poposstt--treatment testintreatment testing for hphp...

Neil H. Stollman, MD, FACG

PostPost--treatment testing for treatment testing for ggHpHp eradication should be eradication should be

standardstandard--ofof--carecare

N il St ll MD FACGNeil Stollman MD, FACG

In the old days…In the old days…

• When treatment regimens were felt to be successful 90+% of the time, routine post-treatment testing (‘test-of-cure’) was felt to be unneccessary, and not cost effective

A till d i th t ll?• Are we still doing that well?

ACG Western Regional Postgraduate Course - Las Vegas, NV Copyright 2015 American College of Gastroenterology

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Recommended Primary Therapies for Recommended Primary Therapies for H. pylori H. pylori Infection: ACG GuidelinesInfection: ACG Guidelines

• Triple therapy: PPI + clarithromycin + amoxicillin (or metronidazole) for 14 days

• Quadruple therapy: PPI (or H2RA) + bismuth + tetracycline + metronidazole for 10 – 14 days

Chey WD, Wong BC. Am J Gastroenterol. 2007;102(8):1808-1825.

Rx Success for “Triple Therapy”Rx Success for “Triple Therapy”

%)

80

90

100

Tre

atm

ent

Su

cces

s (%

30

40

50

60

70

80

Eradication rates: █ >90%; █ 80%–90%; █ 70%–80%; █ <70%.Individual Treatment Studies

ITT

T

0

10

20

Graham DY, Fischbach L. Gut. 2010;59(8):1143-1153.


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Rx Success for “Triple Therapy”Rx Success for “Triple Therapy”%

)

80

90

100 Only 18% of reports demonstrated eradication rates >85%~60% of reports demonstrated eradication rates <80%

Tre

atm

ent

Su

cces

s (%

30

40

50

60

70

80

Eradication rates: █ >90%; █ 80%–90%; █ 70%–80%; █ <70%.Individual Treatment Studies

ITT

T

0

10

20

Graham DY, Fischbach L. Gut. 2010;59(8):1143-1153.

HpHp Eradication Rates of Triple and Quad RxEradication Rates of Triple and Quad Rx

84 290

100

Clarithromycin triple therapy Bismuth quadruple therapy

68.965.6

81.379.3

81.6 78.7

67.4

54.5

77.672.5

84.2 80.678.9 78.9 80.0

74.7

30

40

50

60

70

80

90

Era

dic

atio

n R

ate

(%)

0

10

20

Overall (12 studies)

Eastern hemisphere(7 studies)

Western hemisphere(4 studies)

7 days of therapy

(4 studies)

10 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. 2013;88(1):33-45.


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HpHp Antimicrobial Resistance U.S.Antimicrobial Resistance U.S.

Alaska 2000 to 20082United States 1998 to 20021

Antimicrobial Resistance of H. pylori Isolates

4230

20

19

Alaska, 2000 to 2008(n = 531 isolates)

2513

1

0LevofloxacinTetracyclineAmoxicillin

ClarithromycinMetronidazole

United States, 1998 to 20021

(n = 347 isolates)

NR

0 20 40 60

1. Duck WM, et al. Emerg Infect Dis. 2004;10(6):1088-1094.2. Tveit AH, et al. J Clin Microbiol. 2011;49(10):3638-3643.

0 10 20 30Resistance (%) Resistance (%)

100

90

Metro-sensitive Metro-

i

Clarithro-sensitive

Effect of Metronidazole and Clarithromycin Effect of Metronidazole and Clarithromycin Resistance on Treatment OutcomeResistance on Treatment Outcome

80

70

60

50

40

30

resistant

Clarithro-

rad

icat

ion

Rat

es (

%)

Luther J, et al. Am J Gastroenterol. 2010;105(1):65-73.

20

10

0

resistant

Quadruple therapy Triple therapy

Er


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Predictors of Failure of EradicationPredictors 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• Inadequate duration of therapy

1. Chey WD, Wong BC. Am J Gastroenterol. 2007;102(8):1808-1825.2. Saad RJ, Chey WD. Gastroenterol Hepatol Ann Rev. 2006;1:30-35.3. Zullo A, et al. J Clin Gastroenterol. 2012;46(4):259-261.

