Vonoprazan vs. high-dose esomeprazole in bismuth-containing quadruple therapy for Helicobacter pylori rescue treatment: a retrospective cohort study
- Open Access
- 01.12.2025
- Research
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Abstract
Background
Helicobacter pylori is a spiral-shaped, gram-negative, microaerophilic bacterium that specifically colonizes the gastric epithelium [1]. The overall global prevalence of H. pylori was 43.9% in adults, and it remained notably high at 35.1% among children and adolescents from 2015 to 2022 [2]. It serves as a principal etiological factor in the development of chronic gastritis, peptic ulcers, and non-cardia gastric cancer, as well as gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Furthermore, it may be implicated in an array of other gastrointestinal disorders, including non-ulcer dyspepsia [3]. H. pylori remained a leading pathogen in terms of disability-adjusted life-years (DALYs) burden in 7 out of the 204 countries, accounting for 3.4% [4]. In China, H. pylori infection represents a significant public health concern due to its persistently high incidence in various regions [5]. Consequently, the eradication of H. pylori is essential for the effective prevention and management of gastric diseases.
Recent years have witnessed a decline in the eradication rates of H. pylori, with current estimates around 75% [6]. This decrease is primarily attributed to antibiotic resistance, particularly to clarithromycin, with resistance rates in China reaching up to 50% [7]. Additionally, the effectiveness of acid suppressive agents, such as proton pump inhibitors (PPIs) and potassium-competitive acid blockers (P-CABs), which are integral to H. pylori treatment, can influence eradication success. Higher gastric pH enhances antibiotic efficacy against H. pylori by improving antibiotic stability and solubility, disrupting bacterial survival mechanisms, and enhancing antibiotic penetration and uptake [8]. PPIs include omeprazole, esomeprazole (ESO), lansoprazole, pantoprazole, and rabeprazole, whose metabolic efficacy is significantly influenced by genetic polymorphisms in the cytochrome P450 isoenzyme CYP2C19. To enhance eradication rates in patients with a strong metabolic phenotype, higher doses of PPIs may be required to improve gastric pH and thus enhance antibiotic efficacy [9]. ESO, an L-isomer of omeprazole, is primarily metabolized by CYP3A4, which reduces variability in efficacy related to CYP2C19 polymorphisms. Compared to other PPIs, ESO offers superior acid suppression and antibacterial activity [10, 11].
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Potassium-competitive acid blockers (P-CABs) inhibit H+/K+-adenosine triphosphatase through reversible, K+-competitive ionic binding, which leads to the suppression of gastric acid secretion. Vonoprazan (VON), a pioneering P-CAB, has been approved in multiple regions, including Japan and the United States, for the treatment of acid-related disorders such as erosive esophagitis and H. pylori eradication. It features a relatively high pKa value and demonstrates stability in acidic environments, enabling it to accumulate in the acidic compartments of gastric parietal cells, unlike PPIs [12]. Additionally, the CYP2C19 metabolic pathway has a lesser impact on VON compared to PPIs. As a first-line treatment for H. pylori eradication, P-CAB-based triple therapy is generally considered superior to PPI-based regimens [13]. However, the efficacy of VON in re-treating H. pylori infections remains debated. Re-eradicating H. pylori involves administering a tailored antibiotic regimen within a 12-month period following confirmed failure of initial therapy. Research by Sue et al. indicates that VON-based therapies are more effective than PPI-based treatments as a third-line option [14]. Conversely, a study by Hojo et al. found no significant differences between VON and PPI regimens when used as second-line treatments [15].
This study aims to evaluate the efficacy of VON (20 mg twice daily) versus high-dose ESO (40 mg twice daily) in re-eradicating H. pylori. The choice of re-treatment antibiotic regimens, whether culture-guided or epidemiology-guided, depends on clinical context, resource availability, and regional resistance patterns. Culture-guided regimens provide precise targeting and achieve superior eradication rates in complex cases, though they are limited their invasiveness and cost. In contrast, epidemiology-guided regimens offer a pragmatic and cost-effective first strategy, but their efficacy may be reduced in high-resistance settings.
The growing challenge of antibiotic resistance, particularly in high-incidence regions like China, coupled with the variable effectiveness of acid suppressive therapies, underscores the urgent need for optimized re-treatment strategies for H. pylori infections. This study is crucial to identify the most effective re-eradication approaches, leveraging VON and high-dose ESO within tailored antibiotic regimens, and to provide evidence-based guidance for clinicians facing this persistent public health challenge.
