Mædica - a Journal of Clinical Medicine

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1 MAEDICA a Journal of Clinical Medicine 2017; 12(3): Mædica - a Journal of Clinical Medicine ORIGINAL PAPER A Comparative Study of Efficacy and Safety of Two Eradication Regimens for Helicobacter pylori Infection Carmen Monica PREDA, Doina PROCA, Irina SANDRA, Larisa Elena FULGER, Boroka Claudia HOREANGA, Mircea MANUC, Teodora MANUC, Catalin Andrei DUTEI, Mihaela BARBU, Letitia TUGUI, Adriana-Corina ANDREI, Bogdan Ionut SLAVULETE, Mircea DICULESCU Carol Davila University of Medicine and Pharmacy, Gastroenterology & Hepatology Department, Fundeni Clinical Institute, Bucharest, Romania ABSTRACT Introduction: Helicobacter pylori infection is one of the most frequent diseases around the world, affecting about half of the world population. The infection is known to be associated with upper gastrointestinal diseases. The aim of this paper is to identify which of the following two first-line therapy options (ECA vs ECM see abbreviations below) is more efficient and to assess the improvement in the quality of life among these patients. Material and Methods: 96 patients with proven Helicobacter pylori infection were divided in two treatment groups, as follows: 47 patients received a 10-day triple therapy with esomeprazole 80 mg/day, amoxicillin 2000 mg/day and clarithromycin 1000 mg/day (ECA) and the rest of 49 received a 10-day sequential therapy: esomeprazole 40 mg and amoxicillin 1000 mg twice daily for five days, followed by esomeprazole 40 mg, clarithromycin 500 mg and metronidazole 500 mg (ECM) twice daily for another five days. Assessment of Helicobacter pylori infection was performed using the stool antigen test one month after the patient finished therapy. At the beginning of the study and at the follow-up visit, every subject was asked to complete the Gastrointestinal Quality of Life Index (GIQLI). Results: Twenty three patients did not come for the follow-up visit (24% drop-out rate). The ECA therapy group had an efficacy rate of 94%, while the rate of the ECM treated group was 95% (per protocol analysis). There was no significant difference regarding the baseline characteristics between the two groups. The entire group treatment tolerability was approximately 85%, with no statistical difference between groups (p-value = 0.824). Quality of life improvement was points in the ECA treated group and 13.4 points Address for correspondence: Carmen Monica Preda Fundeni Clinical Institute, Gastroenterology & Hepatology Department, Fundeni Road, No 258, Bucharest, code , Romania Phone: carmenmonica.preda@gmail.com Article received on the 6 th of September 2017 and accepted for publication on the 28 th of September

