Lack of follow-up in Helicobacter pylori eradication treatment: Results from the European registry on Helicobacter pylori management

Abstract

BACKGROUND

The Maastricht VI/Florence consensus recommends the eradication of all Helicobacter pylori (H. pylori) infections. However, retreatment strategies remain inconsistent.

AIM

To evaluate the reasons for and factors associated with non-retreatment after H. pylori eradication treatment failure.

METHODS

A multicenter, prospective registry (European registry on H. pylori management) was used to evaluate the decisions and outcomes of H. pylori management by European gastroenterologists. Patients with at least one eradication failure between 2013 and 2024 were included and classified into retreatment (control) and non-retreatment. The reasons for non-retreatment were categorized as medical- or patient-related. Multivariate logistic regression identified factors associated with non-retreatment from each perspective.

RESULTS

Of the 6904 patients with eradication failure, 950 (14%) were not retreated: 41% due to medical decisions, 50% due to patient decisions, and 9% due to other reasons. Frequent reasons for non-retreatment included previous poor tolerance, noncompliance, unclear indications, and multiple eradication attempts. From a medical perspective, non-retreatment was associated with age ≥ 71 years [odds ratio (OR) = 1.49; 95% confidence interval (CI): 1.04-2.13], previous noncompliance (OR = 4.27; 95%CI: 2.64-6.93), treatment discontinuation due to adverse events (OR = 2.06; 95%CI: 1.19-3.56), and number of previous attempts (OR range: 2.07-9.25). From the patient perspective, the associated factors included male sex (OR = 1.34; 95%CI: 1.10-1.63), two to four previous eradication attempts (OR range: 1.69-3.60) and previous noncompliance (OR = 10.04; 95%CI: 7.37-13.68).

CONCLUSION

Up to 14% of European patients are not retreated after H. pylori eradication failure. Key barriers include advanced age, previous noncompliance and prior eradication failures. The decision to avoid retreatment was often patient-driven, although medical reasons were also relevant, highlighting the importance of shared decision-making and improved patient education.

Key Words: Helicobacter pylori; Eradication treatment; Eradication failure; Retreatment; European registry on Helicobacter pylori management

Core Tip: This multicenter European study found that 14% of patients in whom Helicobacter pylori (H. pylori) eradication treatment failed did not receive retreatment, often due to patient-driven decisions and medical considerations such as advanced age, previous noncompliance, and treatment intolerance. Identifying these barriers emphasizes the need for shared decision-making and enhanced patient education to improve management outcomes. These findings provide crucial insights into real-world challenges in H. pylori infection management and offer guidance for optimizing treatment strategies in line with the recommendations of Maastricht VI/Florence.

INTRODUCTION

Helicobacter pylori (H. pylori) is a gram-negative bacterium that colonizes the stomach in more than half of the global population[1,2]. Although most individuals remain asymptomatic, this infection predisposes them to various clinical manifestations; if untreated, it can result in lifelong infection and subsequent chronic gastric inflammation, which is associated with an increased risk of preneoplastic lesions and gastric adenocarcinoma[3-5]. Current guidelines recommend H. pylori eradication in all cases, irrespective of symptomatology[6,7].

Currently, eradication treatments face several challenges, especially as treatment failures accumulate over time[8]. Traditionally, the most successful therapies have achieved eradication rates over 90%[9]. However, in the past two decades, increasing antimicrobial resistance has significantly hindered treatment efficacy[10,11]. This trend is reflected in the growing number of treatment failures observed. The European registry on H. pylori management (Hp-EuReg) was established in 2013 with the goal of collecting data about diagnostic approaches and eradication therapies, helping to improve the management of adult patients with H. pylori infection. Actually, Hp-EuReg comprises data from more than 85000 cases across 39 countries.

To our knowledge, no studies have evaluated the factors influencing the decision not to prescribe a subsequent treatment following H. pylori eradication failure. Therefore, we aimed to investigate the factors associated with the lack of retreatment after eradication failure in European patients.

MATERIALS AND METHODS

The Hp-EuReg is an international, multicenter, prospective, noninterventional registry that has collected information on H. pylori infection management since 2013 and was promoted by the European Helicobacter and Microbiota Study Group[12].

