To the Editor: Helicobacter pylori (H. pylori) is estimated to affect approximately half of the world's population, especially in most developing countries.[1] Eradication of H. pylori has been proven to promote peptic ulcer healing and reduce the incidence of gastric cancer. Previous studies have reported that the northwest region of China has a high H. pylori infection rate of 51.8%.[2] However, the H. pylori eradication rate is declining every year, primarily due to increasing antibiotic resistance, notably clarithromycin,[3] and various other factors may also impact H. pylori eradication. Consequently, this study was conducted to elaborate on the situation of H. pylori eradication in Northwest China and evaluate the related risk factors for eradication failure to explore possible solutions.
We performed a multicenter, real-world study of bismuth quadruple therapy for H. pylori infection with 32 hospitals (shown in the author's affiliation address 1, 3 and Acknowledgment list) across three provinces (Shaanxi, Shanxi and Xinjiang province) in China and detailed demographic characteristics and clinical information of patients with H. pylori infection were prospectively recorded. Patients between 18 and 75 years of age diagnosed with H. pylori infection between January 2020 and December 2021 were eligible for inclusion. The exclusion criteria were as follows: (1) the presence of malignant tumors (excluding gastric mucosa-associated tissue lymphoma); (2) contraindications or allergies to the study drugs; (3) severe liver, renal, or heart dysfunction; (4) pregnancy or lactation; (5) a history of substance abuse or alcohol abuse in the past year; (6) a history of mental disorder; and (7) refusal to sign the informed consent.
The primary outcome measure of this study was the eradication rate of H. pylori. Secondary outcome measures were risk factors for eradication failure and treatment-related adverse events. The H. pylori infection status before treatment was directly determined by standard detection methods (limited to urea breath tests, histological staining, rapid urease tests, or fecal antigen tests), and H. pylori eradication assessment was determined by urea breath tests and fecal antigen tests.
The drug regimen used in the current study was bismuth quadruple therapy for 14 days. A physician at each center completed all case report forms, recording demographics, endoscopic findings, and prescribed drug regimens. The treatment-related adverse events were assessed by the changes in the Gastrointestinal Symptoms Rating Scale [4] scores at baseline and after therapy. All signs and symptoms described, including abdominal discomfort (pain, distension), heartburn, acid regurgitation, nausea, vomiting, the frequency of defecation, and the change of stool character, were notified as adverse events if they were new or worsened symptoms after eradication therapy. This study was approved by the Ethics Committee of the First Affiliated Hospital of Fourth Military Medical University (No. KY20202101-F-1). The protocol was registered at ClinicalTrials.gov (No. NCT04660123). Written informed consent was obtained from all patients before the trial commenced.
Continuous variables are expressed as the means and standard deviations unless otherwise described, while categorical variables are displayed as frequencies and proportions (%). Associations involving parametric data were analyzed using Student's t test. The chi-squared test or Fisher's exact test was employed for comparisons of categorical data. Independent factors that may be associated with successful eradication were assessed using logistic regression models, which were subsequently used to estimate adjusted odds ratios (AORs) and corresponding 95% confidence intervals (CIs). All analyses were performed using SPSS version 25.0 (IBM, SPSS Inc., Chicago, IL, USA). Two-sided P values <0.05 were considered statistically significant.
A total of 959 patients were diagnosed with H. pylori infection and received 14-day bismuth quadruple therapy. We excluded 136 patients due to drug intolerance, ambiguous outcomes, refusal to follow-up, insufficient medication information, and etc. Ultimately, 823 patients (389 males and 434 females) with a median age of 51 years were eligible for the study. Of the 823 patients, 62 (7.5%) had a prior history of H. pylori treatment, and 761 (92.5%) did not. The demographic and other baseline characteristics of the patients are summarized in Supplementary Table 1, https://links.lww.com/CM9/B403.
Of the 823 patients, eradication was successful in 757 (92.0%) patients, which is consistent with the therapeutic regimen recommended by the Fifth Chinese National Consensus Report (85%–94%).[5] As shown in Supplementary Table 2, https://links.lww.com/CM9/B403, the eradication rate of primary therapy was higher than that of rescue therapy (93.3% vs. 75.8%, P < 0.05). Patients who suffered treatment-related adverse events showed a lower eradication rate than those who did not (73.7% vs. 93.3%, P < 0.05). In addition, we found a geographic difference in the eradication rate, which was lower in Shaanxi Province than in other provinces in Northwest China (89.0% vs. 94.9%, P < 0.05). Non-urban areas also showed a lower eradication rate than urban areas (88.7% vs. 94.6%, P < 0.05).
The eradication rates of each proton pump inhibitor (PPI) and antibiotic combination are shown in Supplementary Table 2, https://links.lww.com/CM9/B403. Therapy consisting of amoxicillin plus metronidazole achieved the highest eradication rate (98.2%), followed by therapy consisting of amoxicillin plus clarithromycin (94.6%), amoxicillin plus levofloxacin (92.4%), amoxicillin plus furazolidone (84.6%), and levofloxacin plus furazolidone (70.7%). The eradication rate was significantly different among the six different antibiotic-based therapies (P < 0.05). We also found the choice of PPI to be a potential factor that influenced the eradication rate. Therapy with lansoprazole achieved the highest eradication rate (98.4%), followed by therapies with esomeprazole (96.7%), rabeprazole (92.3%), omeprazole (91.9%), ilaprazole (83.3%), and pantoprazole (82.3%). The eradication rate was also significantly different among the six different PPI-based therapies (P < 0.05).
