Rethinking Helicobacter pylori Eradication in 2026:

Less is More



Dr. Paul Ng

Specialist in Gastroenterology & Hepatology

What is your next step?

59-year-old school principal having OGD for the first time, for dyspepsia:

Helicobacter pylori-associated antral gastritis with intestinal metaplasia.

What's your next step?

PPI + amoxicillin + clarithromycin

PPI + amoxicillin

PPI + bismuth + amoxicillin + clarithromycin

PPI + bismuth + tetracycline + metronidazole

PCAB + amoxicillin

Clarithromycin in Helicobacter pylori eradication will be obsolete.

Dual therapy will be the mainstream treatment strategy.

Treatment duration is one of the most important considerations. 14 days!

First-line eradication across guidelines

Bismuth quadruple therapy dominates international advice. Hong Kong lists a branded capsule instead.

Regimen (14 days)

Hong Kong 2023

ACG 2024

Maastricht VI

Asian-Pacific

Bismuth quadruple (BQT)

✓

✓

✓

✓

High-dose PPI + amoxicillin dual

✓

–

–

–

P-CAB (vonoprazan) dual

–

✓

–

✓

PPI + clarithromycin + amoxicillin (PAC)

✓

– only if susceptibility confirmed

✓* only if susceptible or resistance below 15%

✓* conditional; varies by country


Sources: Leung WK et al., Hong Kong Med J 2023; Chey WD et al., Am J Gastroenterol 2024; Malfertheiner P et al., Maastricht VI, Gut 2022; Asian-Pacific Helicobacter guidance.

Why the 2023 Hong Kong consensus still kept PAC

10–13%

local clarithromycin resistance, from retrospective cohorts (95% CI 5–18%)

Just under 15%

the guideline cutoff, so clarithromycin stayed a valid first-line option

Shortages

tetracycline 500 mg and bismuth options were limited

Source: Leung WK et al., Hong Kong Med J 2023. Statement 16 lists PAC for 14 days, bismuth quadruple for 10–14 days, or high-dose PPI-amoxicillin dual for 14 days.

A pragmatic compromise

The consensus kept PAC as a local option while the resistance figures sat just below the cutoff.

Two practice traps: short courses and pseudo-BQT

Only 14 days

PAC is endorsed for 14 days, never 7 or 10. Legacy 7-day pre-packs are the main cause of preventable failure.

Classical BQT, not PAC plus bismuth

PPI, bismuth, tetracycline 500 mg QID and metronidazole 400 mg QID for 14 days. Tetracycline resistance stays below 1%.

Sources: Maastricht VI; Leung WK et al., Hong Kong Med J 2023

Presentation Outline

Part 01: Simple & One-Off Eradication

Simple & One-Off Eradication: Achieve highly effective eradication in a single treatment course.

Minimize Antibiotic Exposure: Reduce total drug burden and toxicity while preserving host gut ecology.

Expect RAHS: Anticipate Rebound Acid Hypersecretion (RAHS) dynamics upon cessation of therapy.

Avoid Prolonged Achlorhydria: Prevent extended acid suppression risks by balancing potent suppression with timely recovery.

Why Triple Therapy Was a Workaround

1980s monotherapy failures

Single antibiotics gave poor eradication; metronidazole monotherapy drove rapid resistance.


Marshall BJ, Warren JR. Lancet 1984

1994 Bazzoli breakthrough

PPI + clarithromycin + amoxicillin or metronidazole: 95.4% (62/65), uncontrolled


Bazzoli F et al. Eur J Gastroenterol Hepatol 1994;



The PPI pharmacokinetic flaw

Early PPIs cleared in 1–2 h, letting nocturnal acid break through (pH below 3.0); clarithromycin was added to cover the gap when amoxicillin degraded.

Why Acid Suppression Is Critical

Neutral niche: H. pylori lives in the near-neutral mucus layer (pH 6.0–7.0) and multiplies best when ambient pH is above 6.0.

Acid-induced dormancy: at pH below 4.0 it can enter a dormant coccoid state, where beta-lactams may fail (laboratory findings).

Acid-stable amoxicillin: amoxicillin degrades much faster at low pH than at neutral pH.

