaprevir concentrations in patients with albumin levels

The present study was designed to assess the evolution of simeprevir-resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time in virological non-responders (patients with positive HCV-RNA during and at end of treatment). The study enrolled 136 patients infected with HCV genotype 1b who received 12-week simeprevir-PEG-IFN-ribavirin therapy, and data of 87 patients were available for analysis. Twelve patients (14%) were considered virological non-responders, including 9 (75%) who showed absolute no-response (HCV RNA: ≥3.0 log IU/ml at 12 weeks after start of therapy). Multivariate analysis of these patients identified lack of response to prior treatment, use of low ribavirin dose, and old age as independent and significant determinants of virological non-response. Using ultra-deep sequencing, de novo variants of D168 were detected in all of 9 absolute non-responders. The majority of these variants emerged within 5 weeks of triple therapy. In comparison, de novo variants of Q80 were detected in only 3 of 9 absolute non-responders and emerged at 6–12 weeks. Variants of Q80 detected at baseline increased during the course of treatment in 5 of 9 absolute non-responders, while no such increase was noted in variants of R155 and/or A156 detected at baseline during the 12-week course. De novo variants of R155 and/or A156 were not detected in this study. The results demonstrated the emergence of simeprevir-resistant variants during the early stage of triple therapy. J. Med. Virol. 87:609–618, 2015. © 2015 Wiley Periodicals, Inc.

Aim The factors associated with the outcome of sequential therapy with interferon-α (IFN-α) in order to halt nucleoside/nucleotide analog (NUC) maintenance treatment for chronic hepatitis B were analyzed. Methods A total of 50 patients with chronic hepatitis B who underwent IFN-α sequential therapy for cessation of NUC were enrolled retrospectively. The subjects received NUC plus IFN-α for 4 weeks followed by IFN-α alone for 20 weeks. Natural IFN-α of 6-MU doses was administrated three times a week. A successful response to NUC/IFN-α sequential therapy was defined as serum hepatitis B virus (HBV) DNA below 4.0 log copies/mL, serum alanine aminotransferase (ALT) below 30 IU/L, and hepatitis B e-antigen negativity at 24 months after completing the treatment. Results Multivariate analysis revealed that hepatitis B surface antigen (HBsAg) of 3.0 log U/mL or more (P

Aim Tolvaptan, an oral arginine vasopressin V2 receptor antagonist, became available for hepatic ascites. We evaluated the therapeutic efficacy and safety of tolvaptan administration to treat refractory ascites. Methods Data were collected from 15 hospitalized patients with cirrhosis (hepatitis C, 10; alcoholism, five) after adding tolvaptan (3.75–11.25 mg/day) to conventional diuretics. Bodyweights and serum sodium and creatinine concentrations were measured. Tolvaptan was continued for 4 weeks or longer for a median follow-up period of 42 days (range, 28–56). Results In the first week (introduction phase), tolvaptan significantly reduced median weight (66.6, 65.9 and 63.1 kg on days 0, 1 and 7, respectively; P

Using ultra-deep sequencing technology, the present study was designed to investigate the evolution of simeprevir-resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time. In Toranomon Hospital, 18 Japanese patients infected with HCV genotype 1b, received triple therapy of simeprevir/PEG-IFN/ribavirin (DRAGON or CONCERT study). Sustained virological response rate was 67%, and that was significantly higher in patients with IL28B rs8099917 TT than in those with non-TT. Six patients, who did not achieve sustained virological response, were tested for resistant variants by ultra-deep sequencing, at the baseline, at the time of re-elevation of viral loads, and at 96 weeks after the completion of treatment. Twelve of 18 resistant variants, detected at re-elevation of viral load, were de novo resistant variants. Ten of 12 de novo resistant variants become undetectable over time, and that five of seven resistant variants, detected at baseline, persisted over time. In one patient, variants of Q80R at baseline (0.3%) increased at 96-week after the cessation of treatment (10.2%), and de novo resistant variants of D168E (0.3%) also increased at 96-week after the cessation of treatment (9.7%). In conclusion, the present study indicates that the emergence of simeprevir-resistant variants after the start of treatment could not be predicted at baseline, and the majority of de novo resistant variants become undetectable over time. Further large-scale prospective studies should be performed to investigate the clinical utility in detecting simeprevir-resistant variants.

