Helicobacter pylori infection is the major cause of chronic gastritis, gastric ulcer, duodenal ulcer, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue lymphoma.1,2 With the rising prevalence of clarithromycin-resistant strains, standard triple therapy consisting of a proton pump inhibitor (PPI), clarithromycin, and amoxicillin (or metronidazole) for H. pylori infection has declined to <80% in most countries.3–5 Therefore, several alternative therapies, such as bismuth-containing quadruple therapy or non-bismuth quadruple therapy (e.g., sequential, concomitant or hybrid therapy), were developed to increase the eradication efficacy in areas with high clarithromycin resistance.6,7
Hybrid therapy first reported by Hsu et al. consists of a dual therapy with a PPI and amoxicillin for 7 days followed by a quadruple regimen with a PPI, amoxicillin, clarithromycin, and metronidazole for 7 days.8 It exhibited an excellent eradication rate with 99% by per-protocol (PP) analysis and 97% by intention-to-treat (ITT) analysis in the pilot trial.8 Subsequent randomized controlled studies further demonstrated that hybrid therapy was comparable with or more effective than sequential therapy.9–11 Additionally, a recent multicenter randomized controlled trial showed that both 14-day hybrid and 14-day concomitant therapies cured >90% of patients with H. pylori infections in regions of high clarithromycin and metronidazole resistance.12 Currently, hybrid therapy is a recommended first-line treatment for H. pylori infection in the American College of Gastroenterology guideline,13 Bangkok Consensus Report,14 and Taiwan H. pylori Consensus Report.15
Nonetheless, hybrid therapy requires additional two antibiotics in the last 7 days, which can confuse patients and may dampen enthusiasm for its use. Reversing the sequence of drug administration (a quadruple regimen followed by a dual regimen) can simplify hybrid therapy (Figure 1). It is not necessary for patients to remember to take two additional antibiotics in the last 7 days during anti-H. pylori treatment. A recent randomized controlled study showed that reverse hybrid therapy achieved a higher eradication rate than standard triple therapy.16 Additionally, it is not inferior to bismuth quadruple therapy in the first-line treatment of H. pylori infection and has fewer side effects.17
Currently, whether changing the drug administration sequence of hybrid regimen would influence the eradication efficacy of hybrid therapy remains unclear. To clarify this issue, we conducted the retrospective study to compare the efficacies of reverse hybrid therapy and standard hybrid therapy in the first-line treatment of H. pylori infection.
2.1 Study Participants
From September 2008 to September 2017, consecutive H. pylori-infected patients undergoing a 14-day reverse hybrid therapy or a hybrid therapy who received a complete follow-up were included for the retrospective cohort study. The diagnosis of H. pylori infection was based on at least two positive results of rapid urease test, histology and culture or a positive result of urea breath test. Exclusion criteria were as follows: (1) previous eradication treatment; (2) consumption of antibiotics within the prior 4 weeks; (3) allergy to clarithromycin, amoxicillin, or metronidazole; (4) patients with previous gastric surgery; (5) existence of severe concomitant illness; and (6) pregnancy or lactation. The study was approved by the Institutional Review Board of Kaohsiung Veterans General Hospital (VGHKS18-CT5-06).
2.2 Study design
In total, 252 patients receiving a reverse hybrid therapy (a PPI plus amoxicillin 1 g twice daily for 14 days, and clarithromycin 500 mg plus metronidazole 500 mg twice daily for the final 7 days), and 238 patients receiving a hybrid therapy (a PPI plus amoxicillin 1 g twice daily for 14 days, and clarithromycin 500 mg plus metronidazole 500 mg twice daily for the final 7 days) were included for the study. All patients were prospectively followed up with a standard protocol by well-trained research assistants. The medications were taken 1 hour before breakfast and dinner.
A complete medical history and demographic data were obtained from each patient with a standard checklist. Patients were asked to return at the end of week 2 to assess adverse events and drug adherence. A four-point scale system was used, including none, mild (discomfort annoying but not interfering with daily life), moderate (discomfort sufficient to interfere with daily life), and severe (discomfort resulting in discontinuation of eradication therapy).18 Poor drug adherence was defined as taking <80% of pills.
