Chang Hong Lee

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.

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.

Clevudine myopathy in patients with chronic hepatitis B

Clevudine (L-FMAU) is a thymidine l-nucleoside analogue that was recently introduced for the treatment of chronic hepatitis B virus infection. Previous studies showed that clevudine has potent and sustained antiviral activity without causing viral resistance. No severe adverse event occurred during clinical trials. We describe two cases of drug-induced myopathy during long-term treatment of chronic hepatitis B with clevudine.

Epidemiology and prevention of hepatitis B virus infection

Hepatitis B virus (HBV) infection has been a major global cause of morbidity and mortality. The recognition of the problem led to a worldwide effort to reduce transmission of HBV through routine infant vaccination. HBV infection is the most common cause of chronic liver diseases and hepatocellular carcinoma in Korea. After hepatitis B vaccine era, seroprevalence of hepatits B surface antigen is decreasing, particularly in children. Hepatitis B vaccine is remarkably safe and shows high immunogenicity. Universal childhood immunization with three doses of hepatitis B vaccine in the first year of life is a highly effective method for prevention and control of hepatitis B.

Tenofovir plus lamivudine as rescue therapy for adefovir-resistant chronic hepatitis B in hepatitis B e antigen-positive patients with liver cirrhosis.

Background/Aims: There is no consensus on the management of patients with adefovir (ADV)‐resistant hepatitis B virus (HBV) infection. The aim of this study was to investigate whether tenofovir disoproxil fumarate (TDF) combined with lamivudine (LMV) is effective and safe in patients with resistance to or non‐response to ADV.

Evolution of hepatitis B virus mutation during entecavir rescue therapy in patients with antiviral resistance to lamivudine and adefovir

BACKGROUND The efficacy of entecavir (ETV) monotherapy in treatment-experienced patients with chronic hepatitis B (CHB) is debatable. METHODS A total of 22 hepatitis B e antigen (HBeAg)-positive CHB patients who had shown viral breakthrough or suboptimal response with lamivudine (3TC) and adefovir disoproxil (ADV) therapy were treated with 1.0 mg of ETV. Clinical and virological parameters were monitored every 3 months. Restriction fragment mass polymorphism assays were used to detect antiviral resistance. RESULTS During 3TC and ADV therapy, 11 patients had rtM204V/I mutations, 2 had rtA181V/T or rtN236T, 7 had both and 2 had no 3TC- or ADV-related mutations. After switching to ETV monotherapy, the median change in serum hepatitis B virus (HBV) DNA level was -2.1 log(10) copies/ml. Virological response (HBV DNA<300 copies/ml) was achieved in 1 of 18 patients with pre-existing rt204 mutations, whereas it was achieved in all 4 patients without pre-existing rt204 mutations regardless of the presence of rt181 or rt236 mutations. Changes in mutational patterns during ETV therapy showed that rt204 mutations persisted or re-emerged. Relative abundances of rtM204V/I mutations in total viral populations gradually increased under ETV rescue, whereas those with rtA181V/T and rtN236T mutations decreased. ETV resistance mutations (rtL180M+rtT184I/L[rtS202G]+rtM204V) were detected in five patients with pre-existing rt204 mutations. CONCLUSIONS ETV monotherapy resulted in a limited virological response in patients who had previously failed 3TC and ADV rescue therapy. The limited efficacy might be associated with residual or reselected rtM204V/I mutations leading to ETV resistance. Combination treatment including potent antiviral agents should be recommended for patients with pre-existing rtM204V/I mutations.

Irritable Bowel Syndrome Is More Common in Women Regardless of the Menstrual Phase: A Rome II-based Survey

Functional gastrointestinal disorders are more common in women in relation to the fluctuations of female sex hormones. We tried to know the gender-related differences in the prevalence of irritable bowel syndrome and gastrointestinal symptoms according to the menstrual phase. A total of 253 women before menopause and 252 men below age 50 were examined by a gastroenterologist after completing the questionnaire. Blood tests, endoscopic procedures, and imaging studies were done, if needed. Women were subclassified into three groups according to their menst- ruation period; menstrual phase, proliferative phase, and secretory phase. Finally, 179 men and 193 women were analyzed. Irritable bowel syndrome was more frequently noticed in women than in men (p=0.01). The diarrhea-dominant type was more common in men, while constipation-dominant or alternating types were more common in women (p<0.001). Of 193 women, there was no significant difference in their gastrointestinal symptoms according to their menstrual phase. Regardless of the menstrual phase, gastrointestinal symptoms are more frequent in women. Physicians should consider different symptomatic manifestations between men and women should be considered when evaluating functional gastrointestinal disorders.

