Introduction

 

Helicobacter pylori infection is found in at least 80% of people in developing countries and 30–40% of people in developed countries.[1,2]

 

The indications for H.pylori eradication usually include peptic ulcer disease, MALT lymphoma, gastric atrophy, intestinal metaplasia, gastric remnant in cases of gastric cancer, first-degree relative of those with gastric cancer and dyspepsia.[3,4] Widespread use of eradication therapy has resulted in growth of antibiotic resistance.

 

The current resistance rate to clarithromycin has been reported to be 2–30% and that of metronidazole 15–66%.[5] H. pylori eradication is relatively successful in more than 80% of patients[6]  and it still remains an unsolved problem even with 25 years of comprehensive research.[7]

 

A successful treatment is based on patient and physician compliance to treatment guidelines.[6] Numerous regimens have been suggested for H. pylori eradication in order to attain more effective eradication without increasing bacterial  resistance. The most frequently used treatment for H. pylori eradication is triple or standard therapy, which includes a combination of 2 antibiotics (clarithromycin plus amoxicillin or metronidazole) along with a proton pump inhibitor (PPI) for at least 7 days[8] But this regimen has been described to be losing its efficacy for H. pylori eradication.[7]

 

Cure rate of triple therapy has been demonstrated to be less than 80% in two meta-analysis studies.[9,10] This reduced eradication rate has lead to the development and use of other treatment regimen as the first or second line of treatment. The Maastricht III Consensus Report recommends a bismuthcontaining quadruple therapy as the best second-line treatment option, if available.[11] Eradication rates of 59–95% after firstline treatment failure are reported in a bismuth-based quadruple therapy for 7–10 days.[12]Sequential therapy as an alternative treatment option (combination of amoxicillin and a PPI twice a day for 5 days followed by 5 days of the PPI plus clarithromycin and metronidazole) has been repeatedly shown to be superior to the triple therapy in head-to-head studies. The dominance  of sequential therapy is shown to be due to its lower antibioticresistance especially for clarithromycin.[13] Quinolone based firstline therapies have also come into consideration these days, and some studies reported successful eradication rates using this option.[14]

 

Prevalence of H. pylori in Iran is reported to be nearly 90% in adults.[15] Considering the high antibiotic resistance in Iran  (37% for metronidazole and 16.7% for clarithromycin)[16,17], this randomized clinical trial study was performed to evaluate the efficacy of 4 different H. pylori eradication regimens in Iranian harboring patients with dyspepsia.

 

Methods

 

This was a prospective randomized clinical trial. We enrolled 428 patients referred to Razi hospital in Rasht city with dyspepsia from July 2007 to May 2008. These patients underwent endoscopy and were found to be positive for H. pylori on biopsy.

 

Exclusion criteria included age less than 18, a history of treatment for H. pylori, notable cardiac, liver, respiratory or

renal problems, upper gastrointestinal surgery, gastric malignancy, pyloric stenosis, pregnancy or breastfeeding, and a history of allergy to penicillin or drugs used in the study. Written informed consent was obtained from the patients before enrollment. Approval was obtained through the investigation review board and medical ethics committee at the Guilan University of Medical Sciences.

 

All cases had non-ulcer dyspepsia and endoscopy confirmed this diagnosis. H. pylori infection was confirmed by endoscopy and biopsy results. Rapid urease test (RUT) was applied to biopsies taken from the corpus and antrum, to identify the presence of infection. RUT was considered positive if any color change took place. Patients had not received H. pylori eradication therapy prior to the point of enrolment. Patients were randomly assigned to four treatment groups  (A-D) using computer generated tables of random numbers.Each group included 107 patients. Group A received 20 mg omeprazole, 1g amoxicillin, 500 mg metronidazole and 240 mg bismuth twice daily for 2 weeks. Group B received 20 mg omeprazole, 1 g amoxicillin, and 500 mg clarithromycin twice daily for 10 days. Group C patients were given 20 mg omeprazole, 500 mg clarithromycin twice daily for 2 weeks and 500 mg ciprofloxacin twice a day for the first week. Group D received a sequential treatment including 20 mg omeprazole twice daily for 10 days, 1 g amoxicillin twice daily for the first 5 days, 500 mg metronidazole and 500 mg clarithromycin twice daily for the second 5 days.

 

Patients were given a questionnaire at the beginning of the survey to evaluate the possible side effects of treatment, such  as rash, nausea, vomiting, abdominal discomfort and diarrhea. On return of patients after treatment, questionnaires were gathered and a physician estimated patient compliance. A drug intake of more than 85% was considered good compliance.

 

Eradication was defined as a negative stool antigen test. The stool antigen test was performed using the HpSA enzymelinked  immunosorbent assay (ELISA) (Premier Platinum HpSA, Meridian Diagnostics, Cincinnati, OH, USA) 8 weeks after the  end of treatment course. Patients were assessed for upper gastrointestinal symptoms at the time of stool antigen test. The H. pylori eradication rates were analyzed using both “Intention to Treat” (ITT) and “per Protocol” (PP) analyses. The chi-square test was used to compare the efficacy of the treatment regimens. A p value of less than 0.05 was considered significant. Statistical analyses were done using SPSS 14.0 (SPSS Inc, Chicago, IL, USA).

