Four weeks of off-treatment follow-up is sufficient to determine virologic responses at off-treatment week 12 in patients with hepatitis C virus infection receiving fixed-dose pangenotypic direct-acting antivirals.

Early confirmation of sustained virologic response (SVR) or viral relapse after direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection is essential based on public health perspectives, particularly for patients with high risk of nonadherence to posttreatment follow-ups. A total of 1011 patients who achieved end-of-treatment virologic response, including 526 receiving fixed-dose pangenotypic DAAs, and 485 receiving other types of DAAs, who had available off-treatment weeks 4 and 12 serum HCV RNA data to confirm SVR at off-treatment week 12 (SVR12) or viral relapse were included. The positive predictive value (PPV) and negative predictive value (NPV) of SVR4 to predict patients with SVR12 or viral relapse were reported. Furthermore, we analyzed the proportion of concordance between SVR12 and SVR24 in 943 patients with available SVR24 data. The PPV and NPV of SVR4 to predict SVR12 were 98.5% (95% confidence interval [CI]: 98.0-98.9) and 100% (95% CI: 66.4-100) in the entire population. The PPV of SVR4 to predict SVR12 in patients receiving fixed-dose pangenotypic DAAs was higher than those receiving other types of DAAs (99.8% [95% CI: 98.9-100] vs. 97.1% [95% CI: 96.2-97.8], p < 0.001). The NPVs of SVR4 to predict viral relapse were 100%, regardless of the type of DAAs. Moreover, the concordance between SVR12 and SVR24 was 100%. In conclusion, an off-treatment week 4 serum HCV RNA testing is sufficient to provide an excellent prediction power of SVR or viral relapse at off-treatment week 12 among patients with HCV who are treated with fixed-dose pangenotypic DAAs.

Molecular testing-guided therapy versus susceptibility testing-guided therapy in first-line and third-line Helicobacter pylori eradication: two multicentre, open-label, randomised controlled, non-inferiority trials.

BACKGROUND: Helicobacter pylori infection is an important causal factor of gastric cancer and peptic ulcer disease and is associated with immune thrombocytopenic purpura and functional dyspepsia. In H pylori strains, point mutations in the 23S rRNA and gyrA genes are associated with clarithromycin resistance and levofloxacin resistance, respectively. Whether the efficacy of molecular testing-guided therapy is non-inferior to that of susceptibility testing-guided therapy for H pylori eradication is unclear. Therefore, we aimed to compare the efficacy and safety of molecular testing-guided therapy and traditional culture-based susceptibility testing-guided therapy in first-line and third-line treatment of H pylori infection. METHODS: We did two multicentre, open-label randomised trials in Taiwan. In trial 1 (done at seven hospitals), treatment-naive individuals infected with H pylori who were aged 20 years or older were eligible for study inclusion. In trial 2 (done at six hospitals), individuals aged 20 years or older who failed treatment after two or more eradication therapies for H pylori infection were eligible for enrolment. Eligible patients were randomly assigned (1:1) to receive either molecular testing-guided therapy or susceptibility testing-guided therapy. The randomisation sequence was generated by computer using permuted block randomisation with a block size of 4. All investigators were masked to the randomisation sequence. Clarithromycin and levofloxacin resistance were determined by agar dilution test for measuring minimum inhibitory concentrations in the susceptibility testing-guided therapy group, and by PCR and direct sequencing for detection of 23S rRNA and gyrA mutations in the molecular testing-guided therapy group. Study participants received clarithromycin sequential therapy, levofloxacin sequential therapy, or bismuth quadruple therapy according to the resistance status to clarithromycin and levofloxacin. The 13C-urease breath test was used to determine the status of H pylori infection at least 6 weeks after eradication therapy. The primary outcome was the eradication rate by intention-to-treat analysis. The frequency of adverse effects was analysed in patients with available data. The prespecified margins for non-inferiority were 5% for trial 1 and 10% for trial 2. The trials are ongoing for post-eradication follow-up and registered with ClinicalTrials.gov, NCT03556254 for trial 1, and NCT03555526 for trial 2. FINDINGS: Between March 28, 2018, and April 23, 2021, 560 eligible treatment-naive patients with H pylori infection were recruited and randomly assigned to the molecular testing-guided therapy group or the susceptibility testing-guided therapy group in trial 1. Between Dec 28, 2017, and Oct 27, 2020, 320 eligible patients with refractory H pylori infection were recruited and randomly assigned to the molecular testing-guided therapy group or the susceptibility testing-guided therapy group in trial 2. 272 men and 288 women were recruited for trial 1, and 98 men and 222 women were recruited for trial 2. In first-line H pylori treatment, infection was eradicated in 241 (86%, 95% CI 82-90) of 280 patients in the molecular testing-guided therapy group and 243 (87%, 83-91) of 280 patients in the susceptibility testing-guided therapy group by intention-to-treat analysis (p=0·81). In third-line H pylori treatment, infection was eradicated in 141 (88%, 83-93) of 160 patients in the molecular testing-guided therapy group and 139 (87%, 82-92) of 160 patients in the susceptibility testing-guided therapy group by intention-to-treat analysis (p=0·74). The difference in the eradication rate between the molecular testing-guided therapy group and the susceptibility testing-guided therapy group was -0·7% (95% CI -6·4 to 5·0; non-inferiority p=0·071) in trial 1 and 1·3% (-6·0 to 8·5; non-inferiority p=0·0018 in trial 2 by intention-to-treat analysis. We found no difference in adverse effects across both treatment groups in trial 1 and trial 2. INTERPRETATION: Molecular testing-guided therapy was similar to susceptibility testing-guided therapy in first-line therapy and non-inferior to susceptibility testing guided therapy in third-line treatment of H pylori infection, supporting the use of molecular testing-guided therapy for H pylori eradication. FUNDING: Ministry of Science and Technology of Taiwan, and Centre of Precision Medicine of the Higher Education Sprout Project by the Ministry of Education of Taiwan.

