S.W. Paik

Clinical significance of pre-S mutations in patients with genotype C hepatitis B virus infection

Summary.  We investigated the overall and site‐specific prevalence of pre‐S mutations and its clinical significance in patients with genotype C hepatitis B virus (HBV) infection. Three hundred subjects were included: 50 asymptomatic carriers (AC), 87 chronic hepatitis (CH), 91 liver cirrhosis (LC) and 72 hepatocellular carcinoma (HCC). Pre‐S mutations were determined by nucleotide sequence analysis. Possible correlations between pre‐S mutations and clinical/virological parameters were examined. Pre‐S mutations were detected in 82 cases (27.3%); it was more frequently found in HCC (43.1%) and LC (35.2%) group than in the CH (20.7%) and AC (2.0%) group. Pre‐S2 deletion was the most commonly found mutation (10.7%), followed by pre‐S2 start codon mutation (9.7%), pre‐S1–S2 deletion (3.0%) and both pre‐S2 deletion and start codon mutation (2.7%). Pre‐S2 deletion and pre‐S2 start codon mutation were more frequently detected in advanced diseases (LC and HCC). Pre‐S mutations were associated with older age and higher rates of positive HBV DNA (≥0.5 pg/mL). Advanced disease and positive HBV DNA were shown to be independent predictors of pre‐S mutations by logistic regression analysis. These findings suggest that pre‐S mutations, especially pre‐S2 deletions and pre‐S2 start codon mutations, are common in patients with genotype C HBV infection and are associated with advanced liver disease and active viral replication.

Proton pump inhibitor use significantly increases the risk of spontaneous bacterial peritonitis in 1965 patients with cirrhosis and ascites: a propensity score matched cohort study.

The risk of spontaneous bacterial peritonitis (SBP) associated with proton pump inhibitor (PPI) use has been raised in cirrhotic patients with ascites. However, this is based on case–control studies, often with a small series.

Glecaprevir–Pibrentasvir for 8 or 12 Weeks in HCV Genotype 1 or 3 Infection

BACKGROUND Glecaprevir and pibrentasvir are direct‐acting antiviral agents with pangenotypic activity and a high barrier to resistance. We evaluated the efficacy and safety of 8‐week and 12‐week courses of treatment with 300 mg of glecaprevir plus 120 mg of pibrentasvir in patients without cirrhosis who had hepatitis C virus (HCV) genotype 1 or 3 infection. METHODS We conducted two phase 3, randomized, open‐label, multicenter trials. Patients with genotype 1 infection were randomly assigned in a 1:1 ratio to receive once‐daily glecaprevir–pibrentasvir for either 8 or 12 weeks. Patients with genotype 3 infection were randomly assigned in a 2:1 ratio to receive 12 weeks of treatment with either glecaprevir–pibrentasvir or sofosbuvir–daclatasvir. Additional patients with genotype 3 infection were subsequently enrolled and nonrandomly assigned to receive 8 weeks of treatment with glecaprevir–pibrentasvir. The primary end point was the rate of sustained virologic response 12 weeks after the end of treatment. RESULTS In total, 1208 patients were treated. The rate of sustained virologic response at 12 weeks among genotype 1–infected patients was 99.1% (95% confidence interval [CI], 98 to 100) in the 8‐week group and 99.7% (95% CI, 99 to 100) in the 12‐week group. Genotype 3–infected patients who were treated for 12 weeks had a rate of sustained virologic response at 12 weeks of 95% (95% CI, 93 to 98; 222 of 233 patients) with glecaprevir–pibrentasvir and 97% (95% CI, 93 to 99.9; 111 of 115) with sofosbuvir–daclatasvir; 8 weeks of treatment with glecaprevir–pibrentasvir yielded a rate of 95% (95% CI, 91 to 98; 149 of 157 patients). Adverse events led to discontinuation of treatment in no more than 1% of patients in any treatment group. CONCLUSIONS Once‐daily treatment with glecaprevir–pibrentasvir for either 8 weeks or 12 weeks achieved high rates of sustained virologic response among patients with HCV genotype 1 or 3 infection who did not have cirrhosis. (Funded by AbbVie; ENDURANCE‐1 and ENDURANCE‐3 ClinicalTrials.gov numbers, NCT02604017 and NCT02640157.)

