Yang XE, Zhang SJ, Liu Y, Yao SY, Zhang SX, Liu XM, Liang LX, Wang F. Amoxicillin high-dose dual therapy for Helicobacter pylori primary eradication: Proton pump inhibitor and potassium-competitive acid blocker, which’s better? World J Gastroenterol 2025; 31(13): 100863 [DOI: 10.3748/wjg.v31.i13.100863]
Corresponding Author of This Article
Fen Wang, MD, PhD, Professor, Department of Gastroenterology, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha 410013, Hunan Province, China. wfen-judy@csu.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Randomized Controlled Trial
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Xue-Er Yang, Shuo-Yi Yao, Su-Xin Zhang, Xiao-Ming Liu, Lun-Xi Liang, Fen Wang, Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
Xue-Er Yang, Shuo-Yi Yao, Su-Xin Zhang, Xiao-Ming Liu, Lun-Xi Liang, Fen Wang, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha 410006, Hunan Province, China
Sheng-Jun Zhang, Department of Gastroenterology, The Second People's Hospital of Huaihua, Huaihua 418000, Hunan Province, China
Yuan Liu, Department of Gastroenterology, Yueyang Hospital of Traditional Chinese Medicine, Yueyang 414100, Hunan Province, China
Author contributions: Yang XE contributed to investigation, formal analysis, and writing the original draft; Wang F, Zhang SJ, and Liu Y made conceptualization, methodology, writing, reviewing and editing the article, and supervision; Yao SY, Zhang SX, Liu XM, and Liang LX contributed to methodology, formal analysis, and writing, reviewing and editing the article; Wang F is the corresponding author of the article. All authors have read and agreed to the published version of the manuscript.
Supported by the National Natural Science Foundation of China, No. 82270594; the National Natural Science Foundation for Youths of China, No. 82103151; the Outstanding Youth Foundation of Hunan Province, No. 2022JJ20092; and the Wisdom Accumulation and Talent Cultivation Project of Third Xiangya Hospital of Central South University, No. YX202103.
Institutional review board statement: The study protocols received approval from the Ethics Committee of three medical centers (Fast 21292, Fast 23359, HHSEYYEC-202402-K1).
Clinical trial registration statement: A multi-center, prospective, open-label, randomized controlled study was conducted and registered on clinicaltrials.gov with the registration number NCT06250634.
Informed consent statement: All participants voluntarily agreed to participate in this clinical trial and provided written informed consent prior to enrollment.
Conflict-of-interest statement: The authors declare no conflicts of interest.
CONSORT 2010 statement: The authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement.
Data sharing statement: The data presented in this study are available upon request from the corresponding author.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Fen Wang, MD, PhD, Professor, Department of Gastroenterology, The Third Xiangya Hospital, Central South University, No. 138 Tongzipo Road, Changsha 410013, Hunan Province, China. wfen-judy@csu.edu.cn
Received: August 30, 2024 Revised: February 22, 2025 Accepted: March 18, 2025 Published online: April 7, 2025 Processing time: 216 Days and 22.4 Hours
Abstract
BACKGROUND
Effective acid suppression significantly enhances the eradication rate of Helicobacter pylori (H. pylori).
AIM
To assess the efficacy and safety of high-dose dual therapy (HDDT) utilizing various highly potent antisecretory medications, thereby providing additional clinical guidance for H. pylori eradication.
METHODS
The study population comprised untreated H. pylori patients from three medical centers in central China. From February 10, 2024 to March 31, 2024, 439 subjects were randomly allocated to either the esomeprazole-amoxicillin (EA) or esomeprazole-amoxicillin-clarithromycin-bismuth (B-quadruple) group. Subsequently, from April 1, 2024 to May 10, 2024, 367 subjects were randomly assigned to either the vonoprazan-amoxicillin (VA) or vonoprazan-amoxicillin-clarithromycin (VAC) group. The study recorded treatment efficacy, adverse events, compliance, symptom alleviation, and associated costs.
RESULTS
EA-dual demonstrated non-inferiority to B-quadruple regimen in modified intention-to-treat (mITT) and per-protocol (PP) analyses (P < 0.025). However, the eradication rate of EA was lower than that of the B-quadruple group [70.59% vs 83.49%, 92.86% vs 98.38%, 93.94% vs 98.38%, intention-to-treat (ITT), mITT, PP respectively, P < 0.05]. In ITT, mITT, and PP analyses, VA-dual was non-inferior to VAC treatment (84.15% vs 83.15%, 96.25% vs 92.73%, 96.75% vs 93.75%, P < 0.025). No significant differences were observed in adverse events, compliance, and symptom relief between groups. VA exhibited the lowest cost. Antibiotic use within 2 years, poor compliance, and suburban residence were associated with reduced eradication efficacy (P < 0.05).