Second-line levofloxacin-based quadruple therapy versus bismuth-based quadruple therapy for Helicobacter pylori eradication and long-term changes to the gut microbiota and antibiotic resistome: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Levofloxacin-based therapy or bismuth-based quadruple therapy are the recommended second-line regimens for Helicobacter pylori eradication after failure of clarithromycin-based therapy. However, resistance to levofloxacin has increased in the past decade. Furthermore, little is known about the long-term effects of H pylori eradication on the antibiotic resistome. In this study, we compared these second-line eradication therapies for efficacy, tolerability, and short-term and long-term effects on the gut microbiota, antibiotic resistome, and metabolic parameters. METHODS: We did a multicentre, open-label, parallel group, randomised controlled trial at eight hospitals in Taiwan. Adult patients (age ≥20 years) with persistent H pylori infection after first-line clarithromycin-based therapy were randomly assigned (1:1, permuted block sizes of four) to receive levofloxacin-based sequential quadruple therapy for 14 days (EAML14; esomeprazole 40 mg and amoxicillin 1 g for 7 days, followed by esomeprazole 40 mg, metronidazole 500 mg, and levofloxacin 250 mg for 7 days, all twice-daily) or bismuth-based quadruple therapy for 10 days (BQ10; esomeprazole 40 mg twice daily, bismuth tripotassium dicitrate 300 mg four times a day, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day). All investigators were masked to the randomisation sequence. The primary endpoint was H pylori eradication rate measured by 13C urea breath test 6 weeks after second-line treatment according to both intention-to-treat (ITT) and per-protocol analysis. The microbiota composition and antibiotic resistome of faecal samples collected at baseline (before treatment) and at 2 weeks, 8 weeks, and 1 year after eradication therapy was profiled by shotgun metagenomic sequencing and 16S rRNA gene sequencing. The frequency of adverse effects and changes in the gut microbiota and antibiotic resistome were assessed in all participants with available data. The trial is complete and registered with ClinicalTrails.gov, NCT03148366. FINDINGS: Between Feb 25, 2015, and Dec 11, 2020, 560 patients were randomly assigned to receive EAML14 or BQ10 (n=280 per group; 261 [47%] men and 299 [53%] women). Mean age was 55·9 years (SD 12·7) in the EAML14 group and 54·9 years (12·3) in the BQ10 group. Eradication of H pylori was achieved in 246 (88%) of 280 participants in the EAML14 group and 245 (88%) of 280 in the BQ10 group according to ITT analysis (risk difference -0·4%, 95% CI -5·8 to 5·1; p=0·90). In the per-protocol analysis, 246 (90%) of 273 participants in the EAML14 group and 245 (93%) of 264 participants in the BQ10 group achieved H pylori eradication (risk difference 2·7%, 95% CI -0·2 to 7·4; p=0·27). Transient perturbation of faecal microbiota diversity at week 2 was largely restored to basal state 1 year after EAML14 or BQ10. Diversity recovery was slower with BQ10, and recovery in species abundance was partial after both therapies. On shotgun sequencing, we observed significant increases in total resistome after EAML14 (p=0·0002) and BQ10 (p=4·3 × 10-10) at week 2, which were restored to pretreatment level by week 8. The resistance rates of Escherichia coli and Klebsiella pneumonia to levofloxacin, ciprofloxacin, ampicillin (ampicillin-sulbactam for K pneumonia), and various cephalosporins were significantly increased in the EAML14 group compared with in the BQ10 group at week 2, which were restored to pretreatment levels and showed no significant differences at week 8 and 1 year. The frequency of any adverse effects was significantly higher after BQ10 therapy (211 [77%] of 273 participants) than after EAML14 therapy (134 [48%] of 277; p<0·0001). INTERPRETATION: We found no evidence of superiority between levofloxacin-based quadruple therapy and bismuth-based quadruple therapy in the second-line treatment of H pylori infection. The transient increase in the antibiotic resistome and perturbation of faecal microbiota diversity were largely restored to pretreatment state from 2 months to 1 year after eradication therapy. FUNDING: The Ministry of Science and Technology of Taiwan, the Ministry of Health and Welfare of Taiwan, National Taiwan University Hospital, Taipei Veteran General Hospital, and the Australian Federal Government through the St George and Sutherland Medical Research Foundation. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Declining trends of prevalence of Helicobacter pylori infection and incidence of gastric cancer in Taiwan: An updated cross-sectional survey and meta-analysis.

