Abstract
Background:
With the development of traditional Chinese medicine research, berberine has shown good efficacy and safety in the eradication of Helicobacter pylori (H. pylori). The present study aimed to evaluate the efficacy and safety of triple therapy containing berberine, amoxicillin, and vonoprazan for the initial treatment of H. pylori.
Methods:
This study was a single-center, open-label, parallel, randomized controlled clinical trial. Patients with H. pylori infection were randomly (1:1:1) assigned to receive berberine triple therapy (berberine 500 mg, amoxicillin 1000 mg, vonoprazan 20 mg, A group), vonoprazan quadruple therapy (vonoprazan 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, colloidal bismuth tartrate 220 mg, B group), or rabeprazole quadruple therapy (rabeprazole 10 mg, amoxicillin 1000 mg, clarithromycin 500 mg, colloidal bismuth tartrate 220 mg, C group). The drugs were taken twice daily for 14 days. The main outcome was the H. pylori eradication rate. The secondary outcomes were symptom improvement rate, patient compliance, and incidence of adverse events. Furthermore, factors affecting the eradication rate of H. pylori were further analyzed.
Results:
A total of 300 H. pylori-infected patients were included in this study, and 263 patients completed the study. An intention-to-treat (ITT) analysis showed that the eradication rates of H. pylori in berberine triple therapy, vonoprazan quadruple therapy, and rabeprazole quadruple therapy were 70.0% (70/100), 77.0% (77/100), and 69.0% (69/100), respectively. The per-protocol (PP) analysis showed that the eradication rates of H. pylori in these three groups were 81.4% (70/86), 86.5% (77/89), and 78.4% (69/88), respectively. Both ITT analysis and PP analysis showed that the H. pylori eradication rate did not significantly differ among the three groups (P >0.05). In addition, the symptom improvement rate, overall adverse reaction rate, and patient compliance were similar among the three groups (P >0.05).
Conclusions:
The efficacy of berberine triple therapy for H. pylori initial treatment was comparable to that of vonoprazan quadruple therapy and rabeprazole quadruple therapy, and it was well tolerated. It could be used as one choice of H. pylori initial treatment.
Keywords: Helicobacter pylori, Eradication, Berberine, Vonoprazan, Bismuth, Quadruple therapy
Introduction
Helicobacter pylori (H. pylori) is a gram-negative microaerobic bacterium that mainly lives in the gastric antrum. The primary method of H. pylori infection is person-to-person transmission.[1] The worldwide incidence of H. pylori is approximately 50%.[2] In China, approximately 44.2% of the population is infected with H. pylori.[3] It is the main pathogenic factor of chronic gastritis, peptic ulcer, and gastric cancer.[4] The eradication of H. pylori can reduce the occurrence of H. pylori-related diseases and delay or prevent the occurrence and development of gastric mucosal atrophy and intestinal metaplasia.[5,6,7,8,9,10] Thus, the sixth Chinese national consensus report strongly recommendeds eradication therapy for cases in which H. pylori is confirmed to be positive.[11]
However, with the increase in antibiotic resistance of H. pylori, the eradication rate with the traditional triple regimen is not ideal.[12] According to the current situation of antibiotic resistance, the latest guideline on H. pylori eradication treatment has recommended bismuth quadruple therapy as the major empirical treatment in China.[13] However, in recent years, studies have found that the H. pylori eradication rate fluctuates from 70% to 85% and does not exceed 85%.[14] The reasons for the decline in the H. pylori eradication rate are very complex and mainly related to the increase of antibiotic resistance rate and host gene polymorphism. Therefore, it is necessary to explore other alternative drugs for H. pylori eradication.
