Abstract
Objective
To estimate the effectiveness and safety of triple therapy containing berberine, amoxicillin, and rabeprazole in the eradication of Helicobacter pylori (H. pylori).
Methods
This prospective, randomized controlled, open‐label, noninferiority trial included treatment‐naive patients with H. pylori infection who were randomly allocated at a ratio of 1:1 into the berberine triple therapy group (berberine hydrochloride 300 mg thrice daily, amoxicillin 1 g twice daily, and rabeprazole 10 mg twice daily) or standard bismuth‐containing quadruple therapy group (amoxicillin 1 g twice daily, rabeprazole 10 mg twice daily, clarithromycin 500 mg twice daily, and bismuth tartrate 200 mg twice daily) for 14 days. Negative 13C/14C‐urea breath test at 4 weeks after completion of the therapy was regarded as successful eradication.
Results
Altogether 262 and 262 patients received berberine triple therapy and bismuth‐containing quadruple therapy, respectively. Both intention‐to‐treat (79.8% vs 80.9%, P = 0.742) and per‐protocol analyses (83.6% and 85.1%, P = 0.636) showed comparable eradication rate between the two groups, indicating a noninferior eradication rate (the lower limit of the 95% confidence interval over −10% [−7.9% and −7.87%, respectively]). Adverse events more commonly occurred in the bismuth‐containing quadruple‐therapy group (8.8% vs 16.0%, P = 0.012), while patient compliance and symptom improvement of the two regimens were comparable.
Conclusion
Triple therapy containing berberine, amoxicillin and rabeprazole is noninferior to bismuth‐containing quadruple therapy in the initial treatment for H. pylori eradication.
Keywords: berberine, eradication, Helicobacter pylori, quadruple therapy
We demonstrated in a prospective randomized controlled trial that triple therapy containing berberine, amoxicillin, and rabeprazole can be used as the first‐line treatment for patients with primary Helicobacter pylori (H. pylori) infection. Abbreviation: UBT, urea breath test
1. INTRODUCTION
Helicobacter pylori (H. pylori) infection can be detected in half the world population and 42.01%–84.62% of the population in China. 1 Studies have revealed that H. pylori is a nonnegligible pathogenic factor in various gastrointestinal (GI) diseases such as peptic ulcer, gastric cancer (GC), and gastric mucosa‐associated lymphoid tissue (MALT) lymphoma. In addition, H. pylori infection is related to extra‐GI diseases including diabetes mellitus, coronary heart disease, and hypertension, etc. 2 , 3 , 4 Besides its effectiveness on alleviating GI symptoms and ulcer healing, H. pylori eradication is also important for a complete remission of low‐grade gastric MALT lymphoma at an early stage. 5 , 6 , 7 , 8 In 2015, the Kyoto consensus defined H. pylori gastritis as an infectious disease, and recommended eradication therapy for all adult patients infected with H. pylori. Theoretically, the eradication rate of should reach 80% or higher, and that of the optimal treatment scheme should be over 95%. 9 However, the validity of H. pylori eradication therapy shows a gradual downward trend globally. Eradication failure is mainly attributed to antibiotic resistance, variation among bacterial strains and hosts, as well as ineffective treatments.
