Yasuyuki Aisaka

Serum HBV RNA is a predictor of early emergence of the YMDD mutant in patients treated with lamivudine

Lamivudine (LAM) is a nucleoside analogue widely used for the treatment of chronic hepatitis B virus (HBV) infection. Emergence of resistant strains with amino acid substitutions in the tyrosine‐methionine‐aspartate‐aspartate (YMDD) motif of reverse transcriptase is a serious problem in patients on LAM therapy. The amount of covalently closed circular DNA in the serum is reported to be higher in patients who develop YMDD mutants than in those without mutants. However, there is no useful serum marker that can predict early emergence of mutants during LAM therapy. Analysis of patients who were treated with entecavir (n = 7) and LAM (n = 36) showed some patients had high serum levels of HBV RNA. Median serum levels of HBV RNA were significantly higher in patients in whom the YMDD mutant had emerged within 1 year (n = 6, 1.688 log copies/ml) than in those in whom the YMDD mutant emerged more than 1 year after treatment (n = 12, 0.456 log copies/ml, P = 0.0125) or in whom the YMDD mutant never emerged (n = 18, 0.688 log copies/ml, P = 0.039). Our results suggest that HBV RNA is a valuable predictor of early occurrence of viral mutation during LAM therapy. (HEPATOLOGY 2007;45:1179–1186.)

Effect of vitamin D supplementation on pegylated interferon/ribavirin therapy for chronic hepatitis C genotype 1b : A randomized controlled trial

Chronic HCV–infected patients tend to have vitamin D deficiency, suggesting that vitamin D supplementation may enhance the efficacy of treatment with pegylated interferon (PEG‐IFN) and ribavirin (RBV). We therefore assessed the effects of vitamin D supplementation on viral response to PEG‐IFN/RBV. Eighty‐four patients with HCV genotype 1b were randomized, 42 to oral vitamin D supplementation (1000 IU/day) and 42 to nonsupplementation (control), from week 8 to the end of PEG‐IFN/RBV therapy. The primary end point was undetectable HCV RNA at week 24 (viral response [VR]). VR rate at week 24 was significantly higher in the vitamin D than in the control group (78.6% vs 54.8% P = 0.037). Adverse events were similar in both groups. When patients were subdivided by IL28B SNP rs8099917 genotype, those with the TT genotype group showed a significantly higher VR rate at week 24 with than without vitamin D supplementation (86.2% vs 63.3% vs P = 0.044). Although patients with the TG/GG genotype, who were relatively resistant to PEG‐IFN treatment, had similar VR rates at week 24 with and without vitamin D supplementation, the decline in viral load from week 8 to week 24 was significantly greater with than without vitamin D supplementation. Multivariate analysis showed that rs8099917 genotype and vitamin D supplementation contributed significantly to VR at week 24. SVR rates were similar in the vitamin D and control groups [64.3% (27/42) vs 50% (21/42), P = 0.19]. Vitamin D supplementation may enhance the effects of PEG‐IFN/RBV in HCV genotype 1b–infected patients.

Impact of ribavirin dose reduction on the efficacy of pegylated interferon plus ribavirin combination therapy for elderly patients infected with genotype 1b and high viral loads

Aim:  To examine the impact of ribavirin dose reduction on the efficacy of pegylated interferon (PEG IFN) plus ribavirin combination therapy for elderly patients infected with genotype 1b and high viral loads.