The state of H. pylori in gastric mucosa depends on the pH value of gastric juice. When the pH value is 6.0–8.0, H. pylori exhibits growth and mass reproduction and is sensitive to antibiotics. Moreover, amoxicillin is the most effective antibiotic at neutral pH.[15] Vonoprazan, a new potassium competitive acid blocker, was approved for sale in China in December 2019. Compared with proton pump inhibitors (PPIs), vonoprazan can reach a pH above 6 in the stomach faster and can maintain this pH longer than other drugs.[16,17] Several studies have confirmed that the eradication effectiveness of regimens containing vonoprazan is superior to or not inferior to that of regimens containing PPIs.[18,19,20,21] In addition, research has indicated that some traditional Chinese medicines or their extracts have obvious curative effects on H. pylori. Several studies have confirmed that berberine has an anti-H. pylori effect, reducing the rate of adverse events, and has a certain inhibitory effect on multidrug-resistant strains.[22,23,24,25] Our research group also conducted prospective studies on the berberine-mediated eradication of H. pylori infection, and the results have confirmed that the effectiveness and safety of the berberine quadruple scheme for initial and rescue treatment of H. pylori infection are not inferior to the guideline-recommended therapy.[26,27,28]
Bismuth improves the eradication rate of H. pylori primarily through increasing the susceptibility to drug resistance-inducing antibiotics. Previous studies have shown that the berberine quadruple regimen (used instead of clarithromycin, which highly induces drug resistance) is similar to the bismuth quadruple regimen for the initial treatment of H. pylori.[27] This finding suggests that bismuth does not increase the eradication rate of sensitive antibiotics. Because H. pylori is sensitive to berberine and its resistance rate to amoxicillin is less than 5% in China, we hypothesize that berberine plus amoxicillin could be used for H. pylori treatment without the need for bismuth. In addition, vonoprazan exhibits a stronger acid-inhibiting effect and may provide the appropriate pH value for H. pylori eradication. Therefore, we designed a single-center, open-label, parallel, randomized controlled clinical trial to verify this hypothesis.
Methods
Ethical Approval
This study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee of the First Affiliated Hospital of Air Force Military Medical University (No. KY20212155-C-1). Written informed consent was obtained from all patients prior to their enrollment in this study. In parallel, it was registered at ClinicalTrials.gov (No. NCT05014334).
Study design
This study was a single-center, open-label, parallel, randomized controlled clinical trial conducted in the outpatient department of Xijing Hospital (Xi'an, Shaanxi, China) from August 2021 to March 2022.
The patients who met the inclusion and exclusion criteria were completely randomized, numbered according to the sequence of the patients, and randomly enrolled in a ratio of 1:1:1 to receive berberine triple therapy (A group), vonoprazan quadruple therapy (B group), or rabeprazole quadruple therapy (C group). The randomization table was prepared by a third party in advance. The study followed a randomized block design. At enrollment, each participant was asked to complete a brief questionnaire about demographics. Patients were followed up by telephone or outpatient at the end of the treatment period and 4 weeks after the end of treatment. During follow-up, adverse events and medication status were recorded, and patients were assessed for symptoms at the end of the treatment period and 4 weeks after the end of treatment. All participants were asked to return to the hospital again 4–8 weeks after eradication for a urea breath test to assess the treatment effect.
Subjects
The subjects enrolled in this study was comprised of untreated patients of both sexes with initial H. pylori infection aged 18–70 years who exhibited symptoms of dyspepsia. The exclusion criteria were as follows: patients with allergies or contraindications to the study drugs; patients with severe organ damage and complications; patients with severe or unstable cardiopulmonary or endocrine diseases; patients with continuous ingestion of acid-inhibiting drugs within 2 weeks before the H. pylori test and of antibiotics or bismuth for 1 month or more than 3 times/week before the test; patients with upper gastrointestinal surgery history; patients with symptoms of dysphagia; patients with a history of bleeding or iron-deficiency anemia; patients with a history of malignancy; patients with drug or alcohol abuse within the last 1 year; patients who had recently used corticosteroids, non-steroidal anti-inflammatory drugs, anticoagulants, or antiplatelet aggregators; patients with mental disorders; patients who had participated in other clinical trials in the past 3 months; and patients who refused to participate.
Grouping and medication
Patients who met the inclusion and exclusion criteria were randomly enrolled to receive berberine triple therapy (berberine 500 mg, amoxicillin 1000 mg, vonoprazan 20 mg, A group), vonoprazan quadruple therapy (vonoprazan 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, bismuth 220 mg, B group), or rabeprazole quadruple therapy (rabeprazole 10 mg, amoxicillin 1000 mg, clarithromycin 500 mg, bismuth 220 mg, C group). The medicine was taken 2 times/day for 14 days. Except for antibiotics, which were administered 30 min after meals, other drugs were taken 30 min or 1 h before meals.