Due to the increasing antibiotic resistance, it is difficult to achieve an eradication rate of 80% by using triple therapy. 10 Bismuth‐containing quadruple therapy is therefore recommended as a well‐established first‐line empirical treatment regimen for H. pylori eradication. 11 The resistance rates to amoxicillin, tetracycline, and furazolidone remain low (≤5%), while the resistance/multiresistance rate to other recommended antibiotics is high. Studies have revealed that an increased rate of dual metronidazole and clarithromycin resistance is one of the main causes of treatment failure. 12
Berberine, a traditional Chinese medicine, has long been used in clinical practice as an antibacterial and anti‐inflammatory drug in China, which also has a good inhibitory effect on multidrug‐resistant H. pylori strains. 13 , 14 Previous studies have confirmed that treatment regimen including berberine can not only eradicate H. pylori effectively, but decrease the adverse events (AEs) to a certain extent, leading to a good patient compliance. 15 , 16 , 17 Our previous studies have shown that quadruple therapy containing bismuth, berberine hydrochloride and amoxicillin achieves satisfactory eradication effect as both primary and rescue eradication therapy, which is comparable to the conventional bismuth‐containing quadruple regimen as recommended by consensus. 15 , 17 AEs of H. pylori eradication therapy were reported to be mainly linked to the use of antibiotics and bismuth. Bismuth can promote the efficacy of H. pylori eradication by protecting the mucosal tissue against damage and increase H. pylori susceptibility to antibiotics. 18 , 19 Nevertheless, the eradication rate using H. pylori‐sensitive antibiotics cannot be generally enhanced by the addition of bismuth. 20
Considering a high susceptibility to amoxicillin and almost no resistance to berberine hydrochloride, we speculate that in the bismuth‐based quadruple regimen containing berberine hydrochloride and amoxicillin, bismuth may not improve the susceptibility to amoxicillin and berberine hydrochloride. The triple regimen including berberine hydrochloride combined with amoxicillin and a proton pump inhibitor (PPI) may obtain an equivalent effectiveness to that of the bismuth‐containing quadruple therapy in H. pylori eradication. In this this single‐center, randomized controlled, noninferiority study, we aimed to discriminate the effectiveness and safety of the triple regimen composed of berberine hydrochloride, PPI, and amoxicillin as the first‐line eradication therapy for H. pylori infection.
2. PATIENTS AND METHODS
This open‐label, randomized controlled, prospective, noninferiority study was conducted at the Xijing Hospital (Xi'an, Shaanxi Province, China) from January 2021 to July 2021. The study was approved by the Ethics Committee of Xijing Hospital (no. KY20202119) and followed the CONSORT Statement of Randomized Controlled Studies and the Declaration of Helsinki (Brazil, 2013). Written informed consent was obtained from each patient before their enrollment. The study was registered on ClinicalTrials.gov (registration no. NCT04697186).
2.1. Patient enrollment
Subjects aged 18–70 years who were confirmed to have initial H. pylori infection, dyspepsia, and had never received eradication therapy were recruited in this study. Exclusion criteria were: (a) hypersensitivity to study drug; (b) administration of antibiotics within 1 month or thrice a week and/or PPI within 2 weeks before 13C‐urea breath test (UBT); (c) with severe comorbidities; (d) with dysphagia, gastroduodenal ulcer, MALT lymphoma, or malignancy; (e) with pathologically confirmed high‐grade intraepithelial neoplasia; (f) with coagulation dysfunction, evident bleeding or iron deficiency anemia; (g) sustained use of hormones or nonsteroidal, anti‐inflammatory drugs (NSAIDs), anticoagulants or platelet aggregation inhibitors (except aspirin use <100 mg/day); (h) previous history of drug or alcohol abuse; (i) pregnant or lactating; (j) with psychological disorders; (k) had participated in other clinical trials during the past 3 months before the enrollment; and (l) refused to sign informed consent.
The enrolled patients were then randomly allocated to the berberine triple scheme (the observation group) or bismuth‐containing quadruple treatment (the control group) at a ratio of 1:1. The berberine triple therapy group were treated for 14 days with berberine hydrochloride (Yunnan Mingjing Pharmaceutical, Kunming, Yunnan Province, China) 300 mg thrice daily, amoxicillin (Zhuhai United Laboratories, Zhuhai, Guangdong Province, China) 1 g twice daily, and rabeprazole (Eisai China, Suzhou, Jiangsu Province, China) 10 mg twice daily. While the standard bismuth‐containing quadruple therapy group were treated for 14 days with rabeprazole (Eisai China) 10 mg twice daily, amoxicillin (Zhuhai United Laboratories) 1 g twice daily, clarithromycin (Laiyang Jiangbo Pharmaceutical, Laiyang, Shandong Province, China) 500 mg twice daily, and colloidal bismuth tartrate (Shanxi Xinbaoyuan Pharmaceutical, Datong, Shanxi Province, China) 200 mg twice daily. Rabeprazole and colloidal bismuth tartrate were both taken 30 minutes before meals, whereas amoxicillin, clarithromycin and berberine hydrochloride were administrated 30 minutes after meals.
