[show abstract][hide abstract] ABSTRACT: The aim of this study was to determine the pharmacodynamics of cisplatin following three different treatment procedures for intrahepatic arterial infusion therapy for hepatocellular carcinoma (HCC).
We divided 13 HCC patients into the following three groups: group A, lone injection of cisplatin (n=3); group B, combined injection of cisplatin and lipiodol, with embolization using small gelatin cubes (GCs) (n=5); and group C, injection of suspended lipiodol with cisplatin powder, with embolization using small GCs (n=5). In each group, the free cisplatin concentration in the hepatic vein was measured at 0, 5, 10, and 30 minutes.
The mean free cisplatin concentrations were as follows. For group A, the mean was 48.58 µg/mL at 0 minute, 7.31 µg/mL at 5 minutes, 5.70 µg/mL at 10 minutes, and 7.15 µg/mL at 30 minutes. For the same time points, for group B, the concentrations were 8.66, 4.23, 3.22, and 1.65 µg/mL, respectively, and for group C, the concentrations were 4.81, 2.61, 2.52, and 1.75 µg/mL, respectively. The mean area under the curve (AUC)0-infinity for the free cisplatin concentration was 7.80 in group A, 2.48 in group B, and 2.27 in group C. The AUC0-infinity for the free cisplatin concentration gradually decreased, from group A to group C.
These results indicate that the combination of lipiodol and small GCs may be useful for delaying cisplatin drainage from the liver.
Gut and liver 09/2013; 7(5):576-84. · 1.31 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Renal dysfunction and Fanconi's syndrome associated with hypophosphatemia caused by long-term administration of low-dose adefovir dipivoxil (ADV) has been reported in recent years. The aim of this retrospective study was to determine the incidence and factors associated with renal dysfunction and hypophosphatemia in patients with hepatitis B infection on long-term treatment with ADV and lamivudine (LAM). METHODS: The study subjects were 292 patients treated with 10 mg/day ADV and 100 mg/day LAM for more than 6 months. We evaluated estimated glomerular filtration rate (eGFR), serum creatinine and serum phosphate level at the start of ADV and every 6 months. RESULT: During a median treatment duration of 64 months, 28 (9.6 %) patients developed renal impairment (defined as eGFR < 50 ml/min/1.73 m(2)), and 73 (27.1 %) developed hypophosphatemia, including 14 with persistent hypophosphatemia. The cumulative incidences of renal impairment at 1, 3, and 5 years were 1.4, 7.5, 10.5 %, respectively, and those of hypophosphatemia were 6.8, 20.6, 26.7 %, respectively. Multivariate analysis identified old age, liver cirrhosis and hypertension as determinants of renal impairment, and male sex, HCC, low baseline serum phosphate as determinants of hypophosphatemia. Three of the 14 patients with persistent hypophosphatemia developed Fanconi's syndrome; their serum creatinine level remained normal, but eGFR was lower than at baseline. CONCLUSION: Long-term treatment of hepatitis B with low-dose (10 mg/day) ADV and LAM can potentially cause renal impairment and hypophosphatemia. We advocate regular monitoring of serum phosphate and evaluation of eGFR, in addition to serum creatinine, in such patients.
Journal of Gastroenterology 03/2013; · 3.79 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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 < 0.05). All the patients could take sitagliptin of 50 mg/day without reduction necessitated by sitagliptin-related side-effects. There were no significant changes of average AST and ALT levels during follow up of 48 weeks in both sitagliptin and control groups. CONCLUSION: Our results indicate sitagliptin is effective and safe for the treatment of T2DM complicated with NAFLD.
[show abstract][hide abstract] ABSTRACT: Miriplatin is a novel lipophilic platinum complex that was developed to treat hepatocellular carcinoma (HCC). Although HCC patients frequently have coexisting chronic renal failure, little prospective data are available regarding the clinical toxicity of chemotherapeutic agents used to treat HCC patients with chronic renal failure. In a phase II study, the plasma concentration of total platinum in patients who received miriplatin was very low, and no severe renal toxicity caused by miriplatin injection was reported. Here, we present three cases of HCC with stage 4 chronic renal failure who received transcatheter arterial chemotherapy with miriplatin. All cases were male, ages 72, 84, and 83 years, and had serum creatinine levels of 2.3, 1.6, and 1.9 mg/dL, respectively. Their estimated glomerular filtration rates were 21.9, 20.3, and 22.2 mL/min, respectively. All cases were treated for unresectable HCC with transcatheter arterial chemotherapy with miriplatin. No serious adverse events were observed, and serum creatinine levels did not elevate, even in the patient who experienced renal failure caused by cisplatin administration. These results might suggest that transcatheter arterial chemotherapy with miriplatin can be safely used in HCC patients with chronic renal failure.
