Low-dose versus high-dose amoxicillin in vonoprazan-based dual therapy for Helicobacter pylori eradication: a systematic review and meta-analysis

Low-dose versus high-dose amoxicillin in vonoprazan-based dual therapy for Helicobacter pylori eradication: a systematic review and meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Low-dose versus high-dose amoxicillin in vonoprazan-based dual therapy for Helicobacter pylori eradication: a systematic review and meta-analysis Hao Wang, Ming Gao, Junzhao Liu, Mingyang Yang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6785855/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Vonoprazan-based dual therapy with high dose amoxicillin is comparable to or even better than bismuth quadruple therapy (BQT). It is uncertain whether low-dose amoxicillin can be used instead of high-dose amoxicillin. We conducted a systematic review and meta-analysis to compare the efficacy, safety and compliance in vonoprazan dual therapy with low or high dose amoxicillin. Methods A comprehensive search of the literature from the PubMed, Embase, Cochrane Library, and Web of Science databases was conducted up to December 15, 2024. Trials comparing H. pylori eradication rates and adverse events between vonoprazan-amoxicillin with a low-dose amoxicillin regimen (L-VA) and a high-dose amoxicillin regimen (H-VA) were included. Data were pooled using fixed- or random-effects models and expressed as relative risk (RR) with corresponding 95% confidence interval (CI). Results Seven randomized controlled trials (RCTs) with 1688 patients were included. The H-VA dual therapy showed superior H. pylori eradication rates compared to the L-VA dual therapy (intention-to-treat [ITT]: 84.0% vs. 79.8%; RR=1.05, 95%CI 1.00-1.09; P=0.03; per-protocol [PP]: 89.4% vs. 85.0%; RR=1.06; 95%CI 1.02-1.09; P=0.001). Subgroup analysis by treatment duration showed no significant difference in eradication rates between the H-VA and L-VA groups for 7-day therapy (67.0% vs. 60.2%; RR=1.13; 95%CI 0.92-1.38; P=0.24), 10-day therapy (87.7% vs. 81.7%; RR=1.06; 95%CI 0.97-1.16; P=0.17), and 14-day therapy (85.3% vs. 83.2%; RR=1.02; 95%CI 0.96-1.08; P=0.50) in the ITT analysis. In the PP analysis, the H-VA group had significantly higher eradication rates compared to the L-VA group over 14 days (93.9% vs. 89.9%; RR=1.04; 95%CI 1.00-1.09; P=0.04; I²=0%). The subgroup analysis for 7-day (68.3% vs. 67.7%; RR=1.02; 95%CI 0.85-1.23; P=0.81; I²=0%) and 10-day therapy (90.7% vs. 84.0%; RR=1.07; 95%CI 0.98-1.16; P=0.11; I²=44%) revealed no significant differences. The incidence of adverse events and treatment compliance were similar between the two groups. Conclusion The H-VA dual therapy demonstrated superior efficacy compared to L-VA therapy in the treatment of H. pylori infection. A 14-day course of H-VA was associated with higher eradication rates when compared to L-VA. Safety and compliance were comparable between the two treatment groups. H. pylori Vonoprazan Amoxicillin Dose Duration Meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Helicobacter pylori (H.pylori), a Gram-negative, microaerophilic bacterium, contributes to the development of gastrointestinal diseases, including chronic gastritis, peptic ulcer, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma. The global prevalence of H. pylori infection in adults is still estimated to be around 43.9% despite a decline during the last 3 decades [ 1 ]. The overwhelming majority of evidence suggests that eradicating H. pylori provides significant clinical value and the most notable benefit being a substantial decrease in the incidence of gastric cancer [ 2 – 4 ]. Guidelines and consensus recommend that H. pylori infections should be eradicated whenever possible, unless there are compelling reasons not to [ 5 – 7 ]. With the increasing antibiotic resistance, traditional H. pylori eradication therapies are becoming less effective. Therefore, the treatment regimens for H. pylori should be refined and tailored to improve eradication efficacy. [ 8 ]. Bismuth quadruple therapy (BQT) is currently the preferred first-line treatment in most regions. High-dose proton pump inhibitor (PPI)-amoxicillin dual therapy (HDDT) has been validated to show similar efficacy with fewer adverse effects compared to BQT regimen [ 9 , 10 ]. The minimum inhibitory concentration (MIC) of amoxicillin is significantly impacted by gastric pH, with a higher pH generally leading to increased effectiveness of amoxicillin against H. pylori. Moreover, amoxicillin functions as a time-dependent antibiotic, and therefore, boosting either the dosage or the administration frequency might improve its effectiveness [ 11 ]. A recent systematic review and meta-analysis revealed that HDDT four times daily for 14 days demonstrated superior efficacy and safety compared to standard treatments in regions with high antimicrobial resistance. The potential reason might be a very low percentage of H. pylori strains showing resistance to amoxicillin [ 12 ]. HDDT regimen composed of a double standard dose PPI and high dose amoxicillin (3g, administered 3 or 4 times/day) has been recommended as for first-line H. pylori therapy by Chinese practice guidelines [ 7 ] or as salvage therapy by the 2023 Global Guideline on H. pylori [ 13 ]. However, most of evidence are primarily from Asian countries and unacceptable eradication rates were observed in some other regions [ 14 , 15 ]. An international, multicenter, prospective non-interventional Registry (Hp-EuReg) study demonstrated that overall HDDT effectiveness was only 52% in per-protocol (PP) analysis and 51% in modified intention-to-treat (ITT) analysis [ 16 ]. The eradication rates of HDDT might be significantly affected by the types of PPI, the dosages and the administration frequency of the amoxicillin [ 17 ]. Vonoprazan, a first-in-class potassium-competitive acid blocker (PCAB), has been investigated in combination therapies for the eradication of H. pylori and was first approved in Japan in December 2014. It has already been approved in the United States for use in combination with amoxicillin (VA dual therapy) or with both amoxicillin and clarithromycin (as triple therapy) to treat H. pylori infection in adult patients based on clinical trial findings [ 18 , 19 ]. The recommended dosage for the dual therapy regimen is vonoprazan 20 mg twice daily and amoxicillin 1000 mg three times daily for 14 days. A meta-analysis demonstrated that the efficacy of VA dual therapy is non-inferior to vonoprazan-based triple therapy but superior to the PPI-based triple therapy and has fewer side effects [ 20 ]. It is worth noting that patients with clarithromycin-resistant strains are particularly expected to benefit from vonoprazan/amoxicillin dual therapy [ 21 ]. A series of studies have also demonstrated that VA dual therapy is as effective as BQT in eliminating H. pylori with fewer adverse events and higher adherence [ 22 – 24 ]. High eradication rates, favorable safety profile, and potential for reduced antibiotic use are making VA dual therapy a promising option for managing H. pylori infections. Pharmacokinetic and pharmacodynamic studies suggest vonoprazan is more potent and long-lasting in suppressing acid secretion than PPIs, which can provide higher and more consistent control of intragastric pH compared to PPIs [ 25 , 26 ]. Theoretically speaking, a high dose of amoxicillin may not be essential in VA dual therapy while it originates from HDDT regimen. In recent years, some studies have been trying to explore the potential efficacy of VA dual therapy with different doses of amoxicillin. A prospective, randomised clinical trial performed in Japan showed that vonoprazan combined with low-dose amoxicillin achieved satisfactory H. pylori eradication rates, demonstrating comparable efficacy to vonoprazan-based triple therapy in areas with high clarithromycin resistance [ 27 ]. We therefore conducted a systematic review and meta-analysis of studies to compare the efficacy of low-dose and high-dose amoxicillin in VA dual therapy for eradicating H. pylori. Moreover, we aim to compare the adverse events and compliance rates between the regimens of different amoxicillin doses. The results and conclusions will help clinicians use antibiotics more rationally for eradicating H. pylori in clinical practice. Methods The study was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (number: CRD42024626448) and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for reporting systematic reviews and meta-analyses [ 28 , 29 ]. Search strategy An electronic search was performed across the PubMed, Embase, Cochrane Library and Web of Science databases from their inception through May 1st, 2025, without any language restrictions. The following keywords and/or medical subject heading terms were used: (“Helicobacter pylori” or “H. pylori” or “Hp” or “Campylobacter pylori”) and (“vonoprazan” or “vonaprazan” or “potassium-competitive acid blocker” or “Takecab” or “P-CAB” or “TAK-438”) and (“amoxicillin” or “amoxycillin”). In addition, a manual search of relevant articles was carried out by examining references from related studies and published reviews to find additional relevant citations. Selection criteria The research selection process involves two evaluations, both carried out independently by two reviewers. They evaluate the abstract and title of the article to determine if it is related to the research; if not, it is excluded. Subsequently, the two reviewers evaluate the full-text article based on the established criteria for inclusion. The inclusion criteria for this meta-analysis were in accordance with the PICOS principles. Participants (P): Adults with H. pylori infection diagnosed using one or more of the following methods: 13 C-/ 14 C-urea breath test, rapid urease test, histological examination, H. pylori culture, stool antigen test, or anti-H. pylori antibody blood test, and no previous H pylori eradication treatment. Intervention (I): Two groups were compared-one treated with vonoprazan-amoxicillin in combination with a low-dose amoxicillin regimen (L-VA), and the other with a high-dose amoxicillin regimen (H-VA), where low-dose amoxicillin was defined as less than 3 g/day and high-dose amoxicillin as 3 g/day or more. Outcomes (O): (a) Primary outcome: H. pylori eradication rate; (b) Secondary outcome: incidence of adverse events and compliance. Study design (S): Randomized controlled trials and observational studies were all included. Studies were excluded if they were abstracts, conference proceedings, editorials, or reviews, or meta-analyses, ongoing trials, studies without sufficient data, and duplicate publications were all excluded. Study selection and date extraction Two independent researchers (HW and