The Hp-EuReg protocol was approved by the Ethics Committee of La Princesa University Hospital (Madrid, Spain), which acted as a reference Institutional Review Board (Ethics approval code: Hp-EuReg, 20 December 2012). This research was conducted in accordance with the guidelines of the 1975 Declaration of Helsinki and its subsequent updates. The study was classified by the Spanish agency for medicines and medical devices, and prospectively registered at Clinical Trials.gov under the code No. NCT02328131. Written informed consent was obtained from all participants.

Participants

Data were recorded in an electronic case report form (e-CRF), collected and managed using a web-based application designed to support data capture for research studies (research electronic data capture)[13], hosted at the Spanish Association of Gastroenterology (www.aegastro.es), a nonprofit scientific and medical society focused on gastroenterology research[14].

All adult patients recruited between January 2013 and June 2024 who had prior H. pylori infection and whose eradication treatment failed (verified by a valid eradication confirmatory test) were included. The criteria for country selection, national coordinators, and recruiting investigators are listed in the protocol publication[12]. Eligible investigators were gastroenterologists managing H. pylori-infected patients in centers with access to confirmatory testing methods.

Data management

Following data extraction, the database underwent rigorous review for inconsistencies and data cleaning. The quality control process ensured compliance with the study selection criteria and accurate data collection, maintaining adherence to the highest scientific and ethical standards.

The selected H. pylori-infected patients were divided into non-retreatment group (patients who did not receive retreatment after one or several failures) and a retreatment group (patients who were retreated). The reasons for non-retreatment were prospectively collected by the researchers through predefined questionnaires as part of the e-CRF. In the event of treatment failure, researchers were required to indicate whether a new treatment regimen would be prescribed; if not, the specific reason for non-retreatment was recorded. These reasons were subsequently grouped into three categories: Medical perspective (the gastroenterologist decided not to retreat after failure), patient perspective (the patient decided not to receive rescue therapy after failure), and other reasons.

The reasons for not prescribing retreatment provided by the gastroenterologists were evaluated and classified into following categories: Poor tolerance of the treatment, unclear treatment indication, asymptomatic patient, multiple prior eradication attempts, noncompliance, advanced age and/or the presence of comorbidities, drug allergy, unavailability of the treatment, pregnancy, antibiotic resistance and others. The reasons for the patient’s decision not to undergo retreatment were not collected. Other reasons included death, the corona virus disease 2019 pandemic, patient participation in other studies and missing information.

Statistical analysis

Variable categorization and definitions: Age was categorized into two groups: 18-70 years, and over 70 years. Although the World Health Organization defines an elderly person as someone aged 60 years or older, life expectancy and quality of life have increased in many European countries. Therefore, to better reflect the European context, we chose 70 years as the age cutoff.

The indications for H. pylori treatment were classified a priori as highly recommended or poorly recommended based on scientific evidence and the clinical impact of H. pylori eradication. The highly recommended indications included prior duodenal or gastric ulcers, preneoplastic gastric lesions, a history of resected gastric cancer (either endoscopically or surgically), mucosa-associated lymphoid tissue lymphoma, and being a first-degree relative of a patient with gastric cancer. Poorly recommended indications included non-investigated dyspepsia, dyspepsia with normal gastroscopy (with “normal” defined as the absence of ulcerative or cancerous findings), long-term treatment with proton-pump inhibitors, nonsteroidal anti-inflammatory drugs or acetylsalicylic acid, unexplained iron deficiency anemia, idiopathic thrombocytopenic purpura, vitamin B12 deficiency, and other indications.

Adverse events (AEs) were assessed through open-ended questions and predefined questionnaires and were classified according to the intensity of symptoms into the following categories: Mild (not interfering with daily routine), moderate (affecting daily routine) and intense/severe (not allowing normal daily routine). Serious AEs were defined as those that caused death, hospitalization, disability, congenital anomalies, and/or required intervention to prevent permanent damage.

Compliance was defined, through physician questioning, as taking ≥ 90% of the prescribed medication. For statistical analysis, the non-retreatment group was subdivided by medical and patient perspectives. The “other reasons” subgroup was not evaluated separately in further analyses. The three groups of non-retreated patients (overall, by medical perspective and patient perspective) were then analyzed separately, and each group was compared with the retreatment group (control group) via univariate and multivariate analyses.

Continuous variables were reported as arithmetic mean values and standard deviations or as medians with interquartile ranges (if the variables did not follow a normal distribution). Qualitative variables were reported as absolute relative frequencies and displayed as percentages and corresponding 95% confidence intervals (CIs) when applicable.

