Kwan Soo Byun

Resistance to adefovir dipivoxil in lamivudine resistant chronic hepatitis B patients treated with adefovir dipivoxil

Background: Adefovir dipivoxil (ADV) is a potent nucleotide analogue against both the wild-type and lamivudine (LMV) resistant hepatitis B virus (HBV). The cumulative incidence of ADV resistant mutations in the nucleoside/-tide treatment naïve chronic hepatitis B patient (CHB) at weeks 48, 96, and 144 was 0, 0.8–3%, and ∼5.9%, respectively. Aims: The aim of this study was to characterise the genotypic and phenotypic mutation profiles to ADV in 67 LMV resistant CHB patients who were treated with ADV. Methods: Serum HBV DNA was quantified by real time polymerase chain reaction. The ADV mutant was detected using matrix assisted laser desorption/ionisation time of flight mass spectrometry based genotyping assays, termed restriction fragment mass polymorphism (RFMP). Results: RFMP analysis revealed that a total of 11 amino acid substitutions developed in the rt domain of the HBV polymerase in nine patients. The cumulative incidence of genotypic ADV resistance at months 12 and 24 was 6.4% and 25.4%, respectively. The rtA181V, rtN236T, and rtA181T mutations were detected in five, four, and two of the 67 patients at treatment months 12–17, 3–19, and 7–20, respectively. Serial quantification of serum HBV DNA revealed that two patients with the rtA181V mutation, with or without the rtN236T mutation, and one patient with the rtA181T mutation displayed HBV DNA rebound. Conclusion: Emergence of the ADV mutation in LMV resistant patients who are treated with ADV appeared to present earlier and more frequently than was reported in previous studies on nucleoside/-tide treatment naïve patients.

Twenty‐four‐week clevudine therapy showed potent and sustained antiviral activity in HBeAg‐positive chronic hepatitis B

Clevudine is a pyrimidine analogue with potent and sustained antiviral activity against HBV. The present study evaluated the safety and efficacy of 30 mg clevudine once daily for 24 weeks and assessed the durable antiviral response for 24 weeks after cessation of dosing. A total of 243 hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B patients were randomized (3:1) to receive clevudine 30 mg once daily (n = 182) or placebo (n = 61) for 24 weeks. Patients were followed for a further 24 weeks off therapy. Median serum HBV DNA reductions from baseline at week 24 were 5.10 and 0.27 log10 copies/mL in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained off therapy, with 3.73 log10 reduction at week 34 and 2.02 log10 reduction at week 48. At week 24, 59.0% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (less than 300 copies/mL). The proportion of patients who achieved normalization of alanine aminotransferase (ALT) levels was 68.2% in the clevudine group and 17.5% in the placebo group at week 24 (P < 0.0001). ALT normalization in the clevudine group was well maintained during post‐treatment follow‐up period. The incidence of adverse events (AEs) was similar between the clevudine group and the placebo group. No resistance to clevudine was detected with 24 weeks of administration of drug. Conclusion: A 24‐week clevudine therapy was well tolerated and showed potent and sustained antiviral effect without evidence of viral resistance during treatment period in HBeAg‐positive chronic hepatitis B. (HEPATOLOGY 2007;45:1172–1178.)

Clevudine is highly efficacious in hepatitis B e antigen‐negative chronic hepatitis B with durable off‐therapy viral suppression

Clevudine is a pyrimidine analog with potent and sustained antiviral activity against HBV. In the present study, we evaluated the safety and efficacy of clevudine 30 mg daily for 24 weeks and assessed the durability of antiviral response for 24 weeks after cessation of dosing in hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B (e‐CHB). We randomized a total of 86 patients (3:1) to receive clevudine 30 mg (n = 63) or placebo (n = 23) daily for 24 weeks. We followed patients for an additional 24 weeks after withdrawal of treatment. The median changes in HBV DNA from baseline were −4.25 and −0.48 log10 copies/mL at week 24 in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained after withdrawal of therapy, with 3.11 log10 reduction at week 48. At week 24 and week 48, 92.1% and 16.4% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (<300 copies/mL). The proportion of patients who achieved ALT normalization was 74.6% and 33.3% in the clevudine and placebo groups at week 24, respectively (P = 0.0006). ALT normalization in the clevudine group was well‐maintained during the post‐treatment follow‐up period. The incidence of adverse events was similar in the 2 groups. No resistance to clevudine was detected during treatment. Conclusion: A 24‐week clevudine therapy was well‐tolerated and showed potent and sustained antiviral effect without evidence of viral resistance in e‐CHB patients. However, treatment for longer than 24 weeks would be needed to achieve durable remission. (HEPATOLOGY 2007.)

