Vonoprazan-amoxicillin dual therapy for Helicobacter pylori eradication: Clinical, pharmacogenetic, and microbiome perspectives

Abstract

Helicobacter pylori infection remains a major global health challenge, contributing to chronic gastritis, peptic ulcer disease, and gastric cancer. Rising antimicrobial resistance, host genetic variability, and inconsistent patient adherence have limited the effectiveness of conventional proton pump inhibitor-based eradication regimens. Vonoprazan-amoxicillin (VPZ-AMO) dual therapy is a promising first-line alternative, with high eradication rates, favorable tolerability, and simplified antibiotic exposure demonstrated in multicenter trials across Asia. Evidence suggests that VPZ-AMO dual therapy may outperform traditional proton pump inhibitor-based triple or bismuth quadruple therapies, particularly in populations with high clarithromycin resistance. However, important questions remain regarding its generalizability, optimal dosing, host pharmacogenetic effects, and potential long-term impacts on the gut microbiota. This opinion review summarizes current clinical evidence, highlights unresolved controversies, and outlines future research priorities, including multicenter validation, host factor-guided therapy, microbiome monitoring, and dosing optimization. By integrating these elements into a structured, sequential framework, VPZ-AMO dual therapy is presented as a safe, effective, and adaptable regimen, with substantial potential to improve Helicobacter pylori management and reduce the global burden of associated gastrointestinal diseases.

Key Words: Helicobacter pylori; Vonoprazan-amoxicillin dual therapy; First-line eradication; Antibiotic resistance; Pharmacogenetics; Gut microbiome; Treatment optimization; Antimicrobial stewardship

Core Tip: Vonoprazan-amoxicillin dual therapy is a potent, well-tolerated first-line regimen for Helicobacter pylori eradication, even in regions where clarithromycin resistance is prevalent. This opinion review integrates multicenter evidence, pharmacogenetics, and microbiome considerations, highlights unresolved controversies, and proposes a sequential roadmap for safe, globally applicable implementation to reduce the global burden of associated gastrointestinal diseases.

INTRODUCTION

Helicobacter pylori (H. pylori) infection is one of the most common chronic bacterial infections worldwide, affecting nearly half of the global population. Persistent infection is strongly associated with chronic gastritis, peptic ulcer disease, and gastric cancer, imposing a substantial health burden, particularly in East Asia, Latin America, and Africa[1-4]. Although the prevalence of H. pylori infection has declined globally, it remains elevated in developing regions, underscoring the need for effective eradication strategies[3,5]. Rising antimicrobial resistance, host genetic variability, and inconsistent patient adherence further limit the success of conventional regimens[6-8].

Conventional proton pump inhibitor (PPI)-based triple or quadruple therapies demonstrate variable efficacy across regions. Resistance to clarithromycin and metronidazole has substantially reduced eradication rates, and poor patient compliance remains a major contributor to treatment failure[6,7,9]. Genetic polymorphisms in drug-metabolizing enzymes, including CYP2C19 and CYP3A4, also influence drug pharmacokinetics and treatment outcomes[10-12].

Potassium-competitive acid blockers (P-CABs), such as vonoprazan (VPZ), provide rapid, potent, and sustained acid suppression largely independent of CYP2C19 genotype, offering a key pharmacologic advantage over traditional PPIs[12,13]. This has enabled simpler antibiotic regimens with improved patient adherence. Among these, VPZ-amoxicillin (VPZ-AMO) dual therapy has emerged as a promising first-line alternative. Regional trials in Japan and China, including a multicenter study by Wu et al[14], reported high eradication rates with low-dose, high-frequency regimens, along with favorable tolerability and compliance[11,14]. Meta-analyses indicate that VPZ-AMO dual therapy achieves comparable eradication rates to VPZ-based triple or bismuth-containing quadruple regimens, while maintaining a better safety profile[15-18]. Network meta-analyses further rank VPZ-AMO dual therapy highest for combined efficacy and safety among first-line regimens[7,19].