2 in the ECM treated group (p=ns). Regarding the quality of life improvement, the results were positive, irrespective of type of peptic disease, but the most important results were obtained in peptic ulcer disease, functional dyspepsia and chronic gastritis. Conclusions: Both ECA and ECM regimens are almost equally effective in Helicobacter pylori eradication and significantly improve the quality of life irrespective of type of peptic disease. The limitation of this study was the significant drop-out rate (24%) that may have overestimated the results. Keywords: Helicobacter pylori, antibiotics, first-line therapy, quality of life. Abbreviations: BMI=Body mass index; ECA=Esomeprazole-clarithromycin-amoxicillin; ECM=Esomeprazole-clarithromycin-metronidazole; GERD= Gastroesophageal reflux disease; GIQLI=Gastrointestinal quality of life index; HP=Helicobacter pylori. INTRODUCTION Helicobacter pylori (HP) infection is one of the most frequent diseases around the world, affecting about half of the world population (1, 2). Helicobacter pylori is a Gram-negative, microaerophilic, spiral shaped human pathogen (3, 4), discovered in 1982 by Warren and Marshall (5), which colonizes the gastric mucosa (6). Since 1994, it is considered to be part of the first group carcinogens (7) because of the association with gastric adenocarcinoma and primary B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) (8). The infection is known to be associated with upper gastrointestinal diseases (9) due to acute and chronic inflammation of the gastric mucosa (4). The prevalence of HP infection varies around the world, with a higher prevalence in developing countries and a lower one in the developed world (2, 8). The diagnosis of HP infection is established using invasive and non-invasive tests depending on the availability, cost, reproducibility and clinical manifestations (10-13). The current first-line treatment is the triple therapy regimen that includes proton pump inhibitor and two antibiotics with or without metronidazole: clarithromycin and amoxicillin or metronidazole (2). Unfortunately, the treatment remains a challenge for the doctors because there is no first-line treatment that can cure all the infected patients (14), probably due to increasing antibiotic resistance as a result of erratic antibiotic consumption (15-18). The eradication of HP represents the key aspect in the management of gastrointestinal disorders and in the risk-reduction strategy in gastric carcinoma (19, 20). Recently, a study performed by Ilie M et al. at the Emergency Clinical Hospital Bucharest identified high resistance rates in HP infection: 92.8% for metronidazole, 50% for amoxicillin and 32% for clarithromycin (21). Helicobacter pylori infection seems to have a high prevalence in Romania, with rates that vary between 55% and 69% (23-25). The aim of this paper is to identify which of the following two first-line therapy options is more efficient: 1) esomeprazole 80 mg/day + clarithromycin 1000 mg/day + amoxicillin 2000 mg/day (ECA) for 10 days or 2) sequential therapy with five days of esomeprazole (40 mg) and amoxicillin (1000 mg) twice a day, followed by five days of esomeprazole (40 mg), clarithromycin (500 mg) and metronidazole (500 mg) (ECM) twice daily. The aim was to eradicate the infection and to assess the improvement in the quality of life among these patients. METHODS A prospective randomized, single practitioner trial was conducted, analyzing 96 consenting patients with persistent HP infection observed in the Gastroenterology Department of Fundeni Clinical Institute between October 2013 and September All patients signed an informed consent. The study was approved by the Ethics Committee of Fundeni Clinical Institute. Unfortunately, 23 of them did not come for the follow-up visit, so at the end of the study, data for only 73 patients were available. These 73 patients were divided into two groups: the first one (34 patients) received a 10-day triple therapy 158

3 with esomeprazole 80 mg, amoxicillin 2000 mg and clarithromycin 1000 mg (ECA) once daily, while the second group (39 patients) received a 10-day sequential therapy: esomeprazole 40 mg and amoxicillin 1000 mg twice daily for five days, followed by esomeprazole 40 mg, clarithromycin 500 mg and metronidazole 500 mg (ECM) twice daily for another five days. Assessment of HP infection was performed using the stool antigen test, Quest Diagnostics TM, an enzyme immunoassay with a sensitivity and specificity of 96% for detecting HP infection. For the majority of patients (70 out of 73), an upper gastrointestinal endoscopy was also performed in order to observe the appearance of the esophagus, duodenum and gastric mucosa. At the beginning of the study, every subject was asked to complete the Gastrointestinal Quality of Life Index (GIQLI) (22) that included the items from Table 1. Every item was given a score from four points (most desirable option) to one point (least desirable option). The GIQLI score represents the sum of all item points. One month following the end of therapy, another stool antigen test was performed in order to assess the eradication of the infection, and the GIQLI was recomputed to check for potential improvements. Statistical analysis Statistical analysis was performed with Minitab Statistical Software (version 17, Minitab Inc., State College, Pennsylvania, USA) descriptive statistic used to summarize the data. The chisquare test for group comparisons and 95% CIs were performed. P-value<0.05 was considered significant. RESULTS A total of 96 subjects were enrolled but because 23 of them dropped out, complete data were obtained from only 73 subjects: 34/73 (46%) males and Pain Feeling unfit Troubled by treatment Bloating Endurance Impaired personal relations Epigastric fullness Wake up at night Impaired sexual life Flatus Appearance Regurgitation Belching Sadness Dysphagia Bowel frequency Nervousness Eating speed Abdominal noises Frustration Nausea Restricted eating Happiness Diarrhea Enjoyed eating Bothered by treatment Heartburn Fatigue Cope with stress Bowel urgency Strength Daily activities Constipation Feeling unwell Leisure activities Blood in stool TABLE 1. The items of Gastrointestinal Quality of Life Index 39/73 (54%) females. We developed a database that included all of the characteristics obtained from the subjects. As we can see in Table 2, the only statistical significant parameter was the absence of allergies (p-value = 0.027). In the ECA group there were no allergic subjects, whereas in the ECM group 10 subjects were allergic to tetracycline, penicillin, pollen or another unknown substance. Eradication rates One month after completing the treatment, every patient performed a stool antigen test to confirm the eradication of HP. Overall the infection was cured in 95% of all cases (69 cured subjects). The efficiency rate was 94% (32 sub jects) as per protocol in the group treated with ECA, and 95% (37 subjects) in the group with sequential therapy (ECM). There was no significant difference between patients regarding one regimen or another (p-value = 0.904). Compliance and side-effects The therapy compliance for the entire group was 97%. Two patients from the ECA group did not fully comply with treatment due to allergic reactions, which lead to a compliance rate of 94%, while 159