CONCLUSION
The HDDT based on vonoprazan demonstrated non-inferiority to the VAC triple regimen, suggesting its potential as a recommended first-line treatment for H. pylori eradication. While B-quadruple therapy showed better eradication rate than EA therapy, the latter proved non-inferior in mITT and PP analyses. Notably, antibiotic use within the preceding two years, adherence to treatment protocols, and patient residence emerged as critical factors influencing eradication success.
Core Tip: The global burden of Helicobacter pylori infection is high. Triple and quadruple therapies are both classical regimens. The effect of high-dose dual therapy (HDDT) compared to classical regimens in different regions/populations is unclear. Our study found HDDT based on vonoprazan was non-inferior to the vonoprazan triple regimen. Classical quadruple therapy had a higher eradication rate than HDDT based on esomeprazole, but in modified intention-to-treat and per-protocol analysis, EA therapy was non-inferior to B-quadruple therapy.
Citation: Yang XE, Zhang SJ, Liu Y, Yao SY, Zhang SX, Liu XM, Liang LX, Wang F. Amoxicillin high-dose dual therapy for Helicobacter pylori primary eradication: Proton pump inhibitor and potassium-competitive acid blocker, which’s better? World J Gastroenterol 2025; 31(13): 100863
Helicobacter pylori (H. pylori) is a gram-negative microaerophilic bacterium that colonizes the human stomach with high prevalence[1]. Although the global infection rate of H. pylori decreased from 58.2% in 1980-1990 to 43.1% in 2011-2022, with a particularly sharp decline from 2011 to 2022[2], the burden remains significant. H. pylori infection can lead to peptic ulcers[3], and contribute to the progression from gastritis to gastric cancer[4]. Conversely, successful eradication of H. pylori can partially reverse atrophy and intestinal metaplasia[5], thereby reducing the risk of gastric cancer[6,7].
Various H. pylori eradication therapies have been recommended globally, including clarithromycin-containing triple therapy, bismuth-containing quadruple therapy, and so on[8,9]. However, both therapies have several disadvantages. Triple therapy exhibits low eradication rates[10] and has been associated with increased long-term resistant bacterial communities in the gut[11]. Quadruple therapy, while effective, is hindered by multiple drug combinations, increased side effects, poor patient compliance, and heavy costs[12,13]. The increased resistance to antibiotics such as clarithromycin, metronidazole, and levofloxacin has also affected the therapeutic efficacy of existing regimens[14]. Consequently, there is an urgent need to develop alternative regimens that offer high efficacy, reduced antibiotic usage, fewer adverse events, improved patient compliance and lower costs.
The amoxicillin-proton pump inhibitor (PPI) dual therapy regimen was introduced over three decades ago[15]. The conventional dose dual therapy (amoxicillin 1000 mg, twice daily; PPI 20 mg, twice daily) could only act as a rescue therapy[16] for its low eradication rate (55% to 75%), which was significantly lower than bismuth-containing quadruple (above 90%) and standard triple therapies (approximately 90%)[17]. However, high-dose dual therapy (HDDT) has shown promising results[16]. HDDT comprises a double dose of acid inhibitors and ≥ 3 g/d (administered thrice or more daily) of amoxicillin, with a 14-days treatment course. PPIs being the routinely recommended as the acid inhibitors currently[8]. Vonoprazan, a novel potassium-competitive acid blocker (P-CAB), has demonstrated significant potential in improving H. pylori eradication rates. Compared to traditional PPIs, P-CAB exhibits faster onset, greater potency, and longer duration in inhibiting gastric acid secretion[18]. To evaluate the effectiveness of HDDTs based on different acid inhibitors in China, multi-center, large-scale, prospective randomized controlled clinical trials (RCTs) are urgently required.
This study aimed to evaluate the efficacy, safety, and cost-effectiveness of various treatment regimens for first-line H. pylori eradication. We compared the eradication rates, adverse events, compliance, symptom relief, and drug costs of 14-day esomeprazole-amoxicillin (EA) dual therapy with standard 14-day esomeprazole-amoxicillin-clarithromycin-bismuth (B-quadruple) therapy. Additionally, we assessed 14-day vonoprazan-amoxicillin (VA) dual therapy against 14-day vonoprazan-amoxicillin-clarithromycin (VAC) triple therapy. Furthermore, we investigated factors influencing H. pylori eradication, aiming to provide evidence-based guidance for empirical treatment of primary H. pylori infection.
MATERIALS AND METHODS
Study design and ethical issues
A multi-center, prospective, open-label, randomized controlled study was conducted and registered on clinicaltrials.gov with the registration number NCT06250634. This research adhered to the CONSORT statement guidelines and the principles of the Declaration of Helsinki. The study protocols received approval from the Ethics Committee of three medical centers (Fast 21292, Fast 23359, HHSEYYEC-202402-K1). All participants voluntarily agreed to participate in this clinical trial and provided written informed consent prior to enrollment.
