Note：All the information in this draft can be edited by authors. And the entry will be online only after authors edit and submit it.

1. Introduction

Helicobacter pylori (hence forth referred to as H. pylori) infection affects over half the world’s population [1]. As described by Warren and Marshall in 1983 [2], this infection has been associated with disorders such as peptic ulcers, chronic gastritis, dyspepsia, lymphomas of lymphoid tissue of the gastric mucosa and gastric cancer [3–5]. H. pylori has been reported to cause 90% of duodenal ulcers and 80% of gastric ulcers [6].

The frequency of H. pylori infection and its consequences has influenced the definition of treatment standards. The V Maastricht Consensus for the Treatment of H. pylori Infections (2015) [7] recognizes the implications that antimicrobial resistance has had on the effectiveness of treatments. The Consensus notes the increasing rates of resistance in high and middle-income countries. Levels of resistance to clarithromycin reach 30% in Italy and Japan, 40% in Turkey and 50% in China, among others [8–13]. Therefore, the Consensus recommends that standard triple therapy (the combination of PPI (proton pump inhibitor)-clarithromycin and amoxicillin or metronidazole) without prior susceptibility testing should not be used when resistance to clarithromycin exceeds 15%. Furthermore, another cause of reduction in the eradication rate is the presence of biofilms on the surface of gastric mucosa, which may cause antibiotic treatment to fail. As noted in the literature, H. pylori biofilm formation increases the threat of antimicrobial resistance (AMR) development [14].

At present, the adequate treatment of H. pylori infections requires progress in two areas: improving the quality of existing or new diagnostic tests so that infections are identified more quickly and accurately[15–17] and widening the diagnostic options to detect better AMR before treatment is prescribed.

Non-invasive and invasive methods are currently available for diagnosing H. pylori [1,18]. Most frequently included among the former are the urea breath test (UBT) and the stool antigen test. The invasive diagnostic option is the upper endoscopy, including histological testing, polymerase chain reaction (PCR), culture and rapid urease testing (RUT). PCR tests have been proposed as one of the diagnostic alternatives to avoid endoscopies and to evaluate bacterial resistance. It has been reported that the Amplidiag H. pylory+ClariR Mobidiag essay has a high sensitivity and specificity for the detection of both H. pylori and CLA resistance [19].

Evidence of the role of antimicrobial resistance in reducing the rate of eradication influences the use of other therapeutic options, such as bismuth quadruple therapy, quadruple sequential therapy, quadruple concomitant therapy (QCT) and hybrid therapy [20]. It has been reported that QCT may overcome the declining H. pylori eradication rate [20]. Although quadruple-regimen therapy (bismuth or non-bismuth) has been reported to be useful when resistance to clarithromycin or metronidazole is present, it also increases resistance if treatment is prolonged with multiple antibiotics [21].

The worrying evolution of the increase in AMR, including primary resistance, has generated a growing international consensus on the importance of tailored therapy through analysis of susceptibility prior to the initiation of treatment for H. pylori infection [6,21,22]. However, susceptibility testing is not commonly performed [22]. The high frequency of this infection results in the use of primary care services, causing indications of antibiotics and increasing the chances of antimicrobial resistance. That is why it is particularly important to analyze the economic evaluation of diagnostic alternatives in these diseases that will facilitate the adoption of evidence-based decision strategies regarding antibiotic treatments and, consequently, the potential reduction of AMR. We are particularly interested in the studies that examine the existence of AMR and its effects on the efficiency of antibiotic treatment.

2. Diagnostics of H. pylori Infection Associated with Dyspepsia

Six articles [27–32] examined the cost-effectiveness of a range of test and treat strategies to manage patients attending primary care with dyspepsia as the predominant symptom. Table 2 shows the models’ main characteristics. Two models [30,32] introduced AMR into the analysis: reducing the eradication rate for triple therapy (ranitidine, metronidazole and tetracycline) from 80–100% to 50–100%, arguing that as in China over-the-counter antibiotics are occasionally available, AMR may cause a higher failure rate [30] and reducing the eradication rate, as the prevalence of clarithromycin resistance increases [32]. All articles assess the use of a H. pylori test and in four of them this was found to be the most cost-effective strategy. In one of the other two cases, the most cost-effective strategy was to stratify patients using a score system (using a previously validated predictive model) then referring those at higher risk of organic dyspepsia to endoscopy [29]. In the other one, treating them with empiric PPI even when the prevalence of H. pylori infection varied from 5% to 40% [31]. This last result was reached after authors modelled how the test is actually used in U.S. practice, assuming that clinicians would perform a biopsy in the case of a lack of symptomatic relief, thus reducing the benefits of testing.