The drug information is as follows: berberine hydrochloride tablets (Yunnan Mingjing Pharmaceutical, Kunming, Yunnan, China), amoxicillin capsules (Zhuhai United Laboratories, Zhuhai, Guangdong, China), vonoprazan fumarate tablets (Takeda Pharmaceutical Company Limited, Tianjin, China), rabeprazole sodium enteric-coated capsules (Eisai [China] Pharmaceutical, Suzhou, Jiangsu, China), clarithromycin sustained release tablets (Jiangbo Pharmaceutical, Laiyang, Shandong, China), and colloidal bismuth tartrate capsules (Shanxi Xinbaoyuan Pharmaceutical, Datong, Shanxi, China).
Diagnosis of H. pylori infection
At the time of enrollment, H. pylori infection was assessed by the 13C/14C urea breath test (13C/14C-UBT), H. pylori stool antigen test (HpSAT), H. pylori histology, or H. pylori rapid urease test (RUT). If any of the above test results was positive, H. pylori infection was confirmed. The successful eradication of H. pylori was assessed by 13C/14C-UBT or HpSAT at 4–8 weeks after drug withdrawal. A negative result in one of the above tests indicated the successful eradication of H. pylori.
Safety, symptom improvement and compliance
Patients were informed of possible adverse drug reactions before treatment, and all adverse events and corresponding treatment were recorded in the case report form. Adverse events were graded on a 4-point scale: 0 represented no, 1 represented mild (no treatment needed, drug administration could continue), 2 represented moderate (drug administration could continue after treatment), and 3 represented severe (trial terminated due to adverse reactions) adverse events. During the study, patients were instructed to come to the hospital at any time if they felt unwell.
At the time of enrollment, the time of drug withdrawal, and 4 weeks after drug withdrawal, various clinical symptoms were evaluated according to the severity and frequency of clinical symptoms. The main clinical symptoms included vomiting, nausea, abdominal pain, abdominal distension, diarrhea, constipation, belching, acid regurgitation, and heartburn. The severity and frequency of symptoms were divided into four grades: 0 represented none, 1 represented mild (occasional), 2 represented moderate (often), and 3 represented severe (frequent). The total symptom score was the sum of each symptom severity score and each symptom attack frequency score. The ratio of the difference between the total score of clinical symptoms before and after treatment and the total score of clinical symptoms before treatment was considered the rate of clinical symptom improvement (%). Symptom improvement was defined as a reduction in the total score by at least half after treatment.
Adherence was evaluated by the number of tablets taken, with a medication-taking rate of less than 80% considered poor adherence.
Outcomes
The main consequence of this study was the success rate of H. pylori eradication in the three groups. Adverse events, patient compliance, and the rate of symptom relief (at the time of drug withdrawal and 4 weeks after drug withdrawal) were secondary outcomes.
Sample size and statistical analysis
This study was a parallel controlled clinical trial, and the sample size was designed according to the phase II clinical trial. In addition, our study was based on the sample size of a previous study of bismuth quadruple therapy as a first-line treatment.[29] Therefore, in our study, each group included 100 patients, and a total of 300 patients were included in the three groups to evaluate the efficacy and safety of berberine triple therapy in the initial treatment of H. pylori.
IBM SPSS statistics software, version 25.0 (IBM Inc., New York, USA) was used for statistical analysis. Normally distributed measurement data are expressed as the mean ± standard deviation. Enumeration data are described by n (%). One-way analysis of variance or the Kruskal–Wallis rank sum test was used for measurement data. Chi-squared tests or Fisher's exact tests were used for enumeration data, and pairwise comparisons were performed. The eradication rate of H. pylori was analyzed in the intention-to-treat (ITT) and per-protocol (PP) analysis populations. In the PP analysis population, univariate analysis was performed to analyze the factors affecting the eradication rate of H. pylori. A P value <0.05 was considered statistically significant.
Results
Baseline data of participants
The flow chart of the study is shown in Figure 1. From August 2021 to March 2022, a total of 300 patients with H. pylori infection were enrolled in this study. In Groups A, B, and C, 13/100 (13.0%), 8/100 (8.0%), and 10/100 (10.0%) patients were lost to follow-up, respectively. One, three, and two patients dropped out in these three groups due to adverse reactions, violation of treatment protocol or poor compliance. Ultimately, 300 patients underwent ITT analysis, and 263 patients underwent PP analysis. Baseline demographic data were recorded for all patients at the time of enrollment [Table 1]. Age, sex, body mass index (BMI), education level, smoking, drinking, history of diabetes, or disease status did not significantly differ among the three groups (P >0.05).
Figure 1.
