Post-treatment treatment testing for

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1 Post-treatment treatment testing for Hp eradication should be standard-of-care Neil ilstollman MD, FACG In the old days When treatment regimens were felt to be successful 9+% of the time, routine posttreatment testing ( test-of-cure ) was felt to be unneccessary, and not cost effective Are we still doing that t well? 1

2 Recommended Primary Therapies for H. pylori Infection: ACG Guidelines Triple therapy: PPI + clarithromycin + amoxicillin (or metronidazole) for 14 days Quadruple therapy: PPI (or H 2 RA) + bismuth + tetracycline + metronidazole for 1 14 days Chey WD, Wong BC. Am J Gastroenterol. 27;12(8): Rx Success for Triple Therapy 1 9 ITT Treatment Success (% %) Individual Treatment Studies Eradication rates: >9%; 8% 9%; 7% 8%; <7%. Graham DY, Fischbach L. Gut. 21;59(8):

3 Rx Success for Triple Therapy 1 Only 18% of reports demonstrated eradication rates >85% ~6% of reports demonstrated eradication rates <8% 9 ITT Treatment Success (% %) Individual Treatment Studies Eradication rates: >9%; 8% 9%; 7% 8%; <7%. Graham DY, Fischbach L. Gut. 21;59(8): Hp Eradication Rates of Triple and Quad Rx Eradication Rate (%) Overall (12 studies) Clarithromycin triple therapy Eastern hemisphere (7 studies) Western hemisphere (4 studies) 7 days of therapy (4 studies) Bismuth quadruple therapy days of therapy (3 studies) Active peptic ulcer (5 studies) Non-ulcer dyspepsia (3 studies) Dyspeptic symptoms (3 studies) Adapted from Venerito M, et al. Digestion. 213;88(1):

4 Hp Antimicrobial Resistance U.S. Antimicrobial Resistance of H. pylori Isolates United States, 1998 to 22 1 Alaska, 2 to 28 2 (n = 347 isolates) (n = 531 isolates) Levofloxacin Tetracycline Amoxicillin Clarithromycin Metronidazole NR Resistance (%) Resistance (%) Duck WM, et al. Emerg Infect Dis. 24;1(6): Tveit AH, et al. J Clin Microbiol. 211;49(1): Effect of Metronidazole and Clarithromycin Resistance on Treatment Outcome Clarithro- resistant radication Rates (%) Er Metrosensitive Clarithrosensitive Metro- resistant 1 Quadruple therapy Triple therapy Luther J, et al. Am J Gastroenterol. 21;15(1):

5 Predictors of Failure of Eradication Antimicrobial resistance Especially clarithromycin Need to know patient s antibiotic history Poor adherence Re-treatment with initial (failed) regimen Inadequate duration of therapy 1. Chey WD, Wong BC. Am J Gastroenterol. 27;12(8): Saad RJ, Chey WD. Gastroenterol Hepatol Ann Rev. 26;1: Zullo A, et al. J Clin Gastroenterol. 212;46(4): Effects of Adherence on Outcome Patient nonadherence is an important factor in treatment failure Side effects are reported by app 5% of patients Complicated treatment regimens Patients taking <8% of their treatment regimen have high rates of treatment failure Treatment failure is associated with the emergence of antimicrobial resistance Vakil N, Vaira D. J Clin Gastroenterol. 213;47(5):

6 Symptomatology Is a Poor Marker for Eradication 87 adults with H. pylori associated PUD treated UBT confirmed eradication in 7 (8%) patients t Patients with successful eradication were significantly more likely to have symptomatic improvement than patients without eradication BUT A majority of eradicated patients still had symptoms A majority of eradicated patients still used an H 2 RA or PPI Even if asymptomatic, 9% of patients queried were willing to have eradication testing Fendrick AM, et al. Am J Med. 1999;17(2): Guidelines ACG Guidelines (27) recommend post- treatment t ttesting ti for PUD, CA and persistent t symptoms. ESPHGHAN / NASPHGAN Guidelines 211 Even when children become asymptomatic after treatment, it is recommended that the success of treatment.. be evaluated. The absence of symptoms does not necessarily mean the infection has been eradicated. J Pediatr Gastroenterol Nutr 211;53(2): Evidence-based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori infection in children. 6

7 Conclusion: Confirm Hp death! If, as Dr. Abraham asserts, the only good H. pylori is a dead H pylori shouldn t we confirm death? dead H. pylori, shouldn t we confirm death? As eradication rates fall, it becomes increasingly important to confirm successful treatment. Symptom status is a poor marker of eradication Knowledge is power Patients want to know, it s reassuring to confirm eradication For adults, as is currently recommend for children, post-treatment testing-for-cure should be routine (unless and/or until we return to >9% Rx success) Kill em all? No! The case for selective H pyloricide Neil Stollman MD, FACG 7

