Guidelines

Screening and eradication of Helicobacter pylori for

gastric cancer prevention: the Taipei global consensus

Gut: first published as 10.1136/gutjnl-2020-322368 on 1 October 2020. Downloaded from http://gut.bmj.com/ on August 14, 2023 by guest. Protected by copyright.
Jyh-­Ming Liou ‍ ‍,1,2,3 Peter Malfertheiner,4,5 Yi-­Chia Lee ‍ ‍,1,2,6
Bor-­Shyang Sheu ‍ ‍,7,8 Kentaro Sugano,9 Hsiu-­Chi Cheng,7,10 Khay-­Guan Yeoh ‍ ‍,11
Ping-­I Hsu,12 Khean-­Lee Goh,13 Varocha Mahachai,14 Takuji Gotoda ‍ ‍,15
Wei-­Lun Chang,7 Mei-­Jyh Chen,1,2,16 Tsung-­Hsien Chiang,1,2,16 Chieh-­Chang Chen,1,2
Chun-­Ying Wu ‍ ‍,17,18 Alex Hwong-­Ruey Leow,13 Jeng-­Yih Wu,8 Deng-­Chyang Wu,8
Tzu-­Chan Hong,1,2,19 Hong Lu ‍ ‍,20 Yoshio Yamaoka ‍ ‍,21,22 Francis Megraud,23
Francis K L Chan ‍ ‍,24,25 Joseph JY Sung,24,25 Jaw-­Town Lin ‍ ‍,1,26
David Y Graham ‍ ‍,22 Ming-­Shiang Wu ‍ ‍,1,2 Emad M El-­Omar ‍ ‍,27,28 Asian Pacific
Alliance on Helicobacter and Microbiota (APAHAM)

►► Additional material is ABSTRACT INTRODUCTION

published online only. To view, Objective A global consensus meeting was held Despite a recent decline in incidence, gastric cancer
please visit the journal online
(http://​dx.​doi.o​ rg/​10.​1136/​ to review current evidence and knowledge gaps and remains one of the leading causes of cancer death
gutjnl-2​ 020-​322368). propose collaborative studies on population-­wide worldwide.1 The major breakthrough in research on
screening and eradication of Helicobacter pylori for gastric cancer occurred with the discovery of Helico-
For numbered affiliations see
end of article. prevention of gastric cancer (GC). bacter pylori and proof that the infection was aeti-
Methods 28 experts from 11 countries reviewed ologically related to gastric cancer. The organism
Correspondence to the evidence and modified the statements using the has been classified as a class 1 human carcinogen.2
Professor Ming-­Shiang Wu, Delphi method, with consensus level predefined as H. pylori causes a pattern of gastritis described as
Department of Internal ≥80% of agreement on each statement. The Grading acute-­on-­
chronic inflammation, which leads to
Medicine, National Taiwan
University Hospital, Taipei of Recommendation Assessment, Development and chronic progressive gastric damage and ultimately to
10002, Taiwan; Evaluation (GRADE) approach was followed. gastric atrophy. Gastric cancer is an inflammation-­
m
​ ingshiang@​ntu.e​ du.​tw Results Consensus was reached in 26 statements. At associated malignancy in which the infection directly
an individual level, eradication of H. pylori reduces the and indirectly causes progressive genetic damage to
J-­ML and PM contributed
equally. risk of GC in asymptomatic subjects and is recommended the gastric epithelium that may eventually lead to
unless there are competing considerations. In cohorts gastric adenocarcinoma. Risk of developing gastric
DYG, M-­SW and EME-­O are of vulnerable subjects (eg, first-­degree relatives of cancer in H. pylori infected individuals can be esti-
joint senior authors. patients with GC), a screen-­and-­treat strategy is also mated based on the degree and extent of mucosal
Received 28 June 2020 beneficial. H. pylori eradication in patients with early GC damage and atrophy, recognised as metaplastic
Revised 27 July 2020 after curative endoscopic resection reduces the risk of epithelia with or without intraepithelial neoplasia or
Accepted 12 August 2020 metachronous cancer and calls for a re-­examination on dysplasia. Interventional trials and studies in humans
Published Online First the hypothesis of ’the point of no return’. At the general have shown that eradication of H. pylori can reduce
1 October 2020
population level, the strategy of screen-­and-­treat for H. the risk of gastric cancer, which is related to the
pylori infection is most cost-­effective in young adults in extent of genetic alterations and epigenetic modi-
regions with a high incidence of GC and is recommended fications present at the time of H. pylori eradica-
preferably before the development of atrophic gastritis tion.3–7 However, there is a great gap in translating
and intestinal metaplasia. However, such a strategy may this basic and clinical knowledge into public health
still be effective in people aged over 50, and may be intervention through population-­wide screening and
integrated or included into national healthcare priorities, eradication of H. pylori, which ultimately prevent the
such as colorectal cancer screening programmes, to development of gastric cancer. First, we lack updated
optimise the resources. Reliable locally effective regimens data on the global disease burden of H. pylori infec-
based on the principles of antibiotic stewardship are tion and gastric cancer and we need to better iden-
recommended. Subjects at higher risk of GC, such tify the target populations (general population or
as those with advanced gastric atrophy or intestinal selected vulnerable populations) for such screening
metaplasia, should receive surveillance endoscopy after and eradication programmes. Second, the imple-
eradication of H. pylori. mentation of mass screening requires consideration
© Author(s) (or their
employer(s)) 2020. No Conclusion Evidence supports the proposal that of the choice of non-­invasive test, when to proceed
commercial re-­use. See rights eradication therapy should be offered to all individuals to endoscopy, whether and how to test for eradica-
and permissions. Published infected with H. pylori. Vulnerable subjects should be tion efficacy and how to survey those with advanced
by BMJ. atrophic gastritis, how to implement this programme,
tested, and treated if the test is positive. Mass screening
To cite: Liou J-­M, and eradication of H. pylori should be considered in how to treat asymptomatic H. pylori infected subjects
Malfertheiner P, Lee Y-­C, et al. populations at higher risk of GC. for gastric cancer prevention, and how to identify
Gut 2020;69:2093–2112. subjects at higher risk of gastric cancer for endoscopic
Liou J-­M, et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368    2093
 Guidelines
surveillance after H. pylori eradication. Additionally, there are also pad system for the second round of anonymous voting. The
some concerns about the widespread use of antibiotics, including level of agreement and grade of recommendation for each state-
the emergence of antibiotic resistance of bacteria other than H. ment were shown on the screen in real time. Statements which

Gut: first published as 10.1136/gutjnl-2020-322368 on 1 October 2020. Downloaded from http://gut.bmj.com/ on August 14, 2023 by guest. Protected by copyright.
pylori, the perturbation of gut microbiota, potential effects on the failed to reach ≥80% of agreement during the second round of
risk of extragastric disorders, such as obesity, gastro-­oesophageal voting were further discussed and modified and voting carried
reflux disease, metabolic syndrome, and autoimmune diseases.8 9 In out again, if necessary. Seven statements which failed to reach
December 2013, the International Agency for Research on Cancer consensus of ≥80% despite this process were discarded. A total
(IARC) organised a working group meeting to review the evidence of 26 statements passed this process and were voted on in the
for eradication of H. pylori as a strategy for prevention of gastric third round. Three statements (Nos 8, 10 and 18) which failed
cancer, and published a working group report.10 11 In September to reach ≥80% of agreement in the third round voting were
2019, we held a monothematic scientific conference (10th Asian further discussed and modified. Consensus was then reached in
Pacific topic conference) organised by the Asian Pacific Association the fourth round voting for these three statements.
of Gastroenterology (APAGE), the Japanese Society of Gastroen-
terology (JSGE) and the Gastroenterological Society of Taiwan Role of the funding sources
(GEST) under the theme of “screening and eradication of H. pylori The consensus meeting was funded by GEST with support from
infection for gastric cancer prevention”. After the topic confer- industries, National Taiwan University Hospital, and Ministry of
ence, we held an expert consensus meeting in Taipei to review Science and Technology of Taiwan. The funding sources had no
current evidence, identify knowledge gaps and propose collabora- role in the planning and organisation of the meeting, study design,
tive studies to resolve these concerns on mass screening and eradi- data collection, analysis or interpretation, report writing or the
cation of H. pylori for gastric cancer prevention. decision to submit this manuscript for publication. All authors had
full access to the data and participated in the decision to submit for
publication.
METHODS
Consensus development process
RESULTS
Five major topics were chosen by core members of the organising
The statements that reached consensus are summarised in table 1.
committee (J-­ML, Y-­CL, B-­SS, EME-­O and M-­SW). Drafts of clin-
ical questions (CQs) about each topic were prepared by J-­ML and
were further revised by core members (PM, Y-­CL, DYG, EME-­O DISEASE BURDEN OF H. PYLORI INFECTION ASSOCIATED
and M-­SW). Altogether, 33 CQs were selected for the first round GASTRIC CANCER
of voting. Faculty members selected from members of APAGE, CQ 1. Is gastric cancer still a public health threat and
JSGE, GEST, European Helicobacter and Microbiota Study Group underestimated in the world?
and Healthy Stomach Initiative were assigned to one or two of Statement 1: Although the global age-­standardised incidence and
the five subgroups according to their expertise. The selection of mortality rate of gastric cancer is decreasing, the number of new
core members was based on expertise. The selection of faculty cases of gastric cancer remains high due to an increase of the
members was based on both expertise and geographical represen- elderly population.
tativeness. The faculty members (J-­ML, Y-­CL, B-­SS, H-­CC, KG-­Y, Agreement: agree (96%).
W-­LC, M-­JC, T-­HC, C-­CC, C-­YW, P-­IH and M-­SW) were assigned Grade of recommendation: strong (84%), weak (16%), weak
to perform systematic reviews of CQs 1–3 and to prepare the state- against (0%), strong against (0%).
ments, which were edited in the first steering committee on 20 July Evidence level: moderate.
2019. The revised draft statements were further edited by modera-
tors and core members (J-­ML, PM, Y-­CL, B-­SS, DYG, EME-­O and Comments
M-­SW). The Delphi method was used for consensus development. Gastric cancer remains the fifth most common cancer and the third
The Grading of Recommendation Assessment, Development and leading cause of cancer deaths worldwide.1 The 5-­year survival
Evaluation (GRADE) system was applied for grading of recom- rate of advanced gastric cancer is lower than 30% in Europe.1
mendation and evidence level (online supplementary table 1S and The estimated age-­standardised incidence in 2018 was 15.7 and
2S).12 Consensus level was predefined as ≥80% of agreement on 7.0 per 100 000 in males and in females worldwide, respectively
each statement. according to the GLOBOCAN 2018 database (figure 1A).1 13 The
The supporting evidence for each statement were revised by estimated age-­standardised incidence was as high as 30.2 and 12.5
core members (J-­ML, PM, Y-­CL, B-­SS, DYG, EME-­O and M-­SW) per 100 000 in males and in females in the WHO Western Pacific
and was then emailed to all faculty members 2 weeks before the region, respectively (figure 1A).1 The estimated age-­standardised
face-­to-­face meeting in Taipei. The first voting was done by all incidence was highest in Korea, Mongolia, Japan, China and
faculty members via the electronic voting system 1 week before Kyrgyzstan (figure 1B).1 13 There were more than one million
the meeting. They were asked to indicate their agreement (agree new cases worldwide in 2018 and more than 60% (640 000) of
or not agree), levels of recommendation (strong, weak, weak them occurred in the WHO Western Pacific region (figure 1C).
against or strong against), level of evidence, and reasons for The estimated new cases were highest in China, Japan, India
disagreement for each statement. The statements were further and Korea.1 The estimated lifetime (up to age 74 years) cumu-
revised by the core members (J-­ ML, PM, FM, EME-­ O and lative risk of incidence of gastric cancer was 1.9% and 0.8% in
M-­SW) accordingly. The supporting evidence for each clinical males and females worldwide, respectively, and was highest in
question was presented in the plenary lecture during the topic the WHO Western Pacific region (figure 1D). It is estimated that
conference on 28 and 29 September 2019 in Kaohsiung. The gastric cancer develops in 6.9%, 5.6%, 4.9% and 3.5% of males
face-­to-­face consensus meeting was held on 30 September and in Korea, Mongolia, Japan and China, respectively (figure 1E).1 13
1 October 2019 in Taipei. The statements and level of evidence Although it is expected that the incidence of gastric cancer will
were discussed and revised by all faculty members in a plenary be further reduced in the next two decades, the number of new
session and were then uploaded to the Zuvio electronic voting cases is expected to increase because of the increase of the elderly
2094 Liou J-­M, et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368
 Guidelines