PPAR agonists treatment is effective in a nonalcoholic fatty liver disease animal model by modulating fatty-acid metabolic enzymes.

Background and Aims:  In a previous study, the authors found that reduced expression of peroxisome proliferator‐activated receptor (PPAR)‐α might play an important role in developing nonalcoholic fatty liver disease (NAFLD). The aim of this study was to analyze the effects of PPAR‐α and ‐γ agonists on NAFLD and verify the mechanisms underlying the PPAR‐α and ‐γ agonist‐induced improvements by evaluating the hepatic gene expression profile involved in fatty‐acid metabolism, using the Otsuka–Long Evans–Tokushima fatty (OLETF) rat.

Comparison of the methods for tumor response assessment in patients with hepatocellular carcinoma undergoing transarterial chemoembolization

BACKGROUND & AIMS Recently, new methods, including the concept of viable enhancing tumor such as EASL and mRECIST, have been proposed for substitution of the conventional WHO and RECIST criteria in hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). Herein, we evaluated the differences of four methods and compared the association of these methods with the prognosis of HCC patients undergoing TACE. METHODS We retrospectively reviewed 114 consecutive newly diagnosed HCC patients who underwent TACE as initial treatment. We evaluated the intermethod agreement (κ values) between the methods and compared their association with the prognosis of HCC patients. RESULTS The κ values for EASL vs. WHO, EASL vs. RECIST, mRECIST vs. WHO, and mRECIST vs. RECIST were low, of 0.102, 0.088, 0.112, and 0.122, respectively. However, good correlations were observed for WHO vs. RECIST and EASL vs. mRECIST (κ=0.883, κ=0.759, respectively p<0.001). The median OS was 32.3 months. Hazard ratios (HR) for survival in responders compared with non-responders were 0.21 (95% CI; 0.12-0.37, p<0.001) for EASL and 0.27 (95% CI; 0.15-0.48, p<0.001) for mRECIST. The mean survival of responders was significantly longer than that of non-responders in both EASL (40.8 vs. 16.9 months, p<0.001) and mRECIST (41.1 vs. 20.7 months, p<0.001). In multivariate analysis, EASL response (HR 0.21, 95% CI 0.11-0.40, p<0.001) and mRECIST response (HR; 0.31, 95% CI, 0.17-0.59, p<0.001) were independently associated with survival. CONCLUSIONS The response assessment by EASL and mRECIST could reliably predict the survival of HCC patients undergoing TACE and could be applicable in practice in preference to the conventional WHO and RECIST criteria.

Reduced expression of peroxisome proliferator-activated receptor-α may have an important role in the development of non-alcoholic fatty liver disease

Background:  Although the pathogenesis of non‐alcoholic fatty liver disease (NAFLD) remains poorly understood, metabolic syndrome associated with insulin resistance is the most reproducible factor in the development of NAFLD. Fat accumulation in hepatocytes results from an imbalance in the input, output and oxidation of fatty acid. Peroxisomes contain a battery of fatty acid oxidizing enzymes, the first of which, acyl‐CoA oxidase (AOX), initiates the β‐oxidation spiral. One of the mammalian peroxisome proliferator‐activated receptors (PPAR), PPAR‐α, regulates the transcriptional expression of the enzymes involved in fatty acid β‐oxidation. The aim of the present study was to define the role of PPAR‐α and AOX in the development of NAFLD using the Otsuka Long‐Evans Tokushima fatty (OLETF) rat model.

Cryoglobulinaemia and rheumatic manifestations in patients with hepatitis C virus infection

OBJECTIVES To investigate the association of cryoglobulinaemia and rheumatic manifestations in Korean patients with hepatitis C virus (HCV) infection. METHODS Forty nine Korean patients with HCV infection were recruited. The prevalence, concentration, and type of cryoglobulin (by immunofixation), rheumatoid factor (RF), antinuclear antibody (ANA), and various rheumatological symptoms were investigated and HCV genotype was determined by polymerase chain reaction with genotype specific primer. RESULTS The prevalence of cryoglobulin was 59% in Korean HCV patients and the concentration of cryoglobulin was 9.8 (7.9) g/l (mean (SD)). The type of cryoglobulinaemia was identified in 23 (80%) of 29 HCV patients with cryoglobulinaemia and they were all type III. There were no differences in age, sex, history of operation and transfusion, proportion of liver cirrhosis between the patients with cryoglobulinaemia and those without cryoglobulinaemia. The frequencies of RF and ANA were 14% and 3.4% respectively in HCV patients with cryoglobulinaemia. There was no difference in HCV genotype between the patients with cryoglobulinaemia and those without cryoglobulinaemia. Clinical features of HCV patients were as follows: arthralgia/arthritis (35%), cutaneous manifestation (37%), Raynaud’s phenomenon (8%), paresthesia (44%), dry eyes (22%), dry mouth (10%), oral ulcer (33%), and abdominal pain (14%). However, these rheumatological symptoms did not differ between the two groups. CONCLUSION Although the rheumatological symptoms were not different between HCV patients with and without cryoglobulinaemia, HCV patients showed various rheumalogical manifestations. These result suggests that HCV infection could be included as one of the causes in patients with unexplained rheumatological symptoms.

