Vonoprazan and proton pump inhibitors: Which is superior for Helicobacter pylori eradication?

Abstract

Helicobacter pylori is a worldwide health problem; therefore, eradicating this bacterium is important for the health and economic status of the whole world. There are a variety of anti-secretory and antibiotic combinations for this purpose; however, antibiotic resistance is a major barrier to achieving an appropriate eradication rate (> 90%). Blockage of gastric acid is the main supportive factor of the antibiotic effect on bacteria. Therefore, anti-secretory therapy with high efficacy and safety profiles should be used in eradication regimens. Vonoprazan (VPZ), a member of the potassium competitive acid blockers, is a novel agent with a potent anti-secretory effect. The present study aimed to summarize comparative and safety studies of VPZ and proton pump inhibitors (PPIs), especially the efficacy on Helicobacter pylori eradication. VPZ was reported to have a higher efficacy and safety profile in most studies that compared VPZ-based and PPI-based regimens for eradication therapy. Despite its greater cost, the effectiveness of VPZ emerges as a viable and cost-effective alternative to PPI on gastric acid-related pathologies.

Key Words: Vonoprazan; Proton pump inhibitors; Helicobacter pylori; Potassium competitive acid blockers; Acid-related disorders

Core Tip: In this article, we summarize the current evidence regarding the better choice between proton pump inhibitors and vonoprazan for treating the very common global disease Helicobacter pylori infection. We also comment on a recently published article by Gao et al, where the authors provided real-life experiences managing Helicobacter pylori in the elderly using vonoprazan.

TO THE EDITOR

We read with great interest the recently published article in the World Journal of Gastroenterology by Gao et al[1], and have decided to summarize the current evidence regarding which is better in Helicobacter pylori (H. pylori) eradication treatment, proton pump inhibitors (PPIs) or vonoprazan (VPZ). H. pylori is a gram-negative bacterium, and its prevalence was reported to be 43.1%[2]. This means that more than three billion people have this bacterium in their gastrointestinal system, especially the gastric mucosa. H. pylori is the leading cause of gastritis, peptic ulcer, and gastric cancer. Therefore, the treatment of this bacterium is crucial for improving health worldwide. Between 2000 and 2020, H. pylori treatment was found to increase 8.65 million quality-adjusted life years and 1.23 million life year expectancy, and prevented the recurrence of more than half a million ulcers and nearly 60 thousand ulcer-associated deaths, compared with PPI therapy for peptic diseases[3].

Triple therapies, including a PPI, clarithromycin, amoxicillin, or tinidazole, were used for eradication initially[4]. However, high levels of antibiotic resistance to metronidazole, clarithromycin, and levofloxacin affect the treatment eradication rate and the prevalence of resistance is reported to be > 15% worldwide[5]. Various types of treatment modalities are used to overcome this antibiotic resistance, such as triple therapy, concomitant therapy, sequential therapy, bismuth quadruple therapy, and high-dose dual therapy. All of these modalities include PPI treatment. Therefore the optimal type, dose, and duration of PPI used in eradication therapy are essential in order to reach an eradication rate > 90%. The potency of a PPI is determined based on the omeprazole equivalent (OE). For example, rabeprazole 20 mg was found to be equal to 36 mg OE, esomeprazole 20 mg = 32 mg OE, and pantoprazole 40 mg = 9 mg OE[6]. The efficacy of PPI medication was first validated in the MACH II study, which demonstrated that the combination of omeprazole with either amoxicillin and clarithromycin or metronidazole and clarithromycin achieved a significantly greater eradication rate compared to the use of antibiotics alone[7]. PPIs are essential in the eradication treatment of H. pylori. An intragastric pH > 4 is necessary for the optimal effect of PPIs and the twice-daily dose was reported to maintain intragastric pH > 4 for 15.6-20.4 hours[6]. Regardless of the antibiotic choice, high dose PPI over 14 days was found to be ≥ 90% effective in first-line treatment. However, none of the 7-day therapies achieved optimal cure rates (> 90%)[8].

Given that primary and secondary resistance rates of H. pylori to amoxicillin were reported at low levels and PPIs are essential in eradication treatment, dual therapy with high dose PPI and amoxicillin was used in treatment regimens[5]. PPI and amoxicillin were first used for eradication in 1989; however, the eradication rate did not reach > 90%. Recently, studies have shown that the effect of amoxicillin is related to plasma concentration and minimal inhibitory concentration. Dosing of 0.5 g-four times a day was reported to achieve a plasma concentration higher than the minimal inhibitory concentration[9].