Table 1 Summary of consensus recommendations for screening and eradication of H. pylori for gastric cancer prevention
No. Statement Agree Evidence level Limitations of current evidence and areas for future research

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Disease burden of H. pylori infection-­associated gastric cancer
1 Although the global age-­standardised incidence and mortality rate of 96% Moderate Lack of cancer registration database in many countries or regions;
gastric cancer is decreasing, the number of new cases of gastric cancer updated prevalence of H. pylori needed for more accurate estimation of
remains high due to an increase of the elderly population future disease burden
2-1. Although the prevalence of H. pylori is decreasing in most Western 96% Low Lack of updated prevalence in many countries; potential selection bias,
countries, it remains high in populations with a high incidence of gastric age-­standardised prevalence not reported and accuracy of test not
cancer validated in some studies
2-2. The prevalence of H. pylori in children has fallen below 10% in some 96% Low Lack of updated prevalence in many countries and potential selection
populations, but remains high in many parts of the world bias
3. The worldwide attributable fraction for H. pylori in gastric cancer (GC) is 88% Moderate Estimation based on nested case–control studies in Western
higher than 85%, indicating that the majority of GC can be prevented if populations
H. pylori infection is eliminated from a population
4. Eradication of H. pylori reduces the risk of gastric cancer in infected 92% Moderate Trials conducted in Eastern populations, except one from Columbia,
subjects number of cases of gastric cancer relatively small; progression of
gastric precancerous lesions as primary outcome in several trials, risk
reduction for intestinal type and diffuse type not known, long-­term
adverse consequences not assessed, eradication rate ~70%, reinfection
rate ~2–7%/year
5. Eradication of H. pylori after resection of early gastric cancer is 96% High Nearly all were intestinal type gastric cancer
recommended because it reduces the risk of metachronous gastric cancer
Implementation of H. pylori screening and eradication programme at population level
6. Screening and eradication of H. pylori for gastric cancer prevention is 84% Low Estimation derived from cost-­effectiveness analysis, lack of direct
recommended in populations with a high incidence or high risk of gastric evidence from randomised trial, prevalence of H. pylori should also be
cancer considered
7. Screening and eradication of H. pylori before the development of atrophic 84% Low Lack of direct evidence from randomised trials, the age of development
gastritis and intestinal metaplasia is recommended of precancerous lesions varies according to gender and ethnicity
8. The strategy of screen-­and-­treat for H. pylori infection is most cost-­ 84% Low Assumption based on observational studies rather than randomised
effective in young adults for gastric cancer prevention in regions with a trials, saving related to dyspepsia or peptic ulcer disease rarely
high incidence of gastric cancer considered in the models, benefit reported by life-­years saved rather
than QALYs
9. Young individuals would benefit most from H. pylori eradication because 92% Low Lack of randomised trials showing the reduction of gastric cancer risk
it cures H. pylori related gastritis, reduces the risk of gastric cancer and in young individuals and the transmission
reduces transmission to their children
10. A urea breath test or H. pylori stool antigen test are the preferred 88% Moderate Lack of direct comparison of the accuracy and acceptability of three
tests for mass screening, but a locally validated serology test may be non-­invasive tests in mass screening
considered
11. In H. pylori infected individuals, endoscopy is additionally recommended 100% Low Prospective studies needed for risk stratification in populations with
for those with a higher risk for gastric cancer different incidence of gastric cancer
12. Population-­wide screening and eradication of H. pylori infection should 92% Low Population-­wide screening and eradication programme only in Japan
be integrated or included in national healthcare priorities to optimise the and some regions in China, Korea and Taiwan
resources
Treatment of H. pylori infection in mass eradication programmes
13. There is a trend of increasing resistance rates to clarithromycin and 100% Low Treatment-­experienced subjects not excluded in some, different
levofloxacin worldwide breakpoint of MICs used, lack of updated data in many countries
14. The antibiotic resistance profile of H. pylori in different regions, efficacy, 100% Low Priority of efficacy, adverse effects and cost in community settings
adverse effects and cost should be taken into account in choosing the remains debatable
optimal regimens in the community
15 Reliable locally effective regimens based on the principles of antibiotic 92% Moderate The impact of following the antibiotic stewardship principle needs to
stewardship are recommended be assessed in the community
16. Surveillance of the local antibiotic resistance of H. pylori is recommended 96% Moderate Resistance rate might vary in different regions in the same country and
to identify the optimal empirical therapy for mass eradication of H. pylori may change with time
in that population
17. The reinfection rate after H. pylori eradication is very low 96% Moderate Few studies reported the reinfection rate in the mass screening and
eradication in the community
18. Confirmation test of H. pylori eradication is not mandatory in mass 96% Low Formal cost-­effectiveness analysis using data from prospective trials is
screening, but should be performed in subsets of the population for needed to assess the necessity of confirmation test in all subjects
assessment of treatment efficacy
Potentially adverse consequences of H. pylori eradication
19. As with all antibiotic treatments, H. pylori eradication may lead to an 92% Very low Scarce evidence regarding the long-­term impacts of eradication
increase in antimicrobial resistance, but it should not preclude its use for therapy on the antimicrobial resistance at individual and population
gastric cancer prevention levels
20. Short-­term perturbation of faecal microbiota diversity occurs after H. 88% Low Scarce evidence regarding the long-­term impacts of eradication
pylori eradication, which largely recovers subsequently therapy on the composition of human microbiota, especially at species
level
21–1. Eradication of H. pylori does not increase the risk of new onset GORD 92% High  
21–2. H. pylori eradication therapy does not increase the risk of relapse of 96% Moderate  
GORD
22. H. pylori eradication may be associated with a small increase in body 80% Low Well-­designed randomised trials are needed to assess the impacts of
weight, but does not increase the risk of metabolic syndrome eradication therapy on human metabolism and metabolic disorders

Continued
Liou J-M
­ , et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368 2095
 Guidelines

Table 1 Continued
No. Statement Agree Evidence level Limitations of current evidence and areas for future research

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23. H. pylori eradication does not increase the risk of asthma, inflammatory 80% Very low Lack of evidence from randomised trials or large-­scale prospective
bowel disease and other immune-­related diseases cohort studies
Endoscopic surveillance for gastric cancer after H. pylori eradication
24. Subjects with advanced gastric atrophy or intestinal metaplasia should 92% Low Evidence from retrospective studies with relatively small sample size.
receive surveillance endoscopy to detect gastric cancer after H. pylori Eradication not confirmed in some studies
eradication
25. Surveillance endoscopy is suggested every 2 to 3 years for subjects with 92% Low Large-­scale prospective cohort studies/randomised trials/cost-­
advanced gastric atrophy or intestinal metaplasia, and every 12 months effectiveness analysis are warranted to assess the optimal surveillance
after the removal of neoplasia interval
26. Genetic and epigenetic markers show promise in stratifying gastric 92% Low Studies are needed to assess the role of serum markers, endoscopic
cancer risk after H. pylori eradication, but require further validation in features, histological grading and molecular markers in risk
prospective studies stratification
GORD, gastro-­oesophageal reflux disease; MICs, minimum inhibitory concentrations; QALYs, quality of life years.

population (figure 1F). However, cancer registries are not avail- Middle East and Africa.20 The prevalence of H. pylori in children
able in many countries. The incidence of gastric cancer is probably and adolescents in studies published during 2010–2020 is shown
underestimated in countries with limited medical and endoscopic in figure 2B.
resources. On the other hand, the prevalence of H. pylori infec- However, there are several limitations to the current evidence
tion is decreasing dramatically in other countries. Updated data concerning the global prevalence of H. pylori infection. First,
are needed to produce a more accurate estimate of the current and updated data on the prevalence are limited, making it difficult to
future disease burden of gastric cancer. estimate the true level of H. pylori worldwide. Second, the tests
used to survey the prevalence of H. pylori were heterogeneous
CQ 2. Does H. pylori infection, the major cause of gastric and the accuracy of these tests varied. Third, the methods used to
cancer, remain prevalent in the world? recruit study subjects and the inclusion and exclusion criteria also
Statement 2-1: Although the prevalence of H. pylori is decreasing varied. Fourth, the age-­standardised prevalence of H. pylori infec-
in most Western countries, it remains high in populations with a tion was not reported in the majority of these studies. Since the
high incidence of gastric cancer. prevalence of H. pylori is usually higher in older people and lower
Agreement: agree (96%). in the younger generations, studies that recruit a higher proportion
Grade of recommendation: strong (76%), weak (24%), weak of older people may overestimate the actual disease burden of H.
against (0%), strong against (0%). pylori infection. Therefore, it is crucial to survey the updated prev-
Evidence level: low. alence of H. pylori using the same study protocol and validated
Statement 2-2: The prevalence of H. pylori in children has tests. It is suggested that the age-­standardised prevalence of that
fallen below 10% in some populations, but it remains high in population and the prevalence according to birth years should be
many parts of the world. reported in future studies.
Agreement: agree (96%).
Grade of recommendation: strong (68%), weak (28%), weak CQ 3. What is the proportion of gastric cancer attributable to
against (0%), strong against (4%). H. pylori infection?
Evidence level: low. Statement 3: The worldwide attributable fraction for H. pylori
in gastric cancer is higher than 85%, indicating that the majority
Comments of gastric cancer can be prevented if H. pylori infection is elimi-
A systematic review and meta-­ analysis showed that the preva- nated from a population.
lence of H. pylori infection was highest in Africa (79.1%), Latin Agreement: agree (88%).
America and the Caribbean (63.4%), and Asia (54.7%), but was Grade of recommendation: strong (68%), weak (28%), weak
lower in Northern America (37.1%) and Oceania (24.4%) in the against (0.0%), strong against (4%).
general adult population from 1970 through 2016.14 It was esti- Evidence level: moderate.
mated that 4.4 billion of people are infected with H. pylori world-
wide.14 However, the prevalence of H. pylori is decreasing in the Comments
younger generations (<40 years) in many populations. Recent The aetiology of gastric cancer (adenocarcinoma) is heterogeneous.
studies showed significant reduction in the prevalence of H. Hereditary diffuse-­type gastric cancer accounts for 1–2% of gastric
pylori in several countries, including the United States, Japan and cancer and is attributable to germline mutations in certain genes,
Taiwan.15–17 The updated prevalence of H. pylori during 2015– such as the E-­cadherin gene which is associated with a penetrance
2020 in the world is shown in figure 2A and online supplementary rate of greater than 60%.22 Adenocarcinoma of the cardia accounts
table 3S. for 10–15% of gastric cancer and is mostly associated with gastro-­
The majority of H. pylori infections are acquired in childhood, oesophageal reflux disease, obesity and cigarette smoking.23 The
usually before the age of 10.18 Therefore, the prevalence of H. aetiology of cancer at the gastro-­oesophageal junction is heteroge-
pylori infection in children may reflect the disease burden in that neous, and it can arise in advanced atrophic gastric mucosa attrib-
population decades later. Recent studies showed that the preva- utable to H. pylori if two-­thirds of the tumour extends into the
lence of H. pylori in children has been fallen below 10% in some stomach.24 Epstein-­Barr virus associated with lymphoepitheioma-­
populations, such as Germany, Japan, Korea, Taiwan and Hong like carcinoma accounts for 4–6% of gastric cancer.25 Interactions
Kong.16 19–21 In contrast, the prevalence of H. pylori is still higher of H. pylori infection with dietary habits (eg, high salt diet), cigarette
than 10% in many paediatric populations, such as Latin America, smoking and host genetic factors contribute to the development
2096 Liou J-­M, et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368
 Guidelines