Data analysis: χ² tests were used to compare categorical variables between the non-retreatment groups and the control group (retreatment). Statistical significance was set at a P < 0.05. The variables included in the descriptive and univariate analyses were: Sex, age, ethnic background, indication and reclassified indication (poorly and highly recommended), number of previous attempts, treatment compliance (yes/no), at least one AE (yes/no), severe AEs (yes/no), serious AEs (yes/no), and treatment interruption due to AEs (yes/no).

For the multivariate analysis, logistic regression was performed. The effect was evaluated by calculating odds ratios (ORs) and the corresponding 95%CIs. Retreatment served as the dependent variable and was categorized into a dichotomous variable (categorized as 0 = no and 1 = yes). The independent variables included in the overall and medical perspective models were sex [female (reference category) vs male], age [< 70 years (reference category) vs ≥ 71 years], indication [poorly recommended (reference category) vs highly recommended], number of previous attempts [naive (reference category) vs 2^nd line vs 3^rd to 6^th treatment lines], compliance [yes: ≥ 90% of drug intake (reference category) vs no: < 90%], severe AEs [no (reference category) vs yes], serious AEs [no (reference category) vs yes], and treatment interruption due to AEs [no (reference category) vs yes]. In the patient perspective model, the same variables were included, except “serious AE”, which was not statistically significant in the univariate analysis. A P value < 0.05 was set as the threshold of statistical significance.

RESULTS

Baseline characteristics

A total of 6904 H. pylori-infected patients with prior eradication treatment failure were included, of whom 14% (n = 950) did not receive retreatment. The non-retreatment group was also classified based on the decision to avoid treatment: 41% (n = 393) were not retreated due to medical decisions, 50% (n = 474) due to patient decisions, and 9% (n = 83) due to other reasons (primarily missing information or death). In the overall non-retreatment group, 60% (n = 564) were women, predominantly Caucasian (85%, n = 810), with an average age of 50 years (± 21). Further characteristics of the subgroups are presented in Table 1.

Table 1 Baseline characteristics of the groups, n (%).

Baseline characteristics	Retreatment (n = 5954)	Non-retreatment
		Overall (n = 950)	Medical perspective (n = 393)	Patient perspective (n = 474)
Sex
Male	2100 (35.3)	386 (40.6)	147 (37.4)	206 (43.5)
Female	3850 (64.7)	564 (59.4)	246 (62.6)	268 (56.5)
Age (years)
18-70	5455 (91.6)	851 (89.5)	350 (89.1)	430 (90.7)
≥ 71	475 (7.9)	96 (10.1)	40 (10.9)	44 (9.3)
Ethnic background
Caucasian	5148 (86.6)	810 (85.3)	344 (87.6)	391 (82.5)
Afro-American	70 (1.2)	8 (0.8)	5 (1.3)	1 (0.2)
Asian	79 (1.3)	12 (1.3)	7 (1.8)	3 (0.6)
Others	405 (6.8)	63 (6.6)	34 (8.6)	25 (5.3)
Indication
Non-investigated dyspepsia	1649 (27.7)	166 (17.5)	67 (17)	93 (19.6)
Dyspepsia with a normal gastroscopy	2664 (44.7)	507 (53.5)	203 (51.7)	254 (53.6)
Duodenal ulcer	451 (7.6)	64 (6.7)	24 (6.1)	34 (7.2)
Gastric ulcer	325 (5.5)	74 (7.8)	34 (8.7)	34 (7.2)
Others	390 (6.6)	64 (6.7)	31 (7.9)	25 (5.3)
Preneoplastic lesions1	156 (2.6)	27 (2.8)	12 (3.1)	13 (2.7)
Chronic use of NSAIDs or ASA	13 (0.2)	5 (0.5)	1 (0.3)	3 (0.6)
Chronic use of PPIs	29 (0.5)	3 (0.3)	1 (0.3)	2 (0.4)
Antecedent of resected GC	8 (0.1)	2 (0.2)	2 (0.5)	0 (0)
MALT lymphoma	8 (0.1)	2 (0.2)	2 (0.5)	0 (0)
1st degree relative of a patient with GC	127 (2.1)	13 (1.4)	6 (1.5)	6 (1.3)
Unexplained iron deficiency anemia	103 (1.7)	18 (1.9)	8 (2)	7 (1.5)
Idiopathic thrombocytopenic purpura	4 (0.1)	0 (0)	0 (0)	0 (0)
Vitamin B12 deficiency	27 (0.5)	5 (0.5)	2 (0.5)	3 (0.6)
Indication2
Highly recommended	1075 (18.1)	182 (19.2)	80 (20.4)	87 (18.4)
Poorly recommended	4879 (81.9)	768 (80.8)	313 (79.6)	387 (81.6)

¹Preneoplastic lesions: Chronic atrophic gastritis and intestinal metaplasia.