Long-term Stress and Helicobacter pylori Infection Independently Induce Gastric Mucosal Lesions in C57BL/6 Mice

Background: Long-term psychological stresses may have a role in the pathogenesis of peptic ulcer. However, the interaction between stress and Helicobacter pylori infection in the development of peptic ulcer is not established. The aim of this study was to elucidate the roles of long-term stress and H. pylori infection in the development of gastric mucosal lesions in mice. Methods: The Sydney strain (SS1) of H. pylori was inoculated into the stomach of C57BL/6 mice. Twelve weeks later, mice with or without H. pylori infection were exposed to long-term repeated water-immersion-restraint stress (WIRS) for 12 h per day, 3 times per week, for 8 weeks. Gastric mucosal lesions were evaluated both macroscopically (ulcer index) and microscopically (Updated Sydney System). Results: The long-term WIRS induced mild inflammation, oedema, interstitial haemorrhage and superficial erosions in the stomach of mice both with and without H. pylori infection. The degree of mucosal inflammation or atrophy in H. pylori -infected mice was not influenced by the stress. In the mice without H. pylori infection, the ulcer index of the stressed mice was greater than that of non-stressed mice (1.66 ± 0.39 versus 0.17 ± 0.08, P = 0.007). In the mice with H. pylori infection, the ulcer index (mean ± s x ) of the stressed mice was also greater than that of nonstressed mice (2.31 ± 0.59 versus 0.64 ± 0.22, P = 0.027). Conclusions: The present study showed that long-term stress can induce gastric mucosal inflammation and erosions, and this effect may occur independently of H. pylori infection.

Role of autonomic dysfunction in patients with functional dyspepsia

BACKGROUND The role of autonomic dysfunction in patients with functional dyspepsia is not completely understood. AIMS 1. to prospectively assess abnormalities of autonomic function in patients with functional dyspepsia, 2. to assess whether autonomic dysfunction in these patients is associated with a. visceral hypersensitivity or b. delayed gastric emptying or c. severity of dyspeptic symptoms. PATIENTS A series of 28 patients with functional dyspepsia and 14 healthy volunteers without gastrointestinal symptoms were studied. METHODS All patients and controls were submitted to a battery of five standard cardiovascular autonomic reflex tests, dyspeptic questionnaire, gastric barostat tests and gastric emptying tests. RESULTS 1. Autonomic function tests showed that both sympathetic and parasympathetic scores of dyspeptic patients were significantly higher than in controls; 2. visceral hypersensitivity was confirmed in dyspeptics in response to proximal gastric distension, demonstrating lower pain threshold; 3. delayed gastric emptying occurred more frequently in patients with functional dyspepsia than in controls; 4. epigastric pain and epigastric burning were significantly more prevalent in patients with definite evidence of autonomic dysfunction; 5. No significant association was found between presence of autonomic dysfunction and presence of visceral hypersensitivity or presence of delayed gastric emptying in patients with functional dyspepsia. CONCLUSIONS We concluded that a possible role of autonomic dysfunction in eliciting dyspeptic symptoms could not be determined from alterations in visceral hypersensitivity or delayed gastric emptying. Autonomic dysfunction might not be the major explanation for symptoms associated with functional dyspepsia.

