Hand-Foot Syndrome and Post-Progression Treatment Are the Good Predictors of Better Survival in Advanced Hepatocellular Carcinoma Treated with Sorafenib: A Multicenter Study.

OBJECTIVE: To determine the relationship between treatment outcomes and hand-foot syndrome (HFS), and the relationship between survival rate and post-progression treatment after sorafenib therapy. METHODS: The study assessed 314 patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib at 5 general hospitals in Kagawa Prefecture, Japan. RESULTS: At the start of sorafenib therapy, 23.6% of the patients had HCC of a Child-Pugh class other than A. The initial sorafenib dose was 800 mg in 9.2% of the patients and 400 mg in 64.3%. Time to progression was 129 days (95% CI: 87.3-170.7) and the median overall survival (OS) was 392 days (95% CI: 316.0-468.0). The OS of the patients with Child-Pugh class A HCC was significantly better than that of the patients with Child-Pugh class B HCC (p < 0.0001). The survival curves for Child-Pugh class A-5 points and class A-6 points were significantly different, with that for class A-5 points being better (p < 0.0001). A significant difference was observed between the patients who exhibited HFS and those who did not, with the former exhibiting a better survival rate (p < 0.001). In addition, the survival rate of the patients who received post-progression treatment after sorafenib therapy was significantly better than that of the patients who did not (p < 0.001). CONCLUSION: In sorafenib therapy, patients with HFS and those who received post-progression treatment exhibited good OS.

Comparison of Liver Biopsy Findings with the Digestive Disease Week Japan 2004 Scale for Diagnosis of Drug-Induced Liver Injury.

The liver biopsy remains a valuable tool in the diagnosis of drug-induced liver injury (DILI). The Digestive Disease Week Japan 2004 (DDW-J) scale proposed as an objective tool for the diagnosis of DILI has been widely used in Japan. So far, the histological features have not been compared with DDW-J scale in detail. Herein, we examined the correlation between liver biopsy findings and clinical features, particularly DDW-J scales. A total of 80 patients with liver injuries of unknown cause were enrolled. Based on the histological findings, these cases were categorized into 3 groups: A (DILI was strongly suspected), B (DILI was suspected), and C (DILI should be considered in the differential diagnosis). Histological groups and DDW-J scale were moderately correlated (κ = 0.60). The mean total DDW-J scale scores were as follows: 4.89 for A, 3.26 for B, and 0.75 for C (p < 0.05). While hepatocellular type was coincided in a majority of cases by histological and DDW-J scale evaluation, cholestatic type was not well coincided. In conclusion, biopsy findings and DDW-J scale were well correlated, and the hepatocellular type of liver injuries was well coincided by both evaluations, though there were several discrepant cases, particularly in cholestatic type.

Effectiveness of extending treatment duration in therapy with pegylated interferon and ribavirin for genotype 2 hepatitis C virus infection.

The effectiveness of extending treatment duration as response guided therapy was previously reported for chronic hepatitis C (CHC) genotype 1, but is still controversial for genotype 2. The present study is a retrospective cohort study to investigate the effectiveness of extending treatment duration in therapy with pegylated interferon and ribavirin for patients with CHC genotype 2 by focusing on the timing at which patients obtained undetectable HCV RNA. A total of 306 patients who obtained undetectable HCV RNA by week 24 of treatment and completed 24 weeks of treatment were enrolled. Rapid virological response (RVR) to standard therapy was achieved by 122 patients (51%), and 89% of them obtained sustained virological response (SVR), while 69% of non-RVR patients achieved SVR. Non-RVR patients with undetectable HCV RNA at week 8, and insufficient adherence＜80% pegylated interferon and ribavirin during the first 24 weeks, significantly improved their SVR rate by extended therapy. Among patients receiving extended therapy, drug adherences did not differ between SVR and non-SVR patients, indicating that extending treatment duration might compensate for insufficient antiviral effects due to insufficient drug adherences. This finding might be useful in creating a guideline for extending treatment duration for patients with CHC genotype 2.

Impact of comorbid hepatic steatosis on treatment of chronic hepatitis C in Japanese patients and the relationship with genetic polymorphism of IL28B, PNPLA3 and LDL receptor.

