Brief Article
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. May 21, 2012; 18(19): 2377-2382
Published online May 21, 2012. doi: 10.3748/wjg.v18.i19.2377
Comparison of sequential and 7-, 10-, 14-d triple therapy for Helicobacter pylori infection
Hyuk Soon Choi, Hoon Jai Chun, Sang Hoon Park, Bora Keum, Yeon Seok Seo, Yong Sik Kim, Yoon-Tae Jeen, Soon Ho Um, Hong Sik Lee, Chang Duck Kim, Ho Sang Ryu
Hyuk Soon Choi, Hoon Jai Chun, Sang Hoon Park, Bora Keum, Yeon Seok Seo, Yong Sik Kim, Yoon-Tae Jeen, Soon Ho Um, Hong Sik Lee, Chang Duck Kim, Ho Sang Ryu, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Digestive Disease and Nutrition, Korea University College of Medicine, Seoul 136-705, South Korea
Author contributions: Choi HS and Park SH designed the study and acquired the data; Keum B, Seo YS and Kim YS analyzed the data; Choi HS drafted the paper; Jeen YT, Um SH, Lee HS, Kim CD and Ryu HS revised it critically; Chun HJ reviewed and edited the manuscript and approved the final version.
Correspondence to: Hoon Jai Chun, MD, PhD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Digestive Disease and Nutrition, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Seongbuk-gu, Seoul 136-705, South Korea. drchunhj@chol.com
Telephone: +82-2-9206555 Fax: +82-2-9531943
Received: September 14, 2011
Revised: April 7, 2012
Accepted: April 10, 2012
Published online: May 21, 2012

Abstract

AIM: To compare the effectiveness of sequential therapy for Helicobacter pylori (H. pylori) infection with that of triple therapy of varying durations.

METHODS: The 460 patients enrolled in this study had H. pylori-associated gastritis or a gastric or duodenal ulcer. After screening, H. pylori-infected patients were randomly assigned to receive either conventional triple therapy for 7, 10 or 14 d, or a new 10-d sequential therapy. Each of the 4 treatment groups included 115 patients. The outcomes of eradication therapy were assessed 4 wk after treatment by the urea breath test and histology.

RESULTS: The overall eradication rate was 81.0%, and eradication rates were 75.7% for 7-d conventional triple therapy, 81.9% for 10-d conventional triple therapy, 84.4% for 14-d conventional triple therapy, and 82.0% for 10-d sequential therapy. Neither intention-to-treat analysis nor per protocol analysis showed significant differences in eradication rates using sequential therapy or the standard triple therapy (P = 0.416 and P = 0.405, respectively).

CONCLUSION: There are no significant differences between 10-d sequential eradication therapy for H. pylori and any duration of standard triple treatment in Korean patients.

Key Words: Helicobacter pylori, Sequential therapy, Triple therapy, Gastric ulcer, Duodenal ulcer, Gastritis



INTRODUCTION

Helicobacter pylori (H. pylori), first identified in 1982, is recognized as a risk factor for gastrointestinal ulcers, chronic gastritis, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. The most widely used eradication therapy at this time combines a proton pump inhibitor (PPI) with 2 antibiotics, amoxicillin and clarithromycin. However, the failure rate of this triple therapy is 10%-20%[1-4] and has increased with the emergence of clarithromycin resistance[5-7]. When first-line triple therapy fails, a quadruple regimen of PPI, bismuth, tetracycline, and metronidazole is usually applied. The failure rate of this second-line therapy (20%-30%) is also high, which may stem from metronidazole resistance[6,8,9].

To address an increase in antibiotic resistance in H. pylori in Western countries, a 10-d sequential therapy was proposed. This new regimen includes a PPI plus 1 g of amoxicillin twice daily for the first 5 d followed by a PPI, 500 mg of clarithromycin and 500 mg of tinidazole twice daily for the remaining 5 d. Since Zullo et al[10]. first developed this therapy, it has produced higher eradication rates than triple therapy in several studies[11-15]. However, few studies have reported outcomes of sequential therapy in East Asian countries. Since antibiotic-resistant strains differ in geographical distribution, an H. pylori eradication therapy may vary in effectiveness between regions[16,17].

Furthermore, no universal evidence-based guidelines have been established for the optimal duration of triple therapy. Some countries prefer a 7-d therapy, and in other countries treatment longer than 7-d is deemed mandatory[1,18,19]. Most previous comparative studies tested the sequential regimen against 7-d or 10-d triple therapy.