Molecular epidemiology of hepatitis A virus in Korea

Background: The prevalence of antibodies for hepatitis A virus (anti‐HAV) in adolescents and young adults has decreased remarkably following the economic growth in Korea. As a result, this age group has a high risk for HAV infection paradoxically, and over 1500 cases of clinically overt hepatitis A occurred in 1998. Human isolates of hepatitis A virus (HAV) are categorized within four genotypes (I, II, III, and VII). In some geographic regions, closely related isolates cluster, suggesting endemic spread of the virus, while in other regions multiple genotypes circulate. Virtually no data are available with regard to the genetic relatedness of Korean strains of HAV.

Fanconi's Syndrome Associated with Prolonged Adefovir Dipivoxil Therapy in a Hepatitis B Virus Patient.

Adefovir dipivoxil (ADV) is commonly used as an antiviral agent in the treatment of chronic hepatitis B or human immunodeficiency virus infection. Nephrotoxicity has been shown to occur at daily dosages of 60-120 mg. Fanconis syndrome is a generalized dysfunction of the renal proximal tubular cells, which is usually accompanied by complications. Here we report a case of Fanconis syndrome in a chronic hepatitis B patient who had been treated with a prolonged regimen of ADV at 10 mg/day. A 47-year-old man complained of severe back and chest-wall pain. He had chronic hepatitis B and had been treated with ADV at a daily dose of 10 mg for 38 months. He was hospitalized because of severe bone pain, and laboratory and radiologic findings suggested a diagnosis of Fanconis syndrome with osteomalacia. After discontinuation of the ADV, he recovered and was discharged from hospital. His laboratory findings had normalized within 2 weeks. This case indicates that Fanconis syndrome can be acquired by a chronic hepatitis B patient taking ADV at a conventional dosage of 10 mg/day. Therefore, patients treated with long-term ADV should be checked regularly for the occurrence of ADV-induced Fanconis syndrome.

Tenofovir monotherapy versus tenofovir and entecavir combination therapy in adefovir-resistant chronic hepatitis B patients with multiple drug failure: results of a randomised trial

Objective Little clinical data are available regarding the optimal treatment of patients who harbour adefovir-resistant HBV. Design In this multicentre trial, patients who had adefovir-resistant HBV with serum HBV DNA levels >60 IU/mL were randomised to receive tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n=50) or TDF and entecavir (ETV, 1 mg/day) combination therapy (TDF/ETV, n=52) for 48 weeks. All who completed 48 weeks in either group received TDF monotherapy for 48 additional weeks. Results Baseline characteristics were comparable between groups, including HBV DNA levels (median, 3.38 log10 IU/mL). All patients had adefovir-resistant HBV mutations; rtA181V/T and/or rtN236T. The proportion of patients with HBV DNA <15 IU/mL was not significantly different between the TDF-TDF and TDF/ETV-TDF groups at weeks 48 (62% vs 63.5%; p=0.88) and 96 (64% vs 63.5%; p=0.96). The mean change in HBV DNA levels from baseline was not significantly different between groups at week 48 (−3.03 log10 IU/mL vs −3.31 log10 IU/mL; p=0.38). Virological breakthrough occurred in one patient on TDF-TDF and two patients on TDF/ETV-TDF over 96 weeks; all were attributed to poor drug adherence. At week 96, five and two patients in the TDF-TDF and TDF/ETV-TDF groups, respectively, retained some of their baseline resistance mutations (p=0.44). None developed additional resistance mutations. Safety profiles were comparable in the two groups. Conclusions In patients with adefovir-resistant HBV and multiple-drug failure, TDF monotherapy provided a virological response comparable to that of TDF and ETV combination therapy, and was safe up to 96 weeks. Trial registration number NCT01639066.