Gut and liver 03/2013; 7(2):246-51. · 1.31 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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 (<50 ng/mL, RR = 2.35, P = 0.012) and history of TACE (no history, RR = 2.22, P = 0.041) as predictors of objective response following TACE with miriplatin, and no serious complications were observed. CONCLUSION: Warm temperature, solitary tumors, low AFP level and first TACE are significant and independent predictors of objective response after TACE using miriplatin. These results suggest that warmed miriplatin can be considered as one of the standard treatments for unresectable HCC.
[show abstract][hide abstract] ABSTRACT: Chronic hepatitis B virus (HBV) infection leads to cirrhosis and hepatocellular carcinoma (HCC). Antiviral agents are thought to reduce HCC development, but agent such as lamivudine (LAM) has a high rate of drug resistance. We compared the incidence of HCC in 472 entecavir (ETV)-treated patients and 1143 non-treated HBV patients (control group). Propensity score matching eliminated the baseline differences, resulting in a sample size of 316 patients per cohort. The drug mutation resistance was 0.8% (4/472) in the ETV group. The cumulative HCC incidence rates at 5-year were 3.7% and 13.7% for the ETV, and control groups, respectively (P < 0.001). Cox proportional hazard regression analysis, adjusted for a number of known HCC risk factors, showed that patients in the ETV group were less likely to develop HCC than those in the control group (hazard ratio: 0.37; 95% CI: 0.15 to 0.91; P = 0.030). Both cohorts were applied into 3 previously reported risk scales and risk scores were generated based on age, gender, cirrhosis status, levels of ALT, HBeAg, baseline HBV DNA, albumin, and bilirubin. The greatest HCC risk reduction occurred in high-risk patients who scored higher on respective risk scales. In a group analysis, we compared treatment effect between nucleos(t)ide analogues (NAs) which included matched LAM-treated patients without rescue therapy (n = 182). We found HCC suppression effect greater in etv-treated (P < 0.001) than non-rescued LAM-treated (P = 0.019) cirrhotic patients when they were compared with the control group. Conclusion: Long-term entecavir treatment may reduce the incidence of HCC in HBV-infected patients. The treatment effect was greater in patients at higher risk of HCC. (HEPATOLOGY 2012.).
[show abstract][hide abstract] ABSTRACT: 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 (C(trough) ) at week 4, the parameters of maximum concentration (C(max) ), the area under the concentration time curve (AUC(0-∞) ) and C(trough) 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.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Clearance of hepatitis B surface antigen (HBsAg) is considered the ultimate goal in chronic hepatitis B treatment. One treatment option is long-term nucleot(s)ide analog (NA) therapy. We followed a group of long-term NA therapy patients to evaluate the efficacy of this treatment in promoting clearance and longitudinal declines of HBsAg. METHOD: The study included 791 NA therapy patients who received lamivudine as their first drug. At the baseline, 442 patients were hepatitis B e antigen (HBeAg)+ and 349 were HBeAg-. All analyses were performed after separating the HBeAg+ and HBeAg- cohorts. Cox proportional hazards models were used to determine which factors were associated with HBsAg clearance. RESULTS: HBsAg clearance was observed in 18 (4.1 %) of the HBeAg+ patients and 20 (5.7 %) of the HBeAg- patients at baseline, giving seroclearance rates of 6.4 and 6.9 %, respectively, over the nine-year study period. HBsAg clearance was influenced by several independent factors that varied according to HBeAg cohort. For HBeAg+ patients, these included previous interferon therapy, infection with hepatitis B virus (HBV) genotype A, a ≥0.5 log IU/mL decline in HBsAg level within six months, and clearance of HBeAg at six months. For HBeAg- patients, these included infection with HBV genotype A, decline in HBsAg at six months, and a baseline HBsAg level of <730 IU/mL. CONCLUSION: This study suggests that both direct antiviral potential and host immune response are needed to achieve HBsAg clearance by NA therapy. Viral genotype strongly influenced HBsAg clearance during NA therapy.