2.2. Diagnosis of H. pylori infection and eradication efficacy
H. pylori infection was confirmed when any one of the 13C/14C‐UBT, H. pylori stool antigen test (H. pylori SAT), and rapid urease test (RUT) were positive. Negative 13C/14C‐UBT at 4 weeks after the completion of H. pylori eradication therapy was regarded as a successful eradication.
2.3. Patient outcomes
The major patient outcome was H. pylori eradication rate at 4 weeks after the completion of 14‐day eradication treatment. Secondary outcomes included improvement of clinical symptoms, patient compliance, and AEs. The factors that affected H. pylori eradication rate were also investigated.
Clinical symptoms of the patients at admission, including nausea, abdominal pain, bloating, diarrhea, constipation, belching, reflux, heartburn, were recorded. The severity and frequency of the symptoms were scored from 0 to 3 (0, none; 1, mild; 2, moderate; and 3, severe). The total score for each symptom was calculated using the following formula: total score = frequency score × severity score.
All patients were followed up via telephone during the trial to improve treatment compliance and to record their clinical symptom scores and AEs. Symptom relief and a good patient compliance were defined as a 50% reduction in the total symptom score and at least 80% of medications were taken, respectively.
2.4. Calculation of sample size and statistical analysis
Based on 69%–91% eradication rates with the bismuth‐containing quadruple therapy, an 85% eradication rate was assumed to be achieved in the two groups. 21 , 22 , 23 The noninferiority δ of 10%, double‐sided α level of 0.05, and β power of 90% were considered, together with a 20% withdrawal rate. At least 262 patients in each group were required.
Continuous data were expressed as mean ± standard deviation, and were evaluated using the Student's t‐test. While categorical variables were expressed as numbers or percentages or frequencies, and were evaluated using the Chi‐square or Fisher's exact test. To determine noninferiority in the per‐protocol (PP) population, 95% confidence interval (CI) of the rate difference (RD) between the two groups was estimated by Student's t‐test. Using the lower limit of the RD 95% CI over −10%, the berberine triple therapy was not inferior to bismuth‐containing quadruple therapy, the intention‐to‐treat (ITT) population was also defined as statistically significant (P < 0.05).
3. RESULTS
3.1. Baseline characteristics of the patients
From January 2021 to July 2021, 524 patients were successfully recruited in the trial, among whom 17 were lost to follow‐up, four discontinued against medical advice, one did not receive retesting at 4 weeks after the completion of H. pylori eradication therapy, and three withdrew from the trial due to severe allergic phenomena. Finally, 499 patients completed the full course of the trial (Figure 1 ). Baseline characteristics of the two groups are presented in Table 1.
FIGURE 1.
Flow diagram of the study. Abbreviations: ITT, intention‐to‐treat; PP, per‐protocol
TABLE 1.
