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Treatment of Helicobacter pylori, Comparison of three Regimens, a double Blind Randomized Trial

Abu Safieh Yasser F, Yamin Haneen

Abu Safieh Yasser F, Yamin Hanin, Specialized Arab Hospital, Internal Medicine and GI Department, affiliated with School of Medicine, An-Najah University, Nablus, Palestine

Correspondence to: Yamin Haneen, MD, Specialized Arab Hospital, Internal Medicine and GI Department, affiliated with School of Medicine, An-Najah University, Nablus, Palestine.
dr.haneenya@gmail.com
Received: March 7, 2013
Revised: May 18, 2013
Accepted: May 21, 2013
Published online: July 21, 2013

ABSTRACT

AIM: To compare the effectiveness of standard triple, sequential, and concomitant therapies for eradication of Helicobacter pylori in a randomized, double-blinded, comparative clinical trial conducted in Palestine.

METHODS: Patients who underwent upper endoscopy for a clinical indication and tested positive for rapid urease test (RUT) were included, written consent was signed, and randomly allocated into three groups: Group A received the conventional Triple therapy; Esomeprazole 40 mg OD, Amoxicillin 1g and Clarithromycin 500 mg both given BID for 10 days; Group B received Sequential therapy; Esomeprazole 40 mg OD and Amoxicillin 1g BID for 5 days then Esomeprazole 40 mg OD, Clarithromycin 500 mg BID and Tinidazole 500 mg BID for another 5 days; and Group C received Concomitant therapy; Esomeprazole 40 mg OD, Amoxicillin 1g, Tinidazole 500 mg and Clarithromycin 500 mg all given BID, for 10 days. Stool antigen was done 4 weeks after completion of treatment. Binary logistic regression and X2 test with (P<0.05) were used as appropriate to compare the eradication rates.

RESULTS: Six hundred and seventy three (673) patients were tested by (RUT), of whom 242 patients (36%) had a positive RUT, 203 patients were included in the study and 163 patients completed the study. In Per Protocol analysis, the overall eradication rate was 73%. The eradication rates were 70.2%, 70.9% and 77.2% in Groups, A, B, and C respectively. Although the eradication rate achieved by the concomitant therapy was higher than both sequential and triple therapy, these differences were not statistically significant.

CONCLUSION: The eradication rates were low with the three protocols. The three protocols are equal as first line treatment of H. pylori. The sequential and concomitant therapies were not superior to triple therapy. New regimens that are more effective, with a higher eradication rate need to be developed.

Key words: Helicobacter pylori; Eradication therapies

© 2013 The Authors. Published by ACT Publishing Group Ltd.

Yasser F AS, Haneen Y. Treatment of Helicobacter pylori, Comparison of three Regimens, a double Blind Randomized Trial. Journal of Gastroenterology and Hepatology Research 2013; 2(7): 699-702 Available from: URL: http://www.ghrnet.org/index.php/joghr/article/view/436

INTRODUCTION

Helicobacter pylori infection causes peptic ulcers, gastric mucosa-associated lymphoid tissue lymphoma (MALT lymphoma), and gastric cancer[1]. Standard treatments for H. pylori infection that have been endorsed by U.S. and European authorities rely on clarithromycin or metronidazole in conjunction with other antibiotics and acid inhibitors[2,3]. The prevalence of clarithromycin and metronidazole resistance has increased substantially in recent years, and there has been a corresponding decrease in the eradication rate for H. pylori infection[4]. Eradication rates in most Western countries have declined to unacceptable levels. Eradication therapy fails in approximately 1 in 5 patients[5]. A simple and short treatment regimen that would return eradication levels to those seen at the advent of H. pylori treatment is urgently needed[5]. Such a regimen should have high efficacy against clarithromycin-resistant and metronidazole-resistant strains of H. pylori because these strains are increasingly encountered in routine clinical practice. One successful approach to the problem of clarithromycin resistance has been to administer the drugs sequentially[6,7]. The initial experiments with “sequential therapy” prescribed the dual therapy combination of amoxicillin and a PPI twice a day for 5 days followed by another 5 days of the PPI, plus clarithromycin and tinidazole/metronidazole. This approach has been compared with PPI amoxicillin plus clarithromycin triple therapy and repeatedly been shown to be superior[6-8]. The difference between the two approaches was related to improved results with clarithromycin resistant strains[6,7]. One potential problem with sequential therapy is that it is relatively complex requiring the patient to switch from a dual to a triple therapy at mid point[6,9]. It was therefore proposed that the same four drugs (a PPI, clarithromycin, metronidazole, and amoxicillin) can be given concomitantly as a non sequential 4-drug, 3-antibiotic non-bismuth containing quadruple therapy to overcome this problem[10,11]. Interestingly, the efficacy of this therapy regimen was equivalent to sequential therapy in some studies[12,13]. Several studies in various countries have proven its efficacy with eradication rates above 90 %[14,15]. With application of this regimen the treatment could even be shortened to 5 days[15]. These therapies have not formally been tested in Palestine where H. pylori infection is high, The aim of this study was to compare the efficacy of standard triple, sequential, and concomitant therapies for Helicobacter pylori eradication in a randomized, double-blinded, comparative clinical trial in Palestine.

METHODS

Patients and medications

This study was a randomized, prospective double blind trial performed at the GI clinic in Specialized Arab Hospital, Nablus, Palestine between April 2010 and January 2012. Both the care giver and the patient were blind to treatment. The data analyst and the medical secretary who did randomization were not blind to treatment. Patients presenting with dyspepsia or epigastric pain, and underwent upper endoscopy, with 2 antral biopsies, and tested positive for H. pylori by RUT were included in this study. The exclusion criteria were as follows (1) patients younger than 18 years; (2) allergy to antibiotics; (3) Being on antibiotic or PPI 2 weeks before testing; (4) active upper GI bleeding.