Stepwise logistic regression analyses were performed to explore factors associated with eradication failure. Statistically significant differences were noted between groups by body mass index (BMI), geographical distribution, eradication attempts, adverse events, antibiotic regimen, and choice of PPI (all P < 0.05). Then, further logistic regression analysis indicated that patients living outside Shaanxi Province (AOR = 0.35, 95% CI: 0.15–0.80), patients with high BMI (>25 kg/m2; AOR = 0.38, 95% CI: 0.17–0.82), rescue therapy (AOR = 4.12, 95% CI: 1.86–9.13), and adverse events (AOR = 6.13, 95% CI: 2.75–13.69) were influence factor of eradication, and differences were statistically significant (all P < 0.05). Setting the amoxicillin plus clarithromycin regimen as the reference group, regimens containing amoxicillin plus furazolidone (AOR = 2.83, 95% CI: 1.23–6.50) and levofloxacin plus furazolidone (AOR = 12.63, 95% CI: 3.59–44.42) all showed a higher risk of eradication failure (P < 0.05). Other regimens were not significantly associated with eradication failure [Supplementary Table 2, https://links.lww.com/CM9/B403].
Of the 823 study patients, 57 (6.9%) experienced one or more treatment-related adverse events during medication, and the total frequency of symptoms was 87 times. The analysis of symptoms in Supplementary Table 3, https://links.lww.com/CM9/B403, which showed the prevalence of all symptoms. Overall, the rates of cases with adverse events in the successful and failed eradication groups were 5.5% and 22.7% (P < 0.05), respectively. Supplementary Table 4 (https://links.lww.com/CM9/B403) shows the results for all variables and adverse events. We also explored the potential relationships between baseline data and treatment-related adverse events. Univariate analysis showed that treatment-related adverse events were related to BMI, eradication attempts, and choice of PPI (all P < 0.05). Then, further logistic regression analysis indicated that patients with high BMI (>25 kg/m2; AOR = 2.20, 95% CI: 1.22–3.95) and rescue therapy (AOR = 2.48, 95% CI: 1.13–5.45) were correlated with treatment-related adverse events, and the differences were statistically significant (all P < 0.05). Setting the esomeprazole regimen as the reference group, the regimens containing omeprazole (AOR = 4.16, 95% CI: 1.11–15.59), rabeprazole (AOR = 6.24, 95% CI: 1.84–21.12), lansoprazole (AOR = 3.99, 95% CI: 1.04–15.25), and ilaprazole (AOR = 42.98, 95% CI: 5.82–317.42) showed a significantly higher incidence of adverse events (all P < 0.05).
The main strength of our study is that it included real-world data from 32 hospitals across three provinces in China. However, there were several limitations in our study. First, although this was a multicenter study, some patients were unable to complete treatment or refused follow-up for various reasons, resulting in small sample sizes in some protocols and limiting the reliability of the corresponding results. Furthermore, due to poor compliance, we could not confirm the total number of treatment-related adverse events and may not have identified the true overall rates of adverse events.
In conclusion, this study revealed that a bismuth quadruple regimen achieved a satisfactory H. pylori eradication rate of 92.0% in Northwest China, and the overall incidence of treatment-related adverse events was infrequent at 6.9%. Patients with various geographical distributions, BMIs, times of eradication attempts, adverse events, and antibiotic regimens were correlated with eradication failure. Therefore, the prevention and management of major known and potential risk factors should be recommended and improved through effective measures to improve the H. pylori eradication rate and reduce the burden of gastric cancer in China.
Acknowledgements
We sincerely thank Shengli Zhang from Xi’an Aerospace General Hospital, Junfang Wang from Xunyi County Hospital, Jinbo Teng from Mian County Hospital, Quanxi Qin from Huashan Central Hospital, Haitao Zhang from Shaanxi Aerospace Hospital, Jianping Dong from Taiyuan Eighth People's Hospital, Kun Zhuang from Xi’an Central Hospital, Juan Feng from Xi’an Fengcheng Hospital, Kai Cheng from Qian County Hospital of Traditional Chinese Medicine, Min Ding from Xianyang First People's Hospital, Yanfeng Fan from Central Hospital of China Railway 17th Bureau Group Co. LTD., Xuehui Liu from Second Hospital of Shanxi Medical University, Linglong Xue from General Hospital of Taiyuan Iron & Steel (Group) Co. LTD., Xianglu Liu from Central Hospital of China Railway 12th Bureau Group, Xin Yang from Taiyuan Central Hospital, Li Zhang from Taiyuan Central Hospital (Fendong), Xiaolin Li from Baoji Jintai Hospital, Wencong Gao from Yangling Demonstration Zone Hospital, Ailong Qiu from General Global China Railway Hua Zhou Hospital, Liqiong Zhao from Taiyuan Coal Gasification Staff Hospital, Junrong Liang from 987 Hospital of Joint Logistic Support Force of Chinese People's Liberation Army, Jiehong Wang from The First Affiliated Hospital Of Shaanxi University of Traditional Chinese Medicine, Zhen Wang from Yangqu County People's Hospital, Rong Zhang from Xianyang Hospital of Yan’an University, Zengyu Li from Ningwu County People's Hospital, Shunping Ren from First Affiliated Hospital of Shanxi University of Chinese Medicine, Xueli Guo from Affiliated Hospital of China Institute of Radiation Protection, Yu Luo from Karamay City People's Hospital, Xingming Zheng from Fanshi Hospital of Traditional Chinese Medicine, and Shoujie Liu from Pingyao Hospital of Traditional Chinese Medicine. We would also like to thank other individuals who contributed to the current study in a variety of capacities.
Funding
This work was supported by grants from the National Natural Science Foundation of China (Nos. 82170560 and 81873554).
Conflicts of interest
None.
Data availability statement
The datasets generated and analyzed during the current study are available from the corresponding authors upon reasonable request.
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