Journal of Gastroenterology 10/2012; · 3.79 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objective: Anticarcinogenic activity of ribavirin combination therapy for hepatitis C virus (HCV)-related compensated cirrhosis is still unclear. Methods: In study 1, in 157 consecutive patients with HCV-related compensated cirrhosis, treatment efficacy with interferon plus ribavirin therapy was evaluated for 48 weeks of HCV genotype 1b (HCV-1b) or 24 weeks of HCV-2a/2b. In study 2, in 185 consecutive patients with HCV-related compensated cirrhosis, who showed no sustained virological response following the first course of interferon monotherapy, hepatocarcinogenesis rates were evaluated according to the additional treatment, and they were classified into three groups: no treatment, interferon monotherapy, and ribavirin combination therapy. Results: In study 1, in HCV-1b, rates of sustained virological response and sustained biochemical response were 21 and 56%, respectively. In HCV-2a/2b, rates of sustained virological response and sustained biochemical response were 70 and 78%, respectively. In HCV-1b, sustained biochemical response rates were significantly higher than those of sustained virological response. In study 2, the hepatocarcinogenesis rates in ribavirin combination therapy were significantly lower than those in interferon monotherapy and no treatment, respectively. Conclusion: Ribavirin combination therapy for HCV-related compensated cirrhosis reduces the risk of hepatocarcinogenesis in comparison with interferon monotherapy, and higher rates of sustained biochemical response might be associated with lower hepatocarcinogenesis rates.
[show abstract][hide abstract] ABSTRACT: 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.
Journal of Medical Virology 10/2012; 84(10):1593-9. · 2.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: Substitution of amino acid 70 and/or 91 in the core region of hepatitis C virus (HCV) genotype 1b (HCV-1b) is an important predictor of hepatocellular carcinoma (HCC), but its impact on HCC in nonresponders to interferon (IFN) and ribavirin (RIB) combination therapy is not clear. Methods: A total of 292 patients with HCV-1b-related chronic liver disease who did not achieve a sustained virological response to 24-48 weeks of IFN+RIB combination therapy were included in a follow-up study to investigate the risk factors for HCC. Results: Sixteen patients developed HCC during the follow-up. The cumulative HCC rates were 5.0, 13.1 and 16.9% at the end of 3, 5 and 7 years, respectively. Multivariate analysis identified substitution of core amino acid 70 (Gln70/His70; hazard ratio 4.64, p = 0.018) and low serum levels of high-density lipoprotein cholesterol (<50 mg/dl; hazard ratio 9.35, p = 0.041) as determinants of HCC. Gender, stage of fibrosis and interleukin-28B showed no such relationship. Conclusions: Amino acid substitution in the core region of HCV-1b and low serum levels of high-density lipoprotein cholesterol are significant and independent predictors of HCC in nonresponders to IFN+RIB combination therapy. These results emphasize the importance of viral and lipid metabolic factors in the development of HCC after combination therapy.
[show abstract][hide abstract] ABSTRACT: The aims of this study were to evaluate the efficacy of long-term interferon (IFN) monotherapy on hepatocellular carcinoma (HCC) in patients who showed no virological response to the first course of IFN therapy, define predictive factors for HCC in patients on long-term IFN monotherapy, and evaluate the clinical impact of amino acid (aa) substitutions in the hepatitis C virus (HCV)-1b core region on HCC rate. This retrospective study included 494 consecutive treatment-naive patients infected with HCV-1b who failed to achieve sustained virological response after ≥24-week IFN monotherapy. Of 494 patients, 113 (22.9%) received another course of ≥48-week IFN monotherapy (additional-IFN group), while the remaining 381 (77.1%) received no such therapy (no-additional-IFN group), and 10 years have elapsed since the end of the first IFN monotherapy. The cumulative HCC rate was significantly higher in the no-additional-IFN group than additional-IFN group, and in those with aa substitutions in the core region of Gln70(His 70) and Met 91 than those with Arg 70 and/or Leu 91. Multivariate analysis identified stage of liver fibrosis, liver enzymes, age, treatment group, aa substitution in the core region, low-density lipoprotein cholesterol (LDL-cholesterol), and gender as determinants of HCC, and that additional IFN treatment significantly lowered the cumulative rate of HCC, even in patients with cirrhosis. In conclusion, long-term IFN monotherapy reduces the risk of HCC, even in patients with cirrhosis. Substitution of aa at position 70 and/or 91 in the core region and lipid metabolism are important predictors of HCC in long-term IFN monotherapy.