MG), performed the initial screening of titles and abstracts. Subsequently, full-length articles corresponding to the identified studies were retrieved. Data extraction was conducted, and consensus was achieved on all items by these researchers. The following data were extracted from each study when available: first author's name, study design, country, number of populations, diagnostic criteria, treatment line, post-treatment assessment, detailed medication regimen, treatment duration (in days), H. pylori eradication rates, adverse events, and compliance. The primary outcome was the H. pylori eradication rate, while the secondary outcomes were the incidence of adverse events and compliance. Both intention-to-treat (ITT) and per-protocol (PP) analyses of eradication rates were performed, with subgroup analyses based on treatment duration. Quality assessment The quality of randomized controlled trials (RCTs) was evaluated using the Jadad scale [ 30 ], and the quality of observational studies was assessed using the nine-item Newcastle-Ottawa Quality scale [ 31 ]. High-quality studies were defined as those with a Jadad score of ≥ 2 (out of 5) or a modified Newcastle-Ottawa score of ≥ 5 (out of 9). Any disagreements were resolved by consensus or through discussion with a third reviewer. Statistics analysis A meta-analysis was conducted using RevMan 5.4 software (Cochrane Collaboration, Copenhagen, Denmark). To provide a more conservative estimation, pooled relative risk (RR) values and their corresponding 95% confidence intervals (CI) were computed for each study using the Mantel-Haenszel method with a random effects model, regardless of the presence or absence of heterogeneity [ 32 ]. Both intention-to-treat (ITT) and per-protocol (PP) analyses were performed to assess the H. pylori eradication rate. Statistical heterogeneity among studies was evaluated using Cochran’s Q test and the I² statistic. A p-value of less than 0.10 in Cochran’s Q test was considered statistically significant. Heterogeneity was classified into four levels based on I² values: insignificant (0–25%), low (26–50%), moderate (51–75%), and high (> 75%) [ 33 ]. Subgroup analyses were conducted based on treatment duration. A two-tailed p-value of less than 0.05 was considered statistically significant for differences between the two groups. If the meta-analysis included a sufficient number of studies (n ≥ 10) [ 34 ], publication bias was evaluated through visual inspection of funnel plot and Egger's test [ 35 ], conducted using STATA/SE 12.0 (STATA Corporation, Texas, USA). A p-value below 0.05 was considered indicative of significant publication bias. Results Study selection and enrollment processes We identified 1125 potentially eligible studies through electronic database searches. Of these, 546 were excluded due to duplication. Following a review of titles and abstracts, 535 studies were deemed irrelevant. A full-text review of 44 studies resulted in the exclusion of 37 records, which were either abstracts, letters, conference proceedings, reviews, or studies that lacked sufficient outcome data or did not evaluate the outcomes of L-VA versus H-VA in patients with H. pylori. As a result, seven RCTs were included in the final analysis [ 36 – 42 ]. Figure 1 presents a flowchart illustrating the study selection process. Study characteristics and risk of bias In total, 1688 patients were involved in seven RCTs published over the past three years. The sample sizes of the studies spanned from 110 to 504 patients. The treatment period was 7 days, 10 days, or 14 days. Hu et al. reported the outcomes of L-VA versus H-VA treatment over two durations: 7 days and 10 days [ 36 ]. Specifically, two studies compared L-VA and H-VA treatment for 7 days, three studies examined the treatment for 10 days, and three studies assessed the treatment for 14 days. Liu et al. used two high-dose amoxicillin groups, one with a dose of 1000 mg three times daily and the other with 1250 mg tid [ 40 ]. All the studies included in our meta-analysis were conducted in China. Among these studies, three were multicenter RCTs, while the remaining four were single-center RCTs. The mean Jadad score for all eligible trials was 3 and all were considered high quality, as they had a Jadad score of ≥ 2. The characteristics of the studies are presented in Table 1 . Table 1 Characteristics of included studies Study Country Study design Treatment line Diagnostic criterion Assessed after treatment Number of populations Vonoprazan dose Amoxicillin dose Duration of treatment (day) Jadad score Hu 2022 China Single-center RCT First line (1) histology, or (2) 13 C-UBT 13 C-UBT 119 20 mg bid L: 1000 mg bid H: 1000 mg tid 7, 10 3 Lin 2022 China Multicenter RCT First line 13 C/ 14 C-UBT UBT 169 20 mg bid L: 500 mg qid H: 750 mg qid 7 3 Qian 2022 China Single-center RCT First line Any 2 ways of (1) 13 C-UBT, (2) RUT, (3) histopathology 13 C-UBT 250 20 mg bid L: 1000 mg bid H: 750 mg qid 10 3 Hu 2023 China Single-center RCT First line (1) immunohistochemistry or (2) 13 C-UBT 13 C-UBT 110 20 mg bid L: 1000 mg bid H: 1000 mg tid 14 3 Liu 2024 China Single-center RCT First line (1) pathological examination or (2) 13 C/ 14 C-UBT 13 C/ 14 C-UBT 192 20 mg bid L: 750 mg tid H: 1000 mg tid H: 1250 mg tid 14 3 Hu 2024 China Multicenter RCT First line 13 C-UBT 13 C-UBT 504 20 mg bid L: 1000 mg bid H: 1000 mg tid 14 3 Peng 2024 China Multicenter RCT First line (1) 13 C-UBT or (2) histopathologic examination 13 C-UBT 344 20 mg bid L: 1000 mg bid H: 750 mg qid 10 3 RCT, randomized controlled trial; RUT, rapid urease test; UBT, urea breath test; L, low; H, high; bid, twice a day; tid, three times a day; qid, four times a day. H. pylori eradication rate Overall eradication rate In the ITT analysis, the H-VA group showed significantly higher eradication rates than the L-VA group (84.0% vs. 79.8%; RR = 1.05, 95%CI 1.00-1.09; P = 0.03; I²=0%) (Fig. 2 A). Similarly, in the PP analysis, the H-VA group was associated with higher eradication rates compared to the L-VA group (89.4% vs. 85.0%; RR = 1.06; 95%CI 1.02–1.09; P = 0.001; I²=0%) (Fig. 2 B). Subgroup analysis In the ITT analysis, the subgroup analysis based on treatment duration revealed no statistically significant difference in eradication rates between the H-VA and L-VA groups for 7-day therapy (67.0% vs. 60.2%; RR = 1.13; 95%CI 0.92–1.38; P = 0.24; I²=0%), 10-day therapy (87.7% vs. 81.7%; RR = 1.06; 95%CI 0.97–1.16; P = 0.17; I²=40%), and 14-day therapy (85.3% vs. 83.2%; RR = 1.02; 95%CI 0.96–1.08; P = 0.50; I²=0%) (Fig. 3 A). In the PP analysis, the eradication rates over a 14-day period were significantly higher in the H-VA group than in the L-VA group (93.9% vs. 89.9%; RR = 1.04; 95%CI 1.00-1.09; P = 0.04; I²=0%). The subgroup analysis for 7-day (68.3% vs. 67.7%; RR = 1.02; 95%CI 0.85–1.23; P = 0.81; I²=0%) and 10-day therapy (90.7% vs. 84.0%; RR = 1.07; 95%CI 0.98–1.16; P = 0.11; I²=44%) revealed no statistically significant difference in eradication rates between the H-VA and L-VA groups. (Fig. 3 B). Adverse events The meta-analysis found no statistically significant differences between the L-VA and H-VA groups regarding the number of patients with adverse events. (14.4% vs.16.1%; RR = 0.90; 95%CI 0.72–1.14; P = 0.39; I²=0%). No statistically significant difference was found between the L-VA and H-VA groups in terms of the incidence of diarrhea (3.7% vs. 5.7%; RR = 0.67; 95%CI 0.43–1.03; P = 0.07; I²=0%), nausea/vomiting (4.0% vs. 4.8%; RR = 0.82; 95%CI 0.52–1.28; P = 0.39; I²=0%), abdominal pain (2.7% vs. 2.1%; RR = 1.20, 95%CI: 0.60–2.38, P = 0.61, I²=6%), abdominal bloating (2.6% vs. 3.6%; RR = 0.74; 95% CI 0.41–1.36; P = 0.34; I²=0%), skin rash (1.6% vs. 2.2%; RR = 0.72; 95%CI 0.32–1.62; P = 0.43; I²=0%), constipation (1.7% vs. 0.2%; RR = 3.73; 95%CI 0.93–15.03; P = 0.06; I²=0%), headache (4.5% vs. 3.8%; RR = 1.15; 95%CI 0.52–2.54; P = 0.73; I²=0%), dizziness (0.4% vs. 1.1%; RR = 0.46; 95%CI 0.10–2.05; P = 0.31; I²=0%), and hunger sensation (2.0% vs.1.5%; RR = 1.40; 95%CI 0.45–4.38; P = 0.56; I²=0%) (Fig. 4 ). Compliance All included studies reported compliance, and the meta-analysis showed the compliance was also similar for the L-VA and H-VA dual therapies (96.8% vs. 96.8%; RR = 1.00; 95%CI 0.99–1.01; P = 0.81; I²=0%) (Fig. 5 ). Discussion BQT has been widely used and is currently the most optimized treatment regimen for the first-line H. pylori eradication. Accumulating evidence indicates that VA dual therapy is comparable to the BQT regimen. A multicenter, prospective, randomized, parallel-controlled study showed that the efficacy and safety of a 14-day VA dual therapy are superior to BQT for eradicating H. pylori, and this combination significantly reduces the use of antibiotics [ 43 ]. These results are in line with another study by Ka Shing Cheung et al. in 2024. In this study, ITT analysis showed that VA dual (eradication rate of 96.0%) was non-inferior to BQT therapy (92.0%) (difference: 4.0%, 95% CI: -2.9–11.5%, P < 0.001). PP analysis also revealed non-inferiority (96.7% vs. 97.4%, with difference: -2.9%, P = 0.009). The frequency of adverse events was 39.0% and 71.0% in VA dual and BQT therapies, respectively [ 44 ]. Such excellent outcome of VA dual derives from vonoprazan by increasing gastric acid suppression potently and optimizing antimicrobial activity, while it is well-known that amoxicillin is much more stable and effective with higher intragastric pH by strongly inhibit gastric acid secretion. For this reason, it is very interesting to explore the potential efficacy of VA dual with a low dose amoxicillin (< 3g/daily). To our knowledge, this is the most recent and comprehensive meta-analysis that assessed the efficacy and safety of VA dual therapy with low and high dose amoxicillin for first-line H. pylori eradication. This systematic review and meta-analysis included 7 studies, enrolling 1688 patients without eradication history. In the ITT analysis, the pooled eradication rate in the H-VA group was significantly higher eradication rates than the L-VA group (84.0% vs. 79.8%; RR = 1.05, P = 0.03). In the PP analysis, the pooled eradication rate in H-VA group was better than that of the L-VA group (89.4% vs. 85.0%; RR = 1.06; 95%CI 1.02–1.09; P = 0.001). This finding is contrary to a previous meta-analysis which suggested that H-VA and L-VA dual therapy achieved comparable eradication rates in ITT and PP analysis [ 45 ]. This discrepancy could be attributed to three more studies included in current work that published in 2024 [ 40 – 42 ]. Interestingly, L-VA regimen reach much higher eradication rate in Japan than in China. The reason for this is not clear but it may have something to do with amoxicillin sensitivity. Except for the dose of antibiotic, the outcomes of