Why Treat H. pylori - American College of...

David A. Peura, MD, MACG

H. pylori – How to Handle it if Refractory to the Initial Treatment Course?

David A. Peura, MD, MACG Emeritus Professor

University of Virginia Health Systems

Why Treat H. pylori?

2016 ACG Eastern Regional Postgraduate Course Copyright 2016 American College of Gastroenterology

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Most of the ~4 billion infected people worldwide may not be sick, but…

• 100% develop gastritis, which is associated with alterations in gastric physiology1

• 15% to 20% will develop peptic ulcer2

(~600–800 million)

• 1% will develop gastric cancer1

(~40 million)

• 5% of upper gastrointestinal symptoms will be attributable to infection3

1. Ernst PB, et al. Gastroenterology. 2006;130(1):188-206; 2. Kim EH, et al. Cancers. 2011;3(3):3018-3028; 3. Moayyedi P, et al. Am J Gastroenterol. 2000;95(6):1448-1455.

H. pylori: Disease Associations

1. Ernst PB, et al. Gastroenterology. 2006;130(1):188-206; 2. Malfertheiner P, et al. J Dig Dis. 2010;11(1):2-11; 3. Go MF. Aliment Pharmacol Ther. 2002;16(suppl 1):3-15; 4. Moayyedi P, et al. Am J Gastroenterol. 2003;98(12):2621-2626.

Peptic Ulcer1:7 individuals (lifetime risk, 15%)1 Gastric

Adenocarcinoma2- to 3-fold higher risk2 (lifetime risk, <1%)1

Group 1 carcinogen (plays key role in gastric carcinogenesis, WHO)

Gastric MALT Lymphoma3

GastritisHistological (100%)1

DyspepsiaControversial4


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81%

Effect of H. pylori Eradication on Associated Conditions

*Compared with no treatment or control; calculated as 100% x (1-relative risk).†Calculated as 100% x (1-odds ratio).NNT = number needed to treat; NSAID = nonsteroidal anti-inflammatory drug.

Relative Risk Reduction of H. pylori Eradication*

Duodenal Ulcer1

Gastric Ulcer1

69%

NSAIDUlcer2,†

Gastric Cancer3

Dyspepsia4

57% 35% 18%

1. Ford AC, et al. Am J Gastroenterol. 2004;99(9):1833-1855; 2. Vergara M, et al. Aliment Pharmacol Ther. 2005;21(12):1411-1418; 3. Fuccio L, et al. Ann Intern Med. 2009;151(2):121-128; 4. Talley NJ, et al. Gastroenterology. 2005;129(5):1756-1780.

26 studiesN = 2434NNT = 2

(95% CI = 1.7‒2.3)


(95% CI = 2.3‒5.0)

5 studiesN = 939

6 studiesN = 6695


(95% CI = 6‒20)

General Principles of Diagnosis and Treatment of H. pylori: What We Have

Learned Over 30 Years


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H. Pylori Guidelines for Testing and TreatingACG Guidelines1 Maastricht IV/ Florence

Consensus Report2Second Asia–Pacific

Consensus Guidelines3

Peptic ulcer disease

Gastric MALT lymphoma

Uninvestigated dyspepsia Test-and-treat strategy in populations where the prevalence of H. pylori

infection is ≥20%

Test-and-treat strategy in populations where the prevalence of H. pylori

infection is ≥20%

Test-and-treat strategy in patients without “alarm

features”

Post-endoscopic resection of early gastric cancer

Non-ulcer/functional dyspepsia +/-

GERD - In patients receiving long-term maintenance

treatment with PPI

In patients receiving long-term maintenance treatment with PPI

NSAID use +/-

Unexplained iron deficiency anemia +/-

High risk for gastric cancer +/-

Idiopathic thrombocytopenic purpura -

Vitamin B12 deficiency - -1. Chey WD, Wong BC. Am J Gastroenterol. 2007;102(8):1808-1825; 2. Malfertheiner P, et al. Gut. 2012;61(5):646-664; 3. Fock KM, et al. J Gastroenterol Hepatol. 2009;24(10):1587-1600.