The impact of hepatic steatosis on interferon therapy for patients with chronic hepatitis C (CHC) has been associated with single-nucleotide polymorphisms (SNP) of IL28B, patatin-like phospholipase domain-containing protein 3 (PNPLA3), and low-density lipoprotein (LDL) receptor. Whether this holds true for Japanese patients, however, remains unresolved. The present study prospectively enrolled 226 Japanese patients with CHC, and investigated the impact of hepatic steatosis and its related SNPs, including rs8099917 of IL28B, rs738409 of PNPLA3, and rs14158 of LDL receptor, on outcomes of peg-interferon and ribavirin therapy. In multivariate logistic regression analysis, significant factors affecting the severity of hepatic steatosis were high body mass index and the minor alleles of IL28B SNP (p＝0.020 and 0.039, respectively). The risk alleles of PNPLA3 SNP also showed weak association (p＝0.059). Severe steatosis and the minor alleles of IL28B SNP were significantly associated with null or partial virological response in patients with HCV genotype 1, as were female gender, and low LDL cholesterol (p＝0.049, and ＜0.001, respectively). The SNP genotype of PNPLA3 and LDL receptor did not have a significant impact on therapeutic outcomes. With respect to the SNP sites examined, the SNP of PNPLA3 has a weak association with severe hepatic steatosis, but not with the outcome of interferon therapy.

Efficacy and cost-effectiveness of consensus interferon monotherapy with high-dose induction for hepatitis C patients with genotype 2.

OBJECTIVE: Several treatment strategies for patients with chronic hepatitis C have been compared mainly in terms of their efficacy, and it has been found that pegylated interferon (IFN) plus ribavirin has become the standard therapy, but aged patients may not tolerate ribavirin and the cost-effectiveness of treatment should also be further considered. We conducted a study to evaluate the efficacy, safety, and cost-effectiveness of consensus IFN monotherapy with high-dose induction for patients with chronic hepatitis C in clinical practice. MATERIAL AND METHODS: We consecutively enrolled 104 patients with chronic hepatitis C. Patients were scheduled to receive 12 or 18 µg of consensus IFN daily for 2 weeks, then three times a week for 22 weeks. Efficacy, safety, and cost-effectiveness were assessed. A Markov model was developed to investigate cost-effectiveness in patients with chronic hepatitis C treated by different IFN-based treatment strategies. RESULTS: Of the 104 study patients, a sustained virological response (SVR) was achieved in 66 (63%). Logistic regression analysis revealed that genotype 2, lower hepatitis C virus RNA levels, and patient age were independently associated with SVR. The response rate was significantly higher in patients with genotype 2 (51/66, 77%) versus genotype 1 (15/38, 40%). Cost-effectiveness analysis in patients with genotype 2 revealed that high-dose induction with consensus IFN monotherapy was as highly cost-effective as pegylated IFN plus ribavirin. CONCLUSION: Consensus IFN monotherapy with high-dose induction shows high efficacy and cost-effectiveness in chronic hepatitis C patients with genotype 2 infection. Thus, it may be a reliable alternative in aged patients and for those excluded from standard combination therapy.

Simple scoring system for prediction of hepatocellular carcinoma occurrence after hepatitis C virus eradication by direct-acting antiviral treatment: All Kagawa Liver Disease Group Study.

Direct acting antivirals (DAA) have recently been developed to treat patients with hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved the cure rate of patients. However, the occurrence rate of hepatocellular carcinoma (HCC) following HCV eradication remains unknown. Therefore, the present study aimed to identify predictors of HCC occurrence following DAA treatment. Among 1,454 patients infected with HCV, 1,088 patients who achieved sustained virologic response and who had no history of HCC treatment were recruited between September 2014 and November 2018. The incidence of HCC in patients infected with HCV following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinicopathological characteristics and blood test results. During the present study, 26 patients developed HCC. The incidence of HCC was 0.61, 1.88, 2.82 and 3.71% at 6, 12, 18 and 24 months after treatment with DAA, respectively. The results of multivariate analysis identified age [hazard ratio (HR), 1.0729; P=0.0044] and α-fetoprotein (AFP) level after DAA treatment (HR, 1.0486; P=0.0486) as independent factors that may contribute to HCC occurrence following DAA treatment. By using these two factors, a novel scoring system (0-2 points) was established to predict HCC occurrence following HCV eradication by DAA treatment. The incidence of HCC at 2 years was 0.3% in the 0 points group, 6.27% in the 1 point group and 18.37% in the 2 points group. In conclusion, AFP level after DAA treatment and age at DAA administration were identified as independent predictors of HCC occurrence in patients that were treated with DAA. The scoring system that was established in the present study is simple and easy, and using pre-treatment factors may be a convenient tool to predict the risk of HCC occurrence in HCV-free patients following DAA treatment.