Potassium-competitive acid blockers (P-CABs) represent a novel category of acid suppressants that achieve more potent and prolonged gastric acid suppression compared to PPIs[10]. VPZ has shown superior efficacy over PPIs in managing specific gastric acid-related conditions such as erosive esophagitis, gastric or duodenal ulcers, post-endoscopic submucosal dissection ulcers and H. pylori eradication. VPZ demonstrates greater efficacy than lansoprasole in treating erosive esophagitis (healing rates 92.3%-99% for VPZ and 93.2%-95.5% for lansoprazole). Eradication rates of gastric and duodenal ulcers were 92.6% and 75.9% for VPZ and lansoprazole, respectively. In the management of post-endoscopic submucosal dissection ulcers, VPZ demonstrates efficacy, with healing rates of 94.9% in contrast to 78% for PPIs[11]. As gastric acid blockage is the mainstay of eradication therapy, numerous clinical investigations have increasingly focused on H. pylori eradication with P-CABs, and have proved the therapeutic efficacy of P-CABs in H. pylori patients. VPZ has become prominent due to its enhanced eradication rate of antibiotic-resistant bacteria and its non-inferiority compared to PPI-based therapy[12]. VPZ dual and triple therapies for H. pylori eradication have been approved by the United States Food and Drug Administration since May 2022. VPZ is a new agent used to block acid and there are numerous studies comparing VPZ with PPIs. The aim of the present study was to compare the efficacy and safety profile of VPZ with PPIs for the eradication of H. pylori.

Mechanism of action

PPIs block gastric acid secretion from parietal cells by irreversibly binding and inhibiting the H⁺-K⁺ ATPase enzyme. Inhibition of the H⁺-K⁺ ATPase proton pump requires prior activation of the pump before the PPI is eliminated from the circulation, which correlates with the absorption rate, time to maximum concentration, and the drug’s elimination rate from circulation, all of which are affected by developmental and genetic factors. Given that gastrin secretion postprandially is a significant stimulant of H⁺-K⁺ ATPase, the PPI must be provided sufficiently in advance of a meal to ensure absorption, yet not be completely exhausted by the time the proton pump is activated. Not all pumps are activated and blocked following the initial dose; thus, achieving a steady state necessitates around three days of treatment[13]. PPI metabolism is affected by the CYP2C19 gene polymorphism, and rabeprazole 10 mg and omeprazole 20 mg four times a day were reported to have similar effects on achieving gastric pH > 6 in fast, intermediate, and slow metabolizers of CYP2C19[9].

VPZ binds with H⁺-K⁺ ATPase in a non-covalent and reversible fashion, blocking potassium binding via competitive inhibition. By this mechanism, VPZ induces immediate, significant, and prolonged inhibition of stomach acid secretion, leading to an increase in intragastric pH[10]. VPZ binds H⁺-K⁺ ATPase with high affinity and can bind to either the active or inactive form of the enzyme[14]. Plasma concentrations of VPZ were found to be similar under fed and fasting conditions. Therefore, VPZ can be administered irrespective of food intake[15]. Additionally, gastric pH elevations had a rapid onset and were maintained through 24-hour dosing intervals[14]. The 24-hour intragastric pH greater than 6 on day 7 was significantly elevated, with VPZ 20 mg administered once daily (62.5%) compared to lansoprazole 30 mg administered once daily (16.4%)[16]. No clinically significant variations in VPZ pharmacokinetics were seen based on sex, age, race, or CYP2C19 metabolizer status[14].

VPZ is metabolized by CYP3A4 and it was found that plasma concentration area under the curve of VPZ was 58% higher when 40 mg VPZ was administered with clarithromycin (a strong CYP3A4 inhibitor) than VPZ alone[17]. As VPZ is a CYP2C19 inhibitor, concomitant use with drugs that are substrates of CYP2C19 may affect exposure of the co-administered drugs[14].