²Highly recommended: Preneoplastic lesions, personal history of gastric cancer with surgical and/or endoscopic resection, 1^st degree relatives of patients with gastric cancer, mucosa-associated lymphoid tissue lymphoma, and gastric or duodenal ulcers. Poorly recommended: Functional and uninvestigated dyspepsia, vitamin B12 deficiency, treatment with nonsteroidal anti-inflammatory drugs or acetylsalicylic acid, prolonged treatment with proton pump inhibitors, iron deficiency anemia, idiopathic thrombocytopenic purpura.

NSAID: Nonsteroidal anti-inflammatory drug; ASA: Acetylsalicylic acid; PPI: Proton pump inhibitor; MALT: Mucosa-associated lymphoid tissue; GC: Gastric cancer.

The main reasons the gastroenterologists provided for not prescribing a new treatment included poor tolerance of the treatment (18%), unclear treatment indications (18%), asymptomatic patients (16%), multiple prior eradication treatment attempts (10%), noncompliance (7.4%), advanced age and/or the presence of comorbidities (6.6%), drug allergies (3.8%), no availability of treatment (2.8%), pregnancy (2%), antibiotic resistance (1.5%), and others (14%) (Table 2).

Table 2 Reasons for non-retreatment, n (%).

	Overall (n = 950)	Medical perspective (n = 393)	Patient perspective (n = 474)
Patient decision	474 (49.9)		474 (100)
Medical decision	393 (41.3)
Low tolerance		70 (17.8)
Unclear indication		70 (17.8)
Asymptomatic		62 (15.8)
Others		55 (14)
Multiple previous attempts		41 (10.4)
No compliance		29 (7.4)
Age and/or comorbidities		26 (6.6)
Allergy		15 (3.8)
Treatment not available		11 (2.8)
Pregnancy		8 (2)
Antibiotic resistance		6 (1.5)
Others	83 (8.7)

Overall perspective

When considering medical and patient perspectives, as well as other reasons, within the same analysis group, the initial indication for eradication treatment was classified as highly recommended in 20% of the cases (n = 182), whereas 80% (n = 768) were considered poorly recommended. The initial treatment indication did not significantly influence the retreatment decision (P > 0.05) (Table 3). Univariate analysis of the non-retreatment group also revealed that present one to five previous treatment failures significantly (P < 0.05) influenced the retreatment decision.

Table 3 Factors associated with non-retreatment of Helicobacter pylori after a therapeutic failure-univariate analysis, n (%).

Variables	Retreatment (n = 5954)	Non-retreatment
		Overall (n = 950)		Medical perspective (n = 393)		Patient perspective (n = 474)
		n (%)	P value	n (%)	P value	n (%)	P value
Sex
Male	2100 (35.3)	386 (40.6)	0.002	147 (37.4)	0.397	206 (43.5)	0.000
Female	3850 (64.7)	564 (59.4)		246 (62.6)		268 (56.5)
Age, years
18-70	5455 (91.6)	851 (89.5)	0.018	350 (89.1)	0.116	430 (90.7)	0.329
≥ 71	475 (7.9)	96 (10.1)		40 (10.9)		44 (9.3)
Ethnicity
Caucasian	5148 (86.6)	810 (85.3)	0.084	344 (87.6)	0.012	391 (82.5)	0.000
Afro-American	70 (1.2)	8 (0.8)		5 (1.3)		1 (0.2)
Asian	79 (1.3)	12 (1.3)		7 (1.8)		3 (0.6)
Others	405 (6.8)	63 (6.6)		34 (8.6)		25 (5.3)
Reclassified indication1
Highly recommended	1075 (18.1)	182 (19.2)	0.413	80 (20.4)	0.252	87 (18.4)	0.871
Poorly recommended	4879 (81.9)	768 (80.8)		313 (79.6)		387 (81.6)
Number of previous eradication attempts			0.000		0.000		0.000
None	4381 (73.6)	561 (59.1)		194 (49.4)		320 (67.5)
One attempt	1054 (17.7)	181 (19.1)		82 (20.9)		82 (17.3)
Two attempts	334 (5.6)	105 (11.1)		61 (15.5)		26 (5.5)
Three attempts	115 (1.9)	63 (6.6)		39 (9.9)		21 (4.4)
Four attempts	42 (0.7)	27 (2.8)		12 (3.1)		10 (2.1)
Five attempts	28 (0.5)	13 (1.4)		5 (1.3)		5 (1.1)
Treatment compliance2	5647 (94.8)	739 (77.8)	0.000	303 (77.1)	0.000	358 (75.5)	0.000
At least one AE	1277 (21.4)	234 (24.6)	0.051	103 (26.2)	0.046	116 (24.5)	0.193
Severe AE3	137 (2.3)	44 (4.6)	0.000	24 (6.1)	0.000	18 (3.8)	0.041
Serious AE4	9 (0.2)	5 (0.5)	0.017	5 (1.3)	0.000	0	0.397
Interruption by AE	183 (3.1)	109 (11.5)	0.000	68 (17.3)	0.000	39 (8.2)	0.000