Clinical features of antinuclear antibodies-negative type 1 autoimmune hepatitis.

AIM: Antinuclear antibodies (ANA) are the main serologic markers of type 1 autoimmune hepatitis (AIH); however 20-30% of patients are negative for ANA. We assessed the clinical features of ANA-negative patients. METHODS: A retrospective analysis was performed of 176 patients with type 1 AIH (153 females, median age 55 years). A diagnosis of AIH was made based on the revised scoring system proposed by the International Autoimmune Hepatitis Group. ANA titers were measured using a standard indirect immunofluorescence technique. RESULTS: Thirty-eight patients (22%) had low titers of ANA (1:40 or 1:80), and 114 (65%) had high titers (>/= 1:160). Of 24 ANA-negative patients, 15 were positive for smooth muscle antibodies (SMA). Three of nine both ANA- and SMA-negative patients developed ANA during follow-up. The other six were diagnosed based on histological characteristics. Thirteen ANA-negative patients relapsed after the normalization of serum alanine aminotransferase (ALT) levels. ANA-negative patients more frequently showed acute presentation and, at presentation, had lower serum immunoglobulin G levels, higher serum levels of bilirubin and transaminase, and higher frequencies of histological acute hepatitis and zone 3 necrosis than those with high titers. However, the frequency of advanced stage of fibrosis was similar. The response to corticosteroids was not different among the three groups. CONCLUSIONS: ANA-negative type 1 AIH shows acute-onset more frequently but may include not only acute autoimmune hepatitis, but also acute exacerbation of inactive chronic disease. Regarding the diagnosis of ANA-negative AIH, the determination of ANA during follow-up and the response to immunosuppressive treatment may be helpful.

Clinical features of type 1 autoimmune hepatitis in adolescence and early adulthood.

AIM: The peak age of the presentation of autoimmune hepatitis (AIH) is between 40 years and 50 years. Elderly patients have been reported to have higher frequencies of concurrent thyroid or rheumatic diseases and histological cirrhosis and a lower occurrence of treatment failure. In this study, we assessed the clinical features of Japanese type 1 AIH in adolescence and early adulthood. METHODS: Fifteen patients aged

Efficacy and safety of entecavir in nucleoside-naive, chronic hepatitis B patients: phase II clinical study in Japan.

BACKGROUND AND AIM: Entecavir has demonstrated clinical efficacy for chronic hepatitis B. This study evaluated the efficacy and safety of entecavir in nucleoside-naive Japanese chronic hepatitis B patients. METHODS: In this multicenter, double-blind study, 66 nucleoside-naive Japanese chronic hepatitis B patients were randomized to 0.1 mg entecavir (n = 32) or 0.5 mg entecavir (n = 34) daily for 52 weeks. The primary endpoint was the proportion of patients whose serum hepatitis B virus (HBV) DNA decreased from baseline by > or =2 log(10) copies/mL or became undetectable (<400 copies/mL by polymerase chain reaction assay) at week 48. RESULTS: One hundred percent of patients in both treatment groups achieved the primary efficacy endpoint, with 81% and 68% of patients achieving undetectable HBV DNA in the 0.1 mg and 0.5 mg treatment groups, respectively. Mean changes from baseline in HBV DNA were -4.49 log(10) and -4.84 log(10) copies/mL for the 0.1 mg and 0.5 mg groups, respectively. Significant improvements in necroinflammation were seen in both groups, as assessed by Knodell and New Inuyama classifications. Most adverse events were transient and classified as grade 1 or 2. There were no clinically significant differences in adverse events across the two treatment groups and no discontinuations due to adverse events in either group. CONCLUSIONS: In Japanese nucleoside-naive patients with chronic hepatitis B, 0.1 mg or 0.5 mg entecavir daily provided excellent efficacy and was well tolerated. The 0.5 mg dose was selected for the treatment of nucleoside-naive patients.