Efficacy studies

VPZ has been used in H. pylori treatment protocols since its initial approval in Japan in 2015. Pilot studies showed a high efficacy of 7-day high-dose VPZ triple therapy (92.3%) and 14-day VPZ triple therapy combined with bismuth (96.2%). A prospective study demonstrated a high effectiveness rate (95%) for the 14-day VPZ bismuth triple treatment[12]. The overall eradication rate with VPZ was reported to be 97%, and the eradication rate in the first-line administration of VPZ was 100%[18].

Numerous H. pylori eradication regimens exist, although there are various opinions regarding the efficacy of those based on P-CAB or PPI. Initial studies between 2016 and 2018, reported that VPZ-triple therapy had a higher eradication rate (88.9%-95.7%) than PPI-triple therapy (71.4%-86.7%), especially in populations with a high clarithromycin resistance rate[12]. The study by Murakami et al[19] showed that the eradication rate with first-line VPZ-triple therapy was significantly higher (92.6%) than the lansoprazole-triple (75.9%) regimen. A similar study with rabeprazole-triple therapy in the PPI group showed that the eradication rate with VPZ triple therapy and PPI triple therapy was 95.8% and 69.9%, respectively[20]. The study by Chey et al[21] found that VPZ-based triple (84.7%) therapy resulted in a higher eradication rate than VPZ-dual therapy (78.5%) and the PPI-triple (lansoprazole) regimen (78.8%). Additionally, in patients with clarithromycin-resistant strains, VPZ-based triple and dual regimens had significantly higher eradication rates (65.8% and 69.6%, respectively) than PPI-triple therapy (31.9%)[21]. VPZ based regimens were found to be more efficient than PPI-triple, PPI-quadruple, and tegoprazan regimens on H. pylori eradication. Among the VPZ regimens, two-week VPZ-triple therapy had the best eradication rate[22]. VPZ-quadruple for 14 days, VPZ-triple for 10 days, and VPZ-dual therapies for 14 days were reported to have higher eradication rates compared with the other VPZ and especially PPI regimens[23]. Compared with PPI-based triple therapy, VPZ dual therapy demonstrated superior therapeutic efficacy, safety, and patient compliance rates in the eradication of H. pylori[24]. 20 mg VPZ twice daily and amoxicillin 1000 mg 3 times daily for 14 days had higher eradication rates (87.2%) than VPZ-bismuth-quadruple (79.5%) therapy, and per-protocol analysis demonstrated rates of 94.4% and 96.8%, respectively. Thus, non-inferiority was confirmed between the two groups[25]. Table 1 shows the results of studies comparing VPZ and PPI-based H. pylori eradication regimens[19,21,26-36]. Most studies indicated that VPZ-based therapies, both for 7 days and 14 days, had higher eradication rates. The reported intention-to-treat rates of VPZ regimens were in the range of 56%-97%, and per-protocol analysis rates were in the range of 86%-100%.

Table 1 Summary of selected studies comparing vonoprazan and proton pump inhibitors in Helicobacter pylori eradication.

