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.

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.

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.