Despite these encouraging results, key questions remain. The generalizability of regional trial outcomes, optimal dosing schedules, host genetic influences, and potential long-term effects on the gut microbiome require further investigation[10,20-23]. While VPZ-AMO dual therapy minimally disrupts gut microbial communities compared with multidrug regimens, long-term data on microbiome recovery and resistome dynamics are limited[23-25]. Continuous monitoring for emerging AMO resistance is essential to ensure sustained efficacy[2,26].

In this opinion review, we summarize current clinical advances in VPZ-AMO dual therapy, highlight unresolved controversies, and present the authors’ perspectives on future research priorities. By integrating regional clinical evidence with pharmacogenetic and microbiome considerations, we propose a structured roadmap to translate promising local findings into globally applicable therapeutic strategies.

CURRENT ADVANCES

Clinical trial evidence

Multiple multicenter and randomized trials have confirmed the efficacy and safety of VPZ-AMO dual therapy as a first-line regimen for H. pylori eradication. Wu et al[14] reported eradication rates exceeding 90% with a low-dose, 14-day VPZ-AMO regimen, alongside excellent tolerability. Similar outcomes were observed in Japan by Horii et al[25] and Murakami et al[27], and in China by Han et al[28], indicating consistent performance across populations. The pivotal PHALCON-HP trial in the United States and Europe further demonstrated the superiority of VPZ-AMO dual therapy over PPI-based triple therapy in patients with clarithromycin-resistant strains, providing evidence for broader applicability[29]. Head-to-head comparisons also indicate that VPZ-AMO dual therapy is non-inferior to bismuth-containing quadruple therapy while producing fewer adverse events[30-34]. Recent network meta-analyses rank P-CAB-based dual therapy as the most effective first-line option, balancing efficacy and safety[19].

Host genetic and pharmacokinetic considerations

Variability in treatment outcomes is influenced by host genetic factors and drug metabolism. Sakurai et al[35] reported that VPZ is primarily metabolized via CYP3A4, with minimal influence from CYP2C19 polymorphisms, resulting in more predictable acid suppression than traditional PPIs[11,12,35]. Individual patient characteristics, including metabolic capacity, age, and comorbidities, can further modulate therapeutic response and adverse events[36,37]. Nevertheless, routine CYP3A4/5 genotyping has limited utility in predicting outcomes, highlighting the need for context-based interpretation of pharmacogenetic data[10].

Alternative regimens and special populations

To optimize eradication and minimize antibiotic exposure, alternative dual and triple regimens have been explored. For patients with AMO resistance or penicillin allergy, VPZ-minocycline dual therapy shows efficacy comparable to the VPZ-AMO regimen with only mild adverse events[38-40]. In refractory cases, VPZ-sitafloxacin-AMO triple therapy achieves high eradication rates even in genotypically resistant strains[41,42]. Adjunctive Saccharomyces boulardii improves tolerability without compromising efficacy[36], and VPZ-based regimens provide effective alternatives for penicillin-allergic patients[43].

Systematic reviews and meta-analyses

Evidence from systematic reviews further supports the broad applicability of VPZ-based regimens. Du et al[15] pooled 15 clinical studies, reporting first-line eradication rates of 85%-90% associated with the VPZ-AMO regimen, accompanied by a low adverse event incidence. Benito et al[20] confirmed superiority over PPI-based regimens in clarithromycin-resistant populations, supporting their role in both first-line and rescue therapy. Regional validation remains critical, as local eradication success varies with resistance patterns and patient demographics[16]. Recent meta-analyses show that VPZ-AMO dual therapy is as effective as bismuth quadruple therapy with improved safety, particularly regarding gastrointestinal adverse events[44,45]. A large network meta-analysis confirms that P-CAB-based dual therapy ranks highest for efficacy among first-line regimens[46].

Regional differences and regimen optimization

Variations in eradication rates across regions highlight the need for dose optimization and, when appropriate, extended therapy[22,47]. Trials indicate that 14-day regimens with ≥ 2 g/day AMO achieve consistently high eradication, while 10-day regimens may offer comparable efficacy with improved cost-effectiveness in selected patients[48-52]. Ding et al[53] demonstrated that 10-day bismuth-containing quadruple therapy is non-inferior to 14-day regimens with fewer adverse events, illustrating the flexibility required for regimen selection. In rescue therapy, VPZ-AMO dual therapy remains effective and well-tolerated even in patients with multiple prior treatment failures[54,55].