Effects of Adherence on OutcomeEffects of Adherence on Outcome• Patient nonadherence is an important factor

f lin treatment failure– Side effects are reported by app 50% of patients– Complicated treatment regimens

• Patients taking <80% of their treatment regimen have high rates of treatment failureregimen have high rates of treatment failure

• Treatment failure is associated with the emergence of antimicrobial resistance

Vakil N, Vaira D. J Clin Gastroenterol. 2013;47(5):383-388.


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Symptomatology Is a Poor Marker for EradicationSymptomatology Is a Poor Marker for Eradication

• 87 adults with H. pylori–associated PUD treatedUBT fi d di ti i 70 (80%) ti t– UBT confirmed eradication in 70 (80%) patients

– 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 H2RA or PPI

• Even if asymptomatic, 90% of patients queried were willing to have eradication testing

Fendrick AM, et al. Am J Med. 1999;107(2):133-136.

GuidelinesGuidelines

• ACG Guidelines (2007) recommend post-t t t t ti f PUD CA d ‘ i t ttreatment testing for PUD, CA and ‘persistent symptoms’.

• ESPHGHAN / NASPHGAN Guidelines 2011– “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 2011;53(2):230-43. Evidence-based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori infection in children.


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Conclusion: Confirm Conclusion: Confirm HpHp death!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 >90% Rx success)

Kill ‘em all? No!Kill em all? No!The case for selective H pyloricide…

Neil Stollman MD, FACGNeil Stollman MD, FACG


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Historical PerspectiveHistorical Perspective

• 2012 marked the 30th anniversary of the yidentification 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. 2011;21(4):613-635. 2. Blaser MJ. Lancet. 1997;349(9057):1020-1022.

Are There Possible Benefits of Are There Possible Benefits of H. pyloriH. pylori Infection?Infection?

Obesity1

GERD2,3

Barrett’s esophagus8

Diarrhea9

Esophageal IBD7

1. Roper J, et al. J Clin Endocrinol Metab. 2008;93(6):2350-2357; 2. Raghunath A, et al. BMJ. 2003;326(7392):737; 3. Yaghoobi M, et al. Am J Gastroenterol. 2010;105(5):1007-1013; 4. Dellen ES, et al. Gastroenterology. 2011;141(5):1586-1592; 5. Chen Y, Blaser MJ. J Infect Dis. 2008;198(4):553-560; 6. Chen Y, Blaser MJ. Arch Intern Med. 2007;167(8):821-827; 7. Luther J, et al. Inflamm Bowel Dis. 2010;16(6):1077-1084; 8. Fischbach LA, et al. Helicobacter. 2012;17(3):163-175; 9. Cohen D, et al. Clin Infect Dis. 2012;54(4):e35-e42.

Dermatitis5

Allergy5,6 Asthma5,6

p gEosinophilia4 IBD7


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Study ReferenceChile, Csendes et al 1997

Western Europe

Newton et al 1997

Pieramico and Zanetti 2000

H. pylori H. pylori Prevalence Among Patients With GERD Prevalence Among Patients With GERD

• Pooled analysis (20 studies):– Prevalence of Hp infection was

Gisbert et al 2001

Hackelsberger et al 1998

Manes et al 1999

Liston et al 1996

Werdmuller and Loffeld 1997

North America

Vaezi et al 2000

El-Serag et al 1999

Goldblum et al 1998

Varanasi et al 1998

Vicari et al 1998

Schubert and Schnell 1989

Fallone et al 2000

Far East

Prevalence of Hp infection was significantly lower in patients with GERD c/w those without GERD1

– Odds ratio (95% CI) = 0.60 (0.47–0.78)

• More recent meta-analysis (PUD pts)– Approximately two-fold increased

risk of developing new GERD among Shirota et al 1999

Wu et al 1999

Mihara et al 1996

Haruma et al 2000

Koike et al 2001

Summary

risk of developing new GERD among those with successful eradication versus those with persistent infection2

1. Raghunath A, et al. BMJ. 2003;326(7392):737.2. Yaghoobi M, et al. Am J Gastroenterol. 2010;105(5):1007-1013.

0.10

Odds Ratio

0.16 0.25 0.40 0.63 1.00 1.58 2.51 3.98

Not All Not All H. pylori H. pylori Are Created EqualAre Created Equal• Vacuolating cytotoxin VacA

h i i i l d ( PAI)• cag pathogenicity island (cag-PAI)• babA2

Perhaps there are ‘good’ andare good and‘bad’ Hp?