Human leukocyte antigen DR status and clinical features in Japanese patients with type 1 autoimmune hepatitis.

AIM: Human leukocyte antigen (HLA) DR status affects the clinical features of autoimmune hepatitis. In Caucasians, patients with DR3 have poorer outcomes. In Japan, the relationship between HLA DR status and clinical features has yet to be fully examined. METHODS: We investigated 79 patients with type 1 autoimmune hepatitis who underwent liver biopsy and were screened for HLA DR status by the polymerase chain reaction sequence specific oligonucleotide hybridization method. RESULTS: Fifty-five patients had DR4 and 23 had DR2. Thirteen patients had both DR2 and DR4. None had DR3. Of patients aged <30 years, 70% did not have DR4. A tendency toward higher serum levels of immunoglobulin G was seen in patients with DR4 compared to those without, while patients with neither DR2 nor DR4 had lower serum levels of immunoglobulin G than those with only DR2 and those with only DR4. Patients with DR2 had a lower frequency of concurrentautoimmune disease. Concurrence of thyroid disease was seen only in patients with DR4. The cumulative incidental rate of the normalization of serum alanine aminotransferase levels within six months after the introduction of corticosteroid treatment was not associated with HLA DR status. CONCLUSION: HLA DR status is considered to affect the clinical features of Japanese patients with type 1 autoimmune hepatitis. Japanese patients with DR2 may have different clinical features from others. In addition, diagnoses of type 1 autoimmune hepatitis should be made carefully in Japanese patients with neither DR2 nor DR4 and in those aged <30 years.

A prospective and comparative cohort study on efficacy and drug resistance during long-term lamivudine treatment for various stages of chronic hepatitis B and cirrhosis.

BACKGROUND AND AIMS: A prospective, non-randomized cohort study on long-term lamivudine treatment, comparing efficacy, drug resistance, and prognosis for various stages of chronic hepatitis B virus (HBV)-related liver disease was performed to elucidate the significance and indication of lamivudine for individual patients at each stage of disease. METHODS: A total of 158 cases consisting of 87 chronic hepatitis, 28 compensated cirrhosis, and 43 decompensated cirrhosis, with serum HBV-DNA > 5 log(10) copies/mL and with elevated alanine aminotransferase (ALT) over twice the upper normal limit or complications of hepatic insufficiency, were administered 100 mg of lamivudine daily and monitored for HBV markers, biochemistry, and prognosis. RESULTS: Lamivudine reduced HBV-DNA and ALT equally in all groups. Serum albumin, prothrombin time (%), and platelet count increased in all groups. The increased margin of albumin was the highest in the decompensated cirrhosis and higher in the compensated cirrhosis than the chronic hepatitis groups. Cumulative incidence of virologic breakthrough was 16%, 42%, 49%, and 53% at 12, 24, 36, and 48 months, respectively, and the strongest predictive factor for lamivudine resistance was persistent HBV-DNA at 3 months. Ascites, encephalopathy, and jaundice improved in the majority of patients with decompensated cirrhosis. On the other hand, hepatic failure developed or deteriorated in 10 patients after virologic breakthrough, and nine of them had decompensated cirrhosis. CONCLUSIONS: Lamivudine was effective in reducing HBV-DNA and improving hepatic reserve at all stages and was most beneficial and significant for decompensated cirrhosis. Meanwhile, close monitoring of viral load and immediate rescue treatment for lamivudine resistance is necessary to prevent hepatic failure in decompensated cirrhosis.

Eicosapentaenoic acid supplementation for chronic hepatitis C patients during combination therapy of pegylated interferon alpha-2b and ribavirin.