Summary and outlook

Overall, VPZ-AMO dual therapy demonstrates robust efficacy, favorable tolerability, and substantial potential for broad clinical implementation. Its simplified antibiotic profile aligns with antimicrobial stewardship principles, reducing unnecessary exposure while maintaining high cure rates[2,56]. Future studies should clarify optimal dosing, evaluate host genetic influences, and examine microbiome interactions to refine therapy and support global adoption. Table 1 summarizes key multicenter and single-center trials, including study location, sample size, regimens, eradication rates, adverse events, and relevant considerations, facilitating interpretation of efficacy across populations.

Table 1 Key multicenter vonoprazan-based trials.

Ref.	Region	Center (s)	n	Regimens	Duration	Eradication rate (ITT/PP)	AEs	Notes
Chey et al[29], 2022	United States/Europe	Multiple	1046	VPZ 20 mg BID + AMO 1 g TID (dual); VPZ + AMO + CLA 500 mg BID (triple); lansoprazole triple	14 days	Dual: 77%/79%; triple: 81%/85%	45%-51%	First large Western RCT; dual superior to PPI triple in CLA-resistant strains (70% vs 32%)
Qian et al[33], 2023	China	1	375	VHA: VPZ + AMO 750 mg QID; VA: VPZ + AMO 1 g BID; BQT (esomeprazole + AMO + CLA + bismuth)	10 days	VHA: 91%/93%; VA: 82%/85%; BQT: 88%/91%	VHA: 8%; VA: 9%; BQT: 20%	First head-to-head comparison; VHA noninferior to BQT with fewer AEs
Yan et al[31], 2024	China	3	314	VPZ + AMO 1 g TID (dual) vs BQT (esomeprazole + AMO + CLA + bismuth)	10 days vs 14 days	Dual: 86%/91%; BQT: 89%/91%	Dual: 26%; BQT: 53%	10-day dual noninferior to 14-day BQT; significantly lower AE rate
Cheung et al[34], 2024	China	1	298	VA (VPZ + AMO); VAC (VPZ + AMO + CLA); BQT (bismuth + esomeprazole + tetracycline + metronidazole)	14 days	VA: 96%/97%; VAC: 96%/97%; BQT: 92%/97%	VA: 39%; VAC: 56%; BQT: 71%	High efficacy in high CLA resistance area; VA best safety
Wu et al[14], 2025	China (Sichuan)	17	1717	VPZ 20 mg BID + AMO 0.5-1.0 g TID/QID	14 days	92%-97%/97%	5%-7%	Low-dose QID most tolerable; high compliance
Han et al[28], 2025	China	19	524	VACa (14-day): VPZ + AMO + CLA; VACb (10-day): VPZ + AMO + CLA; EBAC: Esomeprazole + bismuth + AMO + CLA	10-14 days	VACa: 88%/94%; VACb: 83%/91%; EBAC: 73%/81%	30%-37%	VPZ triple noninferior to bismuth quadruple
Song et al[50], 2025	China	Multiple	418	VPZ 20 mg BID + AMO 1 g TID	10 days vs 14 days	10-day: 83%/89%; 14-day: 88%/95%	NR	10-day not noninferior to 14-day; 24-hour pH > 6 for > 75% time
Tao et al[49], 2025	China	Multiple	500	VPZ 20 mg BID + AMO 750 mg QID/1 g TID	7-10 days	7-day: 82%-84%/86%-88%; 10-day: 90%-91%/93%-94%	10%-14%	7-day regimens < 90%; 10-day TID effective
Peng et al[48], 2025	China	13	900	VPZ 20 mg BID + AMO 0.5 g TID/1 g BID/1 g TID	14 days	LVA: 87%/87%; MVA: 92%/92%; HVA: 93%/93%	Similar	≥ 2 g/day AMO noninferior to 3 g/day
Hu et al[66], 2025	China	12	504	VPZ 20 mg BID + AMO 1 g BID (LVA) vs 1 g TID (HVA)	14 days	LVA: 85%/89%; HVA: 87%/92%	12%-17%	LVA noninferior; no lasting gut resistome effect
Zhang et al[30], 2025	China	1	250	VPZ 20 mg BID + AMO 1 g TID	14 days	92%/96%	11%	Noninferior to BQT; reduced antibiotic exposure
Zhang et al[54], 2025	China	4	688	VPZ 20 mg BID + AMO 1 g TID	14 days	74%/82%	13%	Rescue; noninferior to tetracycline-furazolidone quadruple
Gao et al[38], 2025	China	1	120	VPZ 20 mg BID + minocycline 100 mg BID (VM)	14 days	88%/92%	17%	Alternative for AMO resistance/penicillin allergy
Park et al[37], 2025	Korea	Multiple	102	VPZ + AMO + CLA vs tegoprazan 50/100 mg	10 days	VPZ: 85%/88%; tegoprazan 100: 79%/87%	Similar	Tegoprazan 100 mg comparable to VPZ; 50 mg insufficient
Geeratragool et al[41], 2025	Thailand	1	20	VPZ + AMO + sitafloxacin	7 days	70%/68%	15%	Fourth-line salvage; small sample; high genotypic resistance