Study population
From February 2024 to May 2024, patients diagnosed with H. pylori infection and receiving initial treatment were consecutively enrolled from the gastroenterology outpatient departments of three institutions in central China. Patients underwent preliminary screening for eligibility. The specific inclusion criteria were as follows: (1) Age range of 14-90 years; (2) Confirmed H. pylori infection by at least one of the following diagnostic methods: Carbon-13/14 urea breath test (13C/14C-UBT) or immuno-histochemical staining of biopsy specimens. When the disintegrations per minute (DPM) > 100 (14C) or delta over baseline (DOB) > 4 (13C), H. pylori was considered positive; (3) No use of antibiotics, bismuth, or Chinese traditional medicines with antibacterial effects within four weeks prior to 13C/14C-UBT, and no use of H2 receptor antagonists, PPIs, P-CAB, or other drugs affecting H. pylori activity within two weeks before 13C/14C-UBT; and (4) No prior history of H. pylori eradication therapy.
The exclusion criteria are as follows: (1) Patients with serious diseases or clinical conditions that may interfere with the evaluation of study results, such as severe heart, liver, lung, and renal insufficiency, or compromised immunity; (2) Patients with allergies to penicillin or any study-related medications; (3) Patients with mental illness or communication disorders; (4) Pregnant or lactating patients; (5) Patients with severe gastrointestinal diseases, including gastrointestinal tumors, gastrointestinal bleeding, or other organic diseases; and (6) Patients concurrently participating in other clinical trials.
Randomization and intervention
Participants enrolled from February 10, 2024 to March 31, 2024 were allocated to the esomeprazole-based RCT. From April 1, 2024 to May 10, 2024, subjects were assigned to the vonoprazan-based RCT. Patients from various centers were allocated using a computer-generated random numbers table in the order of enrollment. We used a center random method for group allocation concealment. They were further divided in a 1:1 ratio into two treatment groups based on these random numbers. Patients with even numbers were assigned to the HDDT groups, while those with odd numbers were placed in the alternative group.
The 14d-EA group received esomeprazole-based HDDT, comprising esomeprazole enteric-coated tablets (AstraZeneca) 20 mg four times daily and amoxicillin capsules (Hainan General Sanyang Pharmaceutical) 750 mg four times daily. The 14d-B-quadruple group underwent esomeprazole-based bismuth-containing quadruple therapy, consisting of esomeprazole enteric-coated tablets 20 mg twice daily, amoxicillin capsules 1000 mg twice daily, clarithromycin sustained-release tablets (Henan Fusen Pharmaceutical) 500 mg twice daily, and colloidal bismuth tartrate capsules (Shanxi Xinbaoyuan Pharmaceutical) 165 mg three times daily. Both groups received treatment for 14 days. Patients were instructed to take esomeprazole and colloidal bismuth half an hour before meals, while amoxicillin and clarithromycin were to be taken half an hour after meals.
The HDDT based on vonoprazan (14d-VA group) comprises 20 mg twice daily of vonoprazan fumarate tablets (Takeda Pharmaceutical Company Limited) and 1000 mg three times daily of amoxicillin capsules (Hainan General Sanyang Pharmaceutical). The triple therapy (14d-VAC group) based on vonoprazan consists of 20 mg twice daily of vonoprazan fumarate tablets, 1000 mg twice daily of amoxicillin capsules, and 500 mg twice daily of clarithromycin sustained-release tablets (Henan Fusen Pharmaceutical). The treatment duration was 14 days for both regimens. Patients were instructed to take vonoprazan, amoxicillin, and clarithromycin 30 minutes after meals.
Procedures and outcomes
Eligible participants completed comprehensive questionnaires detailing demographic and clinical information. Upon providing informed consent, each subject received thorough written and verbal instructions regarding medication administration. Concurrently, patients were apprised of the significance of adherence to the prescribed regimen, potential adverse effects, and essential precautions. Additionally, participants were explicitly instructed to abstain from tobacco and alcohol consumption throughout the treatment period.
Throughout the patient's medication period (specifically on the 3rd, 7th, and 14th days of intervention), an independent investigator conducted standardized follow-ups via WeChat, text messages, and telephone calls. A standard questionnaire was utilized to record adverse events and patient compliance. Patients experiencing severe adverse reactions were advised to discontinue medication and seek medical attention at the outpatient clinic.
A minimum of four weeks following treatment completion, a 13C/14C-UBT was conducted to reassess the H. pylori infection status. Prior to the urea breath test (UBT) review, PPIs/P-CAB were discontinued for two weeks and antibiotics for four weeks; otherwise, the UBT was postponed. Successful H. pylori eradication was determined when the DPM were < 100 (14C) or the DOB was < 4 (13C). Additionally, patients reported their symptom relief status since treatment. Those who did not attend their review in time were reminded of the importance of re-examination via text message or telephone.
