Background The efficacy of a levofloxacin-based regimen as the first-line treatment and a clarithromycin-based regimen as the second-line treatment for Helicobacter pylori infection remains unknown. The aim of this study was to assess the eradication rates of these two regimens using different administration sequences.
Methods Eligible patients were randomised to receive LAL: levofloxacin (750 mg once a day), amoxicillin (1000 mg twice a day) and lansoprazole (30 mg twice a day) for 7 days, or CAL: clarithromycin (500 mg twice a day), amoxicillin (1000 mg twice a day) and lansoprazole (30 mg twice a day) for 7 days. Patients with positive [13C]urea breath test after treatment were retreated with the rescue regimen in a crossover manner for 10 days.
Result When used as first-line treatment (n=432), the eradication rates of LAL (n=217) and CAL (n=215) were 74.2 and 83.7% (p=0.015) in the intent-to-treat (ITT) analysis, and 80.1 and 87.4% (p=0.046) in the per-protocol (PP) analysis, respectively. When used as second-line treatment, the eradication rates of LAL (n=26) and CAL (n=40) were 76.9 and 60% (p=0.154) in the ITT analysis, and 80 and 61.5% (p=0.120) in the PP analysis, respectively. The overall eradication rates of CAL followed by LAL were better than the reverse sequence in both the ITT analysis (93% vs 85.3%, p=0.01) and the PP analysis (97.6% vs 92.5%, p=0.019). The eradication rate was significantly lower in the presence of levofloxacin resistance in the LAL group (50% vs 84.4%, p=0.018) and clarithromycin resistance in the CAL group (44.4% vs 90.7%, p=0.002).
Conclusion CAL achieved a higher eradication rate than LAL as the first-line treatment, but not as the second-line treatment. The strategy of using CAL as the initial treatment and LAL as the rescue regimen achieved higher eradication rates than the reverse sequence.
Clinical trial number NCT00816140.
- Antibiotics–clinical trials
- Helicobacter pylori
- susceptibility test
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- Antibiotics–clinical trials
- Helicobacter pylori
- susceptibility test
Helicobacter pylori plays a crucial role in the pathogenesis of gastritis, non-ulcer dyspepsia, peptic ulcer diseases and gastric cancer.1 2 Eradication of H pylori can lead to reduction in the recurrence of peptic ulcer diseases and prevention of gastric cancer, and has been recommended in severa consensus conferences.3–5 One of the most commonly used first-line regimens is clarithromycin-based triple therapy for 7–14 days.4 5 With the increasing prevalence of antibiotic resistance to clarithromycin, the eradication rate with standard first-line treatment has fallen to <80% in many countries.6 Therefore, several alternative first-line regimens, including levofloxacin-based treatment and sequential treatment, have been proposed in recent years.7–10 Levofloxacin-based triple therapy have been shown to be effective as the second-line and third-line rescue regimens for those who failed standard treatment, with an eradication rate ranging from 75 to 90%.11–15 Recent studies have also shown that levofloxacin-based triple therapy is effective as the first-line treatment.7 8 Nista et al reported in a study Italy that triple therapy comprising levofloxacin, clarithromycin and esomeprazole for 7 days achieved a higher eradication rate (87%) than clarithromycin-based triple therapy comprising clarithromycin, esomeprazole and either amoxicillin (75%) or metronidazole (72%).7 Gisbert et al reported in a study in Spain that a combination of levofloxacin, amoxicillin and ranitidine bismuth citrate for 10 days produces an eradication rate of 84.4%.8 Since the prevalence of primary levofloxacin resistance is low in many countries, including Taiwan, levofloxacin-based triple therapy might be an attractive alternative to clarithromycin-based treatment.16 17 However, validation of the efficacy of levofloxacin-based treatment as the first-line treatment is required before its clinical application in different countries.