Regimens include dual therapy (vonoprazan + amoxicillin) or triple therapy (vonoprazan + amoxicillin + clarithromycin or other). Data represent first-line or rescue treatment as indicated. Efficacy may vary by population, antibiotic resistance, and dosing schedule. Table consolidates multicenter randomized controlled trials and key comparative studies to highlight clinical evidence and relevant controversies. ITT: Intention-to-treat; PP: Per-protocol; AE: Adverse event; VPZ: Vonoprazan; AMO: Amoxicillin; BID: Twice a day; TID: Three times a day; CLA: Clarithromycin; VHA: Vonoprazan + amoxicillin high-dose; QID: Four times a day; VA: Vonoprazan + amoxicillin; BQT: Bismuth quadruple therapy; VAC: Vonoprazan + amoxicillin + clarithromycin; LVA/MVA/HVA: Low/medium/high-dose vonoprazan + amoxicillin; RCT: Randomized controlled trial; PPI: Proton pump inhibitor; NR: Not reported.

MAJOR CONTROVERSIES/UNRESOLVED ISSUES

Despite high eradication rates reported in regional VPZ-AMO dual therapy trials, several important controversies and knowledge gaps remain. Table 2 summarizes key factors, their sub-items, potential impact on efficacy, and supporting references, providing a consolidated overview to facilitate interpretation of outcomes and guide future research.

Table 2 Key factors affecting vonoprazan-amoxicillin dual therapy efficacy.

Factor1	Sub-items/examples	Potential impact on vonoprazan-amoxicillin efficacy	Ref.
Population/geographic differences	Region, age, sex, dietary habits, healthcare access	Variation in eradication rates across countries, age groups, and healthcare systems	[6,21,46,58]
Host pharmacogenetics	CYP2C19/CYP3A4/CYP3A5 polymorphisms, age-related metabolism	Altered acid suppression, drug pharmacokinetics, variability in eradication success	[10,11,59,60,70]
Gut microbiome impact	Microbial diversity, SCFAs, dysbiosis, probiotic adjuncts	Short- and long-term ecological changes, potential resistome alteration	[23-25,36,56,61]
Antimicrobial resistance	Amoxicillin low but rising clarithromycin/metronidazole resistance; special populations (penicillin allergy, immunocompromised)	Treatment failure, need for alternative regimens, risk of resistance development	[9,26,30,38,40,43,54,55,60,61]
Treatment strategy optimization	Dose, duration, timing relative to meals	Suboptimal dose/duration reduces efficacy; careful selection required for 10-day vs 14-day regimens	[48,49,51,52,63,65-67]

¹Factors include population/geographic differences, host pharmacogenetics, microbiome impact, antimicrobial resistance, and treatment strategy optimization. The table summarizes sub-items, their potential impact on eradication success, and key references supporting each factor.

SCFA: Short-chain fatty acid.

