Second- and Third-Line Therapies for Helicobacter pylori Eradication in Slovenia: Data From 2013-2023 of the European Registry on H. pylori Management.

Complete eradication of Helicobacter pylori is important for preventing the development of gastric cancer. The outcome of H. pylori eradication therapy is mainly dependent on bacterial susceptibility to antimicrobial agents and potent neutralization of intragastric pH across 24 h, especially when using acid-sensitive antimicrobial agents such as clarithromycin (CLR), amoxicillin and sitafloxacin. However, conventional regimens comprising twice-daily doses (bid) of proton pump inhibitors (PPIs) are generally insufficient for maintaining the required gastric acid secretion for 24 h for successful eradication in all H. pylori-positive patients. Further, the increasing prevalence of CLR-resistant strains with each year has led to a decrease in eradication rates of first-line PPI- and CLR-containing therapies in developed countries, including Japan. In 2015, the potassium-competitive acid blocker vonoprazan (VPZ) became clinically available in Japan. VPZ competitively inhibits H+/K+-ATPase activity more potently than PPIs (e.g., omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole). Therefore, a VPZ-containing H. pylori eradication regimen is expected to increase the eradication rate compared with conventional regimens containing a standard dose of PPI. In fact, a recent meta-analysis that investigated the efficacy of first-line eradication therapy showed that a VPZ-containing regimen achieved a higher eradication rate than a PPI-containing regimen. While the Maastricht V/Florence Consensus Report recommends selecting a bismuth or non-bismuth quadruple therapy and concomitant therapy for patients living in areas with high prevalence of CLR resistance, a VPZ-containing regimen demonstrates effectiveness for patients infected with CLR-resistant strains and patients living in areas where the prevalence of CLR-resistant strains is >15%. As a next step, studies are needed to determine the factors affecting the clinical outcome of VPZ-containing therapy and optimal VPZ-containing alternative regimens for tailored treatments. In this review, we summarize the advantages and disadvantages of VPZ in H. pylori eradication therapy.

Optimal clinical management of Helicobacter pylori (H. pylori) infection remains challenging considering its growing antimicrobial resistance. Tailored therapy might enhance treatment success. The aim of this study was to analyse the effectiveness of PCR-guided therapy in H. pylori eradication, both as first-line and rescue therapy. Data were obtained from the prospective, European multicentre Registry on H. pylori Management (Hp-EuReg). Adult PCR-tested (stool and gastric samples) H. pylori-infected patients registered at AEG-REDCap e-CRF were analysed. Effectiveness was evaluated by per protocol (PP) analysis. In total, 265 patients were included (130 treatment-naïve and 135 previously treated), 77% underwent gastric PCR-testing. In the first-line, 52% received 14-day prescriptions, and 31% high-dose proton pump inhibitors (PPIs). In the rescue-line, 55% were prescribed 14-day treatment, and 61% high-dose PPIs. Clarithromycin and fluoroquinolone resistance rates in the first-line were 31% and 33%, and 62% and 53% in the rescue-line, respectively. The overall effectiveness of PCR-guided therapy was 90% (95% first-line and 86% rescue-line). Most frequent first-line regimens were: quadruple concomitant therapy with clarithromycin+amoxicillin+metronidazole (48%), bismuth quadruple therapy as single-capsule containing bismuth+tetracycline+metronidazole (30%) and triple therapy with PPI+clarithromycin+amoxicillin (5.4%), providing an effectiveness of 95%, 97% and 100%, respectively. In the rescue-line, most frequent regimens were: single-capsule bismuth quadruple (43%), PPI-clarithromycin+amoxicillin+metronidazole (27%) and PPI-amoxicillin+moxifloxacin (11%), achieving 87%, 94% and 93% effectiveness, respectively. Adverse event incidence was 15%. PCR-guided therapy showed optimal results in all therapy lines. In regions with high (>15%) clarithromycin resistance, clarithromycin-based first-line therapy could still represent a good option provided pretreatment antibiotic sensitivity is assessed.