H. pylori eradication were obviously affected by treatment duration as well. In terms of PPI-based triple therapy, 14-day treatment is associated with a significantly higher eradication rate, and BQT is generally recommended for 14 days’ treatment [ 7 , 46 ]. However, some studies have shown that 10-day BQT is just as effective as 14-day BQT [ 47 – 50 ]. As for VA dual therapy, 14-day treatment is recommended based on label and pivotal clinical trials. Similarly, some studies also demonstrated that 10-day VA dual therapy with a high dose amoxicillin can provide a satisfactory eradication rate (> 90%). In the current study, we conducted subgroup analysis based on different durations. Only 2 of 7 studies explored the efficacy of VA dual with low and high dose amoxicillin for 7-day treatment [ 36 , 37 ]. In the ITT analysis, the eradication rate was 60.2% in L-VA group while that is 67.0% in H-VA group (RR 1.13, P = 0.24). In the PP analysis, the eradication rate was 67.7% in L-VA group and 68.3% in H-VA group (RR1.02, P = 0.81). Following 10-day treatment, eradication rate was comparable between H-VA and L-VA in the ITT analysis (87.7% vs.81.7%, RR = 1.06, P = 0.17) and in the PP analysis (90.7% vs. 84.0%; RR = 1.07, P = 0.11). Thus, high or low dose amoxicillin with 10-day duration can reach to an acceptable outcome. For 14-day treatment, L-VA and H-VA showed comparable outcomes in ITT analysis (85.3% vs. 83.2%; RR = 1.02; P = 0.50), but the eradication rate was significantly higher in the H-VA group than in the L-VA group (93.9% vs. 89.9%; RR = 1.04; P = 0.04) in the PP analysis. A study that enrolled 150 patients suggested both 10-day and 14-day L-VA treatment can achieve a satisfactory eradication rate in PP analysis [54]. Moreover, Xiang Peng’s study revealed that amoxicillin (750 mg, qid) with 10- or 14-day duration may be a more appropriate choice [ 43 ]. However, Yi Hu’s study indicated that 14-day L-VA therapy was non-inferior to H-VA dual therapy [ 42 ]. When it comes to adverse events, no significant difference was observed between the L-VA and H-VA groups. No serious adverse events were reported in any of the included studies. Yi Hu’s study revealed that the diversity of gut microbiota decreased after treatment, but it returned to baseline levels after 8 to 10 weeks in both the H-VA and L-VA groups. Both groups had good compliance (96.8%), which is an advantage of the simple drug composition. Some limitations exist in this study. First, it included only 7 studies involving 1688 patients. The relatively small sample size may introduce potential sampling bias. Second, all included studies were performed in China, which restricts the generalizability of the findings to populations in other global regions. Third, the included studies differed with respect to the dosage and frequency of low dose amoxicillin used (1000mg bid, 500mg qid and 750mg tid), which limits the comparability of the results of these studies. Fourth, because of the small number of studies included, the possibility of publication bias related to the eradication rate was not assessed. Future larger scale studies are required to cover more areas or populations to confirm the current conclusions. Conclusion The H-VA dual therapy demonstrated superior efficacy compared to L-VA therapy in the treatment of H. pylori infection. A 14-day course of H-VA was associated with higher eradication rates when compared to L-VA. Safety and compliance were comparable between the two treatment groups. Declarations Conflict of interest The authors declare that they have no conflict of interest. Funding This work was supported by grants from the West China Fourth Hospital, Sichuan University, NO. 2025ZNSFSC1778. References Chen YC, Malfertheiner P, Yu HT et al (2024) Global prevalence of Helicobacter pylori infection and incidence of gastric cancer between 1980 and 2022. Gastroenterology 166:605–619 Yan L, Chen Y, Chen F et al (2022) Effect of Helicobacter pylori eradication on gastric cancer prevention: updated report from a randomized controlled trial with 26.5 years of follow-up. Gastroenterology. ;163:154 – 62.e3. Luo X, Qi S, Chen M et al (2024) Maintaining H. pylori negativity after eradication can consolidate its benefit in gastric cancer prevention: a meta-Analysis. Clin Transl Gastroenterol 15:e00742 Pan KF, Li WQ, Zhang L et al (2024) Gastric cancer prevention by community eradication of Helicobacter pylori: a cluster-randomized controlled trial. Nat Med 30:3250–3260 Sugano K, Tack J, Kuipers EJ et al (2015) Kyoto global consensus report on Helicobacter pylori gastritis. Gut 64:1353–1367 Malfertheiner P, Megraud F, Rokkas T et al (2022) Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report[J]. Gut 71:1724–1762 Zhou L, Lu H, Song Z et al (2022) 2022 Chinese national clinical practice on Helicobacter pylori eradication treatment. ;135:2899 – 910 Moss SF, Shah SC, Tan MC et al (2024) Evolving concepts in Helicobacter pylori management. Gastroenterology 166:267–283 Zhou BG, Mei YZ, Zhang M et al (2023) High-dose dual therapy versus bismuth-containing quadruple therapy for Helicobacter pylori eradication: a systematic review and meta-analysis with trial sequential analysis. Th Adv Gastroenterol 16:17562848221147756 Wang H, Kong QZ, Li YY et al (2024) High-dose dual therapy versus bismuth-containing quadruple therapy for the eradication of Helicobacter pylori: A systematic review and meta-analysis. J Dig Dis 25:163–175 Furuta T, Graham DY (2010) Pharmacologic aspects of eradication therapy for Helicobacter pylori infection. Gastroenterol Clin North Am 39:465–480 Yeh JA, Huang HK, Chou AL et al (2024) Helicobacter pylori eradication with high-dose proton pump inhibitor-amoxicillin dual therapy: A systematic review and meta-analysis. Int J Antimicrob Agents 63:107159 Katelaris P, Hunt R, Bazzoli F et al (2023) Helicobacter pylori world gastroenterology organization global guideline. J Clin Gastroenterol 57:111–126 Laine L, Stein C, Neil G (1995) Limited efficacy of omeprazole-based dual and triple therapy for Helicobacter pylori: a randomized trial employing optimal dosing. Am J Gastroenterol 90:1407–1410 Graham DY, Javed SU, Keihanian S et al (2010) Dual proton pump inhibitor plus amoxicillin as an empiric anti-H. pylori therapy: studies from the United States. J Gastroenterol 45:816–820 Fernández-Salazar L, Campillo A, Rodrigo L et al (2022) Effectiveness and safety of high-dose dual therapy: results of the european registry on the management of Helicobacter pylori Infection (Hp-EuReg). J Clin Med 11:3544 Yun J, Wu Z, Qi G et al (2021) The high-dose amoxicillin-proton pump inhibitor dual therapy in eradication of Helicobacter pylori infection. Expert Rev Gastroenterol Hepatol 15:149–157 Furuta T, Yamade M, Kagami T et al (2020) Dual therapy with vonoprazan and amoxicillin is as effective as triple therapy with vonoprazan, amoxicillin and clarithromycin for eradication of Helicobacter pylori. Digestion 101:743–751 Chey WD, Mégraud F, Laine L et al (2022) Vonoprazan triple and dual therapy for Helicobacter pylori infection in the United States and Europe: randomized clinical Trial. Gastroenterology 163:608–619 Feng JH, Cheng J, Lao YJ et al (2023) The efficacy and safety of vonoprazan-amoxicillin dual therapy in eradicating Helicobacter pylori: a systematic review and meta-analysis. Eur J Med Res 28:272 Zhang WL, Lin BS, Li YY et al (2023) Efficacy and safety of vonoprazan and amoxicillin dual therapy for Helicobacter pylori eradication: a systematic review and meta-analysis. Digestion 104:249–261 Chen PY, Tsai FP, Chen MJ et al (2024) Vonoprazan-based versus proton pump inhibitor-based therapy in Helicobacter pylori eradication: an updated systematic review and meta-analysis of randomised trials. Gut 73:872–874 Zhou BG, Jiang X, Ding YB et al (2024) Vonoprazan-amoxicillin dual therapy versus bismuth-containing quadruple therapy for Helicobacter pylori eradication: A systematic review and meta-analysis. Helicobacter 29:e13040 Liu L, Shi H, Shi Y et al (2024) Vonoprazan-based therapies versus PPI-based therapies in patients with H. pylori infection: systematic review and meta-analyses of randomized controlled trials. Helicobacter 29:e13094 Ohkuma K, Iida H, Inoh Y et al (2018) Comparison of the early effects of vonoprazan, lansoprazole and famotidine on intragastric pH: a three-way crossover study. J Clin Biochem Nutr 63:80–83 Abdel-Aziz Y, Metz DC, Howden CW (2021) Review article: potassium-competitive acid blockers for the treatment of acid-related disorders. Aliment Pharmacol Ther 53(7):794–809 Suzuki S, Gotoda T, Kusano C et al (2020) Seven-day vonoprazan and low-dose amoxicillin dual therapy as first-line Helicobacter pylori treatment: a multicentre randomised trial in Japan. Gut 69:1019–1026 Page MJ, McKenzie JE, Bossuyt PM et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71 Arya S, Kaji AH, Boermeester MA (2021) PRISMA reporting guidelines for meta-analyses and systematic reviews. JAMA Surg 156:789–790 Jadad AR, Moore RA, Carroll D et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12 Wells GA, Shea B, O’Connell D et al The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. [cited 2025 Feb 2. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp DerSimonian R (1996) Meta-analysis in the design and monitoring of clinical trials. Stat Med 15:1237–1248 Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560 Sterne J, Sutton AJ, Ioannidis J et al (2011) Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 343:d4002 Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta analysis detected by a simple, graphical test. BMJ 315:629–634 Hu Y, Xu X, Ouyang YB et al (2022) Optimization of vonoprazan-amoxicillin dual therapy for eradicating Helicobacter pylori infection in China: A prospective, randomized clinical pilot study. Helicobacter 27:e12896 Lin Y, Xu H, Yun J et al (2022) The efficacy of vonoprazan combined with different dose amoxicillin on eradication of Helicobacter pylori: an open, multicenter, randomized clinical study. Ann Transl Med 10:987 Qian HS, Li WJ, Dang YN et al (2023) Ten-day vonoprazan-amoxicillin dual therapy as a first-line treatment of Helicobacter pylori infection compared with bismuth-containing quadruple therapy. Am J Gastroenterol 118:627–634 Hu Y, Xu X, Liu XS et al (2023) Fourteen-day vonoprazan and low- or high-dose amoxicillin dual therapy for eradicating Helicobacter pylori infection: A prospective, open-labeled, randomized non-inferiority clinical study. Front Immunol 13:1049908 Liu Z, Sun D, Kou L et al (2024) Vonoprazan-amoxicillin dual therapy with different amoxicillin dosages for treatment-naive patients of Helicobacter pylori infection in China: a prospective, randomized controlled study. Eur J Gastroenterol Hepatol 36:712–719 Peng X, Yao JY, Ma YQ et al (2024) Efficacy and safety of vonoprazan-amoxicillin dual regimen with varying dose and duration for Helicobacter pylori eradication: a multicenter, prospective, randomized study. Clin Gastroenterol Hepatol 22:1210–1216 Hu Y, Zhang ZY, Wang F et al 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. Lancet Microbe,100975. Peng X, Chen HW, Wan Y et al (2023) Combination of vonoprazan and amoxicillin as the first-line Helicobacter pylori eradication therapy: a multicenter, prospective, randomized, parallel-controlled study. Clin Exp Med 23:4011–4019 Cheung KS, Lyu T, Deng Z et al (2024) Vonoprazan dual or triple therapy versus bismuth-quadruple therapy as first-line therapy for Helicobacter pylori infection: a three-arm, randomized clinical trial. Helicobacter 29:e13133 Ju KP, Kong QZ, Li YY et al (2024) Low-dose or high-dose amoxicillin in vonoprazan-based dual therapy for Helicobacter pylori eradication? A systematic review and meta-analysis. Helicobacter 29:e13054 Chey WD, Howden CW, Moss SF et al (2024) ACG clinical guideline: treatment of Helicobacter pylori Infection. Am J Gastroenterol 119:1730–1753 Olmedo L, Calvet X, Gené E et al (2024) Evolution of the use, effectiveness and safety of bismuth-containing quadruple therapy for Helicobacter pylori infection between 2013 and 2021: results from the European registry on H. pylori management (Hp-EuReg). Gut 74:15–25 Ding YM, Duan M, Han ZX et al (2024) Bismuth-containing quadruple therapy for Helicobacter pylori eradication: a randomized clinical trial of 10 and 14 days. Dig Dis Sci 69:2540–2547 Duan M, Kong Q, Wang H et al (2024) Optimal duration of bismuth-containing quadruple therapy for Helicobacter pylori eradication: a systematic review and meta-analysis. Helicobacter 29:e13144 Yang EH, Chen WY, Chiang HC et al (2024) 10-Day versus 14-day bismuth quadruple therapy for first-line eradication of Helicobacter pylori infection: a randomised, open-label, non-inferiority trial. EClinicalMedicine 70:102529 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6785855","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":473019930,"identity":"10a7534a-6c7b-4265-aa62-4bb16a536f6d","order_by":0,"name":"Hao Wang","email":"","orcid":"","institution":"West China Women's and Children's Hospital: Sichuan University West China Second University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Wang","suffix":""},{"id":473019931,"identity":"4fa2a14d-200f-4459-933f-f2cd96adf474","order_by":1,"name":"Ming Gao","email":"","orcid":"","institution":"Chengdu First People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ming","middleName":"","lastName":"Gao","suffix":""},{"id":473019932,"identity":"36183c31-7654-4d4f-93b1-cd1a992626a0","order_by":2,"name":"Junzhao Liu","email":"","orcid":"","institution":"Sichuan University West China Fourth Hospital: West China Fourth Hospital Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Junzhao","middleName":"","lastName":"Liu","suffix":""},{"id":473019933,"identity":"bb1cf8aa-5b6e-4599-bf03-a977cec928b9","order_by":3,"name":"Mingyang Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYNACAyj9oUJCTp4kLYwzzlgYGzaQYhkzb1tFIsMBQuYfP3v41Y2CO3YbgIzXvPMkEhgbmB8+uoFPy5m8NOscg2fJG4AMy7nbJPLYGdiMjXPwaTmQY2acY3A4GcQweLtNopixgYdNGq+W82+gWoAMA945EokNBwhpuZFj/BioxQ7EeMjbQIQWyRtvzJiBWhJADMYZxySMDZsJ+IXvfI7x55w/h+1BjA8faurk5NmbHz7Gp0XhAAObBJBOXABlAGMHj3IQkG9gYP4ApO1hjFEwCkbBKBgFGAAAOIBVDhRbjKYAAAAASUVORK5CYII=","orcid":"","institution":"Sichuan University West China Fourth Hospital: West China Fourth Hospital Sichuan University","correspondingAuthor":true,"prefix":"","firstName":"Mingyang","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2025-05-30 15:08:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6785855/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6785855/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85174264,"identity":"9fe41330-91bd-4c69-9d40-b4f39cfe57a6","added_by":"auto","created_at":"2025-06-23 06:20:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1619854,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow diagram of the study selection process.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6785855/v1/0340e4820babfe938db789a8.png"},{"id":85174266,"identity":"8b8299f2-56ba-4109-b879-103029160792","added_by":"auto","created_at":"2025-06-23 06:20:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3470183,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot for the comparison of L-VA therapy versus H-VA therapy on eradication rates according to (A) ITT analysis, (B) PP analysis. ITT, intention-to-treat analysis; PP, per-protocol analysis\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6785855/v1/6a3915824d7877342e83e565.png"},{"id":85174273,"identity":"d6e04653-22e9-4429-8122-870dbc5cf10e","added_by":"auto","created_at":"2025-06-23 06:20:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":5200571,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot comparing the subgroup analysis of eradication rates between the L-VA and H-VA groups based on treatment duration according to (A) ITT analysis, (B) PP analysis\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6785855/v1/cca0725013939b45f31f2cf3.png"},{"id":85174386,"identity":"3e7ab5a8-fe9d-49ad-b80a-857f514f1cbf","added_by":"auto","created_at":"2025-06-23 06:20:38","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":19502188,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot for the comparison of L-VA therapy versus H-VA therapy on adverse events: (A) number of patients with adverse events, (B) diarrhea, (C) nausea/vomiting, (D) abdominal pain, (E) abdominal bloating, (F) skin rash, (G) constipation, (H) headache, (I) dizziness, and (J) hunger sensation\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-6785855/v1/c22e42d68fc829847fb7b6b5.png"},{"id":85174272,"identity":"20a05d46-2ed4-4da8-9d87-ba205d553045","added_by":"auto","created_at":"2025-06-23 06:20:35","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1761145,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot for the comparison of L-VA therapy versus H-VA therapy on compliance\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-6785855/v1/187637f99bc7e25099e95c02.png"},{"id":87852194,"identity":"d19b2f0f-3745-4c80-98cf-58672c44b2b0","added_by":"auto","created_at":"2025-07-29 16:05:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":30464419,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6785855/v1/482ecbbb-38fe-4f4e-9010-153a7c713fdf.pdf"}],"financialInterests":"","formattedTitle":"Low-dose versus high-dose amoxicillin in vonoprazan-based dual therapy for Helicobacter pylori eradication: a systematic review and meta-analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHelicobacter pylori (H.pylori), a Gram-negative, microaerophilic bacterium, contributes to the development of gastrointestinal diseases, including chronic gastritis, peptic ulcer, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma.\u003c/p\u003e \u003cp\u003eThe global prevalence of H. pylori infection in adults is still estimated to be around 43.9% despite a decline during the last 3 decades [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The overwhelming majority of evidence suggests that eradicating H. pylori provides significant clinical value and the most notable benefit being a substantial decrease in the incidence of gastric cancer [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Guidelines and consensus recommend that H. pylori infections should be eradicated whenever possible, unless there are compelling reasons not to [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. With the increasing antibiotic resistance, traditional H. pylori eradication therapies are becoming less effective. Therefore, the treatment regimens for H. pylori should be refined and tailored to improve eradication efficacy. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBismuth quadruple therapy (BQT) is currently the preferred first-line treatment in most regions. High-dose proton pump inhibitor (PPI)-amoxicillin dual therapy (HDDT) has been validated to show similar efficacy with fewer adverse effects compared to BQT regimen [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The minimum inhibitory concentration (MIC) of amoxicillin is significantly impacted by gastric pH, with a higher pH generally leading to increased effectiveness of amoxicillin against H. pylori. Moreover, amoxicillin functions as a time-dependent antibiotic, and therefore, boosting either the dosage or the administration frequency might improve its effectiveness [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. A recent systematic review and meta-analysis revealed that HDDT four times daily for 14 days demonstrated superior efficacy and safety compared to standard treatments in regions with high antimicrobial resistance. The potential reason might be a very low percentage of H. pylori strains showing resistance to amoxicillin [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. HDDT regimen composed of a double standard dose PPI and high dose amoxicillin (3g, administered 3 or 4 times/day) has been recommended as for first-line H. pylori therapy by Chinese practice guidelines [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] or as salvage therapy by the 2023 Global Guideline on H. pylori [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, most of evidence are primarily from Asian countries and unacceptable eradication rates were observed in some other regions [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. An international, multicenter, prospective non-interventional Registry (Hp-EuReg) study demonstrated that overall HDDT effectiveness was only 52% in per-protocol (PP) analysis and 51% in modified intention-to-treat (ITT) analysis [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The eradication rates of HDDT might be significantly affected by the types of PPI, the dosages and the administration frequency of the amoxicillin [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eVonoprazan, a first-in-class potassium-competitive acid blocker (PCAB), has been investigated in combination therapies for the eradication of H. pylori and was first approved in Japan in December 2014. It has already been approved in the United States for use in combination with amoxicillin (VA dual therapy) or with both amoxicillin and clarithromycin (as triple therapy) to treat H. pylori infection in adult patients based on clinical trial findings [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The recommended dosage for the dual therapy regimen is vonoprazan 20 mg twice daily and amoxicillin 1000 mg three times daily for 14 days. A meta-analysis demonstrated that the efficacy of VA dual therapy is non-inferior to vonoprazan-based triple therapy but superior to the PPI-based triple therapy and has fewer side effects [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. It is worth noting that patients with clarithromycin-resistant strains are particularly expected to benefit from vonoprazan/amoxicillin dual therapy [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A series of studies have also demonstrated that VA dual therapy is as effective as BQT in eliminating H. pylori with fewer adverse events and higher adherence [\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. High eradication rates, favorable safety profile, and potential for reduced antibiotic use are making VA dual therapy a promising option for managing H. pylori infections.