 

Results

 

Mean age of patients enrolled in the study was 40 years. 58% of patients (248) were females and 42% (180) were males.  Demographic data of each group is displayed in (Table 1). There were no significant differences in age and gender between the four groups.

 

The results of H. pylori eradication rates, effects of drugs and presence of upper gastrointestinal symptoms after 8 weeks  are demonstrated in (Table 2). Group B had a significantly higher eradication rate in comparison to other groups (p=0.0001) while group C had the lowest eradication rate. Patient compliance was significantly lower in Group C (6.5%) whereas it was not  significantly different in other groups (A (1.9%), B (0%), D (0.9)). Regimen C was also responsible for the highest rate of adverse drug effects (8.4%, p=0.03) Most frequent complications were nausea in 2 patients and diarrhea in 1, from group A; nausea in 1 patient and abdominal discomfort in 1 patient from group B; nausea in 3 patients, vomiting in 2 and abdominal discomfort in 4 patients from in group C; and nausea and vomiting in 1 patient each from group D.

 

Discussion

 

The growing list of indications for H. pylori eradication has led to the emergence of antibiotic resistance at a scale that needs urgent attention. Studies have described that eradication therapy has a 20-60% drop in efficacy, in presence of clarithromycin resistance.[18,19,20] Considering the resistance of H. pylori to different antibiotics in different regions, finding an appropriate eradication regimen is a concern with worldwide implications. Different rates of H. pylori resistance have been reported in different countries.[21] Genetic factors also play a role in development of these variable cure rates in different regions.[21]

 

Sotoudehmanesh et al. have reported that the most common regimen used in Iran is a 2 week quadruple therapy that consists  of bismuth, omeprazole, metronidazole and amoxicillin.[22] The appropriate combination of drugs has not been yet defined in our country. Considering the rapid growth of antibiotic resistance repeated surveys should be conducted through time to assess necessary changes in treatment. In this trial, we have examined eradication rates of four treatment regimens to achieve a reliable first-line treatment.

 

We have found the most effective first-line treatment to be a 10 days triple therapy based on clarythromycin, amoxicillin and omeprazole. The eradication rate was 90.7% in both ITT and PP analyses. This rate is considered a “good” score and  grade B eradication as per the guidelines developed by Graham et al. in 2007.[23] A quadruple therapy based on bismuth, omeprazole, metronidazole and amoxicillin achieved the second rank. This regimen scores a grade C in both ITT and PP based analyses. Sequential therapy and another triple therapy utilized in this study did not seem to be acceptable treatment options.

 

Different eradication rates of the same regimens are reported in studies from Iran. Keshavarz et al. demonstrated 89% PP eradication rate for the same standard triple therapy, and was very similar to our eradication rate. Patient compliance rate (98%) was also comparable to our study (100%). [24] Mirbagheri et al. achieved a 91.8% per protocol eradication rate for the same triple therapy (regimen B) given for 1 week. A similar quadruple therapy for 10 days resulted in 85% per protocol eradication which is also close to our findings.[25] Bahremand et al. also found similar results regarding triple and quadruple therapy.[26] In contrast some studies have not attained an acceptable eradication rate for a similar quadruple therapy.[27,28] We decided to use 10 days triple and 2 weeks quadruple treatment durations because shorter duration of treatment did not lead to suitable H. pylori treatment.[29]

 

The eradication rates of standard triple therapy have not been reported to be more than 80% in series of studies

conducted in developed countries.[9,10,23] Sequential therapy, a recently developed regimen, has shown to be vigorously effective in H. pylori eradication due to its lower antibiotic resistance formation. This regimen resulted in eradication rates of 81.1% PP and 80.4% ITT, which was lower in comparison to standard triple and quadruple therapy regimens. These finding  are not in compatibility with results from developed countries.[13] Fluoroquinolone based regimens gained notable attention in recent years. In this study we have used ciprofloxacin as a part of a new H. pylori eradication triple therapy. Outcomes of this regimen were significantly poorer than other regimens.

 

With 65.4% ITT and 70% PP eradication rates and a significantly lower compliance makes this regimen an inappropriate treatment  option. Although the current American College of Gastroenterology guidelines suggest levofloxacin (another fluoroquinolone-based treatment) as a salvage regimen in case of persistent H. pylori infection.[30] Its usage has been limited because of possible resistance formation and a higher cost.[14]. But their efficacy in developing countries is yet to be evaluated. In conclusion, standard triple therapy had the highest success rate in our study while quadruple therapy was the second successful regimen. Sequential therapy was not found to be an acceptable treatment option, although studies from other regions do not support this finding. The advantage of triple therapy over sequential therapy in our study necessitates further studies to evaluate possible role of host factors and pathogen specificities.

 

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