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The First-Line Eradication Rate for Helicobacter pylori Infection in Functional Dyspepsia Patients

Takeshi Matsuhisa, Taku Tsukui

Takeshi Matsuhisa, Professor of Medicine, Department of Gastroenterology, Tama-Nagayama University Hospital, Nippon Medical School, 1-7-1, Nagayama, Tama-city, Tokyo, 206-8512, Japan
Taku Tsukui, Professor of Medicine, Department of Gastroenterology, Tama-Nagayama University Hospital, Nippon Medical School, 1-7-1, Nagayama, Tama-city, Tokyo, 206-8512, Japan

Correspondence to: Takeshi Matsuhisa, MD, Professor of Medicine, Department of Gastroenterology, Tama-Nagayama University Hospital, Nippon Medical School, 1-7-1, Nagayama, Tama-city, Tokyo, 206-8512, Japan.
Email: matuhisa@nms.ac.jp
Telephone: + 81-42-3712111
Fax:+81-42-3727381
Received: June 7, 2014
Revised: July 6, 2014
Accepted: July 7, 2014
Published online: July 21, 2014

ABSTRACT

AIM: The eradication rates of a first-line eradication regimen for Helicobacter pylori (H. pylori) infection in patients with functional dyspepsia (FD) and peptic ulcer disease (PUD) were compared. The eradication rates in distinction from proton pump inhibitors (PPIs) were also investigated.

METHODS: A total of 339 H. pylori infected patients were enrolled in this study. PPI [lansoprazole (L) 30 mg bid, omeprazole (O) 20 mg bid or rabeprazole (R) 10 mg bid] was randomly allocated along with amoxicillin (A) 750 mg bid and clarithromycin (C) 400 mg bid (L60A1500C800, O40A1500C800, or R20A1500C800) by the envelope method.

RESULTS: Of 339 patients, 111 had PUD and 126 patients had FD. All patients underwent a gastrointestinal endoscopy for confirmation of the presence of gastroduodenal disease. The eradication rates of H. pylori in PUD patients obtained with the three regimens were similar. On the other hand, the eradication rate in FD patients was lower than that in the PUD patients (69.8%, 81.1%, respectively, P=0.0458). The eradication rate with R20A1500C800 was significantly lower in the FD patients than in the PUD patients, according to both ITT and PP analysis (P=0.0458, P=0.0161, respectively). Data analysis revealed that the lower eradication rate obtained in FD patients was attributable to the use of the R20A1500C800 regimen. The overall frequency of adverse events was 32.9%.

CONCLUSİONS: The eradication rate in the first-line R-based regimen used for FD patients was very low (ITT: 54.1%, PP: 57.1%) compare with L-based regimen.

Key words: The first-line eradication rate; Helicobacter pylori; PPI; Functional dyspepsia; Peptic ulcer disease

© 2014 The Authors. Published by ACT Publishing Group Ltd.

Matsuhisa T, Tsukui T. The First-Line Eradication Rate for Helicobacter pylori Infection in Functional Dyspepsia Patients. Journal of Gastroenterology and Hepatology Research 2014; 3(7): 1156-1161 Available from: URL: http://www.ghrnet.org/index.php/joghr/article/view/782

Introduction

According to a revised edition of the guideline for Helicobacter pylori (H. pylori) Infection Diagnosis and Treatment by the Japanese Society for Helicobacter Research in 2009, eradication of the organism is strongly recommended in all H. pylori infected-patients[1]. This is because it was confirmed in a Japanese multi-center, open-label, randomized controlled trial conducted in 2008 that preventive eradication of H. pylori after endoscopic resection of early gastric cancer can prevent the development of metachronous gastric cancer[2]. In February, 2013, eradication treatment for H. pylori-infected gastritis was authorized for use by the Japanese National Health Insurance system. This enabled us to conduct eradication treatment for all the patients infected with H. pylori as a health insurance treatment.

The first-line eradication regimen for H. pylori infection consists of a proton pump inhibitor (PPI) + amoxicillin (A) + clarithromycin (C) in Japan. Any one of the four currently available PPIs, lansoprazole (L), omeprazole (O), rabeprazole (R) and esomeprazole (E) were originally used for the treatment of peptic ulcer disease (PUD) and reflux esophagitis, were authorized for use in H. pylori eradication regimens in November 2000, April 2002, January 2007, and September 2011, respectively.

