Comparison of vonoprazan dual therapy, quadruple therapy and standard quadruple therapy for Helicobacter pylori infection in Hainan: a single-center, open-label, non-inferiority, randomized controlled trial

Helicobacter pylori (Hp) is a pathogen that primarily resides in the stomach and infects nearly half of the world’s population [1]. In China, the prevalence of Hp infection is approximately 40% [2]. Most people with Hp infection may not display any obvious gastrointestinal symptoms, or may only show mild indigestion symptoms. However, most infected individuals will have varying degrees of chronic gastritis, and about 15–20% of infected individuals might also develop peptic ulcers and, whereas in more severe cases, gastric cancer or mucosa-associated lymphoid tissue lymphoma [3]. According to the 5th National Consensus Report on the Management of Hp Infection in China, Hp eradication therapy has been recommended even for asymptomatic infected patients [4]. Hp is classified as a class I carcinogen by World Health Organization’s International Agency for Research on Cancer [5] and its eradication can serve as an important strategy to reduce the risk of cancer [6]. In China, quadruple therapy (Proton pump inhibitors(PPI) + two kinds of antibiotics + one bismuth agent) is the standard HP eradication treatment regimen [4], which generally has an eradication rate of over 80%, but can exhibit severe shortcomings, such as increasing antibiotic resistance and substantially higher adverse effects [7]. In China, Hp resistance to antibiotics such as clarithromycin (CLR), metronidazole and levofloxacin is continuously increasing [8] and is considered as the main reason for the decline in Hp eradication rates [9].

Successful eradication of Hp is associated with suppression of stomach acid in addition to antibiotic sensitivity [10, 11]. Vonoprazan(VPZ) is a new potassium competitive acid blocker (P-CAB) with strong acid-suppressive effects, which was first approved in Japan in 2015 for the treatment of Hp infection, reflux esophagitis and a range of other gastrointestinal diseases [12]. VPZ specifically acts on wall cells to bind to its H+/K+ ATPase transporter protein ions, thereby rapidly preventing K+ ions from entering the proton pump and substantially blocking H+ ions secretion, thus, acting as an acid suppressor [13]. VPZ can potentially inhibit 100% of gastric acid for 1 week, the average intragastric pH value can be then maintained at around 6.8, which has a stronger and longer-lasting acid-suppressive effect [14]. Eradication regimens with VPZ as an acid-suppressing drug exhibited higher eradication rates than PPI eradication regimens [15‐17]. Therefore, this paper aimed to compare the efficacy and safety of VPZ’s dual therapy with VPZ’s quadruple therapy as well as standard PPI’s therapy for Hp infection eradication in Hainan province.

We found that 2 patients were lost to follow-up and 43 eventually completed treatment in Group V1. 2 were lost to follow-up, 2 were discontinued due to various intolerable adverse effects, and 41 eventually completed treatment in Group V2. 2 patients discontinued the therapy due to intolerable adverse effects and 43 eventually completed treatment in Group V3 (depicted in Fig. 1). Table 1 summarizes the demographic clinical characteristics of enrolled patients. There were no statistically significant differences observed in demographic characteristics between the three groups of patients on different treatment regimens.

According to the findings of the multiple non-inferiority test, the lower limit of the 95%CI for the difference in eradication rates between the two groups (V1 vs V2) and the two groups (V3 vs V2) in the ITT analysis was less than the non-inferiority value, and it did not conform to non-inferiority. However, in the PP analysis, the lower limit of the 95% CI for the difference in eradication rates between the two groups and the two groups was greater than the non-inferiority value. That is, according to the actual eradication rates, the eradication efficacy of V1 and V3 was non-inferior to that of V2, which is consistent with the results obtained from the Kruskal-Wallis H Test (Tables 2–3). Hp was eradicated in 38 patients in group V1, with an eradication rate of 84.4% (38/45, 95%CI 73.4–95.5%) by ITT analysis and an eradication rate of 88.4% (38/43, 95%CI 78.4–98.4%) by PP analysis. Moreover Hp was eradicated in 38 patients in group V2, with an ITT eradication rate of 84.4% (38/45, 95%CI 73.4–95.5%) by ITT analysis and an eradication rate of 92.7% (38/41, 95%CI 84.4–101.0%) by PP analysis. Finally, Hp was also eradicated in 38 patients in group V3, with an eradication rate of 84.4% (38/45, 95%CI 73.4–95.5% by ITT analysis and an eradication rate of 88.4% (38/43, 95%CI 78.4–98.4%) by PP analysis. There was no significant difference in the Hp eradication rate between the three groups (p > 0.05) (Fig. 2 and Table 3). This study involved three subgroups, and in the multiple hypothesis correction test (Table S1), there was no statistical difference in the findings between these subgroups V1, V2, and V3.