Aim To compare the early virological effectiveness, sustained virological response and safety of telaprevir 1500 mg/day with telaprevir 2250 mg/day, when combined in triple therapy with pegylated interferon and ribavirin in Japanese patients with high viral loads of genotype 1 hepatitis C virus. Methods The telaprevir 2250 mg/day and 1500 mg/day groups each contained 60 patients matched by age, sex and history of previous interferon-based treatment. Serum levels of genotype 1 hepatitis C virus RNA, hemoglobin levels, drug adherence and drug discontinuation rates were monitored during and after triple therapy. Results Patients receiving telaprevir 1500 mg/day had significantly lower telaprevir adherence and lower initial ribavirin dose but similar or superior pegylated interferon and ribavirin adherence and a lower rate of telaprevir discontinuation than did those receiving telaprevir 2250 mg/day. The early virological responses and sustained virological response rates were similar in both groups. Hemoglobin levels decreased to a greater extent in patients treated with telaprevir 2250 mg/day. Conclusion Compared to triple therapy including telaprevir 2250 mg/day, that including telaprevir at a reduced dose of 1500 mg/day was associated with lower rates of anemia and similar antiviral efficacy. Such a regimen may meaningfully improve sustained virological response rates, especially among female and elderly Japanese patients.

AIM Treatment of hepatocellular carcinoma located on the liver surface is frequently difficult because direct puncture of the tumor must be avoided during needle insertion. The aim of this study was to investigate the utility of a no-touch pincer ablation procedure that uses a multipolar radiofrequency ablation (RFA) system for a tumor located on the liver surface. METHODS The experimental animals were three pigs, and RFA was performed with two internally cooled bipolar electrodes. Three ablative procedures were compared: linear insertion at regular 13-mm intervals (pattern 1; virtual target tumor size

The aim of this retrospective cohort study was to assess the cumulative incidence and predictive factors for intracerebral hemorrhagic stroke after the termination of interferon (IFN) therapy in Japanese patients with hepatitis C virus (HCV). A total of 4,649 HCV-positive patients treated with IFN were enrolled. The primary goal is the first onset of intracerebral hemorrhagic stroke. The mean observation period was 8.0 years. Evaluation was performed using the Kaplan–Meier method and the Cox proportional hazard model. A P-value of less than 0.05 was considered statistically significant. A total of 28 developed intracerebral hemorrhagic stroke. The cumulative incidence of intracerebral hemorrhagic stroke was 0.3% at 5 years, 0.8% at 10 years, and 1.7% at 15 years. Intracerebral hemorrhagic stroke occurred when patients had age increments of 10 years (hazard ratio: 2.77; 95% confidence interval (CI) 1.48–5.18; P = 0.001), hypertension (hazard ratio: 2.30; 95% CI 1.09–4.83; P = 0.021), liver cirrhosis (hazard ratio: 4.50; 95% CI 2.07–9.78; P

Alfa-fetoprotein (AFP) is used as a marker of early hepatocarcinogenesis. However, the impact of hepatitis B virus surface antigen (HBsAg) on this relationship in patients with HBV infection is not clear. The present study evaluated the relation between HBsAg and AFP levels at the initial visit in 1,610 untreated HBV patients, free of hepatocellular carcinoma (HCC) or severe hepatitis. The cumulative rate of HCC was significantly lower in patients with a low AFP level (≤10 µg/L; below the upper limit of normal) than in those with a high AFP level (≥11 µg/L) at the initial visit. In patients with HBsAg levels more than 500 IU/ml, HBsAg levels correlated significantly and negatively with AFP levels, and significantly with platelet count. Multivariate analysis of data of patients with HBsAg more than 500 IU/ml identified HBsAg (

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. J Med. Virol. 85:1746–1753, 2013. © 2013 Wiley Periodicals, Inc.

Aim The aim of this case–control study was to assess the efficacy and safety of dipeptidyl peptidase-4 inhibitor (sitagliptin) for type 2 diabetes mellitus (T2DM) with non-alcoholic fatty liver disease (NAFLD). Methods Twenty NAFLD patients with T2DM treated by sitagliptin were retrospectively enrolled as the sitagliptin group. These patients were given sitagliptin between January 2010 and July 2011. Another 20 NAFLD patients with T2DM treated only with diet and exercise for 48 weeks were selected as the control group. Serum levels of fasting plasma glucose (FPG), hemoglobin A1C (HbA1c), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured before and 12, 24, 36 and 48 weeks after the initiation of treatment. Results In the sitagliptin group, average HbA1c levels decreased approximately 0.7% at 48 weeks after the initiation of sitagliptin. Next, average FPG levels decreased approximately 15 mg/dL at 48 weeks after the initiation of sitagliptin. The serum levels of HbA1c and FPG in the sitagliptin group decreased with statistical significance compared to those in the control group (P

