Is Tegoprazan-Based Triple Therapy Effective in Regions with High Rates of Clarithromycin Resistance?

Triple therapy (consisting of a proton pump inhibitor [PPI], clarithromycin, and amoxicillin) is the standard first-line regimen for eradicating Helicobacter pylori infection. However, standard triple therapy has an unsatisfactory eradication rate, largely as a result of the increasing rate of antibiotic resistance. In response to the declining effectiveness of the standard triple therapy, treatments with various drug combinations for different durations have been introduced to improve the H. pylori eradication rate. According to the 2020 guidelines of Korea, 7-day triple therapy is the recommended first-line regimen in cases negative for clarithromycin resistance, whereas 14-day triple therapy is recommended in cases in which clarithromycin resistance testing was not performed.¹

A potassium-competitive acid blocker (P-CAB)-based triple therapy has been suggested as an alternative to the standard triple therapy. P-CAB offers stronger and longer-lasting gastric-acid suppression compared to other PPIs. Stronger acid suppression is linked to successful eradication of H. pylori. Based on this, we hypothesized that P-CAB-based triple therapy would be superior to the standard treatment. Vonoprazan, a novel P-CAB approved in Japan, in combination with a triple-therapy regimen, reportedly achieves a higher eradication rate than PPI-based triple therapy.² The Japanese guidelines now recommend vonoprazan-based triple therapy as the first-line regimen.³

Tegoprazan, another P-CAB, has been introduced in Korea for the treatment of H. pylori infection. In this issue of Gut and Liver, Jung et al.⁴ report the first results of 14-day tegoprazan-based triple therapy compared to PPI-based triple therapy. They compared tegoprazan- and rabeprazole-based triple therapies in subjects diagnosed with H. pylori infection. The main finding of their retrospective study was that tegoprazan-based triple therapy showed a similar eradication rate and incidence of adverse events to rabeprazole-based triple therapy. The eradication rate of tegoprazan-based triple therapy was not significantly improved compared to rabeprazole-based triple therapy according to an intention-to-treat (ITT) analysis (76.7% vs 75.4%, p>0.999). In a per-protocol (PP) analysis, there was no significant difference in the eradication, adherence, and adverse-event rates between the tegoprazan and rabeprazole groups (p>0.999, p=0.443, and p=0.604, respectively).

To be suitable for the first-line treatment of H. pylori, a regimen should demonstrate an eradication rate of >85% in an ITT analysis and >90% in a PP analysis.⁵ P-CAB-based triple therapy was expected to achieve a higher eradication rate than PPI-based therapy because of its greater potency and longer-lasting antacid effect. Vonoprazan-based triple therapy is superior to PPI-based triple therapy as a first-line regimen, particularly against clarithromycin-resistant strains, although most of the supporting studies were performed in Japan.² Murakami et al.⁶ noted a significantly higher eradication rate with vonoprazan-based triple therapy (82%) compared to lansoprazole-based triple therapy (40%) in patients with clarithromycin-resistant H. pylori (p<0.0001).

In the work of this study, tegoprazan-based triple therapy did not achieve the target range in the ITT (76.7%) or PP (83.4%) analysis and did not show superior efficacy to PPI-based triple therapy. Choi et al.⁷ reported that tegoprazan-based triple therapy for 7 days did not have a superior eradication rate to tegoprazan. The eradication rate did not reach the target level (ITT analysis, 62.9%; PP analysis, 69.3%). The lower-than-anticipated eradication rate of tegoprazan may be explained by an insufficient tegoprazan dosage, differences in the minimum-inhibitory-concentration distribution among clarithromycin-resistant strains, pharmacological differences between vonoprazan and tegoprazan, and an insufficient treatment duration. The authors of this study postulated that use of a tegoprazan dosage of 50 mg twice daily explains the inadequate eradication rate.

This study found that diabetes was significantly associated with eradication failure. Horikawa et al.,⁸ in a meta-analysis, reported that the pooled risk ratio of H. pylori eradication failure for diabetic compared to nondiabetic patients was 2.19 (95% confidence interval, 1.65 to 2.90; p<0.01). In this study, diabetes patients accounted for 10.2% of tegoprazan group and 8.4% of rabeprazole group. Diabetic patients showed an odds ratio of 2.03 compared to nondiabetic patients (95% confidence interval, 1.05 to 3.95). This indicates a need to prolong the treatment duration or develop a new regimen for eradicating H. pylori in patients with diabetes.

Although this study did not find tegoprazan to have a sufficient H. pylori eradication rate, tegoprazan might be suitable for empirical treatment, particularly in regions with high rates of clarithromycin resistance. The study included patients, irrespective of clarithromycin resistance status, with H. pylori; in Korea, the clarithromycin resistance rate is >17%.¹ Current guidelines recommend routine antibiotic susceptibility testing, which is not always possible in practice.⁹ Tegoprazan was effective in patients for whom the result of resistance testing was not available, showing a similar eradication rate to conventional PPI-based triple therapy.

In conclusion, PPI-based triple therapy is the standard regimen for H. pylori eradication, but the increasing rate of antibiotic resistance necessitates a new approach. P-CAB was expected to have a high eradication rate based on its antacid effect but did not demonstrate efficacy sufficient to replace the standard triple-therapy regimen. Tegoprazan shows potential for empirical treatment in clinics, but further effort is needed to develop novel, more-effective therapies to eradicate H. pylori.