Rabeprazole‐amoxicillin dual therapy as first‐line treatment for H pylori eradication in special patients: A retrospective, real‐life study

Abstract Background The currently recommended quadruple regimens for Helicobacter pylori infection might not be appropriate for every patient, especially in elderly patients or those with multiple comorbidities. Objective To evaluate the efficacy and safety of rabeprazole‐amoxicillin dual therapy in H pylori‐positive elderly patients or those with multiple comorbidities. Methods From November 2013 to May 2017, the clinical data of H pylori‐positive patients ≥60 years old or with multiple comorbidities were collected and reviewed. All patients were given rabeprazole 10 mg three times a day and amoxicillin 1000 mg thrice a day (RA dual therapy) for 14 days as first‐line treatment. H pylori eradication was evaluated by 13C‐urea breath test 6 weeks after treatment. Adverse effects were recorded. Results A total of 198 patients were enrolled, including 116 elderly patients and 82 patients with multiple comorbidities. Successful eradication was achieved in 90.9% (180/198, 95% CI: 86.1%‐94.2%) patients. Adverse effects, which were mainly mild (referring to skin rash, abdominal pain, and diarrhea), occurred in 22 patients (22/198, 11.1%) and resolved spontaneously. Conclusion Dual therapy composed of rabeprazole and amoxicillin as a first‐line treatment appears to be effective and safe for H pylori infection in elderly patients or those with multiple comorbidities. Additional studies are needed to optimize the regimen.


| Study design and participants
This was a retrospective, one-arm study conducted at the Peking University First Hospital. From November 2013 to March 2017, we enrolled H pylori-infected outpatients who could not tolerate triple or quadruple therapies because of (a) being elderly (≥60 years old) with or without comorbidities, (b) younger patients with comorbidities, such as nephritis, arrhythmia, cardiovascular disease taking statins, or warfarin competing with clarithromycin, and thus received rabeprazoleamoxicillin (RA) dual therapy as the first-line treatment. The exclusion criteria included patients receiving proton-pump inhibitors (PPIs) or any antibiotics within 1 month before diagnosis. An upper gastrointestinal endoscopy was performed in all enrolled patients. The data on other factors such as age, sex, diagnosis of upper digestive disease, comorbidities, and concomitant medications were collected.

| Diagnosis and eradication of H pylori infection and treatment regimen
H pylori infection was diagnosed as a positive 13 C-urea breath test ( 13 C-UBT), rapid urease test (RUT), or stool antigen test (SAT). The UBT was used as a common method for the detection of H pylori after eradication treatment and consensually recommended in China. It was also chosen as the method in follow-up examination in our study performed at least 6 weeks after treatment.
RA dual therapy consisted of rabeprazole (10 mg) and amoxicillin (1000 mg) three times daily for 14 days. Rabeprazole was suggested to be taken half an hour before meals and amoxicillin postprandially.

| Statistical analysis
Data collected were analyzed using IBM SPSS Statistics SPSS 20.0 software (IBM Corp.). Continuous variables were expressed as mean ± standard deviation, and categorical variables were expressed as numbers and percentages.   Figure 1). Ten patients failed to the treatment, of whom 3 had diabetes mellitus, 2 had autoimmune diseases, and 2 had chronic kidney diseases.

| Eradication rates of H pylori infection
In the subgroup of 116 elderly patients, the RA dual therapy

| AEs
Twenty-two patients (22/198, 11.1%), 11 in the elderly patient group and 11 in the non-elderly patient group, experienced AEs. Nine of these 22 patients had ≥3 comorbidities. The most common AEs were rash, abdominal pain, and diarrhea ( Table 3). All AEs completely disappeared without any intervention after treatment.
Ten of 22 patients with AEs completed the whole treatment. The remaining 12 patients discontinued treatment, in whom 3 patients achieved successful eradication despite incomplete treatment with a duration of 7-12 days, 1 patient failed, and 8 patients were lost to follow-up (details in Table 4). Four of 12 patients who did not complete the treatment had chronic kidney diseases, and 2 patients had chronic liver diseases.

| D ISCUSS I ON
The antibiotic resistance of H pylori has increased in the past decades, which is the main cause of treatment failure. It has been reported that only 16.3% of isolated H pylori strains are susceptible to all tested antibiotics, while dual or multiple resistances are commonly observed with metronidazole, clarithromycin, and fluoroquinolones. 19 The primary and secondary antibiotic resistance rates of amoxicillin are stabilized at a low level (1%) in the Western Pacific region. 20 Elderly patients fail their intended eradication therapy because of previous multiple exposures to antibiotics. Another Atherosclerosis 9