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Figure 1 Estimated disease burden of gastric cancer in 2018 according to GLOBOCAN database.13 (A) Incidence and mortality of gastric cancer
according to WHO regions.13 (B) Countries with highest incidence of gastric cancer.13 (C) Number of patients with gastric cancer and death according
to WHO regions.13 (D) Cumulative risk of incidence and mortality of gastric cancer according to WHO regions.13 (E) Countries with highest cumulative
risk of incidence of gastric cancer in 2018, ages 0–74.13 (F) Predicted number of incident cases of gastric cancer in the next two decades.13 ASR, age-­
standardised incidence.

of non-­cardia gastric cancer.9 Cohort studies in Japan and Taiwan Agreement: agree (92%).
showed that 1–2% of H. pylori infected subjects developed gastric Grade of recommendation: strong (92%), weak (4%), weak
cancer.26 Interestingly, they showed that none of the H. pylori unin- against (0%), strong against (4%).
fected subjects developed gastric cancer after a median follow-­up Evidence level: moderate.
of 8–10 years.26 Using both enzyme-­linked immunosorbent assay
and multiple antigen immunoblot for detection of H. pylori infec-
tion in four nested case–control studies, Plummer et al estimated CQ 5. Does H. pylori eradication reduce the risk of
that the worldwide attributable fraction of H. pylori for non-­cardia metachronous gastric cancer after curative endoscopic
gastric cancer is 89%, indicating that more than 85% of non-­cardia resection of early gastric cancer?
gastric cancer could be prevented if H. pylori were not present in Statement 5: Eradication of H. pylori after resection of early
that population.27 gastric cancer is recommended because it reduces the risk of
metachronous gastric cancer.
CQ 4. Does H. pylori eradication reduce the risk of gastric Agreement: agree (96%).
cancer in H. pylori infected subjects? Grade of recommendation: strong (88%), weak (8%), weak
Statement 4: Eradication of H. pylori reduces the risk of gastric against (0%), strong against (4%).
cancer in infected subjects. Evidence level: high.
Liou J-M
­ , et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368 2097
 Guidelines
(4–22 years), gastric cancer developed in 71 and 127 subjects
among the treated and non-­treated groups, respectively (risk
ratio (RR) 0.55, 95% CI 0.42 to 0.74). It is noteworthy that

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eradication of H. pylori appears to be ineffective for the
prevention of gastric cancer in the two trials that included
100% of subjects with precancerous lesions, including low-
to high-­grade dysplasia at baseline. 28 35 In subgroup analysis,
Wong et al showed that eradication therapy was significantly
better than placebo in subjects without precancerous lesions at
baseline.3 This indicates that eradication of H. pylori before the
development of precancerous lesions offers better protection
against gastric cancer. A community-­based study conducted in
the Matsu Islands, Taiwan, showed a short-­term reduction of
25% in the incidence of gastric cancer around 5 years after mass
eradication. After long-­term follow-­up of 12 years, a significant
reduction of 53% was observed and a greater reduction of 68%
would be expected by 2025.36 37
There are 3 randomised controlled trials included a total
of 1841 patients with gastric cancer who received curative
endoscopic resection and eradication (n=910) versus no treat-
ment or placebo (n=931) for secondary prevention of gastric
cancer (table 2).4 38 39 The mean age was greater than 60 years
at baseline and more than 70% of them were male. The eradi-
cation rates ranged from 75% to 83%. At the end of follow-­up
(3–6 years), gastric cancer developed in 40 and 87 patients
in the treated and non-­treated groups, respectively (RR 0.48,
95% CI 0.33 to 0.69). Meta-­analysis of another 10 prospective
or retrospective cohort studies also showed that eradication
therapy may reduce the risk of metachronous gastric cancer
after curative endoscopic resection (RR 0.44, 95% CI 0.33 to
0.58).40 The result indicates that eradication therapy is still
Figure 2 Updated global prevalence of H. pylori infection (reference effective for gastric cancer prevention in older patients with
to online supplementary table 3). (A) Prevalence of H. pylori in adults gastric cancer who already have precancerous lesions in their
(2015–2020). (B) Prevalence of H. pylori in children (2010–2020). stomach.
The effectiveness of eradication in healthy H. pylori infected
Comments subjects for gastric cancer prevention is being assessed in another
Seven randomised clinical trials including a total of 8834 two large-­scale double blind randomised trials in China and
healthy H. pylori infected subjects receiving eradication Korea (table 3).41 The effectiveness of H. pylori eradication has
therapy (n=4461) versus no treatment or placebo (n=4373) also been assessed in another randomised controlled trial in
for primary prevention of gastric cancer have been reported the UK, in which the primary outcome is peptic ulcer bleeding.
(table 2).3 5 28–35 The mean age was about 50 years at baseline Three ongoing trials in UK, Taiwan, and Latvia are examining
and about half of them were males. The eradication rates at whether screening and eradication of H. pylori is effective in
baseline ranged from 70% to 84%. At the end of follow-­up reducing the incidence of gastric cancer (table 3).

Table 2 Efficacy of H. pylori eradication in the risk reduction of gastric cancer in randomised trials
Country/trial Mean age (years)/proportion Regimen/ Eradication rate in With precancerous Follow-­up GC/total in treated vs
Study start year of male subjects (%) duration (days) treated/non-­treated lesion at baseline (%)* period (years) non-­treated Risk ratio (95% CI)

Primary prevention     Meta-­analysis 0.55 (0.42 to 0.74)

 Correa et al28 Columbia/1994 51/46% BAM/14 days; 74% (1st+2nd) /15% 100% 6 years 3/437 vs 2/415 1.42 (0.24 to 8.48)
PAC/14 days
(second)
 Leung 2004 and China/1996 52/48% PAC/7 days 74.5%/9.3% 44.6% 10 years 2/276 vs 7/276 0.29 (0.06 to 1.36)
Zhou et al30 31
3
 Wong et al China/1994 42/54% PAM/14 days 83.7% 38.4% 7.5 years 7/817 vs 11/813 0.63 (0.25 to 1.63)
 Saito et al32 Japan/n.a. 20-­59Y/n.a. PAC/7 days 74.4% NA ≥4 years 2/379 vs 3/313 0.55 (0.09 to 3.27)
 Ma et al and Li et China/1995 47/50% PA/14 days 74%/NA 75.7% 22 years 41/1130 vs 78/1128 0.52 (0.36 to 0.76)
al33 34 Y7: 46%/10%
 Wong et al35 China/2002 53/46% PAC/7 days 71.3%/NA 100% 5 years 6/510 vs 3/514 2.02 (0.51 to 8.02)
 Choi et al5 Korea/2012 49/50% PAC/7 days 70.1%/7.1% 57.4% 9 years 10/912 vs 23/914 0.44 (0.21 to 0.91)
Secondary prevention     Meta-­analysis 0.48 (0.33 to 0.69)
 Fukase et al38 Japan/2001 69/76% PAC/7 days 74.9%/5% 75%/49% 3 years 8/272 vs 24/272 0.33 (0.15 to 0.73)
 Choi et al39 Korea/2005 60/68% PAC/7 days 82.6%/10.5% 66.1%/75.7% 6 years 18/444 vs 36/457 0.52 (0.30 to 0.89)
 Choi et al4 Korea/2003 60/75% PAC/7 days 80.4%/5.4% 80.2%/54.7% 6 years 14/194 vs 27/202 0.54 (0.29 to 1.00)

*the extent and severity of precancerous lesions varied among studies.

BAM, bismuth, amoxicillin and metronidazole; GC, gastric cancer; NA, not available; PAC, proton pump inhibitor, amoxicillin, clarithromycin; 1st+2nd, overall eradication rates.

2098 Liou J-­M, et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368

 Guidelines
IMPLEMENTATION OF H. PYLORI SCREENING AND eradication is reported in a meta-­analysis that included 24 studies,
ERADICATION PROGRAMME AT POPULATION LEVEL in which the benefit was most evident in populations with an
CQ 6. Who should we actively screen and treat H. pylori? incidence rate higher than 150 per 100 000 person-­years.6 This

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Statement 6: Screening and eradication of H. pylori for gastric observation is a reflection of the natural history of gastric cancer,
cancer prevention is recommended in populations with a high which is characterised by a long silent (latent) period during which
incidence or high risk of gastric cancer. atrophic gastritis/gastric atrophy is developing. When a sufficient
Agreement: agree (84%). proportion of the population has developed atrophy, the risk
Grade of recommendation: strong (64%), weak (32%), weak switches from linear to exponential (ie, from 150 to 300 to 600
against (0%), strong against (4%). per 100 000 person-­years, etc).6 Thus, eradication in the linear
Evidence level: low. phase will largely prevent gastric cancer altogether, whereas cure
after a sizeable proportion has developed atrophy and a definite
Comments risk will have a more dramatic effect but be overall less effective
There are two levels of questions about the effectiveness of for that population.6 Randomised trials have shown that H. pylori
screening and eradication of H. pylori for gastric cancer preven- eradication can reduce the risk of metachronous gastric cancer in
tion. First, can eradication therapy reduce the risk of gastric patients who have received endoscopic resection of early gastric
cancer in those with H. pylori infection (figure 3A)? Second, can cancer by up to 50%.4 38–40 For all populations, active testing and
screening and eradication of H. pylori reduce the risk of gastric treatment for H. pylori infection will reduce (or prevent) gastric
cancer in the general population (figure 3B). Ten randomised cancer.43 The numerical benefits are greatest in high-­risk popula-
trials showed that eradication of H. pylori can reduce the risk of tions and in these test-­and-­treat should be routinely performed.
gastric cancer in asymptomatic infected subjects. H. pylori may It is important to note that even intermediate- or low-­risk popu-
still be effective in those receiving curative endoscopic resection lations can contain subpopulations or immigrants with higher
for early gastric cancer, as shown in statements 4 and 5. The gastric cancer risk and are candidates for active screening. It is
effectiveness of H. pylori eradication for gastric cancer preven- also important to assess whether the test-­and-­treat strategy could
tion is essentially dependent on the efficacy of the treatment reduce the mortality rate of gastric cancer, which requires a longer
regimen and patients' adherence to it. The accuracy of the test follow-­up period than decline of the incidence rate.
for H. pylori infection, to follow the eradication success and On the individual level, ethnicity, immigration history, family
the reinfection/recrudescence rate is critical (figure 3A). Only history and lifestyle habits, prior endoscopic histories and the
one randomised trial has reported the effectiveness of screening positive results of non-­invasive testing for H. pylori and related
and eradication of H. pylori for gastric cancer prevention, but damage to the gastric mucosa (eg, pepsinogen testing) should
three clinical trials are ongoing that will provide information in be used to identify high-­risk subjects who should receive endo-
the next few years (table 3). The effectiveness of such strategy scopic/histological assessment first or receive immediate treat-
is expected to be higher if the participation rate for H. pylori ment for H. pylori infection.44
screening (p1), the prevalence of H. pylori infection in that The risk and incidence of gastric cancer vary greatly according
population (p2), the true positive rate of the H. pylori test (p3), to ethnicity, gender and geographical regions. Countries or popu-
the participation rate for eradication therapy (p4), the eradica- lations with an incidence of gastric cancer greater than 20 per
tion rate of treatment (p5) and the sustained eradication rate 100 000 person-­years, between 10 and 20 per 100 000 person-­
(p6) are higher. A high false-­negative rate of the H. pylori testing years, and lower than 10 per 100 000 person-­years are defined as
(p7) may reduce effectiveness, whereas a high false-­ positive high-, intermediate- and low-­risk populations according to prior
rate may increase the number of patients receiving unnecessary consensus meetings. The 20 countries with highest incidence of
antibiotics (figure 3B). Additionally, the efficacy of eradication gastric cancer shown in figure 1B are categorised as high-­risk
therapy to reduce gastric cancer can also be influenced by the population accordingly. The annual incidence was greater than
rate of mortality/incidence rate, which is an indirect estimate of 100 per 100 000 person-­years in men aged 55 or older in Korea
early detection.42 and Japan, and in men aged 65 years or older in China and
The magnitude of the protective effect of H. pylori eradication Brazil. Additionally, certain populations from a low-­incidence
also depends on the baseline risk. The relation of the baseline country may have a higher risk of gastric cancer, such as indige-
risk and the magnitude of the protective effect from H. pylori nous populations in Alaska, USA.