\u003c/p\u003e \u003cp\u003ePharmacokinetic and pharmacodynamic studies suggest vonoprazan is more potent and long-lasting in suppressing acid secretion than PPIs, which can provide higher and more consistent control of intragastric pH compared to PPIs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Theoretically speaking, a high dose of amoxicillin may not be essential in VA dual therapy while it originates from HDDT regimen. In recent years, some studies have been trying to explore the potential efficacy of VA dual therapy with different doses of amoxicillin. A prospective, randomised clinical trial performed in Japan showed that vonoprazan combined with low-dose amoxicillin achieved satisfactory H. pylori eradication rates, demonstrating comparable efficacy to vonoprazan-based triple therapy in areas with high clarithromycin resistance [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe therefore conducted a systematic review and meta-analysis of studies to compare the efficacy of low-dose and high-dose amoxicillin in VA dual therapy for eradicating H. pylori. Moreover, we aim to compare the adverse events and compliance rates between the regimens of different amoxicillin doses. The results and conclusions will help clinicians use antibiotics more rationally for eradicating H. pylori in clinical practice.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe study was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (number: CRD42024626448) and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for reporting systematic reviews and meta-analyses [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy\u003c/h2\u003e \u003cp\u003eAn electronic search was performed across the PubMed, Embase, Cochrane Library and Web of Science databases from their inception through May 1st, 2025, without any language restrictions. The following keywords and/or medical subject heading terms were used: (\u0026ldquo;Helicobacter pylori\u0026rdquo; or \u0026ldquo;H. pylori\u0026rdquo; or \u0026ldquo;Hp\u0026rdquo; or \u0026ldquo;Campylobacter pylori\u0026rdquo;) and (\u0026ldquo;vonoprazan\u0026rdquo; or \u0026ldquo;vonaprazan\u0026rdquo; or \u0026ldquo;potassium-competitive acid blocker\u0026rdquo; or \u0026ldquo;Takecab\u0026rdquo; or \u0026ldquo;P-CAB\u0026rdquo; or \u0026ldquo;TAK-438\u0026rdquo;) and (\u0026ldquo;amoxicillin\u0026rdquo; or \u0026ldquo;amoxycillin\u0026rdquo;). In addition, a manual search of relevant articles was carried out by examining references from related studies and published reviews to find additional relevant citations.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSelection criteria\u003c/h3\u003e\n\u003cp\u003eThe research selection process involves two evaluations, both carried out independently by two reviewers. They evaluate the abstract and title of the article to determine if it is related to the research; if not, it is excluded. Subsequently, the two reviewers evaluate the full-text article based on the established criteria for inclusion. The inclusion criteria for this meta-analysis were in accordance with the PICOS principles. Participants (P): Adults with H. pylori infection diagnosed using one or more of the following methods: \u003csup\u003e13\u003c/sup\u003eC-/\u003csup\u003e14\u003c/sup\u003eC-urea breath test, rapid urease test, histological examination, H. pylori culture, stool antigen test, or anti-H. pylori antibody blood test, and no previous H pylori\u003c/p\u003e \u003cp\u003eeradication treatment. Intervention (I): Two groups were compared-one treated with vonoprazan-amoxicillin in combination with a low-dose amoxicillin regimen (L-VA), and the other with a high-dose amoxicillin regimen (H-VA), where low-dose amoxicillin was defined as less than 3 g/day and high-dose amoxicillin as 3 g/day or more. Outcomes (O): (a) Primary outcome: H. pylori eradication rate; (b) Secondary outcome: incidence of adverse events and compliance. Study design (S): Randomized controlled trials and observational studies were all included.\u003c/p\u003e \u003cp\u003eStudies were excluded if they were abstracts, conference proceedings, editorials, or reviews, or meta-analyses, ongoing trials, studies without sufficient data, and duplicate publications were all excluded.\u003c/p\u003e\n\u003ch3\u003eStudy selection and date extraction\u003c/h3\u003e\n\u003cp\u003eTwo independent researchers (HW and MG), performed the initial screening of titles and abstracts. Subsequently, full-length articles corresponding to the identified studies were retrieved. Data extraction was conducted, and consensus was achieved on all items by these researchers. The following data were extracted from each study when available: first author's name, study design, country, number of populations, diagnostic criteria, treatment line, post-treatment assessment, detailed medication regimen, treatment duration (in days), H. pylori eradication rates, adverse events, and compliance. The primary outcome was the H. pylori eradication rate, while the secondary outcomes were the incidence of adverse events and compliance. Both intention-to-treat (ITT) and per-protocol (PP) analyses of eradication rates were performed, with subgroup analyses based on treatment duration.\u003c/p\u003e\n\u003ch3\u003eQuality assessment\u003c/h3\u003e\n\u003cp\u003eThe quality of randomized controlled trials (RCTs) was evaluated using the Jadad scale [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], and the quality of observational studies was assessed using the nine-item Newcastle-Ottawa Quality scale [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. High-quality studies were defined as those with a Jadad score of \u0026ge;\u0026thinsp;2 (out of 5) or a modified Newcastle-Ottawa score of \u0026ge;\u0026thinsp;5 (out of 9). Any disagreements were resolved by consensus or through discussion with a third reviewer.\u003c/p\u003e\n\u003ch3\u003eStatistics analysis\u003c/h3\u003e\n\u003cp\u003eA meta-analysis was conducted using RevMan 5.4 software (Cochrane Collaboration, Copenhagen, Denmark). To provide a more conservative estimation, pooled relative risk (RR) values and their corresponding 95% confidence intervals (CI) were computed for each study using the Mantel-Haenszel method with a random effects model, regardless of the presence or absence of heterogeneity [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Both intention-to-treat (ITT) and per-protocol (PP) analyses were performed to assess the H. pylori eradication rate. Statistical heterogeneity among studies was evaluated using Cochran\u0026rsquo;s Q test and the I\u0026sup2; statistic. A p-value of less than 0.10 in Cochran\u0026rsquo;s Q test was considered statistically significant. Heterogeneity was classified into four levels based on I\u0026sup2; values: insignificant (0\u0026ndash;25%), low (26\u0026ndash;50%), moderate (51\u0026ndash;75%), and high (\u0026gt;\u0026thinsp;75%) [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Subgroup analyses were conducted based on treatment duration. A two-tailed p-value of less than 0.05 was considered statistically significant for differences between the two groups. If the meta-analysis included a sufficient number of studies (n\u0026thinsp;\u0026ge;\u0026thinsp;10) [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], publication bias was evaluated through visual inspection of funnel plot and Egger's test [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], conducted using STATA/SE 12.0 (STATA Corporation, Texas, USA). A p-value below 0.05 was considered indicative of significant publication bias.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection and enrollment processes\u003c/h2\u003e \u003cp\u003eWe identified 1125 potentially eligible studies through electronic database searches. Of these, 546 were excluded due to duplication. Following a review of titles and abstracts, 535 studies were deemed irrelevant. A full-text review of 44 studies resulted in the exclusion of 37 records, which were either abstracts, letters, conference proceedings, reviews, or studies that lacked sufficient outcome data or did not evaluate the outcomes of L-VA versus H-VA in patients with H. pylori. As a result, seven RCTs were included in the final analysis [\u003cspan additionalcitationids=\"CR37 CR38 CR39 CR40 CR41\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents a flowchart illustrating the study selection process.