Sustained acid control: keeping pH above 6 over 24 hours may keep bacteria dividing and amoxicillin active

Amoxicillin acid stability, J Antimicrob Chemother 1997

P-CAB vs PPI: How Each Drug Binds Acid Pumps

PPI

Acid-activated prodrug; needs canalicular acidity (pH ~1.0) to activate. As it neutralises the stomach, activation falls off. Binds active pumps only, with 3–5 days to steady-state inhibition.

P-CAB

Weak base (pKa ~9.3) that accumulates in acidic canaliculi without acid activation. Reversible, high-affinity binding to active and resting pumps; faster onset.

Shin JM, Sachs G. Pharmacol Rev 2008; VA Vonoprazan monograph 2024

Vonoprazan Holds Gastric pH Longer Overnight

PPI:

acid suppression can wane overnight, with night-time pH falling to acidic levels and nocturnal breakthrough

Vonoprazan:

holds pH above 6 for longer, with fewer nocturnal dips

CYP2C19:

no considerable PK difference by polymorphism

Amoxicillin:

sustained acid control keeps levels above MIC through the day

FDA Voquezna label 2025; VA Vonoprazan monograph 2024

Dual Therapy v1.0: Proof of Concept

Biological proof

Taiwan and China trials suggested amoxicillin can eradicate H. pylori when pH is raised

Pharmacological ceiling

Short PPI half-life required frequent dosing; nocturnal acid escape; cure rates varied across trials

Core innovation

Yang et al., 2015 (Taiwan): rabeprazole 20 mg QID + amoxicillin 750 mg QID, 14 days

Yang first-line (ITT): dual 95.3% vs sequential 85.3% vs clarithromycin triple 80.7%

Yang rescue (ITT): dual 89.3% vs sequential 51.8% vs levofloxacin triple 78.6%

Yang JC et al. Clin Gastroenterol Hepatol 2015.

Tai et al., 2019 (Taiwan): esomeprazole 40 mg TID + amoxicillin 750 mg QID, 14 days

Tai (n=240): 14-day dual 91.7% vs 7-day quadruple 86.7% (P=0.21); adverse events 9.6% vs 23.0% (P=0.01)

Tai WC et al. J Antimicrob Chemother 2019.


Vonoprazan Dual Therapy

Vonoprazan 20 mg BID plus amoxicillin 1000 mg TID for 14 days

Sustained pH above 6 supports amoxicillin activity

No clarithromycin: no clarithromycin taste disturbance, and no exposure to local clarithromycin resistance

Study

Regimen and duration

ITT eradication

PHALCON-HP, US/Europe (PubMed 35679950)

Vonoprazan 20 mg BID + amoxicillin 1 g TID, 14 days

77.2% vs 68.5% lansoprazole triple. Clarithromycin-resistant subgroup: 69.6% vs 31.9%

2026 RCT (doi 10.1111/hel.70112)

Vonoprazan 20 mg BID + amoxicillin 1 g TID, 10 days

92.0%

2026 RCT (same study)

Vonoprazan triple therapy, 14 days

89.6%

2026 RCT (same study)

Vonoprazan-bismuth quadruple therapy, 10 days

88.8%


PHALCON-HP: Trial design

Phase 3, randomized 1:1:1, controlled trial in the US and Europe. 1,046 treatment-naive adults, 14 days of treatment.

OPEN-LABEL

Vonoprazan dual therapy

Vonoprazan 20 mg twice daily + amoxicillin 1 g three times daily.

DOUBLE-BLIND

Vonoprazan triple therapy

Vonoprazan 20 mg twice daily + amoxicillin 1 g twice daily + clarithromycin 500 mg twice daily.

DOUBLE-BLIND

Lansoprazole triple therapy

Lansoprazole 30 mg twice daily + amoxicillin 1 g twice daily + clarithromycin 500 mg twice daily.

Primary endpoint: noninferiority of each vonoprazan regimen vs lansoprazole triple therapy, with a 10-percentage-point margin, among patients with strains resistant to neither clarithromycin nor amoxicillin.

Secondary endpoints included superiority vs lansoprazole triple therapy in clarithromycin-resistant infections and in all patients.