8 Neil H. Stollman, MD, FACG Historical Perspective 212 marked the 3th anniversaryy of the identification of H. pylori, BUT Hp infection of humans dates back many thousands of years1 Is our relationship with Hp one of parasitism or commensalism or symbiosis2 Are there potential benefits of Hp infection? Are the potential harms of Hp eradication? 1. Wang AY, Peura DA. Gastrointest Endosc Clin N Am. 211;21(4): Blaser MJ. Lancet. 1997;349(957): Are There Possible Benefits of H. pylori Infection? Obesity1 Diarrhea9 Barrett s esophagus8 GERD2,3 p g Esophageal Eosinophilia4 IBD7 Dermatitis5 Allergy5,6 Asthma5,6 1. Roper J, et al. J Clin Endocrinol Metab. 28;93(6): ; 2. Raghunath A, et al. BMJ. 23;326(7392):737; 3. Yaghoobi M, et al. Am J Gastroenterol. 21;15(5):17-113; 4. Dellen ES, et al. Gastroenterology. 211;141(5): ; 5. Chen Y, Blaser MJ. J Infect Dis. 28;198(4):553-56; 6. Chen Y, Blaser MJ. Arch Intern Med. 27;167(8): ; 7. Luther J, et al. Inflamm Bowel Dis. 21;16(6): ; 8. Fischbach LA, et al. Helicobacter. 212;17(3): ; 9. Cohen D, et al. Clin Infect Dis. 212;54(4):e35-e42. 8

9 H. pylori Prevalence Among Patients With GERD Study Reference Chile, Csendes et al 1997 Western Europe Newton et al 1997 Pieramico and Zanetti 2 Pooled analysis (2 studies): Prevalence of Hp infection was Gisbert et al 21 significantly lower in patients with GERD c/w those without GERD 1 Odds ratio (95% CI) =.6 (.47.78) More recent meta-analysis (PUD pts) Hackelsberger et al 1998 Manes et al 1999 Liston et al 1996 Werdmuller and Loffeld 1997 North America Vaezi et al 2 El-Serag et al 1999 Goldblum et al 1998 Varanasi et al 1998 Vicari et al 1998 Schubert and Schnell 1989 Fallone et al 2 Far East Approximately two-fold increased risk of developing new GERD among Shirota et al 1999 Wu et al 1999 those with successful eradication Mihara et al 1996 Haruma et al 2 versus those with persistent Koike et al 21 infection 2 Summary Odds Ratio 1. Raghunath A, et al. BMJ. 23;326(7392): Yaghoobi M, et al. Am J Gastroenterol. 21;15(5): Not All H. pylori Are Created Equal Vacuolating cytotoxin VacA cag pathogenicity i island (cag-pai) baba2 Perhaps there are good and bad Hp? Image from Suerbaum S, Michetti P. 2 9

10 Might H. pylori Protect Against Barrett s Esophagus and Esophageal Adenocarcinoma? Barrett s esophagus 1 Meta-analysis anal (49 studies): Hp infec on associated with risk of BE RR =.73 (95% CI =.6.88) Significant heterogeneity (P <.1) 4 studies of high quality RR =.46 (95% CI =.35.6) 7 studies examined cag A-positive H. pylori RR =.38 (95% CI =.19.78) Esophageal adenocarcinoma 2 Case-control study >128K patients Hp+ patients one-third as likely as Hp- patients to develop adenocarcinoma of the esophagus (after adjustment for BMI, cigarette smoking, and education) 1. Fischbach LA, et al. Helicobacter. 212;17(3): ; 2. de Martel C, et al. J Infect Dis. 25;191(5): H. pylori and Diarrheal Illnesses 2477 European children (5 8 years) 1 Subjects (%) P< H. pylori + H. pylori Never Rarely Sometimes Often Diarrhea in the prior 3 months Similar results observed in Israeli adult males 2 Potential mechanisms H. pylori induces an inflammatory infiltrate, which protects against diarrhea-inducing infections 1 Potential antimicrobial activity of cecropin-like peptide Rothenbacher D, et al. J Infect Dis. 2;182(5): ; 2. Cohen D, et al. Clin Infect Dis. 212;54(4):e35-e42; 3. Pütsep K, et al. Nature. 1999;398(6729):