BackgroundManagement of Helicobacter pylori (H. pylori) infection requires co‐treatment with proton pump inhibitors (PPIs) and the use of antibiotics to achieve successful eradication.AimTo evaluate the role of dosage of PPIs and the duration of therapy in the effectiveness of H. pylori eradication treatments based on the ‘European Registry on Helicobacter pylori management’ (Hp‐EuReg).MethodsHp‐EuReg is a multicentre, prospective, non‐interventionist, international registry on the routine clinical practice of H. pylori management by European gastroenterologists. All infected adult patients were systematically registered from 2013 to 2022.ResultsOverall, 36,579 patients from five countries with more than 1000 patients were analysed. Optimal (≥90%) first‐line‐modified intention‐to‐treat effectiveness was achieved with the following treatments: (1) 14‐day therapies with clarithromycin‐amoxicillin‐bismuth and metronidazole‐tetracycline‐bismuth, both independently of the PPI dose prescribed; (2) All 10‐day (except 10‐day standard triple therapy) and 14‐day therapies with high‐dose PPIs; and (3) 10‐day quadruple therapies with clarithromycin‐amoxicillin‐bismuth, metronidazole‐tetracycline‐bismuth, and clarithromycin‐amoxicillin‐metronidazole (sequential), all with standard‐dose PPIs. In first‐line treatment, optimal effectiveness was obtained with high‐dose PPIs in all 14‐day treatments, in 10‐ and 14‐day bismuth quadruple therapies and in 10‐day sequential with standard‐dose PPIs. Optimal second‐line effectiveness was achieved with (1) metronidazole‐tetracycline‐bismuth quadruple therapy for 14‐ and 10 days with standard and high‐dose PPIs, respectively; and (2) levofloxacin‐amoxicillin triple therapy for 14 days with high‐dose PPIs. None of the 7‐day therapies in both treatment lines achieved optimal effectiveness.ConclusionsWe recommend, in first‐line treatment, the use of high‐dose PPIs in 14‐day triple therapy and in 10‐or 14‐day quadruple concomitant therapy in first‐line treatment, while standard‐dose PPIs would be sufficient in 10‐day bismuth quadruple therapies. On the other hand, in second‐line treatment, high‐dose PPIs would be more beneficial in 14‐day triple therapy with levofloxacin and amoxicillin or in 10‐day bismuth quadruple therapy either as a three‐in‐one single capsule or in the traditional scheme.

How We Approach Difficult to Eradicate Helicobacter pylori

Different bismuth quadruple therapies containing proton-pump inhibitors, bismuth salts, metronidazole, and a tetracycline have been recommended as third-line Helicobacter pylori eradication treatment after failure with clarithromycin and levofloxacin. To evaluate the efficacy and safety of third-line treatments with bismuth, metronidazole, and either tetracycline or doxycycline. Sub-study with Spanish data of the "European Registry on Hpylori Management" (Hp-EuReg), international multicenter prospective non-interventional Registry of the routine clinical practice of gastroenterologists. After previous failure with clarithromycin- and levofloxacin-containing therapies, patients receiving a third-line regimen with 10/14-day bismuth salts, metronidazole, and either tetracycline (BQT-Tet) or doxycycline (BQT-Dox), or single capsule (BQT-three-in-one) were included. Data were registered at AEG-REDCap database. Univariate and multivariate analyses were performed. Four-hundred and fifty-four patients have been treated so far: 85 with BQT-Tet, 94 with BQT-Dox, and 275 with BQT-three-in-one. Average age was 53years, 68% were women. Overall modified intention-to-treat and per-protocol eradication rates were 81% (BQT-Dox: 65%, BQT-Tet: 76%, BQT-three-in-one: 88%) and 82% (BQT-Dox: 66%, BQT-Tet: 77%, BQT-three-in-one: 88%), respectively. By logistic regression, higher eradication rates were associated with compliance (OR=2.96; 95% CI=1.01-8.84) and no prior metronidazole use (OR=1.96; 95% CI=1.15-3.33); BQT-three-in-one was superior to BQT-Dox (OR=4.46; 95% CI=2.51-8.27), and BQT-Tet was marginally superior to BQT-Dox (OR=1.67; 95% CI=0.85-3.29). Third-line Hpylori eradication with bismuth quadruple treatment (after failure with clarithromycin and levofloxacin) offers acceptable efficacy and safety. Highest efficacy was found in compliant patients and those taking 10-day BQT-three-in-one or 14-day BQT-Tet. Doxycycline seems to be less effective and therefore should not be recommended.

