Economic and health impacts of introducing Helicobacter pylori eradication strategy into national gastric cancer policy in Japan: A cost‐effectiveness analysis

Abstract Background Helicobacter pylori (H. pylori) eradication reduces gastric cancer risk. Since 2013, a population‐wide H. pylori eradication strategy for patients with chronic gastritis has begun to prevent gastric cancer in Japan. The aim of this study was to evaluate the economic and health effects of H. pylori eradication strategy in national gastric cancer prevention program. Materials and Methods We developed a cohort state‐transition model for H. pylori eradication and no eradication over a lifetime horizon from a healthcare payer perspective, and performed one‐way and probabilistic sensitivity analyses. We targeted a hypothetical cohort of H. pylori‐positive patients aged 20, 30, 40, 50, 60, 70, and 80. The main outcomes were costs, quality‐adjusted life‐years (QALYs), life expectancy life‐years (LYs), incremental cost‐effectiveness ratios, gastric cancer cases, and deaths from gastric cancer. Results H. pylori eradication was more effective and cost‐saving for all age groups than no eradication. Sensitivity analyses showed strong robustness of the results. From 2013‐2019 for 8.50 million patients, H. pylori eradication saved US$3.75 billion, increased 11.11 million QALYs and 0.45 million LYs, and prevented 284,188 cases and 65,060 deaths. For 35.59 million patients without eradication, H. pylori eradication has the potential to save US$14.82 billion, increase 43.10 million QALYs and 1.66 million LYs, and prevent 1,084,532 cases and 250,256 deaths. Conclusions National policy using population‐wide H. pylori eradication to prevent gastric cancer has significant cost savings and health impacts for young‐, middle‐, and old‐aged individuals in Japan. The findings strongly support the promotion of H. pylori eradication strategy for all age groups in high‐incidence countries.


More than half of the world's population is infected with
Helicobacter pylori (H. pylori). 1 H. pylori infection causes chronic atrophic gastritis, a common stage of progression to gastric cancer, and is responsible for 98% of the causes of gastric cancer in Japan. 2,3,4,5 Japan has the third highest age-standardized rate for gastric cancer in the world. 6 The incidence of gastric cancer in Japan is almost 10 times higher than that observed in the United States. The Taipei global consensus guidelines for screening and eradication of H. pylori for gastric cancer prevention recommend that mass screening and eradication of H. pylori should be considered in populations at higher risk of gastric cancer and that eradication therapy should be offered to all individuals infected with H. pylori. 7 In the guidelines for the management of H. pylori infection by the Japanese Society for Helicobacter Research, H. pylori eradication treatment is recommended to prevent gastric cancer for patients with H. pylori infection. 8 Figure 1). 12,13 In this study, we aimed to evaluate the economic and health effects of H. pylori eradication strategy in national gastric cancer prevention program in Japan.

| Study design and model structure
We constructed a cohort state-transition model with a Markov cycle tree for two strategies: H. pylori eradication strategy and no eradication strategy, using a healthcare payer perspective and a lifetime horizon. A cycle length of one year was chosen. The halfcycle correction was applied. In the model, decision branches leaded directly to one Markov node per intervention strategy and the first events were modeled within the Markov cycle tree ( Figure 2). We used TreeAge Pro (TreeAge Software Inc., Williamstown, Massachusetts) for the Decision-analytical calculations. As this was a modeling study with all inputs and parameters derived from the published literature and Japanese statistics, ethics approval was not required.

| H. pylori eradication strategy
The H. pylori-positive patient receives first-line eradication treatment (proton-pump inhibitor, clarithromycin, and amoxicillin). The patient who fails first-line eradication treatment receives secondline eradication treatment (proton-pump inhibitor, metronidazole, and amoxicillin). We consider the eradication and compliance rates of first-line and second-line eradication treatments in the model. rates, and mortality due to other causes (Table 1). 12,15 The patient aged 50 and over receives endoscopic screening every year from the year after eradication.