A urea breath test or a follow-up endoscopy with rapid urease test and histological examination was performed at 6 to 8 weeks after the end of anti-H. pylori therapy. Eradication was defined as: (1) a negative result of the urea breath test; or (2) negative results of both rapid urease test and histology.18,19 The antibiotic susceptibility of H. pylori strains were evaluated by E-test (AB Biodisk, Solna, Sweden). Helicobacter pylori strains with a minimal inhibitory concentration value >1 μg/mL, >0.5 μg/mL, and >8 μg/mL were considered to be resistant to clarithromycin, amoxicillin, and metronidazole, respectively.20,21
2.3 Statistical analysis
This retrospective study only included patients who had received follow-up H. pylori tests. The primary outcome was cure of H. pylori infection. Eradication rate was assessed by modified ITT analysis and PP analysis. Modified ITT analysis included all patients who received at least one dose of eradication drugs regardless their drug adherence. The PP analysis excluded the patients with poor drug adherence. The secondary outcomes were the frequencies of adverse events and treatment adherence. The differences in demographic data, eradication rates, adverse events, and drug adherence were determined appropriately by Chi-square test or Fisher exact test. The continuous data were compared by Student t test. SPSS (version 20 for Microsoft Windows) was used for statistical analyses. A p-value <0.05 was considered statistically significant. To search the independent factors affecting eradication rate of hybrid regimens, clinical, endoscopic, and antibiotic susceptibility parameters were analyzed by univariate analysis. Significant parameters in univariate analysis were further analyzed by a logistic regression method to identify the independent factors predicting eradication failure. Clinical and endoscopic variables included age (< 60 or ≧ 60 years); sex; history of current smoking (< 1 pack/week or ≧ 1 pack/week), alcohol use (< 80 g/day or ≧ 80 g/day), ingestion of coffee (< 1 cup/day or ≧1 cup/day), ingestion of tea (< 1 cup/day or ≧ 1 cup/day), coexistence of a systemic disease (yes or no), endoscopic appearance (ulcer or gastritis), type of PPI; and drug adherence (good or poor).
A total of 252 H. pylori-infected patients received a 14-day reverse hybrid therapy (pantoprazole-based treatment, n = 192; dexlansoprazole-based treatment, n = 60), and 238 patients received a 14-day hybrid therapy (pantoprazole-based treatment, n = 165; esomeprazole-based treatment, n = 73). The baseline characteristics of the patients are shown in Table 1. The two patient groups had comparable age, gender, smoking, alcohol consumption, underlying diseases, endoscopic findings, and antibiotic resistance. In this study, 21 patients with poor drug adherence (reverse hybrid therapy, n = 14; hybrid therapy, n = 7) were excluded from PP analysis.
3.1 Eradication of H. pylori
Table 2 displays the clinical outcomes of the two eradication therapies in the treatment of H. pylori infection. Reverse hybrid and hybrid therapies had comparable eradication rate by modified ITT analysis (96.4% vs 96.6%; p = 0.899). Per-protocol analysis showed similar results (96.6% vs 96.5%; p = 1.000). Table 3 displays the impacts of antibiotic resistances on the eradication rates of reverse hybrid and hybrid therapies. In the reverse hybrid therapy group, the eradication rates of H. pylori strains with nonresistance, single clarithromycin resistance, single metronidazole resistance, and dual resistances were 98.8%, 86.7%, 100%, and 87.5%, respectively. In the hybrid therapy group, the corresponding eradication rates were 100%, 80%, 100%, and 100%, respectively. There were no significant differences in the eradication rates between the two therapies for eradicating H. pylori-resistant strains.
3.2 Adverse events and drug adherence
The frequencies of adverse events in the participants receiving reverse hybrid and hybrid therapies were 18.7% and 13.0%, respectively. The two treatments exhibited comparable frequencies of adverse events (p = 0.089). Table 4 demonstrates all the side effects of the two therapies. The reverse hybrid group had a higher frequency of abdominal pain than hybrid group (4.4% vs 0.4%, respectively, p = 0.006). However, there were no significant differences with respect to other adverse effects. In the reverse hybrid group, 13 patients stopped anti-H. pylori treatment due to abdominal pain (n = 1), taste perversion (n = 1), nausea (n = 3), vomiting (n = 1), skin rash (n = 3), fatigue (n = 1), and others (n = 3). On the other hand, in the hybrid group, 10 patients stopped anti-H. pylori treatment due to diarrhea (n = 3), dizziness (n = 1), nausea (n = 3), skin rash (n = 1), and others (n = 2).
In this study, 14 patients in the reverse hybrid group and 7 patients in the hybrid group did not complied with the eradication treatment. The two therapies exhibited comparable drug adherence (94.4% vs 97.1%; p = 0.153).
3.3 Factors influencing efficacy of anti-H. pylori therapy
Table 5 lists the factors affecting eradication rates of anti-H. pylori therapies in all the patients included in this study. There was a significant difference in eradication rate between clarithromycin-resistant and clarithromycin-susceptible stains (87.9% and 99.5%; p = 0.002). The other factors including smoking, presence of peptic ulcer, drug adherence, and metronidazole resistance did not significantly affect eradication efficacy. Multiple regression analysis demonstrated that clarithromycin resistance was the only independent factor predicting eradication failure with an odds ratio of 25.8 (95% CI, 2.9–247.3; p = 0.004).