Molecular-based Helicobacter pylori Susceptibility Testing Is Almost Ready for Prime Time

Summary: Background and Aim: Helicobacter pylori (H. pylori) infection remains a significant public health concern worldwide, including in the Czech Republic. The study aims to provide an overview of the current first-line treatment approaches for H. pylori infection in the Czech Republic based on data from the European Registry on H. pylori Management (Hp-EuReg), and to evaluate the most effective treatment regimens. Methods: Hp--EuReg is an international multicentric registry on the management of H. pylori, from which we extracted data from the Czech Republic from 2019 to January 2024. This registry collects demographic information, diagnostic procedures, treatment prescriptions, and outcomes for H. pylori infection management by gastroenterologists. A modified intention-to-treat (mITT) analysis was performed to evaluate the effectiveness of the treatments. Results: A total of 546 patients from 14 centres in the Czech Republic who receive first-line treatment were analysed. Low-dose (i.e.; 20 mg omeprazole equivalent twice daily) proton pump inhibitors (PPIs) were administered in 89% of patients, and the most common length of treatments was 14 days (40%). The overall mITT effectiveness of first-line treatment was 85%, obtaining 86% when prescriptions were combined either with low-dose (20 mg omeprazole equivalent twice daily), and high dose (80 mg omeprazole equivalent twice daily) PPIs, and 82.5% with standard-dose (40 mg omeprazole equivalent twice daily) PPIs. The effectiveness of 7-day prescriptions was reported to be 83%, lower than that of 10- and 14-day, both of which achieved effectiveness of 86%. The most frequently used treatment scheme was triple therapy with PPI, amoxicillin and clarithromycin, which was used in 67% of patients, reaching 87% effectiveness both with 7- and 14-day prescriptions. Optimal (>90% mITT) effectiveness was obtained with both 10-day, sequential therapy and with 14-day non-bismuth quadruple concomitant therapy including both PPI, amoxicillin, clarithromycin and metronidazole, providing 96% (48/50 patients) and 97% (34/35 patients) cure rates, respectively. The remaining therapies provided all an effectiveness lower than 90%, the lowest one obtained with PPI, clarithromycin and metronidazole (66%; 35/53 patients). Conclusions: In the Czech Republic, the first-line empirical treatment overall effectiveness was suboptimal (<90%); however, 10-day non-bismuth quadruple sequential and 14-day concomitant therapies, both composed of PPI, amoxicillin, clarithromycin and metronidazole, achieved over 90% cure rates. Key-words: Helicobacter pylori – first-line treatment – proton pump inhibitors – Czech Republic