We conducted this study to prospectively compare the H. pylori eradication rate obtained with a 10-d sequential regimen to the rates achieved with the conventional 7-d, 10-d and 14-d triple regimens in a Korean cohort of H. pylori-infected patients.

MATERIALS AND METHODS
Study population

From March 2008 to August 2011, we interviewed and enrolled patients who visited Korea University Anam Hospital with H. pylori-positive gastritis or peptic ulcer (gastric and/or duodenal ulcer) identified in gastroduodenoscopy. H. pylori infection was detected using a urea breath test, rapid urease test, or histopathological investigation. This was a prospective randomized controlled study.

Four hundred and sixty patients tested positive for H. pylori during this time. Study inclusion criteria were H. pylori-associated gastritis, or gastric or duodenal ulcer, and age 18 years or older. Criteria for exclusion from the study were: (1) serious kidney disease that required drug dosage adjustment; (2) previous treatment with antibiotics within the past 4 wk; (3) PPI treatment during the previous 8 wk; (4) previous H. pylori eradication failure; (5) significant cardiopulmonary, endocrine or hepatic disease, or a hematologic disorder; (6) previous surgery of the upper gastrointestinal tract; (7) history of malignancy; (8) history of drug or alcohol misuse; (9) antiulcer medication treatment within previous 4 wk; (10) systemic glucocorticoid or anticoagulation treatment; (11) severe psychiatric or neurological disease; and (12) current pregnancy or lactation. After screening, participants were randomly assigned to treatment groups using a computer generated list. Patients provided written consent to participate, and the Institutional Review Board of Korea University Hospital approved this study. We conducted the study in agreement with the principles of the Declaration of Helsinki, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use and Guidelines for Good Clinical Practice.

Treatment protocol

Eligible patients who had no documented contraindications were randomly assigned to one of four treatments: (1) standard triple therapy (rabeprazole 20 mg + amoxicillin 1.0 g + clarithromycin 500 mg twice daily) for 7 d; (2) standard triple therapy for 10 d; (3) standard triple therapy for 14 d; and (4) a 10-d sequential treatment (amoxicillin 1.0 g + rabeprazole 20 mg twice daily for the first 5 d, followed by rabeprazole 20 mg + clarithromycin 500 mg + tinidazole 500 mg twice daily for the remaining 5 d).

Confirmation of eradication

At least 4 wk after completion of treatment, a urea breath test and histopathological diagnosis were performed to determine if H. pylori had been successfully eradicated. Drug side effects were assessed with a questionnaire.

Statistical analysis

Statistical analyses were performed using Statistical Package for the Social Sciences (SPSS 18.0 for Windows; SPSS Inc., Chicago, IL, United States). Power calculations to determine sample size based on previously published data[20] showed that 420 patients would be required to detect a treatment difference at the 5% level of significance with a power of 80%. Hence the sample size was set at 460 patients to allow for a possible 10% dropout rate.

Univariate analysis, with age, gender, endoscopic diagnosis, smoking, alcohol habits, and medications (NSAID) as variables, was performed using the χ2 test. The H. pylori eradication rate was determined using intention-to-treat (ITT) and per protocol (PP) analyses using the χ2 test. P < 0.05 was considered statistically significant.

RESULTS
Patient characteristics

The mean age of the 460 patients enrolled in this study was 46.8 years. Two hundred and thirty-nine patients were male and 221 were female. Each of the 4 treatment groups included 115 patients. The groups did not differ significantly in gender, previous disease history, endoscopic diagnosis, smoking, alcohol consumption, NSAID and aspirin use, or use of previous medications (Table 1).

Table 1 Clinical characteristics of patients with Helicobacter pylori infection.
7-d eradication10-d eradication14-d eradication10-d sequentialeradicationTotalPvalue
Number of patients115115115115460
Gender0.959
Male60586259239
Female55575356221
Endoscopic diagnosis0.940
GU48525248200
DU40363236144
Gastritis as NUD27273131116
Smokers403653441760.117
Alcohol drinkers424858562040.123
NSAID/ASA12161913600.513
Eradication rates

Twenty-five of the 460 patients did not return to hospital for eradication testing and 8 patients discontinued the medication due to side effects. Eradication results were confirmed in 427 patients; eradication was confirmed in 408 of the 427 patients by the urea breath test and in 19 patients by histopathological examination for H. pylori.