Source: Chey et al. Gastroenterology 2022

PHALCON-HP: Dual Therapy Leads in Resistant Strains

Vonoprazan–amoxicillin dual vs lansoprazole triple therapy

77.2%

Vonoprazan–amoxicillin dual

68.5%

Lansoprazole triple


Performance in clarithromycin-resistant infection

Eradication in Clarithromycin-Resistant Strains (%)

Resistant strains: 69.6% vs 31.9% (p < 0.001)

PPI Triple = lansoprazole triple · PHALCON-HP Phase 3 trial (p < 0.001 in clarithromycin-resistant subgroup)

Side effects and completion

Adverse events: overall treatment-emergent adverse event frequency was similar across regimens

Completion (registry disposition): subject disposition lists 334/349 participants completed in dual and 334/348 in lansoprazole triple.


Reference: Chey WD, Megraud F et al. Gastroenterology 2022


Asian Trials: High-Dose Dual Therapy Performs Well

Study

VA: vonoprazan + amoxicillin, 14 days (ITT)

Comparator: bismuth-containing quadruple regimen

Comparator (ITT)

Peng 2023 (Guangdong, China)

89.9%

Esomeprazole + amoxicillin + clarithromycin + bismuth, 14 days

81.0%

Hu 2023 (mainland China)

88.7%

Esomeprazole + bismuth + amoxicillin + metronidazole; comparator duration not established in abstract

91.8%

7 and 10 days

Not satisfactorily effective in some studies.

Hu 2023: the authors' own prior 7- and 10-day regimens fell short of their >90% target

Tao 2025 (multicentre RCT, treatment-naive, vonoprazan 20 mg BID + amoxicillin, intention-to-treat): 7 days gave 84.0% (1 g TID) and 81.6% (750 mg QID); 10 days gave 91.2% and 90.4%.

Peng et al. Clin Exp Med 2023 (Guangdong, China); Hu et al. Helicobacter 2023 (mainland China); Tao et al. 2025, Optimizing Duration and Dosing Frequency of Vonoprazan-Amoxicillin Dual Therapy for Helicobacter pylori: A Multicenter Randomized Trial

Avoiding Excessive Antibiotic Exposure

Part 02: Minimize Antibiotic Exposure

Two drugs, not three to four: fewer drugs to take each day

No clarithromycin or metronidazole: avoids taste disturbance, nausea and diarrhoea from these drugs

Supports treatment completion: adherence is what links an eradication regimen to cure


Half the Pills, but Completion Still Matters

QUADRUPLE THERAPY

16
pills/day

VONOPRAZAN DUAL

6–8
pills/day

BURDEN

−50–62.5%

  • Adverse events: about 30% with dual vs 34% with triple (PHALCON-HP)
  • Completion depends on the patient's willingness to finish
  • Clarithromycin-resistant strains: triple therapy gave 65.8% vs 69.6% with dual therapy, with more adverse events

Fallone CA et al. Gastroenterology 2016; Chey WD et al. Gastroenterology 2022; Chey WD et al. Am J Gastroenterol 2024

Multi-Drug Regimens Disturb the Gut Microbiome

  • Ecology: multi-antibiotic regimens disturb the gut microbiome
  • Secondary dysbiosis: reported after quadruple therapy, as bloating and altered bowel habits; frequency varies
  • Dual therapy: one antibiotic; microbiome effects need study

Jakobsson HE et al. PLoS ONE 2010

Clarithromycin Benefit Depends on Susceptibility

Nonresistant strains

Vonoprazan triple 84.7% vs dual 78.5%

Dual is vonoprazan plus amoxicillin. Triple adds clarithromycin, with a different amoxicillin schedule.

Clarithromycin-resistant

Vonoprazan triple 65.8% vs dual 69.6%

In resistant infections, the dual regimen was numerically higher. Clarithromycin added no benefit here.

Adverse effects

Clarithromycin can cause dysgeusia.

Overall adverse-event frequency was similar across trial groups. Do not attribute all adverse effects to clarithromycin.



Is the Extra Antibiotic Worth the Exposure?

  • Resistant strains: 65.8% triple vs 69.6% dual
  • Adverse events: about 34% triple vs 30% dual
  • More is less!


Chey WD et al. Gastroenterology 2022

Resistant strain cure vs. adverse events

Resistant strains: 3.8-point cure difference; adverse events about 30% vs 34%

Overcoming RAHS: Review Acid Suppression at Day 14

Part 03: Expect RAHS

Routine habit

Extra PPI is often prescribed after eradication without a clear indication.