Introduction:Helicobacter pylori (H. pylori) associated gastritis has been approved and covered by National Health Insurance as an additional indication for H. pylori eradication in Japan on February 2013. So, it has been an increase of cases of H. pylori eradication. However, H. pylori eradication therapy in patients with penicillin-allergy is uninsured and there has been few study reported. Vonoprazan (VPZ) is a new class of acid suppressants, referred to as a potassium-competitive acid blocker (P-CAB) that has been available in the market in our country since February 2015. Because the acid-inhibitory effect of VPZ is much more potent than that of proton pump inhibitor (PPI), it is expected to have comparable efficacy to PPI in H. pylori eradication therapy. The aim of this study was to evaluate H. pylori eradication therapy compared with a PPI, metronidazole (MNZ), and clarithromycin (CAM) [PPI/MNZ/CAM] and a PPI (or VPZ), MNZ, and sitafloxacin (STFX) [PPI(orVPZ)/MNZ/STFX] in patients with penicillin-allergy. Methods: The subjects were 55 penicillin-allergic patiens with H. pylori infection. Eradication regimen was used a PPI (bid) + MNZ 500mg (bid) + CAM 400-800mg (bid) PPI/MNZ/CAM for 7 days, or a PPI (or VPZ40mg) (bid) + MNZ 500mg (bid) + STFX 200mg (bid) PPI(orVPZ)/MNZ/STFX for 7 days. H. pylori eradication was confirmed with 13C-urea breath test. Results: The eradication rate of PPI/MNZ/CAM regimen was 57.1% (20/35). And, the eradication rates of PPI/MNZ/STFX regimen and VPZ/MNZ/STFX regimen were 80.0% (8/10) and 100% (10/10), respectively. Total eradication rate of PPI/MNZ/STFX regimen and VPZ/MNZ/STFX regimen was 90.0% (18/20). The eradication rate of PPI(orVPZ)/MNZ/STFX regimen was significantly higher than PPI/MNZ/CAM regimen (p < 0.05). No patients discontinued H. pylori eradication therapy because of adverse events. Conclusion: It was thought that PPI(orVPZ)/MNZ/STFX regimen, especially VPZ/MNZ/STFX regimen would be useful as H. pylori eradication therapy in patients with penicillin-allergy.

The efficacy of Helicobacter pylori (H. pylori) eradication therapies encompassing one or more antibiotics and a proton pump inhibitor (PPI) has lately decreased. Vonoprazan (VPZ), a potassium-competitive acid blocker, provides higher gastric acid suppression than PPIs. We performed a meta-analysis evaluating the efficacy and safety of VPZ in H. pylori eradication therapies. Studies were searched in PubMed, Embase, and the Cochrane Library up to June 2023. Efficacy was evaluated by intention-to-treat analysis. Data were combined by meta-analyzing risk differences (RD). Heterogeneity was evaluated by subgrouping. Seventy-seven studies (24 randomized clinical trials) evaluated 44,162 patients (22,297 receiving VPZ and 21,865 PPIs). Overall VPZ efficacy was 88% (95% CI = 87%-90%): 86%, 88%, and 94% for dual/triple/quadruple-VPZ-containing therapies. VPZ efficacy was 87% (86%-89%) in first-line and 90% (87%-93%) in rescue therapy. VPZ performed better than PPIs in treatment-naïve patients (87% vs. 70%; RD = 0.13, 95% CI = 0.11-0.15) and when using triple regimens. No significant differences were observed in rescue and quadruple therapies. In patients with clarithromycin-resistant infection, VPZ-based therapies demonstrated an 81% efficacy (76%-85%), surpassing PPIs (76% vs. 40%; RD = 0.33, 95% CI = 0.24-0.43). For clarithromycin-susceptible strains, VPZ efficacy was 92% (89%-95%), similar to PPIs. VPZ adverse events rate was 19% (16%-21%), comparable to PPI-based regimens (18% vs. 13%, respectively; RD = 0.00, 95% CI = -0.01 to 0.02, p = 0.57). The efficacy of VPZ-based regimens was over 85% in all treatment combinations. In treatment-naïve and clarithromycin-resistant patients, VPZ performed better than PPIs. In rescue therapy, in clarithromycin-susceptible patients or when quadruple regimens were prescribed, this advantage was not confirmed. Tolerability was similar in both regimens.

Helicobacter pylori (HP) eradication therapy is a useful treatment for idiopathic thrombocytopenic purpura (ITP). Some investigators have also reported the effects of proton pump inhibitor (PPI) monotherapy on ITP. We performed a randomized study of HP eradication therapy and PPI monotherapy on ITP. Four of nine patients achieved complete remission (CR), two of nine achieved partial remission (PR) in HP eradication therapy, three of eight achieved CR, and two of eight achieved PR in PPI monotherapy. No significant differences were observed in the CR + PR of these patients between HP eradication therapy and PPI monotherapy. As for cost comparisons, HP eradication therapy is cheaper than PPI monotherapy, but it is less effective.