Ref.	No. patients	Country of study	VPZ regimen	PPI regimen	Eradication rate (ITT%)		Eradication rate (PP%)		Notes
					VPZ	PPI	VPZ	PPI
Miao et al[26], 2023	44	China	VPZ 20 mg + bismuth 220 mg + CLR 500 mg + AMO 1000 mg BID for 14 days	ESO 20 mg + bismuth 220 mg + CLR 500 mg + AMO 1000 mg BID for 14 days	20/22 (90)	17/22 (77)	20/20 (100)	17/18 (94.4)	-
Chen et al[27], 2024	300	China	Berberine 500 mg + AMO 1000 mg + VPZ 20 mg BID for 14 days, VPZ 20 mg + AMO 1000 mg + CLR 500 mg + colloidal bismuth tartrate 220 mg BID for 14 days	RAB 10 mg + AMO 1000 mg + CLR 500 mg + colloidal bismuth tartrate 220 mg BID for 14 days	77/100 (77)	69/100 (69)	77/89 (86.5)	69/88 (78)	-
Bunchorntavakul and Buranathawornsom[28], 2021	122	Thailand	VPZ 20 mg + AMO 1000 mg + CLR 500 mg BID for 7 days	OME 20 mg + AMO 1000 mg + CLR 500 mg BID for 14 days	59/61 (96)	54/61 (88)	59/60 (98.3)	54/58 (93.1)	-
Ang et al[29], 2022	244	Singapore	AMO 1000 mg + CLR 500 mg + VPZ 20 mg BID for 7 days	AMO 1000 mg + CLR 500 mg + OME or ESO or RAB 20 mg BID for 14 days	104/119 (87)	110/125 (88)	104/108 (96)	110/117 (94)	-
Chey et al[21], 2022	1046	United States and Europe	VPZ 20 mg BID + AMO 1000 mg TID for 14 days VPZ 20 mg + AMO 1000 mg + CLR 500 mg BID for 14 days	LAN 30 mg + AMO 1000 mg + CLR 500 mg BID for 14 days	262/222 (84.7)	201/255 (78.8)	198/219 (90)	174/212 (82)	-
Sue et al[30], 2018	147	Japan	VPZ 20 mg + AMO 750 mg + CLR 200 or 400 mg BID for 7 days	LAN 30 mg, RAB 10 mg, or ESO 20 mg BID + AMO 750 mg BID + CLR 200 or 400 mg BID for 7 days	48/55 (87.2)	39/51 (76.4)	48/54 (88.8)	39/45 (86.6)	-
Murakami et al[19], 2016	650	Japan	VPZ 20 mg + AMO 750 mg + CLR 200 or 400 mg BID for 7 days	LAN 30 mg + AMO 750 mg + CLR 200 or 400 mg BID for 7 days	300/329 (91)	242/321 (75)	300/324 (92)	242/320 (75)	Total adverse events (VPZ/PPIs) 34%/41.1%
Maruyama et al[31], 2017	141	Japan	VPZ 20 mg + AMO 750 mg + CLR 200 or 400 mg BID for 7 days	RAB 20 mg or LAN 30 mg + AMO 750 mg + CLR 200 or 400 mg BID for 7 days	68/72 (94)	48/69 (69)	68/70 (97)	48/63 (76)	Total adverse events (VPZ/PPIs) 26.4%/37.7%
Lu et al[32], 2023	234	China	VPZ 20 mg daily + AMO 1000 mg + furazolidone 100 mg + colloidal bismuth 200 mg each BID for 10 days VPZ 20 mg daily + AMO 1000 mg + furazolidone 100 mg + colloidal bismuth 200 mg each BID for 14 days	ESO 20 mg + AMO 1000 mg + furazolidone 100 mg + colloidal bismuth 200 mg BID for 14 days	149/156 (95.5)	73/78 (93.5)	149/151 (98.67)	73/74 (98.64)	-
Huh et al[33], 2022	30	Korea	VPZ 20 mg + bismuth 220 mg + CLR 500 mg + AMO 1000 mg BID for 14 days	LAN 30 mg + bismuth 220 mg + CLR 500 mg + AMO 1000 mg BID for 14 days	12/15 (80)	14/15 (93)	12/12 (100)	14/14 (100)	-
Huang et al[34], 2023	120	China	VPZ 20 mg + AMO 1000 mg BID + bismuth potassium 0.6 g BID for 14 days VPZ 20 mg + AMO 1000 mg + furazolidone 100 mg + bismuth potassium citrate 0.6 g BID for 14 days	ESO 20 mg + AMO 1000 mg + furazolidone 100 mg + bismuth potassium 0.6 g BID for 14 days	39/40 (97)	32/40 (80)	39/40 (97.5)	32/40 (80)	-
Hou et al[35], 2022	533	China mainland, South Korea, and Taiwan	VPZ 20 mg + AMO 1000 mg + CLR 500 mg + bismuth 600 mg for 14 days, then VPZ 20 mg QD for 14 days	LAN 30 mg BID, AMO 1000 mg BID, CLA 500 mg BID, bismuth 600 mg BID for 14 days, then LAN 30 mg QD for 14 days	-	-	193/211 (91)	177/204 (86.7)	-
Hojo et al[36], 2020			7 days VPZ 20 mg bid AMO 750 mg bid MTZ 250 mg bid	7 days RAB 10 mg bid AMO 750 mg bid MTZ 250 mg bid	17/23 (73.9)	19/23 (82.6)	17/19 (89.5)	19/22 (86.4)	Total adverse events (VPZ/PPIs) 47.8%/40%

VPZ: Vonoprazan; PPI: Proton pump inhibitor; ITT: Intention to treat; PP: Per protocol; AMO: Amoxicillin; BID: Twice daily; CLR: Clarithromycin; ESO: Esomeprazole; LAN: Lansoprazole; OME: Omeprazole; QD: Once daily; RAB: Rabeprazole; TID: Three times daily; MTZ: Metronidazole.

