Helicobacter ISSN 1523-5378 doi: 10.1111/hel.12176
Reverse Sequential Therapy Achieves a Similar Eradication Rate as Standard Sequential Therapy for Helicobacter pylori Eradication: A Randomized Controlled Trial Feng-Woei Tsay,*,† Deng-Chyang Wu,‡ Sung-Shuo Kao,* Tzung-Jium Tsai,* Kwok-Hung Lai,* Jin-Shiung Cheng,* Hoi-Hung Chan,* Huay-Min Wang,* Wei-Lun Tsai,* Hui-Hwa Tseng,§ Nan-Jin Peng¶ and Ping-I Hsu* *Division of Gastroenterology, Department of internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan, †Cheng Shiu University, Kaohsiung, Taiwan, ‡Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, §Department of Pathology, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan, ¶Department of Nuclear Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan
Keywords Sequential therapy, reverse sequential therapy, Helicobacter pylori. Reprint request to: Ping-I Hsu, Division of Gastroenterology, Department of Internal Medicine, Kaoshiung Veterans General Hospital, 386 Ta Chung 1st Road, Kaohsiung 813, Taiwan. E-mail: [email protected]
© 2014 John Wiley & Sons Ltd, Helicobacter 20: 71–77
Abstract Background and Aims: Sequential therapy is a two-step therapy achieving a promising eradication rate for Helicobacter pylori infection. The rationale of sequential method has been proposed that amoxicillin weakens bacterial cell walls in the initial phase of treatment, preventing the development of drug efflux channels for clarithromycin and metronidazole used in the second phase. The aim of this prospective, randomized, controlled study was to investigate whether the efficacy of reverse sequential therapy was noninferior to sequential therapy in the treatment of H. pylori infection. Methods: From January 2009 to December 2010, consecutive H. pyloriinfected patients were randomly assigned to receive either sequential therapy (a 5-day dual therapy with pantoprazole plus amoxicillin, followed by a 5-day triple therapy with pantoprazole plus clarithromycin and metronidazole) or reverse sequential therapy (a 5-day triple therapy with pantoprazole plus clarithromycin and metronidazole, followed by a 5-day dual therapy with pantoprazole plus amoxicillin). H. pylori status was examined 6 weeks after the end of treatment by rapid urease and histology or urea breath test. Results: One hundred and twenty-two H. pylori-infected participants were randomized to receive sequential (n = 60) or reverse sequential therapy (n = 62). The eradication rates, by intention-to-treat analysis, were similar: 91.9% (95% confidence interval (CI): 85.1–98.7%) for sequential therapy and 96.7% (95% CI: 92.2–101.2%) for reverse sequential therapy (p = .44). Per-protocol analysis also showed similar results: 91.8% (95% CI: 84.9– 98.7%) for sequential group and 96.7% (95% CI: 92.2–101.2%) for reverse sequential therapy (p = .43). The two treatments exhibited comparable frequencies of adverse events (11.3% vs 6.7%, respectively) and drug compliance (98.4% vs 100%, respectively). The overall resistance rates of antibiotics were clarithromycin 10.5%, amoxicillin 0%, and metronidazole 44.2% of patients, respectively. The dual resistance rate of clarithromycin and metronidazole was 4.2%. Both therapies achieved a high eradication rate for clarithromycin-resistant strains (100% vs 100%, respectively) and metronidazole-resistant strains (81.8% vs 95%, respectively) by intention-to-treat analysis. Conclusions: Ten-day reverse sequential therapy and standard sequential therapy are equally effective for H. Pylori eradication. The finding indicates that the sequence of antibiotics administered in sequential therapy does not influence the efficacy of the treatment.
71
Reverse Sequential Therapy
Helicobacter pylori (H. pylori) is the major cause of chronic gastritis, peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma [1–3]. In most international guidelines [4,5], standard triple therapy consisting of a protonpump inhibitor (PPI), clarithromycin, and amoxicillin (or metronidazole) for 7–14 days is recommended as the choice of treatment for first-line therapy of H. pylori infection. However, the success of standard triple therapy has recently declined to unacceptable levels due to increasing resistance rate of antibiotics [6–8]. Some European studies even reported very poor treatment outcomes of the standard therapy with failure rates of 25–60% [9–11]. Clarithromycin resistance is the major cause of eradication failure in standard triple therapy. Pooled data from 20 studies involving 1975 patients treated with standard triple therapy showed an eradication rate of 88% in clarithromycin-sensitive strains versus 18% in clarithromycin-resistant strains [6]. Therefore, the background rate of clarithromycin resistance is critically important as its presence negatively impacts the efficacy of standard triple therapy. Several strategies including sequential, concomitant, and hybrid therapies have therefore been proposed to increase the eradication rate [12]. A 10-day sequential therapy reported by Zullo in year 2000 consists of a 5-day dual therapy (PPI plus amoxicillin) followed by a 5-day triple therapy (PPI plus clarithromycin and tinidazole) [13]. The mean H. pylori cure rate of sequential therapy is about 93% [14,15]. Several studies have showed that sequential therapies achieved a higher eradication rate than standard triple therapies [16–18]. The novel therapy seems effective for clarithromycin-resistant strains. A randomized, double-blind, placebo-controlled trial demonstrated that the per-protocol (PP) eradication rates of sequential therapy and standard triple therapy for clarithromycin-resistant strains were 89 and 29%, respectively [19]. The rationale of sequential method is based on that amoxicillin may weaken bacterial cell walls in the initial phase of treatment, preventing the development of drug efflux channels that inhibit such drugs as clarithromycin from binding to ribosomes [13]. However, the rationale has not been proved by evidence medicine, and whether the sequence of the two-step therapy in the novel regimen is important remains unknown. We therefore conducted this study to investigate whether the efficacy of reverse sequential therapy was noninferior to sequential therapy in the treatment of H. pylori infection.
72
Tsay et al.
Materials and Methods Patients and Setting The open-labeled, randomized trial was conducted at the Kaohsiung Veterans General Hospital in Taiwan in accordance with the principles of good clinical practice from the Declaration of Helsinki. From January 2009 to December 2010, H. pylori-infected outpatients, at last 18 years old, with endoscopically proven peptic ulcer diseases or gastritis were recruited for the study. During endoscopy, biopsies of gastric mucosa were performed for culture, rapid urease test and histology for the status of H. pylori. The H. pylori infection was defined as follows: 1, positive result of culture; or 2, positive presences of both rapid urease test and histology. Exclusion criteria included 1, patients with previous eradication therapy; 2, consumption of antibiotics, bismuth, or PPIs within previous 4 weeks; 3, known allergy to any antibiotic of the study or PPIs; 4, previous gastric surgery; 5, the coexistence of serious concomitant illness (e.g., decompensated liver cirrhosis, uremia, recent myocardial infarction); and 6, pregnancy or lactation.
Study Design Using a computer-generated number sequence, the eligible H. pylori-infected patients were randomly assigned to a 10-day sequential therapy (a dual therapy with pantoprazole 40 mg twice daily and amoxicillin 1 g twice daily for 5 days, followed by a triple therapy with pantoprazole 40 mg twice daily, clarithromycin 500 mg twice daily, and metronidazole 500 mg twice daily for a further 5 days) or a 10-day reverse sequential therapy (a triple therapy with pantoprazole 40 mg twice daily, clarithromycin 500 mg twice daily, and metronidazole 500 mg twice daily for 5 days, followed by a dual therapy with pantoprazole 40 mg twice daily and amoxicillin 1 g twice daily for a further 5 days). All drugs were taken 1 hour before breakfast and dinner. Patients were asked to avoid alcohol during treatment in order to avert the possible side effects of interaction with metronidazole. Besides, patients were asked to return at the second week to assess drug compliance and adverse effects. To assess eradication efficacy, repeated endoscopy with rapid urease test and histological examination or urea breath test was performed at 8 weeks after the end of anti-H. pylori therapy. Eradication was defined as follows: 1, negative results of both rapid urease test and histology or 2, negative result of urea breath test.
