ORIGINAL ARTICLES

School of Medicine and Life Sciences1, University of Jinan-Shandong Academy of Medical Sciences; Jinan Central Hospital Affiliated to Shandong University2, Jinan; Taishan Medical University3, Taian, China

Comparison of efficacy and safety of ilaprazole and both in initial treatment regimen and retreatment regimen of Helicobacter pylori infection in chronic gastritis

YAO JIN1, SHUHONG ZHANG2,*, JIANMEI PAN2, MENG YUE2, GUOSHAN ZHANG2, DONGXUE YAO2, QIUZHI WANG3

Received January 25, 2019, accepted February 28, 2019 *Corresponding author: Shuhong Zhang, Department of Gastroenterology, Jinan Central Hospital Affiliated to Shandong University, No.105 Jiefang Road, Jinan 250013, China [email protected] Pharmazie 74: 432-438 (2019) doi: 10.1691/ph.2019.9349

The aim of this study was to compare the efficacy and safety of ilaprazole and esomeprazole both in initial treatment regimen and retreatment regimen of H. pylori infection in chronic gastritis and to explore risk factors for eradication failure. A total of 330 patients with chronic gastritis who were confirmed of H. pylori infection were enrolled in this study. 290 of them were initially treated patients and the 40 remained were patients with retreatment. Eradication assessment was performed at least four weeks after the completion of eradication therapy. Results showed that the eradication rates of the ilaprazole group and esomeprazole group were 91.4 % and 88.4 % for per-protocol (PP) analysis (p=0.41) and 89.0 % and 86.2 % for intention-to-treat (ITT) analysis (p=0.48) in initially treated patients. Meanwhile, they were 75.0 % and 72.2 % for PP analysis (p=0.85) and 75.0 % and 70.0 % for ITT analysis (p=0.72) in patients with retreatment. The differences were not statistically significant. There was also no significant difference in safety between the two drugs. A multiple logistic regres- sion analysis showed that demographic factors such as age, gender, alcohol, smoking, coronary heart disease (CHD), hypertension (HTN) and diabetes mellitus (DM) did not affect eradication rates. However, patients with higher DOB values and patients with atrophic gastritis had significantly lower eradication rates than patients with lower DOB values and with non-atrophic gastritis whether the proton pump inhibitor (PPI) in eradication regimens was ilaprazole or esomeprazole. In conclusion, our findings suggest that the efficacy and safety of ilaprazole and esomeprazole were not significantly different both in initial treatment regimen and retreatment regimen of H. pylori infection in chronic gastritis and DOB values and type of chronic gastritis were to be inde- pendent risk factors for eradication failure. In addition, we discovered that a new quadruple regimen containing furazolidone and minocycline which achieved good efficacy and safety can be a promising option for retreatment of H. pylori infection.