Journal of Medical Virology 08/2012; 84(8):1199-207. · 2.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Aim: To evaluate the efficacy of natural human interferon (IFN)-β and ribavirin in elderly patients infected with hepatitis C virus (HCV) genotype 2 and high virus load. Methods: Inclusion criteria were age of 65 years or older, HCV genotype 2 and serum HCV RNA level of 5.0 logIU/mL or more. A total of 33 were enrolled in this retrospective cohort study. IFN-β was administrated i.v. at a dose of 6 million units daily for 4 weeks initially, followed by three times a week for 20 weeks. Ribavirin was given daily for 24 weeks at the dose described based on bodyweight. Fifteen patients were given a standard dose of ribavirin (standard group). Eighteen patients were given a reduction dose of ribavirin that decreased by one tablet per day compared to the standard group (reduction group). Results: Of the 33 study patients, no patient stopped the treatment due to treatment-related adverse events. The dose of IFN-β was reduced in three patients: Two patients belonged to the standard group and one patient belonged to the reduction group. The dose of ribavirin was reduced in 11 patients during combination therapy: nine patients belonged to the standard group and two patients belonged to the reduction group. The sustained virological response (SVR) was 72.2% (13/18) in the reduction group and 80.0% (12/15) in the standard group. There was no significant difference in SVR rate between the reduction and standard groups (P = 0.699). Conclusion: The reduction therapy of IFN-β and ribavirin in elderly chronic hepatitis C patients with genotype 2 and high virus load is one selection of treatment.
Hepatology Research 08/2012; 42(8):750-6. · 2.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: The impact of amino acid (aa) 70 substitution in the core region on hepatocarcinogenesis and survival for liver-related death in patients of HCV genotype 1b (HCV-1b), who had not received antiviral therapy, is unknown. The relationships among aa 70 substitution, IL28B genotype, and hepatocarcinogenesis, are not also clarified. 1,181 consecutive HCV-infected patients, who had not received antiviral therapy, were performed a follow-up study to determine predictive factors of hepatocarcinogenesis and survival for liver-related death. The cumulative hepatocarcinogenesis rates in HCV-1b of Gln70(His70) (glutamine (histidine) at aa 70) were significantly higher than those in HCV-1b of Arg70 (arginine at aa 70) and HCV-2a/2b, respectively. The cumulative survival rates for liver-related death in HCV-1b of Gln70(His70) were significantly lower than those in HCV-1b of Arg70 and HCV-2a/2b, respectively. Multivariate analysis identified gender (male), age (ò60 years), albumin (<3.9 g/dl), platelet count (<15.0×10(4) /mm(3) ), aspartate aminotransferase (ò67 IU/l), and HCV subgroup (HCV-1b of Gln70(His70)) as determinants of both of hepatocarcinogensis and survival rates for liver-related death. In HCV-1b patients, the cumulative change rates from Arg70 to Gln70(His70) by direct sequencing were significantly higher than those from Gln70(His70) to Arg70. In patients of Arg70 at the initial visit, the cumulative change rates from Arg70 to Gln70(His70) in IL28B rs8099917 non TT genotype were significantly higher than those in TT genotype. In conclusion, substitution of aa 70 in the core region of HCV-1b is the important predictor of hepatocarcinogenesis and survival for liver-related death in HCV patients, who had not received antiviral therapy. IL28B genotype might partly affect changes over time of dominant amino acid in core aa 70 of HCV-1b. (HEPATOLOGY 2012.).