BACKGROUND: We aimed to assess the latest prevalence and secular trend of Helicobacter pylori infection and its association with the incidence and mortality of gastric cancer in Taiwan. MATERIALS AND METHODS: Adults naive to H. pylori eradication received 13 C-urea breath test (13 C-UBT), H. pylori stool antigen test, and serology test during 2019-2020 in this prospective screening program. Children and adolescent aged between 7 and 19 years received 13 C-UBT for H. pylori screening. We also conducted a systematic review and meta-analysis to assess the secular trend of prevalence of H. pylori from 1990 to 2020 in Taiwan. The secular trends of age-standardized incidence and mortality of gastric cancer were obtained from the Taiwan Cancer Registry. RESULTS: A total of 1494 participants were enrolled, including 294 children or adolescents and 1200 adults. The overall prevalence of active H. pylori infection by 13 C-UBT was 26.6% (397/1494), which was 30.8% in adults and 9.5% in adolescents/children. The age-standardized prevalence of active H. pylori infection was 32.3% in adults after adjustment of the population structure in Taiwan. Of the 29 studies including 38,597 subjects eligible for the meta-analysis, the pooled prevalence of H. pylori infection decreased from 63.8% (95% CI: 55.9%-71%) in 1990-2000 to 28.2% (95% CI:21.8%-35.6%) in 2016-2020. The age-standardized incidence and mortality of gastric cancer have also declined from 15.2 to 10.75 per 100,000, respectively, in 1999 to 9.29 and 5.4 per 100,000, respectively, in 2019. CONCLUSIONS: The prevalence of H. pylori infection has declined in Taiwan, which correlates with the declining trends of age-standardized incidence and mortality of gastric cancer in Taiwan.

Microelimination of Chronic Hepatitis C by Universal Screening Plus Direct-Acting Antivirals for Incarcerated Persons in Taiwan.

BACKGROUND: Incarcerated persons are a special population with higher hepatitis C virus (HCV) prevalence and should be prioritized for microelimination. In this study, we investigate the seroprevalence and evaluate the effectiveness and safety of direct-acting antiviral (DAA) therapy in custodial settings. METHODS: Incarcerated persons in Yunlin Prison were recruited to receive anti-HCV antibody screening. Patients with positive HCV ribonucleic acid (RNA) were treated with glecaprevir/pibrentasvir (GLE/PIB) in our special chronic hepatitis C (CHC) clinic in prison. The primary endpoint was sustained virologic response at week 12 off therapy (SVR12). RESULTS: A total of 1402 incarcerated persons were invited to anti-HCV screening and 824 (58.7%) accepted. The prevalence of anti-HCV positivity was 33.5% (276 of 824), and the viremic rate (detectable HCV RNA) was 69.2% (191 of 276). According to fibrosis index based on 4 factors, patients with F3 stage were 6 (3.1%), but none met the criteria of F4 stage. However, 6 (3.1%) had liver cirrhosis with splenomegaly, confirmed by findings of ultrasonography. The median log10 HCV RNA level at baseline was 6.235 (2.394-7.403). Genotype (GT) 6 was predominant (39.3%), followed by GT 1a (22.0%) and 1b (14.1%). Mixed GT HCV infection accounted for 3.6% of total infections. In total, 165 patients received GLE/PIB therapy. The overall SVR12 rates were 100%. CONCLUSIONS: Direct-acting antiviral therapy is highly effective and safe for incarcerated patients in Taiwan. Our special prison-based CHC clinic, linking universal screening to medical care, can serve as a model for microelimination of HCV in custodial settings.

Comparison of the effect of clarithromycin triple therapy with or without N-acetylcysteine in the eradication of Helicobacter pylori: a randomized controlled trial.

BACKGROUND: Whether adjunctive N-acetylcysteine (NAC) may improve the efficacy of triple therapy in the first-line treatment of Helicobacter pylori infection remains unknown. Our aim was to compare the efficacy of 14-day triple therapy with or without NAC for the first-line treatment of H. pylori. MATERIAL AND METHODS: Between 1 January 2014 and 30 June 2018, 680 patients with H. pylori infection naïve to treatment were enrolled in this multicenter, open-label, randomized trial. Patients were randomly assigned to receive triple therapy with NAC [NAC-T14, dexlansoprazole 60 mg four times daily (q.d.); amoxicillin 1 g twice daily (b.i.d.), clarithromycin 500 mg b.i.d., NAC 600 mg b.i.d.] for 14 days, or triple therapy alone (T14, dexlansoprazole 60 mg q.d.; amoxicillin 1 g b.i.d., clarithromycin 500 mg b.i.d.) for 14 days. Our primary outcome was the eradication rates by intention to treat (ITT). Antibiotic resistance and CYP2C19 gene polymorphism were determined. RESULTS: The ITT analysis demonstrated H. pylori eradication rates in NAC-T14 and T14 were 81.7% [276/338, 95% confidence interval (CI): 77.5-85.8%] and 84.3% (285/338, 95% CI 80.4-88.2%), respectively. In 646 participants who adhered to their assigned therapy, the eradication rates were 85.7% and 88.0% with NAC-T14 and T14 therapies, respectively. There were no differences in compliance or adverse effects. The eradication rates in subjects with clarithromycin-resistant, amoxicillin-resistant, or either clarithromycin/amoxicillin resistant strains were 45.2%, 57.9%, and 52.2%, respectively, for NAC-T14, and were 66.7%, 76.9%, and 70.0%, respectively, for T14. The efficacy of NAC-T14 and T14 was not affected by CYP2C19 polymorphism. CONCLUSION: Add-on NAC to triple therapy was not superior to triple therapy alone for first-line H. pylori eradication [ClinicalTrials.gov identifier: NCT02249546].

Accuracy of rapid Helicobacter pylori antigen tests for the surveillance of the updated prevalence of H. pylori in Taiwan.