Safety profile

Adverse events in patients taking VPZ were reported to include diarrhea, decreased appetite, pyrexia, intestinal lung disease, pneumonia, anemia, nausea, lower platelet counts, and hepatic function abnormalities. All adverse events were higher in the older group (> 65 years)[37]. A meta-analysis by Jiang et al[22] showed that two-week dual therapy with VPZ and amoxicillin had the lowest incidence of adverse reactions, followed by one-week of dual therapy. The study included PPI-triple, PPI-quadruple and tegoprazan regimens for H. pylori eradication[22]. In the PHALCON-HP study, treatment-emergent adverse events were reported to be higher in the lansoprazole triple group (34.5%) than in the VPZ dual (29.9%) and VPZ triple (34.1%) regimens. The most common adverse events were diarrhea, dysgeusia, and headache[21]. Fourteen-day high dose VPZ dual therapy was reported to be a safer option with a relatively low incidence of adverse events, followed by VPZ-triple-14 days, VPZ-dual-14 days, VPZ-quadruple-14 days, PPI-quadruple-14 days, and VPZ-quadruple-10 days regimens[23]. The reported adverse events were not moderate or severe. In another trial, the incidence of treatment-emergent adverse events was found to be similar to placebo, and the events were mild in severity[38]. The 14-day VPZ-bismuth quadruple regimen was associated with adverse events in 12.7% of patients. Adverse events were mainly mild (81.3%) and included nausea, skin rash, diarrhea, bloating and, abdominal discomfort[39]. In the study by Gao et al, the incidence of adverse events due to VPZ dual therapy with amoxicillin was 9.5% in patients aged over 60 years and no serious adverse events occurred[1].

No significant increase in the incidence of parietal, foveolar, and G cell hyperplasia was observed in patients from the VPZ group compared with the lansoprazole group between week 48 and week 156[40]. In a phase IV randomized trial, VPZ exhibited a comparable safety profile to lansoprazole after five years and sustained healing for a longer duration. No neoplastic alterations in the stomach mucosa were detected[41]. While VPZ and PPIs exhibit no substantial difference in side effects, a recent study indicated that VPZ may provide a greater risk than PPIs in the development of Clostridioides difficile (reported odds ratio were 11.5 and 1.42 for VPZ and PPI, respectively) and the risk was found to be greater in patients aged 60 years or older (reported odds ratio were 15.3 for VPZ and 1.6 for PPI, respectively)[42]. As VPZ is a CYP2C19 inhibitor, concomitant use with drugs that are substrates of CYP2C19 may affect exposure of the co-administered drugs[14]. This effect should be considered, especially in older patients, due to a higher rate of polypharmacy. Given that P-CABs are novel anti-secretory drugs, there are few studies on long-term adverse events such as the risk of cancers or osteoporosis. However, the study by Arai et al[43] showed that the cumulative incidence of gastric cancer was higher in the VPZ group than in the H₂ receptor antagonist group in a duration/dose-dependent manner during the follow-up period (mean = 3.65 years).

Cost-effectiveness

The H. pylori eradication strategy has considerably contributed to the prevention of ulcer recurrence, reduced ulcer-related mortality, and yielded substantial cost savings. The study by Kowada and Asaka indicated that the H. pylori eradication strategy saved 14.07 billion United States dollars between 2000 and 2020 compared to the PPI strategy for peptic diseases[3]. Despite its greater cost, VPZ has emerged as a potentially viable and cost-effective alternative therapy for the treatment of erosive esophagitis[44]. VPZ was determined to be more cost-effective than esomeprazole and lansoprazole in individuals on low-dose aspirin for the secondary prevention of cardiovascular events[45]. VPZ-triple therapy was found to be the most cost-effective regimen followed by rifabutin-triple, VPZ-dual, bismuth-quadruple, and PPI-triple therapies[46].

Conclusion

VPZ-based regimens can be used for both first-line and salvage therapy in H. pylori eradication due to their significant efficacy, safety profile, and cost-effectiveness compared with PPI-based therapies. In patients aged over 60 years, VPZ dual therapy with amoxicillin will increase due to its effectiveness and safety profile[1-24].