Table 3 The efficacy of H. pylori eradication or screen-­and-­eradication strategy in the risk reduction of gastric cancer: ongoing trials
Start year/expected
Country registration number Subjects/design Experiment group Control group Primary outcome Age (years) Sample size/status completion year

Effectiveness of H. pylori eradication

 China/ChiCTR-­TRC-10000979 Healthy subjects/double blind Bismuth quadruple Bismuth + omeprazole Gastric cancer incidence 25–54 94 101/recruitment 2011–2013/NA
therapy + placebo completed
 Korea/NCT02112214 Healthy H. pylori infected Bismuth quadruple Placebo Gastric cancer incidence 40–60 5224/recruitment 2014/2029
subjects/double blind therapy completed
 UK/NCT01506986 H. pylori-­infected aspirin user/ Triple therapy Placebo Peptic ulcer bleeding ≥60 3038/recruitment 2012/2021
double blind completed
Effectiveness of screening and eradication of H. pylori
 UK/ISRCTN71557037 Healthy subjects/open label H. pylori screening No screening Gastric cancer incidence and M: 35–69; 56 000/recruitment 1997/2021
mortality F:45–69 completed
 Taiwan/NCT01741363 Healthy subjects/open label H. pylori screening FIT alone Gastric cancer incidence 50–69 60 000/recruitment 2014/2017
and FIT completed
 Latvia/NCT02047994 Healthy subjects/open label H. pylori screening FIT alone Gastric cancer mortality 40–64 30 000/recruiting 2013/2033
and FIT

FIT, faecal immunochemical test; NA, not available.

Liou J-M
­ , et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368 2099
 Guidelines

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Figure 3 Effectivenss and cost-­effectiveness of screening and eradication of H. pylori for prevention of gastric cancer. (A) Effectiveness of
eradication therapy for H. pylori infected subjects. (B) Effectiveness of screening and eradication of H. pylori: ※may benefit most from screen-­and-­
treat (risk reduction of gastric cancer); *partial or no benefit from screen-­and-­treat; #potential adverse consequences from eradication therapy. (C)
Cost-­effectiveness of mass eradication for young individuals according to different rates of gastric cancer and H. pylori infection. The analyses are
based on a previously developed Markov decision model (Matsu Islands, Taiwan) by modifying the risk of gastric cancer and the rate of H. pylori
infection.52 With the starting age of 20 years, the model makes a comparison of the relative cost-­effectiveness between 1000 individuals with or
without the intervention. The results are presented on the cost-­effective plane (US dollars per life-­year gained); the elliptical circles indicate the 95%
confidence intervals. Four scenarios are demonstrated: (A) both high rates of gastric cancer (35 per 100 000 person-­years) and H. pylori (40%); (B) an
intermediate rate of gastric cancer (17 per 100 000 person-­years) and a high rate of H. pylori (40%); (C) a low rate of gastric cancer (6 per 100 000
person-­years) but a high rate of H. pylori (70%); and (D) low rates of both gastric cancer (6 per 100 000 person-­years) and H. pylori infection (10%).
The results indicate that for high- and intermediate-­risk populations, screening for young individuals is associated with higher effectiveness but a
lower cost (ie, cost saving) as compared with no screening. For the low-­risk populations, screening is associated with the higher effectiveness and the
higher cost, so the choices depend on how much society is willing to pay for a life-­year gained.

CQ 7. When should we actively screen and treat H. pylori? gastric cancer by 23% compared with those who did not receive
Statement 7: We recommend screening and eradication of H. timely treatment.45 The discrepancy in the magnitude of benefit
pylori before the development of atrophic gastritis and intestinal between the expected and observed levels probably reflects the
metaplasia. proportion of patients whose chronic gastritis has progressed
Agreement: agree (84%). to a stage with preneoplastic changes and genetic alterations so
Grade of recommendation: strong (68%), weak (28%), weak they maintained a cancer risk despite getting rid of the bacteria.
against (0%), strong against (4%). The increase in gastric cancer risk and the underlying increase
Evidence level: low. in genetic instability follow a recognisable histological pattern,
starting from chronic active gastritis to progressive atrophic
Comments gastritis with development of metaplastic epithelia. Intraepithe-
It is estimated that more than 85% of non-­cardia gastric cancer lial neoplasia then appears and finally invasive carcinoma (ie, an
is attributable to H. pylori infection.27 However, a pooled anal- updated version of the original Correa cascade).46 H. pylori erad-
ysis based on real-­world data from eradication trials demon- ication stops the progression of injury but is unlikely to entirely
strated only a 46% risk reduction in subjects who received H. reverse the genetic instability that has occurred. Therefore,
pylori treatment as compared with those did not.6 7 A retrospec- screening and eradication of H. pylori is ideally implemented
tive cohort study based on the national health insurance data- before the development of irreversible genetic instability, which
base showed early H. pylori eradication may reduce the risk of is usually reflected histologically in the development of atrophic
2100 Liou J-­M, et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368
 Guidelines
gastritis and metaplasia epithelia.43 Age could be an indicator of inflammation-­associated damage.6 Even though evidence from
gastric precancerous lesion, but this varies according to ethnicity. comparative studies is limited, simulation studies have repeat-
Atrophic gastritis appears at a younger age in North East Asia edly indicated that screening at a younger age (20–40 years) is

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but occurs after the age of 50–55 years in Western populations.47 more cost-­effective because the efficacy of H. pylori eradication
Yet, a retrospective cohort study using the Hospital Authority for averting gastric cancer is greatest at that age.52–54 In addition
database of Hong Kong showed that eradication of H. pylori to the reduction of cancer risk, screening of younger individ-
may also reduce the risk of gastric cancer in subjects older than uals has additional benefits. First, the risk of other H. pylori-­
60 years.48 related diseases can be reduced, such as peptic ulcer disease,
non-­ulcer dyspepsia, iron deficiency anaemia, etc, so the overall
CQ 8. Is screening and eradication of H. pylori cost-effective cost-­effectiveness is augmented.54 Second, curing the infection
for gastric cancer prevention? before young adults begin their families can reduce the risk of
Statement 8: The strategy of screen-­and-­treat for H. pylori infec- intrafamilial transmission. A number of studies have reported
tion is most cost-­effective in young adults for gastric cancer that the presence of an H. pylori infected mother is associated
prevention in regions with a high incidence of gastric cancer. with a higher risk of transmitting H. pylori to their children
Agreement: agree (84%). (OR of 13).56 Thus, screening young adults, but not children or
Grade of recommendation: strong (68%), weak (28%), weak adolescents, is likely to be an effective approach to preventing
against (0%), strong against (4%). transmission to children and protect those who are not infected
Evidence level: low. within the family.

Comments CQ 10. Which test should we use for mass screening of H.

Systematic reviews showed that the screen-­ and-­treat strategy pylori infection?
for H. pylori is cost-­effective for gastric cancer prevention.49 50 Statement 10: Urea breath test or H. pylori stool antigen test
Five variables determine cost-­effectiveness in the sensitivity anal- are the preferred tests for mass screening, but a locally validated
ysis.49 The first is the prevalence of H. pylori. The cost per life-­ serology test may be considered.
year saved (LYS) of the strategy ranges from US$ 10 000 to Agreement: agree (88%).
35 000 in the low-­prevalence regions and US$ 200 to 17 000 in Grade of recommendation: strong (63%), weak (33%), weak
high-­prevalence regions, such as Columbia and Singapore.50 The against (4%), strong against (0%).
second is the estimated proportion of gastric cancer reduced. Evidence level: moderate.
If the cancer reduction rate is ≥15%, the incremental cost-­
effectiveness ratio (ICER) would be less than US$ 50 000 per
Comments
LYS, the most common threshold value.51 The third variable is
Non-­ invasive tests, including the 13C-­ urea breath test (13C-­
age at screening, which depends on the population screened. In
UBT), H. pylori stool antigen (HpSA) test57 and serology test58
Western countries, a study showed that screening at ages >50
are available for mass screening of H. pylori in the community.
has low ICER values, which increase if the screening starting
Direct comparison of the performance of these three tests in
age drops.49 However, in Eastern Asian people, it is more cost-­
mass screening is lacking. In a Cochrane review of hospital-­based
effective when the screening starting age is at 20 to 30 years
studies, indirect comparison showed that 13C-­UBT appears to
rather than at an older age.52–54 Moreover, the strategy may be
be more accurate than serology (diagnostic odds ratio 3.2, 95%
cost-­effective only in Japanese-­Americans after age 10.51 The
CI 1.2 to 8.4) and HpSA test (diagnostic odds ratio 3.4, 95% CI
fourth is the incidence of gastric cancer. In specific high-­risk
1.3 to 8.8).59 However, the diagnostic accuracy was comparable
groups, such as those with early gastric cancer after endoscopic
if the assessment was restricted to seven head-­to-­head studies.59
resection, ICER is less than US$ 4000 per LYS.55 The fifth vari-
Factors that might influence the cost-­ effectiveness for mass
able is the cost of tests or cancer treatment.49 50 Limitations of
screening include the prevalence of H. pylori infection, patient
current evidence include the lack of assumptions based on results
adherence, cost of the test and gastric cancer treatment, addi-
from randomised control trials, savings related to dyspepsia or
tional benefit of the testing, incidence of gastric cancer and esti-
peptic ulcer diseases were rarely considered in the models, and
mated cancer reduction.49 60 13C-­UBT is accurate but is more
benefit reported as life-­years saved in the elderly rather than as
expensive. The HpSA test is as accurate but is less expensive
quality-­adjusted life-­years (QALYs).
than 13C-­UBT. However, the acceptability of the HpSA test for
mass screening might be lower, and delayed delivery of stool
CQ 9. Who will benefit most from the H. pylori treatment for samples might cause degradation of the antigens and, in turn,
gastric cancer prevention? false-­negative results. Serology testing is the least expensive and
Statement 9: Young individuals would benefit most from H. convenient but does not distinguish between active and past
pylori eradication because it cures H. pylori related gastritis, infection. A model showed that 13C-­UBT is more cost-­effective
reduces the risk of gastric cancer and reduces transmission to than HpsA if the prevalence of H. pylori is higher than 25%, but
their children. HpSA is more cost-­effective if the adherence rate is higher than
Agreement: agree (92%). 63%.49 In a mass screening programme for subjects aged 50–69
Grade of recommendation: strong (56%), weak (40%), weak years in Changhua County, Taiwan, a two-­in-­one approach was
against (4%), strong against (0%). used to detect faecal occult blood for colorectal cancer screening
Evidence level: low. and H. pylori antigen for gastric cancer prevention simultane-
ously, thus increasing the beneficial effect of mass screening.61
Comments Locally validated serology tests with high sensitivity may also be
H. pylori infection is usually acquired during childhood so acceptable for mass screening, but it is suggested that eradication
that the patient’s age reflects the duration of the infection and, therapy should be offered after confirmation by 13C-­UBT or the
within a specific population, is an indicator of the extent of the HpSA test.
Liou J-M
­ , et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368 2101
 Guidelines
CQ 11. In addition to non-invasive screening for H. pylori, 20 people/100,000, implementation of a screen-­and-­treat policy
who may benefit from endoscopy for the detection of is straightforward because it can be supported by the higher
asymptomatic gastric cancer? population motivation and better cost-­effectiveness. As shown