Image from Suerbaum S, Michetti P.2


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Might Might H. pylori H. pylori Protect Against Barrett’s Esophagus Protect Against Barrett’s Esophagus and Esophageal Adenocarcinoma?and Esophageal Adenocarcinoma?

Barrett’s esophagus1

• Meta anal sis (49 st dies) Hp infec on associated ith ↓risk of BE• Meta-analysis (49 studies): Hp infec on associated with ↓risk of BE– RR = 0.73 (95% CI = 0.60–0.88)– Significant heterogeneity (P < 0.0001)

• 4 studies of ‘high quality’ – RR = 0.46 (95% CI = 0.35–0.60)

• 7 studies examined cag A-positive H. pylori– RR = 0.38 (95% CI = 0.19–0.78)

Esophageal adenocarcinoma2Esophageal adenocarcinoma2

• 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. 2012;17(3):163-175; 2. de Martel C, et al. J Infect Dis. 2005;191(5):761-767.

H. pylori H. pylori and and Diarrheal IllnessesDiarrheal Illnesses• 2477 European children (5–8 years)1

76 1H. pylori + H. pylori -P<0.001

76.1

16.66.6 0.7

54.3

32.5

11.91.3

0

20

40

60

80

Never Rarely Sometimes Often

Su

bje

cts

(%)

Diarrhea in the prior 3 months

• Similar results observed in Israeli adult males2Similar results observed in Israeli adult males

• Potential mechanisms

– H. pylori induces an inflammatory infiltrate, which protects against diarrhea-inducing infections1

– Potential antimicrobial activity of cecropin-like peptide3

1. Rothenbacher D, et al. J Infect Dis. 2000;182(5):1446-1449; 2. Cohen D, et al. Clin Infect Dis. 2012;54(4):e35-e42; 3. Pütsep K, et al. Nature. 1999;398(6729):671-672.


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Study ID RR (95% CI) % Weight

el-Omar 0.42 (0.28, 0.63) 4.59Mantzaris 0.57 (0.40, 0.82) 4.86Meining 0 23 (0 07 0 74) 1 46

HpHp Infection in IBD patients vs ControlsInfection in IBD patients vs Controls

Meining 0.23 (0.07, 0.74) 1.46Oberhuber 0.87 (0.59, 1.26) 4.73Parente 0.82 (0.69, 0.98) 5.95Wagtmans 0.34 (0.25, 0.47) 5.17Duggan 0.95 (0.73, 1.23) 5.50Corrado 0.07 (0.00, 1.10) 0.32D’Inca 0.73 (0.45, 1.17) 4.11Pearce 0.69 (0.34, 1.38) 2.90Parente 0.76 (0.61, 0.95) 5.70Parlak 1.05 (0.85, 1.30) 5.76Vare 0.66 (0.46, 0.95) 4.82Feeney 1 0.32 (0.14, 0.72) 2.41Feeney 2 0.90 (0.51, 1.61) 3.53Furusu 0.57 (0.32, 1.00) 3.56Guslandi 0.41 (0.19, 0.88) 2.61P i 0 94 (0 63 1 42) 4 56Pascasio 0.94 (0.63, 1.42) 4.56Piodi 0.77 (0.57, 1.05) 5.21Triantafillidis 0.63 (0.46, 0.84) 5.25Pronai 0.33 (0.20, 0.53) 4.10Oliveira 1 1.02 (0.71, 1.47) 4.83Oliveira 2 0.73 (0.52, 1.01) 5.03Sladek 0.25 (0.13, 0.49) 3.04

Luther J, et al. Inflamm Bowel Dis. 2010;16(6):1077-1084.