© 2014 John Wiley & Sons Ltd, Helicobacter 20: 71–77
Reverse Sequential Therapy
Tsay et al.
All participants had completed informed consent. The study was supported by research grants from the Kaohsiung Veterans General Hospital and approved by Institutional Review Board of Kaohsiung Veterans General Hospital (VGHKS97–CT8-06).
Questionnaire A complete personal history and demographic data were obtained from each patient, including age, sex, medical history, and history of smoking, alcohol, coffee, and tea consumption. Smoking was defined as consumption of cigarettes one pack or more within 1 week. Coffee or tea consumption was defined as drinking one cup or more per day. Adverse events were prospectively evaluated. The adverse events were assessed according to a four-point scale system: 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) [20]. Compliance of patients was checked by counting unused medication at the completion of treatment. Poor compliance was defined as taking 1 >0.5, and >8 lg/mL were considered to be resistant to clarithromycin, amoxicillin, and metronidazole, respectively [24].
© 2014 John Wiley & Sons Ltd, Helicobacter 20: 71–77
Statistical Analysis The primary endpoint of the study was eradication rate of H. pylori. The second endpoints were the frequency of adverse events and drug compliance. Chisquare test with or without Yates correction for continuity and Fisher’s exact test were used when appropriate to compare the major outcome between two groups. A p-value < .05 was considered statistically significant. Our hypotheses for sample size calculations were based on the previous study of sequential therapy [18] and prestudy trial of reverse sequential therapy, 93% sequential therapy eradication rate and 96% reverse sequential therapy eradication rates, D (defining equivalence range or noninferiority margin) of 10%, expected difference of 5%, power of 80%, and a of 0.025 (one-sided). Our trial was designed as a noninferiority trial. Fifty-three patients per group (completers) were needed to show noninferiority of the experimental group versus active control group on the basis of the primary efficacy variable. Eradication rates were evaluated by intention-totreat (ITT) and PP analyses. ITT analysis included all patients who had taken at least one dose of study medication. Patients whose infection status was unknown following treatment were considered treatment failures for the purposes of ITT analysis. The PP analysis excluded the patients with unknown H. pylori status following therapy and those with major protocol violations.
Results Baseline Characteristics A total of 122 H. pylori-infected participants were randomized to receive sequential (n = 62) or reverse sequential therapy (n = 60). Demographic and clinical characteristics of patients are shown in Table 1. The two groups had comparable clinical characteristics including age, gender, smoking, drinking, NSAID use, coffee and tea consumption, and endoscopic findings. All the participants in the reverse sequential group had good compliance and were included for PP analysis. In the sequential group, one patient was excluded from PP analysis due to poor compliance.
Eradication of H. pylori Table 2 displays the major outcomes of eradication therapies. ITT analysis demonstrated that sequential and reverse sequential therapies achieved eradication
73
Reverse Sequential Therapy
Tsay et al.
Table 1 Demographic data and endoscopic appearance of sequential and reverse sequential therapy
Characteristics Age (years) (mean SD) Gender (male/female) Smoking Alcohol consumption Ingestion of coffee Ingestion of tea NSAID use Underlying disease Endoscopic findings Gastritis Gastric ulcer Duodenal ulcer GU + DU Antibiotic resistance Amoxicillin Clarithromycin Metronidazole
Sequential (n = 62)
Reverse sequential (n = 60)
p Value
53.1 11.7 34/28 20 (32.3%) 8 (12.9%) 16 (25.8%) 22 (35.5%) 1 (1.6%) 8 (12.9%)
50.1 12.7 39/21 28 (46.7%) 7 (11.7%) 22 (36.7%) 30 (50%) 0 (0%) 11 (18.3%)
.18 .25 .10 .83 .19 .10 1.00 .40
4 (6.5%) 17 (27.4%) 25 (40.3%) 16 (25.8%)
5 (8.3%) 9 (15%) 22 (36.7%) 24 (40%)
0% (0/48) 10% (5/48) 46% (22/48)
0% (0/47) 11% (5/47) 43% (20/47)
.74 .09 .67 .09 – .97 .74
rates of 91.9% (57/62; 95% CI: 85.1–98.7%) and 96.7% (58/60; 95% CI: 92.2–101.2%), respectively. The two study groups had similar eradication rates (p = .44). The PP analysis yielded similar results (sequential, 56/61 (91.8%), 95% CI: 84.9–98.7% vs reverse sequential, 58/60 (96.7%), 95% CI: 92.2– 101.2%, p = .43). There were no statistically significant differences in treatment efficacy between sequential and reverse sequential groups.
Adverse Events and Compliances All the patients received at least one dose of eradication medication and were included in the adverse event analysis. A total of seven (11.3%) patients who
Table 2 The outcomes of sequential and reverse sequential therapy
received sequential therapy and four (6.7%) patients who received reverse sequential therapy reported at least one adverse event during treatment (p = .53). Table 3 shows all the side effects reported by patients. Abdominal pain, diarrhea, dizziness, and nausea were common side effects in both groups. Most patients had well tolerance during treatment. Only one patient in sequential group stopped anti-H. pylori drugs due to severe abdominal pain. Both groups displayed high compliance rates (98.4% vs 100%, respectively, p = 1.00).
Impact of Antibiotic Resistance on Eradication Rates H. pylori strains were isolated from 95 of total 122 enrolled patients who receive bacterial culture during endoscopy initially, and the culture rate of our study was 77.8%. The overall resistance rates of antibiotics were clarithromycin 10.5% (10/95); amoxicillin 0% (0/ 95); and metronidazole 44.2% (42/95) of patients, respectively. The dual resistance rate of clarithromycin and metronidazole was 4.2% (4/95). Table 4 lists the impact of antibiotic resistance on the eradication rates of therapies. In the sequential group, the eradication rate for the clarithromycinsusceptible and resistant strains by ITT analysis was 90.7 and 100%, respectively. No significant differences in eradication rates between the susceptible and resistant strains existed. All the strains in this subgroup were susceptible to amoxicillin. The eradication rate in sequential group for the amoxicilline-susceptible strains was 89.6% by ITT analysis and 89.4% by PP analysis. There was also no significant impact of metronidazole resistance on the successful rates of H. pylori eradication. In the reverse sequential group, there were also no differences in eradication rates between the clarithromycin-susceptible and resistant strains, either by ITT (97.6% vs 100%) or by PP analysis (97.6% vs 100%). The H. pylori eradication rate for the amoxicillin-
Eradication rate Table 3 Adverse events of sequential and reverse sequential therapy Sequential (n = 62) Eradication rate Intention-to-treat Per-protocol Adverse events Compliance
74
91.9% 91.8% 11.3% 98.4%
(57/62) (56/61) (7/62) (61/62)
Reverse sequential (n = 60)
96.7% 96.7% 6.7% 100%
(58/60) (58/60) (4/60) (60/60)
Adverse events
Sequential (n = 62)
Reverse sequential (n = 60)
Abdominal pain Constipation Diarrhea Dizziness/Headache Nausea Other
1 0 1 0 3 4
2 0 0 0 1 1
p Value
.44 .43 .53 1.00
(0/1/0) (0/0/0) (0/0/1) (0/0/0) (2/1/0) (2/1/1)
(1/1/0) (0/0/0) (0/0/0) (0/0/0) (0/1/0) (1/0/0)
© 2014 John Wiley & Sons Ltd, Helicobacter 20: 71–77
Reverse Sequential Therapy
Tsay et al.
susceptible strains was 97.9%, either by ITT analysis or by PP analysis. With respect to metronidazole resistance, eradication rates were similar between susceptible and resistant strains by either ITT or PP analyses (Table 4). The eradication rate of clarithromycin-resistant strains was 80% (4/5) in sequential group and 100% (5/5) in reverse sequential regimen. The resistance of amoxicillin and metronidazole did not cause different outcome in both groups. Four patients with dual resistance strains (two patients in sequential group and another two patients in reverse sequential group) were isolated in the study, and the eradication rate was 100% of both groups.