This is the first study to compare the efficacies of 14-day reverse hybrid and 14-day hybrid therapies for the first-line treatment of H. pylori infection. Our results demonstrated several novel findings. First, the two therapies had an equivalent efficacy (96.6% vs 96.4%) for the treatment of H. pylori infection. Second, the two treatments exhibited comparable overall frequencies of adverse events (18.7% vs 13.0%) and drug adherence (94.4% vs 97.1%). Third, both therapies could achieve a high eradication rate for both clarithromycin-resistant strains (87.0% vs 90.0%) and metronidazole-resistant strains (97.7% vs 100.0%). These findings clearly indicate that the sequence of antibiotic administration in the hybrid regimen did not influence the efficacy of anti-H. pylori therapy. This important finding is consistent with our previous study that showed equivalent efficacies of 10-day reverse sequential and 10-day sequential therapies in the treatment of H. pylori infection.22
The strengths of this study include the large sample size (n = 490) and the large amount of data assessing the impact of antibiotic resistance on the eradication rates of hybrid regimens. Determining the antibiotic resistance of 228 strains allowed us to predict the performance of the two therapies in regions with different prevalence rates of clarithromycin and metronidazole resistance. In the current study, the eradication rates of H. pylori strains with no resistance, resistance to clarithromycin alone, resistance to metronidazole alone, and dual resistance in the patients receiving reverse hybrid therapy were 98.8%, 86.7%, 100%, and 87.5%, respectively, compared with 100%, 80%, 100%, and 100% for those receiving hybrid therapy. These results indicated that both 14-day reverse hybrid therapy and 14-day hybrid therapy can be recommended in areas with either high or low clarithromycin and metronidazole resistance. A recent multicenter randomized controlled trial conducted in Spain and Italy confirmed that 14-day hybrid therapy could cure >90% of patients with H. pylori infection in areas with high clarithromycin and metronidazole resistance.12
In this study, the patients who received reverse hybrid therapy had a higher frequency of abdominal pain than those who received hybrid therapy (4.4% vs 0.4%), although the overall frequencies of adverse events with the two therapies were comparable. The reason for this difference in the frequency of abdominal pain is unknown; however, several studies have shown that anti-H. pylori therapy can lead to dysbiosis of gut microbiota,23,24 and that probiotic supplementation can reduce anti-H. pylori eradication therapy-related dysbiosis, thereby decreasing the frequency of adverse effects.23,25,26 A recent microbiota study also demonstrated that the relative abundance of phylum Proteobacteria in patients with adverse effects was higher than that in patients without adverse effects during anti-H. pylori treatment.27 We therefore hypothesize that reverse hybrid therapy using three antibiotics in the initial phase of treatment may lead to more severe dysbiosis of the gut microbiota and more side effects than hybrid therapy, which uses only one antibiotic in the initial phase of treatment. Further studies are warranted to investigate the mechanisms underlying the association between dysbiosis induced by anti-H. pylori therapy and the development of adverse effects.
Clarithromycin resistance has been reported to be the main reason for the failure of standard triple therapy.28–30 Large-scale randomized controlled trials have also demonstrated that clarithromycin resistance can decrease the efficacy of sequential therapy.30,31 Although several previous randomized studies did not show a significant impact of clarithromycin resistance on the eradication efficacy of hybrid or reverse hybrid therapies,17,32 patients with clarithromycin-resistant strains receiving hybrid or reverse hybrid therapies had a lower eradication rate than those with clarithromycin-susceptible strains (87.9% vs 99.5%) in this study. In addition, multivariate analysis revealed that clarithromycin resistance was an independent predictor of eradication failure with the hybrid regimens. Possible explanations for the discrepancies in the impact of clarithromycin resistance on the eradication rate of hybrid regimens include different study powers, variable metronidazole resistance rates, and different frequencies of CYP2C19 genotypes.
In eradication therapy, PPIs not only increase the activity of antibiotics by reducing gastric acid secretion but also have direct anti-H. pylori activity.33 Most PPIs are metabolized by the hepatic cytochrome P450 system, and particularly CYP2C19. Several studies have reported that the CYP2C19 genotype or the type of PPI was a factor affecting the eradication efficacy of anti-H. pylori therapies.34,35 In the current study, the eradication rates of pantoprazole-, esomeprazole-, and dexilansoprazole-based hybrid treatments were all >95%, and no significant differences in eradication rates were observed between the patients receiving different PPI-based eradication therapies. These findings suggest that the type of PPI does not influence the efficacy of hybrid regimens.
There are several limitations to this study. First, it was not a randomized controlled trial, so the findings in this retrospective cohort study could be due to channeling bias. Nonetheless, all consecutive patients in the study were prospectively followed up according to a standard protocol, and adverse events and drug adherence were recorded by trained assistants via a standardized questionnaire. Second, H. pylori cultures were not routinely performed, which may raise the possibility of selection bias. Nonetheless, we used multivariate analysis to identify the independent factors for eradication outcomes.
In conclusion, 14-day reverse hybrid therapy and hybrid therapy had comparable eradication rates in the first-line treatment of H. pylori infection in this study. Both treatments achieved a high eradication rate for both clarithromycin-resistant and metronidazole-resistant strains.
We thank Miss Joyce Chen for her assistance for editorial assistance in the development of the manuscript. This study was supported by grants (VGHKS18-CT5-06) from the Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
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