1. Introduction and Furuta 2012). However, in China, the efficacy and safety of Helicobacter pylori is the most successful human pathogen ilaprazole and esomeprazole both in initial treatment regimen and infecting about 50 percent of the world’s population. It is a retreatment regimen of H. pylori infection in chronic gastritis has common and treatable cause of chronic gastritis, peptic ulcer never been compared in a randomized trial. disease, gastric adenocarcinoma and gastric mucosa-associated In the present study, we conducted a prospective, open, randomized lymphoid tissue (MALT) lymphoma (Malfertheiner et al. 2017; trial to compare the efficacy and safety of ilaprazole and esomepra- Sugano et al. 2015). In 2014, the International Agency for Research zole both in initial treatment regimen and retreatment regimen of on Cancer suggested that the eradication of H. pylori should be H. pylori infection in chronic gastritis. considered as a strategy for preventing gastric cancer (Herrero et In China, with the increasing resistance rate to clarithromycin and al. 2014). Indeed, H. pylori induced chronic gastritis is considered metronidazole, it is currently recommended to use a bismuth-con- as the most important risk factor for peptic ulcer and gastric cancer taining quadruple therapy, including PPI, bismuth, and two (Sugano et al. 2015). antibiotics as the main first-line initial treatment regimen. This In the eradication therapy for H. pylori infection, PPIs have a quadruple therapy has been validated by foreign studies (Ergul direct antibacterial effect on H. Pylori, probably because they et al. 2013;Srinarong et al. 2014) and recommended by the can directly inhibit the urease activity of H. pylori. In addition, MaastrichtV/Florence Consensus (Malfertheiner et al. 2017) and increasing intragastric pH values can enhance the antibacterial the Toronto Consensus (Fallone et al. 2016). On account of the effect of antibiotics, while reducing the minimum inhibitory antibiotic resistance rate of H. pylori is 0 %-5 % for amoxicillin, concentration, improving the chemical stability of antibiotics in this prospective study, we used PPI, bismuth, amoxicillin and and increasing the concentration of antibiotics in the gastric juice clarithromycin as the initial treatment regimen. For the patients (Labenz 2001). Ilaprazole is the latest proton pump inhibitor that with retreatment, the eradication of H. pylori is becoming increas- is well known for its extended plasma half-life and metabolism ingly difficult. Considering that the resistance rate of H. pylori for which is mainly influenced by cytochrome P450(CYP)3A4 (Seo et levofloxacin has reached 20-50 % in China and a fluoroquino- al. 2012). Esomeprazole is the first PPI containing only the active lone-containing triple regimen is weakly recommended as a rescue isomer and shows a higher eradication rate in the treatment of H. regimen for patients with retreatment by Maastricht V/Florence pylori infection (Lee et al. 2010; McNicholl et al. 2012; Sugimoto Consensus, we decided to use a new combination containing PPI, 432 Pharmazie 74 (2019) ORIGINAL ARTICLES

Table 1: Baseline characteristics of the initially treated patients.

Ilaprazole Esomeprazole Characteristics Total p value group group Gender, n(%) 0.24 Male 59(40.7) 69(47.6) 128(44.1) Female 86(59.3) 76(52.4) 162(55.9) Age,years±SD 48.79±11.29 49.85±13.74 49.32±12.56 0.49

Smoking, n(%) Current smoker 14(9.7) 12(8.3) 26(9.0) 0.68 Ex-smoker 16(11.0) 25(17.2) 41(14.1) 0.13 Never smoker 115(79.3) 108(74.5) 223(76.9) 0.33 Alcohol, n(%) Heavy drinker 5(3.4) 6(4.1) 11(3.8) 0.76 Social drinker 35(24.1) 30(20.7) 65(22.4) 0.48 Nonacohol drinker 105(72.4) 109(75.2) 214(73.8) 0.59 CHD*, n (%) 0.27 Yes 21(14.5) 28(19.3) 49(16.9) No 124(85.5) 117(80.7) 241(83.1) HTN**, n (%) 0.22 Yes 15(10.3) 22(15.2) 37(12.8) No 130(89.7) 123(84.8) 253(87.2) DM***, n (%) 0.43 Yes 6(4.1) 9(6.2) 15(5.2) No 139(95.9) 136(93.8) 275(94.8) DOB value,(mean ±SD) 537.43±407.52 495.01±326.49 516.30±369.32 0.34 Chronic gastritis, n(%) 0.11 Atrophic gastritis 44(30.3) 57(39.3) 101(34.8) Non-atrophic gastritis 101(69.7) 88(60.7) 189(65.2)