Eicosapentaenoic acid (EPA) (1.8 g/day) was administered to 12 chronic hepatitis C patients receiving combination therapy of pegylated interferon (PEG-IFN) alpha-2b and ribavirin for 48 weeks (EPA group). Twelve patients were not administered EPA (control group). All patients also received vitamin E and C (300, 600 mg/day, respectively) during the therapy. Serum alanine aminotransferase improved to a normal level in 8 of 12 patients from the EPA group and 6 of 12 patients from the control group after 12 weeks. Lymphocyte counts decreased significantly after 8 weeks in the control group, but not the EPA group. T-helper (Th) 1 decreased after 4 weeks in the control group, but not in the EPA group (two-way ANOVA; P < 0.05). Th1/Th2 ratios were elevated in 9 of 12 patients in the EPA group, and 3 out of 12 in the control group (P < 0.05) after 8 weeks. After 12 weeks, the arachidonic acid/EPA molar ratio of erythrocyte membrane phospholipid correlated negatively with the leukocyte count (n = 24, r = -0.439, P < 0.05) and the neutrophil count (n = 24, r = -0.671, P < 0.02). The hemoglobin level improved after 48 weeks compared with 24 weeks in only the EPA group. These findings suggest that EPA supplementation may be useful in therapy for chronic hepatitis C.

Systemic inflammatory response syndrome strongly affects the prognosis of patients with fulminant hepatitis B.

BACKGROUND: Hepatitis B virus infection is the most frequent cause of fulminant hepatic failure. Recently, systemic inflammatory response syndrome has been reported to be important in patients with fulminant hepatic failure. However, prognostic factors for fulminant hepatitis B have not been fully examined. In this study, we analyzed prognostic factors for fulminant hepatitis B in order to accurately identify patients with fatal outcomes. METHODS: Of 110 consecutive patients with fulminant hepatic failure, 36 (33%) were diagnosed with fulminant hepatitis B. Five of the 36 patients received liver transplants, and we analyzed prognostic factors associated with fatal outcomes in the other 31 patients, who consisted of 15 men and 16 women with a median age of 45 (range, 20-74) years. RESULTS: Eleven patients (35%) survived without liver transplantation, and the remaining 20 (65%) died. Nonsurvivors were older and had a higher prevalence ratio of systemic inflammatory response syndrome than survivors. Treatments were similar between survivors and nonsurvivors. Using a multivariate Cox proportional hazard model, age (>45 years), systemic inflammatory response syndrome, and ratio of total to direct bilirubin (>2.0) were associated with fatal outcomes. In particular, 1-week and overall survival rates of patients with systemic inflammatory response syndrome at the time of diagnosis were 39% and 8%, respectively, while those of patients without systemic inflammatory response syndrome were 94% and 56%, respectively. CONCLUSIONS: Systemic inflammatory response syndrome strongly affects the short-term prognosis of patients with fulminant hepatitis B, and patients with systemic inflammatory response syndrome might need urgent liver transplantation.

Clinical features of Japanese type 1 autoimmune hepatitis patients with zone III necrosis.

AIM: In Caucasians in northern Europe and North America, type 1 autoimmune hepatitis is characterized by susceptibility to human leukocyte antigens DR3 and DR4, and patients with zone III necrosis more frequently have an acute onset of the disease and a lower frequency of cirrhosis than those without. In Japanese patients, however, type 1 autoimmune hepatitis is primarily associated with DR4, and there are almost no DR3-positive patients. Thus, the clinical features of Japanese patients with type 1 autoimmune hepatitis and zone III necrosis may be different from those reported previously for Caucasians. METHODS: We investigated 160 consecutive patients with type 1 autoimmune hepatitis (20 males and 140 females; median age, 55 years; range, 16-79 years). RESULTS: Forty-seven patients (29%) had zone III necrosis, and these patients had lower serum levels of albumin and higher serum levels of total bilirubin, aspartate aminotransferaseand alanine aminotransferase. Histologically, zone III necrosis was found more frequently in patients with acute hepatitis than in those with chronic hepatitis. However, there was no difference in the frequency of cirrhosis between patients with and without zone III necrosis. In addition, normalization of serum alanine aminotransferase levels within six months after the introduction of corticosteroid treatment was slightly more frequent in patients with zone III necrosis (95% vs. 88%). CONCLUSION: In Japanese patients, zone III necrosis may reflect not only acute autoimmune hepatitis, but also acute exacerbation of pre-existing chronic disease. Furthermore, patients with zone III necrosis may respond better to corticosteroid treatment than those without.