| No eradication strategy
The latest version of Japanese guidelines for effective secondary prevention of gastric cancer recommends upper gastrointestinal series and endoscopy in adults 50 years of age and older. In the model, the H. pylori-positive patient does not receive H. pylori eradication treatment, and the patient aged 50 and over receives annual endoscopic screening annually. When the patient has gastric cancer, the patient receives the standard treatment of gastric cancer.

| Target population
We targeted a hypothetical cohort of Japanese H. pylori-positive chronic gastritis patients who had the initial endoscopic diagnosis needing H. pylori eradication at the age of 20, 30, 40, 50, 60, 70, and 80. Children and adolescents (age <20 y) were not included in the model.

| Epidemiologic parameters and clinical probabilities
Epidemiologic parameters and clinical probabilities were collected using MEDLINE from 2000 to June 2, 2021, national census, and Japanese cancer statistics (Table 1). 2,3,10-12,15-20 We estimated annual age-specific numbers of H. pylori-positive patients with eradication treatment from the literature 10,11 and expert opinion (Table1, Figure   S1A). The numbers of H. pylori-positive patients with and without eradication were estimated from the literature 16 and national census (Table1, Figure S1B). Relative risk of gastric cancer development after successful eradication 15 , and eradication and compliance rates of first-and second-line eradication treatments 19 were obtained from the literature. Age-specific gastric cancer incidence and stagespecific 5-year survival rate were obtained from Japanese cancer statistics. 10

| Costs
Costs were calculated based on the costs from the Japanese national fee schedule 17 and were adjusted to 2019 Japanese yen, using the medical care component of the Japanese consumer price index and were converted to US dollars, using the Organisation for Economic Co-operation and Development (OECD) purchasing power parity rate in 2019 (US$1 = ¥100.64) ( Table 1). 21 All costs were discounted by 3%. 22,23 Incremental cost-effectiveness ratios (ICERs) were calculated and compared to two willingness-to-pay levels of US$50,000 per quality-adjusted life-year (QALY) gained and US$100,000 per QALY gained. 24 Age-specific and total cumulative lifetime cost savings of H. pylori eradication strategy compared with no eradication strategy were calculated.

| Health utilities, effectiveness, and health outcomes
Health status was included to represent possible eight clinical states:  (Table 1). 25,26 The annual discounting of the utilities in this analysis was set at a rate of 3%. 22

| Sensitivity analyses
We performed a one-way sensitivity analysis to determine which strategy was more cost-effective when we tested a single variable over a wide range of possible values while holding all other variables constant, and performed a probabilistic sensitivity analysis using a second-order Monte-Carlo simulation for 10,000 trials to assess the impact of the uncertainty in the model on the base-case estimates.
The uncertainty had a beta distribution in clinical probabilities and accuracies, and a log-normal distribution in costs.

| Base-case analysis
H. pylori eradication strategy was less costly and yielded greater benefits than no eradication strategy for all age groups (

| One-way sensitivity analysis and probabilistic sensitivity analysis
Incremental cost-effectiveness ratio tornado diagram of H. pylori eradication strategy versus no eradication strategy showed that cost-effectiveness was not sensitive to any variables in all age groups ( Figure 3A, Figure S2).
In probabilistic sensitivity analysis using Monte-Carlo simulation for 10,000 trials, the acceptability curve showed that H. pylori eradication strategy was cost-effective 100% of the time at two willingnessto-pay thresholds of US$50,000 per QALY gained and US$100,000 per QALY gained in all age groups ( Figure 3B, Figure S3). Incremental cost-effectiveness scatterplots showed that H. pylori eradication strategy dominated no-eradication strategy in more than 9800 trials in all age groups ( Figure 3C, Figure S4). The results showed strong robustness of H. pylori eradication strategy in all age groups.

| Cumulative lifetime economic and health outcomes
H. pylori-positive patients aged 60 had the highest cumulative lifetime economic and health outcomes (  (Table S1).
In the Markov cohort analysis, the cumulative lifetime potential of gastric cancer cases and deaths from gastric cancer in H. pylori eradication strategy compared with no eradication strategy decreased by 30 to 33% in patients under 50 and by 25 to 28% in patients aged 50 and over ( Figure S5). H. pylori eradication reduced the incidence and mortality of gastric cancer in the younger age groups greater than in the older age groups (Table 2, Figure S5).