Impact of Endoscopic Findings on Eradication Rates In standard sequential groups, there was about 93.5% (58/62) patients with gastric, duodenal, or both ulcers, Table 4 Impact of antibiotic resistance on the eradication rate of sequential and reverse sequential therapy Eradication rate ITT Analysis No (%)
PP Analysis p
Sequential group (n = 48) Clarithromycin-resistant 39/43 (90.7) .43 + 5/5 (100) Amoxicillin-resistant 43/48 (89.6) – + – Metronisazole-resistant 25/26 (96.2) .16 + 18/22 (81.8) Dual-resistanta 41/46 (89) 1.00 + 2/2 (100) Reverse sequential group (n = 47) Clarithromycin-resistant 41/42 (97.6) 1.00 + 5/5 (100) Amoxicillin-resistant 46/47 (97.9) – + – Metronisazole-resistant 27/27 (100) .42 + 19/20 (95) Dual-resistant 44/45 (98) 1.00 + 2/2 (100)
No (%)
p
38/42 (90.5) 4/5 (80) 42/47 (89.4) –
.44
–
25/26 (96.2) 17/21 (81)
.15
40/45 (89) 2/2 (100)
1.00
41/42 (97.6) 5/5 (100)
1.00
46/47 (97.9) –
–
27/27 (100) 19/20 (95)
.42
44/45 (98) 2/2 (100)
1.00
a
Dual-resistant (both resistances of clarithromycin and metronisazole).
© 2014 John Wiley & Sons Ltd, Helicobacter 20: 71–77
and only 6.5% (4/62) patients with gastritis. In reverse sequential group, there was the similar demographic percentage (91.7% (55/60) vs 8.3% (5/60)). The overall eradication rate of patients with ulcers, including standard sequential and reverse groups, was 96.4% (109/113). The overall eradication rate of patients with gastritis was only 66.7% (6/9).
Discussion In this prospective, randomized study, the efficacies of reverse sequential and sequential therapies for H. pylori infection were compared. The successful rates by ITT analysis were 96.7 and 91.9%, respectively. Reverse sequential therapy and standard sequential therapy were equally effective for H. pylori eradication. Some authors have proposed that administration of amoxicillin in the initial phase of sequential therapy is important because amoxicillin may weaken bacterial cell walls and prevent the development of drug efflux channels for subsequent antibiotics used in the second phase [13]. Our study clearly indicates that the sequence of antibiotics used in sequential therapy does not influence the efficacy of the treatment, and amoxicillin can be administered either in the initial phase or in the second phase. Therefore, the advantage of sequential therapy over triple therapy may be based on the addition of a third antibiotic rather than the antibiotic administration sequence. This premise might be transferable as well for other highly effective nonbismuth quadruple regimens, such as hybrid or concomitant therapy. From the results of meta-analysis studies, sequential therapy had reported good eradication rate than standard triple therapy, especially in Italy and Asia [25–27]. However, in Latin American, Greenberg et al. [28] indicated that 14-day triple therapy gets better response than 10-day sequential therapy (82.2.0% vs 76.5%). In children group, Horvath et al. [29] reported that sequential therapy was superior to 7-day triple therapy, but was similar with 10- or 14-day triple therapy. The suboptimal results from above studies should be only applicable to setting in the area with similar antibiotics resistance pattern. Therefore, further trials from areas other than Italy and Asia are required to make sure the efficacy between triple and sequential therapies. The promising data presented here are consistent with a head-to-head noninferiority trial of 10-day sequential and 10-day concomitant therapy by our group showing comparable eradication rates (93.0% vs 93.1%) for H. pylori eradication [24]. Concomitant therapy is a four-drug regimen containing a PPI
75
Reverse Sequential Therapy
(standard dose, b.i.d.), clarithromycin (500 mg, b.i.d.), amoxicillin (1 g, b.i.d.), and metronidazole (500 mg, b.i.d.) which are all given for the entire duration of therapy [30]. This therapy is superior to standard triple therapy for H. pylori eradication [31]. This regimen does not involve changing drugs in the treatment course and can achieve similar eradication rate as sequential therapy [24]. The above data indicate that higher eradication rates of sequential therapy and concomitant therapy as compared with standard triple therapy [16–18,31] are most likely due to adding metronidazole in the regimen. Recently, we have developed a hybrid (dual–quadruple) therapy consisting of a dual therapy with a PPI (standard dose, b.i.d.) and amoxicillin (1 g, b.i.d.) for 7 days followed by a concomitant quadruple therapy with a PPI (standard dose, b.i.d.), amoxicillin (1 g, b.i.d.), clarithromcyin (500 mg, b.i.d.), and metronidazole (500 mg, b.i.d.) for 7 days [32]. The novel therapy provides excellent eradication rates of 99 and 97% according to PP and ITT analysis. It is noteworthy that hybrid therapy has a high efficacy in the treatment of H. pylori strains harboring dual resistance to clarithromycin and metronidazole [32]. However, the two-step therapy with dual–quadruple sequence of drug administration is inconvenient for the instruction of drug administration by doctors. The current study implicates that reverse hybrid therapy with quadruple–dual sequence of drug administration can potentially achieve similar eradication as standard hybrid therapy. For hybrid therapy, the reverse sequence of drug administration may be beneficial for doctor to perform drug instruction and for patients to adequately take antiH. pylori medicines. It merits to conduct further studies to investigate the efficacy of reverse hybrid therapy for H. pylori eradication. Clarithromycin resistance is the major cause of eradication failure for standard triple therapy. In this study, the overall resistance rates of antibiotics were clarithromycin 10.5%; amoxicillin 0%; and metronidazole 44.2%. The dual resistance rate of clarithromycin and metronidazole was 4.2%. Our data showed that both sequential and reverse sequential therapies can achieve high eradication rates for clarithromycin-resistant strains (100 and 100% by ITT analysis, respectively). Both therapies were also effective for eradicating metronidazole-resistant strains. The data were consistent with previous studies showing that sequential therapy is less affected by clarithromycin resistance than standard triple therapy [19]. Graham et al. [33] showed that clarithromycin-containing triple therapy and 10day sequential therapy should not be performed as first-line therapy in local area with higher antibiotics resistance rate (i.e., 7- and 14-day triple therapies fail
76
Tsay et al.
when clarithromycin resistance exceeds 5 and 15%, and 10-day sequential regimen fails when metronidazole resistance exceeds 20%). In our study, the dual resistance rate of clarithromycin and metronidazole was only 4.2%. That might indicate the good response of sequential and reverse sequential therapies. Our study has several limitations. First, the sample size was insufficient to detect small differences in eradication rates between two treatment groups. Second, the study was performed in a single center. The data will need to be confirmed in regions where different patterns of resistant are present. Third, the study population consists of a somewhat biased population from the endoscopic findings. There was about 93% patients with gastric, duodenal, or both ulcers, and only 7% patients with gastritis. Compared with nonulcer dyspepsia patients, peptic ulcer patients tend to show higher eradication rates. Nonetheless, this study is the first to verify comparable eradication rates of sequential and reverse sequential therapies. In conclusion, 10-day reverse-sequential therapy and standard sequential therapy are equally effective for H. Pylori eradication. The finding indicates that the sequence of antibiotics administered in sequential therapy does not influence the efficacy of the treatment.