¹Highly recommended: Preneoplastic lesions, personal history of gastric cancer with surgical and/or endoscopic resection, 1^st degree relatives of patients with gastric cancer, mucosa-associated lymphoid tissue lymphoma, and gastric or duodenal ulcers. Poorly recommended: Functional and uninvestigated dyspepsia, vitamin B12 deficiency, treatment with nonsteroidal anti-inflammatory drugs or acetylsalicylic acid, prolonged treatment with proton pump inhibitors, iron deficiency anemia, idiopathic thrombocytopenic purpura.

²Compliance: > 90% drug intake.

³Severe adverse event: Refers to the intensity of the symptoms.

⁴Serious adverse event: Unexpected medical occurrence, such as life-threatening, risk of hospitalization, or malformations.

AE: Adverse event.

Patient compliance with previous H. pylori eradication treatment appeared to impact the decision to retreat. In the non-retreatment group, 22% (n = 211) of the patients were classified as noncompliant, a significantly higher percentage than that in the retreatment group, reported as 5.2% (n = 307), (P < 0.001) (Table 3).

With respect to safety, at least one AE was reported in 25% (n = 234) of patients who did not receive retreatment, which was not significantly different from the retreatment group. In contrast, serious and severe AEs were significantly more common in the non-retreatment group, with rates of 0.5% vs 0.2% (P < 0.05) and 4.6% vs 2.3% (P < 0.001), respectively. Prior treatment interruption due to AEs occurred in 12% of the non-retreated patients (P < 0.001) (Table 3).

The factors significantly associated with non-retreatment included male sex (OR = 1.30; 95%CI: 1.12-1.50; P < 0.001), age ≥ 71 years (OR = 1.35; 95%CI: 1.06-1.72; P < 0.05), noncompliance (OR = 6.07; 95%CI: 4.97-7.41; P < 0.001), and previous treatment attempts as follows: One attempt (OR = 1.57; 95%CI: 1.30-1.89; P < 0.001), two attempts (OR = 2.82; 95%CI: 2.21-3.61; P < 0.001), three attempts (OR = 5.05; 95%CI: 3.63-7.03; P < 0.001), four attempts (OR = 6.00; 95%CI: 3.61-9.96; P < 0.001) and five attempts (OR = 4.04; 95%CI: 2.04-8.02; P < 0.001) (Table 4).

Table 4 Factors associated with non-retreatment of Helicobacter pylori after a therapeutic failure-multivariate analysis, n (%).