Table 2. Articles related to diagnosing H. pylori infection associated with dyspepsia.

¹ the most cost-effective strategy is in bold; PC, primary care; NA, not reported; PPI, proton pump inhibitor; DSA, deterministic sensitivity analysis; PSA, probabilistic sensitivity analysis; AMR, antimicrobial resistance; UBT, urea breath test; SAG, sensitivity analysis graph.

3. Diagnostics of H. pylori Infection Associated with Duodenal Ulcers

Four articles [33–36] studied the cost-effectiveness of alternative strategies of diagnosing H. pylori infection in patients with duodenal ulcers. Table 3 shows the main characteristics of the models. In two articles [34,35] empirical triple therapy was the most cost-effective approach, considering that the analysis was performed in a country with high prevalence of the infection and first-line therapy was more cost-effective than treatment for recurrent ulcers or long-term maintenance treatment. One model [36] introduced AMR into the analysis, taking into consideration that diagnostic testing can provide rapid and reliable results regarding the presence of clarithromycin resistance. The dual priming oligonucleotide (DPO) PCR test, which gives information regarding clarithromycin resistance, reduced secondary prescriptions, thus making this strategy more cost-effective than other diagnostic approaches, such as rapid urease tests.

Table 3. Articles related to diagnosing H. pylori infection associated with duodenal ulcers.

¹ the most cost-effective strategy is in bold; PC, primary care; NA, not reported; PPI, proton pump inhibitor; DSA, deterministic sensitivity analysis; AMR, antimicrobial resistance; RUT, rapid urease test; SAG, sensitivity analysis graph; DPO-PCR, dual priming oligonucleotide-based multiplex polymerase chain reaction.

4. Diagnostics of. H. pylori Infection

Three articles [37–39] studied the cost-effectiveness of alternative initial strategies of diagnosing H. pylori infection in patients attending primary care with any predominant symptom. Table 4 shows the models’ main characteristics. Two studies [37,39] found that the initial test for H. pylori was the most cost-effective strategy, although this result depended on the prevalence of the H. pylori infection. The other article [38] introduced AMR into its analysis, considering that, if the first antibiotic treatment failed due to clarithromycin-resistance, the patient was treated with metronidazole. In this case, testing for H. pylori was not cost effective in the given modest prevalence of clarithromycin resistance. When the model considered a high prevalence of clarithromycin resistance (>45%), testing was the most cost-effective alternative.

Table 4. Articles related to diagnosing H. pylori infection with other symptoms.

¹ the most cost-effective strategy is in bold; PC, primary care; NA, not reported; DSA, deterministic sensitivity analysis; PSA, probabilistic sensitivity analysis; AMR, antimicrobial resistance; UBT, urea breath test; SAG, sensitivity analysis graph; ELISA, enzyme-linked immunosorbent assay; RUT, rapid urease test; SHPAb, serum H. pylori IgG antibody; UHPAb, urine H. pylori IgG antibody; CE, cost-effectiveness.