The primary outcome measure was the eradication rate, defined as the proportion of H. pylori negative patients in specific groups at least 4 weeks after treatment completion. The eradication rate and corresponding 95% confidence interval (CI) were presented and compared using intention-to-treat (ITT), modified ITT (mITT), and per-protocol (PP) analyses. ITT analysis included all participants, with those who did not complete follow-up or finish UBT after treatment considered eradication failures. The mITT analysis encompassed all randomized participants who received at least one dose of medication and underwent UBT rechecking. PP analysis involved patients with UBT results who consumed at least 80% of the required medication. Secondary outcome measures included adverse event incidence, compliance, symptom relief rate, medical cost, and factors associated with eradication rate. In the adverse event investigation, multiple adverse reactions in the same patient were counted separately. Good compliance was defined as taking at least 80% of the medication. Symptom relief referred to improvement in degree or reduction in frequency of symptoms. Body mass index (BMI) = weight (kg)/ (height (m))2. Body surface area (BSA) (m2) = 0.0061 × height (cm) + 0.0128 × weight (kg) - 0.1529.
Sample size estimation
The sample size estimation was conducted using PASS 15 (NCSS LLC., Kaysville, UT, United States). Based on previous studies[19,20], we anticipated eradication rates of 85% for esomeprazole-based groups and 87.5% for vonoprazan-based groups. To assess the non-inferiority of EA HDDT compared to B-quadruple therapy and VA HDDT compared to VAC triple therapy for H. pylori eradication, we established a power of 80%, a one-sided alpha of 0.025, and a non-inferiority margin of -0.1 (-10%). The calculated sample sizes were 212 for esomeprazole-based groups and 182 for vonoprazan-based groups, accounting for a 5% loss to follow-up rate.
Statistical analysis
Statistical analysis was conducted using SPSS software version 26.0 (IBM Corp., Armonk, NY, United States) and SAS version 9.4 (SAS Institute, Cary, NC, United States). Categorical parameters were presented as frequencies and analyzed using χ2 tests or Fisher's exact probability tests. Continuous data were displayed as mean ± SD and compared using student's t-tests. Additionally, a non-inferiority Z test was applied to compare the eradication rates between the two groups. Non-inferiority was established if the lower boundary of the 95%CI exceeded -10%. The one-sided α level was set at 0.025. Factors related to eradication were analyzed using logistic regression. A P value < 0.05 was considered significant for all analyses, except for the non-inferiority Z test, which required a P value < 0.025. In the non-inferiority test, if P < 0.025, it indicates that the efficacy of the regimen we studied is non-inferior to the standard regimen.
RESULTS
Patient enrollment and baseline characteristics
Figure 1 illustrates the patient recruitment process. Initially, 459 eligible H. pylori-positive subjects were screened for the esomeprazole treatment groups. Subsequently, 439 patients were included and randomly allocated to either the 14d-EA group (221 cases) or the 14d-B-quadruple group (218 cases) for ITT analysis. Among the enrolled patients, 53 in the 14d-EA group and 33 in the 14d-B-quadruple group lacked post-treatment 13C/14C-UBT results. These patients were excluded from mITT and PP analyses. In the PP analysis, 3 patients from the 14d-EA group, despite having post-treatment UBT results, were excluded due to poor compliance (less than 80% of prescribed medications taken).
Figure 1 Flow chart of patient recruitment.
A: The study of 14-day esomeprazole and amoxicillin high-dose dual therapy and 14-day bismuth-containing quadruple therapy (14-day esomeprazole, amoxicillin, clarithromycin, and bismuth therapy); B: The study of 14-day vonoprazan and amoxicillin high-dose dual therapy and 14-day vonoprazan, amoxicillin, and clarithromycin therapy. ITT: Intention-to-treat; mITT: Modified intention-to-treat; PP: Per-protocol; UBT: Urea breath test; EA: Esomeprazole-amoxicillin; B-quadruple: Esomeprazole-amoxicillin-clarithromycin-bismuth; VA: Vonoprazan-amoxicillin; VAC: Vonoprazan-amoxicillin-clarithromycin.
A total of 457 eligible H. pylori-infected patients were screened for vonoprazan-based treatment groups. Ultimately, 367 patients were included and randomly assigned to either the 14d-VA group (183 cases) or the 14d-VAC group (184 cases) for the ITT analysis. Following treatment, 23 cases in the 14d-VA group and 19 cases in the 14d-VAC group did not complete the UBT. These patients were excluded from the mITT and PP analyses. In the PP analysis, an additional 6 patients from the 14d-VA group and 5 from the 14d-VAC group were excluded due to poor compliance.