Who Should Be Tested and Treated For H. pylori in the United States?


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General Principles of H. pylori Testing

• Noninvasive (nonendoscopic) testing is cost-effective and generally preferred to invasive testing (in cases where endoscopy is not indicated)

• Accuracy of test results can be influenced by prevalence of infection, concomitant use of certain medications, or inadequate tissue sampling

• An test of active infection test should be used to initiate therapy in low prevalence populations and to document cure following treatment

• Patient acceptance and compliance with various testing methods differ

• There is no “emergency” to test for cure - 4 weeks after treatment is the minimum time

General Principles of H. pylori Treatment

• Use the best therapy the 1st time• Acid suppression is a key component to effective

treatment• Antibiotic resistance is increasing and, along with patient

compliance, influences treatment success• Regimens containing at least two antibiotics are generally

required for effective treatment• Longer treatment is better than shorter duration (14 days

with PPI triple therapy)1

• Real world eradication rates are ~70%‒80% • Don’t use the same regimen twice• Selection of effective 2nd- and 3rd- course treatment

regimens is challenging

1. Yuan Y Cochrane Database Syst Rev. 2013 Dec 11;12:CD008337


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Factors Associated with H. pylori Treatment Failure

• Patient related– Poor compliance– Asymptomatic vs PUD vs NUD

• Bacteria related– Antibiotic resistance– Cag A + vs Cag A - strains

• Regimen related– Components of therapy ( 2 vs 3 vs 4 drugs)– Duration of therapy ( 5 vs 7 vs 10 vs 14 days)

Wu W Gastroenterol Res Pract. 2012: 723183.

Why PPIs for H. pylori Treatment?

Clarithromycin is also acid labile

A= amoxicillinC = clarithromycin

Mucus concentration of antibiotics is pH dependent

May be an issue with bismuth


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Success Rates of Treatmentsfor H. pylori Infection1

Regimen Per protocol (PP) eradication rate

Intent to treat (ITT) eradication rate

PPI + clarithromycin + amoxicillin / metronidazole

85% 79%

PPI + bismuth + tetracycline + metronidazole

87% 80%

1. Saad RJ, Chey WD. Natl Clin Pract Gastroenterol Hepatol. 2006;3(1):20-21; 2. Luther J, et al. Am J Gastroenterol. 2010;105(1):65-73.3. Gatta L, et al. Am J Gastroenterol. 2009;104(12):3069-3079;

• Triple and quadruple therapy have similar patient compliance and side effects2

• PPI triple therapy eradication rates are decreasing worldwide, in part due to antibiotic resistance

• Sequential therapy may be more effective than triple therapy in some areas of the world3

PPI plus amoxicillin 1 g bid for 5 days

followed by

PPI, clarithromycin 500 mg, tinidazole 500 mg bid for 5 days

Eradication rates 90% (>80% with clarithromycin resistant)

• 10 RCTs involving 2747 patients (most studies from Mediterranean countries)

– 93% eradication sequential therapy vs.77% standard PPI triple therapy– Adherence and side effect profiles similar– Needs validation in other countries

• Standard triple therapy more effective than 10 day sequential therapy in Latin America although some geographical variability

“Sequential” Therapy for H. pylori

Jafri N, Ann Intern Med. 2008;148:923

Greenberg ER Lancet 2011;378 :507 Morgan D JAMA 2013; 309:578

Vaira Ann Intern Med 2007; 146:556


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Global H. Pylori Antibiotic Resistance

Major reasons for H. pylori treatment failure1. Poor patient compliance2. Antibiotic resistance (especially clarithromycin)

De Francesco V J Gastroi Liver Dis December 2010 ;19:409

Failure likely due to macrolide resistance

Treatment Success for PPI Triple Therapy (“Legacy Therapy”) in Southern Europe and Other