Baseline characteristics of the participants
| Variables | Observation group (n = 262) | Control group (n = 262) | P value |
|---|---|---|---|
| Age, years (mean ± SD) | 44.81 ± 12.08 | 45.73 ± 13.00 | 0.400 |
| Sex, n (male/female) | 137/125 | 128/134 | 0.432 |
| BMI, kg/m2 (mean ± SD) | 23.34 ± 3.29 | 22.86 ± 3.37 | 0.100 |
| Ethnicity, n (%) | 1.000 | ||
| Han | 256 (97.7) | 256 (97.7) | |
| Others | 6 (2.3) | 6 (2.3) | |
| Educational level, n (%) | 0.861 | ||
| University and above | 121 (46.2) | 123 (46.9) | |
| High school and below | 141 (53.8) | 139 (53.1) | |
| Smoking, n (%) | 0.419 | ||
| Yes | 63 (24.0) | 51 (19.5) | |
| No | 185 (70.6) | 198 (75.6) | |
| Stop smoking | 14 (5.3) | 13 (5.0) | |
| Alcohol consumption, n (%) | 0.833 | ||
| Yes | 61 (23.3) | 57 (21.8) | |
| No | 185 (70.6) | 191 (72.9) | |
| Stop drinking | 16 (6.1) | 14 (5.3) | |
| Drinking water source, n (%) | 0.287 | ||
| Tap water | 160 (61.1) | 148 (56.5) | |
| Non‐tap water | 102 (38.9) | 114 (43.5) | |
| Decayed tooth, n (%) | 0.544 | ||
| Yes | 68 (26.0) | 62 (23.7) | |
| No | 194 (74.0) | 200 (76.3) | |
| History of drug allergy, n (%) | 0.265 | ||
| Yes | 8 (3.1) | 13 (5.0) | |
| No | 254 (96.9) | 249 (95.0) | |
| Long‐term medication, n (%) | 0.415 | ||
| Yes | 41 (15.6) | 48 (18.3) | |
| No | 221 (84.4) | 214 (81.7) | |
| Concomitant disease, n (%) | 0.907 | ||
| Yes | 44 (16.8) | 45 (17.2) | |
| No | 218 (83.2) | 217 (82.8) | |
| Family history, n (%) | 0.612 | ||
| Yes | 62 (23.7) | 67 (25.6) | |
| No | 200 (76.3) | 195 (74.4) | |
| Fruit intake, n (%) | 0.730 | ||
| 5 units/week | 61 (23.3) | 65 (24.8) | |
| 2–4 units/week | 118 (45.0) | 109 (41.6) | |
| 1 unit/week | 83 (31.7) | 88 (33.6) | |
| Drinking tea, n (%) | 0.448 | ||
| 6–7 days/week | 49 (18.7) | 53 (20.2) | |
| 3–5 days/week | 6 (2.3) | 12 (4.6) | |
| 1–2 days/week | 41 (15.6) | 43 (16.4) | |
| No | 166 (63.4) | 154 (58.8) | |
| Coffee drinking, n (%) | 0.677 | ||
| 6–7 days/week | 5 (1.9) | 8 (3.0) | |
| 3–5 days/week | 4 (1.5) | 2 (0.8) | |
| 1–2 days/week | 35 (13.4) | 32 (12.2) | |
| No | 218 (83.2) | 220 (84.0) | |
| Dairy products, n (%) | 0.857 | ||
| 5–7 times/week | 52 (19.8) | 55 (21.0) | |
| 2–4 times/week | 38 (14.5) | 34 (13.0) | |
| Once weekly | 172 (65.6) | 173 (66.0) | |
| Vegetable intake, n (%) | 0.465 | ||
| ≤250 g/day | 54 (20.6) | 43 (16.4) | |
| 250–500 g/day | 127 (48.5) | 134 (51.1) | |
| >500 g/day | 81 (30.9) | 85 (32.4) | |
Abbreviations: BMI, body mass index; SD, standard deviation.
3.2. H. pylori eradication rates
Of the 499 participants, only 78 experienced eradication failure. The eradication rate of the berberine triple therapy group was 79.8% (209/262) in the ITT analysis and 83.6% (209/250) in the PP analysis, while that of the standard bismuth‐containing quadruple therapy group were 80.9% (212/262) and 85.1% (212/249), respectively. No significant differences were observed between the two groups (ITT analysis, P = 0.742; PP analysis, P = 0.636). Furthermore, the lower limit of RD 95% CI between the two groups was >−10% (−7.9% and −7.87%, respectively), indicating that the eradication rates were noninferior in both groups (Table 2).
TABLE 2.
Helicobacter pylori eradication rates
| ITT analysis | PP analysis | |||
|---|---|---|---|---|
| Observation group | Control group | Observation group | Control group | |
| n/N (%) | 209/262 (79.8) | 212/262 (80.9) | 209/250 (83.6) | 212/249 (85.1) |
| 95% CI | 74.4–84.5 | 75.6–85.5 | 78.4–88.0 | 80.1–89.3 |
| RD 95% CI | −7.9, 5.7 | −7.87, 4.87 | ||
| P value | 0.742 | 0.636 | ||
Abbreviations: CI, confidence interval; ITT, intention‐to treat; PP, per‐protocol; RD, rate difference.