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Statement 11: In H. pylori infected individuals, endoscopy in figure 3C, the relative cost-­effectiveness of mass eradication is
is additionally recommended for those with a higher risk for defined according to the risk of gastric cancer and prevalence of
gastric cancer. H. pylori. For example in Taiwan, since 2004, mass screening and
Agreement: agree (100%). treating H. pylori infection has been implemented in a high-­risk
Grade of recommendation: strong (72%), weak (28%), weak population of the Matsu Islands, and this has been accompanied
against (0%), strong against (0%). by a rapid decline in the incidence of gastric cancer and the risk
Evidence level: low. of peptic ulcer disease.36 In Japan, starting 2013, such a national
policy has been included as one of the healthcare priorities when
Comments people are receiving an endoscopic examination; an accelerating
Some asymptomatic subjects might already have gastric cancer decline of gastric cancer incidence is observed.69 Both policies
or precancerous gastric lesions in their stomach at the time of are supported by the higher effectiveness at the lowest cost in
screening. Therefore, endoscopy should be provided for subjects reducing the burden of H. pylori related disease. In intermediate-­
at higher risk of gastric cancer, including populations with high risk populations, other diseases are more likely to compete for
incidence and individuals with higher risk factors for gastric the limited resources, so the policy making should consider more
cancer, such as older age, male gender, family history of gastric how to optimise the resources—for example, incorporation of
cancer in first-­degree relatives, serum pepsinogen I/II ratio <3 the screening service within the existing healthcare framework
or cigarette smokers.47 62–67 In most high-­ risk populations, a can substantially reduce the cost.70 Even in low-­risk popula-
starting age around 50 years has been generally recommended tions, such an approach is still applicable as there are probably
based on the notion that the endoscopic yield rate for the some high-­risk ethnicities or immigrants from high-­risk areas,71
premalignant gastric lesion and gastric cancer is likely to have for whom, active screening can reduce the cancer risk and also
increased to a level that is considered cost-­effective.44 66 67 The reduce the risk of H. pylori transmission in the community.72
risk of gastric cancer is higher in males and therefore the cut-­off
age for endoscopy should be different in males and females. For TREATMENT OF H. PYLORI INFECTION IN MASS
residents from low-­incidence areas, the diagnostic yield based on ERADICATION PROGRAMMES
the criterion of age is not practical and the magnitude of gastric CQ 13. Is the antibiotic resistance rate of H. pylori increasing
cancer risk must be individualised. For example, family history worldwide?
can be considered a valuable indicator; research has shown a Statement 13: There is a trend of increasing resistance rates to
2.4-­fold increased risk for subjects who had a positive family clarithromycin and levofloxacin worldwide.
history compared with those who did not.66 Reduction of gastric Agreement: agree (100%).
cancer achieved by H. pylori eradication in the vulnerable group Grade of recommendation: strong (76%), weak (24%), weak
of first-­degree relatives is as high as 73%.5 Serological testing against (0%), strong against (0%).
based on levels of pepsinogen I/II levels and ratio can also iden- Evidence level: low.
tify the risk of atrophic gastritis,44 67 which then requires confir-
mation by endoscopy with histology.
Comments
A systematic review and meta-­analysis showed that the overall
CQ 12. How to implement the screen-and-treat strategy for H. prevalence of primary H pylori resistance in Asia-­Pacific regions
pylori at the population level? was 17% (95% CI 15% to 18%) for clarithromycin, 44% (95%
Statement 12: Population-­wide screening and eradication of H. CI 39% to 48%) for metronidazole, 18% (95% CI 15% to 22%)
pylori infection should be integrated or included in the national for levofloxacin, 3% (95% CI 2% to 5%) for amoxicillin and
healthcare priorities to optimise the resources. 4% (95% CI 2% to 5%) for tetracycline between 1990, and
Agreement: agree (92%). 2016.73 They further showed a significant increase of clarithro-
Grade of recommendation: strong (64%), weak (32%), weak mycin (21%) and levofloxacin resistance (27%) in this region
against (0%), strong against (0%). during 2011–2015, compared with those reported before 2000,
Evidence level: low. whereas resistance to amoxicillin, tetracycline and metronida-
zole remained stable.73 A similar trend is observed globally.74
Comments A comprehensive review of the global prevalence of resistance
To adopt this strategy as a healthcare policy, one must consider showed that the primary and secondary resistance rates to clari-
multiple steps, including the invitation, participation, testing and thromycin and levofloxacin were ≥15% in the majority of WHO
referral, before the eradication treatment. The service should be regions.74 However, there are some limitations of the current
delivered by following the principle of an organised screening evidence. First, data from numerous countries are lacking, espe-
programme.68 Priorities must be set by considering which cially the updated prevalence of resistance after 2016. Second,
patients to screen, when is the best time to screen, whether this some studies included strains from treated patients, which may
strategy is cost-­effective and how to increase the diagnostic yield, overestimate the actual primary resistance rate. Third, the
in order to integrate the policy into national healthcare systems. methods and the break points of minimum inhibitory concen-
To realise population-­wide screening and eradication of H. trations used to determine the antibiotic resistance varied in
pylori, one needs to consider whether the presence of other different studies. Fourth, the study periods of the published arti-
diseases will compete with the limited resources or whether cles varied greatly. Finally, the samples were obtained from a
screening services can be integrated into the established frame- single centre and the sample sizes were small in several studies.
work to reduce the cost.68 In high-­ risk populations, such as Therefore, surveillance of the updated prevalence of primary
countries with an annual incidence of gastric cancer greater than antibiotic resistance of H. pylori is warranted.
2102 Liou J-­M, et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368
 Guidelines
CQ 14. Are there special considerations in choosing the monitored such that use of the preferred regimen can be discon-
optimal regimens for mass eradication of H. pylori in the tinued if resistance begins to undermine its effectiveness. Highly
community? successful regimens can also be used empirically if treatment

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Statement 14: The antibiotic resistance profile of H. pylori in success is monitored so that their use can be stopped if resistance
different regions, efficacy, adverse effects and cost should be begins to undermine their effectiveness.
taken into account in choosing the optimal regimens in the
community. Antimicrobials and proton pump inhibitors
Agreement: agree (100%). As shown in box 1, a wide range of antimicrobial agents and
Grade of recommendation: strong (68%), weak (32%), weak antimicrobial doses have been used successfully. The optimum
against (0%), strong against (0%). dosing adopted in a certain region (area) or for the individual
Evidence level: low. patient must depend on both the treatment regimen and the host
(eg, CYP2C19). In the presence of actual or suspected metro-
CQ 15. Should we modify the treatment of H. pylori mass nidazole resistance, higher doses of metronidazole and longer
eradication for gastric cancer prevention? duration are typically best (ie, 1600–2000 mg of metronidazole
Statement 15: Reliable locally effective regimens based on the given four times a day for 14 days). The optimum proton pump
principles of antibiotic stewardship are recommended. inhibitors (PPIs)/potassium-­competitive acid blockers (P-­CABs)
Agreement: agree (92%). and dosing regimen may vary, depending on the population (eg,
Grade of recommendation: strong (76%), weak (20%), weak drug metabolism, degree of corpus gastritis) and the composi-
against (0%), strong against (4%). tion of the regimen (ie, variably influenced by gastric acidity),
Evidence level: moderate. and will need to be considered for its effect on acid suppres-
sion rather than the names or number of milligrams of the drugs
CQ 16. Should susceptibility testing guided therapy be used.77–79
adopted or is empirical therapy according to the local
prevalence of antibiotic resistance preferred for mass H. Box 1 Components of effective H. pylori therapies
pylori eradication?
Statement 16: Surveillance of the local antibiotic resistance of H.
Components and dosing frequency
pylori is recommended to identify the optimal empirical therapy
for mass eradication of H. pylori in that population. Antimicrobial agents
Agreement: agree (96%). ►► Amoxicillin: 500–3000 mg/day
Grade of recommendation: strong (84%), weak (16%), weak ►► Bismuth: most use 300–600 mg /two to four times a day
against (0%), strong against (0%). ►► Clarithromycin (macrolides): 400–1000 mg/day
Evidence level: moderate. ►► Metronidazole/tinidazole: 800–1000 mg/day in triple therapy
►► Metronidazole/tinidazole: 1600–2000 mg/day in bismuth
Comments quadruple therapy
These recommendations are based on the recent recognition ►► Fluoroquinolones (levofloxacin): 500 mg/day
that H. pylori should be considered and treated as any other ►► Tetracycline HCl: 500 mg four times a day
common bacterial infection by applying the principles of antimi- ►► Rifabutin: 150–300 mg/day
crobial stewardship. This change represents a radically different ►► Furazolidone: 100 mg three times a day
approach from treatment than has been used since the discovery ►► Nitazoxanide: 500 mg twice a day
of H. pylori and requires much of the available data to be re-­ex-
Antisecretory drugs
amined and some discarded. Antimicrobial stewardship is a
►► Proton pump inhibitors: 20 mg (or 40 mg*) omeprazole or
multifaceted approach that requires considering treatment poli-
equivalent dose* two times a day.
cies, guidelines, surveillance of regional emerging resistance and
►► Potassium competitive acid blockers: vonoprazan 20 mg b.i.d.
prevalence reports of antibiotic resistance. Furthermore, antimi-
crobial stewardship demands continuous education and audits of Not recommended
practice by healthcare organisations to optimise prescribing.75 It ►► Doxycycline
also includes coordinated interventions designed to improve and ►► Nitazoxanide
measure appropriate use of antimicrobial agents by promoting ►► Probiotics
selection of the optimal drug regimen, including dosing, dura-
tion of treatment and route of administration.75–77 Elements of antimicrobial stewardship
►► Optimise prescribing
►► Promote responsible antibiotic use
Effective therapy
►► Ensure sustainable access to effective treatment (ie, prevent
Subjects to be considered when selecting a regimen for treat-
development of resistance)
ment of an infectious disease include effectiveness, simplicity,
tolerability, adverse effects, the prevalence of antibiotic resis- Problems with effective anti-H. pylori therapy
tance in the community, dose, duration and costs. In the specific ►► Inoculum effect (preexistence of a population of resistant
condition of gastric infection, optimal control of gastric pH is strains)
needed, because this has a fundamental influence on the anti- ►► Persister effect (presence of non-­replicating or slowly
biotic bioavailability in the stomach.24 44 77 78 The requirement replicating bacterial population that requires the duration of
for excellent adherence emphasises the need for patient educa- treatment to be prolonged)
tion and for use of regimens with problems of adherence only
*The use of higher dosage and the definition of equivalent dose remain
when necessary. Only locally highly reliably regimens should
controversial.
be used empirically and, if used, treatment success should be
Liou J-M
­ , et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368 2103
 Guidelines

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Figure 4 An example of decision-­making for the appropriate use of antibiotics for H. pylori eradication.