BACKGROUND: The updated prevalence of Helicobacter pylori (H. pylori) is lacking in Taiwan. We aimed to assess the accuracy of Vstrip® H. pylori Stool Antigen Rapid Test (Vstrip®HpSA) in the detection and surveillance of the updated prevalence of H. pylori in Taiwan. METHODS: A total of 347 adult subjects including 152 volunteers and 195 symptomatic patients were recruited. Stool samples were collected for detection of H. pylori using Vstrip® HpSA, ImmunoCard STAT!® HpSA and Premier Platinum HpSA® PLUS. All subjects who have completed the stool sample collections were included in the ITT analysis. The sensitivity, specificity, and accuracy of Vstrip® HpSA were calculated compared to gold standard test with 13C-Urea breath test. RESULTS: The un-adjusted prevalence of H. pylori infection was 22.5% (95% CI: 18.3-27%) in 2018. The age-standardized prevalence of H. pylori was 21.8% in asymptomatic adults in Taiwan. The sensitivity, specificity, and accuracy of the Vstrip® HpSA, and ImmunoCard STAT!® HpSA tests were 91% (95% CI: 82-96%) versus 76.9% (95% CI: 66-86%), 97% (95% CI: 94.1-98.6%) versus 97% (95% CI: 94.1-98.6%), and 95.7% (95% CI: 92-97%) versus 92.5% (95% CI: 89-95%), respectively. CONCLUSION: The age-standardized prevalence of H. pylori infection in Taiwan was 21.8% in asymptomatic adults in 2018. The Vstrip® HpSA had equivalent performance as the ImmunoCard STAT!® HpSA, and can be used in future mass screening of H. pylori infection for gastric cancer prevention.

Long-term changes of gut microbiota, antibiotic resistance, and metabolic parameters after Helicobacter pylori eradication: a multicentre, open-label, randomised trial.

BACKGROUND: In first-line treatment of Helicobacter pylori, we have previously shown that the eradication frequency was 83·7% (95% CI 80·4-86·6) for triple therapy for 14 days (T14; lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg, all given twice daily), 85·9% (82·7-88·6) for concomitant therapy for 10 days (C10; lansoprazole 30 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, all given twice daily), and 90·4% (87·6-92·6) for bismuth quadruple therapy for 10 days (BQ10; bismuth tripotassium dicitrate 300 mg four times a day, lansoprazole 30 mg twice daily, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day). In this follow-up study, we assess short-term and long-term effects of these therapies on the gut microbiota, antibiotic resistance, and metabolic parameters. METHODS: This was a multicentre, open-label, randomised trial done at nine medical centres in Taiwan. Adult patients (>20 years) with documented H pylori infection were randomly assigned (1:1:1, with block sizes of six) to receive T14, C10, or BQ10. We assessed long-term outcomes (reinfection frequency, changes in the gut microbiota, antibiotic resistance, and metabolic parameters) in patients with available data, excluding all protocol violators and those with unknown post-treatment H pylori status. Faecal samples were collected before treatment and 2 weeks, 2 months, and at least 1 year after eradication therapy. Amplification of the V3 and V4 hypervariable regions of the 16S rRNA was done followed by high-throughput sequencing. Susceptibility testing for faecal Escherichia coli and Klebsiella pneumoniae was done. This trial is complete and registered with ClinicalTrials.gov, NCT01906879. FINDINGS: Between July 17, 2013, and April 20, 2016, 1620 participants were randomly assigned to the three treatment groups (540 [33%] per group). 1214 (75%) attended 1-year follow-up and are included in this analysis. Compared with baseline, alpha diversity was significantly reduced 2 weeks after T14 (p=0·0002), C10 (p<0·0001), and BQ10 (p<0·0001) treatment. Beta diversity was also significantly altered 2 weeks after T14 (p=0·0010), C10 (p=0·0001), and BQ10 (p=0·0001). Alpha diversity and beta diversity were restored at week 8 (p=0·14 and p=0·918, respectively) and 1 year (p=0·14 and p=0·918) after T14, but were not fully recovered at week 8 and after 1 year in patients treated with C10 (p=0·0001 and p=0·013 at week 8; p=0·019 and p=0·064 at 1 year) and BQ10 (p<0·0001 and p=0·0002; p=0·001 and p=0·029). A transient increase at week 2 after T14 and C10 of the resistance rates of E coli to ampicillin-sulbactam (12% [15/127] to 66% [38/58] for T14, 7% [10/135] to 64% [28/44] for C10), cefazolin (13% [16/127] to 43% [25/58] for T14, 10% [13/135] to 41% [18/44] for C10), cefmetazole (8% [10/127] to 26% [15/58] for T14, 4% [5/135] to 18% [8/44] for C10), levofloxacin (8% [10/127] to 35% [20/58] for T14, 7% [10/135] to 32% [14/44] for C10), gentamicin (13% [19/146] to 47% [27/58] for T14, 15% [22/149] to 45% [20/44] for C10), and trimethoprim-sulfamethoxazole (33% [48/146] to 86% [50/58] for T14, 28% [42/148] to 86% [38/44] for C10; p<0·05 in paired samples in the above analyses) returned to basal state at week 8 and after 1 year. Although bodyweight and body-mass index slightly increased, there were significant improvements in metabolic parameters, with a decrease in insulin resistance, triglycerides, and LDL and an increase in HDL. Overall, there was no significant change in the prevalence of metabolic syndrome at week 8 and 1 year after T14, C10, and BQ10. INTERPRETATION: Eradication of H pylori infection has minimal disruption of the microbiota, no effect on antibiotic resistance of E coli, and some positive effects on metabolic parameters. Collectively, these results lend support to the long-term safety of H pylori eradication therapy. FUNDING: National Taiwan University Hospital and Ministry of Science and Technology of Taiwan.

Real-world effectiveness and safety of glecaprevir/pibrentasvir in Asian patients with chronic hepatitis C.