Long-term impact of entecavir monotherapy in chronic hepatitis B patients with a partial virologic response to entecavir therapy

Abstract Objective. Partial virologic response (PVR) in chronic hepatitis B (CHB) patients during antiviral therapy is associated with an increased risk of occurrence of viral resistance and treatment failure. The aim of this study was to evaluate the clinical and virological responses of partial responders to long-term entecavir (ETV) monotherapy. Material and method. In this open-labeled prospective study, 128 treatment-naïve CHB patients treated with 0.5 mg ETV once daily for more than 12 months were monitored at baseline and at 3-month intervals during treatment. Results. At baseline, the mean age of subjects was 47.0 ± 13.0 years, and the median duration of treatment was 27 months; 85 subjects (66.4%) were HBeAg-positive, and 47 patients (36.7%) had liver cirrhosis. Eighteen of 128 patients (14.0%) showed PVR to 48 weeks of ETV treatment, and 13 patients were followed up for over 24 months. Among them, 9 of 13 patients (69.2 %) achieved a complete virologic response (VR, HBV-DNA < 60 IU/mL) during prolonged ETV treatment. Four showed persistent PVR, but only one patient with poor compliance developed genetic resistance to ETV at month 27. The occurrence of PVR was independently associated with a high viral load, more than 7 log10 IU/mL (p = 0.014). Conclusions. CHB patients with a high viral load, more than 7 log log10 IU/mL, are related to the occurrence of PVR during ETV monotherapy. Long-term ETV monotherapy may be effective for suppressing serum HBV DNA levels in treatment- naïve CHB patients with a PVR to ETV.

Clinical features of acute viral hepatitis B in Korea: a multi-center study

Background/Aims The incidence of Hepatitis B has significantly declined since the introduction of an HBV vaccination program. The aim of this study was to investigate recent clinical features of acute viral hepatitis B (AVH-B) in Korea. Methods A total of 2241 patients with acute viral hepatitis were enrolled and their data were collected from nine medical-centers between January 2006 and December 2009. Results One hundred nineteen (5.3%) of the 2241 were diagnosed as AVH-B. Among 78 patients with AVH-B whose data were analyzed, 50 were male, and the mean age was 38.6 years. In an initial test, mean AST, ALT and total-bilirubin levels were 1296.2 IU/L, 2109.6 IU/L and 9.3 mg/dl, respectively. Positivity frequencies for HBeAg and anti-HBe were 55.1% and 67.9%, respectively, and the mean HBV DNA level was 5.2 log10 copies/ml. The mean length of hospitalization was 11.6 days. During follow-up, AST, ALT and total bilirubin levels were normalized or near-normalized in all patients without serious complications. Sixty-three of 66 (95.4%) patients showed HBsAg loss and 37 (56.1%) patients showed HBsAg seroconversion. Only 3 patients (4.5%) showed persistent hepatitis B viremia. There was no case of death or liver transplantation. Nine patients (11.3%) had received anti-viral agents and their clinical outcomes were not significantly different from those of patients treated without antiviral agents. Conclusions The prevalence of AVH-B among acute hepatitis patients is relatively low in Korea. AVH-B infection can be cured without complications in almost all patients, regardless of antiviral treatment.

Predictive value of Refit Model for End-Stage Liver Disease, Refit Model for End-Stage Liver Disease-Na, and pre-existing scoring system for 3-month mortality in Korean patients with cirrhosis

The Model for End‐Stage Liver Disease (MELD) has been widely used for predicting short‐term mortality in patients with cirrhosis in the U.S. A modification of the MELD score was published in 2011. This was validated for Korean patients with cirrhosis.