Aim Laparoscopy-guided liver biopsy is the most accurate method for assessing liver fibrosis but have several limitations. We designed a non-invasive method, called magnetic resonance laparoscopy (MRL), based on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging, to assess liver fibrosis in patients with chronic hepatitis B and C virus. Methods We prospectively analyzed 49 patients with normal liver and 353 patients with chronic viral hepatitis, laparoscopic liver biopsy was performed on 109 patients and 244 patients were diagnosed as having liver cirrhosis clinically. The MRL findings of the liver surface were classified into three categories: (i) smooth (essentially smooth surface of the entire liver or with limited areas of depression); (ii) partially irregular (several interconnected depressions on the surface mainly in the left lobe of the liver); and (iii) diffusely irregular (nodules present on the liver surface). Patients with diffusely irregular liver surface was diagnosed as liver cirrhosis. Results The liver surface changed with the progression of liver fibrosis from smooth, partially irregular to diffusely irregular, irrespective of viral type. The sensitivity, specificity, positive and negative predictive values for the diagnosis of cirrhosis according to the surface findings on MRL were 96%, 100%, 95% and 95%, respectively. The cirrhotic liver showed: (i) disappearance of impression of the right ribs; (ii) enlargement of the lateral segment; and (iii) atrophy of the right lobe according to Child-Pugh classification. Conclusion Our data indicated that MRL is a potentially useful non-invasive examination for evaluation of liver fibrosis associated with viral hepatitis.

Aim Patients with unresectable hepatocellular carcinoma (HCC) often undergo transcatheter arterial chemoembolization (TACE). Miriplatin is a lipophilic cisplatin derivative used in TACE that is effective in HCC. However, the difference in antitumor efficacy between warmed versus room temperature miriplatin is unclear. Methods Chemotherapy efficacy was evaluated by dynamic computed tomography 1–3 months after TACE, according to the Modified Response Evaluation Criteria in Solid Tumors. A total of 203 patients with HCC who received TACE with miriplatin for the first time were included in a follow-up study to retrospectively investigate its efficacy and safety. Overall, 45 patients underwent TACE with warmed (40°C) miriplatin and 158 patients received TACE with room temperature miriplatin. Results Seventy patients (44.3%) treated with room temperature miriplatin and 32 patients (71.1%) who received warmed miriplatin experienced complete or partial responses. Multivariate analysis identified miriplatin temperature (warmed miriplatin, risk ratio (RR) = 2.26, P = 0.047), tumor number (solitary, RR = 3.48, P = 0.007), α-fetoprotein (AFP) level (

Aim To evaluate the efficacy of a new ablation procedure for the stepwise hook extension technique using a SuperSlim needle for radiofrequency ablation (RFA) treatment of hepatocellular carcinoma (HCC), a randomized controlled trial was performed. Methods Thirty patients with HCC measuring 20 mm or less were randomly treated with a conventional four stepwise expansion technique (group 1) and the new stepwise expansion technique (group 2; the electrode was closed in the shaft after the same three steps of the conventional procedure and then fully extended). All patients underwent the RFA procedure using a 10-hook expandable electrode of 17-G diameter (LeVeen SuperSlim 30 mm). We compared the ablation time, required energy and ablated lesions in the two groups. Results The long and short diameters of RFA-induced necrosis were significantly larger in group 2 (37 and 28 mm) than group 1 (30 and 26 mm, P = 0.001 and =0.045, respectively). Irregular and small needle expansion resulting in the parachute-like or irregularly shaped ablated zone was observed in more cases in group 1 than in group 2. The new technique made all tines expand uniformly and largely, which produced a near-oval ablated zone of which the long axis is perpendicular to the needle shaft. Conclusion The two kinds of stepwise procedures allow the selection of a more suitable procedure according to the tumor size and shape in each RFA.

Aim The aims of this study are to assess the antiviral effects, safety and telaprevir (TVR) pharmacokinetics in two cohorts given TVR every 8 h (q8h) at doses of 500 mg and 750 mg with peginterferon-α-2b and ribavirin in chronic hepatitis C patients. Methods Twenty chronic hepatitis C (HCV) patients with genotype 1b in high viral loads were randomly assigned to two TVR-based regimens of 750 mg q8h (group A) and 500 mg q8h (group B) in combination with peginterferon-α-2b and ribavirin for 12 weeks. Results Although the difference was not statistically significant other than trough concentration (Ctrough) at week 4, the parameters of maximum concentration (Cmax), the area under the concentration time curve (AUC0–∞) and Ctrough tended to be higher in group A than those in group B. The antiviral effects were similar in the two groups (sustained virological response rates [SVR], 40% in group A, 50% in group B). The discontinuation rates by anemia were 30% in group A and 20% in group B. Serum creatinine concentrations were lower in group B than those in group A. Conclusion Although the exposure to TVR tended to be lower in 500 mg q8h than that in 750 mg q8h, the SVR rates in both groups were similar. The result suggests that the 500 mg q8h dose may be one option for treatment. In addition, the present findings indicate that the development of adverse events which increase with a TVR-based regimen, specifically anemia and creatinine, could be avoided by dose adjustment of TVR.

