Effects of amoxicillin dosage on cure rate, gut microbiota, and antibiotic resistome in vonoprazan and amoxicillin dual therapy for Helicobacter pylori: a multicentre, open-label, non-inferiority randomised controlled trial.

Background: Vonoprazan and amoxicillin (VA) dual therapy as a mainstream Helicobacter pylori regimen has gained momentum worldwide, but the optimum dosages remain unclear. We aimed to compare the efficacy and safety of VA dual therapy with 2 g amoxicillin or 3 g amoxicillin, and to assess the short-term effects of therapy on the gut microbiota and antibiotic resistome.

Methods: We conducted an open-label, non-inferiority randomised controlled trial at 12 centres in China. Individuals infected with H pylori, aged 18-70 years, and without previous eradication therapy were recruited. Participants were randomly assigned at a 1:1 ratio (block size of six) to receive vonoprazan (20 mg twice a day) with either low-dose amoxicillin (1 g twice a day; LVA therapy) or high-dose amoxicillin (1 g three times a day; HVA therapy) for 14 days. Gastric biopsies were collected before treatment for detection of antibiotic resistance. Stool samples were collected at baseline, week 2, and week 8-10 for shotgun metagenomic sequencing. The primary outcome was the eradication rate of H pylori, assessed by C urea breath test, in both intention-to-treat and per-protocol analyses. Secondary outcomes were adverse events, adherence, antibiotic resistance, and alterations to the gut microbiota and antibiotic resistome. The margin used to establish non-inferiority was -0·10. The trial was registered with ClinicalTrials.gov, NCT05649709.

Findings: Between Feb 13, 2023, and Jan 25, 2024, 504 patients (204 [40%] male and 300 [60%] female; mean age 43 years [SD 13]) were randomly assigned to LVA therapy or HVA therapy (n=252 in each group). No infections were resistant to amoxicillin. The H pylori eradication rate was 85·3% (215 of 252; 95% CI 80·4 to 89·2) in the LVA group and 86·5% (218 of 252; 81·7 to 90·2) in the HVA group in the intention-to-treat analysis (p=0·70) and 88·8% (213 of 240; 84·1 to 92·2) and 92·4% (218 of 236; 88·3 to 95·1), respectively, in the per-protocol analysis (p=0·18). The efficacy of LVA was non-inferior to HVA in the intention-to-treat analysis (risk difference -1·2%, 95% CI -7·3 to 4·9, p=0·0022) and the per-protocol analysis (-3·6%, -9·0 to 1·7, p=0·0085). 31 (12%) patients in the LVA group and 43 (17%) patients in the HVA group reported adverse events. Adherence to therapy was 97% in the LVA group and 96% in the HVA group. The diversity of gut microbiota decreased after treatment but was restored to baseline at week 8-10 in both groups. The abundance of beta-lactam-related resistance genes was increased at week 2 after treatment, and was restored to pretreatment level at week 8-10 for the LVA group but not the HVA group.

Interpretation: LVA dual therapy was effective and non-inferior to HVA dual therapy as first-line treatment of H pylori infection and showed a non-lasting effect on the abundance of beta-lactam-related resistance genes. High amoxicillin dosage (eg, 3 g per day) is not required to achieve high cure rates with vonoprazan dual therapy.

Funding: National Natural Science Foundation of China, Project for Academic and Technical Leaders of Major Disciplines in Jiangxi Province, and Key Research and Development Program of Jiangxi Province.