The most common adverse reaction to standard quadruple therapy was abdominal pain (Table 4). The incidence of nausea was markedly higher in group V2 in comparison to the other two treatment regimens (P < 0.05). The incidence of adverse reactions in groups V1, V2 and V3 were 2.3% (1/43), 19.5% (8/41) and 14.0% (6/43) respectively. The incidence of adverse reactions in groups V1 was significantly less in comparison to the other two treatment regimens (p < 0.05). In the multiple hypothesis correction test (Table S2), there was no statistical difference in the nausea between these subgroups V1, V2, and V3. While V1 differ V2 in the incidence of adverse reactions.

The V3 group incurred the highest medical costs and cost-benefit ratios (Table 5). The V1 and V2 regimen incurred lower medical costs, lower cost-effectiveness ratios as well as higher economic benefits than the V3 regimen.

The success rate of HP eradication regimens involving PPIs is continuously decreasing due to increased antibiotic resistance as well as their insufficient acid-suppressive effect,.Therefore, it is difficult to improve the therapeutic efficacy of PPIs even when their dosage is increased [21]. VPZ can effectively control the gastric PH above 4.0 most of the time with a dose of 20 mg twice daily, which can exhibit as strong and a long period acid-suppressing effect [22‐24]. we observed that patients with successful Hp eradication displayed a higher range of fluctuation in 24-hour gastric pH than those with failed eradication, and a higher pH has been reported to be beneficial for Hp eradication [25]. Amoxicillin and clarithromycin, which are commonly used in Hp eradication, showed the best antibacterial effect at a pH of 6–7 [26].

As indicated in Table 6, our results are similar to the recent findings of Lifen Lu et al. who reported that VPZ quadruple therapy, whether administered for 10 days or 14 days, can achieve eradication rates higher than 90% and was not inferior to standard PPI quadruple therapy [19]. VPZ has been included as an acid-suppressing drug in first-line and second-line Hp eradication regimens and the secondary eradication rate was found to be above 90% in Japan [34]. Interestingly, in a study by YI Hu and Wen Gao, the eradication rate of high-dose AMX in combination with VPZ was also observed to be above 85% [27, 28], but some studies have shown that the eradication rate of VPZ dual therapy was not satisfactory [7]. According to PP analysis, the VPZ dual therapy in this study demonstrated an acceptable eradication effect (eradication rate > 85%). Perhaps enhanced acid suppression and prolonged treatment duration are beneficial in improving the eradication rate of VPZ dual therapy[7，30–31]. Consider quadruple therapy if dual therapy is controversial.due to，In studies of VPZ quadruple therapy, Hp eradication rate mostly exceeded 90% [19, 29, 30]. In addition to dual and quadruple therapies, the VPZ triple therapy in foreign studies also seems to have good eradication results, but prolonged treatment time does not show an advantage in triple therapy [33].

In terms of adverse reactions, adverse reactions observed in the VPZ regimen were mainly dizziness and nausea, especially nausea was apparently more frequent in VPZ quadruple therapy, whereas major adverse reaction in standard PPI therapy group was pronounced abdominal pain. Additionally, in previously reported studies on quadruple therapy, although a high eradication rate was achieved, the incidence of adverse reactions was relatively as high as 30% for VPZ quadruple therapy and 27.1% for standard PPI quadruple therapy [29]. Moreover, in addition to common GI adverse effects, HP regimens containing VPZ have been reported to cause systemic reactions such as chest pain, generalized pain and dizziness [35]. The higher incidence of adverse reactions associated with VPZ quadruple therapy and standard therapy can significantly affect patients’ compliance and quality of life during the treatment, which should be taken into consideration. Therefore, VPZ dual therapy can be a good choice for the treatment of Hp infection.

Our study has some limitations: (1) It was a single-centre randomized controlled trial and the sample size was small, further multi-centre, large sample studies are still needed to validate our results; (2) This study did not differentiate between patients who had been initially eradicated of Hp and those who were re-eradicated of Hp, and HP infections were not cultured in these study participants, lacking data on HP drug resistance. Drug resistance may adversely affect eradication rates and influence study results; (3) participants were not monitored for 24 hours for PH, which may also adversely affect eradication rates.

In conclusion, VPZ dual therapy and quadruple therapy shows promise of not being worse than the standard quadruple therapy by a clinically relevant margin. More studies might be needed to definitively determine if the new therapy is equally effective or even superior. In other aspects, VPZ dual therapy is safer, less economically costly.