Population and geographic variability

The generalizability of trial results across populations and regions remains uncertain. Differences in antibiotic resistance, dietary habits, and healthcare infrastructure can influence outcomes, limiting extrapolation from one region to another[6,46,57]. Studies from Thailand and Egypt highlight substantial regional variability, with some populations achieving suboptimal eradication despite similar VPZ-based regimens. These findings emphasize the need for region-specific optimization rather than universal adoption of a single protocol[21,58].

Host pharmacogenetic factors

Genetic polymorphisms in CYP3A4, CYP3A5, and CYP2C19 contribute to variability in drug metabolism and acid suppression, affecting eradication outcomes. Although VPZ is primarily metabolized via CYP3A4, individual differences can still influence therapeutic response, suggesting a potential role for genotype-guided precision therapy[10,59,60]. Routine CYP genotyping remains debated, as VPZ’s acid-suppressive effect is largely independent of CYP2C19[11,12]. Age-related metabolic differences, particularly higher enzymatic activity in adolescents, may further reduce cure rates in younger populations, highlighting the importance of age- and metabolism-specific considerations[61].

Gut microbiome impact

The long-term ecological effects of VPZ-AMO dual therapy on gut microbial communities are not fully understood. Although dual therapy generally involves lower antibiotic exposure than triple or quadruple regimens, shifts in microbial diversity and composition may occur, potentially affecting colonization resistance and overall microbial balance[6,23,62]. Emerging evidence suggests that VPZ-AMO dual therapy induces minimal and transient changes, with most parameters returning to baseline within 8-10 weeks post-treatment[23-25]. Adjunctive probiotics, such as Saccharomyces boulardii, may help mitigate dysbiosis, though optimal strategies remain to be defined[36,61]. These findings underscore the need for longitudinal microbiome monitoring in future studies.

Antimicrobial resistance

While AMO resistance remains low, rising clarithromycin and metronidazole resistance presents ongoing challenges. Suboptimal dosing or poor adherence can accelerate resistance development. Special populations, including penicillin-allergic or immunocompromised patients, may require modified regimens, complicating standardization and increasing treatment failure risk[9,43,54,63]. VPZ-based regimens incorporating minocycline or tetracycline offer alternatives for penicillin-allergic patients but require validation in larger cohorts[38,40]. VPZ-AMO dual therapy remains effective as a rescue option in patients with multiple prior treatment failures, although efficacy declines with repeated therapy, emphasizing the importance of early, effective first-line treatment[30,55].

Treatment strategy optimization

Variations in dosing schedules and treatment duration further complicate clinical application. Evidence suggests that low-dose, 10-day regimens may be less effective than higher-dose, 14-day courses, even when tolerability is high[63-65]. Randomized trials indicate that 14-day regimens with ≥ 2 g/day AMO achieve non-inferior efficacy compared with higher doses, supporting dose reduction without compromising cure rates[48,66]. Optimal duration remains debated: While 10-day regimens may improve cost-effectiveness and convenience, they may not consistently achieve > 90% eradication across all populations, requiring careful patient selection[49,51,52]. Timing relative to meals may also influence efficacy, with postprandial dosing potentially enhancing absorption and treatment success[67].

Summary

VPZ-AMO dual therapy demonstrates substantial promise, but uncertainties remain regarding population-specific efficacy, pharmacogenetic influences, microbiome effects, antimicrobial resistance, and optimal treatment strategies. Well-designed multicenter trials and longitudinal studies are essential for safe and effective global implementation[46,56,59]. Integrating antimicrobial stewardship principles with emerging microbiome insights will be critical to sustain long-term efficacy and ensure optimal patient outcomes[2,66].

AUTHOR PERSPECTIVES

Based on current evidence, several key perspectives emerge to guide the optimization of VPZ-AMO dual therapy and inform future research directions.

Multicenter validation for global applicability

Although multiple regional studies report high eradication rates and favorable tolerability[14,21,68,69], generalizability to broader populations remains uncertain. Trials from Thailand and Egypt demonstrated lower-than-expected eradication rates, highlighting substantial regional variability[21,58]. Future research should involve multicenter, multinational cohorts to validate efficacy across diverse geographic regions, antibiotic resistance profiles, and healthcare systems. Standardized protocols should be combined with region-specific adaptations based on local resistance patterns and patient characteristics[19,46]. Such validation is essential for developing globally applicable clinical guidelines and ensuring consistent therapeutic outcomes.