Among the 427 patients, 107 patients received the 7-d conventional triple therapy, 105 received the 10-d conventional triple therapy, 109 received the 14-d conventional triple therapy, and 106 received the 10-d sequential therapy (Figure 1).

Figure 1
Figure 1 Flow diagram for patients enrolled in the study.

The overall eradication rate among the 427 patients was 81.0%. The eradication rates according to group were as follows: 70.4%/75.7% (ITT/PP) for the 7-d conventional triple therapy group, 74.7%/81.9% for the 10-d conventional triple therapy group, 80.0%/84.4% for the 14-d conventional triple therapy group, and 75.6%/82.0% for the 10-d sequential therapy group. Neither the ITT nor the PP analysis showed a significant difference in eradication rates between the new 10-d sequential therapy and the standard triple therapy (P = 0.416 and P = 0.405, respectively) (Table 2).

Table 2 Helicobacter pylori eradication rates according to treatment group.
7-deradication10-deradication14-deradication10-dsequentialeradicationTotalPvalue
ITT70.4% 81/11574.7% 86/11580.0% 92/11575.6% 87/11575.2% 346/4600.416
PP75.7% 81/10781.9% 86/10584.4% 92/10982.0% 87/10681.0% 346/4270.405
Compliance and side-effects

The compliance was greater than 95% for all of the triple conventional groups and the 10-d sequential therapy group. In the latter group, 15 patients showed side effects including problems with taste (n = 1), loose stools (n = 3), nausea/vomiting (n = 4), epigastric discomfort (n = 3), abdominal distention (n = 3) and itching (n = 1) (Table 3). For the triple therapy, reported side effects included problems with taste, loose stools, abdominal discomfort, nausea, vomiting, epigastric discomfort, and itching. Most side effects were not severe (Table 3).

Table 3 Adverse events.
7-deradication10-deradication14-deradication10-dsequentialeradication
Taste alterations1111
Loose stools3323
Abdominal distention2333
Nausea/vomiting2434
Epigastric discomfort3233
Itching0101
Total11141215
DISCUSSION

We compared the H. pylori eradication rates obtained after 10-d sequential therapy with those achieved after 7-, 10- and 14-d conventional triple therapy and found no significant differences.

Triple therapy, which is currently used most widely, combines a PPI with 2 antibiotics such as clarithromycin and amoxicillin[2]. However, resistance to clarithromycin now stands at 13.8%-16.7%[5,21], and recent reports place the rate of H. pylori eradication at 74%-83.6%[18,22].

The Maastricht III consensus report published in 2005 recommends a quadruple therapy, which includes a PPI, bismuth, tetracycline, and metronidazole, as a second-line eradication therapy[1]. The effectiveness of quadruple therapy is compromised, however, by resistance to metronidazole in H. pylori[8,23,24]. The prevalence of metronidazole resistance in Korea has increased from 33.3% in 1994, to 47.7% in 1999, to 66.2% in 2003[25].

In Western countries, increased resistance to triple therapy fosters much discussion. Notably, an increase in clarithromycin resistance found through large-scale studies in several European countries is linked to extensive use of this antibiotic in both children and adults, and to an increasing rate of failure to eradicate H. pylori using conventional therapy[20,26-28]. Nevertheless, European guidelines for H. pylori treatment specify triple therapy with a PPI, amoxicillin, and clarithromycin or metronidazole for 14 d, or quadruple therapy with a PPI, amoxicillin, clarithromycin, and metronidazole for 10-14 d[1,29].

Zullo et al[10] reported a new 10-d sequential therapy for H. pylori in 2000. This regimen includes a PPI plus 1 g of amoxicillin for the first 5 d followed by a PPI, 500 mg of clarithromycin, and 500 mg of tinidazole for the remaining 5 d. Some studies report that this regimen yields a higher H. pylori eradication rate than triple therapy[11,30,31] and improves the rate in children as well as in adults[32,33]. The mechanisms underlying the effects of the 10-d sequential treatment are not known; however, the early administration of amoxicillin appears to weaken the cell walls of H. pylori, reducing resistance to clarithromycin and enhancing the treatment effects[28,34]. The 5-d PPI and amoxicillin regimen may reduce the numbers of H. pylori by 50%, which when followed by 5 d of triple therapy, is thought to improve the overall effectiveness of the regimen[35,36]. In addition, the use of 3 or more antibiotics improves the treatment effects[20].