TA B L E 1 Baseline characteristics of patients
Urticaria 7 Hashimoto's thyroiditis 6 Gallbladder polyps 6 Osteoporosis 6 Nephritis 6 Fatty liver 6 Anemia 5 Asthma 5 Kidney stone 5 multi-region prospective study concluded that compared to patients <40 years old, elderly patients exhibit higher resistance rates to clarithromycin, azithromycin, levofloxacin, and moxifloxacin. The resistance rate to amoxicillin remained low in both groups. 21 Higher antibiotic resistance in the elderly population reduced the efficacy of therapies containing these antibiotics.
Bismuth-containing quadruple therapy could partially overcome antibiotic resistance. However, AEs occurred in more than 50% of the levofloxacin-containing bismuth quadruple therapy and standard bismuth-containing quadruple therapy, compared with 26.2% in triple therapy. 22 There were also many competing conditions when it came to the elderly or people with multiple diseases compared to younger ones, considering the possibility of interaction with concomitant medicines. 23,24 Moreover, renal dysfunction and chronic liver disease might affect drug metabolism and induce drug accumulation. The presence of arrhythmia, prolonged QTc interval, and heart diseases might also limit the use of clarithromycin because of a potentially increased risk of heart problems or death.
Clarithromycin inhibits cytochrome P450 enzyme 3A4 (CYP3A4), which was associated with a doubled risk of hospitalization with rhabdomyolysis or other statin-related AEs according to a systematic review recently. 25 Calcium channel blockers (CCBs), which are used in patients with hypertension, were also metabolized by CYP3A4.
Clarithromycin might interact with CCBs and be associated with a higher risk of acute renal injury. 26 Fluoroquinolones might cause a significant decrease in blood glucose, resulting in hypoglycemic F I G U R E 1 Flowchart of the study. In total, 198 subjects were reviewed. A total of 180 cases successfully eradicated H pylori, in which 167 patients were free of any AEs. The RA dual therapy failed in 10 patients. Eight patients were lost to follow-up coma, particularly in elderly people and patients with diabetes. In our study, hypertension, dyslipidemia, and diabetes mellitus were the top three comorbidities, and the choice of antibiotics was, thus, restricted. As for patients older or with multiple comorbidities, a dual regimen with fewer antibiotics would be an option.
Dual therapy, which was composed of PPI+ amoxicillin, was not traditional therapy, even though it had already been used as early as 1998. 27 Amoxicillin was proven to be sensitive in most cases 4 and could work especially in a relatively high pH environment. 28 The dose of amoxicillin was assumed as ideal in 3 g/d in most reports. 27 The other factor that affected the efficacy of treatment was the ability to reliably maintain a relatively high intragastric pH, where the potency of PPIs was involved. Rabeprazole was introduced to the dual regimen because it was less likely to interact with other drugs, such as clopidogrel, warfarin, and tacrolimus, due to its cytochrome P450 2C19 (CYP2C19) polymorphism. CYP2C19 and IL-1β polymorphisms are not significant independent factors of H pylori eradication using rabeprazole-based hybrid therapy. 29 Rabeprazole has also been reported to possess potential antibacterial properties in an in vitro study. 30 As standard PPI therapy (twice-daily dosing) often failed to induce a reliable high intragastric pH, rabeprazole was designed to be given three times per day in our study, which was 30 mg daily, to enhance the acid inhibition effect. 31 At present, the efficacy of the dual regimen remains controversial in different studies, probably due to different durations, dosages, and dose intervals of PPI and amoxicillin. 27 It was supposed that 14 days of dual therapy (40 mg omeprazole and 1000 mg amoxicillin three times daily) was more effective than 10 days of therapy (40 mg esomeprazole and 1000 mg amoxicillin three times daily). 32 The

Manifestation of AEs n
Rash 9 Abdominal pain 5  37 Given the ground of similar efficacy, 38 less pill exposure, lower risk of major drug interactions, and lower potential for AEs, amoxicillin-based dual therapy may be considered as an alternative therapy in special patients. 39 In our study, a 14-day dual regimen consisting of 10 mg rabeprazole and 1000 mg amoxicillin 3 times per day achieved a satisfactory eradication rate of 90.9% as the first-line treatment.
In the case of the 10 patients who failed the eradication treatment, 1 patient had a history of cigarette smoking, 1 patient discontinued the treatment on the 5th day due to AEs, and 6 patients took other medications concurrently. Diabetes mellitus was the most common comorbidity observed in these 10 patients. Previous studies indicated that age ≥ 45 years, insufficient compliance, a short duration of treatment, diabetes mellitus, and cigarette smoking were independent predictive factors of treatment failure. [40][41][42] AEs occurred in 11.1% (22/198) of patients involved in dual therapy, which remained mild and tolerable similar to most reports. 27 Skin rash, diarrhea, and abdominal pain were the most frequently occurred AEs. All AEs disappeared spontaneously after treatment.
13 patients (13/22) with AEs had successful eradication, and 3 of them discontinued the treatment between the 7th and 12th day of treatment. One case showed failure of treatment, and 8 cases were lost to follow-up.
There are limitations to our study. First, a prospective, well-designed study would always be better than a retrospective study. At the beginning of our study, the RA regimen was considered an alternative regimen for patients with old age or multiple comorbidities.
However, the continuous involvement of more and more patients since the eradication rate is encouraging. A prospective study has been designed and performed recently. Second, it was performed in one hospital as a single-center study. Third, there was no control group for comparison. Fourth, the patients involved in the study were special, either elderly or with multiple comorbidities. A randomized multicenter trial would be designed to observe its effect in a future study. Since most of the dual therapy studies published were performed in Asia, there might be bias caused by population characteristics.
In conclusion, the RA dual regimen was effective and safe as a first-line treatment for H pylori infection in special patients. Our study revealed the real clinical practice situation and actual demand of a group of special patients who were older or had multiple comorbidities. A 14-day RA dual regimen was an ideal choice, which was effective and safe regardless of antibiotic resistance background or CYP2C19 polymorphism status. To improve the efficacy of dual therapy, further studies are warranted, which examine the following effects: (a) to increase the dose of PPI to enhance acid inhibition to induce a more reliable intragastric pH environment 31 ; (b) to change PPI to vonoprazan, which might be more powerful in combination with amoxicillin in some reports 43 ; and (c) to give amoxicillin more frequently since it is time-dependent, such as 0.75 g four times per day.

ACK N OWLED G EM ENTS
None of the personal or funding interests declared.

CO N FLI C T O F I NTE R E S T
All authors declare no conflicts of interest related to this article.