Flow diagram of the study. A group: Berberine triple therapy; B group: Vonoprazan quadruple therapy; C group: Rabeprazole quadruple therapy; ITT: Intention-to-treat; PP: Per-protocol.
Table 1.
Baseline characteristics of participants infected with H. pylori in initial eradication therapy.
| Characteristics | A group (N = 100) | B group (N = 100) | C group (N = 100) | Statistics | P values |
|---|---|---|---|---|---|
| Age (years), mean ± SD | 44.36 ± 12.40 | 46.49 ± 11.60 | 44.29 ± 12.10 | 0.849* | 0.429 |
| Sex, male/female | 42/58 | 41/59 | 47/53 | 0.842† | 0.670 |
| BMI (kg/m2), mean ± SD | 22.56 ± 3.00 | 23.26 ± 2.90 | 23.22 ± 3.37 | 1.620* | 0.200 |
| Smoking, n (%) | 8.586† | 0.072 | |||
| Yes | 7 (7.0) | 13 (13.0) | 21 (21.0) | ||
| No | 85 (85.0) | 80 (80.0) | 71 (71.0) | ||
| Stop smoking | 8 (8.0) | 7 (7.0) | 8 (8.0) | ||
| Drinking, n (%) | 1.721† | 0.785 | |||
| Yes | 22 (22.0) | 26 (26.0) | 21 (21.0) | ||
| No | 73 (73.0) | 69 (69.0) | 71 (71.0) | ||
| Stop drinking | 5 (5.0) | 5 (5.0) | 8 (8.0) | ||
| Drinking water source, n (%) | 2.027† | 0.409 | |||
| City water | 96 (96.0) | 94 (94.0) | 98 (98.0) | ||
| Non-city water | 4 (4.0) | 6 (6.0) | 2 (2.0) | ||
| Degree of education, n (%) | 0.360† | 0.875 | |||
| University and above | 57 (57.0) | 53 (53.0) | 56 (56.0) | ||
| High school and below | 43 (43.0) | 47 (47.0) | 44 (44.0) | ||
| Diabetes, n (%) | 1.097† | 0.684 | |||
| Yes | 3 (3.0) | 4 (4.0) | 6 (6.0) | ||
| No | 97 (97.0) | 96 (96.0) | 94 (94.0) | ||
| Diseases, n (%) | 8.812† | 0.058 | |||
| Chronic gastritis | 49 (49.0) | 48 (48.0) | 49 (49.0) | ||
| Peptic ulcer | 1 (1.0) | 1 (1.0) | 8 (8.0) |
A group: Berberine triple therapy; B group: Vonoprazan quadruple therapy; C group: Rabeprazole quadruple therapy. Data are presented as the mean ± SD; *F value; †χ2 value. BMI: Body mass index; SD: Standard deviation; H. pylori: Helicobacter pylori.
H. pylori eradication efficacy
In total, 86, 89, and 88 patients were eligible for PP analysis in Groups A, B, and C, respectively. Among them, 70 cases, 77 cases, and 69 cases in the three groups were successfully eradicated. As shown in Table 2, PP analysis showed that the eradication rates of H. pylori in Groups A, B, and C were 81.4% (70/86), 86.5% (77/89), and 78.4% (69/88), respectively. ITT analysis results showed that the eradication rates of H. pylori in the three groups were 70.0% (70/100), 77.0% (77/100), and 69.0% (69/100), respectively. No significant difference was found among the three groups in either ITT or PP analysis (all P >0.05).
Table 2.
H. pylori eradication rates in each therapy group.
| Items | Group | Eradication rates, n/N (%) | χ 2 value | P values |
|---|---|---|---|---|
| ITT analysis | A group | 70/100 (70.0) | 1.265* | 0.545* |
| B group | 77/100 (77.0) | 0.418† | 0.819† | |
| C group | 69/100 (69.0) | 2.062‡ | 0.371‡ | |
| PP analysis | A group | 70/86 (81.4) | 0.854* | 0.412* |
| B group | 77/89 (86.5) | 0.241† | 0.706† | |
| C group | 69/88 (78.4) | 2.013‡ | 0.171‡ |
A group: Berberine triple therapy; B group: Vonoprazan quadruple therapy; C group: Rabeprazole quadruple therapy; *gourp A vs. group B; †A group vs. C group; ‡B group vs. C group; ITT: Intention-to treat; PP: Per-protocol; H. pylori: Helicobacter pylori.