3.3. Factors affecting H. pylori eradication rate
The factors affecting the validity of the two treatment strategies were analyzed in the PP population (Table 3), showing that the efficacy of the two treatment schemes was not affected by patients’ age, sex, body mass index (BMI), status of cigarette smoking, alcohol drinking, dietary habits, or AEs.
TABLE 3.
Factors affecting the validity of Helicobacter pylori eradication in the per‐protocol population
| Subgroup eradication rate, % (n/N) | Observation group (n = 250) | Control group (n = 249) |
|---|---|---|
| Age | ||
| <43 years | 87.2 (102/117) | 89.4 (93/104) |
| ≥43 years | 80.5 (107/133) | 82.1 (119/145) |
| P value | 0.152 | 0.108 |
| Sex | ||
| Male | 82.4 (108/131) | 84.7 (105/124) |
| Female | 84.9 (101/119) | 85.6 (107/125) |
| P value | 0.604 | 0.838 |
| BMI | ||
| <18.5 kg/m2 | 92.3 (12/13) | 100 (25/25) |
| 18.5–23.9 kg/m2 | 81.1 (107/132) | 83.5 (116/139) |
| 24.0–27.9 kg/m2 | 82.4 (70/85) | 80.0 (52/65) |
| >28.0 kg/m2 | 100 (20/20) | 95.0 (19/20) |
| Z | 0.867 | 0.993 |
| P value | 0.386 | 0.321 |
| Ethnicity | ||
| Han | 84.4 (206/244) | 84.8 (207/244) |
| Others | 50.0 (3/6) | 100 (5/5) |
| P value | 0.057 | 1.000 |
| Education level | ||
| University and above | 86.2 (100/116) | 88.9 (104/117) |
| High school and below | 81.3 (109/134) | 81.8 (108/132) |
| P value | 0.300 | 0.117 |
| Smoking | ||
| Yes | 84.5 (49/58) | 91.8 (45/49) |
| No | 84.3 (150/178) | 83.0 (156/188) |
| Stop smoking | 71.4 (10/14) | 91.7 (11/12) |
| P value | 0.448 | 0.242 |
| Alcohol consumption | ||
| Yes | 89.7 (52/58) | 81.5 (44/54) |
| No | 82.4 (145/176) | 85.6 (155/181) |
| Stop drinking | 75.0 (12/16) | 92.9 (13/14) |
| P value | 0.272 | 0.531 |
| Drinking water source | ||
| Tap water | 84.9 (129/152) | 82.3 (116/141) |
| Non‐tap water | 81.6 (80/98) | 88.9 (96/108) |
| P value | 0.500 | 0.146 |
| Decayed tooth | ||
| Yes | 84.8 (56/66) | 80.0 (48/60) |
| No | 83.2 (153/184) | 86.8 (164/189) |
| P value | 0.750 | 0.199 |
| History of drug allergy | ||
| Yes | 87.5 (7/8) | 100 (13/13) |
| No | 83.5 (202/242) | 84.3 (199/236) |
| P value | 1.000 | 0.226 |
| Long‐term medication | ||
| Yes | 78.9 (30/38) | 86.9 (40/46) |
| No | 84.4 (179/212) | 84.7 (172/203) |
| P value | 0.400 | 0.741 |
| Concomitant disease | ||
| Yes | 76.7 (33/43) | 88.1 (37/42) |
| No | 85.0 (176/207) | 84.5 (175/207) |
| P value | 0.182 | 0.555 |
| Family history | ||
| Yes | 85 (51/60) | 82.8 (53/64) |
| No | 83.2 (158/190) | 85.9 (159/185) |
| P value | 0.737 | 0.544 |
| Fruit intake | ||
| 5 units/week | 84.5 (49/58) | 85.9 (55/64) |