Variables	Retreatment (n = 5954)	Non-retreatment
		Overall (n = 950)			Medical perspective (n = 393)			Patient perspective (n = 474)
		n (%)	P value	OR (95%CI)	n (%)	P value	OR (95%CI)	n (%)	P value	OR (95%CI)
Sex
Male	2100 (35.3)	386 (40.6)	0.000	1.30 (1.12-1.50)	147 (37.4)	0.116		206 (43.5)	0.004	1.34 (1.10-1.63)
Female	3850 (64.7)	564 (59.4)			246 (62.6)			268 (56.5)
Age, years
18-70	5455 (91.6)	851 (89.5)	0.015	1.35 (1.06-1.72)	350 (89.1)	0.028	1.49 (1.04-2.13)	430 (90.7)	0.282
≥ 71	475 (7.9)	96 (10.1)			40 (10.2)			44 (9.3)
Reclassified indication1
Highly recommended	1075 (18.1)	182 (19.2)	0.989		80 (20.4)	0.536		87 (18.4)	0.765
Poorly recommended	4879 (81.9)	768 (80.8)			313 (79.6)			387 (81.6)
Number of previous eradication attempts
One attempt	1054 (17.7)	181 (19.1)	0.000	1.57 (1.30-1.89)	82 (20.9)	0.000	2.07 (1.57-2.73)	82 (17.3)	0.109
Two attempts	334 (5.6)	105 (11.1)	0.000	2.82 (2.21-3.61)	61 (15.5)	0.000	4.89 (3.54-6.74)	26 (5.5)	0.006	1.69 (1.16-2.44)
Three attempts	115 (1.9)	63 (6.6)	0.000	5.05 (3.63-7.03)	39 (9.9)	0.000	9.25 (6.15-13.93)	21 (4.4)	0.000	2.91 (1.78-4.76)
Four attempts	42 (0.7)	27 (2.8)	0.000	6.00 (3.61-9.96)	12 (3.1)	0.000	7.84 (3.96-15.53)	10 (2.1)	0.000	3.60 (1.75-7.41)
Five attempts	28 (0.5)	13 (1.4)	0.000	4.04 (2.04-8.02)	5 (1.3)	0.002	4.73 (1.75-12.77)	5 (1.1)	0.073
Treatment compliance2	5647 (94.8)	739 (77.8)	0.000	6.07 (4.97-7.41)	303 (77.1)	0.000	4.27 (2.64-2.93)	358 (75.5)	0.000	10.04 (7.37-13.68)
Severe AE3	137 (2.3)	44 (4.6)	0.665		24 (6.1)	0.621		18 (3.8)	0.535
Serious AE4	9 (0.2)	5 (0.5)	0.642		5 (1.3)	0.261		NA	NA
Interruption by AE	183 (3.1)	109 (11.5)	0.053		68 (17.3)	0.010	2.06 (1.19-3.56)	39 (8.2)	0.000	0.34 (0.22-0.55)

¹Highly recommended: Preneoplastic lesions, personal history of gastric cancer with surgical and/or endoscopic resection, 1^st degree relatives of patients with gastric cancer, mucosa-associated lymphoid tissue lymphoma, and gastric or duodenal ulcers. Poorly recommended: Functional and uninvestigated dyspepsia, vitamin B12 deficiency, treatment with nonsteroidal anti-inflammatory drugs or acetylsalicylic acid, prolonged treatment with proton pump inhibitors, iron deficiency anemia, idiopathic thrombocytopenic purpura.

²Compliance: > 90% drug intake.

³Severe adverse event: Refers to the intensity of the symptoms.

⁴Serious adverse event: Unexpected medical occurrence, such as life-threatening, risk of hospitalization, or malformations.

AE: Adverse event; NA: Not appliable; OR: Odds ratio; CI: Confidence interval.

Medical perspective

The indication for the first H. pylori eradication attempt in this subgroup followed the same pattern observed in the overall non-retreatment group: 20% (n = 80) of the patients had a highly recommended indication and 80% (n = 313) had a poorly recommended indication. There was no significant difference compared with the control group (P > 0.05), nor did this factor influence the retreatment decision (Table 3).

Previous failures of H. pylori eradication influenced the gastroenterologist’s decision to retreat patients, as the proportion of patients with several treatment attempts was significantly greater in the non-retreatment group (P < 0.05). Additionally, noncompliance was observed in 23% (n = 90) of the non-retreatment subgroup and in 5.2% (n = 307) of the retreatment subgroup (P < 0.001) (Table 3).

In terms of tolerance, the incidence of at least one AE in the non-retreatment group was 26% (n = 103, P < 0.05). Both serious and severe AEs were significantly more common in the non-retreated patients, with incidence rates of 1.3% vs 0.2% (P < 0.001) and of 6.1% vs 2.3% (P < 0.001), respectively. Prior treatment interruption due to AEs was more common in the non-retreated patients and occurred in 17% vs 3% of the retreated patients (P < 0.001) (Table 3).