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.

Aim: To evaluate the efficacy of reduction therapy of natural human interferon (IFN)-β and ribavirin in elderly patients with hepatitis C virus (HCV) genotype 1b and high viral load who had complications of anemia, low bodyweight (

AIM The aim of this study was to evaluate the prevalence and predictive factors of diabetes in hepatitis virus positive liver cirrhotic patients with fasting plasma glucose (FPG) level of

Aim: Malignancies that include hepatocellular carcinoma often occurred in patients with chronic liver disease. The aim of this retrospective match control study was to assess the cumulative development incidence and predictive factors for total malignancies in elderly Japanese patients with non-alcoholic hepatic diseases (NAFLD) or hepatitis C virus (HCV). Methods: A total of 1600 NAFLD patients with age of ≥60 years were enrolled, and 1600 HCV patients with age of ≥60 years were selected as control by matching 1:1 with NAFLD group for age, sex, and follow-up period. The primary goal is the first development of malignancies. Evaluation was performed by the use of the Wilcoxon rank sum test, the Kaplan–Meier method, and Cox proportional hazard model. The mean observation period is 8.2 years in both NAFLD and HCV group, respectively. Results: The number of patients with the development of malignancies was 167 in the NAFLD group and 395 in the HCV group. The 10th development rate of malignancies was 13.9% in the NAFLD group and 28.2% in the HCV group (risk ratio 2.27; P colon cancer 31 cases (18.6%) > prostate cancer 21 cases (12.6%). Conclusions: The incident rates of hepatocellular carcinoma in all the malignancies were approximately 6% in the NAFLD group and two-thirds in the HCV group.

Aim: The micro-total analysis system (µTAS), a fully automated immunoassay system using microchip capillary electrophoresis, is highly sensitive and able to quickly assay the AFP-L3%. The clinical usefulness of this system was studied. Methods: We retrospectively enrolled 250 patients who underwent curative treatment for primary hepatocellular carcinoma (HCC) (93 patients underwent hepatic resection and 157, radiofrequency ablation [RFA]). Results: The sensitivity for µTAS AFP-L3% was 40.3% at the cutoff value of 5% in a range of AFP less than 20 ng/mL where the conventional method was unable to determine AFP-L3%. The sensitivity for AFP-L3% remained high even at stage I and at tumor size less than 2 cm (42.5% and 46.0%, respectively). Recurrence rate of patients with AFP-L3% greater than 5% was significantly higher than that of patients with less than 5% (P = 0.001). Furthermore, in resected patients, the postoperative AFP-L3% remained elevated with value greater than 5% was related to HCC recurrence (P = 0.001). Multivariate analysis revealed that multiple tumors (P = 0.004), preoperative AFP-L3% greater than 5% (P = 0.003), albumin less than 3.5 g/dL (P = 0.008), and RFA (P = 0.003) were significant prognostic factors of recurrence. Conclusions: The µTAS was found to be a highly sensitive assay for AFP-L3% in patients with curative treatment of HCC. A cutoff value of 5% was useful for predicting recurrence after the curative treatment and detecting small tumors and early stage HCC. Additionally, postoperative AFP-L3% was found to be a prognostic factor of HCC recurrence.

Aim: The aim of this retrospective cohort study is to assess the development incidence and predictive factors for chronic kidney disease (CKD) after the termination of interferon therapy in hepatitis C virus (HCV) positive Japanese patients with liver cirrhosis. Methods: A total of 650 HCV positive, liver cirrhotic patients who were treated with interferon and showed an estimated glomerular filtration rate (eGFR) of ≥60 mL/min per 1.73 m2 after the termination of interferon therapy were enrolled. CKD was defined as an eGFR of