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy characteristics and risk of bias\u003c/h3\u003e\n\u003cp\u003eIn total, 1688 patients were involved in seven RCTs published over the past three years. The sample sizes of the studies spanned from 110 to 504 patients. The treatment period was 7 days, 10 days, or 14 days. Hu et al. reported the outcomes of L-VA versus H-VA treatment over two durations: 7 days and 10 days [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Specifically, two studies compared L-VA and H-VA treatment for 7 days, three studies examined the treatment for 10 days, and three studies assessed the treatment for 14 days. Liu et al. used two high-dose amoxicillin groups, one with a dose of 1000 mg three times daily and the other with 1250 mg tid [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. All the studies included in our meta-analysis were conducted in China. Among these studies, three were multicenter RCTs, while the remaining four were single-center RCTs. The mean Jadad score for all eligible trials was 3 and all were considered high quality, as they had a Jadad score of \u0026ge;\u0026thinsp;2. The characteristics of the studies are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of included studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTreatment line\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDiagnostic criterion\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAssessed after treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNumber of populations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVonoprazan dose\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eAmoxicillin dose\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDuration of treatment (day)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eJadad score\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c12\" namest=\"c12\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHu 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSingle-center RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFirst line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1) histology, or (2) \u003csup\u003e13\u003c/sup\u003eC-UBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003csup\u003e13\u003c/sup\u003eC-UBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e20\u0026thinsp;mg bid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eL: 1000\u0026thinsp;mg bid\u003c/p\u003e \u003cp\u003eH: 1000\u0026thinsp;mg tid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e7, 10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLin 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMulticenter RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFirst line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003csup\u003e13\u003c/sup\u003eC/\u003csup\u003e14\u003c/sup\u003eC-UBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eUBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e169\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e20\u0026thinsp;mg bid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eL: 500\u0026thinsp;mg qid\u003c/p\u003e \u003cp\u003eH: 750 mg qid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQian 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSingle-center RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFirst line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAny 2 ways of\u003c/p\u003e \u003cp\u003e(1) \u003csup\u003e13\u003c/sup\u003eC-UBT,\u003c/p\u003e \u003cp\u003e(2) RUT,\u003c/p\u003e \u003cp\u003e(3) histopathology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003csup\u003e13\u003c/sup\u003eC-UBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e20\u0026thinsp;mg bid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eL: 1000\u0026thinsp;mg bid\u003c/p\u003e \u003cp\u003eH: 750 mg qid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHu 2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSingle-center RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFirst line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1) immunohistochemistry or (2) \u003csup\u003e13\u003c/sup\u003eC-UBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003csup\u003e13\u003c/sup\u003eC-UBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e20\u0026thinsp;mg bid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eL: 1000\u0026thinsp;mg bid\u003c/p\u003e \u003cp\u003eH: 1000 mg tid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiu 2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSingle-center RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFirst line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1) pathological examination or (2) \u003csup\u003e13\u003c/sup\u003eC/\u003csup\u003e14\u003c/sup\u003eC-UBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003csup\u003e13\u003c/sup\u003eC/\u003csup\u003e14\u003c/sup\u003eC-UBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e192\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e20\u0026thinsp;mg bid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eL: 750\u0026thinsp;mg tid\u003c/p\u003e \u003cp\u003eH: 1000 mg tid H: 1250 mg tid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHu 2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMulticenter RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFirst line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003csup\u003e13\u003c/sup\u003eC-UBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003csup\u003e13\u003c/sup\u003eC-UBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e504\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e20\u0026thinsp;mg bid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eL: 1000\u0026thinsp;mg bid H: 1000 mg tid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeng 2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMulticenter RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFirst line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1) \u003csup\u003e13\u003c/sup\u003eC-UBT or\u003c/p\u003e \u003cp\u003e(2) histopathologic examination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003csup\u003e13\u003c/sup\u003eC-UBT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e344\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e20\u0026thinsp;mg bid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eL: 1000\u0026thinsp;mg bid H: 750 mg qid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eRCT, randomized controlled trial; RUT, rapid urease test; UBT, urea breath test; L, low; H, high; bid, twice a day; tid, three times a day; qid, four times a day.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eH. pylori eradication rate\u003c/h2\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003eOverall eradication rate\u003c/h2\u003e \u003cp\u003eIn the ITT analysis, the H-VA group showed significantly higher eradication rates than the L-VA group (84.0% vs. 79.8%; RR\u0026thinsp;=\u0026thinsp;1.05, 95%CI 1.00-1.09; P\u0026thinsp;=\u0026thinsp;0.03; I\u0026sup2;=0%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Similarly, in the PP analysis, the H-VA group was associated with higher eradication rates compared to the L-VA group (89.4% vs. 85.0%; RR\u0026thinsp;=\u0026thinsp;1.06; 95%CI 1.02\u0026ndash;1.09; P\u0026thinsp;=\u0026thinsp;0.001; I\u0026sup2;=0%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup analysis\u003c/h2\u003e \u003cp\u003eIn the ITT analysis, the subgroup analysis based on treatment duration revealed no statistically significant difference in eradication rates between the H-VA and L-VA groups for 7-day therapy (67.0% vs. 60.2%; RR\u0026thinsp;=\u0026thinsp;1.13; 95%CI 0.92\u0026ndash;1.38; P\u0026thinsp;=\u0026thinsp;0.24; I\u0026sup2;=0%), 10-day therapy (87.7% vs. 81.7%; RR\u0026thinsp;=\u0026thinsp;1.06; 95%CI 0.97\u0026ndash;1.16; P\u0026thinsp;=\u0026thinsp;0.17; I\u0026sup2;=40%), and 14-day therapy (85.3% vs. 83.2%; RR\u0026thinsp;=\u0026thinsp;1.02; 95%CI 0.96\u0026ndash;1.08; P\u0026thinsp;=\u0026thinsp;0.50; I\u0026sup2;=0%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). In the PP analysis, the eradication rates over a 14-day period were significantly higher in the H-VA group than in the L-VA group (93.9% vs. 89.9%; RR\u0026thinsp;=\u0026thinsp;1.04; 95%CI 1.00-1.09; P\u0026thinsp;=\u0026thinsp;0.04; I\u0026sup2;=0%). The subgroup analysis for 7-day (68.3% vs. 67.7%; RR\u0026thinsp;=\u0026thinsp;1.02; 95%CI 0.85\u0026ndash;1.23; P\u0026thinsp;=\u0026thinsp;0.81; I\u0026sup2;=0%) and 10-day therapy (90.7% vs. 84.0%; RR\u0026thinsp;=\u0026thinsp;1.07; 95%CI 0.98\u0026ndash;1.16; P\u0026thinsp;=\u0026thinsp;0.11; I\u0026sup2;=44%) revealed no statistically significant difference in eradication rates between the H-VA and L-VA groups. (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eAdverse events\u003c/h2\u003e \u003cp\u003eThe meta-analysis found no statistically significant differences between the L-VA and H-VA groups regarding the number of patients with adverse events. (14.4% vs.16.1%; RR\u0026thinsp;=\u0026thinsp;0.90; 95%CI 0.72\u0026ndash;1.14; P\u0026thinsp;=\u0026thinsp;0.39; I\u0026sup2;=0%). No statistically significant difference was found between the L-VA and H-VA groups in terms of the incidence of diarrhea (3.7% vs. 5.7%; RR\u0026thinsp;=\u0026thinsp;0.67; 95%CI 0.43\u0026ndash;1.03; P\u0026thinsp;=\u0026thinsp;0.07; I\u0026sup2;=0%), nausea/vomiting (4.0% vs. 4.8%; RR\u0026thinsp;=\u0026thinsp;0.82; 95%CI 0.52\u0026ndash;1.28; P\u0026thinsp;=\u0026thinsp;0.39; I\u0026sup2;=0%), abdominal pain (2.7% vs. 2.1%; RR\u0026thinsp;=\u0026thinsp;1.20, 95%CI: 0.60\u0026ndash;2.38, P\u0026thinsp;=\u0026thinsp;0.61, I\u0026sup2;=6%), abdominal bloating (2.6% vs. 3.6%; RR\u0026thinsp;=\u0026thinsp;0.74; 95% CI 0.41\u0026ndash;1.36; P\u0026thinsp;=\u0026thinsp;0.34; I\u0026sup2;=0%), skin rash (1.6% vs. 2.2%; RR\u0026thinsp;=\u0026thinsp;0.72; 95%CI 0.32\u0026ndash;1.62; P\u0026thinsp;=\u0026thinsp;0.43; I\u0026sup2;=0%), constipation (1.7% vs. 0.2%; RR\u0026thinsp;=\u0026thinsp;3.73; 95%CI 0.93\u0026ndash;15.03; P\u0026thinsp;=\u0026thinsp;0.06; I\u0026sup2;=0%), headache (4.5% vs. 3.8%; RR\u0026thinsp;=\u0026thinsp;1.15; 95%CI 0.52\u0026ndash;2.54; P\u0026thinsp;=\u0026thinsp;0.73; I\u0026sup2;=0%), dizziness (0.4% vs. 1.1%; RR\u0026thinsp;=\u0026thinsp;0.46; 95%CI 0.10\u0026ndash;2.05; P\u0026thinsp;=\u0026thinsp;0.31; I\u0026sup2;=0%), and hunger sensation (2.0% vs.1.5%; RR\u0026thinsp;=\u0026thinsp;1.40; 95%CI 0.45\u0026ndash;4.38; P\u0026thinsp;=\u0026thinsp;0.56; I\u0026sup2;=0%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eCompliance\u003c/h2\u003e \u003cp\u003eAll included studies reported compliance, and the meta-analysis showed the compliance was also similar for the L-VA and H-VA dual therapies (96.8% vs. 96.8%; RR\u0026thinsp;=\u0026thinsp;1.00; 95%CI 0.99\u0026ndash;1.01; P\u0026thinsp;=\u0026thinsp;0.81; I\u0026sup2;=0%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eBQT has been widely used and is currently the most optimized treatment regimen for the first-line H. pylori eradication. Accumulating evidence indicates that VA dual therapy is comparable to the BQT regimen. A multicenter, prospective, randomized, parallel-controlled study showed that the efficacy and safety of a 14-day VA dual therapy are superior to BQT for eradicating H. pylori, and this combination significantly reduces the use of antibiotics [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. These results are in line with another study by Ka Shing Cheung et al. in 2024. In this study, ITT analysis showed that VA dual (eradication rate of 96.0%) was non-inferior to BQT therapy (92.0%) (difference: 4.0%, 95% CI: -2.9\u0026ndash;11.5%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). PP analysis also revealed non-inferiority (96.7% vs. 97.4%, with difference: -2.9%, P\u0026thinsp;=\u0026thinsp;0.009). The frequency of adverse events was 39.0% and 71.0% in VA dual and BQT therapies, respectively [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Such excellent outcome of VA dual derives from vonoprazan by increasing gastric acid suppression potently and optimizing antimicrobial activity, while it is well-known that amoxicillin is much more stable and effective with higher intragastric pH by strongly inhibit gastric acid secretion. For this reason, it is very interesting to explore the potential efficacy of VA dual with a low dose amoxicillin (\u0026lt;\u0026thinsp;3g/daily).