Seven-day vonoprazan-based triple therapy as first-lineHelicobacter pylori treatment in comparison with extended sequential therapy.

Background and Aim: Vonoprazan as a new acid blocker has more potency and longer lasting acid suppression than proton pump inhibitors. Whether the efficacy of vonoprazan-based triple therapy is comparable with or even better than that of currently recommended first-line therapies is still unknown. Our study aims to compare the eradication rate and major adverse effects between 7-day vonoprazan-based triple therapy with high-dose amoxicillin and 14-day extended sequential therapy. Methods: We performed a retrospective analysis from the database of 13C-urea breath test at Fu Jen Catholic University Hospital. All patients with a definite diagnosis of Helicobacter pylori infection by rapid urease test, urea breath test, stool antigen test, or pathology report were recruited. Patients receiving first-line regimens with vonoprazan-based triple therapy or extended sequential therapy were included. The respective eradication rate determined by 13C-urea breath test and major adverse effects were demonstrated. Results: Totally, 106 patients were recruited in the vonoprazan-based triple therapy group and 357 in the extended sequential therapy group. There was no significant difference in eradication rate between vonoprazan-based triple therapy with high-dose amoxicillin and extended sequential therapy (83.0 vs 88.8%, P = 0.12). Major adverse effects occurred in 13 of the extended sequential therapy group but none in the other group (0% vs 3.6%, P = 0.046). Conclusions: Seven-day vonoprazan-based triple therapy with high-dose amoxicillin is a potential first-line anti-Helicobacter pylori regimen alternative to current standard treatment, with the advantages of simplicity, short treatment duration, low pill burden, and fewer major adverse effects.

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.

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.

Multinational, double-blind, randomised, placebo-controlled, prospective study of esomeprazole in the prevention of recurrent peptic ulcer in low-dose acetylsalicylic acid users: the LAVENDER study.

OBJECTIVES: To evaluate if esomeprazole prevents recurrent peptic ulcer in adult patients with a history of peptic ulcer receiving low-dose acetylsalicylic acid (ASA, aspirin) for cardiovascular protection in East Asia. METHODS: In this prospective, randomised, double-blind, placebo-controlled trial conducted in Japan, Korea and Taiwan, eligible patients receiving low-dose ASA for cardiovascular protection (81-324 mg/day) were randomised to esomeprazole 20 mg/day or placebo for ≤72 weeks. All patients received concomitant mucosal protection (gefarnate 100 mg/day). The primary endpoint was time to ulcer recurrence (Kaplan-Meier analysis). Efficacy findings are presented up to week 48, as per a planned interim analysis within the study protocol. RESULTS: A total of 364 patients (79.9% men; mean age, 67.1 years) comprised the full analysis set (esomeprazole, n=182; placebo, n=182). There was a statistically significant difference in the time to ulcer recurrence between esomeprazole and placebo (HR 0.09; 96.65% CI 0.02 to 0.41; p<0.001). The estimated ulcer-free rate at week 12 was 99.3% (esomeprazole) and 89.0% (placebo). The high estimated ulcer-free rate for esomeprazole was maintained through to week 48 (98.3% vs. 81.2% of placebo-treated patients). No factors, other than female gender, reduced time to ulcer recurrence in addition to the effect of esomeprazole (p<0.001). Treatment with esomeprazole was generally well tolerated. CONCLUSIONS: Daily esomeprazole 20 mg is efficacious and well tolerated in reducing the recurrence of peptic ulcer in East-Asian patients with a history of ulcers who are taking low-dose ASA for cardiovascular protection. CLINICALTRIALGOV IDENTIFIER: NCT01069939.

Controlled trial of ligation plus vasoconstrictor versus proton pump inhibitor in the control of acute esophageal variceal bleeding.