Patient stratification based on host pharmacogenetic factors

Individual variability in CYP2C19 and CYP3A4 polymorphisms, acid secretion, and age-related metabolism can influence intragastric pH, drug pharmacokinetics, and eradication success[21,59,70]. While VPZ’s acid-suppressive effect is largely independent of CYP2C19, a key advantage over traditional PPIs, the impact of CYP3A4/5 polymorphisms on drug exposure and outcomes remains incompletely characterized[10,11]. Incorporating genotyping, age, and comorbidity assessments into treatment planning enables precision therapy, optimizing dosing and minimizing treatment failures. Special populations, including children, adolescents, and patients with penicillin allergy or multiple prior treatment failures, may particularly benefit from genotype- or susceptibility-guided approaches[55,70,71].

Long-term gut microbiome monitoring

VPZ-AMO dual therapy generally has a limited impact on gut microbial communities compared with triple or quadruple regimens, although effects may vary with antibiotic dose and combination[23-25]. Comparative studies confirm that dual therapy induces less disruption of microbial diversity and composition than bismuth-containing quadruple or clarithromycin-containing triple regimens, with most parameters returning to baseline within 8-10 weeks post-treatment[23,24]. Prospective studies should assess microbial diversity, short-chain fatty acids, and functional microbiome changes during and after therapy. High-dose AMO may have a more persistent effect on beta-lactam resistance genes, emphasizing careful dose selection to minimize long-term resistome alterations[66]. Adjunctive interventions, including probiotics or dietary strategies, may help mitigate ecological disruption and improve outcomes. Supplementation with Saccharomyces boulardii or other probiotics has shown promise, though optimal strains, dosages, and timing require further study[36,61].

Sequential research roadmap

Collectively, these perspectives support a structured, sequential roadmap: (1) Validation of VPZ-AMO dual therapy in multicenter, geographically diverse populations; (2) Treatment tailoring based on host pharmacogenetics and clinical characteristics; and (3) Monitoring and management of microbiome effects to ensure safety and sustainability. Adherence to antimicrobial stewardship principles, including minimizing unnecessary antibiotic exposure and preserving key agents such as AMO, will be essential for sustaining long-term success. Following this structured approach will facilitate translation of promising regional findings into globally effective first-line H. pylori eradication strategies[2,56]. Figure 1 illustrates this framework, integrating author perspectives and highlighting research priorities for global application.

Figure 1 Sequential roadmap for vonoprazan-amoxicillin dual therapy research. This figure presents a horizontal, stepwise framework for future research on vonoprazan-amoxicillin dual therapy. The roadmap consists of five consecutive modules: (1) Multicenter validation, confirming efficacy across geographic regions and populations; (2) Host factor-guided therapy, integrating pharmacogenetic profiling, age, and comorbidity to tailor dosing; (3) Microbiome monitoring, tracking gut microbial diversity, short-chain fatty acids, and resistome dynamics; (4) Dosing optimization, adjusting dose, duration, and combination strategies for maximal efficacy and safety; and (5) Implementation research, evaluating cost-effectiveness, adherence, and policy considerations. Arrows indicate sequential progression from validation to implementation. This schematic integrates author perspectives and highlights critical steps to translate regional clinical findings into globally effective first-line Helicobacter pylori eradication strategies. VPZ-AMO: Vonoprazan-amoxicillin; SCFA: Short-chain fatty acid.

FUTURE DIRECTIONS

Expanding multicenter and cross-regional validation

Although regional studies report high eradication rates associated with VPZ-AMO dual therapy[14,72], differences in antibiotic resistance, patient demographics, and healthcare infrastructure may limit generalizability. Studies from non-Asian populations show variable outcomes, highlighting the need for validation across diverse geographic and ethnic settings[29,58]. Large-scale, multinational, multicenter trials are essential to confirm eradication rates and tolerability, particularly in regions with high clarithromycin or metronidazole resistance[69,73]. Special populations, such as immunocompromised patients, should be included to assess drug-drug interactions and efficacy in clinically complex groups[74].