Duration of treatment therapy or an alternative proven highly reliable empiric therapy

The recent guidelines have recommended treatment duration is suggested.
of 14 days unless a shorter period is locally proved to be non-­ Treatment failures occur and provide feedback to the clinician
inferior and reliably produces a suitably high success rate.24 62 80 about the effectiveness of their current regimens, which when
The optimum duration of treatment is based on overcoming the shared, provides information to the community about current
persister effect and takes into account the fact that PPIs do not regimens. All consensus groups recommend routine testing for
achieve full effectiveness in acid suppression until after 3 or 4 cure to ensure treatment success. This information should also
days of administration.78 P-­CABs, however, achieve full effec- be collected and shared to inform when previously effective regi-
tiveness on day 1 of administration and provide higher and more mens are beginning to lose effectiveness.
consistent pH control. This suggests that shorter durations may
be equally effective.79 81 82 Future studies are warranted to assess
CQ 17. Is the reinfection rate high after mass eradication of
the efficacy of high-­dose dual therapy containing P-­CABs and the
optimum duration of treatments with P-­CABs.
H. pylori?
Statement 17: The reinfection rate after mass H. pylori eradica-
tion is very low.
Susceptibility-guided therapy versus empirical therapy
Agreement: agree (96%).
Ideally all antimicrobial therapies are susceptibility-­ based.83
Grade of recommendation: strong (72%), weak (28%), weak
By definition, this includes that both regimens are designed to
against (0%), strong against (0%).
take into account patient- and population-­specific susceptibility
Evidence level: moderate.
results as well as highly successful empirically derived regimens,
in which susceptibility is identified by trial and error rather than
by direct testing. Antimicrobial stewardship includes the goal of Comments
ensuring sustainable access to effective therapies, which means Recurrence after confirmed eradication of H. pylori infection
that the regimen must not promote antimicrobial resistance— can occur either by recrudescence or reinfection. Recrudes-
that is, higher than necessary doses must not be used, durations cence is defined as reappearance of the original strain which
should not be longer than necessary, and especially, antibiotics is undetected by the false negative confirmatory test. Rein-
that cannot benefit the patient (unnecessary antibiotics) should fection is defined as infection by a new strain after successful
not be given. Ideally, the best results can be achieved by a step- eradication therapy. A previous study showed that of the 10
wise approach using the most effective, best tolerated regimen strains obtained from patients who experienced recurrence
first and the most complicated last (figure 4). Such an approach during the first year, four strains were genetically different
has been tested in highly resistant populations in China and has from the initial strain, although this could be related to the
proved to be simple and highly effective.84 dominance of a recrudescent strain.85 86 The other six were
However, cost and convenience dictate that a proven reliable identical to the initial strains.85 However, all the four strains
highly effective empiric regimen would generally be preferred obtained from patients who experienced recurrent infections
initially, if such a regimen is available. In practice, antimicrobial after the second year were different from the initial strains.85
therapy for most infections relies on a regimen proved to be Factors that might contribute to recrudescence include thera-
highly effective locally with the expectation that ongoing antimi- peutic regimen, shorter length of treatment, confirmatory test
crobial surveillance programmes or test of cure in the majority of provided less than 4 weeks after the end of treatment and pres-
patients will inform when it is necessary to change and will also ence of coccoid forms and biofilm of H. pylori.87 88 The recur-
provide appropriate recommendations (ie, antimicrobial stew- rence rate in hospital-­based studies varies between different
ardship in action). In patients for whom empirical therapy fails countries and ethnic populations and is higher in countries
in a mass eradication programme, susceptibility testing guided with higher prevalence of H. pylori infection and lower
2104 Liou J-­M, et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368
 Guidelines
human development index.87 88 A recent systematic review of clarithromycin resistance erm(B) genes.93–97 These studies
and meta-­analysis showed that the global annual recurrence collectively showed that the antibiotic resistance rates of
rates after H. pylori eradication in clinical settings without surrogate intestinal bacteria are increased shortly after H.

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mass eradication was 4.3%.87 High reinfection/recrudescence pylori eradication.93–99 The long-­term phenotypic and geno-
has been reported in some areas such as Alaska, Vietnam and typic changes of antibiotic resistance of intestinal microflora
Bangladesh which may require modifications, such as treat- were assessed in three studies.93 The antibiotic resistance of E.
ment of the entire community at one time89–91 The annual coli was significantly increased 2 weeks after triple therapy or
recurrence rate in the gastric cancer prevention study in Shan- concomitant therapy, but not after bismuth quadruple therapy.
dong (not mass screening and eradication) was nearly 7% per Interestingly, the antibiotic resistance was restored to basal
person-­year.29 However, the annual reinfection/recrudescence state at 2 months and 1 year.97 Hsu et al also showed that the
rate was only 1% in mass in the Matsu Islands, where the increase in the abundance of erm(B) gene in faecal samples
participation rates for screening and eradication therapy were at week 8 was restored to pretreatment level by week 48.98
82% among the total population.40 This indicates that if the However, limitations of the above studies include the small
majority of infected subjects are treated in the community, the sample size, susceptibility testing tested only in some surrogate
reinfection rate would be very low. bacteria and the long-­term changes assessed in few studies.
However, it is not wise, and not acceptable, to preclude the
CQ 18. Is a confirmation test for successful treatment of H. use of antibiotics to treat H. pylori infection for prevention
pylori needed after mass eradication? of gastric cancer because of this concern considering that
Statement 18: Confirmation test of H. pylori eradication is not the emergence of antibiotic resistance is multifactorial.100 101
mandatory in mass screening, but should be performed in subsets A recent review showed that the relative contribution of
of the population for assessment of treatment efficacy. misuse or overuse of antibiotics in humans and animals,
Agreement: agree (96%). contamination of the environment, suboptimal dosing of
Grade of recommendation: strong (67%), weak (33%), weak antibiotics and healthcare transmission as a driver for anti-
against (0%), strong against (0%) microbial resistance are moderate to high, whereas that of
Evidence level: low. mass drug administration for human health is classified as
low to moderate. 101 Overall, there is insufficient evidence
to reach a conclusion about the effect of mass eradication
Comments
therapy on antibiotic resistance in the community, and more
A confirmation test after H. pylori eradication therapy
large-­s cale studies are needed to investigate this subject
is recommended for symptomatic H. pylori infected
patients.24 62 78 Ideally, a confirmation test should also be
offered to all asymptomatic subjects in mass screening, CQ 20. Does H. pylori eradication lead to long-term
although this will increase the cost. Additionally, it is disturbance of gut microbiota in adults?
important to monitor the eradication rate of the regimen Statement 20: Short-­ term perturbation of faecal microbiota
used in that population. For example, the eradication rate diversity occurs after H. pylori eradication, which largely
of omeprazole and amoxicillin was 62% (703/1130) in the recovers subsequently.
Shandong study, whereas the eradication rate of 10-­ day Agreement: agree (88%).
bismuth quadruple therapy was 72.9% in the mass eradi- Grade of recommendation: strong (48%), weak (48%), weak
cation programme in Linqu County, China. 3 92 Since the against (4%), strong against (0%).
effectiveness of H. pylori eradication for gastric cancer Evidence level: low.
prevention is expected to be higher if the eradication rate
is higher, it is recommended that a confirmation test should
Comments
be performed at least in subsets of the population to assess
Recent studies have shown that the diversity of gastric micro-
treatment efficacy.
biota is lower in H. pylori infected subjects than in non-H.
pylori infected subjects.101 102 After successful eradication
POTENTIALLY ADVERSE CONSEQUENCES OF H. PYLORI of H. pylori, the diversity of gastric microbiota could be
ERADICATION restored to a level similar to that in non-H. pylori infected
CQ 19. Does treatment of H. pylori with antibiotics increase subjects.103 Several studies showed significant perturbation of
the antibiotic resistance rate of other bacteria? α-­diversity and β-­diversity of faecal microbiota shortly after
Statement 19: As with all antibiotic treatments, H. pylori eradi- H. pylori eradication, and the extent of perturbation was
cation may lead to an increase in antimicrobial resistance, but it significantly greater in patients receiving concomitant therapy
should not preclude its use for gastric cancer prevention. and bismuth quadruple therapy than in those receiving triple
Agreement: agree (92%). therapy.97 98 104–106 There was a trend towards gradual recovery
Grade of recommendation: strong (58%), weak (38%), weak of diversity at 2–3 months after completion of eradication
against (4%), strong against (0%). therapy with all regimens, but the speed of recovery was faster
Evidence level: very low. in those receiving triple therapy.97 Relatively few studies have
reported the long-­ term changes of faecal microbiota.97 104
Comments Two studies showed that the diversity at 1 year was restored
Emergence of antibiotic resistance with the widespread use to pretreatment state in patients receiving triple therapy, and
of antibiotics is one of the major concerns that limit mass was largely recovered in patients receiving bismuth quadruple
screening and eradication of H. pylori for gastric cancer therapy and concomitant therapy.97 104 However, significant
prevention.8 We identified five studies that assessed the short-­ changes in the composition and abundance at genus level
term changes of phenotypic resistance of intestinal micro- were seen 1 year after eradication therapy.104 Because the 16S
flora and three studies that reported the short-­term changes rRNA method was used in the majority of studies, in-­depth
Liou J-M
­ , et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368 2105
 Guidelines
sequencing using shotgun metagenomics sequencing is recom- CQ 22. Does H. pylori eradication lead to the increase of
mended in future studies. metabolic syndrome in adults?
Statement 22: H. pylori eradication may be associated with a