| DISCUSS ION
To the best of our knowledge, this is the first study to assess the economic and health impacts of population-wide H. pylori eradication strategy in national gastric cancer prevention program covered by National Health Insurance in the world.
We demonstrated that population-wide H. pylori eradication strategy reduced costs, prevented gastric cancer, and reduced deaths from gastric cancer for all age groups in the modeling study with real-life settings in Japan, even though most older adults with gastric mucosal atrophy require more than 10 years of follow-up endoscopic screening after successful H. pylori eradication. 27 Japan. This means that the promotion of H. pylori eradication strategy focused on primary prevention of gastric cancer not only saves many lives from gastric cancer, but also leads to significant cost savings in the national budget.
It is well known that the benefits of H. pylori eradication on the reduction of gastric cancer risk in the younger age groups are greater than those in the older age groups. Young individuals would benefit most from H. pylori eradication because it cures H. pylori related gastritis, reduces the risk of gastric cancer, and reduces transmission to their children. 7 This modeling study using the constant risk of gastric cancer development after successful eradication treatment demonstrated that H. pylori eradication reduced the incidence and mortality of gastric cancer in the younger age groups greater than in the older age groups. If we could modify to reduce the risk of gastric cancer development after successful eradication treatment in the younger age groups, more significant effects on reducing the incidence and mortality of gastric cancer could be shown in the younger age groups.
Surveillance of the local antibiotic resistance of H. pylori is recommended to identify the optimal empirical therapy for H. pylori eradication in the country. 7 Chiang et al demonstrated no change of the antibiotic resistance rate of H. pylori through the selection of effective eradication regimens and retesting those who had completed H. pylori treatments in mass H. pylori eradication program. 29 Guo et al found that successful H. pylori eradication potentially restored gastric microbiota to a similar status as found in uninfected individuals, and showed beneficial effects on gut microbiota. 30 Liou et al showed that H pylori eradication had no effect on antibiotic resistance of E coli and no significant change in the prevalence of metabolic syndrome. 31 These recent studies suggested that H. pylori eradication strategy with effective regimens and high compliance rates could provide significant benefits with minimal adverse effects in high-risk countries.
Several economic analyses suggested that H. pylori screening followed by eradication treatment is cost-effective to prevent gastric cancer, particularly in high-risk populations. [32][33][34][35][36][37][38][39][40] Han et al demonstrated that H. pylori screening and eradication treatment effectively reduced the morbidity of gastric cancer and cancer-related costs in asymptomatic infected individuals in China. 33 Chen et al showed that populationbased screen-and-treat strategy for H pylori infection proved cheaper and more effective for preventing gastric cancer, peptic ulcer disease, and nonulcer dyspepsia in asymptomatic general population compared with no-screen strategy in China. 34   In conclusion, we demonstrated in the modeling study with real-life settings that national policy using population-wide H. pylori eradication to prevent gastric cancer has significant cost savings and health impacts for young-, middle-, and old-aged individuals in Japan. The findings strongly support the promotion of H. pylori eradication strategy for all age groups in high-incidence countries. Based on cost-effectiveness, introducing H. pylori eradication strategy into national gastric cancer policy should be considered in high-risk countries around the world.

ACK N OWLED G M ENTS
The authors thank Professor Kenji Fujimori, Department of Health Administration and Policy, Tohoku University School of Medicine, for his contribution to providing access to unpublished data from the claims database in Hokkaido (the north island of Japan) combined with the National Database used to estimate the model parameter values.
No funding was received for this study.

CO N FLI C T S O F I NTE R E S T
The author has no conflicts of interest to declare.

AUTH O R CO NTR I B UTI O N S
AK had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. AK and MA approved the final version of the manuscript, and involved in concept, design, and critical revision of the manuscript for important intellectual content. AK involved in acquisition, analysis, interpretation of data, drafting of the manuscript, and administrative, technical, or material support. MA involved in supervision.