Zinc supplementation prevents the increase of transaminase in chronic hepatitis C patients during combination therapy with pegylated interferon alpha-2b and ribavirin.

We investigated the effects of zinc supplementation on clinical observations in chronic hepatitis C patients receiving pegylated interferon (PEG-IFN) alpha-2b plus ribavirin combination therapy. Patients were randomly allocated to receive 150 mg polaprezinc (zinc group, n=11) or no supplement (control group, n=12) daily in addition to PEG-IFN alpha-2b plus ribavirin therapy and 300 mg vitamin E and 600 mg vitamin C supplementation daily for 48 wk. Among the patients who continued treatment, the serum alanine aminotransferase (ALT) level at 12 wk in the zinc group was significantly lower than that in the control group. All patients in the zinc group (9/9) and 67% (8/12) of the control patients at 24 wk, and all patients in the zinc group (7/7) and 60% (6/10) of the control patients at 48 wk showed a decrease in serum ALT levels to within the normal range (7-44 U/L). HCV RNA disappeared in all patients (7/7) in the zinc group and in 8 of 10 control patients at 48 wk. Polaprezinc supplementation decreased plasma thiobarbituric acid reactive substances and prevented the decrease of polyunsaturated fatty acids of erythrocyte membrane phospholipids. No significant differences were observed in the dosage of medicines or other clinical data during the treatment. These observations indicate that polaprezinc supplementation may have induced some antioxidative functions in the liver which resulted in reduced hepatocyte injury during PEG-IFN alpha-2b plus ribavirin therapy.

[A case of gastric arteriovenous malformation forming faded depression].

A 48-year-old man was referred to our hospital because of anemia. Upper gastrointestinal endoscopy showed discolored depressive lesion like gastric cancer, 30mm in diameter, in the greater curvature of the upper gastric body. During the endoscopic examination, pulsative bleeding from the lesion was occurred and we performed clipping hemostasis. We diagnosed a gastric arteriovenous malformation by endoscopic ultrasonograph and angiography. A pylorus preserving-gastrectomy was performed and Pathohistological examination revealed arterio-venous connection in the submucosal layer of the gastric wall.

Low frequency of drug-resistant virus did not affect the therapeutic efficacy in daclatasvir plus asunaprevir therapy in patients with chronic HCV genotype-1 infection.

BACKGROUND: The efficacy of a direct-acting antiviral agent (DAA) is compromised by the development of drug resistance. The associations between resistance-associated virus (RAV) and therapeutic outcomes have not been well-understood. METHODS: A total of 30 patients with HCV genotype-1b were enrolled and treated for 24 weeks with asunaprevir (ASV) and daclatasvir (DCV). Viral sequences in non-structural (NS) regions 3 and 5A in serum and liver tissue before treatment were examined with direct sequencing, next-generation sequencing (NGS) and the PCR-invader method to evaluate the importance of drug-resistance in the prediction of the outcomes of ASV plus DCV therapy. RESULTS: Of 30 patients (22 treatment-naive patients, 2 interferon-intolerant patients and 6 non-responders), 25 patients (83.3%) achieved sustained virological response (SVR) 24 weeks after the treatment. Viral breakthrough occurred in three treatment-naive patients and one non-responder. One treatment-naive patient experienced viral relapse. Among 25 patients without RAV, 24 obtained SVR, whereas 5 patients had RAV with a 1.3 to 88% frequency, resulting in various therapeutic outcomes. As for HCV compartments, similar RAVs were detected in serum and liver tissue for a patient obtaining SVR despite HCV NS5A Y93H and another developed viral breakthrough although no RAV was detected. Direct sequencing could not detect RAVs in low frequency (1.3 to 12%) for three of four patients. CONCLUSIONS: Low frequency of RAVs might not affect the outcomes of ASV plus DCV therapy. Deep sequencing and PCR-invader methods can detect clinically significant RAVs for ASV plus DCV therapy.