*coronary heart disease,**hypertension,***diabetes mellitus. bismuth, tetracycline and furazolidone as the retreatment regimen 2.2. Comparison of effi cacy of ilaprazole group and which is recommended by the Fifth Chinese National Consensus esomeprazole group Report (Liu et al. 2018). The resistance rates of H. pylori to tetra- cycline and furazolidone in China are still very low, which are 0-5 The eradication rates are shown in Figs. 1 and 2. The eradication % and 0-1 %, respectively. But considering that tetracycline is rates of the ilaprazole group and esomeprazole group were 91.4 difficult to obtain clinically and H. pylori has a lower resistance for % [95 %confidence interval(CI): 86.7 %-96.1 %] and 88.4 % (95 minocycline in vitro drug sensitivity test, we included minocycline %CI:83.1 %-93.7 %) for per-protocol (PP) analysis (p=0.41) and 89.0 with longer half-life and better safety in the eradication regimen %(95 %CI:83.9 %-94.1 %) and 86.2 % (95 %CI:80.6 %-91.8 %) for for patients with retreatment. There have been no reports on the intention-to-treat (ITT) analysis (p=0.48) in initially treated patients. quadruple regimen containing furazolidone and minocycline for Meanwhile, they were 75.0 % (95 %CI:51.0 %-91.0 %) and 72.2 % the retreatment therapy of H. pylori infection until now, which is (95 %CI:46.0 %-90.0 %) for PP analysis(p=0.85) and 75.0 % (95 the novelty of this study. %CI:51.0 %-91.0 %) and 70.0 % (95 %CI:46.0 %-88.0 %) for ITT analysis (p=0.72) in patients with retreatment. The eradication rates of the ilaprazole group and esomeprazole group were not significantly 2. Investigations and results different both in initially treated patients and patients with retreatment. 2.1. Baseline characteristics of the subjects A total of 330 patients were enrolled in this study and 290 of 2.3. Comparison of safety of ilaprazole group and esome- them were initially treated while the 40 remaining ones were patients having had eradication therapy for H. pylori at least once prazole group in the past two years. A total of 315 patients completed the treat- The side effects of the subjects are shown in Table 3. The inci- ment, and 13 initially treated patients and 2 patients with retreat- dence of side effects was 11.0 % in the ilaprazole group and 12.4 ment were dropped out because their medication compliance % in the esomeprazole group in initial therapies. The incidence of was below 85 % and they took drugs that affected the efficacy side effects was 10.0 % in the ilaprazole group and 15.0 % in the of the test drugs. The baseline characteristics of the subjects are esomeprazole group in rescue therapies. None of the above data shown in Table 1 and Table 2. There was no significant differ- were statistically different. The most common side effects were ence between the ilaprazole and esomeprazole groups regarding nausea, vomiting, abdominal pain and diarrhea. These symptoms demographic factors and clinical factors including age, gender, were mostly mild and non-specific and none of them required alcohol, smoking, CHD, HTN, DM, DOB values and type of hospitalization. In addition, all side effects were resolved at the chronic gastritis both in initially treated patients and patients end of treatment or after discontinuation and there were no records with retreatment (all P>0.05). of any severe hepatotoxicity or nephrotoxicity. Pharmazie 74 (2019) 433 ORIGINAL ARTICLES

Table 2: Baseline characteristics of the patients with retreatment

Ilaprazole Esomeprazole Characteristics Total p value group group Gender, n(%) 0.34 Male 8(40.0) 11(55.0) 19(47.5) Female 12(60.0) 9(45.0) 21(52.5) Age,years±SD 40.80±14.00 47.67±14.60 44.05±14.51 0.15

Smoking, n(%) 1.00 Smoker 3(15.0) 3(15.0) 6(15.0) Never smoker 17(85.0) 17(85.0) 34(85.0) Alcohol, n(%) 0.38 Drinker 2(10.0) 4(20.0) 6(15.0) Nonacohol drinker 18(90.0) 16(80.0) 34(85.0) CHD*, n (%) 0.68 Yes 3(15.0) 4(20.0) 7(17.5) No 17(85.0) 16(80.0) 33(82.5) HTN**, n (%) 0.29 Yes 3(15.0) 1(5.0) 4(10.0) No 17(85.0) 19(95.0) 36(90.0) DM***, n (%) 0.55 Yes 1(5.0) 2(10.0) 3(7.5) No 19(95.0) 18(90.0) 37(92.5) DOB value,(mean ±SD) 546.50±434.14 523.33±335.95 535.53±385.72 0.86 Chronic gastritis, n(%) 0.33 Atrophic gastritis 6(30.0) 9(45.0) 15(37.5) Non-atrophic gastritis 14(70.0) 11(55.0) 25(62.5)