The demographic and clinical characteristics of the ITT population, including sex, age, fixed occupation, ethnic group, BMI, BSA, native place, education status, place of residence, smoking habits, alcohol consumption, past medical history, family history of H. pylori infection, and digestive symptoms etc., were summarized for the two esomeprazole treatment groups and the two vonoprazan treatment groups in Tables 1 and 2. No significant differences were observed in baseline characteristics between the compared groups (all P > 0.05). Similar results were obtained in the mITT and PP analyses (Supplementary Tables 1 and 2).
Table 1 Baseline characteristics of patients, n (%).
The eradication rates of H. pylori in the esomeprazole-based and vonoprazan-based treatment groups are presented in Table 3, encompassing ITT, mITT, and PP analyses.
Table 3 Eradication rates of each treatment group.
Analysis
14d-EA group
14d-B-quadruple group
Difference from 14d-B-quadruple group (adjusted 95%CI for difference)
The efficacy of 14d-B-quadruple eradication was significantly higher than that of the 14d-EA group, with statistically significant differences observed in ITT, mITT, and PP analyses (ITT: 83.49% vs 70.59%, P = 0.001; mITT: 98.38% vs 92.86%, P = 0.01; PP: 98.38% vs 93.94%, P = 0.028). Non-inferiority analysis revealed that in the ITT analysis, 14d-EA was not non-inferior to 14d-B-quadruple therapy (P = 0.7676). However, in the mITT and PP analyses, the EA dual regimen demonstrated non-inferiority to the B-quadruple regimen (mITT, P = 0.0206; PP, P = 0.0037).
No statistically significant difference in eradication rates was observed between the VA and VAC groups (ITT: 84.15% vs 83.15%, P = 0.795; mITT: 96.25% vs 92.73%, P = 0.165; PP: 96.75% vs 93.75%, P = 0.212). The VA eradication rate demonstrated non-inferiority to VAC therapy (all P values < 0.01 in ITT, mITT, and PP analyses).
Adverse events, compliance, relief of symptoms and drug cost
The overall incidence of adverse events in both treatment groups based on esomeprazole was 6.83% (30/439). Specifically, the 14d-EA group exhibited an adverse event incidence of 4.98% (11/221), while the 14d-B-quadruple group showed 8.72% (19/218). No statistically significant difference was observed between the two groups (P = 0.121). The primary manifestations included alterations in bowel habits, skin rash, bitter taste in mouth, abdominal discomfort, nausea, poor appetite, and dizziness, etc., with symptoms generally being mild (Table 4). Both groups demonstrated excellent compliance, with the 14d-EA group achieving 98.19% (217/221) and the 14d-B-quadruple group reaching 98.62% (215/218), (P = 1.000). Of the 439 enrolled patients, 102 were asymptomatic prior to treatment. Among the 337 symptomatic patients, 322 experienced symptom relief post-treatment, resulting in a total symptom remission rate of 95.55%. The symptom remission rates for the 14d-EA group and 14d-B-quadruple group were 94.55% and 96.51%, respectively, with no significant difference observed (P = 0.382).
Table 4 Adverse events, compliance and relief of symptoms in the 14d-EA group and the 14d-B-quadruple group, n (%).
Adverse events, compliance and relief of symptoms
Total (n = 439)
14d-EA group (n = 221)
14d-B-quadruple group (n = 218)
P value
Patients with adverse events (yes/no)
30/409 (6.83)
11/210 (4.98)
19/199 (8.72)
0.121
Variety of adverse events
Changes in bowel habits (yes/no)
7/432 (1.59)
2/219 (0.90)
5/213 (2.29)
0.435
Skin rash (yes/no)
5/434 (1.14)
3/218 (1.36)
2/216 (0.92)
1.000
Bitter taste in mouth (yes/no)
5/434 (1.14)
0/221 (0.00)
5/213 (2.29)
0.070
Abdominal discomfort (yes/no)
5/434 (1.14)
2/219 (0.90)
3/215 (1.38)
0.988
Nausea (yes/no)
3/436 (0.68)
0/221 (0.00)
3/215 (1.38)
0.242
Poor appetite (yes/no)
3/436 (0.68)
2/219 (0.90)
1/217 (0.46)
1.000
Dizziness (yes/no)
2/437 (0.46)
2/219 (0.90)
0/218 (0.00)
0.499
Others (yes/no)
5/434 (1.14)
1/220 (0.45)
4/214 (1.83)
0.360
Discontinued drugs because of adverse events (yes/no)
4/435 (0.91)
1/220 (0.45)
3/215 (1.38)
0.606
Good compliance (yes/no)
432/7 (98.41)
217/4 (98.19)
215/3 (98.62)
1.000
Relief of symptoms (yes/no)
322/15 (n = 337) (95.55)
156/9 (n = 165) (94.55)
166/6 (n = 172) (96.51)
0.382
The incidence of adverse events was 10.63% (39/367) across both vonoprazan-based groups. No significant difference was observed between the 14d-VA group and the 14d-VAC group [9.84% (18/183) vs 11.41% (21/184), P = 0.624]. Common manifestations included abdominal discomfort, nausea/vomiting, bitter taste in mouth, diarrhea, sour regurgitation/heartburn, dry mouth, constipation, poor appetite, dizziness/fatigue, increased salivation and so on. No serious adverse events occurred during the study period (Table 5). Both groups demonstrated good compliance, with 95.63% (175/183) in the 14d-VA group and 96.74% (178/184) in the 14d-VAC group (P = 0.579). Among the total 367 patients, 75 patients reported no symptoms. Of the remaining 292 patients, 272 participants experienced symptom relief. The overall symptom relief rate was 93.15%. The symptom relief rates were 92.14% in the 14d-VA group and 94.08% in the 14d-VAC group, with no significant difference between the two groups (P = 0.513).