The H. pylori eradication rates were compared between patients with functional dyspepsia (FD) and PUD, and among regimens including one of the three PPIs (L, O or R) in this prospective, open, randomized single-center study.

METHODS

Patients

This study was conducted from January 2008 to December 2013. A total of 339 patients with H. pylori infection who visited the out-patient clinic of the Department of Gastroenterology, Tama-Nagayama University Hospital, Nippon Medical School were enrolled in this study. The exclusion criteria included a history of previous H. pylori eradication, history of upper gastrointestinal tract surgery except for endoscopic treatment of gastric cancer, history of drug allergy to PPI, A or C, serious concomitant illness, pregnant or lactating women, and regular users of non-steroidal anti-inflammatory drugs (NSAIDs). Patients with a history of treatment with a PPI or histamine-2 receptor antagonist (H2RA), or treatment with any antibiotic within 4 weeks prior to the study commencement were also excluded. During the eradication treatment period, concomitant use of antibacterial or antiprotozoal agents, PPIs, H2RAs, NSAIDs, and corticosteroids was prohibited. Before the eradication therapy, gastrointestinal endoscopy was performed in all the patients to confirm the presence of gastroduodenal disease. Written informed consent for participation in this study was obtained from all the patients under the approval of Ethics Committee of Tama-Nagayama University Hospital.

The subjects were started on first-line triple therapy with a PPI (L 30 mg bid, O 20 mg bid or R 10 mg bid), A (750 mg bid), and C (400 mg bid) administered for 7 days (L60A1500C800, O40A1500C800, or R20A1500C800) for eradication of H. pylori infection. All PPIs are double the doses of these drugs used in the treatment of PUD and reflux esophagitis. The LANSAP®800, packaged drugs set, was used in the L60A1500C800 group. As E was not brought out when this study started, it was not included in these groups. Using the envelope method, the patients were randomly allocated to one of the three treatment groups described above.

Diagnosis of H. pylori infection

The diagnosis of H. pylori infection was made by the histological method, using biopsy specimens stained with hematoxylin-eosin and a Giemsa stain. H. pylori specific antibody immune staining was performed as appropriate for the histological diagnosis of H. pylori infection. Biopsy specimens for histological examination were obtained endoscopically in accordance with the triple-site gastric biopsy method as reported previously[3,4]. The pathologist examining the specimens was blinded to all clinical information. The 13C-urea breath test (UBT) and/or H. pylori stool antigen test (HpSA) (Premier Platinum HpSA® PLUS) (Meridian Bioscience, Inc., Cincinnati, OH, USA) was also used for the diagnosis in some cases, when the histological diagnosis was negative, but H. pylori infection was, nevertheless, suspected. The Ubit tablet® (Otsuka Pharmaceuticals, Tokyo, Japan), containing 100 mg of 13C-urea was used for the 13C-UBT, and patients in whom the Δ13C value at 20 minutes after ingestion was 2.5‰ or higher were deemed as H. pylori positive, and those with values lower than 2.5‰ deemed as H. pylori negative[5].

Diagnosis of H. pylori eradication

The 13C-UBT, performed more than 6 weeks after the treatment, was used to confirm the eradication of H. pylori in response to the treatment. Δ13C values lower than 2.5‰ were deemed to represent successful eradication, values between 2.5 and 5.0‰ were considered as being in the gray zone, and values higher than 5.0‰ were considered as representing treatment failure[6]. In case of gray zone, the 13C-UBT was performed again 2 to 3 months later.

Statistical analysis

The eradication rates in each group were evaluated by intention-to-treat (ITT) analysis and per protocol (PP) analysis and compared using Fisher’s exact test. The 95% confidence intervals (CIs) were also calculated. For continuous quantities (age, and body mass index), we performed an analysis of variance and for P values less than 0.05, performed t-tests among each group. For ratios (gender, smoker, drinker, and adverse events), Fisher's Exact test was performed using the cross table of 2×3. P values lesser than 0.05 were considered to be statistically significant.

An acceptable eradication rate is defined higher than 90% in the PP analysis[7].

RESULTS

Patient profile

There were no differences in the mean age, the male/female ratio, the body mass index (BMI), smoking status, or alcohol drinking status among the patients receiving the three regimens (Table 1). 100% of the L60A1500C800 group, 100% of the O40A1500C800 group and 99.6% of the R20A1500C800 group were compliant, resulting in a mean of 99.9%.