BACKGROUND: Glecaprevir/pibrentasvir (GLE/PIB) is a pangenotypic direct-acting antiviral agent for the treatment of chronic hepatitis C virus (HCV) infection. Real-world data of GLE/PIB in Asian patients other than Japanese are limited. We thus investigated the effectiveness and safety profile of GLE/PIB in Taiwanese patients with chronic hepatitis C (CHC). METHODS: CHC patients who received 8, 12, or 16 weeks of GLE/PIB between August and October of 2018 were consecutively enrolled. The treatment duration was determined according to drug label. The hepatic fibrosis was staged according to liver histology, transient elastography, fibrosis index based on 4 factors (FIB-4), or findings of ultrasonography/endoscopy. The primary endpoint was sustained virological response at week 12 off therapy (SVR12). The safety profiles were also assessed. RESULTS: A total of 110 CHC patients with 51% of males were enrolled. The median age was 70 years. A majority (82%) of patients were infected with HCV genotype 2. Forty-six (42%) and 64 (58%) patients had advanced hepatic fibrosis and compensated cirrhosis, respectively. Forty-five (41%) non-cirrhotic patients were treated for 8 weeks. The overall SVR12 rates were 100%, regardless of baseline clinical characteristics. The common adverse events (AEs) were pruritus (12%), anorexia (6%), and fatigue (5%). Nine (8%) serious AEs unrelated to GLE/PIB occurred. Three (2%) patients had Grade 3 elevation of total bilirubin level. None had premature treatment termination, hepatic decompensation, or death. CONCLUSION: Interferon-free GLE/PIB regimen is highly effective and safe for Asian chronic hepatitis C patients with advanced hepatic fibrosis or compensated cirrhosis.

Efficacies of Genotypic Resistance-Guided vs Empirical Therapy for Refractory Helicobacter pylori Infection.

BACKGROUND & AIMS: We aimed to compare the efficacy of genotypic resistance-guided therapy vs empirical therapy for eradication of refractory Helicobacter pylori infection in randomized controlled trials. METHODS: We performed 2 multicenter, open-label trials of patients with H pylori infection (20 years or older) failed by 2 or more previous treatment regimens, from October 2012 through September 2017 in Taiwan. The patients were randomly assigned to groups given genotypic resistance-guided therapy for 14 days (n = 21 in trial 1, n = 205 in trial 2) or empirical therapy according to medication history for 14 days (n = 20 in trial 1, n = 205 in trial 2). Patients received sequential therapy containing esomeprazole and amoxicillin for the first 7 days, followed by esomeprazole and metronidazole, with levofloxacin, clarithromycin, or tetracycline (doxycycline in trial 1, tetracycline in trial 2) for another 7 days (all given twice daily) based on genotype markers of resistance determined from gastric biopsy specimens (group A) or empirical therapy according to medication history. Resistance-associated mutations in 23S ribosomal RNA or gyrase A were identified by polymerase chain reaction with direct sequencing. Eradication status was determined by 13C-urea breath test. The primary outcome was eradication rate. RESULTS: H pylori infection was eradicated in 17 of 21 (81%) patients receiving genotype resistance-guided therapy and 12 of 20 (60%) patients receiving empirical therapy (P = .181) in trial 1. This trial was terminated ahead of schedule due to the low rate of eradication in patients given doxycycline sequential therapy (15 of 26 [57.7%]). In trial 2, H pylori infection was eradicated in 160 of 205 (78%) patients receiving genotype resistance-guided therapy and 148 of 205 (72.2%) patients receiving empirical therapy (P = .170), according to intent to treat analysis. The frequencies of adverse effects and compliance did not differ significantly between groups. CONCLUSIONS: Properly designed empirical therapy, based on medication history, is an acceptable alternative to genotypic resistance-guided therapy for eradication of refractory H pylori infection after consideration of accessibility, cost, and patient preference. ClinicalTrials.gov ID: NCT01725906.

14 day sequential therapy versus 10 day bismuth quadruple therapy containing high-dose esomeprazole in the first-line and second-line treatment of Helicobacter pylori: a multicentre, non-inferiority, randomized trial.

Background: Whether extending the treatment length and the use of high-dose esomeprazole may optimize the efficacy of Helicobacter pylori eradication remains unknown. Objectives: To compare the efficacy and tolerability of optimized 14 day sequential therapy and 10 day bismuth quadruple therapy containing high-dose esomeprazole in first-line therapy. Methods: We recruited 620 adult patients (≥20 years of age) with H. pylori infection naive to treatment in this multicentre, open-label, randomized trial. Patients were randomly assigned to receive 14 day sequential therapy or 10 day bismuth quadruple therapy, both containing esomeprazole 40 mg twice daily. Those who failed after 14 day sequential therapy received rescue therapy with 10 day bismuth quadruple therapy and vice versa. Our primary outcome was the eradication rate in the first-line therapy. Antibiotic susceptibility was determined. ClinicalTrials.gov: NCT03156855. Results: The eradication rates of 14 day sequential therapy and 10 day bismuth quadruple therapy were 91.3% (283 of 310, 95% CI 87.4%-94.1%) and 91.6% (284 of 310, 95% CI 87.8%-94.3%) in the ITT analysis, respectively (difference -0.3%, 95% CI -4.7% to 4.4%, P = 0.886). However, the frequencies of adverse effects were significantly higher in patients treated with 10 day bismuth quadruple therapy than those treated with 14 day sequential therapy (74.4% versus 36.7% P < 0.0001). The eradication rate of 14 day sequential therapy in strains with and without 23S ribosomal RNA mutation was 80% (24 of 30) and 99% (193 of 195), respectively (P < 0.0001). Conclusions: Optimized 14 day sequential therapy was non-inferior to, but better tolerated than 10 day bismuth quadruple therapy and both may be used in first-line treatment in populations with low to intermediate clarithromycin resistance.