logistic regression analysis showed that demographic factors including age, gender, alcohol, smoking, CHD, HTN and DM did not affect eradication rates (all P≥0.05). However, patients with higher DOB values (≥1000) had a significantly lower eradication rate (66.7 % vs 94.4 %,45.5 % vs 92.1 %) than patients with lower DOB values (<1000) both in the ilaprazole group and the esome- prazole group (P=0.00,0.00). Patients with atrophic gastritis had a significantly lower eradication rate (83.7 % vs 94.8 %,77.8 % vs 95.2 %) than patients with non-atrophic gastritis both in the ilaprazole group and the esomeprazole group (P=0.04,0.00). DOB values and type of chronic gastritis were regarded to be indepen- dent risk factors for eradication failure in initially treated patients. Fig. 1: Eradication rates of ilaprazole group and esomeprazole group in initially treated patients using PP analysis and ITT analysis. 3. Discussion In this single-center prospective study, we detected that the effi- cacy and safety of ilaprazole and esomeprazole were not signifi- cantly different both in initial treatment regimen and retreatment regimen of H. pylori infection in chronic gastritis and DOB values and type of chronic gastritis were to be independent risk factors for eradication failure in initially treated patients. In addition, we were pleased to find that the quadruple regimen containing furazolidone and minocycline has achieved good efficacy and safety and can be a new option for retreatment of H. pylori infection. Ilaprazole and esomeprazole are second-generation PPIs which overcome the limitations of the first-generation PPIs, such as slow onset, induration of acid secretion inhibition and the influence of CYP2C19 polymorphisms on metabolism. Esomeprazole has been Fig. 2: Eradication rates of ilaprazole group and esomeprazole group in patients with used in China for more than fifteen years and has become the most retreatment using PP analysis and ITT analysis. popular PPI. Meanwhile, as the latest proton pump inhibitor, ilapra- zole has been used in China for a relatively short time and there are less studies about its use in eradication therapy of H. pylori infection. 2.4. Exploration of risk factors for eradication failure Our results show that both ilaprazole-based and esomeprazole-based Risk factors that may affect the eradication rates of H. pylori infec- quadruple therapies for H. pylori infection can achieve more than 85 tion in initially treated patients are shown in Table 4. A multiple % eradication rates for initially treated patients and more than 70

434 Pharmazie 74 (2019) ORIGINAL ARTICLES

Table 3: Side effects of ilaprazole group and esomeprazole group

Initial treatment regimen Retreatment regimen

Side effects P P Ilaprazole group,n(%) Esomeprazole group,n(%) Ilaprazole group,n(%) Esomeprazole group,n(%) value value Total 16(11.0) 18(12.4) 0.72 2(10.0) 3(15.0) 0.63 Nausea 5(3.4) 6(4.1) 0(0.0) 1(5.0) Vomiting 2(1.4) 2(1.4) 0(0.0) 0(0.0) Abdominal pain 3(2.1) 5(3.4) 1(5.0) 0(0.0) Diarrhea 2(1.4) 3(2.1) 0(0.0) 1(5.0) Dizziness 0(0.0) 1(0.7) 0(0.0) 0(0.0) Fatigue 2(1.4) 1(0.7) 1(5.0) 1(5.0) erythra 1(0.7) 0(0.0%) 0(0.0) 0(0.0) parageusia 1(0.7) 0(0.0%) 0(0.0) 0(0.0)

Table 4: Multiple logistic regression analysis on the major risk factors for eradication failure in the initially treated patients

Ilaprazole group Esomeprazole group Groups Eradication rate Eradication rate Relative risk 95% CI** p value Relativerisk 95% CI** p value n (%) n (%)