Table 5 Adverse events, compliance and relief of symptoms in the 14d-VA group and the 14d-VAC group, n (%).
Adverse events, compliance and relief of symptoms
Total (n = 367)
14d-VA group (n = 183)
14d-VAC group (n = 184)
P value
Patients with adverse events (yes/no)
39/328 (10.63)
18/165 (9.84)
21/163 (11.41)
0.624
Variety of adverse events
Abdominal discomfort (yes/no)
10/357 (2.72)
3/180 (1.64)
7/177 (3.80)
0.341
Nausea/vomiting (yes/no)
8/359 (2.18)
4/179 (2.19)
4/180 (2.17)
1.000
Bitter taste in mouth (yes/no)
7/360 (1.91)
3/180 (1.64)
4/180 (2.17)
1.000
Diarrhea (yes/no)
7/360 (1.91)
4/179 (2.19)
3/181 (1.63)
0.994
Sour regurgitation/heartburn (yes/no)
5/362 (1.36)
2/181 (1.09)
3/181 (1.63)
1.000
Dry mouth (yes/no)
4/363 (1.09)
2/181 (1.09)
2/182 (1.09)
1.000
Constipation (yes/no)
3/364 (0.82)
1/182 (0.55)
2/182 (1.09)
1.000
Poor appetite (yes/no)
3/364 (0.82)
2/181 (1.09)
1/183 (0.54)
0.996
Dizziness/fatigue (yes/no)
3/364 (0.82)
1/182 (0.55)
2/182 (1.09)
1.000
More saliva (yes/no)
2/365 (0.54)
1/182 (0.55)
1/183 (0.54)
1.000
Others (yes/no)
4/363 (1.09)
1/182 (0.55)
3/181 (1.63)
0.619
Discontinued drugs because of adverse events (yes/no)
3/364 (0.82)
2/181 (1.09)
1/183 (0.54)
0.996
Good compliance (yes/no)
353/14 (96.19)
175/8 (95.63)
178/6 (96.74)
0.579
Relief of symptoms (yes/no)
272/20 (n = 292) (93.15)
129/11 (n = 140) (92.14)
143/9 (n = 152) (94.08)
0.513
The drug costs of the four regimens were calculated and compared. The cost of 14d-EA dual therapy was 594.52 CNY/patient (82.8 USD), which was 10.1% higher than that of 14d-B-quadruple therapy [539.81 CNY/patient (75.2 USD)]. The cost of 14d-VA dual therapy was 287.72 CNY/patient (40.1 USD), while the cost of 14d-VAC therapy was 348.09 CNY/patient (48.5 USD), representing a 17.3% expense reduction per patient.
Factors affecting eradication rates
Table 6 presents the factors associated with eradication efficacy based on the mITT population. In both esomeprazole-based and vonoprazan-based treatments, the absence of antibiotic use within the past two years and good compliance were significantly associated with higher eradication rates (all P < 0.05). Additionally, the area of residence demonstrated a relationship with eradication rates in both treatment groups. Patients residing in urban areas exhibited higher eradication rates compared to those in suburban areas (both P-adjusted < 0.05), while rural patients showed no significant difference from either group. Other factors, including sex, age, BMI, BSA, smoking, drinking habits, past medical history, family history of H. pylori infection, digestive symptoms, and so on, did not significantly impact the treatment efficacy.
Table 6 Univariate analysis of factors related to eradication rates, n (%).
Additionally, a multivariate analysis of the eradication rate for esomeprazole regimens was performed. The analysis revealed that no antibiotic use in the past two years (P = 0.014) and good compliance (P = 0.005) are independent predictors of successful eradication. When considering suburban residence as the standard, urban residence is associated with successful eradication (P = 0.002). Analysis of vonoprazan regimens yielded similar results (Table 7).
Table 7 Multivariate analysis of factors related to eradication rates.