| 2–4 units/week | 84.1 (95/113) | 82.5 (85/103) |
| 1 unit/week | 82.3 (65/79) | 87.8 (72/82) |
| Z | 0.366 | 0.421 |
| P value | 0.714 | 0.673 |
| Drinking tea | ||
| 6–7 days/week | 85.1 (40/47) | 84.0 (42/50) |
| 3–5 days/week | 66.7 (4/6) | 100 (12/12) |
| 1–2 days/week | 78.9 (30/38) | 87.8 (36/41) |
| No | 84.9 (135/159) | 83.6 (122/146) |
| Z | 0.531 | 0.642 |
| P value | 0.595 | 0.521 |
| Coffee drinking | ||
| 6–7 days/week | 100 (5/5) | 85.7 (6/7) |
| 3–5 days/week | 100 (4/4) | 100 (2/2) |
| 1–2 days/week | 80.0 (28/35) | 90.6 (29/32) |
| No | 83.5 (172/206) | 84.1 (175/208) |
| Z | 0.209 | 0.987 |
| P value | 0.835 | 0.324 |
| Dairy products | ||
| 5–7 times/week | 85.7 (42/49) | 88.7 (47/53) |
| 2–4 times/week | 89.5 (34/38) | 81.3 (26/32) |
| Once weekly | 81.6 (133/163) | 84.8 (139/164) |
| Z | 1.046 | 0.418 |
| P value | 0.296 | 0.676 |
| Vegetable intake | ||
| <250 g/day | 86.5 (45/52) | 87.5 (35/40) |
| 250–500 g/day | 82.0 (100/122) | 86.3 (107/124) |
| >500 g/day | 84.2 (64/76) | 82.4 (70/85) |
| Z | 0.223 | 0.881 |
| P value | 0.823 | 0.378 |
| Adverse events | ||
| Yes | 93.8 (15/16) | 87.1 (27/31) |
| No | 82.9 (194/234) | 84.9 (185/218) |
| P value | 0.433 | 0.954 |
Abbreviation: BMI, body mass index.
3.4. AEs, compliance, and symptom improvement
All patients received telephone follow‐up during the trial to improve treatment compliance and to record their clinical symptom scores and AEs. Compared with the standard bismuth‐containing quadruple therapy group, The overall rate of AEs in the berberine triple therapy group was relatively low (8.8% vs 16.0%, P = 0.012) (Table 4). Common AEs included nausea, diarrhea, dysgeusia, bloating, fever, anorexia, and weakness (excluding bismuth‐related melena), which improved spontaneously approximately 2 weeks after treatment was discontinued (Table 5). Compared to the standard bismuth‐containing quadruple therapy group, the incidence of dysgeusia was significantly lower in the berberine triple therapy group (4.3% vs 26.2%, P = 0.043). Differences were not observed in patient compliance and symptom relief between the two groups.
TABLE 4.
Rates of adverse events, compliance, and symptom improvement
| Variables (n/N, %) | Observation group | Control group | P value |
|---|---|---|---|
| Overall adverse events | 23/262 (8.8) | 42/262 (16.0) | 0.012 |
| Compliance rate | 246/262 (93.9) | 237/262 (90.5) | 0.143 |
| 2‐week symptom improvement | 207/250 (82.8) | 207/249 (83.1) | 0.921 |
| 6‐week symptom improvement | 236/250 (94.4) | 237/249 (95.2) | 0.695 |
TABLE 5.