Prolonged Negative HCV-RNA Status Led to a Good Outcome in Chronic Hepatitis C Patients with Genotype 1b and Super-High Viral Load

Objective: We examined whether a sustained negative HCV-RNA status for 48 weeks affects the outcome in patients with genotype 1b and super-high viral load, and also investigated whether the outcome is affected by the induction therapy of twice-daily pre-administrated interferon (IFN)-β. Methods: 78 eligible patients were divided into four groups. 40 were patients assigned to the short treatment protocol. 13 patients received 3 MU IFN-β twice daily for 2 weeks followed by IFN-α2b+ribavirin for 22 weeks (β-induction group: group 1). 27 patients received IFN-α2b+ribavirin for 24 weeks (standard combination group: group 2). 38 patients were assigned to the maintenance treatment protocol. All of the 13 in the β-induction group (group 3) and 21 of 25 patients in the standard combination group (group 4) who were negative HCV-RNA PCR at week 24 had IFN monotherapy to maintain a negative HCV-RNA result for 48 weeks. Results: An HCV-RNA-negative status at week 24 was observed in 96% (25/26) of groups 1 and 3 versus in 79% (41/52) of groups 2 and 4 (p < 0.01). The sustained virological response (SVR) was 38% (5/13) in group 1 and 11% (3/27) in group 2 (p < 0.05). In the maintenance treatment, SVR was observed in 46% (6/13) of group 3 and 32% (8/25) of group 4 (NS). Conclusions: A sustained negative HCV-RNA status for 48 weeks might be associated with viral elimination in patients with genotype 1 and super-high viral load.

Comparison of Outcome of Hepatic Arterial Infusion Chemotherapy Combined with Radiotherapy and Sorafenib for Advanced Hepatocellular Carcinoma Patients with Major Portal Vein Tumor Thrombosis

Objective: To compare the outcome of hepatic arterial infusion chemotherapy combined with radiotherapy (HAIC + RT) versus sorafenib monotherapy in patients with advanced hepatocellular carcinoma (HCC) and major portal vein tumor thrombosis (PVTT). Methods: This retrospective study included 108 HCC patients with PVTT of the main trunk or first branch and Child-Pugh ≤7. Sixty-eight received HAIC + RT and 40 received sorafenib. Patients were then assigned to the HAIC + RT group (n = 36) and the sorafenib group (n = 36) through case-control matching. The decision to treat with HAIC + RT or sorafenib was left to the attending physician. Results: The median overall, progression-free, and postprogression survival were significantly longer in the HAIC + RT group than in the sorafenib group (9.9 vs. 5.3, p = 0.002; 3.9 vs. 2.1, p = 0.048; and 3.7 vs. 1.9 months, p = 0.02, respectively). Multivariate analysis identified HAIC + RT (hazard ratio = 2.02; 95% confidence interval, 1.14–3.57; p = 0.01) as a significant and independent determinant of overall survival. Conclusions: In patients with advanced HCC and major PVTT, survival was significantly longer in those treated with HAIC + RT than with sorafenib.

Comparison of clinical outcome of hepatic arterial infusion chemotherapy and sorafenib for advanced hepatocellular carcinoma according to macrovascular invasion and transcatheter arterial chemoembolization refractory status: Distinguish between HAIC and SOR

Sorafenib is the standard treatment for patients with advanced hepatocellular carcinoma (HCC) with distant metastasis, unresectable HCC, and HCC refractory to transcatheter arterial chemoembolization (TACE) or with macroscopic vascular invasion (MVI). Also, hepatic arterial infusion chemotherapy (HAIC) has been used for advanced HCC in Southeast and East Asian countries. However, clearer information is needed for choosing appropriately between these therapies.

Effect of prolonged administration of pegylated interferon/ribavirin therapy in genotypes 2a and 2b: propensity score-matched analysis.

Chronic hepatitis C genotype 2 patients show high susceptibility to pegylated interferon plus ribavirin therapy (PEG/RBV). However, the differences in response to therapy between genotypes 2a and 2b, and the efficacy of prolonged therapy for refractory patients have not been evaluated. We investigated the differences in response to PEG/RBV between each genotype and examined the efficacy of prolonged therapy.

