Helicobacter pylori (H. pylori) is closely related to chronic gastritis, peptic ulcer, gastric cancer, gastric mucosa-associated lymphoid tissue lymphoma, and other digestive system diseases. Eradication of H. pylori is the most effective treatment. With the increasing resistance rate of clarithromycin and quinolones, the eradication rate of traditional triple therapy is only 80% (Graham and Fischbach, 2010), which is far from meeting the clinical needs. In recent years, quadruple therapy has been recommended as the first choice for H. pylori eradication, and the recommended course of treatment is 10 or 14 days (Malfertheiner et al., 2017). According to the Management of H. pylori infection-the Maastricht V/Florence Consensus Report and the ACG Clinical Guideline of Treatment of Helicobacter pylori Infection, dual therapy can be used for remedial treatment (Malfertheiner et al., 2017; Chey et al., 2018).

A number of studies have found that increasing the dose and frequency of amoxicillin and proton pump inhibitors (PPI) can improve the efficacy of an amoxicillin/PPI dual regimen (Sugimoto et al., 2012; Graham and Dore, 2016). First, some studies found that H. pylori entered the active replication state when pH > 6, and the pathogen was highly sensitive to amoxicillin (Labenz, 2001). Therefore, the use of PPI to inhibit gastric acid fully and continuously is conducive to the successful eradication of H. pylori. Second, amoxicillin is pH-dependent, which suggests that amoxicillin has higher stability and antibacterial effect with an increase in pH value (Sugimoto et al., 2012). Third, the effect of amoxicillin is time-dependent because it is absorbed rapidly, enters the plasma circulation, and excretes through the urine in a short time, and the bactericidal effect of multiple administrations is better (Graham and Dore, 2016). Therefore, a high dose of amoxicillin can improve the curative effect. The Maastricht-V Consensus and the H. pylori treatment consensus published by the American Gastroenterological Society in 2017 recommend that PPI be administered twice a day, which can maintain the gastric acid suppression effect and is conducive to eradication (Malfertheiner et al., 2017; Chey et al., 2018). Sugimoto et al. (2012) studied the correlation between the administration frequency of PPI and the effect of gastric acid inhibition. Their study found that the 24 h mean intragastric pH was associated with the frequency of administration of 40 mg of rabeprazole: intragastric pH 4.8 once daily, 5.7 twice a day, and 6.0 after four doses of rabeprazole. In this study, the gastric acid inhibition effect can be maintained by administration twice a day.

Therefore, this study aimed to investigate the eradication rate of H. pylori with dual therapy and bismuth quadruple therapy for 10 or 14 days. In this study, Ilaprazole was used as a PPI. Ilaprazole is a classic generation of PPI, which can effectively, stably, and lastingly inhibit gastric acid secretion and is not affected by CYP2C19 gene polymorphism. It has been used to treat acid-related diseases. In selecting antibiotics, the three antibiotics recommended by the Maastricht V/Florence Consensus Report and ACG Clinical Guideline (Malfertheiner et al., 2017; Chey et al., 2018), clarithromycin, metronidazole, and levofloxacin, have a high resistance rate and a low clinical cure rate. On the contrary, the resistance rate of the other three antibacterial drugs for eradicating H. pylori, amoxicillin (0–5%), tetracycline (0–5%), and furazolidone (0–1%), are still low (Liu et al., 2018). Regarding treatment choices, the guidelines point out that the recommended course of empirical treatment is 10 or 14 days. If the 10-day course of treatment can achieve a local eradication rate close or equal to 90%, then the 10-day treatment plan can be used as the first-line treatment option (Malfertheiner et al., 2017; Liu et al., 2018). In this experiment, the course of treatment for eradicating H. pylori was 10 or 14 days. The safety and effectiveness of the three regimens, as the first-line treatment for the Ningxia area H. pylori infection patients, provide high-efficiency treatment programs, improve the eradication rate in Ningxia, and control the source of infection, which is of great significance for the prevention and treatment of gastric-related diseases and gastric cancer.