Gender 0.65 0.42 Male 51(92.7) 0.75 0.21-2.61 59(90.8) 0.64 0.22-1.87 Female 76(90.5) 1.34 0.38-4.69 63(86.3) 1.56 0.53-4.56 Age 0.27 0.53

<50 years old 63(88.7) 2.03 0.58-7.09 51(86.4) 1.39 0.49-3.95

≥50 years old 64(94.1) 0.49 0.14-1.72 71(89.9) 0.72 0.25-2.04

Smoking Current smoker 12(85.7) 1.89 0.37-9.78 0.45 11(91.7) 0.58 0.07-4.83 0.61

Ex-smoker 13(92.9) 0.87 0.10-7.45 0.90 22(95.7) 0.29 0.04-2.32 0.24

Never smoker 102(91.9) 1.00 0.73 89(86.4) 1.00 0.46 Alcohol Heavy drinker 3(75.0) 3.48 0.33-37.03 0.30 2(66.7) 4.85 0.40-18.33 0.21 Social drinker 30(93.8) 0.70 0.14-3.40 0.66 23(82.1) 2.11 0.66-6.77 0.21 Nonacohol drinker 94(91.3) 1.00 0.50 97(90.7) 1.00 0.26 CHD 0.62 0.99 Yes 17(94.4) 0.59 0.07-4.85 23(88.5) 0.99 0.26-3.77 No 110(90.9) 1.70 0.21-14.02 99(88.4) 1.01 0.27-3.83 HTN 0.37 0.81 Yes 11(84.6) 2.11 0.41-10.87 18(90.0) 0.83 0.17-3.94 No 116(92.1) 0.47 0.09-2.44 104(88.1) 1.21 0.25-5.79 DM 0.38 0.82 Yes 4(80.0) 2.80 0.29-27.23 6(85.7) 1.29 0.15-11.45 No 123(91.8) 0.36 0.04-3.49 116(88.5) 0.78 0.09-6.89 DOB value 0.00* 0.00* <1000 117(94.4) 0.12 0.03-0.45 117(92.1) 0.07 0.02-0.28 ≥1000 10(66.7) 8.36 2.24-31.19 5(45.5) 14.04 3.64-54.22 Chronic gastritis 0.04* 0.00* Atrophic gastritis 36(83.7) 3.54 1.05-11.88 42(77.8) 5.71 1.74-18.81 Non-atrophic 91(94.8) 0.28 0.08-0.95 80(95.2) 0.18 0.05-0.58 gastritis

*P<0.05, **confidence interval.

% for patients with retreatment which are a high rates according to Chemically, all the available PPIs are composed of a benzimid- published studies. Furthermore, treatment-related side effects were azole ring and a pyridine ring, but vary in the specific side ring infrequent and mild and did not require hospitalization. substitution. The chemical structural formulas of ilaprazole and Pharmazie 74 (2019) 435 ORIGINAL ARTICLES