After a positive (RUT), patients were randomly allocated into three groups: Group (A) received the standard Triple therapy; Esomeprazole 40 mg OD, Amoxicillin 1 g, and Clarithromycin 500 mg both given bid for 10 days. Group (B) received Sequential therapy; Esomeprazole 40 mg OD and Amoxicillin 1 g bid for 5 days then Esomeprazole 40 mg bid, Clarithromycin 500 mg, and Tinidazole 500 mg both given bid for another 5 days. Group (C) received concomitant therapy; Esomeprazole 40 mg OD, Amoxicillin 1 g, Tinidazole 500 mg, and Clarithromycin 500 mg, all given bid, for 10 days. Eradication of H. pylori was assessed; by stool antigen testing was done by Specialised Arab Hospital Lab. (ACON Labs, Foresight® H. pylori antigen EIA Test Kit) done four weeks after completion of treatment. Simple randomization was used in this study. Randomization was done by sealed opaque envelopes, with a given number for each patient, was done by our medical secretary.

The three groups were followed by regular telephone calls during treatment period and were asked about side effects. Compliance assessment was done by counting pills at the end of treatment period.

Statistical analysis

Per protocol analysis was used to compare the eradication rates among the three treatment regimens. SPSS version 15 was used in data analysis. Continuous variables were presented using mean and standard deviation and frequency tables were used to describe categorical variables. X2 (P<0.05) was used. Intension to treat was used to have analysis of eradication rate for the three groups.

RESULTS

The total number of unique patients who underwent upper endoscopy during the study period was 1122, of those 673 patients were tested by RUT. The total number of positive RUT was 242 (36%). 39 patients were excluded for different reasons listed in the methods. A total of 203 patients were included in the study. Of those, 163 patients completed the study (80% completion rate); 40 patients did not like to continue the study despite repeated attempts and call phones. As shown in table 1 and 2, the three patient groups did not differ significantly in age, sex, gastroscopic diagnosis, or dropout rates.

The overall eradication rate was 73% (119/163). In an ITT the eradication rate was, 119/203 (59%). In per protocol analysis, the eradication rates were 70.2%, 70.9% and 77.2% in groups A, B and C respectively. As shown in table 3, the eradication rate achieved by the concomitant therapy was numerically higher than that by both sequential and triple therapy. However, No statistical significance was found among any of the three groups.

It was found that the overall eradication rate was 76.6% for female and 69.8% for males (Table 3) with no statistical significance between the two groups (p=0.325).

Patient compliance with the therapies was very good and not different among the three groups. The complete follow up rate was 80%. No serious side effects were reported by the patients

DISCUSSION

The aim of this study was to compare the efficacy of triple, sequential and concomitant therapies to determine the best first line treatment in Palestine. Surprisingly, there was no statistical significance in the eradication rates between any of the treatment regimens.

The eradication rates achieved by the three protocols were relatively low between 70 and 77%. For triple therapy, the results were similar to other countries as the eradication rates with triple therapy have declined to unacceptable low rates in most countries by the early 2000s[14]. However, the eradication rates of sequential and concomitant therapies that were obtained in this study were lower than other countries[8,13,16-18].

The sequential therapy had been evaluated in various randomized trials and therapeutic success was confirmed overall with respect to the standard triple therapy[19]. Moreover, several studies showed that concomitant therapy is equally effective as sequential therapy[12,13]. The rationale for the different eradication success rates in different areas of the world can be attributed mainly to H. pylori resistance, which shows great variety even within individual societies.

Despite its increasing resistance; the current standard triple therapy, as recommended for H. pylori eradication by different clinical societies and their guidelines based on a PPI combined with clarithromycin and amoxicillin and/or metronidazole, continues to be the first-line option indifferent countries around the globe[20-26].

The combination of PPI-amoxicillin-levofloxacin is a good option as second-line therapy. In the case of failure of second-line therapy, the patients should be evaluated using a case-by-case approach. European guidelines recommend culture before the selection of a third-line treatment based on the microbial antibiotic sensitivity. H. pylori isolates after two eradication failures are often resistant to both metronidazole and clarithromycin. The alternative candidates for third-line therapy are quinolones, tetracycline, rifabutin and furazolidone[27-30]. None of the previous options is guaranteed to achieve high eradication rates. Thus, therapies based on new antibiotics should be introduced to overcome the problem of resistance.

We have an ethical question, is it ethical to use any of these therapies? And what would be the best alternative eradication therapy of this global microorganism[31]? There are no clear answers especially at a place of relatively limited resources.

CONCLUSION

H. pylori is still a major health problem in our region (36% prevalence in this study) triple, sequential and concomitant use of different antibiotics may not add much to eradication rates, and an urgent new regimen with novel antibiotics is mandatory. The eradication rates were low with the three protocols, less than 80%, and were not significantly different as first line treatment of H. pylori. The sequential and concomitant therapies were not superior to standard triple therapy in our study.

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Peer reviewers: Claudio Chiesa, MD, Institute of Translational Pharmacology, National Research Council, Via del Fosso del Cavaliere, 100, 00133-Rome, Italy; Orhan Sezgin, Professor Dr., Gastroenterology Department, Faculty of Medicine, Mersin University, Mersin, 33100, Turkey.

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