Efficacy of acotiamide on postprandial distress syndrome and epigastric pain syndrome depending on the estimated gastric acid secretion level.

BACKGROUND/AIMS: Gastric acid secretion is suspected to be a pivotal contributor to the pathogenesis of functional dyspepsia. The present study investigates the potential association of the gastric acid secretion estimated by measuring serum pepsinogen with therapeutic responsiveness to the prokinetic drug acotiamide. METHODS: Dyspeptic patients consulting participating clinics from October 2017 to March 2019 were prospectively enrolled in the study. The dyspeptic symptoms were classified into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). Gastric acid secretion levels were estimated by the Helicobacter pylori infection status and serum pepsinogen using established criteria and classified into hypo-, normo-, and hyper-secretion. Each patient was then administered 100 mg acotiamide thrice daily for 4 weeks, and the response rate to the treatment was evaluated using the overall treatment efficacy scale. RESULTS: Of the 86 enrolled patients, 56 (65.1%) and 26 (30.2%) were classified into PDS and EPS, respectively. The estimated gastric acid secretion was not significantly different between PDS and EPS. The response rates were 66.0% for PDS and 73.1% for EPS, showing no significant difference. While the response rates were stable, ranging from 61.0% to 75.0% regardless of the estimated gastric acid secretion level among subjects with PDF, the rates were significantly lower in hyper-secretors than in non-hyper-secretors among subjects with EPS (42.0% vs 83.0%, P = 0.046). CONCLUSION: Although acotiamide is effective for treating EPS as well as PDS overall, the efficacy is somewhat limited in EPS with gastric acid hypersecretion, with gastric acid suppressants, such as proton pump inhibitors, being more suitable.

Distribution of hepatitis B virus genotypes among patients with chronic infection in Japan shifting toward an increase of genotype A.

Acute hepatitis B virus (HBV) infection has been increasing through promiscuous sexual contacts, and HBV genotype A (HBV/A) is frequent in patients with acute hepatitis B (AHB) in Japan. To compare the geographic distribution of HBV genotypes in patients with chronic hepatitis B (CHB) in Japan between 2005 and 2006 and between 2000 and 2001, with special attention to changes in the proportion of HBV/A, a cohort study was performed to survey changes in genotypes of CHB patients at 16 hospitals throughout Japan. Furthermore, we investigated the clinical characteristics of each genotype and examined the genomic characteristics of HBV/A isolates by molecular evolutionary analyses. Of the 1,271 patients, 3.5%, 14.1%, and 82.3% were infected with HBV/A, -B, and -C, respectively. In comparison with our previous survey during 2000 and 2001, HBV/A was twice as frequent (3.5% versus 1.7%; P = 0.02). The mean age was lower in the patients with HBV/A than in those with HBV/B or -C. Based on phylogenetic analyses of 11 full-length genomes and 29 pre-S2/S region sequences from patients, HBV/A isolates were imported from Europe and the United States, as well as the Philippines and India. They clustered with HBV/A from AHB patients and have spread throughout Japan. HBV/A has been increasing in CHB patients in Japan as a consequence of AHB spreading in the younger generation through promiscuous sexual contacts, aided by a tendency of HBV/A to induce chronic hepatitis. The spread of HBV/A infection in Japan should be prevented by universal vaccination programs.

Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1.

BACKGROUND: The present study explored the treatment outcome of daclatasvir (DCV) and asunaprevir (ASV) therapy combining oral direct-acting antiviral agents (DAAs) for chronic hepatitis C (HCV) including liver cirrhosis according to resistance-associated variants (RAVs) in NS3/NS5A region. METHODS: Overall, 641 patients enrolled in Japan with HCV-1b received DCV and ASV for 24 weeks. Baseline drug-resistant mutations L31F/I/M/V, Q54H, P58S, A92K, and Y93H in the HCV NS5A region and V36A, T54A/S, Q80K/L/R, R155K/T/Q, A156S/V/T, and D168A/E/H/T/V in the HCV NS3/4A region were assessed by direct sequencing. RESULTS: Overall, 86.9 % (543/625) of patients had SVR12, which was significantly higher in NS5A 93Y (wild) (88.3 %) compared with NS5A 93H at baseline (48.0 %), indicating the SVR12 rate was significantly lower in patients with 93H mutations. Additionally, 66.7 % (18/27) of patients with prior triple therapy including simeprevir (SMV) failure had virological failure. The virological failure rate of DCV/ASV therapy after SMV failure was significantly higher in those with preexisting NS3/4A 168 substitutions compared with without substitutions at baseline [84.2 % (16/19) vs. 28.6 % (2/7), p = 0.014]. The number of patients with multiple RAVs or deletions in NS5A increased from 0 to 85 % in failed patients. Alanine aminotransferase elevation was a frequent adverse event causing discontinuation of DCV/ASV therapy, although 87.5 % (14/16) patients achieved SVR12, subsequently. CONCLUSIONS: History of SMV therapy and pre-existing NS5A Y93H were associated with virological failure of DCV/ASV therapy, resulting in the emergence of multiple RAVs. Patients with RAVs at baseline should be assessed to optimize future DAA therapies.

Spatial and chronological differences in hepatitis B virus genotypes from patients with acute hepatitis B in Japan.