\u003c/p\u003e \u003cp\u003eTo our knowledge, this is the most recent and comprehensive meta-analysis that assessed the efficacy and safety of VA dual therapy with low and high dose amoxicillin for first-line H. pylori eradication. This systematic review and meta-analysis included 7 studies, enrolling 1688 patients without eradication history. In the ITT analysis, the pooled eradication rate in the H-VA group was significantly higher eradication rates than the L-VA group (84.0% vs. 79.8%; RR\u0026thinsp;=\u0026thinsp;1.05, P\u0026thinsp;=\u0026thinsp;0.03). In the PP analysis, the pooled eradication rate in H-VA group was better than that of the L-VA group (89.4% vs. 85.0%; RR\u0026thinsp;=\u0026thinsp;1.06; 95%CI 1.02\u0026ndash;1.09; P\u0026thinsp;=\u0026thinsp;0.001). This finding is contrary to a previous meta-analysis which suggested that H-VA and L-VA dual therapy achieved comparable eradication rates in ITT and PP analysis [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. This discrepancy could be attributed to three more studies included in current work that published in 2024 [\u003cspan additionalcitationids=\"CR41\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Interestingly,\u003c/p\u003e \u003cp\u003eL-VA regimen reach much higher eradication rate in Japan than in China. The reason for this is not clear but it may have something to do with amoxicillin sensitivity.\u003c/p\u003e \u003cp\u003eExcept for the dose of antibiotic, the outcomes of H. pylori eradication were obviously affected by treatment duration as well. In terms of PPI-based triple therapy, 14-day treatment is associated with a significantly higher eradication rate, and BQT is generally recommended for 14 days\u0026rsquo; treatment [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. However, some studies have shown that 10-day BQT is just as effective as 14-day BQT [\u003cspan additionalcitationids=\"CR48 CR49\" citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. As for VA dual therapy, 14-day treatment is recommended based on label and pivotal clinical trials. Similarly, some studies also demonstrated that 10-day VA dual therapy with a high dose amoxicillin can provide a satisfactory eradication rate (\u0026gt;\u0026thinsp;90%).\u003c/p\u003e \u003cp\u003eIn the current study, we conducted subgroup analysis based on different durations. Only 2 of 7 studies explored the efficacy of VA dual with low and high dose amoxicillin for 7-day treatment [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. In the ITT analysis, the eradication rate was 60.2% in L-VA group while that is 67.0% in H-VA group (RR 1.13, P\u0026thinsp;=\u0026thinsp;0.24). In the PP analysis, the eradication rate was 67.7% in L-VA group and 68.3% in H-VA group (RR1.02, P\u0026thinsp;=\u0026thinsp;0.81). Following 10-day treatment, eradication rate was comparable between H-VA and L-VA in the ITT analysis (87.7% vs.81.7%, RR\u0026thinsp;=\u0026thinsp;1.06, P\u0026thinsp;=\u0026thinsp;0.17) and in the PP analysis (90.7% vs. 84.0%; RR\u0026thinsp;=\u0026thinsp;1.07, P\u0026thinsp;=\u0026thinsp;0.11). Thus, high or low dose amoxicillin with 10-day duration can reach to an acceptable outcome. For 14-day treatment, L-VA and H-VA showed comparable outcomes in ITT analysis (85.3% vs. 83.2%; RR\u0026thinsp;=\u0026thinsp;1.02; P\u0026thinsp;=\u0026thinsp;0.50), but the eradication rate was significantly higher in the H-VA group than in the L-VA group (93.9% vs. 89.9%; RR\u0026thinsp;=\u0026thinsp;1.04; P\u0026thinsp;=\u0026thinsp;0.04) in the PP analysis. A study that enrolled 150 patients suggested both 10-day and 14-day L-VA treatment can achieve a satisfactory eradication rate in PP analysis [54]. Moreover, Xiang Peng\u0026rsquo;s study revealed that amoxicillin (750 mg, qid) with 10- or 14-day duration may be a more appropriate choice [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. However, Yi Hu\u0026rsquo;s study indicated that 14-day L-VA therapy was non-inferior to H-VA dual therapy [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhen it comes to adverse events, no significant difference was observed between the L-VA and H-VA groups. No serious adverse events were reported in any of the included studies. Yi Hu\u0026rsquo;s study revealed that the diversity of gut microbiota decreased after treatment, but it returned to baseline levels after 8 to 10 weeks in both the H-VA and L-VA groups. Both groups had good compliance (96.8%), which is an advantage of the simple drug composition.\u003c/p\u003e \u003cp\u003eSome limitations exist in this study. First, it included only 7 studies involving 1688 patients. The relatively small sample size may introduce potential sampling bias. Second, all included studies were performed in China, which restricts the generalizability of the findings to populations in other global regions. Third, the included studies differed with respect to the dosage and frequency of low dose amoxicillin used (1000mg bid, 500mg qid and 750mg tid), which limits the comparability of the results of these studies. Fourth, because of the small number of studies included, the possibility of publication bias related to the eradication rate was not assessed. Future larger scale studies are required to cover more areas or populations to confirm the current conclusions.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe H-VA dual therapy demonstrated superior efficacy compared to L-VA therapy in the treatment of H. pylori infection. A 14-day course of H-VA was associated with higher eradication rates when compared to L-VA. Safety and compliance were comparable between the two treatment groups.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of interest\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by grants from the West China Fourth Hospital, Sichuan University, NO. 2025ZNSFSC1778.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChen YC, Malfertheiner P, Yu HT et al (2024) Global prevalence of Helicobacter pylori infection and incidence of gastric cancer between 1980 and 2022. Gastroenterology 166:605\u0026ndash;619\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYan L, Chen Y, Chen F et al (2022) Effect of Helicobacter pylori eradication on gastric cancer prevention: updated report from a randomized controlled trial with 26.5 years of follow-up. Gastroenterology. ;163:154\u0026thinsp;\u0026ndash;\u0026thinsp;62.e3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuo X, Qi S, Chen M et al (2024) Maintaining H. pylori negativity after eradication can consolidate its benefit in gastric cancer prevention: a meta-Analysis. Clin Transl Gastroenterol 15:e00742\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan KF, Li WQ, Zhang L et al (2024) Gastric cancer prevention by community eradication of Helicobacter pylori: a cluster-randomized controlled trial. Nat Med 30:3250\u0026ndash;3260\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSugano K, Tack J, Kuipers EJ et al (2015) Kyoto global consensus report on Helicobacter pylori gastritis. Gut 64:1353\u0026ndash;1367\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMalfertheiner P, Megraud F, Rokkas T et al (2022) Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report[J]. Gut 71:1724\u0026ndash;1762\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou L, Lu H, Song Z et al (2022) 2022 Chinese national clinical practice on Helicobacter pylori eradication treatment. ;135:2899\u0026thinsp;\u0026ndash;\u0026thinsp;910\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoss SF, Shah SC, Tan MC et al (2024) Evolving concepts in Helicobacter pylori management. Gastroenterology 166:267\u0026ndash;283\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou BG, Mei YZ, Zhang M et al (2023) High-dose dual therapy versus bismuth-containing quadruple therapy for Helicobacter pylori eradication: a systematic review and meta-analysis with trial sequential analysis. Th Adv Gastroenterol 16:17562848221147756\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang H, Kong QZ, Li YY et al (2024) High-dose dual therapy versus bismuth-containing quadruple therapy for the eradication of Helicobacter pylori: A systematic review and meta-analysis. J Dig Dis 25:163\u0026ndash;175\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFuruta T, Graham DY (2010) Pharmacologic aspects of eradication therapy for Helicobacter pylori infection. Gastroenterol Clin North Am 39:465\u0026ndash;480\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYeh JA, Huang HK, Chou AL et al (2024) Helicobacter pylori eradication with high-dose proton pump inhibitor-amoxicillin dual therapy: A systematic review and meta-analysis. Int J Antimicrob Agents 63:107159\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKatelaris P, Hunt R, Bazzoli F et al (2023) Helicobacter pylori world gastroenterology organization global guideline. J Clin Gastroenterol 57:111\u0026ndash;126\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLaine L, Stein C, Neil G (1995) Limited efficacy of omeprazole-based dual and triple therapy for Helicobacter pylori: a randomized trial employing optimal dosing. Am J Gastroenterol 90:1407\u0026ndash;1410\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGraham DY, Javed SU, Keihanian S et al (2010) Dual proton pump inhibitor plus amoxicillin as an empiric anti-H. pylori therapy: studies from the United States. J Gastroenterol 45:816\u0026ndash;820\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFern\u0026aacute;ndez-Salazar L, Campillo A, Rodrigo L et al (2022) Effectiveness and safety of high-dose dual therapy: results of the european registry on the management of Helicobacter pylori Infection (Hp-EuReg). J Clin Med 11:3544\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYun J, Wu Z, Qi G et al (2021) The high-dose amoxicillin-proton pump inhibitor dual therapy in eradication of Helicobacter pylori infection. Expert Rev Gastroenterol Hepatol 15:149\u0026ndash;157\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFuruta T, Yamade M, Kagami T et al (2020) Dual therapy with vonoprazan and amoxicillin is as effective as triple therapy with vonoprazan, amoxicillin and clarithromycin for eradication of Helicobacter pylori. Digestion 101:743\u0026ndash;751\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChey WD, M\u0026eacute;graud F, Laine L et al (2022) Vonoprazan triple and dual therapy for Helicobacter pylori infection in the United States and Europe: randomized clinical Trial. Gastroenterology 163:608\u0026ndash;619\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFeng JH, Cheng J, Lao YJ et al (2023) The efficacy and safety of vonoprazan-amoxicillin dual therapy in eradicating