To assess the efficacy and safety of HDDT using different acid inhibitors compared to traditional regimens for first-line treatment of H. pylori infection, we conducted a multi-center, prospective, randomized controlled study. The key findings are as follows: (1) The 14-day bismuth-based quadruple therapy demonstrated superior eradication rates compared to the 14-day EA HDDT; however, the EA therapy was non-inferior to bismuth-quadruple therapy in mITT and PP analyses; (2) Non-inferiority analysis revealed that 14-day VA HDDT was not inferior to 14-day VAC triple therapy; (3) All patients exhibited good compliance with no serious adverse reactions; (4) The vonoprazan-based HDDT had the lowest cost; and (5) Factors associated with H. pylori eradication failure included antibiotic use within the past two years, poor compliance, and residence in suburban areas.
HDDT has gained attention due to its advantages such as satisfactory eradication effect, simplified drug combination, and fewer side effects[16,21,22]. In our study, the eradication rate of HDDTs exceeded 90% in PP analysis, aligning with the Kyoto Consensus recommendations[23]. Multiple genes related to penicillin binding protein simultaneously mutation is the necessary condition for the emergence of amoxicillin resistance, but this is very rare[24,25]. Therefore, the primary and secondary resistance rates of amoxicillin are very low[26], justifying its selection as a bactericidal drug in dual therapy. The efficacy of dual therapy relies on abundant amoxicillin and sufficient gastric acid suppression[19]. First, amoxicillin is time-dependent and defecates in about 6-8 hours[27,28]. To maintain plasma concentrations of amoxicillin above the minimum inhibitory concentration for enough period, frequent dosing (3 or 4 times a day) would be required. Second, H. pylori is in the replication state when intragastric pH is more than 6, which is sensitive to amoxicillin, and can be easily eradicated[29,30]. In addition, amoxicillin is relatively stable in this environment of high pH[31]. Besides, esomeprazole 20 mg administered every 6 hours (4 times daily) can maintain an intragastric pH > 6, whereas the conventional twice-daily dose is insufficient for potent gastric acid suppression[32]. Third, the efficacy of H. pylori eradication is also influenced by patients' cytochrome P450 2C19 (CYP2C19) genotype[33]. Gastric pH is directly affected by CYP2C19 genotypes, regardless of the PPI type. Poor metabolizers exhibit better peak values and maintenance of gastric pH compared to rapid metabolizers[34,35]. Due to the high proportion of intermediate and rapid metabolizers in CYP2C19 genotyping among Chinese patients[36], esomeprazole is typically administered four times daily in HDDT. However, our study revealed that the eradication rate of 14d-EA therapy was still lower than that of 14d-B-quadruple therapy. This could be attributed to the high probability of patients mistaking or missing doses due to frequent administration. Furthermore, the acid-inhibition ability of PPI may not be strong enough, preventing double doses of PPI and amoxicillin from achieving effects similar to combined drugs. Consequently, traditional B-quadruple therapy remains a classical regimen for clinical use based on specific needs.
The substitution of esomeprazole with vonoprazan presents a promising solution to address the aforementioned limitations. There is a meta-analysis showing that vonoprazan-based therapy is superior to traditional PPI-based therapy in eradicating H. pylori, making it an efficient first-line treatment option[37]. The 2022 Maastricht VI/Florence consensus[9] noted that currently available PPIs often struggle to maintain the required acid suppression level or duration within 24 hours, failing to achieve the pH target for treatment. In contrast, P-CABs act rapidly and can simplify the complex eradication program, offering new options for H. pylori eradication. Firstly, traditional PPIs require an acidic environment for activation and only inhibit activated H+/K+-ATPase, whereas P-CABs (such as tegoprazan and vonoprazan) do not require acid and can bind to both resting and activated H+/K+-ATPase[38]. Consequently, PPI-antibiotic combinations necessitate taking PPIs before meals and antibiotics after, causing inconvenience. P-CABs, however, are unaffected by fed conditions, allowing administration during fasting or after meals[39]. Secondly, unlike PPIs, which require multiple doses to achieve maximum acid inhibition, P-CABs achieve this effect with the first administration[38,40]. Thirdly, P-CABs are primarily metabolized by cytochrome P450 3A4 (CYP3A4)[41], and are unaffected by CYP2C19 polymorphisms, resulting in negligible inter-individual differences. Clinical studies have demonstrated that the HDDT of amoxicillin-vonoprazan[42] is equivalent to bismuth-containing quadruple regimens, with fewer adverse reactions and better treatment compliance. For patients with multiple treatment failures, the H. pylori eradication rate of VA HDDT can exceed 90%, making it a viable simplified rescue treatment[43].