The study was approved by the ethics committee and the ethics committee approval document (LW2021038).

This study was a prospective, single-center, open-label, randomized, controlled clinical trial. Between August 1, 2019, and June 1, 2020, 450 patients with an H. pylori infection and 39 patients who were lost to follow-up at the Ningxia Hui Autonomous Region People’s Hospital were included in this study. The design of this study is outlined in a flow chart (Figure 1). The patients were randomly assigned to the IAFB-14-day group, the IAFB-10-day group, or the IA-14-day group according to the ratio of 1:1:1. In the IAFB-14-day group, 16 patients did not undergo the 13C-UBT after 4–6 weeks of treatment, and one patient stopped taking the drugs because of a rash after 2 days of treatment. Of the patients in the study, 14 patients in the IAFB-10-day group and eight patients in the IA-14-day group did not undergo the 13C-UBT after 4–6 weeks of treatment.

Antibiotic resistance is the most critical factor leading to eradication failure in H. pylori treatment. Currently, six kinds of antibiotics are recommended for its eradication, among which clarithromycin, metronidazole, and levofloxacin have high resistance rates, which significantly affect the eradication rate. In contrast to the high resistance rates of the three antibiotics mentioned, the current resistance rates of amoxicillin, tetracycline, and furazolidone are still low (Su et al., 2013; Liu et al., 2018). In the course of treatment, an increase in bismuth can increase the eradication rate of drug-resistant strains by 30–40%. At present, the guidelines recommend that bismuth quadruple therapy should be considered first when choosing the initial empirical treatment plan, and this method is recommended for 10 or 14 days. If it can be confirmed that the eradication rate of some local methods is close or up to 90% after 10 days of treatment, this plan can still be selected for treatment (Fallone et al., 2016; Malfertheiner et al., 2017).

In recent years, several domestic and foreign studies have shown that the success rate of dual therapy is low, which means that it is not suitable for the eradication of H. pylori in empirical first-line treatment. A study in South Korea has demonstrated that the eradication rate of combined therapy using amoxicillin and dexlansoprazole was 52% (Yoon et al., 2017). In the study by Taraq, 13 patients were treated for H. pylori infection with amoxicillin and dexamethasone. The results showed that the success rate of treatment according to the plan and intention was 53.8% (Attumi and Graham, 2014). However, these studies had small sample sizes and used different PPI, dosage, and frequency of PPI and amoxicillin, and they also lacked antibiotic resistance and CYP2C19 detection data. CYP2C19 is involved in hydroxylation metabolism of PPI. CYP2C19 gene polymorphism brings complexity to the use of PPI and is an important factor affecting individual differences in PPI efficacy (Denisenko et al., 2018).

In the present study, a 14-day combination of 5 mg of Ilaprazole twice a day and 750 mg of amoxicillin four times a day for 14 days resulted in an eradication rate of H. pylori similar to that of bismuth. Some recently published meta-analyses on combination therapy also draw similar conclusion that the high-dose double group and quadruple group had the same compliance with the eradication rate of H. pylori, but the high-dose double group was safer than quadruple group (Gao et al., 2020; Yun et al., 2021). However, dual therapy regimens have been less studied in other countries (e.g., Europe or the United States) and acquired lower cure rate in Korea (Kwack et al., 2016), so further clinical studies are needed to determine whether they can be used in other areas.