There were 5 histological H. pylori negative cases, which revealed H. pylori positive by UBT and/or HpSA. Three cases were UBT positive, 1 case was HpSA positive, and 1 case was HpSA negative and UBT positive. These cases were divided into L60A1500C800 (2 cases), O40A1500C800 (1 case), and R20A1500C800 (2 cases) group.

Of the enrolled patients, 111 had PUD and the remaining 228 did not have PUD (non-PUD). The patients in the non-PUD group consisted of those with gastric erosion, gastric adenoma, gastric polyp, atrophic gastritis or FD. Patients with FD made up 126 of the non-FD group.

Eradication rates

The overall eradication rate of H. pylori was 76.7% according to ITT analysis and 80.0% according to PP analysis (Table 2). There were no significant differences in the eradication rate among the three treatment groups in either the ITT or PP analysis (Table 2).

When the results were stratified according to the diagnosis of PUD and non-PUD, the eradication rates were 81.1% and 74.6%, respectively, according to the ITT analysis, and 84.7% and 78.0%, respectively, according to PP analysis (Table 2). There was no differences in the eradication rate between PUD and non-PUD (Table 2). There were no differences in the H. pylori eradication rate among the PUD patients receiving L60A1500C800, O40A1500C800, and R20A1500C800, according to both ITT and PP analysis (Table 2). There was also no diffference in the eradication rate among these groups of non-PUD patients (Table 2).

On the other hand, the overall eradication rate of H. pylori in the FD patients was significantly lower than that in the PUD patients, according to ITT analysis (P=0.0458) (Table 2). The eradication rate with R20A1500C800 was significantly lower in the FD patients than in the PUD patients, according to both ITT and PP analysis (P=0.0482, P=0.0161, respectively) (Table 2). There were no difference in the eradication rates between PUD and FD patients in L60A1500C800 and O40A1500C800 group. There was a significant difference in the eradication rate in FD patients between the L60A1500C800 and R20A1500C800 groups, according to both ITT and PP analysis (P=0.0360, P=0.0287, respectively) (Table 2).

All eradication rates were lower than 85%, unacceptable, according to PP analysis (Table 2).

There were four, two, and two gray zone cases in the 13C-UBT following treatment in the L60A1500C800, O40A1500C800, and R20A1500C800 treatment groups, respectively. In the L60A1500C800 treatment group, two cases were revealed to show treatment failure, and two cases were revealed to be in the gray zone again two months after the 13C-UBT. Two cases in the O40A1500C800 treatment group and one case in the R20A1500C800 treatment group were found to be H. pylori-positive by two months after the 13C-UBT. One patient from the R20A1500C800 treatment group did not come for the follow-up 13C-UBT.

Adverse events

The number of cases included in the analysis of adverse events was 113, 112 and 109, respectively, from the L60A1500C800, O40A1500C800, and R20A1500C800 treatment groups, representing a total of 334 cases (Table 3). A total of 131 adverse events were reported from 110 patients. The overall frequency of adverse events was 32.9%. There were no differences in the occurred frequency of adverse events among the treatment groups (Table 3). Loose stools and diarrhea were the most frequent adverse events encountered with all the regimens (18.6%, 25.0% and 13.8%, respectively). The frequency of dysgeusia and glossitis in the O40A1500C800 treatment group was significantly lower than that in the L60A1500C800 treatment group (P=0.0346) (Table 3). Most of the adverse events were also mild to moderate in intensity and self-limiting. One patient from the R20A1500C800 treatment group discontinued the eradication therapy by the proposal from the patient because of the development of eruptions.

DISCUSSION

In Japan, eradication treatment for PUD became covered by the Japanese National Health Insurance system in November 2000, and since then the number of PUD patients has reduced drastically. In February 2013, eradication treatment for H. pylori infected gastritis began to be performed, and the number of eradication treatments increased approximately threefold. Before eradication treatment for H. pylori infected gastritis became covered by insurance, as we noticed that the eradication rate for some FD cases was lower than that of PUD cases, we examined the eradication rate divided into PUD and FD groups and compared the eradication rate in each regimen as a prospective, open, randomized single-center study.