As shown in Table 3, in the PP analysis population, univariate analysis results found that sex had a significant impact on the H. pylori eradication rate in the C group (P <0.05), while no effect was found in the other two groups. In addition, age, BMI, education level, smoking, drinking, disease status, and history of diabetes had no significant effect on the eradication rate of H. pylori among the three groups (all P >0.05).
Table 3.
Factors affecting H. pylori eradication in the PP populations.
| Affecting factors | A group (N = 86) | B group (N = 89) | C group (N = 88) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Eradication rates, n (%) | χ2 value | P values | Eradication rates, n (%) | χ2 value | P value | Eradication rates, n (%) | χ2 value | P values | |||
| Age | 3.552 | 0.088 | 2.985 | 0.159 | 1.244 | 0.306 | |||||
| <43 years | 31/34 (91.2) | 33/35 (94.3) | 30/41 (73.2) | ||||||||
| ≥43 years | 39/52 (75.0) | 44/54 (81.5) | 39/47 (83.0) | ||||||||
| Sex | 1.124 | 0.394 | 1.374 | 0.347 | 9.647 | 0.004 | |||||
| Male | 25/33 (75.8) | 33/36 (91.7) | 27/42 (64.3) | ||||||||
| Female | 45/53 (84.9) | 44/53 (83.0) | 42/46 (91.3) | ||||||||
| BMI | 0.045 | 1.000 | 0.292 | 0.755 | 0.219 | 0.790 | |||||
| <24 kg/m2 | 50/61 (82.0) | 45/53 (84.9) | 44/55 (80.0) | ||||||||
| ≥24 kg/m2 | 20/25 (80.0) | 32/36 (88.9) | 25/33 (75.8) | ||||||||
| Smoking | 0.377 | 0.849 | 0.305 | 1.000 | 4.669 | 0.101 | |||||
| Yes | 3/4 (75.0) | 10/11 (90.9) | 11/18 (61.1) | ||||||||
| No | 61/74 (82.4) | 63/74 (85.1) | 53/63 (84.1) | ||||||||
| Stop smoking | 6/8 (75.0) | 4/4 (100.0) | 5/7(71.4) | ||||||||
| Drinking | 0.945 | 0.686 | 2.817 | 0.228 | 0.632 | 0.749 | |||||
| Yes | 12/16 (75.0) | 22/23 (95.7) | 13/17 (76.5) | ||||||||
| No | 54/65 (83.1) | 52/62 (83.9) | 51/64 (79.7) | ||||||||
| Stop drinking | 4/5 (80.0) | 3/4 (75.0) | 5/7 (71.4) | ||||||||
| Drinking water source | 0.959 | 0.588 | 3.193 | 0.133 | 0.976 | 0.387 | |||||
| City water | 66/82 (80.5) | 74/84 (88.1) | 68/86 (79.1) | ||||||||
| Non city water | 4/4 (100.0) | 3/5 (60.0) | 1/2(50.0) | ||||||||
| Degree of education | 0.020 | 1.000 | 4.673 | 0.058 | 1.594 | 0.298 | |||||
| University and above | 38/47 (80.9) | 45/48 (93.8) | 36/49 (73.5) | ||||||||
| High school and below | 32/39 (82.1) | 32/41 (78.0) | 33/39 (84.6) | ||||||||
| Diabetes | 0.468 | 1.000 | 0.653 | 1.000 | 0.524 | 0.606 | |||||
| Yes | 2/2 (100.0) | 4/4 (100.0) | 4/6 (66.7) | ||||||||
| No | 68/84 (81.0) | 73/85 (85.9) | 65/82 (79.3) | ||||||||
| Diseases | 0.221 | 1.000 | 0.199 | 1.000 | 0.329 | 1.000 | |||||
| Chronic gastritis | 36/44 (81.8) | 35/42 (83.3) | 37/47 (78.7) | ||||||||
| Peptic ulcer | 1/1 (100.0) | 1/1 (100.0) | 7/8 (87.5) | ||||||||
A group: Berberine triple therapy; B group: Vonoprazan quadruple therapy; C group: Rabeprazole quadruple therapy; BMI: Body mass index; PP: Per-protocol; H. pylori: Helicobacter pylori.