References

1. Guevara, B.; Cogdill, A.G. Helicobacter pylori: A Review of Current Diagnostic and Management Strategies. Dis Sci. 2020, 65, 1917–1931.
2. Warren, J.R.; Marshall, B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1983, 1, 1273–1275.
3. Hu, Y.; Wan, J.-H.; Li, X.-Y.; Zhu, Y.; Graham, D.Y.; Lu, N.-H. Systematic review with meta-analysis: The global recurrence rate of Helicobacter pylori. Pharmacol Ther. 2017, 46, 773–779.
4. Plummer, M.; Franceschi, S.; Vignat, J.; Forman, D.; de Martel, C. Global burden of gastric cancer attributable to Helicobacter pylori. Int J. Cancer 2015, 136, 487–490.
5. Chey, W.D.; Leontiadis, G.I.; Howden, C.W.; Moss, S.F. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. J. Gastroenterol. 2017, 112, 212–239.
6. Kasahun, G.G.; Demoz, G.T.; Desta, D.M. Primary Resistance Pattern of Helicobacter pylori to Antibiotics in Adult Population: A Systematic Review. Drug Resist. 2020, 13, 1567–1573.
7. Malfertheiner, P.; Megraud, F.; O'morain, C.A.; Gisbert, J.P.; Kuipers, E.J.; Axon, A.T.; Bazzoli, F.; Gasbarrini, A.; Atherton, J.; Graham, D.Y.; et al. Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report. Gut 2017, 66, 6–30.
8. Boyanova, L.; Gergova, G.; Evstatiev, I.; Spassova, Z.; Kandilarov, N.; Yaneva, P.; Markovska, R.; Mitov, I. Helicobacter pylori resistance to six antibiotics by two breakpoint systems and resistance evolution in Bulgaria. Dis (Lond) 2016, 48, 56–62.
9. Megraud, F.; Coenen, S.; Versporten, A.; Kist, M.; Lopez-Brea, M.; Hirschl, A.M.; Andersen, L.P.; Goossens, H.; Glupczynski, Y. Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption. Gut 2013, 62, 34–42.
10. Saracino, I.M.; Zullo, A.; Holton, J.; Castelli, V.; Fiorini, G.; Zaccaro, C.; Ridola, L.; Ricci, C.; Gatta, L.; Vaira, D. High prevalence of primary antibiotic resistance in Helicobacter pylori isolates in Italy. Gastrointestin. Liver Dis. 2012, 21, 363–365.
11. Kobayashi, I.; Murakami, K.; Kato, M.; Kato, S.; Azuma, T.; Takahashi, S.I.; Uemura, N.; Katsuyama, T.; Fukuda, Y.; Haruma, K.; et al. Changing antimicrobial susceptibility epidemiology of Helicobacter pylori strains in Japan between 2002 and 2005. Clin. Microbiol. 2007, 45, 4006–4010.
12. Toros, A.B.; Ince, A.T.; Kesici, B.; Saglam, M.; Polat, Z.; Uygun, A. A new modified concomitant therapy for Helicobacter pylori eradication in Turkey. Helicobacter 2011, 16, 225–228.
13. Lu, H.; Zhang, W.; Graham, D.Y. Bismuth-containing quadruple therapy for Helicobacter pylori: Lessons from China. J. Gastroenterol. Hepatol. 2013, 25, 1134–1140.
14. Yonezawa, H.; Osaki, T.; Kamiya, S. Biofilm Formation by Helicobacter pylori and Its Involvement for Antibiotic Resistance; Manfredi, M., Ed.; BioMed Research International Hindawi Publishing Corporation: London, UK, 2015.
15. O’Morain, N.R.; Dore, M.P.; O’Connor, A.J.P.; Gisbert, J.P.; O’Morain, C.A. Treatment of Helicobacter pylori infection in 2018. Helicobacter 2018, 23 (Suppl. S1), e12519.
16. Delgado, J.S.; García-Iglesias, P.; Titó, L.; Puig, I.; Planella, M.; Gené, E.; Saló, J.; Martínez-Cerezo, F.; Molina-Infante, J.; Gisbert, J.P.; et al. Update on the management of Helicobacter pylori infection. Position paper from the Catalan Society of Digestology. Hepatol. 2018, 41, 272–280.
17. González-Carbajal Pascual, M.; Martínez Leyva, L. MAASTRICHT III and dyspepsia. Reasons for a discrepancy. Cubana Med. 2008, 47, 4, ISSN 0034-7523.
18. Saleem, N.; Howden, C.W. Update on the Management of Helicobacter pylori Infection. Treat. Options Gastroenterol. 2020, 18, 476–487.
19. Pichon, M.; Pichard, B.; Barrioz, T.; Plouzeau, C.; Croquet, V.; Fotsing, G.; Chéron, A.; Vuillemin, É.; Wangermez, M.; Haineaux, P.A.; Vasseur, P. Diagnostic Accuracy of a Noninvasive Test for Detection of Helicobacter pylori and Resistance to Clarithromycin in Stool by the Amplidiag H. pylori+ClariR Real-Time PCR Assay. Clin. Microbiol. 2020, 58(4): e01787-19.
20. Zou, Y.; Qian, X.; Liu, X.; Song, Y.; Song, C.; Wu, S.; An, Y.; Yuan, R.; Wang, Y.; Xie, Y. The effect of antibiotic resistance on Helicobacter pylori eradication efficacy: A systematic review and meta-analysis. Helicobacter 2020, 25, e12714.