Although the eradication rates obtained with three PPIs (L, O and R) by a Japanese multicenter study have been reported, all of the cases consisted of PUD patients[8-10]. These reported H. pylori eradication rates obtained with the three regimens, L60A1500C800, O40A1500C800, and R20A1500C800[8-10], are consistent with the data of our present study. However, our eradication rate in FD patients (69.8%) was lower than that of PUD patients (81.1%). The lower eradication rate in the FD patients as compared with that in the PUD patients was only noted in the patients treated with R20A1500C800 (54.1%). There was no difference in the eradication rate between PUD and FD patients in the L60A1500C800 and O40A1500C800 treatment group.

We can find many different Japanese reports about eradication rates with PPI plus A and C[11-14]. Some reports consist of PUD or gastric ulcer patients only and some reports consist of PUD and FD patients. Miwa et al reported that in patients with PUD and FD there was no difference in the eradication rate yielded by R 10 mg bid plus A 500 mg tds and C 200 mg bid administered for 7 days (R20A1500C400) and R 20 mg bid plus A 500 mg tds and C 200 mg bid administered for 7 days (R40A1500C400) in either PUD or FD patients; the eradication rates (ITT, PP) were 87.0%, 89.7% in the R20A1500C400 group, and 85.6%, 89.8% in the R40A1500C400 group[14]. However, this is an eradication rate for PUD and FD combined together, and looking at the breakdown, the number of PUD patients is much more than that of FD patients (270 cases and 38 cases, respectively) and it is difficult to compare this with our study results. On the other hand, the eradication rate of FD yielded by R 20 mg bid plus A 1,000 mg bid and C 500 mg bid for 7 days (R40A2000C1000) was significantly higher than that yielded by R10 mg bid plus A 1,000 mg bid and C 500 mg bid for 7 days (R20A2000C1000) or O 20 mg bid plus A 1,000 mg bid and C 500 mg bid for 7 days (O40A2000C1000) (ITT analysis: 100%, 84.4%, 82.8%, respectively, P=0.007, PP analysis: 100%, 86.7%, 92.0%, respectively, P=0.035) in Thai study[15]. They concluded that R40A2000C1000 is necessary for successful H. pylori eradication in patients with FD[15]. It seems useful to use R 20 mg bid, seeing that our study with R20A1500C800 resulted in a lower eradication rate.

Previous European studies have also reported higher eradication rates in PUD patients than FD patients[16-18]. Described in the background are the following points. Only one-half to two-thirds of Western-type isolates H. pylori possess the cytotoxin-associated gene (cagA), whereas nearly all East Asia-type isolates possess cagA[19]. In Japan, nearly 100% of the strains possess cagA[20]. The vacuolating cytotoxin gene (vacA) is present in all H. pylori strains. It is reported that the vacA s1/m1 and s1/m2 strains, which are mostly cagA- positive, seemed to be easier to eradicate than the vacA s2/m2 strain, which is mostly cagA-negative[21]. According to a European report, the cagA-positive strain is more prevalent in patients with PUD than in those with FD[22]. However, there are some counter-opinions to the report that presented a lower eradication rate for FD[23]. Almost all H. pylori-infected Japanese possess cagA, regardless of the presence of disease, e.g., PUD and FD[20]. Consequently we cannot accept these European concepts in Japan. Therefore, it seems that there are some other reasons for the lower eradication rate in FD patients administered with R20A1500C800.

Among the many causes of eradication treatment failure, C resistance is the most frequent[24,25]. Miki et al reported that effective treatment of H. pylori depends on the susceptibility to CAM and that the odds ratio for failure in the CAM-resistant versus CAM-susceptible cases was 498.363 (95%CI: 37.949-6544.714, P < 0.001)[24]. However, as the patients in our study were randomized to one of the three eradication regimens, it is difficult to consider that C-resistant FD cases were concentrated in the R20A1500C800 treatment group.

There is a genetic polymorphism of cytochrome P450 (CYP) 2C19. It is classified into three groups: without mutation named the homozygous extensive metabolizer (homEM), with one mutation named the heterozygous extensive metabolizer (hetEM), and with two mutations named the poor metabolizer group (PM). According to a meta-analysis, the efficacy of H. pylori eradication therapy with O is dependent on the CYP2C19 genotype, while that of the regimens containing L or R was independent of the aforementioned CYP2C19 metabolizer phenotype[26]. In Japan, there was no difference in patients with PUD in the eradication rate by the triple therapy with O40A1500C400, L60A1500C400 or R20A1500C400[12]. There was no significant difference in regard to CYP2C19 among these treatment groups[12]. Although we did not investigate CYP2C19 genetic polymorphism in our present study, it is unrealistic to think that homEM has been concentrated in the R20O1500C800 treatment group, and thus the reason for the lower eradication rate cannot be explained.