In our patient cohort, the 10-d sequential therapy did not achieve a higher eradication rate than the standard triple therapy. This discrepancy may reflect in part genetic differences in H. pylori strains in the East and West[37]. In addition, the high rate of antibiotic resistance in Korea, in particular to metronidazole, may contribute to geographical variations in treatment effectiveness. Factors in addition to location and antibiotic resistance that may affect H. pylori eradication include patient age and compliance, gastric acid concentration, individual response to PPI, and differences in prevalence of H. pylori Cag A genotype[38]. We did not investigate gastric acid concentration, antibiotic resistance (or minimal inhibitory concentrations), or H. pylori genotypes; and as all subjects were recruited at a single center, geographical differences in H. pylori sensitivity and in treatment protocol did not emerge in this study.

The optimal treatment duration using triple therapy is not established. A meta-analysis performed by Fuccio et al[39] concluded that extending triple therapy beyond 7 d does not significantly improve outcome compared to the standard 7-d regimen. However, individual studies report higher eradication rates using 10 or 14 d of triple therapy as compared to 7 d[40,41]. Guidelines in the United States and Europe favor longer durations of triple therapy[1,19]. Previous comparative studies of the sequential regimen involved the 7-d and 10-d triple therapy. The present study aimed to clarify the relationship of treatment duration to the H. pylori eradication rate.

Data from East Asian countries on use of sequential therapy are limited, and further study is needed to determine the optimal duration of treatment for the triple therapy in Asian populations. Several comparative studies of sequential therapy conducted in Korea differed in outcome. Three of these studies produced higher eradication rates for sequential therapy and another failed to detect a significant difference[38,42-45]. This lack of concordance may be related to known regional variations in prevalence of H. pylori resistance to antibiotics, especially clarithromycin, in Korea[17].

In conclusion, we detected no significant differences between the 10-d sequential eradication therapy for H. pylori and any duration of the standard triple treatment tested (7-, 10- and 14-d regimens) in a group of Korean patients. More research is needed to determine whether this finding also holds true for patients from other East Asian countries.

COMMENTS
Background

Helicobacter pylori (H. pylori), first identified in 1982, has been identified as a risk factor for gastrointestinal ulcer, chronic gastritis, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. To date, the most widely used eradication therapy is administration of a proton pump inhibitor (PPI) and 2 types of antibiotics; amoxicillin and clarithromycin. However, the success rate of these multiple antibiotics to eradicate H. pylori has decreased in recent years. An increase in the antibiotic resistance of H. pylori has been reported in Western countries, and a 10 d sequential eradication therapy was proposed to address this problem.

Research frontiers

The 10-d sequential therapy includes a PPI plus 1 g amoxicillin for the first 5 d followed by a PPI, clarithromycin 500 mg, and tinidazole 500 mg for the remaining 5 d. There is no established evidence about the duration of triple therapy. Guidelines for the duration of triple therapy varies according to region. So, a Korean research team evaluated whether H. pylori eradication with 10 d of sequential therapy is better than the conventional 7-, 10- and 14-d triple therapy in a Korean cohort.

Applications

The researchers concluded that there was no significant difference between 7-, 10-, 14-d standard triple treatment and 10-d sequential therapy in eradication of H. pylori in a Korean cohort of patients. Data from East Asian countries on use of sequential therapy are limited, and further study is needed to determine the optimal duration of treatment for triple therapy in Asian populations.

Terminology

Sequential therapy is a new regimen to eradicate H. pylori includes a PPI plus 1 g of amoxicillin twice daily for the first 5 d followed by a PPI, 500 mg of clarithromycin and 500 mg of tinidazole twice daily for the remaining 5 d.

Peer review

This is an interesting study aimed at comparing the eradication rate of a 7, 10 and 14 d triple therapy vs sequential therapy in Korean patients. Interestingly, the authors found that the eradication rate provided by sequential therapy is similar to that of standard therapy of the same duration. Therefore, the final message is that the most important factor in the eradication of H. pylori is the duration of the therapy instead of the way of administration of antibiotics and PPI.

Footnotes

Peer reviewers: Angelo Zullo, MD, Gastroenterologia ed Endoscopia Digestiva, Ospedale Nuovo Regina Margherita, Via E. Morosini, 30, 00153 Roma, Italy; Francesco Franceschi, MD, PhD, Assistant Professor, Internal Medicine, Catholic University of Rome, Gemelli Hospital, Largo A Gemelli 8, 00168 Rome, Italy

S- Editor Cheng JX L- Editor Cant MR E- Editor Zheng XM

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