cline, and plays a significant role in the eradication therapy of H. pylori infection. A pooled-data analysis in Italy suggested that the incidence of adverse events in the eradication regimen containing furazolidone was common (about 30 %)(Zullo et al. 2012), however , the incidence of adverse events of furazolidone-con- taining regimen is not elevated compared to clarithromycin- and amoxicillin-based quadruple therapy in our study that are consis- tent with recent studies (Xie et al. 2018; Zhang et al. 2018). Minocycline, a derivative of tetracycline, which can bind to the 30S subunit of the bacterial ribosome to block protein synthesis, Fig. 3: 2D strueture of ilaprazole. has a very broad antimicrobial spectrum. Minocycline can be used for eradication of H. pylori because of its close to 100 % oral absorption rate, strong tissue penetration, wide distribution and longer half-life compared with tetracycline. The exact metabolic pathway of minocycline has not been thoroughly studied so far, so we have no way to know whether it affects the metabolism of ilaprazole. A prospective study conducted on minocycline-based triple therapy against H. pylori showed good efficacy and safety (Murakami et al. 2006). Esomeprazole, the S-isomer of , can improve the pharmacokinetic and pharmacodynamic characteristics. Further- more, esomeprazole is primarily metabolized via CYP2C19 and Fig. 4: 2D strueture of esomeprazole. has minimal first-pass metabolism and lower intrinsic clearance (Johnson and Hedge 2002). According to the above, compared with omeprazole (a racemic mixture of S- and R- optical isomers), the esomeprazole are shown in Figs. 3 and 4. The chemical structures pharmacokinetic characteristics of esomeprazole are transformed and mechanism of action to inhibit gastric acid secretion are into a more significant acid inhibition (Lind et al. 2000). Esome- essentially the same in all PPIs. They quickly pass through the prazole has limited potential to interact with other drugs which is activated membrane of parietal cell and specifically and selectively similar to omeprazole (Johnson and Hedge 2002). In the initial accumulate in the strongly acidic secretory canaliculus where PPIs treatment of H. pylori, a study of drug interactions with esomepra- undergo an acid-catalyzed conversion to the thiophilic sulfon- zole has shown that regardless whether the dosage of esomeprazole amides (Kromer 2001; Stedman and Barclay 2000). This reactive was 40 mg once daily or 20 mg twice daily, esomeprazole had no species interacts with the outer surface of the H+,K+-ATPase and impact on the pharmacokinetics of amoxicillin (Andersson et al. forms a disulfide bond with one or more key cysteines located in 2001). However, the pharmacokinetics of one of the metabolites of the α-subunit of the enzyme. This covalent binding inactivates the clarithromycin were altered (Rodrigues et al. 1997), but the further H+,K+-ATPase and leads to a specific and persistent impairment of metabolic steps have not been fully explored. Meanwhile, clari- gastric acid secretion. The formation of disulfide bond is irrevers- thromycin had almost no effect on the metabolic rate of esome- ible, and the activity of the proton pump cannot be restored before prazole probably due to the fact that esomeprazole has an affinity new H+,K+-ATPases are formed and inserted into the membrane of for CYP2C19 about three times higher than CYP3A4 (Andersson parietal cells (Scarpignato et al. 2006). et al. 2001). In rescue therapies, unfortunately, there were also no Ilaprazole is the latest PPI with the longest half-life and shows studies on drug interactions between esomeprazole, furazolidone a strong, stable, long-lasting suppression of gastric acid secre- and