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small increase in body weight, but does not increase the risk of
CQ 21. Does H. pylori eradication lead to new-onset metabolic syndrome.
gastro-oesophageal reflux disease (GORD)? Does H. pylori Agreement: agree (80%).
eradication aggravate the severity of symptoms in patients Grade of recommendation: strong (48%), weak (44%), weak
with existing GORD? against (8%), strong against (0%).
Statement 21-1: Eradication of H. pylori does not increase the Evidence level: low.
risk of new onset GORD.
Agreement: agree (92%).
Grade of recommendation: strong (76%), weak (16%), weak Comments
against (8%), strong against (0%). H. pylori has been associated with obesity, metabolic syndrome
Evidence level: high. and insulin resistance in earlier observational studies.116 117 Case–
Statement 21-2: H. pylori eradication therapy does not control studies showed an inverse association of H. pylori and
increase the risk of relapse of GORD. body weight.117 Some cohort studies showed an increase of body
Agreement: agree (96%). weight after H. pylori eradication.99 A randomised controlled
Grade of recommendation: strong (72%), weak (24%), weak trial also showed a trivial increase in body mass index 1 year after
against (4%), strong against (0%). H. pylori eradication.118 The mean body mass index increased
Evidence level: moderate. from 27.5 to 27.8 kg/m2 and 27.0 to 27.2 kg/m2 in the eradica-
tion group and placebo groups, respectively.118 The increase in
body weight is probably attributed to the restoration of ghrelin
Comments secretion or the relief of dyspeptic symptoms.119 Yet, the clinical
Gastric acid secretion of hosts following H. pylori infection may significance of this trivial increase in body weight remains ques-
be unchanged, increase or decrease, depending on the pattern of tionable. Some studies have shown that insulin resistance, fasting
gastritis (pan-­gastritis, antrum-­predominant gastritis or corpus-­ glucose, total cholesterol and triglyceride levels were reduced
predominant gastritis). Eradication of H. pylori can cure gastritis, after H. pylori eradication.92 97 99 120 The changes in these meta-
restore acid secretion and influence the severity of reflux symp- bolic parameters might be attributed to alterations in the gut
toms in some patients with existing GORD.107 However, H. microbiota. However, these findings remain controversial and
pylori eradication in populations of infected subjects, on average, further well-­designed randomised trials are warranted to clarify
does not increase the risk of developing GORD. A large-­scale the impact of H. pylori eradication on metabolic parameters.
randomised controlled trial involving 1558 infected subjects
showed that H. pylori eradication therapy did not influence the
CQ 23. Does H. pylori eradication increase the risk of asthma,
prevalence of reflux symptoms at 2 years.108 A meta-­analysis of
inflammatory bowel disease and other immune-related
randomised controlled trials including only H. pylori-­infected
diseases in adults?
subjects free from GORD at baseline also showed that there was
Statement 23: H. pylori eradication does not increase the risk of
no association between eradication of H. pylori and the devel-
asthma, inflammatory bowel disease and other immune-­related
opment of new cases of GORD.109 In addition, current evidence
diseases in adults.
shows that H. pylori eradication does not increase the relapse
Agreement: agree (80%).
risk of GORD. Several randomised controlled trials revealed
Grade of recommendation: strong (52%), weak (44%), weak
that eradication of H. pylori did not increase the recurrence rates
against (4%), strong against (0%).
of reflux symptoms or erosive oesophagitis in infected patients
Evidence level: very low.
with pre-­existing GORD (online supplementary table 4S).110 111
Therefore, the presence of GORD should not preclude practi-
tioner from H. pylori eradication therapy, although H. pylori Comments
infection and GORD are negatively associated at a population Some reports demonstrated inverse association of early exposure
level.112 to H. pylori with risk for asthma, which may be attributed to the
Currently, whether H. pylori eradication exaggerates reflux activation of Th1 cells and inhibition of Th2 allergic response by
symptoms in patients with GORD receiving long-­ term acid H. pylori.121 122 Although meta-­analysis suggested that patients
suppression remains controversial. A randomised controlled with asthma have lower prevalence rates of H. pylori infection,
trial from a western population showed H. pylori eradication little is known about whether eradication of H. pylori may
did not worsen reflux disease in patients with GORD receiving increase the risk of asthma in adults.122 Systematic review and
long-­term acid suppression.113 However, another randomised meta-­analysis showed an inverse association between H. pylori
controlled trial from a Chinese population demonstrated that infection and inflammatory bowel disease (IBD).123 A retrospec-
H. pylori eradication led to worsened control of reflux disease in tive cohort study using health insurance showed that eradication
patients undergoing long-­term low-­dose PPI therapy.114 None- of H. pylori is associated with a significantly increased risk of
theless, long-­term use of PPI in H. pylori-­infected subjects may IBD and certain autoimmune diseases in Taiwan.124 However,
lead to the development of precancerous lesions, although the other studies have shown that H. pylori eradication therapy is
findings remain contradictory.113 115 In another study, Kuipers not associated with onset of IBD, and some studies even showed
et al showed that eradication of H pylori can reduce gastric that eradication therapy may reduce the severity of rheumatoid
mucosal inflammation and lead to regression of corpus glan- arthritis and thyroid autoantibodies.125–127 More large-­ scale
dular atrophy.113 Therefore, eradication of H. pylori eradication prospective studies are needed to clarify the effects of H. pylori
is recommended in patients with GORD receiving long-­term eradication on the incidence of IBD and autoimmune diseases
acid-­suppression therapy. in adults.
2106 Liou J-­M, et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368
 Guidelines
ENDOSCOPIC SURVEILLANCE FOR GASTRIC CANCER AFTER metaplasia are 1.24 (95% CI 0.80 to 1.76) and 3.38 (95%
H. PYLORI ERADICATION CI 2.13 to 4.85) cases per 1000 person-­years, respectively.139
CQ 24. Who needs surveillance endoscopy after H. pylori Advanced-­stage atrophy and intestinal metaplasia are defined

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eradication? as OLGA stage III/IV and OLGIM stage III/IV, respectively. The
Statement 24: Subjects with advanced gastric atrophy or intes- definition is based on the study following the “MAnagement of
tinal metaplasia should receive surveillance endoscopy to detect Precancerous conditions and lesions in the Stomach (MAPS)”
gastric cancer after H. pylori eradication. guideline, which showed that 3.8% of patients with OLGIM
Agreement: agree (92%). stages III/IV and/or serum pepsinogen I/II ratio ≤3 progressed to
Grade of recommendation: strong (68%), weak (32%), weak high-­grade dysplasia or cancer.140 Whereas the American Gastro-
against (0%), strong against (0%). enterology Association (AGA) recommends that routine endo-
Evidence level: low. scopic surveillance should not be carried out, the 2019 MAPS-2
consensus and British Society of Gastroenterology guidelines
recommend endoscopic surveillance intervals of within 6 to 12
Comments
months for patients with low- or high-­grade gastric dysplasia,
Patients may remain at risk of future gastric cancer even after
every 3 years for patients with precancerous lesions in advanced
H. pylori eradication, especially those with preneoplastic
OLGA/OLGIM stages III/IV, and a follow-­up period longer than
lesions, such as atrophic gastritis, intestinal metaplasia (IM) and
3 years, or even not suggested, for patients with precancerous
dysplasia. The residual risk ranges from 21 to 128 per 100 000
lesion confined only to the gastric antrum as with low OLGA/
person-­years, depending on pre-­existing histology and genetic
OLGIM stages.141–143 Endoscopic surveillance every 1 or 3 years
factors. Risk stratification is needed to identify those with the
for extensive precancerous conditions was also shown to be
highest risk, for endoscopic surveillance. Two Japanese studies
cost-­effective.144 145 However, the OLGIM system is relatively
showed that patients with severe atrophy on endoscopy (O2-­O3
complex in routine clinical practice in countries with a high inci-
based on the Kimura-­ Takemoto Classification System) had
dence of gastric cancer, such as Japan. Precise risk stratifications
significantly higher risk (HR 9.3–14.4) of gastric cancer after a
according to age, blood test with new biomarkers, history and
mean follow-­up of 5.6–6.4 years.128 129 Patients with intestinal
certain new earlier pathological precancerous lesion, such as
metaplasia at either antrum (HR 3.6) or corpus (HR 3.7) are
CGI/SPEM, are promising for guiding the surveillance intervals
at higher risk of gastric cancer after H. pylori eradication.128
after H. pylori eradication to further reduce the mortality due to
Severe atrophy on histology (operative link on gastritis assess-
gastric cancer.
ment (OLGA) stage III–IV) also correlates with a increased risk
of gastric cancer (incidence rate/103 person-­ years 19.7–36.5
for stage III and 41.2–63.1 for stage IV) in two Italian cohort CQ 26. What is the role of molecular markers in the risk
studies.130 131 The operative link on gastric intestinal metaplasia stratification of future gastric cancer risk after H. pylori
assessment (OLGIM) had a higher interobserver agreement eradication?
than the OLGA classification in a cross-­sectional study.132 The Statement 26: Genetic and epigenetic markers show promise
severity of gastric intestinal metaplasia can also be assessed by the in stratifying gastric cancer risk after H. pylori eradication, but
narrow-­band imaging on endoscopy.133 Lower serum pepsinogen require further validation in prospective studies.
I or pepsinogen I/II ratio before eradication therapy may be Agreement: agree (92%).
an alternative marker for risk stratification.134 135 However, it Grade of recommendation: strong (52%), weak (48%), weak
is noteworthy that gastric cancer may develop even 10 years against (0%), strong against (0%).
after eradication therapy in patients who have no, or only mild, Evidence level: low.
precancerous lesions at baseline.136 Further prospective studies
are warranted to validate the combination of endoscopic and
histological grading of gastric atrophy/intestinal metaplasia.
Comments
Molecular markers which mark genetic and epigenetic alter-
Serum biomarkers may provide better prediction of future risk
ations of significance in gastric carcinogenesis may be useful in
of gastric cancer after H. pylori eradication.
risk stratification after H. pylori eradication.146 DNA methyla-
tion is a key epigenetic modification, and accumulation of aber-
CQ 25. What is the appropriate endoscopic interval for rant DNA methylation, resulting in an epigenetic field defect, has
subjects who retain the gastric cancer risk? been shown to be associated with gastric cancer risk.147 148 The
Statement 25: Surveillance endoscopy is suggested every 2 to risk of developing metachronous gastric cancers was higher in
3 years for subjects with advanced gastric atrophy or intestinal those with higher methylation level of miR-­124a-3.148A nation-
metaplasia, and every 12 months after the removal of neoplasia. wide, prospective multicentre cohort study for for prediction of
Agreement: agree (92%). the risk of gastric cancer in 2000 healthy individuals after H.
Grade of recommendation: strong (52%), weak (44%), weak pylori eradication is in progress in Japan (UMIN000016894).
against (4%), strong against (0%). Following the same protocol, this genetic approach has been
Evidence level: low. proved to be effective for risk stratification after H. pylori erad-
ication.148 To examine the genomic landscape of IM in gastric
Comments carcinogenesis, a prospective pre-­ disease high-­risk cohort
Two cohort studies showed that more gastric cancers were (Gastric Cancer Epidemiology Programme) comprising 2980
detected at an early stage in patients who received surveil- subjects with mean age 59±7 years was enrolled, and 5 years
lance endoscopy for precancerous conditions than in those not of surveillance were completed in 2016.149 Twenty-­one cases of
surveyed.137 138 The median time interval between the initial early gastric neoplasia, defined as high-­grade dysplasia, carci-
endoscopy and the diagnosis of cancer was 25 months (range noma in situ or adenocarcinoma, were detected during surveil-
12~30).138 A meta-­analysis showed that the incidence rates of lance. Comprehensive genomic profiling, using next-­generation
gastric cancer in patients with atrophic gastritis and intestinal sequencing to characterise IM biopsies, was performed, and
Liou J-M
­ , et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368 2107
 Guidelines
three genomic alterations which showed associations with lesions rather than the development of gastric cancer was the
disease progression of IM to early gastric neoplasia were iden- primary outcome in several trials. Additionally, the eradication
tified.149 Shorter telomere lengths and the presence of somatic rates were lower than 80% in the majority of trials, and 5–15%

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copy-­number alterations correlate with progression of intestinal of participants in the control (placebo) group were negative for
metaplasia, whereas normal epigenomic patterns were associ- H. pylori, which may lead to bias toward the null. Although
ated with regression.148 A customised molecular test to identify we expect higher risk reduction of gastric cancer in a younger
this high-­risk subset of patients with IM for targeted endoscopic population, the mean ages were 50 years and >60 years in trials
surveillance is being developed, and will be validated in an inter- conducted for primary and secondary prevention of gastric
national, prospective multicentre cohort study. cancer, respectively. Third, the assumptions used in the cost-­
effectiveness analysis were based on observational studies rather
LIMITATIONS OF THE CONSENSUS than randomised trials and the saving related to dyspepsia or
The limitations of the supporting evidence for each statement peptic ulcer disease were rarely considered in the models. Fourth,
are shown in table 1. First, updated incidence of gastric cancer since the risk of gastric cancer differs according to gender and
and prevalence of H. pylori are lacking in many countries, which ethnicity, the starting age for gastric cancer prevention might
may lead to bias in the estimation of the level of global disease. differ accordingly. Yet, few studies examined this topic. Fifth,
Second, most of the trials reporting the effectiveness of H. pylori among the 26 statements, only two are of high evidence level
eradication on gastric cancer prevention were conducted in and most are of low evidence level. The low level of evidence
Eastern populations, and progression of gastric precancerous might be an explanation for voting 'strong against' by some

Figure 5 Study flow of the proposed collaborative cohort study. Prevalence of H. pylori defined as (N1 +n2/N) X 100%; outcomes: standardised
incidence rate and standardised mortality rate of gastric cancer, other Gi cancers in the screened group* as compared with the general population.
13
C-­UBT, 13C-­urea breath test; EGD, esophagogastroduodenoscopy, HP, H. pylori; HpSA, H. pylori stool antigen (test); ICF, informed consent form; SNP,
single nucleotide polymorphism.
2108 Liou J-­M, et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368
 Guidelines
experts (4%) for statements 2-2, 3, 4, 5,6,7,8 and 15 . Further after H. pylori eradication. Well-­designed studies and trials are
well-­designed prospective trials or cohort studies are warranted warranted to fill the knowledge gaps of the unresolved concerns.
on these issues. Finally, more well-­designed prospective studies