A meta-analysis showed that extending the duration of clarithromycin-based treatment from 7 to 14 days led to a 12% higher eradication rate.18 Several studies also showed that a 10 day levofloxacin-based treatment achieved a higher eradication rate than a 7 day treatment when used for second-line and third-line treatment of H pylori infection.11 12 On the other hand, some studies have demonstrated that high dose (750 mg) and short course (5 days) levofloxacin is as effective as the traditional dose (500 mg) and course (10 days) in the treatment of mild-to-severe community-acquired pneumonia.19 20 The incidence of adverse effects was not higher in the high dose and short course group compared with the traditional dose and course group.19 20 Potential benefits of high dose and short course levofloxacin treatment include increasing compliance and reducing bacterial resistance rates.21 However, whether increasing the dosage of levofloxacin from 500 to 750 mg per day may augment the efficacy of triple therapy in eradication of H pylori and shorten the treatment duration remains unknown. Therefore, we aimed to evaluate whether a triple therapy with a higher dosage of levofloxacin (750 mg) for 7 days can achieve an eradication rate better than or equivalent to the standard clarithromycin-based treatment for 7 days as the first-line treatment.
Another important issue to be addressed is whether an effective rescue regimen is available after failure of levofloxacin-based treatment. Although the efficacy of each regimen as first-line treatment is important, the cumulative eradication rates after two or three treatments may be even more crucial in the treatment of H pylori infection.14 22 Clarithromycin-based treatment has generally been used as the first-line option.4 5 However, whether it could serve as an effective rescue regimen after failure of initial levofloxacin-based treatment remains unknown. Therefore, we aimed to assess the cumulative eradication rates after two treatments with levofloxacin-based and clarithromycin-based triple therapies using different administration sequences.
Materials and methods
This prospective, multicentre, open label, randomised trial was conducted in the National Taiwan University Hospital in Taipei (Northern Taiwan) and the E-DA Hospital in Kaohsiung (Southern Taiwan) from May 2007 to April 2009. The study protocol was approved by the Institutional Review Boards of the National Taiwan University Hospital and the E-DA Hospital. The ClinicalTrials.gov registration identifier is NCT00816140. The recommendations of the CONSORT statement for the quality of reports of a parallel-group, randomised trial were followed in this study.
Patients with dyspepsia or acid regurgitation who underwent upper endoscopy were invited to receive tests for H pylori infection. Patients with documented H pylori infection who were aged >20 years and were willing to receive eradication treatment for H pylori were considered eligible for enrolment. Patients were excluded from the study if any one of the following criteria was present: (1) children and teenagers aged <20 years; (2) previous eradication treatment for H pylori; (3) history of gastrectomy; (4) gastric malignancy, including adenocarcinoma and lymphoma; (5) previous allergic reaction to antibiotics (amoxicillin, clarithromycin, levofloxacin) and proton pump inhibitors (lansoprazole); (6) use of proton pump inhibitors (lansoprazole) and antibiotics (amoxicillin, clarithromycin, levofloxacin) in the past 4 weeks; (7) active upper gastrointestinal bleeding within the previous 1 week; (8) contraindications to the treatment drugs; (9) pregnant or lactating women; and (10) severe concurrent disease or malignancy. Written informed consent was obtained from all patients prior to enrolment.
Determination of H pylori status
Prior to enrolment, the H pylori infection status was determined by (1) rapid urease test (CLO test) from antrum biopsy; (2) histological examination (Giemsa stain) of antral and body samples (two from the antral mucosa and two from the corpus mucosa); and (3) culture. Positive results in any two of the three tests were defined as positive for H pylori infection. Patients with only one positive test were not eligible for enrolment. Post-treatment H pylori status was determined by [13C]urea breath test ([13C]UBT) at least 6 weeks after the completion of treatment. All subjects were asked to stop any proton pump inhibitor or H2 blocker for at least 2 weeks before post-treatment [13C]UBT. The urea kit (Helico-BT, HWANG'S Pharmaceutical Co., Yun-Lin, Taiwan) used in this study was dissolved in water and mixed with orange juice following the manufacturer's instructions. Samples were assayed with an infrared spectrometer at the Taipei Institute of Pathology. A positive result was defined according to the results of our previous validation study as a delta value of >3.5 units, which had a sensitivity, specificity and accuracy of 97.8, 96.8 and 97.5%, respectively.23 Successful eradication of H pylori was defined as a negative [13C]UBT result.