Acknowledgements and Disclosures The authors are indebted to Drs Hsien-Chung Yu and KungHung Lin for recruiting the patients and performing the endoscopies and study nurses Yu-Shan Chen and Lee-Ya Wang at the Kaohsiung Veterans General Hospital. Competing interests: All the authors disclose no conflict of interests.
References 1 Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med 2002;347:1175–86. 2 Hsu PI, Lai KH, Lo GH, et al. Risk factors for ulcer development in patients with non-ulcer dyspepsia: a prospective two year follow up study of 209 patients. Gut 2002;51:15–20. 3 Hsu PI, Lai KH, Hsu PN, et al. Helicobacter pylori infection and the risk of gastric malignancy. Am J Gastroenterol 2007;102:1–6. 4 Malfertheiner P, Megraud F, O’Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 2007;56:772–81. 5 Fock KM, Katelaris P, Sugano K, et al. Second Asia-Pacific conference. Second Asia-Pacific consensus guidelines for Helicobacter pylori infection. J Gastroenterol Hepatol 2009;24:1587–600. 6 Megraud F. H. pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut 2004;53:1374–84. 7 Hsu PI, Kao SS. Therapy of Helicobacter pylori infection: many drugs for which association? In: Manfredi M, de’Angelis GL, eds. Helicobacter Pylori: Detection Methods, Diseases and Health
© 2014 John Wiley & Sons Ltd, Helicobacter 20: 71–77
Tsay et al.
8
9
10
11
12 13
14
15
16
17
18
19
20
Implications. New York: Nova Science Publishers, 2013;347–62. Rimbara E, Fischbach LA, Graham DY. Optimal therapy for Helicobacter pylori infections. Nat Rev Gastroenterol Hepatol 2011;8:79–88. Gumurdulu Y, Serin E, Ozer B, et al. Low eradication rate of Helicobacter pylori with triple 7–14 days and quadruple therapy in Turkey. World J Gastroenterol 2004;10:668–71. Bigard MA, Delchier JC, Riachi G, et al. One-week triple therapy using omeprazole, amoxycillin and clarithromycin for the eradication of Helicobacter pylori in patients with non-ulcer dyspepsia: influence of dosage of omeprazole and clarithromycin. Aliment Pharmacol Ther 1998;12:383–8. De Francesco V, Margiotta M, Zullo A, et al. Prevalence of primary clarithromycin resistance in Helicobacter pylori strains over a 15 year period in Italy. J Antimicrob Chemother 2007; 59:783–5. Chuah SK, Tsay FW, Hsu PI, Wu DC. A new look at antiHelicobacter pylori therapy. World J Gastroenterol 2011;17:3971–5. Zullo A, Vaira D, Vakil N, et al. High eradication rates of Helicobacter pylori with a new sequential treatment. Aliment Pharmacol Ther 2003;17:719–26. Gatta L, Vakil N, Leandro G, Di MF, Vaira D. Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children. Am J Gastroenterol 2009;104:3069–79. Graham DY, Akiko S. New concepts of resistance in the treatment of Helicobacter pylori infections. Nat Clin Pract Gastroenterol Hepatol 2008;5:321–31. Jafri NS, Horning CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection in patients na€ıve to treatment. Ann Intern Med 2008;148:923–31. Gisbert JP, Calvet X, O’connor A, Megraud F, O’Morain CA. Sequential therapy for Helicobacter pylori eradication: a critical review. J Clin Gastroenterol 2010;44:313–25. Tsay FW, Tseng HH, Hsu PI, et al. Sequential therapy achieves a higher eradication rate than standard triple therapy in Taiwan. J Gastroenterol Hepatol 2012;27:498–503. Vaira D, Zullo A, Vakil N, et al. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial. Ann Intern Med 2007;146:556–63. Hsu PI, Lai KH, Lin CK, et al. A prospective randomized trial of esomeprazole- versus pantoprazole-based triple therapy for Helicobacter pylori eradication. Am J Gastroenterol 2005;100:2378–92.
© 2014 John Wiley & Sons Ltd, Helicobacter 20: 71–77
Reverse Sequential Therapy
21 Wu DC, Hsu PI, Tseng HH, et al. Helicobacter pylori Infection: a randomized, controlled study comparing 2 rescue thterapies after failure of standard triple therapies. Medicine 2011;90:180–5. 22 Peng NJ, Lai KH, Liu RS, et al. Endoscopic 13C-urea breath test for the diagnosis of Helicobacter pylori infection. Dig Liver Dis 2003;35:73–7. 23 Hsu PI, Wu DC, Wu JY, et al. Is there a benefit to extending the duration of Helicobacter pylori sequential therapy to 14 days? Helicobacter 2011;16:146–52. 24 Wu DC, Hsu PI, Wu JY, et al. Sequential and concomitant therapy with 4 drugs are equally effective for eradication of H. pylori Infection. Clin Gastroenterol Hepatol 2010;8:36–41. 25 Kate V, Kalayarasan R, Ananthakrishnan N. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a systematic review of recent evidence. Drugs 2013;73:815–24. 26 Yoon H, Lee DH, Kim N, et al. Meta-analysis: is sequential therapy superior to standard triple therapy for Helicobacter pylori infection in Asian adults? J Gastroenterol Hepatol 2013;28:1801– 9. 27 Zullo A, Hassan C, Ridola L, et al. Standard triple and sequential therapies for Helicobacter pylori eradication: an update. Eur J Intern Med 2013;24:16–9. 28 Greenberg ER, Anderson GL, Morgan DR, et al. 14-day triple, 5-day conconmitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomized trial. Lancet 2011;378(9790):507–14. 29 Horvath A, Dziechciarz P, Szajewska H. Meta-analysis: sequential therapy for Helicobacter pylori eradication in children. Aliment Pharmacol Ther 2012;36:534–41. 30 Kao SS, Chen WC, Hsu PI, et al. 7-Day nonbismuth-containing concomitant therapy achieves a high eradication rate for Helicobacter pylori in Taiwan. Gastroenterol Res Pract 2012;2012:463985. doi:10.1155/2012/463985. 31 Essa AS, Kramer JR, Graham DY, Treiber G. Meta-analysis: four-drug, three-antibiotic, non-bismuth-containing “concomitant therapy” versus triple therapy for Helicobacter pylori eradication. Helicobacter 2009;14:109–18. 32 Hsu PI, Wu DC, Wu JY, Graham DY. Modified sequential Helicobacter pylori therapy: proton-pump inhibitor and amoxicillin for 14 days with clarithromycin and metronidazole added as a quadruple (hybrid) therapy for the final 7 days. Helicobacter 2011;16:139–45. 33 Graham DY, Lee YC, Wu MS. Rational Helicobacter pylori therapy: evidence based medicine rather than medicine based evidence. Clin Gastroenterol Hepatol 2014;12:177–86.