This study demonstrates certain advantages of VA HDDT over VAC triple therapy. Primarily, the efficacy of 14d-VA HDDT was comparable to 14d-VAC triple therapy. Moreover, 14d-VA HDDT eliminates the need for an additional antibiotic, which could not only reduce the treatment costs but also weaken potential antimicrobial resistance. This approach may also enhance patient compliance. Previous research indicates that VA dual therapy causes less disruption to gut microbiota compared to VAC triple therapy. The gut microbiota composition after one week and eight weeks of treatment in the VA group does not significantly differ from baseline[44]. Consequently, 14d-VA HDDT shows promise as a potential optimal regimen for future treatment protocols.
Adverse reactions in H. pylori eradication therapy are inevitable. Our research findings indicate that the incidence of adverse events in 14d-EA therapy and 14d-B-quadruple therapy was less than 10%. Notably, bitter taste and nausea were observed exclusively in the 14d-B-quadruple group, both of which are common adverse reactions associated with bismuth[45,46]. Adverse events in both the 14d-VA group and 14d-VAC group remained mild and tolerable. Consequently, this study suggests that the adverse reactions were not significantly influenced by the types of acid suppressors and antibiotics employed. Considering that the majority of included patients were symptomatic, their primary concern was symptom relief. Thus, we analyzed symptom relief across different groups. The common symptoms reported by our participants, including epigastric distention and pain, and so on, which were consistent with conditions such as gastritis and peptic ulcer etc.[47,48]. The alleviation of these symptoms could partially represent the improvement in H. pylori-related diseases. Importantly, the symptom relief rates did not differ significantly between groups.
Antibiotic use within the past two years, poor compliance, and residence in suburban areas were identified as the primary risk factors for treatment failure. Prior exposure to antibiotics was associated with an increased risk of treatment failure, which escalated progressively with the cumulative duration of use[49]. This correlation may be attributed to the fact that previous antibiotic exposure is associated with H. pylori antibiotic resistance, and when acid suppression is inadequate, the eradication rate is more susceptible to the influence of antibiotic use history. Complex regimens, treatment duration, and adverse drug reactions are likely the main factors affecting patient compliance during medication[50,51]. In this study, despite standardized follow-up conducted by an independent investigator at least three times via WeChat, text messages, or telephone calls during each patient's medication period, some participants still exhibited poor compliance. The H. pylori eradication rate in these non-compliant patients was low (33.33% in esomeprazole-based groups and 72.73% in vonoprazan-based groups), indicating that reinforcing medication adherence is a crucial measure for improving H. pylori eradication rates[52]. Furthermore, contaminated water, food, and poor sanitary conditions may play a key role in the spread of H. pylori in suburban areas[53,54].
Our study reported therapies based on different acid suppressors specifically in first-line treatment of H. pylori. The regimens were designed according to clinical experience to improve the empiric treatment of H. pylori. However, this study has several limitations. Firstly, bias in clinical trials without blinding is inevitable, potentially affecting the reporting of adverse events and symptom relief. Therefore, these findings require further verification in randomized controlled double-blind trials. Secondly, antimicrobial susceptibility testing, 24-hour intragastric pH, and CYP2C19 genotype were not assessed, precluding evaluation of HDDT efficacy in drug-resistant strains and the degree of gastric acid inhibition. Nevertheless, amoxicillin resistance rates remain low in the Asia-Pacific region (4% to 8%)[55], mitigating the impact of this omission. Additionally, the frequent use of esomeprazole (four times daily) and vonoprazan's effective acid inhibition partially compensate for the lack of gastric acid inhibition evaluation in PPI or P-CAB-based therapies. Thirdly, this study is not applicable to patients with penicillin allergy or regions with high amoxicillin resistance, as all regimens included amoxicillin. Lastly, the type, dose, and frequency of antibiotics in patients' 2-year antibiotic use history were not fully surveyed, and further stratified analysis of risk factors related to H. pylori eradication should be conducted.
CONCLUSION
In conclusion, the HDDT based on vonoprazan demonstrated comparable eradication rates to VAC therapy for treating newly diagnosed H. pylori infections in central China. This regimen exhibited a low incidence of adverse reactions (below 10%), good compliance, and high symptom relief rates while reducing antibiotic consumption. The eradication rate of B-quadruple therapy exceeded that of EA therapy; however, EA therapy was found to be non-inferior in the mITT and PP analyses. Consequently, vonoprazan-based HDDT merits recommendation as a first-line treatment for H. pylori infection, while bismuth-based quadruple therapy remains a classical regimen.
ACKNOWLEDGEMENTS
We would like to thank all the participants in the study.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade B, Grade B
Novelty: Grade A, Grade B, Grade B
Creativity or Innovation: Grade A, Grade B, Grade B
Scientific Significance: Grade B, Grade B, Grade B
P-Reviewer: Li Q; Ye F S-Editor: Qu XL L-Editor: A P-Editor: Wang WB
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