Frequency of adverse events in the two groups
| Adverse events (n, %) | Observation group (n = 23) | Control group (n = 42) | P value |
|---|---|---|---|
| Diarrhea | 8 (34.8) | 9 (21.4) | 0.241 |
| Nausea | 11 (47.8) | 11 (26.2) | 0.078 |
| Abdominal pain | 2 (8.7) | 4 (9.5) | 1.000 |
| Dizziness | 1 (4.3) | 3 (7.1) | 1.000 |
| Bloating | 1 (4.3) | 2 (4.8) | 1.000 |
| Dysgeusia | 1 (4.3) | 11 (26.2) | 0.043 |
| Anorexia | 2 (8.7) | 0 (0) | 0.122 |
| Rash | 3 (13.0) | 6 (14.3) | 1.000 |
| Vomiting | 0 (0) | 4 (9.5) | 0.323 |
| Fever | 0 (0) | 1 (2.4) | 1.000 |
| Fatigue | 0 (0) | 2 (4.8) | 0.536 |
4. DISCUSSION
H. pylori is an infectious bacterium with a high global infection rate. It is closely related to both GI and extra‐GI diseases. 3 , 4 , 24 In the whole‐age stage, regardless of whether the infected person has accompanying symptoms or not, H. pylori eradication may prevent the occurrence of GC. 25 , 26 , 27 If H. pylori cannot be eradicated, the infection will continue for life. 28 Current consensus recommends that eradication therapy should be implemented as long as H. pylori infection is detected, unless there are competing considerations, the initial therapy should achieve an ideal eradication success. 5 , 11 Successful initial eradication can avoid subsequent repeated treatment and testing, reducing medical costs, self‐anxiety, and negative effects on gut microbiota. 29
Recently, the easy availability and extensive application of antibiotics have become the direct factors for mutation, secondary, and multidrug resistance of H. pylori strains. As the prevalence of antibiotic resistance increases, treatment regimens for H. pylori eradication continue to escalate from the initial dual regimen (PPI plus amoxicillin), a 7‐day triple regimen (PPI plus two antibiotics), to the 14‐day bismuth‐containing quadruple regimen. An eradication rate below 80% using the triple therapy is no longer acceptable. 10 In China, the resistance rate of H. pylori to clarithromycin (20%–55.2%), metronidazole (40%–90.6%), and levofloxacin (20%–50%) is high, while that to amoxicillin (0%–7.7%), tetracycline (0%–5%), and furazolidone (0%–0.91%) remains low. 30 , 31 , 32 However, it is difficult to exert too much effect clinically due to numerous AEs, complicated administration, and nonavailability. Therefore, the selection of treatment strategies recommended by the guidelines remain limited and may not reach a satisfactory level. 33 , 34
High‐dose dual therapy with PPI and amoxicillin has been recommended as both initial and rescue therapies for H. pylori eradication. Increasing the drug dose without changing the dosing frequency of PPI–amoxicillin dual therapy has comparable efficacy and patient compliance for H. pylori eradication compared with conventional mainstream guidelines. 35 , 36 While changing the frequency of drug regimen without changing the dose, PPI–amoxicillin dual therapy administered four times daily achieved better efficacy and safety than currently recommended regimens (especially first‐line therapy), mainly in Asia. 37 However, despite the increasing eradication rate, a decreasing patient compliance to a frequent drug dosing and a possible increase of AEs related to large‐dose drug use may influence the efficacy and safety of the treatment regimes. Therefore, more studies are needed to further improve the efficacy of first‐line eradication therapy of H. pylori.
Berberine is an alkaloid derived from Coptis chinensis and possesses various biological activities. It is widely used in clinical practice because of the unique antimicrobial, antibacterial, and anti‐inflammatory effects. The potency of berberine on reducing the activity of H. pylori is seldom affected by the internal and external environments, especially against multidrug‐resistant strains. This effect is significantly enhanced with clarithromycin, which may be due to a synergy between them. 38 , 39 , 40 Berberine could specifically inactivate urease by combining with the sulfhydryl group of urease active site (nickel metal center) in the dose‐dependent manner. Furthermore, berberine promotes the separation of nickel from the urease dimer and interfered with the maturation of urease. 41 , 42
Clinical studies have found that berberine combined with traditional triple therapy or alternatives to antibiotics with high resistance rate in bismuth‐containing quadruple regimen shows higher H. pylori eradication and cure rates in the treatment of H. pylori‐related gastritis and peptic ulcer. It also reduces the recurrence rate of ulcers. 15 , 16 , 17 In addition, berberine interacts with antibiotics, illustrating that it has a certain eradication consequence on multidrug‐resistant H. pylori strains when used in combination with other antibiotics. 14
The H. pylori nomogram model has demonstrated that bismuth can enhance the eradication rate by at least 30%, 18 , 19 though it is unlikely to improve the treatment effectiveness. 20 In addition, compared with PPIs, bismuth may cause a higher rate of AEs.