Computer-aided diagnosis for identifying and delineating early gastric cancers in magnifying narrow-band imaging.

BACKGROUND AND AIMS: Magnifying narrow-band imaging (M-NBI) is important in the diagnosis of early gastric cancers (EGCs) but requires expertise to master. We developed a computer-aided diagnosis (CADx) system to assist endoscopists in identifying and delineating EGCs. METHODS: We retrospectively collected and randomly selected 66 EGC M-NBI images and 60 non-cancer M-NBI images into a training set and 61 EGC M-NBI images and 20 non-cancer M-NBI images into a test set. After preprocessing and partition, we determined 8 gray-level co-occurrence matrix (GLCM) features for each partitioned 40 × 40 pixel block and calculated a coefficient of variation of 8 GLCM feature vectors. We then trained a support vector machine (SVMLv1) based on variation vectors from the training set and examined in the test set. Furthermore, we collected 2 determined P and Q GLCM feature vectors from cancerous image blocks containing irregular microvessels from the training set, and we trained another SVM (SVMLv2) to delineate cancerous blocks, which were compared with expert-delineated areas for area concordance. RESULTS: The diagnostic performance revealed accuracy of 96.3%, precision (positive predictive value [PPV]) of 98.3%, recall (sensitivity) of 96.7%, and specificity of 95%, at a rate of 0.41 ± 0.01 seconds per image. The performance of area concordance, on a block basis, demonstrated accuracy of 73.8% ± 10.9%, precision (PPV) of 75.3% ± 20.9%, recall (sensitivity) of 65.5% ± 19.9%, and specificity of 80.8% ± 17.1%, at a rate of 0.49 ± 0.04 seconds per image. CONCLUSIONS: This pilot study demonstrates that our CADx system has great potential in real-time diagnosis and delineation of EGCs in M-NBI images.

Impact of amoxicillin resistance on the efficacy of amoxicillin-containing regimens for Helicobacter pylori eradication: analysis of five randomized trials.

BACKGROUND: The impact of amoxicillin resistance on the efficacy of regimens containing amoxicillin for Helicobacter pylori eradication remains unknown. OBJECTIVES: To investigate whether the efficacy of an amoxicillin-containing regimen is affected by amoxicillin resistance and to identify the optimal breakpoint for amoxicillin resistance. METHODS: This was a pooled analysis of five randomized trials conducted in Taiwan from 2007 to 2016. Patients who received amoxicillin-containing regimens were recruited. MICs were determined by agar dilution testing. Meta-analysis was performed to assess the risk ratio of eradication failure in amoxicillin-resistant strains compared with susceptible strains of seven different regimens. We performed further the pooled analysis and logistic regression in patients treated with clarithromycin triple therapy to identify the optimal breakpoint for amoxicillin resistance. RESULTS: A total of 2339 patients with available amoxicillin MICs were enrolled. Meta-analysis showed that the presence of amoxicillin resistance was consistently associated with increased risk of treatment failure of amoxicillin-containing regimens at different breakpoints (risk ratio: 1.41, 95% CI 1.12-1.78, P = 0.004 when the cut-off was 0.5 mg/L). The heterogeneity was low (I2 = 0%, P = 0.615). Pooled analysis also showed that amoxicillin resistance was an independent risk factor for treatment failure of clarithromycin triple therapy at different breakpoints. The best correlation was observed when the breakpoint of amoxicillin resistance was ≥0.125 mg/L (kappa coefficient 0.298), at which the resistance rate was 11.1% (110 of 990). CONCLUSIONS: The efficacies of amoxicillin-containing regimens are affected by amoxicillin resistance and the optimal breakpoint MIC is ≥ 0.125 mg/L.

Concomitant, bismuth quadruple, and 14-day triple therapy in the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial.

BACKGROUND: Whether concomitant therapy is superior to bismuth quadruple therapy or 14-day triple therapy for the first-line treatment of Helicobacter pylori infection remains poorly understood. We aimed to compare the efficacy and safety of 10-day concomitant therapy, 10-day bismuth quadruple therapy, and 14-day triple therapy in the first-line treatment of H pylori. METHODS: In this multicentre, open-label, randomised trial, we recruited adult patients (aged >20 years) with H pylori infection from nine medical centres in Taiwan. Patients who had at least two positive tests from the rapid urease test, histology, culture, or serology or who had a single positive 13C-urea breath test for gastric cancer screening were eligible for enrolment. Patients were randomly assigned (1:1:1) to either concomitant therapy (lansoprazole 30 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, all given twice daily) for 10 days; bismuth quadruple therapy (bismuth tripotassium dicitrate 300 mg four times a day, lansoprazole 30 mg twice daily, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day) for 10 days; or triple therapy (lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg, all given twice daily) for 14 days. A computer-generated permuted block randomisation sequence with a block size of 6 was used for randomisation, and the sequence was concealed in an opaque envelope until the intervention was assigned. Investigators were masked to treatment allocation. The primary outcome was the eradication frequency of H pylori with first-line therapy assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01906879. FINDINGS: Between July 17, 2013, and April 20, 2016, 5454 patients were screened for eligibility. Of these, 1620 patients were randomly assigned in this study. The eradication frequencies were 90·4% (488/540 [95% CI 87·6-92·6]) for 10-day bismuth quadruple therapy, 85·9% (464/540 [82·7-88·6]) for 10-day concomitant therapy, and 83·7% (452/540 [80·4-86·6]) for 14-day triple therapy in the intention-to-treat analysis. 10-day bismuth quadruple therapy was superior to 14-day triple therapy (difference 6·7% [95% CI 2·7-10·7, p=0·001), but not 10-day concomitant therapy. 10-day concomitant therapy was not superior to 14-day triple therapy. The frequency of adverse events was 67% (358/533) in patients treated with 10-day bismuth quadruple therapy, 58% (309/535) in patients treated with 10-day concomitant therapy, and 47% (252/535) in patients treated with 14-day triple therapy. INTERPRETATION: Bismuth quadruple therapy is preferable to 14-day triple therapy in the first-line treatment in the face of rising prevalence of clarithromycin resistance. Concomitant therapy given for 10 days might not be optimum and a longer treatment length should be considered. FUNDING: National Taiwan University Hospital and Ministry of Science and Technology of Taiwan.