Geographic Areas

Rimbara Nat. Rev. Gastroenterol. Hepatol 2011; 8:78


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Graham DY Clinical Gastroenterology and Hepatology 2014; 12:177

Success of Clarithromycin-containing Regimens Based on Predicted Resistance to Clarithromycin

and Metronidazole

Modeling not actual clinical data

Treatment Success of Concomitant Quadruple Therapy

Graham Gut 2010;59:1143Grey Bars are 2009 and 2010 studies

Continuing shortage of tetracycline since 2010


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“Combination Pill” Quadruple Therapy Vs. Standard Therapy for H. pylori

Malfertheiner Lancet 2011; 377:905

In this study 10 days of bismuth, tetracycline, and metronidazole were given in a combination capsule (Pylera® 3 capsules QID) plus OME 20 mg BID or 7

days of standard PPI triple therapy

Quadruple Therapy Standard Therapy

European Multicenter Trial

Doxycycline Vs. Tetracycline: Meta-analysis of H. pylori Eradication

Niv Y Digestion 2016;93:167–173Doxycycline doses 100 mg- 300 mg/day


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Randomized Study of Levofloxacin, Omeprazole, Nitazoxanide, and Doxycycline (LOAD) v. Triple Therapy for

the Eradication of Helicobacter pylori

Trend toward fewer patients receiving LOAD (9.2%) therapy having HP recurrence compared to LAC therapy (16.7%) at 1 year

Basu PP Am J Gastroenterol 2011; 106:1970

Study population 63% Asian, 12% African-American, 11% LatinoLevofloxacin 250 mg (qd) omeprazole 40 mg (qd), nitazoxanide 500 mg (bd), doxycycline 100 mg (qd)Lansoprazole 30 mg, amoxicillin 1000 mg, clarithromycin 500 mg (all bd) for 10 days

Bismuth as an Adjunct to Standard 14-day PPI Triple Therapy

From Dore MP, et al. Gut 2016;0:1–9. doi:10.1136/gutjnl-2015-311019clarithromycin resistance 26.5%metronidazole resistance 45.5%


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Bismuth as an Adjunct to Levofloxacin Regimen: Subsequent and 1st Rx

Gisbert J Aliment Pharmacol Ther 2015; 41: 768

Literature search

Eradication 73%-90%

High Dose PPI and Amoxicillin Dual Therapy as 1st Line and Subsequent Rx

Yang J Clinical Gastroenterology and Hepatology 2015;13:895ST = sequential therapy

14 dy 10 dy 7 dy


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Suggested Treatments for H. pylori:30 Years After Its Discovery

• Initial therapy (<15% macrolide resistance) PPI, amox 1 g, clari 500 mg bid for 10-14 days – substitute met 500 mg if PNC allergic (consider adding bismuth)– Sequential therapy - PPI plus amox 1 g bid for 5 days followed by PPI,

clari 500 mg, imidazole 500 mg bid for 5 days if >15% macrolide resistance

– Concomitant therapy - PPI, amox 1 g, clari 500 mg, imidazole 500 mg, bid for 14 days if met or dual resistance high

• Secondary therapy quadruple therapy PPI bid, bis 525 mg, met 250-500 mg, TCN 500 mg or a commercially available combination capsule qid for 10-14 days (could be used as initial therapy but compliance is an issue)

• Rescue Therapy – failed 2 or more of the above – PPI, levofloxacin 250 mg, amox 1 g, bid for 14 days (consider bismuth)– Rifabutin 150 mg qd, and amox 1.5 g & double dose PPI tid for 14 days– PPI, amox 1 gm tid for 14 days (my personal choice)

Crowe S Treatment regimens for Helicobacter pylori UpToDate® Accessed 5/16/16Graham DY Clinical Gastroenterology and Hepatology 2014; 12:177

Kim SY Br J Clin Pharmacol 2012; 73:140

Nobel Prize Festivities December 2005


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Why Treat H. pylori - American College of...

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