Culture and antibiotic susceptibility test
The biopsy specimens were cultured on plates containing Brucella chocolate agar with 7% sheep blood and incubated for 7 days under microaerobic conditions (5% O2, 10% CO2, 85% N2). All cultures were stored at −80°C. The minimum inhibitory concentrations (MICs) were determined by agar dilution test. The resistance breakpoints for amoxicillin, clarithromycin and levofloxacin were defined as 0.5, 1 and 1 μg/ml, respectively.17 24
Interventions and randomisation
Using a block randomisation with a block size of 4, patients who met the inclusion criteria and did not have any of the exclusion criteria were randomised to receive one of the following regimens: (group A) LAL regimen: levofloxacin 750 mg once daily, amoxicillin 1000 mg twice daily and lansoprazole 30 mg twice daily for 7 days; or (group B) CAL regimen: clarithromycin 500 mg twice daily, amoxicillin 1000 mg twice daily and lansoprazole 30 mg twice daily for 7 days (figure 1). The physicians and study nurses enrolled the participants. The randomisation sequence was concealed until interventions were assigned. The pharmacists in the National Taiwan University Hospital gave the allocation sequence and assigned participants to their groups by central telephone. Patients who remained positive for H pylori after the initial treatment as determined by the [13C]UBT were re-treated with a rescue regimen in a crossover manner but the treatment periods were extended to 10 days (figure 1). For example, patients who were treated with the CAL regimen for 7 days as initial treatment were re-treated with the LAL regimen for 10 days as the rescue regimen, and vice versa.
The primary end point of the study was the eradication rate after first-line, second-line and two treatments with levofloxacin-based and clarithromycin-based regimens with different sequences in a crossover manner. The secondary end points were the adverse effects and patient compliance. The patients were informed of the common side effects of the antibiotics under study, including diarrhoea, taste disturbance, nausea, bloating, loss of appetite, vomiting, abdominal pain, constipation, headache and skin rash, at the time of enrolment. Enrolled patients were asked to record these symptoms during treatment. A standardised interview was also arranged at the end of treatment to assess the adverse events and compliance. Compliance was considered low when <80% of the pills were taken.
Sample size estimation and statistical analysis
We assumed the eradication of the CAL regimens to be 80% and estimated a sample size of at least 200 in each group in order to detect a 10% difference in the eradication rate to give a statistical power of 80% at a 5% significance level on a two-sided test. Intent-to-treat (ITT) and per-protocol (PP) statistical analyses were performed in the assessment of the primary end point. All randomised patients who had taken the study medications were included in the ITT analysis. All protocol violators, such as patients with unknown study medication ingestion, not taking at least 80% of treatment drugs, or with unknown post-treatment H pylori status were excluded from the PP analysis. Categorical data were compared using the χ2 test employing Yates correction for continuity or the Fisher exact test as appropriate. Continuous data were compared with Student t test and expressed as mean (SD). Logistic regression analyses were used to compute the ORs and the 95% CI. All p values were two-tailed, with the level of statistical significance specified as 0.05. The statistical analyses were performed using the SPSS 10.0 statistical software for Windows.
Participant flow for this study is shown in figure 1. A total of 1173 patients were screened and 457 patients (39%) were positive for H pylori. Nine patients did not fulfil the enrolment criteria and 16 patients refused to participate in this trial. Therefore, 432 patients were enrolled. The baseline demographic data, including age, gender, cigarette smoking, alcohol consumption, tea consumption, body weight and endoscopic diagnosis were not different between the two groups before first-line and second-line eradication treatments, as shown in table 1.
Primary end point: H pylori eradication rates
As first-line treatments, the eradication rates of levofloxacin-based (group A) and clarithromycin-based (group B) regimens were 74.2% (161/217) and 83.7% (180/215) (p = 0.015) in the ITT analysis, and 80.1% (161/201) and 87.4% (180/206) (p=0.046) in the PP analysis, respectively (table 2). The use of levofloxacin-based treatment was associated with an increased risk of treatment failure compared with clarithromycin-based treatment in both the ITT (OR 1.79, 95% CI 1.12 to 2.87, p=0.016) and the PP analysis (OR 1.72, 95% CI 1.01 to 2.94, p=0.048) using logistic regression analysis.
As second-line treatment, the eradication rates of levofloxacin-based (group B) and clarithromycin-based (group A) regimens were 76.9% (20/26) and 60% (24/40) (p=0.154) in the ITT analysis, and 80% (20/25) and 61.5% (24/39) (p=0.120) in the PP analysis, respectively (table 2). The use of clarithromycin was not significantly associated with an increased risk of treatment failure compared with levofloxacin as the second-line treatment in both the ITT (OR 2.22, 95% CI 0.73 to 6.74, p=0.159) and the PP analysis (OR 2.50, 95% CI 0.77 to 8.08, p=0.126).