Levofloxacin Sequential Therapy vs Levofloxacin Triple Therapy in the Second-Line Treatment of Helicobacter pylori: A Randomized Trial.

OBJECTIVES: The efficacy of levofloxacin triple therapy has fallen below 80% in the second-line treatment of Helicobacter pylori (H. pylori). We aimed to assess whether the levofloxacin sequential therapy is more effective than levofloxacin triple therapy in the second-line treatment. METHODS: This open-label, randomized, multicenter trial was conducted between 2012 and 2015. H. pylori-infected subjects who failed from clarithromycin-based regimens (N=600) were randomized (1:1) to receive levofloxacin sequential therapy (LS: lansoprazole and amoxicillin for the first 5 days, followed by lansoprazole, levofloxacin, and metronidazole for another 5 days) or levofloxacin triple therapy (LT: lansoprazole, amoxicillin, and levofloxacin for 10 days). Successful eradication was defined as negative (13)C-urea breath test at least 6 weeks after treatment. Our primary outcome was the eradication rate by intention-to-treat (ITT) and per-protocol (PP) analyses. Antibiotic resistance was determined by agar dilution test. RESULTS: The prevalence of clarithromycin, levofloxacin, and metronidazole resistance was 60, 17.6, and 36.9%, respectively. The eradication rates of LS and LT were 84.3% (253/300) and 75.3% (226/300), respectively, in the ITT analysis (P=0.006) and 86.3% (253/293) and 78.8% (223/283), respectively, in the PP analysis (P=0.021). The efficacies of both LS and LT were affected by levofloxacin resistance. The secondary resistance of levofloxacin was 66.7 and 73.9% after LS and LT, respectively. The efficacies of LS and LT were not affected by the CYP2C19 polymorphism. CONCLUSIONS: Levofloxacin sequential therapy was more effective than levofloxacin triple therapy, and it is recommended in the second-line treatment for H. pylori ( TRIAL REGISTRATION NUMBER: NCT01537055).

Sequential therapy for 10†days versus triple therapy for 14†days in the eradication of Helicobacter pylori in the community and hospital populations: a randomised trial.

OBJECTIVE: Significant heterogeneity was observed in previous trials that assessed the efficacies of sequential therapy for 10 days (S10) versus triple therapy for 14 days (T14) in the first-line treatment of Helicobacter pylori. We aimed to compare the efficacy of S10 and T14 and assess the factors affecting their efficacies. DESIGN: We conducted this open-label randomised multicentre trial in eight hospitals and one community in Taiwan. 1300 adult subjects with H pylori infection naïve to treatment were randomised (1:1) to receive S10 (lansoprazole and amoxicillin for the first 5 days, followed by lansoprazole, clarithromycin and metronidazole for another 5 days) or T14 (lansoprazole, amoxicillin and clarithromycin for 14 days). All drugs were given twice daily. Successful eradication was defined as negative 13C-urea breath test at least 6 weeks after treatment. Our primary outcome was the eradication rate by intention-to-treat (ITT) and per-protocol (PP) analyses. Antibiotic resistance was determined by agar dilution test. RESULTS: The eradication rates of S10 and T14 were 87.2% (567/650, 95% CI 84.4% to 89.6%) and 85.7% (557/650, 95% CI 82.8% to 88.2%) in the ITT analysis, respectively, and were 91.6% (556/607, 95% CI 89.1% to 93.4%) and 91.0% (548/602, 95% CI 88.5% to 93.1%) in the PP analysis, respectively. There were no differences in compliance or adverse effects. The eradication rates in strains susceptible and resistant to clarithromycin were 90.7% and 62.2%, respectively, for S10, and were 91.5% and 44.4%, respectively, for T14. The efficacy of T14, but not S10, was affected by CYP2C19 polymorphism. CONCLUSIONS: S10 was not superior to T14 in areas with low clarithromycin resistance. TRIAL REGISTRATION NUMBER: NCT01607918.

The Primary Resistance of Helicobacter pylori in Taiwan after the National Policy to Restrict Antibiotic Consumption and Its Relation to Virulence Factors-A Nationwide Study.