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or trials are warranted to assess the potential extragastroduo- Author affiliations
1
denal beneficial effects and long-­term adverse consequences, as Division of Gastroenterology and Hepatology, Department of Internal Medicine,
National Taiwan University Hospital, Taipei, Taiwan
well as the optimal endoscopic surveillance interval following 2
Department of Internal Medicine, National Taiwan University College of Medicine,
H. pylori eradication in patients with preneoplastic changes, the Taipei, Taiwan
subset requiring long-­term follow-­up after successful H. pylori 3
Department of Medicine, National Taiwan University Cancer Center, Taipei, Taiwan
4
eradication.150 Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-­von-­
Guericke University Magdeburg, Magdeburg, Germany
5
Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
6
FUTURE COLLABORATIVE RESEARCH PROPOSAL Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
7
We designed a prospective cohort study to examine the problems Department of Internal Medicine and Institute of Clinical Medicine, National Cheng
Kung University Hospital, College of Medicine, National Cheng Kung University,
raised above (figure 5). Detailed information of this proposal Tainan, Taiwan
is available in the online supplemental materials. Researchers 8
Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical
who are interested in this collaborative research may contact University Hospital, Kaohsiung, Taiwan
9
the authors. Alternatively, the protocol is open access and Department of Medicine, Jichi Medical School, Tochigi, Japan
10
Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare,
the researchers may conduct this trial independently. In brief,
Tainan, Taiwan
healthy adult subjects (n=14 400 in Taiwan) will be screened 11
Department of Medicine, Yong Loo Lin School of Medicine, National University of
for H. pylori infection by serology test and H. pylori stool Singapore, Singapore
12
antigen test (HpSA). Those with only one positive test will be Division of Gastroenterology and Hepatology, Department of Internal Medicine, An
confirmed by 13C-­UBT. Endoscopy, histology and culture of H. Nan Hospital, China Medical University, Tainan, Taiwan
13
Department of Gastroenterology and Hepatology, University of Malaya, Kuala
pylori will be done in subgroup of subjects. Antibiotic resistance Lumpur, Malaysia
of H. pylori will be determined. We will link to the database of 14
Department of Medicine, Faculty of Medicine, Chulalongkorn University and King
vital statistics in Taiwan to assess the short-­term and long-­term Chulalongkorn Memorial Hospital, Bangkok, Thailand
15
outcomes as follows. At the end of the cross-­sectional survey, Division of Gastroenterology and Hepatology, Department of Medicine, Nihon
the age-­standardised prevalence, the antibiotic resistance rate of University School of Medicine, Tokyo, Japan
16
Integrated Diagnostics and Therapeutics, National Taiwan University Hospital,
H. pylori, and the age-­standardised and specific incidence and National Taiwan University College of Medicine, Taipei, Taiwan
mortality of gastric cancer will be reported. The standardised 17
Institute of Biomedical Informatics, School of Medicine, National Yang-­Ming
incidence rate and standardised mortality rate of gastric cancer University, Taipei, Taiwan
18
and extragastric diseases in the screened group versus the Division of Translational Research, Department of Medical Research, Taipei Veterans
General Hospital, Taipei, Taiwan
general population, and the cost-­effectiveness of the programme 19
Department of Internal Medicine, National Taiwan University Hospital Bei-­Hu
in countries with different prevalence of H. pylori and incidence Branch, Taipei, Taiwan
of gastric cancer, will be the long-­term endpoints. 20
Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology
and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of
Medicine, Shanghai Jiao Tong University, Shanghai, China
CONCLUSIONS 21
Oita University Faculty of Medicine, Yufu, Oita, Japan
22
Gastric cancer is attributable to H. pylori infection in nearly 90% Department of Medicine, Michael E DeBakey VA Medical Center and Baylor College
(non-­cardia) of patients, and will remain an important global of Medicine, Houston, Texas, USA
23
French National Reference Centre for Helicobacters, Bacteriology laboratory,
health problem due to the increase in the elderly population. Pellegrin Hospital, Bordeaux, & INSERM U1053, University of Bordeaux, Bordeaux,
At an individual level, eradication of H. pylori reduces the risk France
of gastric cancer in healthy subjects and in patients with early 24
Institute of Digestive Disease, Chinese University of Hong Kong, Shatin, Hong Kong,
gastric cancer following curative endoscopic resection and is China
25
Department of Medicine and Therapeutics, The Chinese University of Hong Kong,
recommended for all H. pylori infected subjects unless there are
Shatin, Hong Kong, China
competing considerations, such as those with limited life expec- 26
Digestive Medicine Center, China Medical University Hospital, Taichung, Taiwan
tancy. At a population level, the strategy of screen-­ and-­treat 27
Department of Medicine, University of New South Wales, Sydney, New South Wales,
for H. pylori infection is most cost-­effective in young adults in Australia
28
regions with a high incidence of gastric cancer and is recom- Microbiome Research Centre, St George & Sutherland Clinical School, University of
New South Wales, Sydney, NSW, Australia
mended preferably before the development of atrophic gastritis
and intestinal metaplasia in high-­ risk populations. However, Twitter Emad M El-­Omar @emadelomar
population-­wide screening and eradication of H. pylori infec- Acknowledgements The authors would like to express their special thanks to the
tion should be integrated or included into the national health- Eighth Core Laboratory, Department of Medical Research, National Taiwan University
care priorities to optimise the resources. In the face of global Hospital for their technological support. DYG, M-­SW, and EME-­O shared the co-­
rising resistance rates to clarithromycin and levofloxacin, we senior and co-­corresponding authorships in this work.
recommend proven locally effective regimens based on the prin- Contributors Drafts of clinical questions (CQs) about each topic were prepared
ciples of antibiotic stewardship. As with all antibiotic therapies, by J-­ML and were further revised by core members (PM, Y-­CL, DYG, EME-­O and
M-­SW). Faculty members (J-­ML, Y-­CL, B-­SS, H-­CC, KG-­Y, W-­LC, M-­JC, T-­HC, C-­CC,
H. pylori eradication may lead to a short-­term perturbation of
C-­YW, P-­IH and M-­SW) were assigned to perform systematic review of CQs
faecal microbiota diversity and an increase in antimicrobial resis- 1 to 4 and to prepare the statements, which were edited in the first steering
tance, but these should not preclude its use for prevention of committee. The revised draft statements were further edited by moderates and
gastric cancer. H. pylori eradication does not increase the risk core members (J-­ML, PM, Y-­CL, B-­SS, DYG, EME-­O and M-­SW). Faculty members
of new-­onset GORD. There is no evidence to suggest that H. (J-­ML, Y-­CL, B-­SS, H-­CC, KG-­Y, W-­LC, M-­JC, T-­HC, C-­CC, C-­YW, P-­IH and M-­SW)
drafted the comments after the consensus meeting. J-­ML drafted the article, which
pylori eradication may increase the risk of metabolic syndrome, was critically revised by co-­first author PM and three senior authors, DYG, M-­SW
autoimmune disease and IBD in adults. Subjects with higher risk and EME-­O. All authors commented on drafts and approved the final version. All
of gastric cancer, such as those with advanced gastric atrophy authors had full access to the data and participated in the decision to submit for
or intestinal metaplasia, should receive surveillance endoscopy publication.

Liou J-M
­ , et al. Gut 2020;69:2093–2112. doi:10.1136/gutjnl-2020-322368 2109
 Guidelines
Funding The study was funded by the National Taiwan University Hospital (grant 12 Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of
number: NTUH 107-­P05; 109-­P03), the Ministry of Science and Technology, recommendations. BMJ 2004;328:1490.
Executive Yuan, ROC, Taiwan (grant number: TCTC 108-2321-­B-002 -040 - and 13 Global cancer Observatory (GCO). Available: https://​gco.​iarc.​fr/
MOST 108-2314-­B-002 -187, 108-2314-­B-002 -209 -), the Ministry of Health and 14 Hooi JKY, Lai WY, Ng WK, et al. Global prevalence of Helicobacter pylori infection:

Gut: first published as 10.1136/gutjnl-2020-322368 on 1 October 2020. Downloaded from http://gut.bmj.com/ on August 14, 2023 by guest. Protected by copyright.
Welfare of Taiwan (grant number: MOHW107-­TDU-­B-211-123002, MOHW108-­ systematic review and meta-­analysis. Gastroenterology 2017;153:420–9.
CDC-­C-114-112102), the “Center of Precision Medicine” from The Featured 15 Sonnenberg A, Turner KO, Genta RM. Low prevalence of Helicobacter pylori-­positive
Areas Research Center Program within the framework of the Higher Education peptic ulcers in private outpatient endoscopy centers in the United States. Am J
Sprout Project by the Ministry of Education (MOE) in Taiwan (grant number: Gastroenterol 2020;115:244–50.
NTU-­107L9014-1), the Liver Disease Prevention & Treatment Research Foundation, 16 Watanabe M, Ito H, Hosono S, et al. Declining trends in prevalence of
Taiwan, and the Gastroenterological Society of Taiwan (GEST). The GEST received Helicobacter pylori infection by birth-­year in a Japanese population. Cancer Sci
funding from the Takeda Taiwan Co. Ltd (APTC-01), the Eisai Co. Ltd, the Swiss 2015;106:1738–43.
Pharmaceutical Co. (APTC-02), Ltd, the Panion & BF Biotech Inc. (APTC-03), and the 17 Chen M-­J, Fang Y-­J, Wu M-­S, et al. Application of Helicobacter pylori stool antigen
Harvester Trading Co. LTD (APTC-04). for the 10th Asian Pacific Topic Conference. test to survey the updated prevalence of Helicobacter pylori infection in Taiwan. J
DYG is supported in part by the Office of Research and Development Medical Gastroenterol Hepatol 2020;35:233–40.
Research Service Department of Veterans Affairs, Public Health Service grant 18 Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med
DK56338 which funds the Texas Medical Center Digestive Diseases Center. EME-­O 2002;347:1175–86.
is funded by grants from the Australian Federal Government to the St George and 19 Tang MYL, Chung PHY, Chan HY, et al. Recent trends in the prevalence of
Sutherland Medical Research Foundation. The funding source had no role in study Helicobacter pylori in symptomatic children: a 12-­year retrospective study in a
design, data collection, analysis or interpretation, report writing or the decision to tertiary centre. J Pediatr Surg 2019;54:255–7.
submit this paper for publication. 20 Curado MP, de Oliveira MM, de Araújo Fagundes M. Prevalence of Helicobacter
pylori infection in Latin America and the Caribbean populations: a systematic review
Competing interests J-­ML reports receiving lecture fees from Takeda and meta-­analysis. Cancer Epidemiol 2019;60:141–8.
Pharmaceuticals (Taiwan) and Abbott Laboratories. PM reports receiving advisory 21 Bauer S, Krumbiegel P, Richter M, et al. Influence of sociodemographic factors on
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article or uploaded as supplementary information. associated gastric cancer. Cancer Treat Rev 2018;66:15–22.
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ORCID iDs development of gastric cancer. N Engl J Med 2001;345:784–9.
Jyh-M­ ing Liou http://​orcid.​org/​0000-​0002-​7945-​5408 27 Plummer M, Franceschi S, Vignat J, et al. Global burden of gastric cancer attributable
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Khay-G ­ uan Yeoh http://​orcid.​org/​0000-​0002-​7802-​4606 antioxidant supplements and anti-­Helicobacter pylori therapy. J Natl Cancer Inst
Takuji Gotoda http://o​ rcid.​org/​0000-​0001-​6904-​6777 2000;92:1881–8.
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