The overall eradication rates of the clarithromycin-based regimen as initial treatment followed by levofloxacin-based treatment as the rescue regimen (group B) were better than the reverse sequence (group A) in both the ITT analysis (93% vs 85.3%, p=0.01) and the PP analysis (97.6% vs 92.5%, p=0.019). Group A was associated with an increased risk of treatment failure compared with group B in both the ITT (OR 2.36, 95% CI 1.21 to 4.40, p=0.011) and the PP analysis (OR 3.24, 95% CI 1.16 to 9.1, p=0.025).
Secondary end point: adverse effects and compliance
Patients who received initial clarithromycin-based treatment had a higher rate of taste distortion than patients who received levofloxacin-based treatment (18.9% vs 7.8%, p=0.021, table 3). In contrast, patients who received levofloxacin-based treatment had a higher rate of nausea (11.5% vs 4.2%, p=0.005) and vomiting (4.6% vs 1.4%, p=0.051) than those who received clarithromycin-based treatment. In the second-line treatment, the adverse effect rates were not significantly different between the LAL and CAL regimens. The loss to follow-up rate and the adherence rate were also similar between the LAL and CAL regimens in the first-line and second-line treatments.
Primary and secondary antibiotic resistance rate
Before first-line eradication treatment, the distributions of antibiotic resistance to clarithromycin, levofloxacin and amoxicillin were similar between the two groups (table 4). The overall primary resistance rates to clarithromycin, levofloxacin and amoxicillin were 7.5, 5.7 and 2.5%, respectively. Among group B patients who failed initial CAL treatment, the secondary clarithromycin resistance rate rose from 33.3 to 83.3%, whereas the secondary levofloxacin and amoxicillin resistance rate remained as low as 8.3 and 8.3%, respectively (table 4). Among group A patients who failed initial LAL treatment, the secondary levofloxacin resistance rate rose from 21.7 to 43.8%, whereas the secondary amoxicillin resistance rate remained as low as 5.9%. It is noteworthy that the secondary clarithromycin resistance rate also rose from 13.6 to 29.4% after levofloxacin-based treatment.
Eradication rates according to antibiotic resistance
Among patients who received the LAL regimen, the presence of levofloxacin resistance was associated with a lower eradication rate (50% vs 84.4%, p=0.018), as shown in table 5. Similarly, the eradication rate was also lower in the presence of clarithromycin resistance (44.4% vs 90.7%, p=0.002) among patients who received the CAL regimen. Among patients with strains susceptible to levofloxacin in the LAL group and to clarithromycin in the CAL group, we found that the eradication rates were 84.4% in the LAL group and 90.7% in the CAL group (table 5). The results showed that the CAL regimen appears more effective than the LAL regimen by 6.3% as first-line treatment after excluding the factor of antibiotic resistance.
This randomised, multicentre, parallel-group study showed that CAL treatment for 7 days achieved a higher eradication rate than high dose (750 mg) levofloxacin-based treatment for 7 days (83.7% vs 74.2%). However, CAL for 10 days was not effective (60%) as a rescue regimen for those who failed LAL. The strategy (group B) of using a clarithromycin-based regimen as the first-line treatment, followed by a levofloxacin-based regimen as the second-line treatment achieved higher cumulative eradication rates than the reverse strategy (group A) (93% vs 85.3%). We further showed that the prevalence of clarithromycin and levofloxacin resistance rates was <10% in Taiwan. The presence of levofloxacin resistance (50% vs 84.4%) was associated with a lower eradication rate for levofloxacin-based treatment. The findings of this study are novel and interesting and have important implications for the treatment of H pylori infection.
The efficacy of a levofloxacin-based regimen as the first-line treatment had been evaluated in several other studies. Levofloxacin-based triple therapy for 7 days was shown to achieve higher eradication rates than clarithromycin-based triple therapy.7 However, Antos et al reported similar eradication rates for these two regimens.25 26 In contrast to their results, our data showed that clarithromycin-based triple therapy achieved a higher eradication rate than levofloxacin-based triple therapy as the first-line treatment. The contradictory results might be attributed to the differences in the prevalence of resistance to clarithromycin and levofloxacin, the dosage of levofloxacin, the duration of treatment, the impact of amoxicillin resistance and ethnic differences.