77
Reverse Sequential Therapy Achieves a Similar Eradication Rate as Standard Sequential Therapy for Helicobacter pylori Eradication: A Randomized Controlled Trial Feng-Woei Tsay,*,† Deng-Chyang Wu,‡ Sung-Shuo Kao,* Tzung-Jium Tsai,* Kwok-Hung Lai,* Jin-Shiung Cheng,* Hoi-Hung Chan,* Huay-Min Wang,* Wei-Lun Tsai,* Hui-Hwa Tseng,§ Nan-Jin Peng¶ and Ping-I Hsu* *Division of Gastroenterology, Department of internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan, †Cheng Shiu University, Kaohsiung, Taiwan, ‡Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, §Department of Pathology, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan, ¶Department of Nuclear Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan
Keywords Sequential therapy, reverse sequential therapy, Helicobacter pylori. Reprint request to: Ping-I Hsu, Division of Gastroenterology, Department of Internal Medicine, Kaoshiung Veterans General Hospital, 386 Ta Chung 1st Road, Kaohsiung 813, Taiwan. E-mail: [email protected]
© 2014 John Wiley & Sons Ltd, Helicobacter 20: 71–77
Abstract Background and Aims: Sequential therapy is a two-step therapy achieving a promising eradication rate for Helicobacter pylori infection. The rationale of sequential method has been proposed that amoxicillin weakens bacterial cell walls in the initial phase of treatment, preventing the development of drug efflux channels for clarithromycin and metronidazole used in the second phase. The aim of this prospective, randomized, controlled study was to investigate whether the efficacy of reverse sequential therapy was noninferior to sequential therapy in the treatment of H. pylori infection. Methods: From January 2009 to December 2010, consecutive H. pyloriinfected patients were randomly assigned to receive either sequential therapy (a 5-day dual therapy with pantoprazole plus amoxicillin, followed by a 5-day triple therapy with pantoprazole plus clarithromycin and metronidazole) or reverse sequential therapy (a 5-day triple therapy with pantoprazole plus clarithromycin and metronidazole, followed by a 5-day dual therapy with pantoprazole plus amoxicillin). H. pylori status was examined 6 weeks after the end of treatment by rapid urease and histology or urea breath test. Results: One hundred and twenty-two H. pylori-infected participants were randomized to receive sequential (n = 60) or reverse sequential therapy (n = 62). The eradication rates, by intention-to-treat analysis, were similar: 91.9% (95% confidence interval (CI): 85.1–98.7%) for sequential therapy and 96.7% (95% CI: 92.2–101.2%) for reverse sequential therapy (p = .44). Per-protocol analysis also showed similar results: 91.8% (95% CI: 84.9– 98.7%) for sequential group and 96.7% (95% CI: 92.2–101.2%) for reverse sequential therapy (p = .43). The two treatments exhibited comparable frequencies of adverse events (11.3% vs 6.7%, respectively) and drug compliance (98.4% vs 100%, respectively). The overall resistance rates of antibiotics were clarithromycin 10.5%, amoxicillin 0%, and metronidazole 44.2% of patients, respectively. The dual resistance rate of clarithromycin and metronidazole was 4.2%. Both therapies achieved a high eradication rate for clarithromycin-resistant strains (100% vs 100%, respectively) and metronidazole-resistant strains (81.8% vs 95%, respectively) by intention-to-treat analysis. Conclusions: Ten-day reverse sequential therapy and standard sequential therapy are equally effective for H. Pylori eradication. The finding indicates that the sequence of antibiotics administered in sequential therapy does not influence the efficacy of the treatment.
71
Reverse Sequential Therapy
Helicobacter pylori (H. pylori) is the major cause of chronic gastritis, peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma [1–3]. In most international guidelines [4,5], standard triple therapy consisting of a protonpump inhibitor (PPI), clarithromycin, and amoxicillin (or metronidazole) for 7–14 days is recommended as the choice of treatment for first-line therapy of H. pylori infection. However, the success of standard triple therapy has recently declined to unacceptable levels due to increasing resistance rate of antibiotics [6–8]. Some European studies even reported very poor treatment outcomes of the standard therapy with failure rates of 25–60% [9–11]. Clarithromycin resistance is the major cause of eradication failure in standard triple therapy. Pooled data from 20 studies involving 1975 patients treated with standard triple therapy showed an eradication rate of 88% in clarithromycin-sensitive strains versus 18% in clarithromycin-resistant strains [6]. Therefore, the background rate of clarithromycin resistance is critically important as its presence negatively impacts the efficacy of standard triple therapy. Several strategies including sequential, concomitant, and hybrid therapies have therefore been proposed to increase the eradication rate [12]. A 10-day sequential therapy reported by Zullo in year 2000 consists of a 5-day dual therapy (PPI plus amoxicillin) followed by a 5-day triple therapy (PPI plus clarithromycin and tinidazole) [13]. The mean H. pylori cure rate of sequential therapy is about 93% [14,15]. Several studies have showed that sequential therapies achieved a higher eradication rate than standard triple therapies [16–18]. The novel therapy seems effective for clarithromycin-resistant strains. A randomized, double-blind, placebo-controlled trial demonstrated that the per-protocol (PP) eradication rates of sequential therapy and standard triple therapy for clarithromycin-resistant strains were 89 and 29%, respectively [19]. The rationale of sequential method is based on that amoxicillin may weaken bacterial cell walls in the initial phase of treatment, preventing the development of drug efflux channels that inhibit such drugs as clarithromycin from binding to ribosomes [13]. However, the rationale has not been proved by evidence medicine, and whether the sequence of the two-step therapy in the novel regimen is important remains unknown. We therefore conducted this study to investigate whether the efficacy of reverse sequential therapy was noninferior to sequential therapy in the treatment of H. pylori infection.
72
Tsay et al.
Materials and Methods Patients and Setting The open-labeled, randomized trial was conducted at the Kaohsiung Veterans General Hospital in Taiwan in accordance with the principles of good clinical practice from the Declaration of Helsinki. From January 2009 to December 2010, H. pylori-infected outpatients, at last 18 years old, with endoscopically proven peptic ulcer diseases or gastritis were recruited for the study. During endoscopy, biopsies of gastric mucosa were performed for culture, rapid urease test and histology for the status of H. pylori. The H. pylori infection was defined as follows: 1, positive result of culture; or 2, positive presences of both rapid urease test and histology. Exclusion criteria included 1, patients with previous eradication therapy; 2, consumption of antibiotics, bismuth, or PPIs within previous 4 weeks; 3, known allergy to any antibiotic of the study or PPIs; 4, previous gastric surgery; 5, the coexistence of serious concomitant illness (e.g., decompensated liver cirrhosis, uremia, recent myocardial infarction); and 6, pregnancy or lactation.
Study Design Using a computer-generated number sequence, the eligible H. pylori-infected patients were randomly assigned to a 10-day sequential therapy (a dual therapy with pantoprazole 40 mg twice daily and amoxicillin 1 g twice daily for 5 days, followed by a triple therapy with pantoprazole 40 mg twice daily, clarithromycin 500 mg twice daily, and metronidazole 500 mg twice daily for a further 5 days) or a 10-day reverse sequential therapy (a triple therapy with pantoprazole 40 mg twice daily, clarithromycin 500 mg twice daily, and metronidazole 500 mg twice daily for 5 days, followed by a dual therapy with pantoprazole 40 mg twice daily and amoxicillin 1 g twice daily for a further 5 days). All drugs were taken 1 hour before breakfast and dinner. Patients were asked to avoid alcohol during treatment in order to avert the possible side effects of interaction with metronidazole. Besides, patients were asked to return at the second week to assess drug compliance and adverse effects. To assess eradication efficacy, repeated endoscopy with rapid urease test and histological examination or urea breath test was performed at 8 weeks after the end of anti-H. pylori therapy. Eradication was defined as follows: 1, negative results of both rapid urease test and histology or 2, negative result of urea breath test.