Comparative Efficacy and Safety of Potassium-Competitive Acid Blocker– and Proton Pump Inhibitor–Based Bismuth Quadruple Therapy for Helicobacter pylori Eradication: A Network Meta-Analysis

To evaluate whether eradication therapy is more effective in peptic ulcer disease (PUD) than in non-ulcer dyspepsia (NUD). We retrospectively studied 481 patients with NUD (183 patients) or PUD (298 patients) infected with Helicobacter pylori included in several prospective clinical trials. Three eradication regimens were given: (1) proton pump inhibitor (PPI) plus clarithromycin, plus either amoxycillin or metronidazole for 7 days (297 patients); (2) ranitidine bismuth citrate (RBC) plus clarithromycin plus amoxycillin for 7 days (79 patients); and (3) RBC plus clarithromycin plus amoxycillin plus metronidazole for 5 days (105 patients). H. pylori eradication was defined as a negative 13C-urea breath test 4 weeks after completing treatment. H. pylori eradication rates were 82% (95% CI 78-87%) with PPI plus two antibiotics for 7 days, 85% (95% CI 75-91%) with RBC plus two antibiotics for 7 days, and 91% (95% CI 86-97%) with RBC plus three antibiotics for 5 days (P < 0.05 compared with the first regimen). Overall, the H. pylori eradication rate in patients with NUD was 78% (95% CI 71-84%), while in patients with PUD it was 89% (95% CI 86-93%) (P < 0.001). Both the combination of PPI plus two antibiotics for 7 days and the combination of RBC plus three antibiotics for 5 days were more effective in PUD than in NUD patients. However, RBC plus clarithromycin plus amoxycillin for 7 days was equally effective in both diseases. RBC plus two antibiotics for 7 days achieved better results than the same therapy with PPI only in NUD patients (84% v. 59%, P < 0.01), but both regimens were similar when prescribed in PUD patients (86% v. 88%). In the multivariate analysis, the type of therapy, the diagnosis (NUD v. PUD), and the product variable of therapy (with RBC plus 2 antibiotics for 7 days) and diagnosis (interaction variable) were the only variables that influenced H. pylori eradication. The odds ratio (OR) for the effect of RBC versus PPI plus two antibiotics for 7 days in patients with NUD was 4 (95% CI 1.7-9.7; P < 0.01), whereas in patients with PUD no statistical significance was achieved (OR 0.79; 95% CI 0.2-3.9). Overall, H. pylori eradication therapy is more effective in PUD than in NUD patients. This advantage of eradication therapies in PUD patients seems to be observed with 7-day PPI-based triple regimens, and with 5-day RBC-based quadruple therapy, while the 7-day RBC-based triple regimen seems to be equally effective in both diseases.

Bismuth-based quadruple therapy (BQT) is recommended as the first-line empirical therapy for Helicobacter pylori eradication as it is not associated with resistance. However, few studies have investigated the use of potassium-competitive acid blockers for BQT. To investigate the efficacy and safety profiles of tegoprazan-based BQT (TBMT) versus lansoprazole-based BQT (LBMT) for H. pylori eradication. We included patients older than 18 with an H. pylori infection without a history of H. pylori eradication who visited four university-affiliated hospitals between March 2020 and December 2021. H. pylori infection was diagnosed using a rapid urease test or Giemsa staining. Patients were randomly assigned to the TBMT or LBMT group. 217 subjects were randomly allocated to receive either TBMT (n = 108) or LBMT (n = 109) therapy. Intention-to-treat (ITT) eradication rates of TBMT and LBMT were 80.0% and 77.4% (95% confidence interval [CI]: -8.4 to 13.7, p = 0.0124), respectively. Corresponding modified ITT rates were 90.3% and 84.5% (95% CI: -3.6 to 15.2, p = 0.0005), respectively. Per-protocol (PP) eradication rates of TBMT and LBMT were 90.2% and 82.4% (95% CI: -2.5 to 18.2, p = 0.0003), respectively. There was no significant difference in the rate of adverse events between the TBMT and LBMT groups (39.1% vs. 43.4%, p = 0.5211). TBMT showed higher eradication rates than that of LBMT in ITT, m-ITT, and PP analysis. TBMT showed a noninferior eradication rate and similar adverse events to LBMT as a first-line eradication regimen. Our results suggest that tegoprazan might be substituted for proton pump inhibitors in H. pylori eradication regimens.