In our study, the low prevalence of clarithromycin resistance (7.5%) in Taiwan might account for the higher eradication rate (83%) of clarithromycin-based treatment. However, the eradication rates of levofloxacin-based treatment were lower (74.2% in ITT analysis and 80.1% in PP analysis) despite the low levofloxacin resistance rate (5.7%). There were several possible explanations for this result. First, the treatment duration of 7 days might not be adequate for a levofloxacin-based regimen. A recent meta-analysis has shown that a longer (10 day) therapeutic scheme achieved a higher eradication rate than a shorter (7 day) duration for a levofloxacin-based regimen as second-line treatment.11 12 In this study, we chose to treat patients with a clarithromycin-based regimen for 7 days instead of ≥10 days in the first-line treatment because local data from Taiwan showed an eradication rate of >80–85% for 7 day clarithromycin-based treatment,27 which was considered to be acceptable according to the Maastricht III guidelines.4 Levofloxacin-based triple therapy for 7 days was also shown to achieve an eradication rate of >90% as first-line treatment in previous studies.7 However, our result showed that a higher dose (750 mg daily) of levofloxacin given once daily for 7 days might not be adequate as first-line treatment. Whether a standard dose of levofloxacin for 10 days would achieve a higher eradication rate than the high dose levofloxacin for 7 days remains unknown. However, a recent study showed that administrtion of 500 mg of levofloxacin once daily and 500 mg twice daily achieved a similar eradication rate.28 Secondly, whether the efficacy of levofloxacin-based treatment is affected more by intragastric pH than clarithromycin-based treatment should also be considered. Since the antibiotic resistance rate and compliance rate were not statistically different between the LAL and CAL groups, the differences in the eradication rate of these two groups might be attributed to the intragastric pH and the CYP2C19 polymorphism. Whether levofloxacin is more labile to gastric acid in the treatment of H pylori infection and requires a higher dose proton pump inhibitor, especially those with extensive metaboliser of CYP2C19, should be clarified in future studies.
Our study showed that the strategy of using a clarithromycin-based regimen as first-line treatment, followed by a levofloxacin-based regimen as second-line treatment achieved a higher eradication rate than the reverse sequence. This finding is novel and interesting. In the past, most studies focused only on the efficacy of one regimen either as an initial treatment or as a rescue regimen. However, the concept of focusing on the cumulative eradication rate of a treatment strategy consisting of consecutive treatment rather than only on the eradication rate of one treatment has attracted attention in recent years.29 30 The impact of the sequence of administration of clarithromycin-based treatment and quadruple therapy on the cumulative eradication rate has been reported in a previous randomised trial.31 Gomollón et al found that the strategy of clarithromycin-based treatment as the first-line regimen, followed by quadruple therapy as the rescue regimen achieved a higher eradication rate (92%) than the reverse strategy (73%).31
The reasons for the different eradication rates with different sequences of administration of clarithromycin-based and levofloxacin-based treatment are not clear. The use of fluoroquinolones has been demonstrated to lead to rapid accumulation of bacterial resistance in several studies.32–34 Among patients who failed first-line levofloxacin-based treatment, we found that the levofloxacin resistance rate rose from 21.7 to 43.8%. It is noteworthy that the clarithromycin resistance rate also rose from 13.6 to 29.4%. In contrast, the levofloxacin resistance rates were not significantly changed before and after the clarithromycin-based regimen (from 6.7 to 8.3%). Our results indicated that the use of a levofloxacin-based regimen might also increase the rate of resistance to clarithromycin, which in turn would lead to the inadequate eradication rate of a clarithromycin-based regimen as second-line treatment. The activation of the efflux pump might be responsible for this phenomenon. Previous studies have shown that some quinolone-resistant mutants are related to activation of the efflux pump, which pumps unwanted toxic substances out of the cell and protects the bacteria from damage.35 Activation of the efflux pump after chloramphenicol treatment of H pylori has also been demonstrated in a recent study.36 However, the data in this study are not sufficient to support this hypothesis. Further in vitro studies are warranted to assess whether the use of levofloxacin would activate the efflux pump which in turn would lead to the resistance to other antibiotics. If this finding could be confirmed by other studies, it will have great impact on the selection of first-line antibiotics not only for H pylori infection but also for other bacterial infections. However, more clinical trials are also needed to confirm this finding before any conclusion can be drawn.