minocycline. But in our esomeprazole-based quadruple rescue tion (Du et al. 2012). Unlike other PPIs, such as omeprazole, therapies, both furazolidone and minocycline showed good effi- and esomeprazole, ilaprazole is rarely metabolized cacy and safety. by CYP2C19 and was not affected by CYP2C19 polymor- In our study, both in initial therapies and rescue therapies, we phisms (Seo et al. 2012). Ilaprazole has two metabolic pathways routinely added bismuth in eradication regimens because there is including a non-enzymatic pathway and a CYP3A4-mediated no resistance against the substance which is safe to use (Ford et al. enzymatic pathway (Cao et al. 2012; Li et al. 2008; Zhou et al. 2008). Bismuth, in addition to forming a protective membrane in 2009). A randomized, open-label, one-way crossover, two parallel the stomach and stimulating the epithelial cells of the gastrointes- sequences study showed that ilaprazole did not significantly tinal mucosa to secrete mucus which is conducive to the self-repair affect the exposure of clarithromycin (Jin et al. 2018) in the initial of epithelial cells, can also interact with gastric acid and form therapy of H. pylori infection. Meanwhile, some findings suggest bismuth oxychloride, an amorphous precipitate, which is a highly that PPIs may increase the bioavailability of amoxicillin in triple active antimicrobial substance with poor solubility. The major therapy, but no significant changes in amoxicillin exposure have effect of bismuth is to increase the eradication rate by additional been reported in the drug interaction studies between amoxicillin 30-40 % against drug-resistant strains (Dore et al. 2016). Therefore, and PPIs (Gustavson et al. 1995; Hassan-Alin et al. 2006). An unless there are contraindications of bismuth or in a region known additional report (Cao et al. 2012) indicated that the metabolism to be low-resistance, a bismuth-containing quadruple regimen of ilaprazole might be slightly affected by clarithromycin which is should be applied to the empirical eradication of H. pylori as far metabolized by CYP3A4, but those findings were not statistically as possible. As for the treatment course of our trial, all subjects significant because a non-enzymatic pathway plays a considerable enrolled received a 14-day eradication regimen. Seven empirical role in the metabolism of ilaprazole. regimens recommended by the Fifth Chinese National Consensus In rescue therapies, we innovatively chose a furazolidone- and Report all based on a 14-day course have achieved more than 90 % minocycline-based regimen and achieved good results. Unfortu- H. pylori eradication rates (Liu et al. 2018). Therefore, whether it nately, there were no studies on drug interactions between ilapra- is initial therapy or rescue therapy, extending the course to 14 days zole, furazolidone and minocycline. Furazolidone, a synthetic should be a suitable choice. nitrofuran antibiotic, which acts as a bacteriostatic action by inhib- Some recent reports on the initial therapies of H. pylori infection iting the oxidoreductase system in bacteria, is widely used as an revealed that, in addition to pharmacokinetic factors, other factors antibiotic for the treatment of enteric infections globally probably affecting the eradication rate of H. pylori consist of demographic because it is absorbed orally by only 5 %, but maintains a high factors, bacterial factors, and type of chronic gastritis (Fischbach concentration in the intestine. We can conclude that furazolidone and Evans 2007; Kang et al. 2012; Morgan et al. 2013; Namiot et has almost no effect on the metabolism of ilaprazole and minocy- al. 2008; Pan et al. 2016; van Doorn et al. 2000; Yuan et al. 2013). 436 Pharmazie 74 (2019) ORIGINAL ARTICLES