Helicobacter pylori (HP) eradication therapy is a useful treatment for idiopathic thrombocytopenic purpura (ITP). Some investigators have also reported the effects of proton pump inhibitor (PPI) monotherapy on ITP. We performed a randomized study of HP eradication therapy and PPI monotherapy on ITP. Four of nine patients achieved complete remission (CR), two of nine achieved partial remission (PR) in HP eradication therapy, three of eight achieved CR, and two of eight achieved PR in PPI monotherapy. No significant differences were observed in the CR + PR of these patients between HP eradication therapy and PPI monotherapy. As for cost comparisons, HP eradication therapy is cheaper than PPI monotherapy, but it is less effective.

Potassium-Competitive Acid Blockers (P-CABs) have been used in Helicobacter pylori (H. pylori) eradication therapies in recent years. However, the efficacy and safety of P-CABs compared to Proton-Pump Inhibitors (PPIs) in this setting remain controversial. The efficacy and safety of P-CABs and PPIs for H. pylori eradication were compared in a meta-analysis based on a systematic literature search of major electronic databases for relevant Randomized Controlled Trials (RCTs). Seven studies and 1,168patients were included. The pooled eradication rate determined by Intention-To-Treat (ITT) analysis was90.2% for P-CAB-based and 75.5% for PPI-based triple therapy (pooled RR [95%CI]=1.17[1.08-1.28], p < 0.001). The Per-Protocol (PP) analysis also demonstrated significant superiority of P-CABs (pooled eradication rate=92.4%vs.77.8%; pooled RR [95%CI]=1.14[1.03-1.26], p < 0.01). In a subgroup evaluation, P-CABs were significantly better than PPIs as a first-line eradication therapy, in both the ITT analysis (pooled eradication rate=91.8%vs.76.4%; pooled RR [95%CI]=1.18 [1.10-1.28], p < 0.0001) and the PP analysis (pooled eradication rate=93.0%vs.78.6%; pooled RR [95%CI]=1.13[1.02-1.26], p < 0.05). However, P-CABs were not superior to PPIs when administered as salvage therapy, as determined in the ITT (75.0%vs.66.0%, pooled RR [95%CI]=1.11[0.69-1.78], p=0.66) and PP (85.7%vs.70.0%, pooled RR [95%CI]=1.20[0.82-1.75], p=0.34) analyses. In a subgroup analysis limited to Japanese patients, both the ITT analysis (pooled eradication rate=89.6%vs.73.9%; RR [95%CI]=1.21[1.14-1.29], p < 0.01) and the PP analysis (pooled eradication rate=92.0%vs.75.7%; RR[95%CI]=1.18[1.06-1.32], p < 0.01) showed that P-CABs were significantly superior compared to PPIs as triple eradication therapy. However, in the subgroup analysis of patients from other countries, there was no significant difference in either the ITT analysis (pooled eradication rate=93.8%vs.85.2%; RR[95%CI]=1.10[0.99-1.22], p=0.07) or PP analysis (pooled eradication rate=95.0%vs.90.8%; RR[95%CI]=1.05[0.98-1.14], p=0.17). The incidence of adverse events associated with the two regimens did not significantly differ (P-CABsvs.PPIs: 33.6%vs.40.0%; RR [95%CI]=0.84 [0.71‒1.00], p=0.05). The incidence of serious adverse events and dropout rate due to adverse events also did not differ (p=0.44 and p=0.67, respectively). The efficacy of P-CAB-based triple therapy is superior to that of PPI-based triple therapy as a first-line approach to H. pylori eradication, particularly in Japanese patients. As salvage therapy, the efficacy of the two treatments did not significantly differ. The tolerability of P-CAB-based and PPI-based triple therapy was comparable, as was the incidence of adverse events.