At the same time, from the adverse reactions of different treatment regimens, the incidence of adverse reactions to the dual therapy was significantly lower than the bismuth quadruple therapy. The primary adverse reaction in the combined therapy group was abdominal distension, while the main adverse reactions in the bismuth quadruple therapy group were abdominal pain and diarrhea, which were related to bismuth (Mégraud and Lehours, 2007). The compliance of patients in the bismuth quadruple therapy group was lower than the dual group, which may be related to the variety of drugs, the complexity of the medication methods, and more adverse reactions. We also analyzed the results of the drug sensitivity culture, the gene, and the immunohistochemistry results of globular transformation in patients with treatment failure. The results showed that the drug resistance rates of clarithromycin, metronidazole, levofloxacin, and tetracycline were 75.0, 93.8, 81.3, and 0%, respectively. The drug resistance rate of amoxicillin and furazolidone was 12.5%. In the follow-up, we will continue to assess the drug sensitivity culture of H. pylori in patients with treatment failure to further improve the experimental results. Drug resistance, the CYP2C19 gene, and Immunohistochemistry were analyzed in the three groups. The results showed no statistical difference between the groups, which may be related to the small number of gastric mucosa samples taken under gastroscopy in this study; the sample size will continue to be increased in follow-up experiments.

The results of this study showed that the drug cost of dual therapy was lower than the 14-day bismuth quadruple therapy, and the cost per patient was about $13.61. For patients, this reduces the burden of treatment, increases the willingness to choose this regimen, and increases treatment compliance. Considering long-term treatment for the prevention and treatment of drug resistance in the future and economic benefits to patients, only amoxicillin is selected for the combined treatment because it dramatically improves the patient’s compliance, reduces the occurrence of adverse reactions, and reduces the economic cost to patients.

In addition, the secondary drug resistance rate of amoxicillin is low, and there is a wide range of retreatment options after failure. In treating patients with an initial infection of H. pylori, compared with bismuth quadruple therapy, the use of amoxicillin can effectively avoid multiple and large-scale drug resistance, which is of great significance for the future treatment of H. pylori and its retreatment after failure.

There were still some limitations to this study. First, we did not monitor the 24 h intragastric pH during the whole treatment process, so we were unable to evaluate whether the administration of 5 mg of Ilaprazole twice a day successfully inhibited gastric acid secretion and maintained a 24 h intragastric pH > 6.0. Second, the sample size was not large enough, which may have led to potential bias in the sampling selection. The age and history of cup/glass sharing in the dual therapy group were significantly higher than in the bismuth quadruple therapy group. Although there was no effect on the eradication results, there was still bias. Third, this study was a single-center study, and the subject population has certain limitations.

Before combination therapy can become a first-line treatment alternative, we need to further study and explore dual therapy. First, a multicenter study should be conducted to expand the sample size and reduce bias. Second, PPI with stronger efficacy and longer duration should be selected to achieve appropriate intragastric pH. Vonoprazan, a newly developed potassium competitive acid blocker, is mainly metabolized by the CYP3A4 pathway in vivo, which is not affected by CYP2C19 gene polymorphism, and it has a long half-life and long acid inhibition (Echizen, 2016; Jung et al., 2017; Graham and Dore, 2018). Therefore, vonoprazan could be tried instead of PPI to eradicate H. pylori. In the treatment of H. pylori, the traditional PPI was replaced in the dual therapy. Third, to determine the best dose, frequency, and course of treatment, each drug in the dual therapy should be varied to achieve the maximum efficacy and formulate an optimal plan. Fourth, the choice of PPI in the dual therapy can be customized according to different genotypes of CYP2C19 or other genes (Flores-Treviño et al., 2018).

To sum up, when selecting empirical treatment options for patients with initial H. pylori infection, our findings suggest that Ilaprazole-based dual 14-day therapy and bismuth quadruple 10-day therapy have similar eradication rates compared with bismuth quadruple 14-day therapy, and all can be considered as first-line options for empirical treatment. However, Ilaprazole-based dual 14-day therapy takes a variety of drugs, is simple to administer, has fewer adverse effects, has lower drug costs, and has a broader range of remedial treatment options available after treatment failure. Therefore, Ilaprazole-based dual 14-day therapy should be given priority when choosing a first treatment regimen for H. pylori-positive patients. Bismuth-containing regimens should be given priority, as appropriate, for the first eradication treatment in patients who smoke.