BACKGROUND: Endoscopic therapy combined with vasoconstrictor was generally recommended to treat acute variceal bleeding. However, up to 30% of patients may still encounter treatment failure. OBJECTIVES: This trial was to evaluate the efficacy of combination with endoscopic variceal ligation (EVL) and proton pump inhibitor (PPI) infusion in patients with acute variceal bleeding. METHODS: Cirrhotic patients presenting with acute esophageal variceal bleeding were rescued by emergency EVL. Soon after arresting of bleeding varices, eligible subjects were randomized to two groups. Vasoconstrictor group received either somatostatin or terlipressin infusion. PPI group received either omeprazole or pantoprazole. End points were initial hemostasis, very early rebleeding rate, and adverse events. RESULTS: Sixty patients were enrolled in vasoconstrictor group and 58 patients in PPI group. Both groups were comparable in baseline data. Initial hemostasis was achieved in 98% in vasoconstrictor group and 100% in PPI group (P = 1.0). Very early rebleeding within 48-120 h occurred in one patient (2%) in vasoconstrictor group and one patient (2%) in the PPI group (P = 1.0). Treatment failure was 4% in vasoconstrictor group and 2% in PPI group (P = 0.95). Adverse events occurred in 33 patients (55%) in vasoconstrictor group and three patients (6%) in PPI group (P < 0.001). Two patients in vasoconstrictor group and one patient in PPI group encountered esophageal ulcer bleeding. CONCLUSIONS: After successful control of acute variceal bleeding by EVL, adjuvant therapy with PPI infusion was similar to combination with vasoconstrictor infusion in terms of initial hemostasis, very early rebleeding rate, and associated with fewer adverse events.

Efficacy of genotypic resistance-guided sequential therapy in the third-line treatment of refractory Helicobacter pylori infection: a multicentre clinical trial.

OBJECTIVES: The efficacy of sequential therapy and the applicability of genotypic resistance to guide the selection of antibiotics in the third-line treatment of Helicobacter pylori have not been reported. We aimed to assess the efficacy of genotypic resistance-guided sequential therapy in third-line treatment. METHODS: Genotypic and phenotypic resistances were determined in patients who failed at least two eradication therapies by PCR with direct sequencing and agar dilution test, respectively. The patients were retreated with sequential therapy containing esomeprazole and amoxicillin for the first 7 days, followed by esomeprazole and metronidazole plus clarithromycin, levofloxacin or tetracycline for another 7 days (all twice daily), according to genotypic resistance determined using gastric biopsy specimens. Eradication status was determined by the (13)C-urea breath test. Trial registered at clinicaltrials.gov (identifier: NCT01032655). RESULTS: The overall eradication rate was 80.7% (109/135, 95% CI 73.3%-86.5%) in the intention-to-treat analysis. The presence of amoxicillin resistance (OR 6.83, 95% CI 1.62-28.86, P = 0.009) and prior sequential therapy (OR 4.77, 95% CI 1.315-17.3, P = 0.017), but not tetracycline resistance (tetracycline group), were associated with treatment failure. The eradication rates in patients who received clarithromycin-, levofloxacin- and tetracycline-based sequential therapies were 78.9% (15/19), 92.2% (47/51) and 71.4% (25/35) in strains susceptible to clarithromycin, levofloxacin and tetracycline, respectively. CONCLUSIONS: A simple molecular method guiding sequential therapy can achieve a high eradication rate in the third-line treatment of refractory H. pylori infection.

Empirical modified sequential therapy containing levofloxacin and high-dose esomeprazole in second-line therapy for Helicobacter pylori infection: a multicentre clinical trial.

OBJECTIVES: Sequential therapy appears to achieve a higher Helicobacter pylori eradication rate than triple therapy. We assessed the efficacy and tolerability of modified sequential therapy containing levofloxacin and high-dose esomeprazole in second-line therapy. METHODS: Patients who failed first-line triple therapy with clarithromycin, amoxicillin and a proton pump inhibitor were eligible in this multicentre trial. Eligible patients were treated with esomeprazole 40 mg and amoxicillin 1 g for the first 5 days, followed by esomeprazole 40 mg, levofloxacin 250 mg and metronidazole 500 mg for another 5 days (all given twice daily). Eradication was confirmed with a (13)C-urea breath test 6 weeks after therapy. Drug susceptibility, presence/absence of gyrA mutation and CYP2C19 genotype were also determined. RESULTS: A total of 142 patients were enrolled. The eradication rate was 95.1% [135/142, 95% confidence interval (CI) 91.5%-98.6%] in the intention-to-treat analysis and 96.4% (133/138, 95% CI 93.3%-99.5%) in the per protocol analysis. Four patients (2.8%) failed to take at least 80% of the drugs due to adverse effects. The eradication rates were 50% (4/8) and 97.7% (43/44) in patients with and without metronidazole resistance, respectively (P = 0.001). The eradication rates were 84.6% (11/13) and 95.1% (58/61) in patients with and without gyrA mutation, respectively (P = 0.210). The eradication rates were not affected by the CYP2C19 polymorphism (P = 0.421). CONCLUSIONS: This modified sequential therapy achieved an excellent eradication rate (>95%) in second-line treatment and the eradication rate appeared to be affected by metronidazole resistance.