21. Kim, S.Y.; Chung, J.-W. Best Helicobacter pylori Eradication Strategy in the Era of Antibiotic Resistance. Antibiotics 2020, 9, 436.
22. Savoldi, A.; Carrara, E.; Graham, D.Y.; Conti, M.; Tacconelli, E. Prevalence of Antibiotic Resistance in Helicobacter pylori: A Systematic Review and Meta-analysis in World Health Organization Regions. Gastroenterology 2018, 155, 1372–1382.e17.
23. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. BMJ 2009, 339, b2535–b2535.
24. Pulia, M.S.; O’Brien, T.P.; Hou, P.C.; Schuman, A.; Sambursky, R. Multi-Tiered Screening and Diagnosis Strategy for COVID-19: A Model. for Sustainable Testing Capacity in Response to Pandemic. Med. 2020, 52, 207–214.
25. Bhise, V.; Rajan, S.S.; Sittig, D.F.; Morgan, R.O.; Chaudhary, P.; Singh, H. Defining and Measuring Diagnostic Uncertainty in Medicine: A Systematic Review. Gen. Intern. Med. 2018, 33, 103–115.
26. Husereau, D. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. BMJ 2013, 346, 1049.
27. Chey, W.D.; Fendrick, A.M. Noninvasive Helicobacter pylori testing for the “test-and-treat” strategy: A decision analysis to assess the effect of past infection on test choice. Intern. Med. 2001, 161, 2129–2132.
28. Makris, N.; Barkun, A.; Crott, R.; Fallone, C.A. Cost-effectiveness of alternative approaches in the management of dyspepsia. J. Technol. Assess. Health Care 2003, 19, 446–464.
29. García-Altés, A.; Rota, R.; Barenys, M.; Abad, Á.; Moreno, V.; Pons, J.M.; Piqué; J. Cost-effectiveness of a “score and scope” strategy for the management of dyspepsia. J. Gastroenterol. Hepatol. 2005, 17, 709–719.
30. You, J.H.S.; Wong, P.-L.; Wu, J.C.Y. Cost-effectiveness of Helicobacter pylori “test and treat” for patients with typical reflux symptoms in a population with a high prevalence of H. pylori infection: A Markov model analysis. J. Gastroenterol. 2006, 41, 21–29.
31. Holmes, K.P.; Fang, J.C.; Jackson, B.R. Cost-effectiveness of six strategies for Helicobacter pyloridiagnosis and management in uninvestigated dyspepsia assuming a high resource intensity practice pattern. BMC Health Serv. Res. 2010, 10, 344.
32. Papaefthymiou, A.; Liatsos, C.; Georgopoulos, S.D.; Apostolopoulos, P.; Doulberis, M.; Kyriakos, N.; Giakoumis, M.; Papadomichelakis, M.; Galanopoulos, M.; Katsinelos, P.; et al. Helicobacter pylori eradication regimens in an antibiotic high-resistance European area: A cost-effectiveness analysis. Helicobacter 2020, 25, e12666.
33. Rich, M.; Scheiman, J.M.; Tierney, W.; Fendrick, A.M. Is upper gastrointestinal radiography a cost-effective alternative to a Helicobacter pylori “test and treat” strategy for patients with suspected peptic ulcer disease? J. Gastroenterol. 2000, 95, 651–658.
34. Ghoshal, U.C.; Das, A. Management strategies for duodenal ulcer in India in the Helicobacter pylori era: An economic analysis. Med J. India 2002, 15, 140–144.
35. Ghoshal, U.C.; Aggarwal, R.; Sreenivasa Baba, C. Recurrent duodenal ulcer haemorrhage: A pharmacoeconomic comparison of various management strategies. Expert Opin. Pharmacother. 2003, 4, 1593–603.
36. Cho, J.-H.; Jeon, S.R.; Kim, H.G.; Jin, S.-Y.; Park, S. Cost-effectiveness of a tailored Helicobacter pylori eradication strategy based on the presence of a 23S ribosomal RNA point mutation that causes clarithromycin resistance in Korean patients. Gastroenterol. Hepatol. 2019, 34, 700–706.
37. Vakil, N.; Rhew, D.; Soll, A.; Ofman, J.J. The cost-effectiveness of diagnostic testing strategies for Helicobacter pylori. J. Gastroenterol. 2000, 95, 1691–1698.
38. Omata, F.; Shimbo, T.; Ohde, S.; Deshpande, G.A. Cost-Effectiveness Analysis of Helicobacter Pylori Diagnostic Methods in the Patients with Atrophic Gastritis. Gastroenterology 2017, 152, S448–S448.
39. Beresniak, A.; Malfertheiner, P.; Franceschi, F.; Liebaert, F.; Salhi, H.; Gisbert, J.P. Helicobacter pylori “Test-and-Treat” strategy with urea breath test: A cost-effective strategy for the management of dyspepsia and the prevention of ulcer and gastric cancer in Spain—Results of the Hp-Breath initiative. Helicobacter 2020, 25, e12693.

This entry is adapted from the peer-reviewed paper 10.3390/antibiotics10010055