© 2014 John Wiley & Sons Ltd, Helicobacter 20: 71–77
Reverse Sequential Therapy
Tsay et al.
All participants had completed informed consent. The study was supported by research grants from the Kaohsiung Veterans General Hospital and approved by Institutional Review Board of Kaohsiung Veterans General Hospital (VGHKS97–CT8-06).
Questionnaire A complete personal history and demographic data were obtained from each patient, including age, sex, medical history, and history of smoking, alcohol, coffee, and tea consumption. Smoking was defined as consumption of cigarettes one pack or more within 1 week. Coffee or tea consumption was defined as drinking one cup or more per day. Adverse events were prospectively evaluated. The adverse events were assessed according to a four-point scale system: 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) [20]. Compliance of patients was checked by counting unused medication at the completion of treatment. Poor compliance was defined as taking 1 >0.5, and >8 lg/mL were considered to be resistant to clarithromycin, amoxicillin, and metronidazole, respectively [24].
© 2014 John Wiley & Sons Ltd, Helicobacter 20: 71–77
Statistical Analysis The primary endpoint of the study was eradication rate of H. pylori. The second endpoints were the frequency of adverse events and drug compliance. Chisquare test with or without Yates correction for continuity and Fisher’s exact test were used when appropriate to compare the major outcome between two groups. A p-value < .05 was considered statistically significant. Our hypotheses for sample size calculations were based on the previous study of sequential therapy [18] and prestudy trial of reverse sequential therapy, 93% sequential therapy eradication rate and 96% reverse sequential therapy eradication rates, D (defining equivalence range or noninferiority margin) of 10%, expected difference of 5%, power of 80%, and a of 0.025 (one-sided). Our trial was designed as a noninferiority trial. Fifty-three patients per group (completers) were needed to show noninferiority of the experimental group versus active control group on the basis of the primary efficacy variable. Eradication rates were evaluated by intention-totreat (ITT) and PP analyses. ITT analysis included all patients who had taken at least one dose of study medication. Patients whose infection status was unknown following treatment were considered treatment failures for the purposes of ITT analysis. The PP analysis excluded the patients with unknown H. pylori status following therapy and those with major protocol violations.
Results Baseline Characteristics A total of 122 H. pylori-infected participants were randomized to receive sequential (n = 62) or reverse sequential therapy (n = 60). Demographic and clinical characteristics of patients are shown in Table 1. The two groups had comparable clinical characteristics including age, gender, smoking, drinking, NSAID use, coffee and tea consumption, and endoscopic findings. All the participants in the reverse sequential group had good compliance and were included for PP analysis. In the sequential group, one patient was excluded from PP analysis due to poor compliance.
Eradication of H. pylori Table 2 displays the major outcomes of eradication therapies. ITT analysis demonstrated that sequential and reverse sequential therapies achieved eradication
73
Reverse Sequential Therapy
Tsay et al.
Table 1 Demographic data and endoscopic appearance of sequential and reverse sequential therapy
Characteristics Age (years) (mean SD) Gender (male/female) Smoking Alcohol consumption Ingestion of coffee Ingestion of tea NSAID use Underlying disease Endoscopic findings Gastritis Gastric ulcer Duodenal ulcer GU + DU Antibiotic resistance Amoxicillin Clarithromycin Metronidazole
Sequential (n = 62)
Reverse sequential (n = 60)
p Value
53.1 11.7 34/28 20 (32.3%) 8 (12.9%) 16 (25.8%) 22 (35.5%) 1 (1.6%) 8 (12.9%)
50.1 12.7 39/21 28 (46.7%) 7 (11.7%) 22 (36.7%) 30 (50%) 0 (0%) 11 (18.3%)
.18 .25 .10 .83 .19 .10 1.00 .40
4 (6.5%) 17 (27.4%) 25 (40.3%) 16 (25.8%)
5 (8.3%) 9 (15%) 22 (36.7%) 24 (40%)
0% (0/48) 10% (5/48) 46% (22/48)
0% (0/47) 11% (5/47) 43% (20/47)
.74 .09 .67 .09 – .97 .74
rates of 91.9% (57/62; 95% CI: 85.1–98.7%) and 96.7% (58/60; 95% CI: 92.2–101.2%), respectively. The two study groups had similar eradication rates (p = .44). The PP analysis yielded similar results (sequential, 56/61 (91.8%), 95% CI: 84.9–98.7% vs reverse sequential, 58/60 (96.7%), 95% CI: 92.2– 101.2%, p = .43). There were no statistically significant differences in treatment efficacy between sequential and reverse sequential groups.
Adverse Events and Compliances All the patients received at least one dose of eradication medication and were included in the adverse event analysis. A total of seven (11.3%) patients who
Table 2 The outcomes of sequential and reverse sequential therapy
received sequential therapy and four (6.7%) patients who received reverse sequential therapy reported at least one adverse event during treatment (p = .53). Table 3 shows all the side effects reported by patients. Abdominal pain, diarrhea, dizziness, and nausea were common side effects in both groups. Most patients had well tolerance during treatment. Only one patient in sequential group stopped anti-H. pylori drugs due to severe abdominal pain. Both groups displayed high compliance rates (98.4% vs 100%, respectively, p = 1.00).
Impact of Antibiotic Resistance on Eradication Rates H. pylori strains were isolated from 95 of total 122 enrolled patients who receive bacterial culture during endoscopy initially, and the culture rate of our study was 77.8%. The overall resistance rates of antibiotics were clarithromycin 10.5% (10/95); amoxicillin 0% (0/ 95); and metronidazole 44.2% (42/95) of patients, respectively. The dual resistance rate of clarithromycin and metronidazole was 4.2% (4/95). Table 4 lists the impact of antibiotic resistance on the eradication rates of therapies. In the sequential group, the eradication rate for the clarithromycinsusceptible and resistant strains by ITT analysis was 90.7 and 100%, respectively. No significant differences in eradication rates between the susceptible and resistant strains existed. All the strains in this subgroup were susceptible to amoxicillin. The eradication rate in sequential group for the amoxicilline-susceptible strains was 89.6% by ITT analysis and 89.4% by PP analysis. There was also no significant impact of metronidazole resistance on the successful rates of H. pylori eradication. In the reverse sequential group, there were also no differences in eradication rates between the clarithromycin-susceptible and resistant strains, either by ITT (97.6% vs 100%) or by PP analysis (97.6% vs 100%). The H. pylori eradication rate for the amoxicillin-
Eradication rate Table 3 Adverse events of sequential and reverse sequential therapy Sequential (n = 62) Eradication rate Intention-to-treat Per-protocol Adverse events Compliance
74
91.9% 91.8% 11.3% 98.4%
(57/62) (56/61) (7/62) (61/62)
Reverse sequential (n = 60)
96.7% 96.7% 6.7% 100%
(58/60) (58/60) (4/60) (60/60)
Adverse events
Sequential (n = 62)
Reverse sequential (n = 60)
Abdominal pain Constipation Diarrhea Dizziness/Headache Nausea Other
1 0 1 0 3 4
2 0 0 0 1 1
p Value
.44 .43 .53 1.00
(0/1/0) (0/0/0) (0/0/1) (0/0/0) (2/1/0) (2/1/1)
(1/1/0) (0/0/0) (0/0/0) (0/0/0) (0/1/0) (1/0/0)
© 2014 John Wiley & Sons Ltd, Helicobacter 20: 71–77
Reverse Sequential Therapy
Tsay et al.
susceptible strains was 97.9%, either by ITT analysis or by PP analysis. With respect to metronidazole resistance, eradication rates were similar between susceptible and resistant strains by either ITT or PP analyses (Table 4). The eradication rate of clarithromycin-resistant strains was 80% (4/5) in sequential group and 100% (5/5) in reverse sequential regimen. The resistance of amoxicillin and metronidazole did not cause different outcome in both groups. Four patients with dual resistance strains (two patients in sequential group and another two patients in reverse sequential group) were isolated in the study, and the eradication rate was 100% of both groups.