Complex Pattern of Resistance-Associated Substitutions of Hepatitis C Virus after Daclatasvir/Asunaprevir Treatment Failure.

BACKGROUNDS & AIMS: We aimed to clarify the characteristics of resistance-associated substitutions (RASs) after treatment failure with NS5A inhibitor, daclatasvir (DCV) in combination with NS3/4A inhibitor, asunaprevir (ASV), in patients with chronic hepatitis C virus genotype 1b infection. METHODS: This is a nationwide multicenter study conducted by the Japanese Red Cross Liver Study Group. The sera were obtained from 68 patients with virological failure after 24 weeks of DCV/ASV treatment. RASs in NS5A and NS3 were determined by population sequencing. RESULTS: The frequency of signature RASs at position D168 of NS3 was 68%, and at positions L31 and Y93 of NS5A was 79 and 76%, respectively. The frequency of dual signature RASs in NS5A (L31-RAS and Y93-RAS) was 63%. RASs at L28, R30, P32, Q54, P58, and A92 in addition to dual signature RAS were detected in 5, 5, 1, 22, 2, and 0 patients, respectively. In total, triple, quadruple, and quintuple RASs in combination with dual signature RAS were detected in 35, 10, and 1.5% patients, respectively. These RASs were detected in patients without baseline RASs or who prematurely discontinued therapy. Co-existence of D168 RAS in NS3 and L31 and/or Y93 RAS in NS5A was observed in 62% of patients. CONCLUSION: Treatment-emergent RASs after failure with DCV/ASV combination therapy are highly complex in more than 50% of the patients. The identification of complex RAS patterns, which may indicate high levels of resistance to NS5A inhibitors, highlights the need for RAS sequencing when considering re-treatment with regimens including NS5A inhibitors.

Successful treatment of advanced hepatocellular carcinoma by combined administration of 5-fluorouracil and pegylated interferon-alpha.

We report a case of hepatocellular carcinoma (HCC) treated successfully by transarterial chemoembolization (TACE) followed by combination therapy of 5-fluorouracil (5-FU) and pegylated interferon-alpha (PEG-IFN-alpha). In the present case, the patient had massive and advanced HCC with a diameter of over 8 cm located in segment 7 (S7) of the liver. Furthermore, the tumor invaded into the major branch of the portal vein (Vp3). After TACE, combined administration of 5-FU and PEG-IFN-alpha was performed for 5 mo. HCC was totally eradicated and the serum levels of tumor markers were markedly decreased by the treatment. Although it has been reported that the combined use of conventional IFN-alpha and 5-FU showed striking effects on HCC in some cases, this case may suggest the more promising effect of PEG-IFN-alpha with a long-lasting effect, in the combined use with 5-FU for the treatment of massive advanced HCC.

Effects of eicosapentaenoic acid supplementation in the treatment of chronic hepatitis C patients.

Eicosapentaenoic acid (EPA) has been shown to exert anti-inflammatory actions. To evaluate the effects of EPA on chronic hepatitis C, we administered EPA ethyl ester capsules to patients receiving the combination therapy of interferon alpha-2b and ribavirin. EPA (1,800 mg/d) was supplemented in combination with vitamin E (300 mg/d) and C (600 mg/d) to 5 chronic hepatitis C patients (EPA group). Five patients were administered vitamin E and C but not EPA (control group). Blood samples were obtained before and after 4, 8, 12 and 24 wk of therapy and analyzed for fatty acid compositions of erythrocyte and plasma and serum 8-hydroxy-2'-deoxyguanosine. EPA in erythrocyte membrane rose to 3 fold the basal level in the EPA group, while it decreased significantly in the control group after 24 wk of therapy. Lymphocyte counts in the EPA group increased to 120.8 +/- 25.4% after 4 wk of therapy and maintained the basal level throughout therapy, whereas the counts decreased significantly in controls. The serum alanine aminotransferase level was improved significantly in the EPA group. Changes in lymphocyte counts following 24 wk of therapy correlated with the EPA level in erythrocyte. The serum 8-hydroxy-2'-deoxyguanosine level at 24 wk in the EPA group was significantly lower than that in controls. These observations may suggest the beneficial effect of EPA supplementation in the treatment of chronic hepatitis C patients.