Rates of adverse events, compliance, and symptom improvement
Because one patient in Group C seriously violated the treatment protocol, a total of 299 patients in the three groups were evaluated to the rates of adverse events. As shown in Table 4, overall adverse reactions occurred in 27/100(27.0%) patients in Group A, 34/100 (34.0%) patients in Group B, and 26/99 (26.3%) patients in Group C, and no significant difference was found between the groups (P >0.05). The common adverse reactions were bitterness and gastrointestinal reactions. The incidences of bitterness in Group B 23/100 (23.0%) and Group C 22/99 (22.2%) were higher than that in Group A 2/100(2.0%). Among gastrointestinal reactions, the incidence of nausea in Group A 13/100(13.0%) was higher than that in Group B 3/100(3.0%) and Group C 3/99 (3.0%), and the difference was statistically significant (P <0.05). The incidence of abdominal pain, abdominal distension, diarrhea, poor appetite, or rash did not significantly differ among the three groups (P >0.05). The adverse reactions gradually disappeared after drug withdrawal. In addition, as shown in Table 5, patient compliance (all >95%) and the symptom improvement rate (at the time of drug withdrawal and 4 weeks after drug withdrawal) were similar among the three groups (P >0.05).
Table 4.
Rates of adverse events in each therapy group of H. pylori eradication.
| Items | A group, n/N (%) | B group, n/N (%) | C group, n/N (%) | Statistics | P value |
|---|---|---|---|---|---|
| Overall adverse events | 27/100 (27.0) | 34/100(34.0) | 26/99 (26.3) | 1.156* | 0.357 |
| 0.014† | 1.000 | ||||
| 1.414‡ | 0.280 | ||||
| Bitterness | 2/100 (2.0) | 23/100 (23.0) | 22/99 (22.2) | 19.182* | 0 |
| 20.160† | 0 | ||||
| 0.017‡ | 1.000 | ||||
| Nausea | 13/100 (13.0) | 3/100 (3.0) | 3/99 (3.0) | 6.793* | 0.016 |
| 6.688† | 0.016 | ||||
| Fisher§ | 1.000 | ||||
| Diarrhea | 3/100 (3.0) | 2/100 (2.0) | 1/99 (1.0) | Fisher§ | 1.000 |
| Fisher§ | 0.621 | ||||
| Fisher§ | 1.000 | ||||
| Abdominal pain | 6/100 (6.0) | 1/100 (1.0) | 1/99 (1.0) | Fisher§ | 0.118 |
| Fisher§ | 0.118 | ||||
| Fisher§ | 1.000 | ||||
| Abdominal distension | 6/100(6.0) | 3/100 (3.0) | 2/99 (2.0) | Fisher§ | 0.498 |
| Fisher§ | 0.279 | ||||
| Fisher§ | 1.000 | ||||
| Anorexia | 4/100 (4.0) | 2/100 (2.0) | 0/99 (0) | Fisher§ | 0.683 |
| Fisher§ | 0.121 | ||||
| Fisher§ | 0.497 | ||||
| Rash | 3/100 (3.0) | 2/100 (2.0) | 1/99 (1.0) | Fisher§ | 1.000 |
| Fisher§ | 0.621 | ||||
| Fisher§ | 1.000 |
A group: Berberine triple therapy; B group: Vonoprazan quadruple therapy; C group: Rabeprazole quadruple therapy. *, A gourp vs. B group; †, A group vs. C group; ‡, B group vs. C group; §Fisher's exact test; H. pylori: Helicobacter pylori.
Table 5.
Compliance and symptom improvement rates in each therapy group of H. pylori eradication.
| Items | A group, n/N (%) | B group, n/N (%) | C group, n/N (%) | χ2 value | P values |
|---|---|---|---|---|---|
| Compliance rate | 99/100 (99.0) | 97/100 (97.0) | 98/100 (98.0) | 0.255* | 0.614 |
| 0† | 1.000 | ||||
| 0‡ | 1.000 | ||||
| 2-week symptom improvement | 63/86 (73.3) | 67/89 (75.3) | 66/88 (75.0) | 0.094* | 0.863 |
| 0.069† | 0.863 | ||||
| 0.002‡ | 1.000 | ||||
| 6-week symptom improvement | 75/86 (87.2) | 75/89 (84.3) | 78/88 (88.6) | 0.309* | 0.668 |
| 0.083† | 0.819 | ||||
| 0.720‡ | 0.511 |
A group: Berberine triple therapy; B group: Vonoprazan quadruple therapy; C group: Rabeprazole quadruple therapy. *, A gourp vs. B group; †, A group vs. C group; ‡, B group vs. C group; H. pylori: Helicobacter pylori.