[show abstract][hide abstract] ABSTRACT: Patients who do not achieve sustained virological response to telaprevir/peginterferon (PEG-IFN)/ribavirin need to be identified. Predictive factors of virological response to the triple therapy in non-responders to previous PEG-IFN/ribavirin therapy are not clear. The aims of this study were to determine the predictive factors of virological response to a 24-week regimen of triple therapy in 15 non-responders to previous PEG-IFN/ribavirin therapy among 61 Japanese adults infected with HCV genotype 1. Overall, sustained virological response and end-of-treatment response were achieved by 27% and 60%, respectively. Telaprevir-resistant variants (by direct sequencing) appeared during or after treatment in 82% of patients who did not show sustained virological response, but disappeared at the end of study, except for one patient with resistant variant at baseline. Substitution at aa 70 (Arg70) and type of previous response to PEG-IFN/ribavirin (partial response) were identified as significant determinants of sustained virological response. In addition, alpha-fetoprotein level (<10 µg/L) and type of previous response (partial response) were identified as significant determinants of end-of-treatment response. Prediction of response to therapy based on the combination of these factors had high sensitivity, specificity, positive, and negative predictive values. In conclusion, this study identified amino acid substitution of the core region, alpha-fetoprotein level, and type of previous response as predictors of virological response to telaprevir/PEG-IFN/ribavirin in patients infected with HCV genotype 1b who had not responded to previous PEG-IFN/ribavirin therapy.
Journal of Medical Virology 07/2012; 84(7):1097-105. · 2.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hepatitis C virus (HCV) of genotype 1b is the most prevalent worldwide, and the least responsive to interferon-based treatments. A combination therapy with two direct-acting antivirals has shown promising results in patients with HCV-1b, but the prevalence of drug-resistant variants before treatment is not known in the Japanese population.
To detect HCV variants resistant to NS3 protease inhibitors or the NS5A inhibitor (BMS-790052) in hepatitis patients infected with HCV-1b.
Drug-resistant mutations were determined in the 362 hepatitis patients infected with HCV-1b who had not received direct-acting antivirals before.
Amino-acid substitutions resistant to NS3 inhibitors (V36A, T54S, Q80H and D168E) were detected in 15 of the 307 (4.9%) patients, who had been examined, and T54S (3.3%) predominated over V36A (0.3%), Q80R (0.7%) and D168E (0.7%) in them. Amino-acid substitutions resistant to BMS-790052 (L31M and/or Y93H) were detected in 33 of the 294 (11.2%) patients, and Y93H (8.2%) predominated over L31M (2.7%). One of the 239 (0.4%) patients, who had been examined for amino-acid substitutions in both NS3 and NS5A regions, possessed HCV-1b variants resistant to NS3 inhibitors (T54S) and BMS-790052 (L31M).
Mutations conferring resistance to NS3 inhibitors or BMS-790052 were frequent in our treatment-naive study population, but double mutants with possible resistance to both drugs were rare. Since single mutations did not result in treatment failure in a previous pilot trial combining BMS-790052 and an NS3 inhibitor, larger trials of this drug regimen appear warranted in the Japanese population.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 06/2012; 54(4):352-4. · 3.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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 (<50 kg), diabetes mellitus and/or hypertension. Methods: Inclusion criteria were age of 65 years or older, HCV genotype 1b, and serum HCV RNA level of 5.0 logIU/mL or higher. A total of 23 subjects with hemoglobin level of less than 13 g/dL, low bodyweight, diabetes mellitus and/or hypertension were enrolled in this study (reduction-dose group). IFN-β was administrated i.v. at a dose of 6 million units daily for 4 weeks initially, followed by three times a week for 44 weeks. Ribavirin was given daily for 48 weeks at a decreased dose of one tablet per day compared to the ordinary dose described based on bodyweight. As a control, another 22 patients without anemia, low bodyweight and/or complications treated with the standard dose of ribavirin (standard-dose group) were enrolled. Results: Patients' rates with further dose reduction or discontinuation of treatment was 26.1% (6/23) in the reduction-dose group and 77.3% (17/22) in the standard-dose group. The sustained virological response (SVR) was 39.1% (9/23) in the reduction-dose group and 27.3% (6/22) in the standard-dose group (P = 0.404). Based on genetic variations near the IL28B gene (rs8099917), SVR was 44.1% (15/34) in patients with TT and 0% (0/11) in patients with TG (P = 0.008). Conclusion: The reduction therapy of IFN-β and ribavirin in elderly HCV patients with genotype 1b, high viral load, IL28B gene (rs8099917) of TT who had complications of anemia, low bodyweight, diabetes mellitus and/or hypertension is one possible selection of treatment.
