Efficacy of fourteen-day once-daily vonoprazan-based quadruple therapy for Helicobacter pylori in high clarithromycin-resistance regions (ONCE-VONO Trial)

Vonoprazan, a novel and potent acid suppressant, has recently been incorporated into Helicobacter pylori eradication regimens. However, the data on combination of vonoprazan with levofloxacin remains scarce. This study represents one of the first evaluations comparing 7-day and 14-day once-daily regimens containing vonoprazan, levofloxacin, clarithromycin-MR, and bismuth for H. pylori eradication in regions characterized by high clarithromycin and metronidazole resistance. Between March 2022 and December 2023, patients presenting with dyspepsia who underwent upper gastrointestinal endoscopy at a tertiary care hospital in Thailand were recruited. Those testing positive for H. pylori infection were randomly assigned to receive either a 7-day or 14-day once-daily regimen comprising vonoprazan 40 mg, clarithromycin-MR 1 g, levofloxacin 500 mg, and bismuth subsalicylate 1,048 mg. CYP3A4 polymorphism testing and antimicrobial susceptibility assessment (using either the Epsilometer test or the GenoType^® HelicoDR assay) were performed. Eradication was confirmed by a negative ¹³C-urea breath test conducted no sooner than four weeks after completing therapy. A total of 312 dyspeptic patients who underwent EGD were screened, and 102 (32.7%) were diagnosed with H. pylori infection. The study enrolled and randomized these patients into two treatment groups: 51 received the 7-day once-daily vonoprazan-based bismuth therapy, and 51 received the 14-day regimen. Baseline characteristics were similar between the two groups, except for a higher prevalence of hypertension in the 7-day regimen group (49% vs. 27.5%, p = 0.025). The eradication rates for the 7-day regimen were 88.2% (45/51) in the intention-to-treat (ITT) analysis and 89.6% (43/48) in the per-protocol (PP) analysis. Similarly, the 14-day regimen achieved eradication rates of 88.2% (45/51) in the ITT analysis and 93.8% (45/48) in the PP analysis. The risk difference for eradication in the PP analysis was 4.17% (95% CI: -6.86 to 15.19, p = 0.71). Adverse events were comparable between the two regimens, occurring in 35.3% (18/51) of patients in the 7-day regimen and 38.8% (19/51) in the 14-day regimen (p = 0.130). The most frequently reported adverse event was black stool (35.3% vs. 38.8%, p = 0.130). Other adverse events included nausea and vomiting (15.7% vs. 22.5%, p = 0.742), bitter taste (17.7% vs. 18.4%, p = 1.000), and dizziness (7.8% vs. 6.1%, p = 0.113). All adverse events resolved spontaneously without requiring medical intervention, and no serious adverse events were reported. The 14-day regimen demonstrated excellent eradication rate (> 90%) regardless of CYP3A4 polymorphisms. These findings suggest that vonoprazan, levofloxacin, clarithromycin-MR, and bismuth for 14 days is a promising alternative first-line treatment option, particularly in regions with high clarithromycin and metronidazole resistance.