OBJECTIVE: The Taiwan Government issued a policy to restrict antimicrobial usage since 2001. We aimed to assess the changes in the antibiotic consumption and the primary resistance of H. pylori after this policy and the impact of virulence factors on resistance. METHODS: The defined daily dose (DDD) of antibiotics was analyzed using the Taiwan National Health Insurance (NHI) research database. H. pylori strains isolated from treatment naïve (N=1395) and failure from prior eradication therapies (N=360) from 9 hospitals between 2000 and 2012 were used for analysis. The minimum inhibitory concentration was determined by agar dilution test. Genotyping for CagA and VacA was determined by PCR method. RESULTS: The DDD per 1000 persons per day of macrolides reduced from 1.12 in 1997 to 0.19 in 2008, whereas that of fluoroquinolones increased from 0.12 in 1997 to 0.35 in 2008. The primary resistance of amoxicillin, clarithromycin, metronidazole, and tetracycline remained as low as 2.2%, 7.9%, 23.7%, and 1.9% respectively. However, the primary levofloxacin resistance rose from 4.9% in 2000-2007 to 8.3% in 2008-2010 and 13.4% in 2011-2012 (p=0.001). The primary resistance of metronidazole was higher in females than males (33.1% vs. 18.8%, p<0.001), which was probably attributed to the higher consumption of nitroimidazole. Neither CagA nor VacA was associated with antibiotic resistance. CONCLUSIONS: The low primary clarithromycin and metronidazole resistance of H. pylori in Taiwan might be attributed to the reduced consumption of macrolides and nitroimidazole after the national policy to restrict antimicrobial usage. Yet, further strategies are needed to restrict the consumption of fluoroquinolones in the face of rising levofloxacin resistance.

Distinct aetiopathogenesis in subgroups of functional dyspepsia according to the Rome III criteria.

BACKGROUND AND OBJECTIVE: Whether there is distinct pathogenesis in subgroups of functional dyspepsia (FD), the postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) remains controversial. We aimed to identify the risk factors of FD and its subgroups in the Chinese population. METHODS: Patients with dyspepsia and healthy subjects who underwent gastric cancer screening were enrolled in this multicentre study from 2010 to 2012. All patients were evaluated by questionnaire, oesophagoduodenoscopy, histological examination and Helicobacter pylori tests. Subgroups of FD were classified according to the Rome III criteria. Psychiatric stress was assessed by the short form Brief Symptom Rating Scale. CagA and VacA genotypes were determined by PCR. RESULTS: Of 2378 patients screened for eligibility, 771 and 491 fulfilled the diagnostic criteria of uninvestigated dyspepsia and FD, respectively. 298 (60.7%) and 353 (71.9%) individuals were diagnosed with EPS and PDS, respectively, whereas 169 (34.4%) had the overlap syndrome. As compared with 1031 healthy controls, PDS and EPS shared some common risk factors, including younger age (OR 0.95; 99.5% CI 0.93 to 0.98), non-steroidal anti-inflammatory drugs (OR 6.60; 99.5% CI 3.13 to 13.90), anxiety (OR 3.41; 99.5% CI 2.01 to 5.77) and concomitant IBS (OR 6.89; 99.5% CI 3.41 to 13.94). By contrast, H. pylori (OR 1.86; 99.5% CI 1.01 to 3.45), unmarried status (OR 4.22; 99.5% CI 2.02 to 8.81), sleep disturbance (OR 2.56; 99.5% CI 1.29 to 5.07) and depression (OR 2.34; 99.5% CI 1.04 to 5.36) were associated with PDS. Moderate to severe antral atrophy and CagA positive strains were also more prevalent in PDS. CONCLUSIONS: Different risk factors exist among FD subgroups based on the Rome III criteria, indicating distinct aetiopathogenesis of the subdivisions that may necessitate different therapeutic strategies.

Sequential versus triple therapy for the first-line treatment of Helicobacter pylori: a multicentre, open-label, randomised trial.

BACKGROUND: Whether sequential treatment can replace triple therapy as the standard treatment for Helicobacter pylori infection is unknown. We compared the efficacy of sequential treatment for 10 days and 14 days with triple therapy for 14 days in first-line treatment. METHODS: For this multicentre, open-label, randomised trial, we recruited patients (≥20 years of age) with H pylori infection from six centres in Taiwan. Using a computer-generated randomisation sequence, we randomly allocated patients (1:1:1; block sizes of six) to either sequential treatment (lansoprazole 30 mg and amoxicillin 1 g for the first 7 days, followed by lansoprazole 30 mg, clarithromycin 500 mg, and metronidazole 500 mg for another 7 days; with all drugs given twice daily) for either 10 days (S-10) or 14 days (S-14), of 14 days of triple therapy (T-14; lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg for 14 days; with all drugs given twice daily). Investigators were masked to treatment allocation. Our primary outcome was the eradication rate in first-line treatment by intention-to-treat (ITT) and per-protocol (PP) analyses. This trial is registered with ClinicalTrials.gov, number NCT01042184. FINDINGS: Between Dec 28, 2009, and Sept 24, 2011, we enrolled 900 patients: 300 to each group. The eradication rate was 90·7% (95% CI 87·4-94·0; 272 of 300 patients) in the S-14 group, 87·0% (83·2-90·8; 261 of 300 patients) in the S-10 group, and 82·3% (78·0-86·6; 247 of 300 patients) in the T-14 group. Treatment efficacy was better in the S-14 group than it was in the T-14 group in both the ITT analysis (number needed to treat of 12·0 [95% CI 7·2-34·5]; p=0·003) and PP analyses (13·7 [8·3-40], p=0·003). We recorded no significant difference in the occurrence of adverse effects or in compliance between the three groups. INTERPRETATION: Our findings lend support to the use of sequential treatment as the standard first-line treatment for H pylori infection. FUNDING: National Taiwan University Hospital and National Science Council.