In the current study, we detected that demographic factors such as breath test (UBT) with a sensitivity of 88-95 % and specificity of 95-100 % to detect the age, gender, alcohol, smoking, CHD, HTN and DM did not affect presence of H. pylori (Howden and Hunt 1998). Patients who met any of the following criteria were excluded from the study: [1] age under 16 or over 70 years; [2] pregnancy the eradication rate both in the ilaprazole group and the esomepra- or lactation; [3] serious systemic disease; [4] history of gastrointestinal malignancy or zole group. In addition, there was a report claiming that in patients surgery; [5] received antibiotic and/or PPI treatment(s) within 2 weeks before study with poor metabolizer (PM) genotype whose metabolism of PPIs commencement; [6] allergy or hypersensitivity to the test drugs. At the beginning of was much slower, the bioavailability of PPIs was more than 20 the study, we used standard questionnaires to understand the history of past infection and eradication of H. pylori and basic characteristics of patients such as gender, age, times that of homozygous extensive metabolizers (HomEM) smoking, drinking, and basic diseases. All patients were recruited from the outpatients (Dickson and Stuart 2003). However, we did not conduct further of the Gastroenterology department in Jinan Central Hospital Affiliated to Shandong research in the current study. University from June to December 2018. All subjects agreed to take part in this clinical The bacterial factors that may lead to eradication failure mainly study and provided written informed consent. Among them, the minor obtained the consent of himself and his legal guardians. This study was approved by the Medical include high bacterial load, strain types and antibiotic resistance Ethics Committee of Jinan Central Hospital Affiliated to Shandong University. We (Kang et al. 2012; Morgan et al. 2013; Pan et al. 2016). There is guarantee that this clinical trial was carried out in accordance with The Code of Ethics a report claiming that DOB values measured by 13C-UBT might of the World Medical Association (Declaration of Helsinki). be significantly related to H. pylori bacterial load and grade of gastritis activity (Zagari et al. 2005). We detected that patients with 4.2. Study design higher DOB values had significantly lower eradication rates than The initially treated patients and patients with retreatment were randomly assigned patients with lower DOB values in our study. That means a high to the test groups at a 1:1 ratio using a simple randomized grouping method which bacterial load might reduce the efficacy of eradication therapy. is based on a randomized system provided by the Department of Biostatistics of the Other than this, the genotype of H. pylori is also closely related School of Public Health, Nanjing Medical University. The specific grouping and erad- ication regimens are shown in Fig. 5. In all eradication regimens, PPIs and bismuth to the eradication efficacy. The main virulence factors of H. pylori were taken before meals and two antibiotics were taken after meals. Each subject was include vacuolating toxin A (VacA) and cytotoxin associated gene required to disinfect their tableware daily after the start of the medication to avoid A protein (CagA). The VacA gene exists in all H. pylori strains re-infection. which has 6 recombinants, s1a /m1, s1a /m2, s1b /m1, s1b /m2, s2 /m2 and s2 /m1 (Brennan et al. 2018). CagA encoding proteins that enhance the pathogenicity of H. pylori exist only in some strains. In the area of this study, patients who infected with H. pylori VacA s1m2 CagA+ strain has a higher proportion. Therefore, we no longer tested the genotype of H. pylori in each subject. The patients included in this study were not submitted to bacterial culture and drug sensitivity test which are time-consuming, expensive, and are rarely performed in most developing countries. Therefore, we could not demonstrate the effect of drug resistance on eradication efficacy by our results. In this prospective study, we detected that the initially treated patients with atrophic gastritis had a significantly lower eradica- tion rate than patients with non-atrophic gastritis. This discovery is consistent with a retrospective study that showed the incidence of gastric atrophy and intestinal metaplasia were significantly higher in patients with eradication failure (Kalkan et al. 2016). Gastric atrophy means loss of glandular structure and a reduction of gastric secretion, which is the result of a chronic inflammatory process. Fig. 5: Flow chart of patients assignment and study methodology. It has been documented that H. pylori gradually evolved into gastric adenocarcinoma through multiple steps such as promoting active inflammation, chronic gastritis, gastric atrophy, intestinal 4.3. Effi cacy, safety and compliance evaluation metaplasia and dysplasia (de Vries et al. 2008). The Kyoto global During the study, we regularly contacted the subjects to record medication and side consensus report held that eradication of H. pylori could achieve effects. Subjects who took drugs that affected the efficacy and safety of the test drugs, the maximum benefit before the harm of H. pylori to gastric mucosa whose medication compliance was below 85 %, and who had critical side effects that required hospitalization were excluded from PP analysis. Eradication assessment progressed to atrophy (Sugano et al. 2015). However, currently, using 13C-UBT was performed at least four weeks after the completion of eradication there are few studies on the relationship of the presence and the therapy. grade of gastric atrophy and the eradication rate of H. pylori, so the exact mechanism for this result cannot be explained. We did not explore the risk factors for eradication failure in 4.4. Statistical analysis patients with retreatment, which is one of limitations in our study. Statistical analyses were performed with the SPSS 19.0. Categorical variables were compared using the χ2 test or Fisher’s exact test, and continuous variables were A prospective trial exploring predictors of failed eradication in compared using Student’s t-test. Categorical variables were provided as number furazolidone- and amoxicillin-based quadruple therapy demon- (percentage) while values for continuous variables were provided as mean±standard strated that in addition to the above risk factors, prior treatment deviation. Multiple logistic regression analysis was used to determine major risk failures itself may lead to the failure of retreatment (Zhang et al. factors for eradication failure, and 95 % confidence intervals (CIs) were provided. Values of p <0.05 was considered statistically significant. 2018). Apart from this, Labenz (2001) postulated that during the long-term application of PPIs, the distribution of H. pylori infec- Conflict of interest: None declared. tion may change, so that the density of H. pylori in the antrum decreased while the infection in the corpus and fundus persisted. 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