Discussion
H. pylori infection remains a global public health problem that is closely related to the occurrence of various upper gastrointestinal diseases. Although approximately 85% of H. pylori-infected people are asymptomatic, the remaining 15% progress to peptic ulcers, and approximately 1% eventually develop gastric cancer.[30] The eradication of H. pylori will lower the occurrence of H. pylori-related diseases and relieve symptoms.[5,6,31] At present, bismuth-containing quadruple therapy is recommended as the main empirical treatment therapy in China. However, the failure of H. pylori eradication remains common in clinical practice, for which antibiotic resistance and host gene polymorphism are the main reasons.
Currently, the rate of bacterial drug resistance is increasing. According to previous studies, the overall resistance rates of H. pylori to clarithromycin, metronidazole, levofloxacin, and amoxicillin were 27.22%, 39.66%, 22.48%, and 4.55%, respectively.[32] The resistance of H. pylori to antibiotics in China is also worrisome. The primary resistance rates to clarithromycin, metronidazole, and levofloxacin all exceeded 15%. In contrast, the resistance rates to amoxicillin, tetracycline, and furazolidone are low, all less than 5%.[33] The increasing rate of antibiotic resistance leads to a decline in the H. pylori eradication rate. A prospective study identified dual clarithromycin and metronidazole resistance as an independent risk factor for H. pylori eradication failure.[34] The results of another meta-analysis showed that the rate of H. pylori eradication decreased by more than 16% in the single-drug resistance group and by more than 40% in the dual-drug resistance group compared with the antibiotic-sensitive group.[35] Clarithromycin is one of the antibiotics commonly used in eradication treatment, and its increased resistance rate has become an independent risk factor for H. pylori eradication failure, which greatly weakens the efficacy of PPI-based triple therapy and standard bismuth quadruple therapy.[36] Therefore, finding alternative drugs with a low resistance rate is a clinical problem that needs to be solved.
In recent years, domestic and international clinical trials have gradually demonstrated the many benefits of traditional Chinese medicine, new acid-inhibiting drugs, probiotics, and other new therapies. Berberine is widely used in the treatment of infectious diseases, tumors, cardiovascular diseases, and metabolic diseases and protects against digestive system diseases.[37,38,39] Previous studies have confirmed that berberine has an anti-H. pylori effect; it inhibits the proliferation of H. pylori by inhibiting the activities of arylamine N-acetyltransferase and urease.[40,41] Several clinical trials have confirmed the effectiveness of berberine therapy in eradicating H. pylori and its ability to kill multidrug-resistant strains.[24] Berberine is widely used in clinical practice, inexpensive, easy to obtain, and safe, and it has wide application prospects. It is usually administered at a dosage of 300 mg (3 times/day) in anti-H. pylori treatment, and recently, some scholars have also used 500 mg (2 times/day) in therapy with good safety.[26] Because other drugs in the protocol were administered 2 times/day and to avoid the reduction in compliance caused by complex medication therapy, we defined the dose of berberine at 500 mg (2 times/day) in the present study.
In addition, vonoprazan, a novel potassium competitive acid blocker, creates a suitable gastric environment for H. pylori treatment by maintaining a high gastric pH value. Compared with PPIs, the acid-inhibiting effect of vonoprazan is stronger and more durable. The CYP3A4 enzyme plays a dominant role in its metabolism, and CYP2C19 genotype polymorphism does not affect its pharmacokinetics. Vonoprazan administered at 20 mg (2 times/day) effectively inhibited gastric acid secretion for 24 h, and the average pH in the stomach reached 6.8 after 7 days of continuous administration.[17,42] In recent years, vonoprazan (20 mg, 2 times/day) has been used by many scholars to eradicate H. pylori and has shown a high eradication rate compared with PPIs.[19,20] In particular, studies have found that vonoprazan-based treatment regimen regimens have a better eradication rate than PPIs-based regimens in clarithromycin-resistant strains.[18] Therefore, we speculate that vonoprazan (20 mg, 2 times/day) can provide good eradication conditions for H. pylori in our study.