Impact of Endoscopic Findings on Eradication Rates In standard sequential groups, there was about 93.5% (58/62) patients with gastric, duodenal, or both ulcers, Table 4 Impact of antibiotic resistance on the eradication rate of sequential and reverse sequential therapy Eradication rate ITT Analysis No (%)
PP Analysis p
Sequential group (n = 48) Clarithromycin-resistant 39/43 (90.7) .43 + 5/5 (100) Amoxicillin-resistant 43/48 (89.6) – + – Metronisazole-resistant 25/26 (96.2) .16 + 18/22 (81.8) Dual-resistanta 41/46 (89) 1.00 + 2/2 (100) Reverse sequential group (n = 47) Clarithromycin-resistant 41/42 (97.6) 1.00 + 5/5 (100) Amoxicillin-resistant 46/47 (97.9) – + – Metronisazole-resistant 27/27 (100) .42 + 19/20 (95) Dual-resistant 44/45 (98) 1.00 + 2/2 (100)
No (%)
p
38/42 (90.5) 4/5 (80) 42/47 (89.4) –
.44
–
25/26 (96.2) 17/21 (81)
.15
40/45 (89) 2/2 (100)
1.00
41/42 (97.6) 5/5 (100)
1.00
46/47 (97.9) –
–
27/27 (100) 19/20 (95)
.42
44/45 (98) 2/2 (100)
1.00
a
Dual-resistant (both resistances of clarithromycin and metronisazole).
© 2014 John Wiley & Sons Ltd, Helicobacter 20: 71–77
and only 6.5% (4/62) patients with gastritis. In reverse sequential group, there was the similar demographic percentage (91.7% (55/60) vs 8.3% (5/60)). The overall eradication rate of patients with ulcers, including standard sequential and reverse groups, was 96.4% (109/113). The overall eradication rate of patients with gastritis was only 66.7% (6/9).
Discussion In this prospective, randomized study, the efficacies of reverse sequential and sequential therapies for H. pylori infection were compared. The successful rates by ITT analysis were 96.7 and 91.9%, respectively. Reverse sequential therapy and standard sequential therapy were equally effective for H. pylori eradication. Some authors have proposed that administration of amoxicillin in the initial phase of sequential therapy is important because amoxicillin may weaken bacterial cell walls and prevent the development of drug efflux channels for subsequent antibiotics used in the second phase [13]. Our study clearly indicates that the sequence of antibiotics used in sequential therapy does not influence the efficacy of the treatment, and amoxicillin can be administered either in the initial phase or in the second phase. Therefore, the advantage of sequential therapy over triple therapy may be based on the addition of a third antibiotic rather than the antibiotic administration sequence. This premise might be transferable as well for other highly effective nonbismuth quadruple regimens, such as hybrid or concomitant therapy. From the results of meta-analysis studies, sequential therapy had reported good eradication rate than standard triple therapy, especially in Italy and Asia [25–27]. However, in Latin American, Greenberg et al. [28] indicated that 14-day triple therapy gets better response than 10-day sequential therapy (82.2.0% vs 76.5%). In children group, Horvath et al. [29] reported that sequential therapy was superior to 7-day triple therapy, but was similar with 10- or 14-day triple therapy. The suboptimal results from above studies should be only applicable to setting in the area with similar antibiotics resistance pattern. Therefore, further trials from areas other than Italy and Asia are required to make sure the efficacy between triple and sequential therapies. The promising data presented here are consistent with a head-to-head noninferiority trial of 10-day sequential and 10-day concomitant therapy by our group showing comparable eradication rates (93.0% vs 93.1%) for H. pylori eradication [24]. Concomitant therapy is a four-drug regimen containing a PPI
75
Reverse Sequential Therapy
(standard dose, b.i.d.), clarithromycin (500 mg, b.i.d.), amoxicillin (1 g, b.i.d.), and metronidazole (500 mg, b.i.d.) which are all given for the entire duration of therapy [30]. This therapy is superior to standard triple therapy for H. pylori eradication [31]. This regimen does not involve changing drugs in the treatment course and can achieve similar eradication rate as sequential therapy [24]. The above data indicate that higher eradication rates of sequential therapy and concomitant therapy as compared with standard triple therapy [16–18,31] are most likely due to adding metronidazole in the regimen. Recently, we have developed a hybrid (dual–quadruple) therapy consisting of a dual therapy with a PPI (standard dose, b.i.d.) and amoxicillin (1 g, b.i.d.) for 7 days followed by a concomitant quadruple therapy with a PPI (standard dose, b.i.d.), amoxicillin (1 g, b.i.d.), clarithromcyin (500 mg, b.i.d.), and metronidazole (500 mg, b.i.d.) for 7 days [32]. The novel therapy provides excellent eradication rates of 99 and 97% according to PP and ITT analysis. It is noteworthy that hybrid therapy has a high efficacy in the treatment of H. pylori strains harboring dual resistance to clarithromycin and metronidazole [32]. However, the two-step therapy with dual–quadruple sequence of drug administration is inconvenient for the instruction of drug administration by doctors. The current study implicates that reverse hybrid therapy with quadruple–dual sequence of drug administration can potentially achieve similar eradication as standard hybrid therapy. For hybrid therapy, the reverse sequence of drug administration may be beneficial for doctor to perform drug instruction and for patients to adequately take antiH. pylori medicines. It merits to conduct further studies to investigate the efficacy of reverse hybrid therapy for H. pylori eradication. Clarithromycin resistance is the major cause of eradication failure for standard triple therapy. In this study, the overall resistance rates of antibiotics were clarithromycin 10.5%; amoxicillin 0%; and metronidazole 44.2%. The dual resistance rate of clarithromycin and metronidazole was 4.2%. Our data showed that both sequential and reverse sequential therapies can achieve high eradication rates for clarithromycin-resistant strains (100 and 100% by ITT analysis, respectively). Both therapies were also effective for eradicating metronidazole-resistant strains. The data were consistent with previous studies showing that sequential therapy is less affected by clarithromycin resistance than standard triple therapy [19]. Graham et al. [33] showed that clarithromycin-containing triple therapy and 10day sequential therapy should not be performed as first-line therapy in local area with higher antibiotics resistance rate (i.e., 7- and 14-day triple therapies fail
76
Tsay et al.
when clarithromycin resistance exceeds 5 and 15%, and 10-day sequential regimen fails when metronidazole resistance exceeds 20%). In our study, the dual resistance rate of clarithromycin and metronidazole was only 4.2%. That might indicate the good response of sequential and reverse sequential therapies. Our study has several limitations. First, the sample size was insufficient to detect small differences in eradication rates between two treatment groups. Second, the study was performed in a single center. The data will need to be confirmed in regions where different patterns of resistant are present. Third, the study population consists of a somewhat biased population from the endoscopic findings. There was about 93% patients with gastric, duodenal, or both ulcers, and only 7% patients with gastritis. Compared with nonulcer dyspepsia patients, peptic ulcer patients tend to show higher eradication rates. Nonetheless, this study is the first to verify comparable eradication rates of sequential and reverse sequential therapies. In conclusion, 10-day reverse-sequential therapy and standard sequential therapy are equally effective for H. Pylori eradication. The finding indicates that the sequence of antibiotics administered in sequential therapy does not influence the efficacy of the treatment.