The results of our study showed that eradication rate of H. pylori in the PP analysis was above 80%, and there was no statistical difference between the berberine triple therapy and the bismuth‐containing quadruple therapy. Furthermore, the lower limit of the RD 95% CI between the two groups was >−10% (−7.9% and −7.87%, respectively), indicating that the eradication rate was noninferior in both the berberine triple therapy group and the standard bismuth‐containing quadruple therapy group. In addition, clinical symptom improvement and patient compliance were comparable between the two groups. However, the overall incidence of AEs in the berberine triple therapy group was relatively low (8.8% vs 16.0%, P = 0.012). Among all AEs, compared to the standard bismuth‐containing quadruple therapy group, dysgeusia rarely occurred in the berberine triple therapy group (4.3% vs 26.2%, P = 0.043). We speculate that this may be related to the combined use of bismuth and clarithromycin in the quadruple therapy. AEs in both groups were mild or moderate, which disappeared about 2 weeks after treatment was discontinued. Considering its eradication effectiveness, good safety, low medical cost and easy availability, we suggest a combined use of berberine hydrochloride, amoxicillin, and rabeprazole as a new triple regimen with excellent clinical prospects.
The study of Shang et al 43 indicated that the resistance rate of H. pylori to clarithromycin in Gansu Province, China was 54.72%, and the dual, triple, and quadruple resistance rate exceeded 20%. Xie et al yielded similar results that exceeded 30% in northwest China. 44 According to the Chinese consensus, bismuth‐containing quadruple treatment is the preferred regimen in northwest China. We did not use berberine, amoxicillin, bismuth, and rabeprazole as control in the current study, because our previous study has compared efficacy of a modified quadruple therapy of PPI, berberine, amoxicillin and bismuth with that of the standard bismuth‐containing quadruple therapy, showing a comparable eradication rate. 45 It is speculated that the effectiveness of berberine, amoxicillin, and rabeprazole triple therapy and berberine, amoxicillin, bismuth quadruple therapy is equivalent. This also confirms that H. pylori is not resistant to berberine. As drug resistance rate to amoxicillin is low, the combination of berberine and amoxicillin is H. pylori‐sensitive.
Our subgroup analysis of the factors affecting the eradication rate showed that the efficacy of both regimens was not affected by patient's age, sex, BMI, smoking, alcohol consumption, dietary habits, or AEs. It might be due to the small sample size of this study. Further confirmation of our results with studies with large sample sizes is needed.
There were some limitations to our study. First, the vast majority of subjects in the study were from northwest China, and further studies are required to verify whether the berberine triple regimen is feasible in other regions. Second, quadruple therapy of berberine, amoxicillin, rabeprazole, and bismuth was not used as an additional control, and the effect of bismuth could not have been fully excluded. Finally, gastric pH value, cytochrome P450 2C19 (CYP2C19) genotype, and antibiotic susceptibility of H. pylori in our patients were not assessed.
In conclusion, our study preliminarily demonstrated the efficiency and safety of the new triple regimen including berberine hydrochloride, amoxicillin, and rabeprazole for initial eradication of H. pylori, providing an innovative eradication regimen of H. pylori. Furthermore, 2‐week berberine triple regimen was well tolerated with an acceptable eradication rate and low AEs. This triple therapy can be considered for H. pylori eradication in the local region.
CONFLICT OF INTEREST
The authors declared that they had no conflicts of interest.
ACKNOWLEDGMENTS
We thank the study participants and the clinical teams involved in the study. This work was partially supported by grants from the National Natural Science Foundation of China (no. 82170560) and the Project from State Key Laboratory of Cancer Biology (no. CBSKL2019ZZ07).
Chen XX, Chen YX, Bi HX, et al. Efficacy and safety of triple therapy containing berberine hydrochloride, amoxicillin, and rabeprazole in the eradication of Helicobacter pylori . J Dig Dis. 2022;23(10):568‐576. doi: 10.1111/1751-2980.13146
Funding information National Natural Science Foundation of China, Grant/Award Number: 82170560; State Key Laboratory of Cancer Biology, Grant/Award Number: CBSKL2019ZZ07
Contributor Information
Jun Ye Liu, Email: junyeliu@fmmu.edu.cn.
Yong Quan Shi, Email: shiyquan@fmmu.edu.cn.
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