In our study, the eradication rates of H. pylori in response to the new triple therapy consisting of berberine, amoxicillin, and vonoprazan were 70.0% and 81.4% by ITT and PP analyses, respectively, which were comparable and did not significantly differ from the rates of vonoprazan quadruple therapy and rabeprazole quadruple therapy. At present, relatively few clinical studies have examined the eradication of H. pylori by berberine triple therapy. The therapeutic result of the berberine-containing regimen obtained by our research group is comparable to that of standard bismuth quadruple therapy.[26,27,28] A study compared the eradication efficacy of the berberine quadruple therapy (300 mg, 3 times/day) with that of bismuth quadruple therapy. The eradication rates of H.pylori were 87.5% and 87.1% in PP analysis, with no statistical significance (P >0.05),[27] and an analogous result was obtained in our trial.
The improvement rate of clinical symptoms was similar among the three groups (P >0.05). The incidence of adverse events in berberine triple therapy was similar to those in vonoprazan quadruple therapy and rabeprazole quadruple therapy. Among adverse events, the incidence of bitterness in vonoprazan quadruple therapy and rabeprazole quadruple therapy was higher than that in berberine triple therapy, and the difference was statistically significant (P <0.05), which may be associated with the intake of bismuth and clarithromycin. One study also showed that the bitterness symptoms of patients were significantly improved when the clarithromycin dose was reduced from 500 mg to 250 mg.[29] The incidence of nausea in the berberine triple therapy group was significantly higher than that in the vonoprazan quadruple therapy and rabeprazole quadruple therapy groups (P <0.05). The adverse events in patients were mild, did not require treatment, and gradually disappeared after drug withdrawal.
In the PP analysis population, univariate analysis showed that the H. pylori eradication rate of females was higher in the rabeprazole quadruple therapy group (P <0.05), and no significant difference was found between the other two groups (P >0.05). A study involving 190 H. pylori-infected patients showed that the incidence of H. pylori eradication failure was higher in females than in males.[36] At present, few reports on the influence of sex on the eradication rate of H. pylori have been published. This study is inconsistent with our results, which may be related to the small sample size of the study. Future studies with large sample sizes are needed for further validation. Age, BMI, education level, smoking, drinking, disease status, and history of diabetes in the three groups had no obvious impact on the eradication rate of H. pylori (P >0.05).
A H. pylori nomogram model form Dore et al[43] showed that the addition of bismuth increased the eradication rate by 30% in H. pylori-resistant strains. However, a randomized controlled clinical trial conducted in China in 2019 showed that adding bismuth to the sensitive antibiotic combination did not significantly change the eradication rate of H. pylori.[44] In addition, as a heavy metal element, bismuth is associated with many adverse events, including toxic effects on the nervous system and kidney, toxic encephalopathy, bismuth-related osteoarthropathy, and other adverse events (such as melena, black tongue, diarrhea, headache, and dizziness).[45] Therefore, many western scholars have been worried about its implications in terms of patient safety and remain skeptical of bismuth. Our results showed that the new triple therapy, which uses fewer drugs and avoids the use of bismuth, had an efficacy similar to that of quadruple therapy in the eradication of H. pylori, thereby avoiding the potential adverse events of bismuth. Therefore, berberine and amoxicillin combined with vonoprazan triple therapy is safe and effective.
Our study had the below limitations. First, this study was a single-center trial with approximately 65% of the patients originating from the surrounding areas of Shaanxi Province, and further validation is needed in other regions. Second, the small sample size of the study might have led to a reduction in statistical test efficiency. Furthermore, H. pylori antibiotic sensitivity, gastric pH, and host gene polymorphism were not evaluated in this study; thus, large-sample and multicenter clinical studies are still needed for further validation in the future.
In conclusion, the efficacy of berberine triple therapy for the initial eradication of H. pylori is comparable to that of vonoprazan quadruple therapy and rabeprazole quadruple therapy. Berberine triple therapy was found to be well tolerated, safe, and economical while avoiding the use of bismuth and its potential adverse events. Therefore, the new triple therapy provides a safe and effective alternative for the initial eradication of H. pylori.
Acknowledgments
We thank the study participants and the clinical teams. This work was supported by Shaanxi Key Research & Development Projects (No. 2023-ZDLSF-35).
Conflicts of interest
None.
Footnotes
How to cite this article: Chen SS, Shen WN, Liu YH, Dong Q, Shi YQ. Efficacy and safety of triple therapy containing berberine, amoxicillin, and vonoprazan for Helicobacter pylori initial treatment: A randomized controlled trial. Chin Med J 2023; 136: 1690–1698. doi: 10.1097/CM9.0000000000002696
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