Substitution of amino acid (aa) 70 and/or 91 in the core region of HCV genotype 1b (HCV-1b) is an important predictor of hepatocarcinogenesis, but its impact on the development of hepatocellular carcinoma (HCC) following eradication of HCV RNA by antiviral therapy is not clear. 1,273 patients with HCV-related chronic liver disease, with sustained virological response, defined as negative HCV RNA at 24 weeks after cessation of interferon monotherapy or interferon plus ribavirin combination therapy, were included in a follow-up study to evaluate the impact of aa substitution in the core region on hepatocarcinogenesis. Twenty six patients developed HCC during the follow-up. The cumulative rates of new HCC were 3.2%, 4.8%, and 8.6% at the end of 5, 10, and 15 years, respectively. The rates in patients infected with HCV-1b/Gln70(His70) [glutamine (histidine) at aa 70] were significantly higher than in patients infected with HCV-1b/Arg70 (arginine at aa 70) (P = 0.007; log-rank test) and HCV-2a/2b (P

Aim: Diabetes is present in patients with chronic liver disease caused by hepatitis C virus (HCV). The aim of this case–control study is to assess the efficacy and safety of dipeptidyl peptidase-4 inhibitor (sitagliptin) for type 2 diabetes mellitus (T2DM) with chronic liver disease caused by HCV. Methods: Sixteen HCV positive patients with T2DM treated by sitagliptin were retrospectively enrolled. These patients were given sitagliptin between December 2009 and January 2010. Another 16 HCV patients with T2DM treated only with diet and excise for 48 weeks were selected as the control group. Serum levels of fasting plasma glucose (FPG), hemoglobin A1C (HbA1C), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured before and 12, 24, 36 and 48 weeks after the initiation of treatment. Results: In the sitagliptin group, the average HbA1C level decreased approximately 0.8% at 48 weeks after the initiation of sitagliptin. Next, the average FPG level decreased approximately 20 mg/dL during follow up after the initiation of sitagliptin. All the patients were able to take sitagliptin of 50 mg/day without reduction because of sitagliptin-related side-effects. On the other hand, in the control group, the average HbA1C and FPG level did not change with statistical significance during follow up of 48 weeks. Regarding aminotransferase, there were no significant changes of average AST and ALT level during follow up of 48 weeks in both the sitagliptin group and control group. Conclusion: Our results indicate that sitagliptin is effective and safe for the treatment of T2DM complicated with HCV positive chronic liver disease.

Background: Stage progression of 374 small hepatocellular carcinomas (HCC) was retrospectively analysed. Patients and methods: During 8 years, 236 patients with the early stage of HCC received radiofrequency ablation (RFA), and 138 underwent surgery as an initial therapy. More patients of young age and with better liver function tended to undergo surgical treatment. Based on 1892 patient-year data, the Markov model analysed the stepwise progression of early stage (multiple up to three nodules, 3 cm or less each) to intermediate stage (four nodules or more, or larger than 3 cm), to advanced stage (portal invasion, extrahepatic metastasis or Child–Pugh C) and to death. Results: The recurrence rates after RFA and surgery were 53.3 and 40.6% in the third year. The annual progression rates from the early stage to the intermediate stage, advanced stage and death were 5.40, 1.63 and 1.73% in the RFA group and 3.90, 1.87 and 0.62% in the surgery group respectively. The progression rate from the early to the intermediate stage was significantly lower (2.34% annually) in the younger patient group (

Aim: The aim of this study was to elucidate whether the histopathological characteristics of hepatocellular carcinoma (HCC) can be predicted from baseline dynamic computed tomography (CT) images. Methods: This retrospective study included 86 consecutive patients with HCC who underwent surgical resection between January 2000 and September 2008. The arterial- and portal-phase dynamic CT images obtained preoperatively were classified into four enhancement patterns: Type-1 and Type-2 are homogeneous enhancement patterns without or with increased arterial blood flow, respectively; Type-3, heterogeneous enhancement pattern with septum-like structure; and Type-4, heterogeneous enhancement pattern with irregular ring-like structures. We also evaluated the predictive factors for poorly-differentiated HCC, specific macroscopic type of HCC (simple nodular type with extranodular growth [SNEG] and confluent multinodular [CMN]) by univariate and multivariate analyses. Results: The percentages of poorly-differentiated HCC according to the enhancement pattern were three of 51 nodules (6%) of Type-1 and -2, three of 24 (13%) of Type-3, and eight of 11 (73%) of Type-4. The percentages of SNEG/CMN according to the enhancement pattern were 12 of 51 nodules (24%) of Type-1 and -2, 13 of 24 (54%) of Type-3, and five of 11 (45%) of Type-4. Multivariate analysis identified Type-4 pattern as a significant and independent predictor of poorly-differentiated HCC (P