Effectiveness of Locoregional Therapy Before Living Donor Liver Transplantation in Patients With Hepatocellular Carcinoma Who Meet the Milan Criteria

BACKGROUND Many patients are diagnosed with hepatocellular carcinoma (HCC) within the Milan criteria. In Korea, these patients are preferentially treated with locoregional therapy (LRT) instead of living donor liver transplantation. We investigated the effectiveness of LRT in liver transplant recipients who met the Milan criteria at the time of HCC diagnosis and investigated risk factors for HCC recurrence. METHODS We retrospectively reviewed the medical records of patients diagnosed with HCC who met the Milan criteria between 2002 and 2008. RESULTS We performed 101 liver transplants for HCC during the study period. Seventy-one patients (70%) underwent pretransplant LRT. The disease-free survival rates at 1, 3, and 5 years in patients who received LRT were 96.6%, 93.1%, and 93.1%, and in those who did not receive LRT, 94.2%, 83.4%, and 83.4%, respectively. There were no differences between the 2 groups. Multivariate analysis showed that a low Model for End-Stage Liver Disease (MELD) score and microvascular invasion were independent predictors of HCC recurrence after transplantation. The MELD scores and rate of microvascular invasion were not statistically different in patients with or without previous LRT. CONCLUSION Pretransplant LRT for patients with HCC who met the Milan criteria at the time of diagnosis did not provide a clear benefit with respect to HCC recurrence after transplantation. If patients have suitable living donors, those who meet the Milan criteria should undergo a liver transplantation as soon as possible.

Non-alcoholic fatty liver diseases and risk of colorectal neoplasia.

Non‐alcoholic fatty liver disease (NAFLD) is associated with colorectal neoplasia. Yet, NAFLD ranges from simple steatosis to steatohepatitis with advanced fibrosis.

Clinical significance of core gene mutations during the course of genotype C chronic hepatitis B virus infection.

BACKGROUND/AIMS The aim of this study was to investigate the association of HBV core gene mutations with disease severity in HBV-infected patients. METHODOLOGY We included 249 genotype C HBV infected patients: 39 asymptomatic carriers (AC), 68 with chronic hepatitis (CH), 75 with liver cirrhosis (LC), and 67 with HCC. HBV DNA was extracted from patient sera and the HBV core gene was analyzed by PCR and sequencing. RESULTS The overall frequency of a codon substitution, which was caused by a missense mutation in the HBV core region, was 4.5±9.0/patient. The codon substitutions were predominantly clustered in the mid-core regions; 22.3% of codon substitutions were found in codons 13, 87, 97 and 130. The rate of substitution for codon 13 was higher in CH and LC than in AC. For codons 87 and 130, AC had a lower substitution rate compared to the other 3 groups. The substitution rate for codon 97 was higher in CH and HCC than in AC. CONCLUSIONS Core gene mutations were frequently detected during the course of chronic HBV infection, and some mutational hot spots were correlated with severe forms of disease. Thus, these mutations might play a pathophysiological role in the disease progression in HBV infected patients.

Ribavirin dose and treatment outcome of Korean patients with genotype 1 chronic hepatitis C.

BACKGROUND/AIMS The current recommendation of ribavirin dose for the treatment of chronic hepatitis C is based on study results of Western patients, and might not be optimal for Korean patients because of different body frames. METHODOLOGY A total of 163 treatment-naive genotype 1 chronic hepatitis C patients who received combination therapy with pegylated interferon a-2a and ribavirin were reviewed. RESULTS Under current ribavirin dosing, only 49% of patients started therapy with ribavirin dose of 13-15mg/kg (targeted dose), while 45% and 6% of patients started therapy with ribavirin dose =16mg/kg and <13mg/kg, respectively. Patients who started therapy with higher ribavirin dose experienced more ribavirin dose modification during treatment (55%, 31% and 11% for ribavirin dose of =16mg/kg, 13-15mg/kg and <13mg/kg, respectively, p=0.002). The sustained virological response (SVR) rate was 66%, 63% and 56% for ribavirin dose of =16mg/kg, 13-15mg/kg and <13mg/kg, respectively (p=0.775). CONCLUSIONS A certain proportion of Korean patients started therapy with a higher than targeted ribavirin dose, which resulted in more ribavirin dose modifications without definite additional benefit in achieving SVR. Therefore, the ribavirin dosing regimen might need to be reassessed.