Hepatology Research 04/2012; 42(10):949-57. · 2.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: Few studies have investigated the long-term effects of interferon (IFN) therapy for chronic hepatitis B (CHB). In this retrospective study, we investigated the efficacy of and predictors of response to IFN therapy in CHB patients.
We analyzed data for 615 Japanese CHB patients (hepatitis B e antigen [HBeAg]-positive 414, HBeAg-negative 201) treated with IFN, and conducted follow up for a median duration of 8.1 years (range 0.5-23.2). Responders were defined as patients who showed continuously normalized alanine transaminase (ALT) levels, HBeAg clearance, and low hepatitis B virus (HBV) DNA levels at 6 months post-treatment or for a span of more than 6 months until each test point at 1, 3, 5, and 10 years.
The IFN response rates of all patients were 21, 18, 21, 23, and 25% at 6 months and 1, 3, 5, and 10 years, respectively. On multivariate analysis, significant determinants of the outcome of IFN therapy were as follows: at 6 months and 1 year, young age, low HBV DNA levels, and long duration of treatment; at 3 years, long duration of treatment, young age, and high level of albumin; at 5 years, high level of albumin, female, and pretreated with IFN; and at 10 years, HBeAg-negative. Sixty-nine of the 615 patients (11%) achieved seroclearance of hepatitis B surface antigen (HBsAg). On multivariate analysis, age ≥30 years, HBV genotype A, and male were all independent factors predicting the achievement of HBsAg seroclearance.
HBeAg, HBV DNA level, age, sex, albumin, duration of treatment, pretreatment with IFN, and HBV genotype were important factors in determining long-term response to IFN therapy.
Journal of Gastroenterology 02/2012; 47(7):814-22. · 3.79 Impact Factor
[show abstract][hide abstract] ABSTRACT: The aim of this study was to determine the incidence and risk factors of hepatocellular carcinoma (HCC), and to elucidate the utility of two non-invasive predictive procedures for liver fibrosis: the aspartate aminotransferase (AST) to platelet ratio index (APRI) and the BARD score (which includes the following three variables: body mass index, AST/alanine aminotransferase ratio, and diabetes) in the prediction of HCC in a large population of Japanese patients with non-alcoholic fatty liver disease (NAFLD).
This was a retrospective cohort study conducted at a public hospital. Study subjects included 6,508 patients with NAFLD diagnosed by ultrasonography. The median follow-up period was 5.6 years. The primary end point was the onset of HCC. Evaluation was performed using Kaplan-Meier methodology and Cox's proportional hazards analysis.
In all, 16 (0.25%) new cases with HCC were diagnosed during the study. The cumulative rates of NAFLD-related HCC were 0.02% at year 4, 0.19% at year 8, and 0.51% at year 12. The annual rate of new HCC was 0.043%. Multivariate analysis identified serum AST level ≥40 IU/L (hazard ratio (HR): 8.20; 95% confidence interval (95% CI): 2.56-26.26; P<0.001), platelet count <150 × 10(3)/μl (HR: 7.19; 95% CI: 2.26-23.26; P=0.001), age ≥60 years (HR: 4.27; 95% CI: 1.30-14.01; P=0.017), and diabetes (HR: 3.21; 95% CI: 1.09-9.50; P=0.035) as independent risk factors for HCC. With regard to the APRI, 184 patients (2.83%) were considered to have significant fibrosis (equivalent to non-alcoholic steatohepatitis (NASH) stage 3-4). The cumulative rate of HCC was significantly higher in this group (HR: 25.03; 95% CI: 9.02-69.52; P<0.001). In contrast, regarding the BARD score, 3,841 (59%) patients were considered to have advanced fibrosis (NASH stage 3-4). However, no significant associations between the BARD score and the incidence of HCC were observed (HR: 1.16; 95% CI: 0.40-3.37; P=0.780).
This retrospective study indicates that the annual incidence rate of HCC among Japanese NAFLD patients is low. Elderly NAFLD patients with diabetes, elevated serum AST, and especially thrombocytopenia (suggested to be associated with advanced liver fibrosis) should be monitored carefully during follow-up that includes using the APRI to ensure early diagnosis and treatment of HCC.
The American Journal of Gastroenterology 02/2012; 107(2):253-61. · 7.55 Impact Factor