The strength of this randomised comparative trial includes the large sample size as compared with previous studies and the novel finding that clarithromycin-based treatment was not effective as a rescue regimen after failure of levofloxacin treatment. We demonstrated that the strategy of using the CAL regimen as initial treatment and rescue with the LAL regimen provided a better eradication rate than the reverse sequence. Furthermore, the MIC tests before and after levofloxacin-based and clarithromycin-based treatments are available in this study. Nevertheless, there are also some limitations in this study. First, the successful culture rate after failure of first-line treatment was low (∼50%). This might be attributed to the low H pylori density at 6–8 weeks after first-line treatment. Therefore, the paired pretreatment and post-treatment susceptibility tests were only available in some patients. The susceptibility test results of primary resistance were also available in only 64.6% of patients. However, some molecular tests which can accurately detect antibiotic resistance to clarithromycin and levofloxacin using gastric biopsy specimens have become commercially available recently.37 Further studies using the new DNA strip test to compare the eradication rates among patients with strains susceptible to levofloxacin and clarithromycin are warranted. Secondly, the unsatisfactory eradication rate of clarithromycin-based treatment for those who failed levofloxacin-based treatment requires further validation in other countries. Moreover, the underlying mechanisms, such as the activation of the efflux pump or other mechanisms, should be assessed in future in vitro studies. Finally, although previous studies showed that 7 day clarithromycin triple therapy could achieve an acceptable eradication rate (80–85%) in Taiwan, further studies to assess whether the 14 day treatment can achieve a more satisfactory eradication rate (>90%) are warranted.
In conclusion, we found that clarithromycin-based treatment was not effective as a rescue regimen for those who failed levofloxacin-based triple therapy. We further demonstrated that the strategy of using clarithromycin-based triple therapy as initial treatment, followed by levofloxacin-based treatment as the rescue regimen achieved a higher eradication rate than the reverse strategy. However, whether levofloxacin-based treatment could be used as the first-line treatment in different countries or regions should depend on the local prevalence of levofloxacin resistance and the local eradication rates. Nevertheless, an effective rescue regimen should be available before levofloxacin-based triple therapy can be recommended as the first-line treatment. Whether increasing the treatment duration to 10 days or increasing the dosage of the proton pump inhibitor could lead to higher eradication rates of levofloxacin-based triple therapy as first-line treatment also deserve further investigation.
Significance of this study
What is already known about this subject?
The eradication rate with clarithromycin-based triple therapy as first-line treatment for Helicobacter pyloriinfection has fallen below 80% in many countries.
Levofloxacin-based triple therapy has been shown to be effective as second-line and third-line treatment.
Some studies from Europe showed that levofloxacin-based triple therapy was also effective as first-line treatment.
What are the new findings?
Clarithromycin-based triple therapy achieved a higher eradication rate than high dose (750 mg) levofloxacin-based triple therapy in the treatment of H pylori infection.
However, clarithromycin-based triple therapy is not effective (60%) as a rescue regimen for those who fail levofloxacin-based treatment.
The strategy of using clarithromycin-based treatment as the first-line treatment, followed by levofloxacin-based treatment as second-line treatment achieved a higher cumulative eradication rate than the reverse strategy.
The presence of levofloxacin resistance was associated with a lower eradication rate for levofloxacin-based triple therapy.
How might it impact on clinical practice in the foreseeable future?
The result from this clinical trial indicated that the use of clarithromycin-based treatment as first-line treatment, followed by levofloxacin-based treatment as the second-line treatment is the preferred strategy rather than the reverse sequence in the treatment of H pylori infection.
J-M Liou and J-TL contributed equally to this work.
Guarantors of the article, J-ML, M-SW; concept and design, J-ML, J-TL, M-SW; analysis and interpretation of the data, J-ML, J-TL, M-SW; collection and assembly of the data, -ML, M-SW, J-TL, C-YC, M-JC, C-CC, T-YC, Y-CL, W-HS, H-PW; drafting of the article, J-ML, M-SW; critical revision, J-ML, J-TL, M-SW; final approval, J-ML, M-SW, J-TLin.
Funding The study was funded by the National Clinical Trial Center of National Taiwan University Hospital (grant no. NCTRC200707). J-ML received research grants from the National Science Council, Executive Yuan, ROC, Taiwan (grant no. 97-2314-B-002-116-MY3). The study drugs and urea breath test used in the present study were sponsored by the Daiichi Sankyo Taiwan.
Competing interests None.
Ethics approval This study was conducted with the approval of the National Taiwan University Hospital.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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