From a medical perspective, factors associated with not retreating a patient included age ≥ 71 years (OR = 1.49; 95%CI: 1.04-2.13; P < 0.05), noncompliance (OR = 4.27; 95%CI: 2.64-2.93; P < 0.001) and lack of response to previous treatment attempts: One attempt (OR = 2.07; 95%CI: 1.57-2.73; P < 0.001), two attempts (OR = 4.89; 95%CI: 3.54-6.74; P < 0.001), three attempts (OR = 9.25; 95%CI: 6.15-13.93; P < 0.001), four attempts (OR = 7.84; 95%CI: 3.96-15.53; P < 0.001) and five attempts (OR = 4.73; 95%CI: 1.75-12.77; P < 0.01). Additionally, a significant association was observed with previous discontinuation of H. pylori treatment due to AEs (OR = 2.06; 95%CI: 1.19-3.56; P = 0.01) (Table 4).

Patient perspective

From a patient perspective, among the 474 patients in the non-retreatment subgroup, 18% (n = 87) had highly recommended indications, whereas 82% (n = 387) had poorly recommended indications. There was no significant difference compared with the control group (P > 0.05), nor did this distribution influence the retreatment decision. According to the univariate analysis, the presence of two to four previous treatment failures significantly influenced the patient’s choice for no retreatment (P < 0.05). Noncompliance with eradication treatment was also significantly greater in non-retreated patients than in retreated patients (25% vs 5.2%, respectively; P < 0.001) (Table 3).

AEs occurred in 25% (n = 116) of the non-retreated patients, with no significant difference compared with the retreatment group. No serious AEs were reported in the non-retreatment subgroup, although 3.8% of these patients experienced severe AEs, whereas 2.3% of the retreatment group experienced severe AEs (P < 0.05). Finally, prior treatment interruption due to AEs was significantly more common in the non-retreatment subgroup, with 8.2% of cases, than in the retreatment subgroup, with 3.1% (P < 0.001) (Table 3).

The factors associated with the decision not to pursue retreatment from the patient’s perspective included male sex (OR = 1.34; 95%CI: 1.10-1.63; P < 0.01), previous treatment attempts two attempts (OR = 1.69; 95%CI: 1.16-2.44; P < 0.01), three attempts (OR = 2.91; 95%CI: 1.78-4.76; P < 0.001), and four attempts (OR = 3.60; 95%CI: 1.75-7.41; P < 0.001), as well as noncompliance (OR = 10.04; 95%CI: 7.37-13.68; P < 0.001). In this subgroup, treatment discontinuation due to AEs appeared to be a favorable factor (OR = 0.34; 95%CI: 0.22-0.55; P < 0.001) against the decision not to retreat (Table 4). Neither the indication for treatment nor the presence of AEs was associated with the decision not to retreat in any of the groups (Table 3).

DISCUSSION

Current guidelines recommend treating H. pylori infection regardless of the presence of symptoms or associated clinical conditions[6,7]. To our knowledge, this study provides the first comprehensive evaluation of the factors contributing to the absence of retreatment after at least one failed eradication attempt, incorporating both medical and patient perspectives.

In our cohort, 14% of the patients with a history of H. pylori infection and failed eradication treatment did not undergo retreatment. Patients placed restrictions on retreatment more often than physicians did (50% vs 41%), although the specific reasons for not receiving retreatment were not collected in the patient subgroup. From a medical perspective, the most common reasons for non-retreatment included poor tolerance (18%), unclear indications (18%), asymptomatic patients (16%), multiple prior eradication attempts (10%), and previous noncompliance (7.4%).

The most common factors influencing the decision of non-retreatment were noncompliance with previous treatment(s) and multiple prior treatment attempts. From a medical standpoint, advanced patient age and treatment discontinuation due to AEs were key factors. Notably, the only patient-related factor associated with non-retreatment was male sex.

We evaluated the indication by separating it into two groups (poorly and highly recommended), expecting that the highly recommended group would be retreated more frequently. In this context, the initial treatment indication was classified as highly recommended in approximately 20% of patients, but this did not influence the decision to retreat. The absence of a difference between these groups aligns with the Maastricht VI/Florence consensus, which recommends treatment in all cases of H. pylori infection regardless of the presence of symptoms, as a preventive strategy for gastric cancer[6].

We determined that the number of previous therapeutic failures and noncompliance were major barriers for retreatment. In both the medical and patient-perspective subgroups, previous treatment attempts negatively influenced the decision to retreat, despite evidence that the efficacy of rescue regimens remains relatively high even after two unsuccessful attempts[6,15]. For example, in a recent metanalysis assessing efficacy of current second-line regimens in different geographic areas, various therapeutic schemes presented an eradication rate over 80%, suggesting that rescue treatment can still offer a strong chance of success[16].