It is recognized that more virulent H. pylori strains causes stronger inflammation[27]. The more antibiotics used for the eradication treatment reach the gastric mucosa in patient with a high inflammation score[16], and makes it easy to cure the patient[28]. In our data, the mean inflammation score according to triple site gastric biopsy (#1-#3)[3,4] of FD was lower than that of PUD (1.69, 1.83, respectively, P=0.0066) (data was not shown). This experience may support the difficulty of eradication treatment in FD patients. Therefore, the eradication for FD patients compared with that for PUD patients requires powerful and fast inhibition of acid secretion. Since antibiotics used for eradication treatment do not show enough antibacterial effects in high acid levels, eradication treatment with not only powerful inhibition of acid secretion but also rapid onset of efficacy is required[29]. The reason why the eradication rate is low only in the R20A1500C800 group seems to lie in the insufficient inhibition of acid secretion compared with those of L and O.

There are many reports that have debated the acid reduced effect of PPIs. In a crossover study conducted in H. pylori-negative Japanese homEM and hetEM volunteers, R 10 mg od produced a faster rise of intragastric pH and stronger inhibition of gastric acid secretion from day one of administration than L 30 mg od or O 20 mg od[30]. However, in the subsequent report, there was no significant difference in the acid secretion-inhibitory effect between O (20 mg od) and R (10 mg od) in the subjects with the homEM group in a crossover study in H. pylori-negative Japanese volunteer[31]. Moreover, the median intragastric pH and pH at 5, 6 and 8 hours after administration of O on day one in the subjects with the hetEM and PM group were significantly higher than the corresponding results after administration of R, which implies O inhibits acid secretion faster than R[31]. Furthermore, in a crossover study conducted in H. pylori-negative Japanese volunteers in the subjects with the homEM and hetEM, L 30 mg orally disintegrating (OD) tablet od induced a significantly faster inhibition of gastric acid secretion than R 10mg od on day 1 (after the second hour, fourth hour of the study, respectively)[30]. While R included in LANSAP®800 is not an OD tablet but a capsule, OD tablets and capsules are recognized as a bio-equivalent to the respective dose[32]. To take these reports into consideration, there is such a large variety of reports on acid secretion inhibitory effect, that it is difficult to generalize which PPI is most powerful. Although overseas (USA, Germany and, South Korea), L 30 mg bid, O 20 mg bid, or R 20 mg bid are used for H. pylori eradication treatment[33-36], only in Japan R 10 mg bid is used. The low eradication rate in FD patients treated with R20A1500C800 may be due to the slow and weak acid suppression. In FD of which the inflammation score is low and thus eradication is made difficult, it seems necessary to change to the same dosage as in overseas, R 20 mg bid; from R20A1500C800 to R40A1500C800 in order to suppress the acid secretion.

In conclusion, the eradication rates yielded by L60A1500C800, O40A1500C800 and R20A1500C800 in patients with PUD were similar. On the other hand, the eradication rate in patients with FD was lower than that in patients with PUD. The lower eradication rate of FD attributed to the R20A1500C800 treatment group. Excluding R20A1500C800 group, there was no difference in eradication rate between PUD and FD. The cause of the low eradication rate yielded by R20A1500C800 in subjects with FD with mild inflammation seemed to be due to the insufficient acid secretion inhibitory effect. The number of cases of H. pylori infected FD treated with eradication therapy has been increasing. Though R 20 mg bid is not authorized for use by the Japanese National Health Insurance system, to increase the dose of R in the first-line RAC regimen, R40A1500C800, would be desirable in FD patients to reduce the risk of treatment failure.

CONFLICT OF INTERESTS

There are no conflicts of interest with regard to the present study.

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Peer reviewers: Hidekazu Suzuki, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Giovanni D. De Palma, Department of Chirurgia Generale, Geriatrica ed Endoscopia Diagnostica ed Operativa. Università Federico II di Napoli. Via Pansini 5, 80131 Napoli, Italy.

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