Acknowledgements and Disclosures The authors are indebted to Drs Hsien-Chung Yu and KungHung Lin for recruiting the patients and performing the endoscopies and study nurses Yu-Shan Chen and Lee-Ya Wang at the Kaohsiung Veterans General Hospital. Competing interests: All the authors disclose no conflict of interests.
References 1 Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med 2002;347:1175–86. 2 Hsu PI, Lai KH, Lo GH, et al. Risk factors for ulcer development in patients with non-ulcer dyspepsia: a prospective two year follow up study of 209 patients. Gut 2002;51:15–20. 3 Hsu PI, Lai KH, Hsu PN, et al. Helicobacter pylori infection and the risk of gastric malignancy. Am J Gastroenterol 2007;102:1–6. 4 Malfertheiner P, Megraud F, O’Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 2007;56:772–81. 5 Fock KM, Katelaris P, Sugano K, et al. Second Asia-Pacific conference. Second Asia-Pacific consensus guidelines for Helicobacter pylori infection. J Gastroenterol Hepatol 2009;24:1587–600. 6 Megraud F. H. pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut 2004;53:1374–84. 7 Hsu PI, Kao SS. Therapy of Helicobacter pylori infection: many drugs for which association? In: Manfredi M, de’Angelis GL, eds. Helicobacter Pylori: Detection Methods, Diseases and Health
© 2014 John Wiley & Sons Ltd, Helicobacter 20: 71–77
Tsay et al.
8
9
10
11
12 13
14
15
16
17
18
19
20
Implications. New York: Nova Science Publishers, 2013;347–62. Rimbara E, Fischbach LA, Graham DY. Optimal therapy for Helicobacter pylori infections. Nat Rev Gastroenterol Hepatol 2011;8:79–88. Gumurdulu Y, Serin E, Ozer B, et al. Low eradication rate of Helicobacter pylori with triple 7–14 days and quadruple therapy in Turkey. World J Gastroenterol 2004;10:668–71. Bigard MA, Delchier JC, Riachi G, et al. One-week triple therapy using omeprazole, amoxycillin and clarithromycin for the eradication of Helicobacter pylori in patients with non-ulcer dyspepsia: influence of dosage of omeprazole and clarithromycin. Aliment Pharmacol Ther 1998;12:383–8. De Francesco V, Margiotta M, Zullo A, et al. Prevalence of primary clarithromycin resistance in Helicobacter pylori strains over a 15 year period in Italy. J Antimicrob Chemother 2007; 59:783–5. Chuah SK, Tsay FW, Hsu PI, Wu DC. A new look at antiHelicobacter pylori therapy. World J Gastroenterol 2011;17:3971–5. Zullo A, Vaira D, Vakil N, et al. High eradication rates of Helicobacter pylori with a new sequential treatment. Aliment Pharmacol Ther 2003;17:719–26. Gatta L, Vakil N, Leandro G, Di MF, Vaira D. Sequential therapy or triple therapy for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children. Am J Gastroenterol 2009;104:3069–79. Graham DY, Akiko S. New concepts of resistance in the treatment of Helicobacter pylori infections. Nat Clin Pract Gastroenterol Hepatol 2008;5:321–31. Jafri NS, Horning CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection in patients na€ıve to treatment. Ann Intern Med 2008;148:923–31. Gisbert JP, Calvet X, O’connor A, Megraud F, O’Morain CA. Sequential therapy for Helicobacter pylori eradication: a critical review. J Clin Gastroenterol 2010;44:313–25. Tsay FW, Tseng HH, Hsu PI, et al. Sequential therapy achieves a higher eradication rate than standard triple therapy in Taiwan. J Gastroenterol Hepatol 2012;27:498–503. Vaira D, Zullo A, Vakil N, et al. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial. Ann Intern Med 2007;146:556–63. Hsu PI, Lai KH, Lin CK, et al. A prospective randomized trial of esomeprazole- versus pantoprazole-based triple therapy for Helicobacter pylori eradication. Am J Gastroenterol 2005;100:2378–92.
© 2014 John Wiley & Sons Ltd, Helicobacter 20: 71–77
Reverse Sequential Therapy
21 Wu DC, Hsu PI, Tseng HH, et al. Helicobacter pylori Infection: a randomized, controlled study comparing 2 rescue thterapies after failure of standard triple therapies. Medicine 2011;90:180–5. 22 Peng NJ, Lai KH, Liu RS, et al. Endoscopic 13C-urea breath test for the diagnosis of Helicobacter pylori infection. Dig Liver Dis 2003;35:73–7. 23 Hsu PI, Wu DC, Wu JY, et al. Is there a benefit to extending the duration of Helicobacter pylori sequential therapy to 14 days? Helicobacter 2011;16:146–52. 24 Wu DC, Hsu PI, Wu JY, et al. Sequential and concomitant therapy with 4 drugs are equally effective for eradication of H. pylori Infection. Clin Gastroenterol Hepatol 2010;8:36–41. 25 Kate V, Kalayarasan R, Ananthakrishnan N. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a systematic review of recent evidence. Drugs 2013;73:815–24. 26 Yoon H, Lee DH, Kim N, et al. Meta-analysis: is sequential therapy superior to standard triple therapy for Helicobacter pylori infection in Asian adults? J Gastroenterol Hepatol 2013;28:1801– 9. 27 Zullo A, Hassan C, Ridola L, et al. Standard triple and sequential therapies for Helicobacter pylori eradication: an update. Eur J Intern Med 2013;24:16–9. 28 Greenberg ER, Anderson GL, Morgan DR, et al. 14-day triple, 5-day conconmitant, and 10-day sequential therapies for Helicobacter pylori infection in seven Latin American sites: a randomized trial. Lancet 2011;378(9790):507–14. 29 Horvath A, Dziechciarz P, Szajewska H. Meta-analysis: sequential therapy for Helicobacter pylori eradication in children. Aliment Pharmacol Ther 2012;36:534–41. 30 Kao SS, Chen WC, Hsu PI, et al. 7-Day nonbismuth-containing concomitant therapy achieves a high eradication rate for Helicobacter pylori in Taiwan. Gastroenterol Res Pract 2012;2012:463985. doi:10.1155/2012/463985. 31 Essa AS, Kramer JR, Graham DY, Treiber G. Meta-analysis: four-drug, three-antibiotic, non-bismuth-containing “concomitant therapy” versus triple therapy for Helicobacter pylori eradication. Helicobacter 2009;14:109–18. 32 Hsu PI, Wu DC, Wu JY, Graham DY. Modified sequential Helicobacter pylori therapy: proton-pump inhibitor and amoxicillin for 14 days with clarithromycin and metronidazole added as a quadruple (hybrid) therapy for the final 7 days. Helicobacter 2011;16:139–45. 33 Graham DY, Lee YC, Wu MS. Rational Helicobacter pylori therapy: evidence based medicine rather than medicine based evidence. Clin Gastroenterol Hepatol 2014;12:177–86.
77