Regarding treatment compliance, the non-retreatment group had a greater proportion of noncompliant patients (approximately 25%), compared with the retreatment group, in which only 5% were noncompliant with previous eradication therapy. Previous publications have shown that compliance is one of the most relevant factors for achieving H. pylori eradication, regardless of the treatment regimen[17,18]. These findings highlight the importance of patient education when a treatment is prescribed to reduce noncompliance rates, which could impact future treatments and clinical outcomes.

Furthermore, AEs associated with previous H. pylori eradication attempts occurred in approximately 25% of the non-retreated patients, with both severe and serious AEs being more frequent in this group. This greater incidence of severe and serious AEs may contribute to the greater rate of noncompliance in the non-retreatment group. In our analysis, while the presence of AEs did not significantly impact retreatment decisions, prior treatment interruption due to AEs played a pivotal role in the medical perspective subgroup. In these cases, gastroenterologists were more likely to avoid prescribing a new treatment. However, interesting observations emerged from the patient perspective subgroup. When patients discontinued previous H. pylori treatment due to an AE, this appeared to serve as a positive factor in favor of retreatment; this may reflect how patients perceive the intensity of AEs during treatment and how this perception can evolve over time, potentially resulting in greater openness to trying another treatment. This is supported in the study by Gebeyehu et al[19], in which 421 patients were interviewed after H. pylori eradication treatment; the patients that presented AEs classified them with a mild intensity and there was no mention to serious AEs by the patients. Overall, we would like to reinforce the relevance of patients’ participation in their own therapeutic decisions.

Additionally, advanced age influenced retreatment decisions. Age over 70 years significantly affected decisions in the overall cohort and in the medical perspective subgroup. This finding may be explained by the common association of comorbidities in this population, which could influence physicians’ decisions. Our findings reinforce that, to date, age remains an important factor in medical decision-making, although it may not fully reflect the profile of the elderly population. Indeed, current evidence from Japanese cohorts indicates that the effectiveness and safety of H. pylori eradication therapies do not differ significantly among younger, elderly and super-elderly patients[20].

Interestingly, from the patient perspective subgroup, male patients tended to forgo retreatment. This observation might reflect sex differences in health awareness, risk perception, and how the importance of H. pylori eradication is perceived not only from a medical standpoint but also from a sociocultural perspective. Several studies in different health contexts support our findings: Men are generally less likely to seek health care, to use preventive health services and tend to have a lower level of engagement with health issues[21-25]. These findings suggest a potential opportunity to improve retreatment rates through public health education, especially among men.

Our study has several inherent limitations related to its observational and noninterventional design. It is important to consider potential limitations in terms of patient diversity or the generalizability of findings across different health care systems, as the study was based on a European registry. The number of included cases depended on the number of patients attending the participating centers and the commitment of the recruiting investigators. Consistent with this, socioeconomic status and health care access were not recorded, which may have influenced the results, as these factors could act as potential confounders in the analysis of variables associated with non-retreatment. However, the large sample size could have mitigated some of these potential limitations. Another point is that the study assessed the reasons for non-retreatment from medical and patient perspectives. Nevertheless, shared decision-making between patients and physicians is increasing in clinical practice, and this overlap was not accounted for in the study design. Furthermore, the specific reasons why patients declined further treatment were not recorded, nor were other reasons for non-retreatment, excluding medical and patient reasons.

The strengths of this study include its large sample size and multicenter design, which allows the inclusion of a large European cohort, representing real-life clinical practice across multiple Western countries. To our knowledge, this study is the first to address why patients are not retreated after treatment failure and provides new information about H. pylori management.

CONCLUSION

In conclusion, up to 14% of patients in whom H. pylori eradication failed did not receive retreatment. The decision to avoid retreatment was often patient-driven, although medical reasons were also relevant. From both perspectives, prior noncompliance and previous treatment failure(s) were the main factors associated with non-retreatment. These findings highlight the importance of shared decision-making and improved patient education to optimize treatment outcomes.

ACKNOWLEDGEMENTS

The authors thank the support from the European Helicobacter and Microbiota Study Group, the Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), the United Kingdom Research and Innovation and from Diasorin, Juvisé, Biocodex, and Zambon. Also, we thank the Spanish Association of Gastroenterology for providing the e-CRF service free of charge.