No universal stop date

Review at day 14; continue only while an indication persists, such as bleeding ulcer or severe esophagitis.

Rebound acid

Hypertrophied acid-secreting cells can cause rebound after stopping. Small omeprazole studies saw it after 90 days; evidence after a 14-day vonoprazan course is lacking.

Symptom options

Alginates or H2RAs may relieve symptoms (expert opinion, not guideline advice). Avoid reflexive long-term PPI use.

Waldum HL et al. 1996

Rebound Reflux

  • Acid output can recover after eradication as inflammation eases; this is a physiological explanation, not a proven marker of cure
  • New heartburn may unmask reflux, especially with hiatal hernia or a weak lower esophageal sphincter
  • Symptoms do not correlate with cure rate


Kyoto global consensus report, Gut 2016; Chey WD et al. Am J Gastroenterol 2024


With great power comes great responsibility.

Vonoprazan suppresses acid more strongly than PPIs. That power is why its long-term profile needs care.


Vonoprazan

PPIs

Short-term side effects

Overall adverse events similar, RR 1.08 (95% CI 0.89–1.31); less diarrhoea in one meta-analysis; ADRs in 2.3% of 1,174 Japanese patients over 12 months

Any, serious and discontinuation events not significantly different (77 studies, Xu 2023)

Gastric changes at 5 years

No malignant change or neuroendocrine tumours; parietal cell hyperplasia 97.1%, foveolar hyperplasia 14.7%; median gastrin 625 pg/mL

Parietal cell hyperplasia 86.5%, foveolar hyperplasia 1.9%; median gastrin 200 pg/mL (VISION, Uemura 2025)

Long-term signals

Unknown beyond 5 years and in other populations

Associations with C. difficile, fractures, B12 and magnesium deficiency, kidney disease and dementia; few proven causal (Malfertheiner 2017; Dhar 2020)

Sources: Uemura et al., Clin Gastroenterol Hepatol 2025; Simadibrata et al., J Gastroenterol Hepatol 2022; Xu et al., Ther Adv Gastroenterol 2023; Gong et al., Rev Esp Enferm Dig 2022; Manabe et al., Expert Opin Drug Saf 2025; Malfertheiner et al., Nat Rev Gastroenterol Hepatol 2017; Dhar et al., 2020.

Costs of Chronic Hypochlorhydria

HIP FRACTURE

OR 1.44

Long-term PPI >1 yr

SIBO RISK

OR 2.28

Pooled studies

C. DIFFICILE

OR 1.74

Pooled meta-analysis

Acid helps ionize dietary calcium; the effect of PPIs on calcium absorption is uncertain.

Acid normally kills most swallowed microbes; suppressed acid is associated with SIBO and C. difficile infection.

Yang YX et al. JAMA 2006; Lo WK, Chan WW 2013; Kwok CS et al. 2012.


Long-Term PPIs and Gastric Cancer: A Contested Signal

  • 63,397 eradicated patients; median follow-up 7.6 years
  • Adjusted HR 2.44 (95% CI 1.42–4.20): association, not proof of cause
  • Risk rises with duration: HR 5.04 (≥1 yr) to 8.34 (≥3 yrs)
  • No risk signal with H2RAs: H2RA maintenance showed HR 0.72, used as a negative control, not as proof of safety
  • Validity questioned: the Canadian Association of Gastroenterology has serious reservations (confounding by indication, no baseline atrophy or IM data)

Reference: Cheung KS et al. Gut 2018.

Gastric Cancer Hazard Ratio by Duration

Associated risk by PPI duration vs H2RA (HKU cohort, n=63,397; observational)

Conclusions

Vonoprazan and amoxicillin 14-day dual therapy is a viable option as first-line Helicobacter pylori eradication.

Clarithromycin adds marginal benefit, if any, when used as first-line without susceptibility testing, and adds potential adverse effects; its incremental value depends on susceptibility and setting.

Rebound acid hypersecretion should be anticipated and actively counseled.

Prolonged iatrogenic achlorhydria has unknown long-term outcomes and should be an important clinical consideration when treating any acid-related disorders.

Thank you

Questions welcome