4 Characteristic Total ECA ECM p-value 73 patients 34 patients 39 patients Sex M 45.94% 41.18% 59% Urban area 64.86% 70.58% 60% Age Mean Standard deviation Median Range Smoking Smoker 13.51% 5.88% 10% Non-smoker 75.68% 82.30% 70% Ex-smoker 10.81% 11.76% 20% Alcohol consumption No 54.05% 64.71% 45% Yes 8.11% 0.00% 15% Occasionally 37.84% 35.29% 40% Fried food consumption 64.86% 52.94% 75% Snacks consumption 29.73% 29.41% 30% Spices consumption 56.76% 52.94% 60% No allergies 86.49% % 75% BMI Mean Standard deviation Median Range Normal physical examination 62.16% 47.06% 75% Positive surgical case history 43.24% 47.00% 40% Diagnosis HP positive chronic gastritis 35.14% 29.41% 40% Dyspepsia 8.21% 0.00% 15% GERD 10.81% 11.76% 10% Duodenitis. Chronic gastritis 5.41% 11.76% 0% GERD. Chronic gastritis 27.03% 35.29% 20% Duodenal and gastric ulcer 2.70% 0.00% 5% GERD. Duodenal ulcer 2.70% 5.88% 0% Duodenal ulcer 5.41% 5.88% 5% Gastric ulcer 2.70% 0.00% 5% TABLE 2. Subjects characteristics divided by group of therapy the ECM group had a rate of 100%. The p-value was for compliance in both groups. In 12 subjects (six from the ECA group and six from the ECM group), main drug-related side-effects occurred, including oral candidiasis (5%) (the most common side-effect), urticarial rash, nausea, insomnia, heartburn, tendinitis and dizziness. All side-effects were self-limiting, except for oral candidiasis, that received specific therapy. The entire group treatment tolerability was approxi- 160

5 Characteristic Total ECA ECM p-value Total ECA ECM Total ECA ECM Total ECA ECM Mean Standard deviation Median Range p-value TABLE 3. GIQLI before and after eradication of Helicobacter pylori mately 85%, with no statistical diffe rence between groups (p-value = 0.824). Quality of life improvement Every patient included in this study had to answer the questions from the Gastrointestinal Quality of Life Index (GIQLI) (Table 1) before therapy and one month after completing the treatment. Table 3 shows the GIQLI score before and after the eradication of the infection as well as the difference between those two. Overall, there is an improvement of points after eradication: points in ECA treated group and 13.4 points in the ECM treated group. In the entire group, four patients were not responsive to treatment, for whom the quality of life worsened and the score decreased by 14.5 points. For the 69 pa tients who responded to therapy, the score increased by points. Although the improvement was higher for the ECM treated subjects, there was no statistical significant difference (p-value=0.643). Diagnosis GIQLI improvement HP positive chronic gastritis 12.37±14.16 Dyspepsia 15.8±14.18 GERD 12.18±14.24 Duodenitis. Chronic gastritis 1.5±2.53 GERD. Chronic gastritis 10.79±14.06 Duodenal and gastric ulcer 16±3.02 GERD. Duodenal ulcer 4±4.22 Duodenal ulcer 8±2.16 Gastric ulcer 31±4.04 TABLE 4. GIQLI improvement in gastrointestinal dysfunction Regarding the relationship between gastrointestinal dysfunction and quality of life improvement, we obtained positive results, irrespective of peptic disease, though the most important results were obtained in peptic ulcer disease, functional dyspepsia and chronic gastritis (Table 4). DISCUSSIONS This is the first head-to-head comparison of two first-line eradication regimens for HP infection in Romania. Our country is an area of low clarithromycin resistance but high metronidazole resistance, as the study of Ilie M et al. suggests (21), these data showing that triple therapy should be more effective than sequential therapy. The aim of the current study is to determine the eradication rate in Romania obtained with standard triple therapy and sequential therapy, and to find out which of the two regimens improves the GIQLI of Romanian patients. Overall, data suggest that both regimens are equally effective in HP eradication, with an eradication rate of approximately 95% (per protocol) and a good tolerability of approximately 85%, and no severe drug reactions. The eradication rate in our work is even better than in the study published in 2016 by Arama S et al. These authors report a 84.2% eradication rate for 14 days triple therapy and 42.3% for seven days triple therapy, their data outlining the importance of therapy duration (27). The lower eradication rate obtained by Arama S et al. can be explained by the use of lansoprazole 60 mg/day, while in our study, we used esomeprazole, the most recommended proton pump inhibitor. Interestingly, Arama S et al. did not report any drop-out rate, but according to our data, 24% of patients did not come back for the follow-up visit. 161