Predicting the response to 48‐week combination therapy with peginterferon α‐2b plus ribavirin from the estimated HCV RNA load index after negative serum change in genotype 1b hepatitis C patients

Aim:  We estimated viral dynamics after serum hepatitis C virus (HCV) RNA became negative and assessed the relation between the estimated viral load at the end of treatment (EVE) index and the response to the combination therapy with peginterferon α‐2b plus ribavirin.

W1794 Assessment of the Development of Hepatocellular Carcinoma in the Hepatitis C Virus Eradicated Patients After Interferon Therapy

Background: About 70-90% of all hepatocellular cancer (HCC) occur within an established background of chronic liver disease, especially cirrhosis. Surveillance in high risk patients has been recommended, cost-efficacy is uncertain. AIM: To retrospectively evaluate the impact of biannual HCC screening with alpha-fetoprotein and imaging at a VA medical center with introduction of a dedicated hepatitis C team in 2003. Method: Patients with liver masses between January, 1998 and December, 2007 were identified with local tumor registry data. Retrospective data abstraction from electronic medical records was performed and HCC cases were confirmed. Data including gender, age, body mass index (BMI), hepatitis B, C serology, alcohol use, tumor stage, survival, treatment, and pathology report were documented in excel format. Probability curves obtained with Kaplan Meier method were compared using the Log-Rank test. Patients were divided in a preand post-HCC screening group. Result: Fifty-one cases of liver masses were identified, 44 cases were confirmed HCC and used for further analysis. Mean survival was 10.1 months in unscreened patients (95% confidence interval [CI], 2.6-17.6), and 10.5 months in the screened group (95% CI, 6.015.0) (p .45). Kaplan Meyer overall survival for stage I and II patients was 20% and 21%, respectively and declines to 16% and 13% in stage III and IV. Survival rate for patients with surgery was 40% and declined considerably with local treatment. Only 41% of HCC were single lesion; 69%weremultifocal lesion. All 28 patients who did not receive surveillance for HCC were diagnosed before 2003. Since 2003, all HCC cases were captured by surveillance. Ten patients were diagnosed with local HCC stages (I-IIIA), 2 with advanced stage (IIIB IV), 2 had an unknown stage. In the unscreened group 15 patients were diagnosed with advanced tumor stage (IIIC IV), 4 had unknown stage. Alcohol use was common (86%). HCV positive tested 26% and 26% were not tested in the pre-screening group; 34% and 16% in the post-screening group, respectively. From multiple regression analysis the only independent predictor of survival was tumor stage (I-II versus III-IV) at the time of diagnosis, but significance (p .075) could not be established likely due to small sample size. Conclusion: A dedicated hepatitis C team accomplished biannual HCC surveillance in patients at risk which led to diagnosis at an earlier stage (62.5 % versus 32%) however did not improve overall survival. Cost-efficacy of HCC screening in the veterans population needs to be further evaluated.

A case of jevenile primary biliary cirrhosis with remarkable enlarged lymphnodes.

症例は21歳男性, 黄疸, 頸部リンパ節腫脹を主訴に当科紹介入院となった. 直接優位の血清ビリルビン値の上昇と肝逸脱酵素の上昇を認め, 抗ミトコンドリア抗体160倍, M2分画705U/mlと陽性を示した. 腹部造影CTでは, 著明な脾腫と肝門部リンパ節腫大を認めた. 肝生検組織像では, chronic non-suppurative destructive cholangitis (CNSDC) を認めPBCと診断した. リンパ節生検像では反応性, 過形成性に増大したリンパ濾胞を認めた. その後一度肝機能検査値の再上昇と全身倦怠感のため再入院したが, 現在は外来通院加療中である. 平成5年度厚生省特定疾患難治性肝炎調査研究班によるPBC全国調査では, 20歳代に発症した男性のPBCの報告はない. また, 本症例では著明な腹部リンパ節と表在リンパ節の腫大とを認めたが, これまで全身的非特異的反応性リンパ節腫脹を認めたとの報告は少なく, 興味深い一例と考えた.