Methods
Study design
This retrospective cohort study was conducted to evaluate real-world clinical outcomes of H. pylori re-eradication therapies using existing patient data. We systematically reviewed medical records of 328 patients who received rescue therapy for confirmed H. pylori infection at Nanjing First Hospital between January 2019 and December 2021. To ensure therapeutic consistency, all treatment protocols were standardized by a five-member Gastroenterologist panel in accordance with the Fifth Chinese National Consensus Report on H. pylori Infection Management.
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Ethics approval and consent to participate
The study received approval from the Ethics Committee of Nanjing First Hospital, under the reference number KY20221124-09. The data are anonymous, and the requirement for informed consent was therefore waived. The study adhered to the relevant EQUATOR guidelines, and the STROBE checklist is included in the supplementary materials.
Study population
This retrospective study enrolled patients meeting the following criteria: 1) ≥ 1 confirmed H. pylori eradication failure, defined by positive retesting 4–8 weeks post-treatment using: a positive 13 C-urea breath test (13 C-UBT; delta over baseline [DOB] ≥ 4‰), ≥ 2 positive rapid urease tests of gastric tissues, positive histology (immunohistochemical staining-confirmed H. pylori morphotypes: spiral/curved rods or coccoid forms on gastric epithelial cells), OR positive culture; 2) initiation of re-treatment within 12 months of failed eradication. The exclusion criteria encompassed patients who did not undergo a re-evaluation post-treatment, and individuals with unsuccessful H. pylori culture results. Participants were stratified into two treatment groups based on physician choices and patient-specific factors: one receiving a VON-based quadruple therapy regimen (comprising VON 20 mg, two antibiotics, and bismuth potassium citrate 220 mg, administered twice daily for 14 days) and the other receiving a high-dose ESO-based quadruple therapy regimen (comprising ESO 40 mg, two antibiotics, and bismuth potassium citrate 220 mg, administered twice daily for 14 days). The antibiotics utilized in the study were amoxicillin (1,000 mg twice daily) and furazolidone (100 mg twice daily). A negative result from the 13 C-UBT conducted 4 to 8 weeks after re-eradication was defined as a successful re-eradication.
Treatment outcomes
Basic clinical data and the re-eradication outcomes were obtained from medical records or telephone conversations with the patients. A negative 13 C-UBT result was defined as a delta over baseline (DOB) value < 4‰.
Bias
The study encountered two principal biases. First, information bias was mitigated by excluding incomplete data and retrieving patient examination reports to verify registration outcomes, ensuring a comprehensive double-checking process. Second, selection bias was minimized by endeavoring to include all patients who underwent multiple evaluations for H. pylori infection at our center. Nonetheless, the single-center design of the study made complete elimination of selection bias challenging. Potential confounding factors, including differences in patient adherence to treatment protocols and variations in baseline clinical characteristics, could not be controlled for in this retrospective design.
Statistical analysis
Data analysis was conducted using SPSS version 17.0 (IBM SPSS, Chicago, IL, USA). Categorical variables were expressed as proportions, while continuous variables were reported as means ± standard deviations (SDs). The Fisher’s exact test or chi-square test was utilized to compare categorical variables. Continuous variables were compared using one-way analysis of variance (one-way ANOVA). A p-value of less than 0.05 was considered statistically significant.
Results
Demographic characteristics of all individuals
A total of 114 H. pylori-infected patients requiring re-eradication treatment were allocated to the VON-containing quadruple therapy group (group VON). Within this group, 61 patients were assigned to the individualized precision treatment subgroup (group VON-P), while the remaining 53 patients were assigned to the empirical treatment subgroup (group VON-E). In the ESO-containing quadruple therapy group (group ESO), which included 214 H. pylori-infected patients requiring re-eradication treatment, 71 were allocated to the individualized precision treatment subgroup (group ESO-P) and the remaining 143 to the empirical treatment subgroup (group ESO-E) (see Fig. 1). Table 1 presents the demographic characteristics of all participants. No significant differences were found between the groups with respect to age, sex, alcohol consumption, smoking habits, or family history of cancer.