Genotypes of hepatitis B virus (HBV) were determined in 485 patients with acute hepatitis B from all over Japan. They were A in 92 (19%), Ba in 26 (5%), Bj in 32 (7%), C in 330 (68%) and D in 5 (1%). Sexual contacts were the main route of transmission in them. Overall, HBV persisted in only 5 of the 464 (1%) followed patients. Genotypes C accounted for more than 68% in northern as well as southern areas, contrasting with genotype A accounting for 34% in and around the Metropolitan areas. During 24 years from 1982 to 2005, genotype A increased from 5% to 33%, while genotype B gradually decreased from 26% to 8%. Fulminant hepatitis was significantly more frequent in infection with genotype Bj (41%) than those with the other genotypes (p<0.01). The core-promoter double mutation (T1762/A1764) and precore stop-codon mutation (A1896) were more frequent in patients with fulminant than acute self-limited hepatitis (57% versus 15% and 58% versus 10%, respectively, p<0.01 for both). In conclusion, genotype A distributes unevenly over Japan, prevails in younger patients through sexual transmission and has increased with years. Furthermore, fulminant outcome was more frequent in patients with genotype Bj than those with the other genotypes.

Recommendation of lamivudine-to-entecavir switching treatment in chronic hepatitis B responders: Randomized controlled trial.

AIM: In the 2007-2008 guidelines of the study group (Ministry of Health, Labor and Welfare of Japan), lamivudine (LAM)-continuous treatment was recommended in patients treated with LAM for more than 3 years who maintained hepatitis B virus (HBV) DNA less than 2.6 log copies/mL, because in these patients LAM resistance might exist and switching treatment to entecavir (ETV) might cause ETV resistance. However, there was no evidence on whether switching treatment to ETV- or LAM-continuous treatment was better in those patients. In the present study, we performed a randomized controlled trial of LAM-to-ETV switching treatment. METHODS: Twenty-seven patients treated with LAM for more than 3 years whose HBV DNA levels were less than 2.6 log copies/mL were enrolled and randomly divided into two groups, LAM-continued group or switching to ETV group. Then, we examined incidence of virological breakthrough (VBT) and breakthrough hepatitis (BTH) in each group. RESULTS: There was no BTH in any of the patients. VBT was observed in six patients of the LAM group (6/15, 40%), and no patient of the ETV group (0/11, 0%) (P = 0.02). The differences of the proportion of cumulated VBT using a log-rank test with Kaplan-Meier analysis were significant between the LAM and ETV groups (P = 0.025). CONCLUSION: In patients treated with LAM for more than 3 years maintaining HBV DNA less than 2.6 log copies/mL, switching treatment to ETV is recommended at least during the 2 years' follow-up period.

Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection.

The outcome of acute hepatitis B virus (HBV) infection is variable, influenced by host and viral factors. From 1982 through 2004, 301 patients with acute HBV infection entered a multi-center cross-sectional study in Japan. Patients with fulminant hepatitis (n = 40) were older (44.7 +/- 16.3 vs. 36.0 +/- 14.3 years, P < .0017), less predominantly male (43% vs. 71%, P = .0005), less positive for hepatitis B e antigen (HBeAg) (23% vs. 60%, P < .0001), less infected with subgenotype Ae (0% vs. 13%, P < .05), and more frequently with Bj (30% vs. 4%, P < .0001) than those with acute self-limited hepatitis (n = 261). Precore (G1896A) and core-promoter (A1762T/G1764A) mutations were more frequent in patients with fulminant than acute self-limited hepatitis (53% vs. 9% and 50% vs. 17%, P < .0001 for both). HBV infection persisted in only three (1%) patients, and they represented 2 of the 23 infected with Ae and 1 of the 187 with the other subgenotypes (9% vs. 0.5%, P = .032); none of them received antiviral therapy. In multivariate analysis, age 34 years or older, Bj, HBeAg-negative, total bilirubin 10.0 mg/dL or greater, and G1896A mutation were independently associated with the fulminant outcome. In in vitro transfection experiments, the replication of Bj clone was markedly enhanced by introducing either G1896A or A1762T/G1764A mutation. In conclusion, persistence of HBV was rare (1%) and associated with Ae, whereas fulminant hepatitis was frequent (13%) and associated with Bj and lack of HBeAg as well as high replication due to precore mutation in patients with acute HBV infection.

Influence of hepatitis B virus genotypes on the development of preS deletions and advanced liver disease.

Hepatitis B virus (HBV) mutants with deletions in the preS region have not been evaluated for association with viral genotypes. In a case-control study, HBV DNA samples collected from 80 each of carriers infected with HBV genotype B or C were examined for preS deletions. PreS deletion mutants were found in a total of 37 of 160 (23%) HBV carriers. Carriers with preS deletion mutants were older (56.0 +/- 12.7 vs 49.3 +/- 16.9 years, P < 0.05), were infected more frequently with HBV genotype C (84% vs 40%, P < 0.05), and had more advanced disease, such as liver cirrhosis and hepatocellular carcinoma (54% vs 31%; P < 0.05), than did those without such mutants. In a multivariate analysis, genotype C (odds ratio [OR] = 9.3, P < 0.001) and advanced liver disease (OR = 3.1, P < 0.01) were the most significant variables in association with preS deletions. A direct repeat sequence (TCAGG) was found at the start or at the end of preS1 deletions in 6 of the 20 (30%) cases examined, and preS2 deletions in these cases were clustered over the 5'-terminal half of this region. These results indicate that the development of preS deletion mutants depends on HBV genotypes and that it may be associated with progressive liver disease.