0.1 51

Overall (I-squared = 75.8%, P=0.000) 0.64 (0.54, 0.75) 100.00

HpHp: Reduced Risk for Atopic Disorders: Reduced Risk for Atopic DisordersAsthma and dermatitis1

1. Chen Y, Blaser MJ. J Infect Dis. 2008;198(4):553-560.

Childhood H. pylori (and an antigen rich environment) may be important to development of the immune system2


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Association of Association of H. pylori H. pylori and Asthmaand AsthmaH. pylori + H. pylori – Odds Ratio Odds Ratio

Study Events Total Events Total WeightM-H, Random,

95% CIM-H, Random,

95% CI

A. Baccioglu 2008 8 74 5 16 1.0% 0.27 [0.07, 0.97]

Anne McCune 2002 68 1079 171 2165 11.1% 0.78 [0.59, 1.05]

Asbjoms dottir H 2006 23 175 39 267 4.5% 0.88 [0.51, 1.54]

D. Jarvis 2004 60 208 167 613 8.9% 1.08 [0.76, 1.53]

Donna Fullerton 2008 62 643 151 1732 10.3% 1.12 [0.82, 1.52]

Noam Zevit 2008 233 3175 345 3784 17.2% 0.79 [0.66, 0.94]

W. Uter 2003 121 243 495 990 11.5% 0.99 [0.75, 1.31]

Yu Chen 2007 229 3720 296 3943 16.9% 0.81 [0.68, 0.97]

Yu Chen 2008 267 2625 679 4787 18.6% 0.69 [0.59, 0.80]

Wang Q, et al. Helicobacter. 2013;18(1):41-53.

Total (95% CI) 11942 18297 100.0% 0.84 [0.74, 0.96]

Total events 1071 2348

Heterogeneity: τ2 = 0.02; χ2 = 16.63, df = 8 (p = 0.03); I2 = 52%

Test for overall effect: Z = 2.64 (p = 0.008) 0.01 0.1 1 10 100

Favors experimental Favors control

Association of Association of HpHp andand Esophageal EosinophiliaEsophageal Eosinophilia

• US Pathology Database

• 165,017 patients in the U.S. who underwent esophageal and gastric biopsies from 2008 to 2010

Esophageal eosinophilia histologically

consistent with EoE

No esophageal eosinophilia

Unadjusted OR(95% CI)

Adjusted OR(95% CI)a

Unadjusted and Adjusted ORs for the Association Between Esophageal Eosinophilia and H. pylori Gastritis

Dellen ES, et al. Gastroenterology. 2011;141(5):1586-1592.

EoE eosinophilia (95% CI) (95% CI)

Normal gastric biopsy specimens

841 30,481 1.00 (ref) 1.00 (ref)

Chronic active gastritis without H. pylori 44 1851 0.86 (0.64–1.17) 1.01 (0.74–1.38)

Chronic active gastritis with H. pylori 193 10,131 0.69 (0.59–0.81) 0.79 (0.68–0.93)


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Data in support of Data in support of HpHp eradication NUD inconsistenteradication NUD inconsistent• 337 patients with NUD and H. pylori

infection randomized to:Omeprazole + amoxicillin +– Omeprazole + amoxicillin + clarithromycin x 14 days

– Placebo• At 12 months, no difference in:

– Relief of symptoms– Rate of antacid use– Most SF-36 scores ea

n S

ymp

tom

Sco

re

Omeprazole, amoxicillin, and clarithromycin

Placebo

3

2

1

– Development of PUD

Talley NJ, et al. N Engl J Med. 1999;341(15):1106-1111.

Me

0

Finally, current Finally, current ACG ACG Guidelines (as flawed as they are) Guidelines (as flawed as they are) do NOT recommend universal eradicationdo NOT recommend universal eradication

• Established indications for diagnosis and treatmentActi e PUD– 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. 2007;102(8):1808-1825.


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Most Most people people with with H. pylori H. pylori diedie with itwith it, , not not because of itbecause 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

ConclusionConclusion

• In many cases, H. pylori infection is asymptomatic and could possibly beasymptomatic 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 populationssymptomatic and/or high risk populations only, is the recommended and most appropriate current strategy.


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poposstt--treatment testintreatment testing for hphp...

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