11 Hp Infection in IBD patients vs Controls Study ID RR (95% CI) % Weight el-omar.42 (.28,.63) 4.59 Mantzaris.57 (.4,.82) 4.86 Meining 23(7.23 (.7, 74).74) Oberhuber.87 (.59, 1.26) 4.73 Parente.82 (.69,.98) 5.95 Wagtmans.34 (.25,.47) 5.17 Duggan.95 (.73, 1.23) 5.5 Corrado.7 (., 1.1).32 D Inca.73 (.45, 1.17) 4.11 Pearce.69 (.34, 1.38) 2.9 Parente.76 (.61,.95) 5.7 Parlak 1.5 (.85, 1.3) 5.76 Vare.66 (.46,.95) 4.82 Feeney 1.32 (.14,.72) 2.41 Feeney 2.9 (.51, 1.61) 3.53 Furusu.57 (.32, 1.) 3.56 Guslandi.41 (.19,.88) 2.61 Pascasio 94(63.94 (.63, 142) 1.42) Piodi.77 (.57, 1.5) 5.21 Triantafillidis.63 (.46,.84) 5.25 Pronai.33 (.2,.53) 4.1 Oliveira (.71, 1.47) 4.83 Oliveira 2.73 (.52, 1.1) 5.3 Sladek.25 (.13,.49) 3.4 Overall (I-squared = 75.8%, P=.).64 (.54,.75) Luther J, et al. Inflamm Bowel Dis. 21;16(6): Hp: : Reduced Risk for Atopic Disorders Asthma and dermatitis 1 Childhood H. pylori (and an antigen rich environment) may be important to development of the immune system 2 1. Chen Y, Blaser MJ. J Infect Dis. 28;198(4):

12 Association of H. pylori and Asthma H. pylori + H. pylori Odds Ratio Odds Ratio Study Events Total Events Total Weight M-H, Random, 95% CI A. Baccioglu %.27 [.7,.97] Anne McCune %.78 [.59, 1.5] Asbjoms dottir H %.88 [.51, 1.54] D. Jarvis % 1.8 [.76, 1.53] Donna Fullerton % 1.12 [.82, 1.52] Noam Zevit %.79 [.66,.94] W. Uter %.99 [.75, 1.31] Yu Chen %.81 [.68,.97] Yu Chen %.69 [.59,.8] M-H, Random, 95% CI Total (95% CI) %.84 [.74,.96] Total events Heterogeneity: τ 2 =.2; χ 2 = 16.63, df = 8 (p =.3); I 2 = 52% Test for overall effect: Z = 2.64 (p =.8) Favors experimental Favors control Wang Q, et al. Helicobacter. 213;18(1): Association of Hp and Esophageal Eosinophilia US Pathology Database 165,17 patients in the U.S. who underwent esophageal and gastric biopsies from 28 to 21 Unadjusted and Adjusted ORs for the Association Between Esophageal Eosinophilia and H. pylori Gastritis Normal gastric biopsy specimens Chronic active gastritis without H. pylori Chronic active gastritis with H. pylori Esophageal eosinophilia histologically consistent with EoE No esophageal eosinophilia Unadjusted OR (95% CI) Adjusted OR (95% CI) a 841 3, (ref) 1. (ref) ( ) 1.1 ( ) 193 1, (.59.81).79 (.68.93) Dellen ES, et al. Gastroenterology. 211;141(5):

13 Data in support of Hp eradication NUD inconsistent 337 patients with NUD and H. pylori infection randomized to: Omeprazole + amoxicillin + clarithromycin x 14 days Placebo At 12 months, no difference in: Relief of symptoms Rate of antacid use Most SF-36 scores Development of PUD Me ean Symptom Score Omeprazole, amoxicillin, and clarithromycin Placebo Talley NJ, et al. N Engl J Med. 1999;341(15): Finally, current ACG Guidelines (as flawed as they are) do NOT recommend universal eradication Established indications for diagnosis and treatment Active PUD Confirmed history of PUD (not previously treated for H. pylori) Gastric MALT lymphoma (low grade) After endoscopic resection of early gastric cancer Uninvestigated dyspepsia (depending upon H. pylori prevalence) Controversial indications for diagnosis and treatment Non-ulcer dyspepsia GERD Persons using NSAIDs Unexplained iron deficiency anemia Populations at higher risk for gastric cancer Chey WD, Wong BC. Am J Gastroenterol. 27;12(8):

14 Most people with H. pylori die with it, not because of it. The widespread eradication of H. pylori could have unintended consequences, such as possible increased IBD, allergies, asthma, GERD/BE, diarrhea.not to mention the consequences of widespread antibiotic overuse Conclusion In many cases, H. pylori infection is asymptomatic and could possibly be beneficial. In asymptomatic individuals without increased gastric cancer risk, there is no reason to test for infection Selective testing and treating, particularly in symptomatic and/or high risk populations only, is the recommended and most appropriate current strategy. 14