Integrating host pharmacogenetic stratification

Genetic variability in CYP2C19, CYP3A4, and CYP3A5 significantly affects acid suppression, drug metabolism, and eradication outcomes[21,70]. While VPZ provides CYP2C19-independent acid suppression, the impact of CYP3A4/5 polymorphisms remains incompletely understood[10,12]. Future trials should incorporate pharmacogenetic testing to guide individualized therapy, optimizing dosing and duration for populations with altered metabolism, including children, adolescents, and older adults[61,70]. Host comorbidities and age-related pharmacokinetic changes should also be considered to maximize efficacy and minimize adverse events.

Monitoring and mitigating long-term gut microbiome effects

VPZ-AMO dual therapy generally causes minimal short-term disruption of gut microbiota compared with triple therapy[24,25]. Nevertheless, long-term ecological impacts remain insufficiently studied. Future research should track microbiome diversity, composition, and functional metabolites, including short-chain fatty acids, to evaluate recovery and potential dysbiosis. Even short-course AMO therapy can transiently increase beta-lactam resistance gene abundance, emphasizing the importance of careful dose selection[7,66]. Adjunctive interventions, such as probiotics or dietary strategies, may mitigate microbial perturbations and improve outcomes, with Saccharomyces boulardii showing particular promise[62,75,76].

Optimizing dosing, treatment duration, and combination strategies

Standard 7- to 14-day VPZ-AMO regimens may require adaptation based on local resistance patterns, host factors, and adherence[72,77,78]. Future studies should evaluate flexible schedules, including shorter high-dose courses or combinations with bismuth or other adjuvants, to maximize efficacy while minimizing adverse events and costs[21,68,72]. Evidence indicates that 14-day regimens with ≥ 2 g/day AMO achieve comparable efficacy to higher doses, supporting strategies that reduce antibiotic exposure without compromising cure rates[48,66]. Alternative dual therapies, such as VPZ-minocycline, warrant further investigation in prospective trials for patients with AMO resistance or penicillin allergy[38,40].

Incorporating pharmacoeconomic and implementation research

Global adoption of VPZ-AMO dual therapy requires data on cost-effectiveness, accessibility, and real-world adherence[72,73]. Future studies should integrate economic evaluations, patient-reported outcomes, and health system feasibility to guide policy and public health decisions. Experience from nationally centralized drug procurement programs in China demonstrates that medication costs can be substantially reduced without compromising efficacy, providing a scalable model for resource-limited settings[4,72]. Comparative cost-effectiveness analyses between VPZ-AMO and alternative regimens will be essential to inform guideline recommendations and reimbursement policies[36,51].

Summary

Collectively, these directions, including multicenter validation, host factor-guided therapy, microbiome monitoring, dosing optimization, and implementation research, form a structured roadmap for global VPZ-AMO adoption. Following this sequential approach will facilitate translation of regional findings into widely effective first-line H. pylori eradication strategies. Ultimately, VPZ-AMO dual therapy can become a cornerstone of antimicrobial stewardship-aligned H. pylori management, delivering high cure rates with minimal ecological impact and sustained global effectiveness[2,56].

CONCLUSION

VPZ-AMO dual therapy is a highly promising first-line option for H. pylori eradication, offering robust efficacy, favorable tolerability, and potential for broad global implementation. Regional trials consistently demonstrate high eradication rates in adult and pediatric populations; however, critical knowledge gaps remain, including generalizability, host genetic variability, and potential long-term effects on the gut microbiome. Systematic, multicenter, cross-regional studies that integrate pharmacogenetic stratification, microbiome monitoring, and optimized dosing strategies are essential to translate regional successes into universally effective clinical practice. A structured research roadmap, encompassing multicenter validation, host factor-guided therapy, ecological assessments, treatment optimization, and implementation research, will maximize therapeutic potential, ensure patient safety, and support evidence-based decision-making by clinicians and policymakers. Implementing this sequential, integrated approach will facilitate global adoption of VPZ-AMO dual therapy, ultimately improving patient outcomes and reducing the worldwide burden of H. pylori-associated gastrointestinal diseases.