Genotypic resistance in Helicobacter pylori strains correlates with susceptibility test and treatment outcomes after levofloxacin- and clarithromycin-based therapies.

The accuracy of genotypic resistance to levofloxacin (gyrA mutations) and its agreement with treatment outcomes after levofloxacin-based therapy have not been reported. We aimed to assess the correlation. Helicobacter pylori strains isolated from patients who received levofloxacin-based and clarithromycin-based triple therapies in a previous randomized trial were analyzed for point mutations in gyrA and 23S rRNA. PCR followed by direct sequencing was used to assess the gyrA and 23S rRNA mutations. An agar dilution test was used to determine the MICs of clarithromycin and levofloxacin. We found that the agreement between genotypic and phenotypic resistance to levofloxacin was best when the MIC breakpoint was >1 µg/ml (kappa coefficient, 0.754). The eradication rates in patients with and without gyrA mutations were 41.7% and 82.7%, respectively (P = 0.003). The agreement between genotypic and phenotypic resistance to clarithromycin was best when the MIC breakpoint was >2 µg/ml (kappa, 0.694). The eradication rates in patients with and without 23S rRNA mutations were 7.7% and 93.5%, respectively (P < 0.001). The agreements (kappa coefficient) between therapeutic outcomes after clarithromycin-based triple therapy and genotypic and phenotypic resistance were 0.671 and 0.356, respectively. The agreements (kappa coefficient) between therapeutic outcomes after levofloxacin-based triple therapy and genotypic and phenotypic resistance were 0.244 and 0.190, respectively. In conclusion, gyrA and 23S rRNA mutations in H. pylori strains appeared to be better markers than phenotypic resistance in the prediction of treatment outcomes. The optimal breakpoints for levofloxacin and clarithromycin resistance appeared to be >1 µg/ml and >2 µg/ml, respectively.

Levofloxacin-based and clarithromycin-based triple therapies as first-line and second-line treatments for Helicobacter pylori infection: a randomised comparative trial with crossover design.

BACKGROUND: The efficacy of a levofloxacin-based regimen as the first-line treatment and a clarithromycin-based regimen as the second-line treatment for Helicobacter pylori infection remains unknown. The aim of this study was to assess the eradication rates of these two regimens using different administration sequences. METHODS: Eligible patients were randomised to receive LAL: levofloxacin (750 mg once a day), amoxicillin (1000 mg twice a day) and lansoprazole (30 mg twice a day) for 7 days, or CAL: clarithromycin (500 mg twice a day), amoxicillin (1000 mg twice a day) and lansoprazole (30 mg twice a day) for 7 days. Patients with positive [(13)C]urea breath test after treatment were retreated with the rescue regimen in a crossover manner for 10 days. RESULT: When used as first-line treatment (n=432), the eradication rates of LAL (n=217) and CAL (n=215) were 74.2 and 83.7% (p=0.015) in the intent-to-treat (ITT) analysis, and 80.1 and 87.4% (p=0.046) in the per-protocol (PP) analysis, respectively. When used as second-line treatment, the eradication rates of LAL (n=26) and CAL (n=40) were 76.9 and 60% (p=0.154) in the ITT analysis, and 80 and 61.5% (p=0.120) in the PP analysis, respectively. The overall eradication rates of CAL followed by LAL were better than the reverse sequence in both the ITT analysis (93% vs 85.3%, p=0.01) and the PP analysis (97.6% vs 92.5%, p=0.019). The eradication rate was significantly lower in the presence of levofloxacin resistance in the LAL group (50% vs 84.4%, p=0.018) and clarithromycin resistance in the CAL group (44.4% vs 90.7%, p=0.002). CONCLUSION: CAL achieved a higher eradication rate than LAL as the first-line treatment, but not as the second-line treatment. The strategy of using CAL as the initial treatment and LAL as the rescue regimen achieved higher eradication rates than the reverse sequence.