Table 1
Clinical characteristics of enrolled patients
Table 2
Comparison of H. pylori re-eradication rates between high-dose ESO-containing therapy (Group ESO) and VON-containing therapy (Group VON)
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Table 3
Comparison of H. pylori re-eradication rates between individualized precision treatment groups ESO-P and VON-P
Table 4
Comparison of H. pylori re-eradication rates between empirical treatment groups ESO-E and VON-E
Table 5
Comparison of H. pylori re-eradication rates between empirical treatment group ESO-E and individualized precision treatment group ESO-P
Table 6
Comparison of H. pylori re-eradication rates between empirical treatment group VON-E and individualized precision treatment group VON-P
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Table 7
H. pylori re-eradication rates in culture-guided subgroups: ESO-P vs. VON-P stratified by prior treatment failures
Fig. 1
Flowchart depicting the study design
Re-eradication rates between H. pylori infected patients in group VON and group ESO
The study found no statistically significant difference in re-eradication rates between quadruple therapy regimens containing VON and those containing ESO, irrespective of whether the treatment was tailored to the individual patient or administered empirically. Re-eradication rates were evaluated at an interval of 4–8 weeks post-therapy. The overall re-eradication rates observed were 86.0% (98/114, 95% CI: 78.4–91.2%) for the VON-containing group (group VON) and 89.2% (191/214, 95% CI: 84.4–92.7%) for the ESO-containing group (group ESO). No significant difference in eradication rates was observed between the two groups (X2 = 0.767, P = 0.381), as shown in Table 2. Among patients receiving individualized precision treatment, the re-eradication rates for groupESO-P and groupVON-P were 87.3% (62/71, 95% CI: 77.6–93.2%) and 86.9% (53/61, 95% CI: 76.2–93.2%), respectively, with no statistically significant difference (X2 = 0.006, P = 0.940) (See Table 3). Similarly, among patients receiving empirical treatment, the re-eradication rates did not differ significantly between the ESO-E group and the VON-E group (90.2%, 129/143, 95% CI: 84.2–94.1% vs. 84.9%, 45/53, 95% CI: 72.9–92.1%; X² = 1.092, P = 0.296), as presented in Table 4. Furthermore, no significant differences in H. pylori re-eradication rates were observed between the ESO-E group and the ESO-P group (X2 = 0.412, P = 0.521), nor between the VON-E group and the VON-P group (X² = 0.092, P = 0.762), as indicated in Tables 5 and 6. No significant efficacy differences were observed across treatment lines in analyzable culture-guided cohorts (Table 7). Specifically, second/third-line eradication rates were comparable between ESO-P (89.6%, 43/48; 95% CI: 77.3–96.0) and VON-P (86.4%, 19/22; 95% CI: 66.7–95.3) groups (P = 0.700). For beyond third-line therapies, ESO-P achieved 87.5% (28/32; 71.9–95.2) versus VON-P’s 91.3% (42/46; 79.7–96.6) success (P = 0.710).
Discussions
In addressing the challenge of H. pylori eradication failure, our study presents evidence that therapeutic strategies individualized based on H. pylori drug susceptibility profiles or the regional epidemiological patterns of drug sensitivity can significantly enhance treatment outcomes. Specifically, the use of high ESO or VON been shown to achieve re-eradication rates exceeding 80% with no statistically significant differences between the two. This highlights the critical role of acid suppression therapy as an adjunct in the re-treatment regimen, while reaffirming antibiotics as the central of effective re-eradication. The synergistic effect of high-intensity acid suppression with the administration of appropriately sensitive antibiotics is pivotal in improving the success rates of H. pylori re-eradication.