Helicobacter pylori: a systematic review and meta-analysis. Eur J Med Res 28:272\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang WL, Lin BS, Li YY et al (2023) Efficacy and safety of vonoprazan and amoxicillin dual therapy for Helicobacter pylori eradication: a systematic review and meta-analysis. Digestion 104:249\u0026ndash;261\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen PY, Tsai FP, Chen MJ et al (2024) Vonoprazan-based versus proton pump inhibitor-based therapy in Helicobacter pylori eradication: an updated systematic review and meta-analysis of randomised trials. Gut 73:872\u0026ndash;874\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou BG, Jiang X, Ding YB et al (2024) Vonoprazan-amoxicillin dual therapy versus bismuth-containing quadruple therapy for Helicobacter pylori eradication: A systematic review and meta-analysis. Helicobacter 29:e13040\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu L, Shi H, Shi Y et al (2024) Vonoprazan-based therapies versus PPI-based therapies in patients with H. pylori infection: systematic review and meta-analyses of randomized controlled trials. Helicobacter 29:e13094\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOhkuma K, Iida H, Inoh Y et al (2018) Comparison of the early effects of vonoprazan, lansoprazole and famotidine on intragastric pH: a three-way crossover study. J Clin Biochem Nutr 63:80\u0026ndash;83\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbdel-Aziz Y, Metz DC, Howden CW (2021) Review article: potassium-competitive acid blockers for the treatment of acid-related disorders. Aliment Pharmacol Ther 53(7):794\u0026ndash;809\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuzuki S, Gotoda T, Kusano C et al (2020) Seven-day vonoprazan and low-dose amoxicillin dual therapy as first-line Helicobacter pylori treatment: a multicentre randomised trial in Japan. Gut 69:1019\u0026ndash;1026\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePage MJ, McKenzie JE, Bossuyt PM et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArya S, Kaji AH, Boermeester MA (2021) PRISMA reporting guidelines for meta-analyses and systematic reviews. JAMA Surg 156:789\u0026ndash;790\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJadad AR, Moore RA, Carroll D et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1\u0026ndash;12\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWells GA, Shea B, O\u0026rsquo;Connell D et al The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. [cited 2025 Feb 2. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ohri.ca/programs/clinical_epidemiology/oxford.asp\u003c/span\u003e\u003cspan address=\"http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDerSimonian R (1996) Meta-analysis in the design and monitoring of clinical trials. Stat Med 15:1237\u0026ndash;1248\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiggins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557\u0026ndash;560\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSterne J, Sutton AJ, Ioannidis J et al (2011) Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 343:d4002\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEgger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta analysis detected by a simple, graphical test. BMJ 315:629\u0026ndash;634\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu Y, Xu X, Ouyang YB et al (2022) Optimization of vonoprazan-amoxicillin dual therapy for eradicating Helicobacter pylori infection in China: A prospective, randomized clinical pilot study. Helicobacter 27:e12896\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin Y, Xu H, Yun J et al (2022) The efficacy of vonoprazan combined with different dose amoxicillin on eradication of Helicobacter pylori: an open, multicenter, randomized clinical study. Ann Transl Med 10:987\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQian HS, Li WJ, Dang YN et al (2023) Ten-day vonoprazan-amoxicillin dual therapy as a first-line treatment of Helicobacter pylori infection compared with bismuth-containing quadruple therapy. Am J Gastroenterol 118:627\u0026ndash;634\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu Y, Xu X, Liu XS et al (2023) Fourteen-day vonoprazan and low- or high-dose amoxicillin dual therapy for eradicating Helicobacter pylori infection: A prospective, open-labeled, randomized non-inferiority clinical study. Front Immunol 13:1049908\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Z, Sun D, Kou L et al (2024) Vonoprazan-amoxicillin dual therapy with different amoxicillin dosages for treatment-naive patients of Helicobacter pylori infection in China: a prospective, randomized controlled study. Eur J Gastroenterol Hepatol 36:712\u0026ndash;719\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeng X, Yao JY, Ma YQ et al (2024) Efficacy and safety of vonoprazan-amoxicillin dual regimen with varying dose and duration for Helicobacter pylori eradication: a multicenter, prospective, randomized study. Clin Gastroenterol Hepatol 22:1210\u0026ndash;1216\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu Y, Zhang ZY, Wang F et al 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. Lancet Microbe,100975.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeng X, Chen HW, Wan Y et al (2023) Combination of vonoprazan and amoxicillin as the first-line Helicobacter pylori eradication therapy: a multicenter, prospective, randomized, parallel-controlled study. Clin Exp Med 23:4011\u0026ndash;4019\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheung KS, Lyu T, Deng Z et al (2024) Vonoprazan dual or triple therapy versus bismuth-quadruple therapy as first-line therapy for Helicobacter pylori infection: a three-arm, randomized clinical trial. Helicobacter 29:e13133\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJu KP, Kong QZ, Li YY et al (2024) Low-dose or high-dose amoxicillin in vonoprazan-based dual therapy for Helicobacter pylori eradication? A systematic review and meta-analysis. Helicobacter 29:e13054\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChey WD, Howden CW, Moss SF et al (2024) ACG clinical guideline: treatment of Helicobacter pylori Infection. Am J Gastroenterol 119:1730\u0026ndash;1753\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOlmedo L, Calvet X, Gen\u0026eacute; E et al (2024) Evolution of the use, effectiveness and safety of bismuth-containing quadruple therapy for Helicobacter pylori infection between 2013 and 2021: results from the European registry on H. pylori management (Hp-EuReg). Gut 74:15\u0026ndash;25\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDing YM, Duan M, Han ZX et al (2024) Bismuth-containing quadruple therapy for Helicobacter pylori eradication: a randomized clinical trial of 10 and 14 days. Dig Dis Sci 69:2540\u0026ndash;2547\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDuan M, Kong Q, Wang H et al (2024) Optimal duration of bismuth-containing quadruple therapy for Helicobacter pylori eradication: a systematic review and meta-analysis. Helicobacter 29:e13144\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang EH, Chen WY, Chiang HC et al (2024) 10-Day versus 14-day bismuth quadruple therapy for first-line eradication of Helicobacter pylori infection: a randomised, open-label, non-inferiority trial. EClinicalMedicine 70:102529\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"H. pylori, Vonoprazan, Amoxicillin, Dose, Duration, Meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-6785855/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6785855/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eVonoprazan-based dual therapy with high dose amoxicillin is comparable to or even better than bismuth quadruple therapy (BQT). It is uncertain whether low-dose amoxicillin can be used instead of high-dose amoxicillin. We conducted a systematic review and meta-analysis to compare the efficacy, safety and compliance in vonoprazan dual therapy with low or high dose amoxicillin.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eA comprehensive search of the literature from the PubMed, Embase, Cochrane Library, and Web of Science databases was conducted up to December 15, 2024. Trials comparing H. pylori eradication rates and adverse events between vonoprazan-amoxicillin with a low-dose amoxicillin regimen (L-VA) and a high-dose amoxicillin regimen (H-VA) were included. Data were pooled using fixed- or random-effects models and expressed as relative risk (RR) with corresponding 95% confidence interval (CI).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eSeven randomized controlled trials (RCTs) with 1688 patients were included. The H-VA dual therapy showed superior H. pylori eradication rates compared to the L-VA dual therapy (intention-to-treat [ITT]: 84.0% vs. 79.8%; RR=1.05, 95%CI 1.00-1.09; P=0.03; per-protocol [PP]: 89.4% vs. 85.0%; RR=1.06; 95%CI 1.02-1.09; P=0.001). Subgroup analysis by treatment duration showed no significant difference in eradication rates between the H-VA and L-VA groups for 7-day therapy (67.0% vs. 60.2%; RR=1.13; 95%CI 0.92-1.38; P=0.24), 10-day therapy (87.7% vs. 81.7%; RR=1.06; 95%CI 0.97-1.16; P=0.17), and 14-day therapy (85.3% vs. 83.2%; RR=1.02; 95%CI 0.96-1.08; P=0.50) in the ITT analysis. In the PP analysis, the H-VA group had significantly higher eradication rates compared to the L-VA group over 14 days (93.9% vs. 89.9%; RR=1.04; 95%CI 1.00-1.09; P=0.04; I²=0%). The subgroup analysis for 7-day (68.3% vs. 67.7%; RR=1.02; 95%CI 0.85-1.23; P=0.81; I²=0%) and 10-day therapy (90.7% vs. 84.0%; RR=1.07; 95%CI 0.98-1.16; P=0.11; I²=44%) revealed no significant differences. The incidence of adverse events and treatment compliance were similar between the two groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion \u003c/strong\u003eThe H-VA dual therapy demonstrated superior efficacy compared to L-VA therapy in the treatment of H. pylori infection. A 14-day course of H-VA was associated with higher eradication rates when compared to L-VA. Safety and compliance were comparable between the two treatment groups.\u003c/p\u003e","manuscriptTitle":"Low-dose versus high-dose amoxicillin in vonoprazan-based dual therapy for Helicobacter pylori eradication: a systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-23 06:20:30","doi":"10.21203/rs.3.rs-6785855/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ad172b68-0f30-46a8-bec1-59f1c8250dc3","owner":[],"postedDate":"June 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-29T15:56:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-23 06:20:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6785855","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6785855","identity":"rs-6785855","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}