6 We have to outline that the high efficacy of the regimen used by us is also due to the high dose of esomeprazole (80 mg/day), which was administered according to the Maastricht V consensus recommendations. In Romania, this regiment is not used as widely as it should be in daily practice. The importance of this dose is also confirmed by de Francesco et al., as they reported a value of 78.2% for standard dose (esomeprazole 40 mg/day) and 85.5% for high dose (80 mg/day) at per-protocol analysis (28). In contrast with these authors, our results were even better, the more so as they were obtained by a shorter thera py duration. Very recently, in Italy, di Ciaula et al. reported a 89% eradication rate for the 10 day sequential therapy in intention-to treat, which is comparable with our results (29). The issue of safety for HP eradication therapy is very important, as some authors report severe adverse events such as pseudomembranous colitis (30). In our study, there is a 15% incidence of none serious adverse events, which is comparable with data from the literature (28, 29). Both regimens seem to have a similar tolerability. Our study involved patients from 13 different Romanian counties and we can affirm that both groups were homogenous with respect to all characteristics described in Table 2. There are few data regarding the impact of eradication therapy on health related quality of life. Accor ding to the HEROES trial on functional dyspepsia, patients in the antibiotic group improved symptomatically better than those in the control group (31). In gastroesophageal reflux disease (GERD), the quality of life in reflux and dyspepsia improved one year after HP eradication (32). Our results suggest that the quality of life improves irrespective of the therapy used as long as the infection is eradicated. The impact on quality of life is positive in all peptic disease, but it is most important in peptic ulcer disease (22.3 points), functional dyspepsia (15.8 points) and chronic gastritis (12.4 points). Based on the data obtained from our study, it could be suggested that an empirical clarithromycin-containing regimen could remain the first-line therapeutic approach in clinical practice in Romania. Sequential therapy is more complex and requires changing antibiotic drugs during the treatment course, which can be confusing for patients. Therefore, concomitant therapy is easier to meet patients adherence than sequential therapy, while tolerability is similar between the two regimens. Despite the encouraging results obtained by us, we have to take into account the significant drop-out rate (24%) that may overestimate both the response to therapy regimens and the GIQLI. Although GIQLI has improved with bacterial eradication and worsened in subjects who failed eradication, it had a personal subjective compound that could not be measured or eliminated from the study. CONCLUSION This study shows that the 10-day triple therapy containing esomeprazole, amoxicillin and clarithromycin is almost as effective as the 10-day sequential therapy containing esomeprazole, amoxicillin, metronidazole and clarithromycin (94% vs 95% success rate in intention-to-treat) in Helicobacter pylori eradication. Also, the tolerability for these regimens was high (85%) and their few side-effects were mild. Bacteria eradication improves the quality of life irrespective of the therapy used (12.38 points), although the score in the ECM group was sightly higher (13.4 vs 11.18). The improvement is undeniable for all gastrointestinal dysfunctions but the most important results were obtained in peptic ulcer disease, functional dyspepsia and chronic gastritis. The limitation of this study is the significant drop-out rate (24%) that may have overestimated the results. Conflicts of interest: none declared. Financial support: none declared. 162

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