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A reduction in the global eradication rate of H. pylori with standard triple therapy to below 80% has been observed, primarily due to increasing antibiotic resistance and the impact of acid suppressive agents [5]. In response to these challenges, the use of VON in H. pylori eradication regimens has been extensively studied. While VON-containing regimens have demonstrated superior efficacy compared to PPI-based regimens as first-line therapies, limited evidence exists regarding their use in salvage treatments [14‐19]. Dong et al. reported no significant differences in efficacy between second-line VON- and PPI-containing triple therapies, with eradication rates of 83.4% vs. 82.0% (P = 0.79 in intention-to-treat (ITT) analysis and 89.3% vs. 90.1% (P = 0.06) in per-protocol (PP) analysis [16]. Similarly, another study comparing VON with rabeprazole (RPZ) as part of second-line treatments found no significant differences in eradication rates: 73.9% vs. 82.6% (ITT; P = 0.72) and 89.5% vs. 86.4% (PP; P = 1.00). Both groups exhibited comparable safety profiles, with minimal treatment discontinuations due to side effects [15]. However, Sue et al. observed that a third-line VON-containing regimen achieved higher eradication rates than a lansoprazole-containing regimen in per-protocol analysis (83.3% vs. 57.1%, P = 0.043), though no significant differences were noted in ITT analysis (75.8% vs. 53.3%, P = 0.071) [14]. The studies reviewed had limited sample sizes (fewer than 100 participants each) and utilized varying types and dosages of PPIs, resulting in differing levels of acid suppression. Specifically, the lansoprazole employed in Sue et al.‘s research exhibited comparatively weaker acid-suppressing effects and a longer onset time, which may account for the observed discrepancies in their findings relative to other studies.
Our study employed high-dose ESO, noted for its potent acid suppression and tolerability within the PPI class. The findings revealed no significant difference in re-eradication rates between the high-dose ESO-based therapy and VON-based therapy groups (89.2% vs. 86.0%, X² = 0.767, P = 0.381). Among patients receiving individualized precision treatment, the re-eradication rates were 87.3% for ESO-P and 86.9% for VON-P (X² = 0.006, P = 0.940). For empirical treatment, the rates were 90.2% for ESO-E and 84.9% for VON-E (X² = 1.092, P = 0.296). There were no significant differences between ESO-E and ESO-P (X² = 0.412, P = 0.521) or between VON-E and VON-P (X² = 0.092, P = 0.762). Therefore, we suggest that, compared to the direct use of the relatively expensive VON for suppression, the use of antibiotics guided by local epidemiological sensitivity or drug susceptibility results, combination with ESO, can also achieve favorable eradication outcomes. From a health economics perspective, in areas with a strong public health foundation, empirical treatment can undoubtedly save public health resources while achieving good treatment. However, in areas without such a foundation, individualized treatment is a more efficient therapeutic approach.
This study has several notable limitations inherent to its design and scope. Primarily, its retrospective, single-center nature constrained both the depth and breadth of data collection, limiting the range of clinical characteristics available for analysis. This design also introduces potential for bias stemming from clinician decision-making and patient choices that were not fully quantified. Additionally, key potential confounding factors, such as the precise timing of medication administration, were not systematically recorded. While pharmacy dispensing records confirmed complete medication distribution, actual patient adherence was not objectively verified through methods like electronic monitoring, leaving consumption patterns uncertain. Furthermore, the absence of systematic documentation of adherence and adverse events limits the overall quality of the study. Lastly, the relatively small sample size may limit the statistical power and generalizability of the findings. These limitations notwithstanding, our real-world data provide clinically relevant insights.
Conclusions
In the context of H. pylori antibiotic resistance, enhanced acid suppression and sensitivity-based antibiotics are potential treatment options. This study suggests that H. pylori re-eradication therapy based on antibiotic susceptibility results or regional epidemiological drug sensitivity characteristics, using either high-dose ESO or VON, shows good eradication rates (greater than 80%) without statistical differences. This implies that in H. pylori re-eradication, acid suppression serves as an adjunctive therapy, while antibiotics are the core treatment. Using sensitivity-based antibiotics in conjunction with high-intensity acid suppression can facilitate the re-eradication of H. pylori. While our data suggest comparable efficacy between epidemiology- and susceptibility-guided approaches, this finding warrants validation in large randomized trials before broad implementation.
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Acknowledgements
It is acknowledged that in the data collection we obtained valuable help from Helicobacter pylori Research Key Laboratory, Nanjing Medical University.
Declarations
Ethics approval and consent to participate
The study was approved by the Ethics Committee of Nanjing First Hospital.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
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Xuetian Qian
is a PhD who is mainly engaged in Helicobacter pylori eradication research.
Bo Gao
is a chief nurse who is mainly engaged in Helicobacter pylori infection research.
Zhenqiu Chen
is a undergraduate undergraduate who is mainly engaged in Helicobacter pylorieradication research.
Zhenyu Zhang
is a MD who is mainly engaged in Helicobacter pylori eradication research.
Zongdan Jiang
is a MD who is mainly engaged in Helicobacter pylori eradication and infection research.
